A Randomized, Double-Blind, Multicenter, Phase III Study to Compare Efficacy and Safety of HLX10 in Combination With Chemotherapy in Previously Untreated Patients With ES-SCLC
Phase: PHASE3
Conditions: Extensive Stage Small Cell Lung Cancer
Sponsor: Shanghai Henlius Biotech

1 
SUPPLEMENT 1 
Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in 
Patients with Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized 
Clinical Trial 
Ying Cheng∗ et al. 
This supplement contains the following items: 
1.
Original protocol
2.
Final protocol
3.
Summary of changes to the protocol
4.
Statistical analysis plan
 Correspondence to: Ying Cheng, Department of Oncology, Jilin Cancer Hospital, 1066 Jinhu Road, High-tech 
Zone, Changchun 130000, China; E-mail: jl.cheng@163.com. 

Shanghai Henlius Biotech, Inc. 
Protocol Number: HLX10-005-SCLC301  
Version: V1.0 
Investigational Product: HLX10 
Version Date: 4 Mar., 2019 
I 
A Randomized, Double-Blind, Multicenter, Phase III Study to Evaluate 
HLX10 (Recombinant Humanized Anti-PD-1 Monoclonal Antibody 
Injection) in Combination with Chemotherapy (Carboplatin-Etoposide) in 
Previously Untreated Patients with Extensive Stage Small Cell Lung Cancer 
(ES-SCLC) 
Clinical Trial l Protocol 
Investigational Product 
 
HLX10 
Protocol Number 
EudraCT 
 HLX10-005-SCLC301 
2019-XXXXXX-XX 
Sponsor 
Study Phase 
Indication 
 Shanghai Henlius Biotech, Inc.7/F,Innov Tower, Zone A, 
No.1801 HongMei Rd, Xuhui District, Shanghai, 200233 China 
III 
Previously Untreated and Extensive Stage Small Cell Lung 
Cancer (ES-SCLC) 
Leading Site 
 Jilin Cancer Hospital 
Principal Investigator 
 Professor Cheng Ying 
Version No. 
 V1.0 
Version Date 
 4 Mar., 2019 
Confidentiality Statement 
It is hereby declared that all the contents of this protocol belong to Shanghai Henlius Biotech, Inc. Except 
for the investigator/Ethics Committee/relevant government departments and personnel authorized by the 
Sponsor, no one may forward or copy the protocol without permission. 

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Protocol Number: HLX10-005-SCLC301  
Version: V1.0 
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Version Date: 4 Mar., 2019 
II 
Signature Page for Principal Investigator (Leading Site) 
 
I have read and become familiar with this protocol, confirmed the schedule in the protocol and the 
necessary contents including the implementation, and clearly understood the responsibilities related to 
this trial protocol. I agree to, and will perform my duties in strict accordance with the laws and 
regulations of local authority, Declaration of Helsinki, Good Clinical Practice and this protocol. 
 
 
 
 
 
 
 
 
Leading Site: Jilin Cancer Hospital 
 
 
 
 
 
 
 
 
 
 
Professor Cheng Ying (Signature) 
 
Date of Signing 
(dd/mm/yyyy) 
 
 
 
 
 
 
 
 

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Protocol Number: HLX10-005-SCLC301  
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Version Date: 4 Mar., 2019 
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Signature Page for Principal Investigator (Participating Site) 
 
I have read and become familiar with this protocol, confirmed the schedule in the protocol and the 
necessary contents including the implementation, and clearly understood the responsibilities related to 
this trial protocol. I agree to, and will perform my duties in strict accordance with the laws and 
regulations of local authority, Declaration of Helsinki, Good Clinical Practice and this protocol. 
 
 
 
 
 
 
                                        
 
Principal Investigator (Print) 
 
 
Principal Investigator (Signature) 
 
 
 
Study Site 
 
Date of Signing (dd/mm/yyyy) 
 
 

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Signature Page for Sponsor 
 
 
I have read and become familiar with this protocol, confirmed the schedule in the protocol and the 
necessary contents including the implementation, and clearly understood the responsibilities related to 
this trial protocol. I agree to, and will perform my duties in strict accordance with the laws and 
regulations of local authority, Declaration of Helsinki, Good Clinical Practice and this protocol. 
 
 
 
 
 
 
Sponsor: Shanghai Henlius Biotech, Inc. 
 
 
 
 
 
 
 
Eugene Liu, Vice President for Medical Affairs 
(Signature) 
 
Date of Signing (dd/mm/yyyy) 
 
 
 
 
 
 
 
 
 
 
 
 
Cheng Jiancheng, Director of Biostatistics (Signature)  
Date of Signing (dd/mm/yyyy) 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Number: HLX10-005-SCLC301  
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Version Date: 4 Mar., 2019 
1 
Table of Contents 
TABLE OF CONTENTS .................................................................................................................................................... 1 
ABBREVIATIONS ............................................................................................................................................................. 5 
SYNOPSIS ........................................................................................................................................................................... 8 
STUDY PROCEDURES .................................................................................................................................................. 24 
1 
INTRODUCTION ................................................................................................................................................... 28 
1.1 
DISEASE BACKGROUND AND TREATMENT STATUS ................................................................................................ 28 
1.2 
RESEARCH DEVELOPMENT AND BASIS FOR DOSE SELECTION ............................................................................... 29 
1.2.1 
Introduction to HLX10 ............................................................................................................................... 29 
1.2.2 
Non-clinical studies on HLX10 .................................................................................................................. 29 
1.2.3 
Clinical studies of HLX10 .......................................................................................................................... 35 
1.2.4 
Basis for selection of chemotherapy as a control group .............................................................................. 36 
1.2.5 
Basis for combined treatment ..................................................................................................................... 36 
1.2.6 
Basis for HLX10 dose selection.................................................................................................................. 37 
1.3 
ASSESSMENT FOR RISKS AND BENEFITS ................................................................................................................ 37 
1.3.1 
Potential benefits ......................................................................................................................................... 37 
1.3.2 
Identified and potential risks ....................................................................................................................... 38 
1.3.3 
Overall benefits: risk and ethical assessment .............................................................................................. 39 
2 
OBJECTIVES ......................................................................................................................................................... 39 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................................. 39 
2.2 
SECONDARY OBJECTIVE ........................................................................................................................................ 39 
3 
STUDY PROTOCOL .............................................................................................................................................. 40 
3.1 
OVERALL STUDY DESIGN ...................................................................................................................................... 40 
3.2 
ENDPOINTS ............................................................................................................................................................ 40 
3.2.1 
Primary endpoint ......................................................................................................................................... 40 
3.2.2 
Secondary endpoints ................................................................................................................................... 40 
3.3 
RANDOMIZATION, BLINDING, AND UNBLINDING ................................................................................................... 41 
3.4 
NUMBER OF SUBJECTS .......................................................................................................................................... 41 
3.5 
ELIGIBILITY ........................................................................................................................................................... 42 
3.5.1 
Inclusion criteria ......................................................................................................................................... 42 
3.5.2 
Exclusion criteria ........................................................................................................................................ 44 
3.5.3 
Criteria for discontinuation ......................................................................................................................... 47 
3.6 
EARLY TERMINATION OF STUDY/CLOSURE OF STUDY SITE ................................................................................... 48 
3.7 
STUDY TREATMENT ............................................................................................................................................... 48 
3.7.1 
Information on study drugs ......................................................................................................................... 48 
3.7.2 
Route of administration and dosage ............................................................................................................ 49 
3.7.3 
Dose modification ....................................................................................................................................... 50 
3.7.4 
Packaging and labeling ............................................................................................................................... 55 
3.7.5 
Storage, management, and dispensing ........................................................................................................ 56 

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3.7.6 
Concomitant medication ............................................................................................................................. 56 
3.7.7 
Medication compliance ............................................................................................................................... 58 
4 
STUDY PROCEDURES AND VISITS .................................................................................................................. 58 
4.1 
STUDY PROCEDURES ............................................................................................................................................. 58 
4.1.1 
Demographics and medical history ............................................................................................................. 58 
4.1.2 
Prior and concomitant medications ............................................................................................................. 58 
4.1.3 
Adverse events ............................................................................................................................................ 59 
4.1.4 
Quality of life assessment ........................................................................................................................... 59 
4.1.5 
Echocardiography ....................................................................................................................................... 60 
4.1.6 
12-lead ECG ............................................................................................................................................... 61 
4.1.7 
Complete physical examination .................................................................................................................. 61 
4.1.8 
Symptom-directed physical examination .................................................................................................... 61 
4.1.9 
Height, weight and vital signs ..................................................................................................................... 61 
4.1.10 
ECOG scores............................................................................................................................................... 61 
4.1.11 
Local laboratory tests .................................................................................................................................. 62 
4.1.12 
Central laboratory assessments ................................................................................................................... 63 
4.1.13 
Tumor imaging ............................................................................................................................................ 64 
4.1.14 
Biomarker sample collection ...................................................................................................................... 65 
4.2 
SCREENING PERIOD (DAY -28 TO -1) ..................................................................................................................... 66 
4.3 
TREATMENT PERIOD .............................................................................................................................................. 67 
4.4 
END-OF-TREATMENT VISIT ................................................................................................................................... 71 
4.5 
FOLLOW-UP PERIOD .............................................................................................................................................. 72 
4.5.1 
Safety follow-up period .............................................................................................................................. 72 
4.5.2 
Survival follow-up ...................................................................................................................................... 73 
4.6 
STUDY ASSESSMENTS ........................................................................................................................................... 74 
4.6.1 
Efficacy assessment .................................................................................................................................... 74 
4.6.2 
Safety assessment ....................................................................................................................................... 74 
4.7 
ADVERSE EVENTS ................................................................................................................................................. 74 
4.7.1 
Definition of AE .......................................................................................................................................... 74 
4.7.2 
Definition of SAE ....................................................................................................................................... 77 
4.7.3 
Documentation of AEs ................................................................................................................................ 79 
5 
OTHER REASONABLE INTERPRETATIONS ................................................................................................. 81 
5.1 
Determination of Predictability ................................................................................................................... 82 
5.2 
Reporting of SAEs ...................................................................................................................................... 83 
5.3 
Follow-Up of AEs ....................................................................................................................................... 84 
5.4 
Pregnancy ................................................................................................................................................... 84 
6 
STATISTICAL METHODOLOGY ....................................................................................................................... 85 
6.1 
SAMPLE SIZE ESTIMATION..................................................................................................................................... 85 
6.2 
BLINDED SAMPLE SIZE RE-ESTIMATION ................................................................................................................ 85 
6.3 
STATISTICAL ANALYSIS SETS................................................................................................................................. 86 
6.3.1 
Intent-to-treat (ITT) set ............................................................................................................................... 86 
6.3.2 
Per protocol set (PPS) ................................................................................................................................. 86 

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6.3.3 
Safety set (SS) ............................................................................................................................................. 86 
6.3.4 
Pharmacokinetic set (PKS) ......................................................................................................................... 86 
6.4 
INTERIM ANALYSIS AND FINAL ANALYSIS ............................................................................................................. 86 
6.5 
STATISTICAL ANALYSIS METHODS ........................................................................................................................ 87 
6.5.1 
Demographics, medical history, and baseline characteristics ..................................................................... 87 
6.5.2 
Medication compliance ............................................................................................................................... 87 
6.5.3 
Efficacy analysis ......................................................................................................................................... 87 
6.5.4 
Safety analysis ............................................................................................................................................ 89 
6.5.5 
Pharmacokinetic analysis and immunogenicity analysis ............................................................................ 89 
6.5.6 
Biomarker analysis ..................................................................................................................................... 89 
6.5.7 
Analysis of subject-reported outcome variables ......................................................................................... 89 
7 
ETHICS.................................................................................................................................................................... 90 
7.1 
ETHICAL REQUIREMENTS ...................................................................................................................................... 90 
7.2 
INFORMED CONSENT ............................................................................................................................................. 90 
7.3 
CONFIDENTIALITY FOR THE SUBJECT .................................................................................................................... 91 
8 
DATA MANAGEMENT ......................................................................................................................................... 91 
8.1 
DATABASE SETUP .................................................................................................................................................. 91 
8.2 
DATA CHECKS ....................................................................................................................................................... 91 
8.3 
DATABASE LOCK ................................................................................................................................................... 92 
9 
STUDY MANAGEMENT ...................................................................................................................................... 92 
9.1 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................................................... 92 
9.1.1 
Training ....................................................................................................................................................... 93 
9.1.2 
Clinical monitoring ..................................................................................................................................... 93 
9.1.3 
Audit ........................................................................................................................................................... 94 
9.1.4 
Data management ....................................................................................................................................... 94 
9.1.5 
Missing and useless data ............................................................................................................................. 95 
9.2 
DOCUMENTATION AND RETENTION OF STUDY DATA ............................................................................................. 95 
9.3 
FOLLOW-UPS AND MEDICAL MEASURES AFTER STUDY COMPLETION .................................................................. 95 
10 
RESPONSIBILITIES ............................................................................................................................................. 96 
10.1 
RESPONSIBILITIES OF THE INVESTIGATOR ......................................................................................................... 96 
10.2 
RESPONSIBILITIES OF THE SPONSOR ................................................................................................................. 97 
11 
CONFIDENTIALITY AND PUBLICATION OF TRIAL RESULTS ................................................................ 98 
12 
REFERENCE .......................................................................................................................................................... 98 
13 
APPENDICES ....................................................................................................................................................... 101 
APPENDIX 1: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS..................................................................... 101 
APPENDIX 2-1: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST 1.1) .................................................... 102 
APPENDIX 2-2: MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS ......................................................... 108 
APPENDIX 3:QUALITY OF LIFE SCALE EORTC QLQ-C30, EQ-5D-5L, EORTC QLQ-LC13 ....................................... 113 
ANNEX 4: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) - PERFORMANCE STATUS SCALE ............................... 119 

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APPENDIX 5: FRIDERICIA CORRECTION FORMULA ........................................................................................................ 120 
APPENDIX 6: COCKCROFT AND GAULT FORMULA ......................................................................................................... 121 
APPENDIX 7: HEART FUNCTIONAL CLASSIFICATION OF NEW YORK HEART ASSOCIATION ............................................ 122 
APPENDIX 8: GUIDELINES FOR DOSE MODIFICATION AND TREATMENT FOR IMMUNE-RELATED TOXICITY ................... 123 
APPENDIX 9: PROHIBITED TRADITIONAL CHINESE MEDICINES ..................................................................................... 146 
 
 
 
List of Tables 
TABLE 1. PRINCIPLES FOR CHEMOTHERAPY MODIFICATIONS ............................................................................................... 53 
TABLE 2. CARBOPLATIN MODIFICATIONS FOR HEMATOLOGICAL TOXICITIES ........................................................................ 53 
TABLE 3. CARBOPLATIN DOSING MODIFICATIONS BASED ON NON-HEMATOLOGICAL TOXICITIES IN PREVIOUS TREATMENTS 54 
TABLE 4. ETOPOSIDE DOSING MODIFICATION FOR SUBJECTS WITH RENAL IMPAIRMENT ....................................................... 55 
TABLE 5. LOCAL LABORATORY TESTS .................................................................................................................................. 62 
TABLE 6. PK AND ADA BLOOD SAMPLING .......................................................................................................................... 64 
TABLE 7. EVALUATION OF CAUSALITY BETWEEN AE AND STUDY DRUG .............................................................................. 82 
 
List of Figures 
FIGURE 1. OVERALL STUDY DESIGN ..................................................................................................................................... 23 
FIGURE 2. SCHEMATIC OF STUDY TREATMENT ..................................................................................................................... 69 
 
 
 
 
 
 
 
 
 
 
 
 

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Abbreviations 
Abbreviation 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse events 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial prothrombin time 
ASCO  
American Society of Clinical Oncology 
AST 
Aspartic transaminase 
ATC 
Anatomical, Therapeutic and Chemical Classification System 
BUN 
Blood urea nitrogen 
CHO 
Chinese hamster ovary cells 
CI 
Confidence interval 
CMH 
Cochran–Mantel–Haenszel test 
CR 
Complete response 
Cr 
Creatinine 
CRA 
Clinical research associate 
CRO 
Contract research organization 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte antigen 4 
DCR 
Disease control rate 
DFS 
Disease free survival 
DOR 
Duration of response 
12-ECG 
12 lead electrocardiography 
ECOG  
Eastern Cooperative Oncology Group 
eCRF  
Electronic case report form 
EDC 
Electronic data capture system 
ES-SCLC 
Extensive stage small cell lung cancer 
EQ-5D-5L 
5-level EQ-5D version 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer 
Quality of Life Scale 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
FFPE 
Formalin-fixed paraffin embedded 
FT3 
Free triiodothyronine 

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Abbreviation 
Explanation 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
Hb 
Haemoglobin 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV  
Hepatitis C virus 
HR 
Hazard Ratio 
HRQoL 
Health-related quality of life 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
IDMC 
Independent Data Monitoring Committee 
IRB  
Institutional Review Board 
IRC 
Independent Review Committee 
IRRC 
Independent Radiology Review Committee 
ITT  
Intent-to-treatment set 
IVIG 
Intravenous immunoglobulin 
IWRS 
Interactive web response system 
LFT 
Liver function test 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite instability 
NA 
Not applicable 
NCCN 
National Comprehensive Cancer Network 
NMPA 
National Medical Products Administration 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PCP 
Pneumocystis pneumonia 
PD 
Progressive disease 
PD-L1 
Programmed cell death-ligand 1 
PET-CT 
Positron emission tomography - computerized tomography 
PD-1 
Programmed cell death-ligand 1 
PFS  
Progression-free survival 
PI 
Principal Investigator 

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Abbreviation 
Explanation 
PK 
Pharmacokinetics 
PKS 
PK set 
PLT 
Platelet 
PPS 
Per protocol set 
PR  
Partial response 
QC 
Quality control 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RO 
Receptor occupancy 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Safety analysis set 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SOP 
Standard operating procedure 
SS 
Safety set 
T3 
Triiodothyronine 
T4 
Thyroxine 
TB 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
TMB 
Tumor mutation burden 
TNF-α 
Tumor necrosis factor α 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
Ultrasound 
VALG 
Veterans Administration Lung Study Group 
irAEs 
Immune-related adverse events 
 
 
 
 
 
 
 
 
 
 

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Synopsis 
Investigational 
Product 
HLX10 (Recombinant Humanized Anti-PD-1 Monoclonal Antibody 
Injection) 
Active Ingredient 
Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection 
Title 
A Randomized, Double-Blind, Multicenter, Phase III Study to Evaluate 
HLX10 (Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection) 
in Combination with Chemotherapy (Carboplatin-Etoposide) in Previously 
Untreated Patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC) 
Protocol Number 
HLX10-005-SCLC301 
Sponsor 
Shanghai Henlius Biotech, Inc. 
Trial Phase 
Registered Clinical Phase III Study 
Study Sites 
60-70 sites worldwide 
Subjects 
Patients with extensive stage small cell lung cancer (ES-SCLC) 
Objectives 
Primary Objective 
• To evaluate the clinical efficacy of HLX10 combining with 
chemotherapy versus placebo combining with chemotherapy in 
previously untreated patients with ES-SCLC. 
Secondary Objectives 
• To evaluate the safey and tolerabilityof HLX10 combining with 
chemotherapy versus placebo combining with chemotherapy in 
previously untreated patients with ES-SCLC. 
• To measure the exposure following HLX10 administration 
Exploratory 
• Exploratory population pharmacokinetic (PopPK) analysis 
Stages 
This trial is divided into three stages: screening (28 days), treatment (until 
loss of clinical benefit, death, intolerable toxicity, withdrawal of informed 
consent, or occurrence of other reasons specified in the protocol, whichever 

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occurs first), and follow-up (including safety follow-up period and survival 
follow-up period). 
Planned 
Enrollment 
Approximately 489 (326 for HLX10 and 163 for placebo) 
Study Design 
This is a randomized, double-blind, multicenter, clinical Phase III study to 
evaluate the clinical efficacy, safety and tolerability of HLX10 or placebo in 
combination with chemotherapy in patients with previously untreated ES-
SCLC, to collect PK parameters and to investigate the biomarker related to 
efficacy. 
Subjects in this study will be randomized to arm A or B at 2:1 ratio as follows: 
• Arm A (HLX10): HLX10 + chemotherapy (carboplatin-etoposide) 
• Arm B (control): placebo + chemotherapy (carboplatin-etoposide) 
Randomization are stratified by PD-L1 expression level (negative, positive, not 
available), brain metastasis (yes versus no), and age (≥ 65 years versus < 65 
years). 
After screening, subjects meeting the inclusion criteria and not meeting the 
exclusion criteria will be enrolled. Included subjects will be treated with 
HLX10 or placebo in combination with chemotherapy once every 3 weeks, 
until loss of clinical benefit, death, intolerable toxicity, withdrawal of informed 
consent, or occurrence of other reasons specified in the protocol (whichever 
occurs first). 
Treatment should be discontinued when they have evidence of disease 
progression as assessed by RECIST v1.1. However, considering the limited 
availability and efficacy or greater toxicity of treatment options after 
withdrawal, and for better adaptation to standard clinical practice, the subject 
who meets all the following conditions may continue the treatment as 
determined by the investigator and after appropriate discussion with the subject 
and obtaining the informed consent. 
(1) With no clinical signs and symptoms (including worsening of laboratory 
findings) indicating a significant disease progression. 
(2) A stable Eastern Cooperative Oncology Group (ECOG) performance status 
score. 

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(3) No rapid disease progression or tumor progression requiring urgent 
alternative medical intervention at critical anatomical sites (e.g., spinal cord 
compression). 
(4) The major organ function meets the inclusion and exclusion criteria of this 
study. 
(5) The subject should sign the supplementary informed consent formto 
continue treatment. 
The primary objective of this study is to compare the PFSs of HLX10 in 
combination with chemotherapy versus placebo in combination with 
chemotherapy, as assessed by an Independent Radiology Review Committee 
(IRRC) using RECIST v1.1. 
Study Drugs, 
Dosage, Regimen 
and Route of 
Administration 
This study drugs are administered as per a every 3-week (21-day) cycle as 
follows: 
Investigational product: HLX10 or placebo 
4.5 mg/kg by intravenous infusion (IV) on Day 1 of each 3-week (21-day) 
cycle. 
Other study drugs: combined chemotherapy 
The following regimen will be given every 21-day (3-week) cycle for a 
maximum of 4 cycles.  
• Etoposide: 100 mg/m2, IV, on Days 1, 2, and 3 of each cycle. 
• Carboplatin: AUC = 5, IV, on Day 1 of each cycle up to a dose of 800 mg. 
Refer to Figure 2 "Schematic of study treatment" for the regimen of each 
treatment arm. On Day 1 of dosing in each treatment cycle, subjects are given 
HLX10 or placebo intravenously first, followed by intravenous carboplatin + 
etoposide. Vital signs are closely monitored during the administration. HLX10 
or placebo is administered via a blinded infusion, carboplatin + etoposide (up 
to 4 cycles) via an open-label infusion, and subjects will continue receiving 

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etoposide on Days 2 and 3. Treatment with study drug will continue until 
disease progression, intolerable toxicity, discontinuation decided by subject or 
investigator, death, withdrawal of informed consent, pregnancy, incompliance 
with protocol or procedure requirements, administrative reasons, or other 
reasons specified in the protocol, whichever occurs first. If chemotherapy is 
not used due to toxicity or other reasons in a certain cycle, it is not counted as 
the number of combined chemotherapy cycles. After completing 4 cycles of 
chemotherapy, even if the subject does not meet the above criteria, the 
chemotherapy will not be continued. 
Prophylactic 
Medications, 
Dosage and 
Method  
Prophylactic and other supportive treatment for nausea and vomiting may be 
given according to local medical practice before and after carboplatin and 
etoposide administration. 
Dose Modification 
General Principles for Dose Modification 
Any modified or delayed doses should be recorded in the source document and 
eCRFs. Adverse events are assessed for severity according to CTCAE v4.03. 
• 
For concomitant conditions already present at baseline, dose modifications 
may be determined by the investigator based on changes in severity of 
toxicity. For example, if the subject already has a Grade 1 weakness at 
baseline, and the severity increases to Grade 2 during treatment, it may be 
considered to make dose modification according to Grade 1 toxicity due 
to 1-grade increase in toxicity. 
• 
If multiple toxicities of different severities occur at the same time, the dose 
should be adjusted according to the most severe toxicity. 
• 
If the toxicity is related to one of the study drugs only (for example, 
HLX10, carboplatin or etoposide) as assessed by the investigator, dose 
modification of that study drug only with reference to the corresponding 
dose modification principle is acceptable, and the subject can continue 
receiving the other study treatment in the absence of other 
contraindications. 

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• 
If the toxicity is associated with only one of the chemotherapy medications 
as assessed by the investigator, the dose of the other chemotherapy 
medication may not be adjusted. 
• 
In the event that a delay is required for reasons of toxicity (not definitively 
related to which drug), similar delays of all study drugs at the same time 
are required if recovery to a re-dosing level is expected within 2 weeks. 
• 
If HLX10/placebo, carboplatin, or etoposide is interrupted due to toxicity, 
study treatment must be restarted, keeping HLX10/placebo in sync with 
the chemotherapy treatment cycles. 
Principles for Chemotherapy Modification 
In the event of intolerance to etoposide/carboplatin, the dose may be 
modified with reference to the following principles. 
Dose Level 
Etoposide Dosing 
Regimen 
Carboplatin Dosing Regimen 
Starting Dose 
100 mg/m2, 
IV, 
on Days 1, 2, and 3 of each 
3-week (21-day) cycle 
AUC = 5, NMT 
800 mg, IV, 
on Day 1 of each 
3-week (21-day) cycle 
First Dose 
Reduction 
75% of starting dose 
75% of starting dose 
Second Dose 
Reduction 
50% of starting dose 
50% of starting dose 
 If treatment is delayed due to intolerance to chemotherapy, chemotherapy 
may be delayed to the next cycle of administration, with the maximum 
permissible interval for chemotherapy not exceeding 6 weeks.Principles for 
HLX10 or Placebo Modification 
In the event of HLX10- or placebo-related toxicity, a delay in HLX10 or 
placebo is allowed rather than dose adjustment. Subjects who miss a scheduled 
infusion should be actively contacted to arrange another visit as soon as 
possible for administration. Administration of HLX10 or placebo may be 
delayed, but a dosing interval of up to 12 weeks is considered intolerable, 
where HLX10 will be permanently discontinued and the subject should 
withdraw from the trial. For a treatment delay due to intolerance to HLX10 or 
placebo, chemotherapy should be administered as scheduled, and HLX10 or 
placebo may be postponed to the next cycle with no more than 12 weeks 

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between doses; for a treatment delay due to intolerance to chemotherapy, 
chemotherapy may be postponed to the next cycle with an interval no more 
than 6 weeks. 
Endpoints 
Primary Endpoint 
• Progression free survival (PFS, assessed by IRRC according to RECIST 
v1.1) 
Secondary Endpoints 
• Overall survival (OS) 
• PFS (assessed by the investigator according to RECIST v1.1 and 
modified RECIST criteria) 
• Objective response rate (ORR, assessed by IRRC and investigator 
according to RECIST v1.1 criteria) 
• Duration of response (DOR, assessed by IRRC and investigator 
according to RECIST v1.1 criteria) 
• Incidence rates of AEs and SAEs 
• Pharmacokinetics (PK): serum HLX10 concentration 
• Immunogenicity evaluation: positive anti-drug antibody (ADA)  
• Relationship between PD-L1 expression level, MSI, TMB in tumor 
tissues and efficacy 
• Quality of life assessment  
Inclusion/Exclusion 
Criteria 
Inclusion Criteria 
1. Voluntary participation in clinical studies; fully understand, be informed 
about the study and have signed the informed consent form (ICF); 
willingness to follow and ability to complete all trial procedures. 
2. Aged ≥ 18 years and ≤ 75 years at the time of signing the ICF. 
3. Histologically or cytologically diagnosed with ES-SCLC (according to the 
Veterans Administration Lung Study Group (VALG) staging system). 

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4. No prior systemic therapy for ES-SCLC (including systemic 
chemotherapy, molecular targeted therapy, biological therapy, and other 
investigational therapies, etc.). 
5. Patients who have received chemoradiotherapy for previous limited stage 
SCLC must be treated with curative intent and have a treatment-free 
interval of at least 6 months from the last course of chemotherapy, 
radiotherapy, or chemoradiotherapy to the diagnosis of extensive stage 
SCLC.  
6. At least one measurable lesion as assessed by the IRRC according to 
RECIST v1.1 within 4 weeks prior to randomization. 
Note: Measurable lesions mustnot be from previously irradiated sites. 
If the lesion at the previously irradiated site is the only selectable 
target lesion, anteroposterior images showing significant progression 
of the lesion should be provided by the investigator. 
7. Every effort should be made to provide tumor tissues that meet the 
requirements for the determination of PD-L1 expression level. Subjects 
are assessed for an evaluable PD-L1 expression category (negative, 
positive, or not available) by the central laboratory for randomization. 
Note: It is recommended to provide formalin-fixed tumor tissue 
samples, paraffin-embedded tumor specimens (preferred), or FFPE 
tumor specimens or newly prepared unstained serial tissue sections 
(preferably adhesive slides) within 6 months prior to the first dose of 
study medication. A relevant pathology report must also be provided 
for the above specimens. Freshly collected specimens, radical 
resections, core needle biopsy, excisions, incisions, punch or clamp 
biopsies are acceptable (newly obtained tissues are preferred). Fine-
needle aspirations (i.e., samples that lack a complete tissue structure 
and provide only cell suspension and/or cell smear), brush biopsies, 
and cell pellet samples from pleural or peritoneal effusions are 

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unacceptable. For detailed requirements for tissue samples, see the 
laboratory manual. 
8. Prior antineoplastic therapy must have been ≥ 2 weeks from the first dose 
in this study with treatment-related AEs resolved to NCI-CTCAE Grade ≤ 
1 (except for Grade 2 alopecia). 
9. An ECOG PS score of 0 or 1.   
10. An expected survival ≥ 12 weeks. 
11. Subjects with prior denosumab use that can and agree to switch to 
bisphosphonate therapy for bone metastases starting prior to 
randomization and throughout treatment; 
12. Adequate major organ functions as defined by the following criteria 
(withoutblood transfusions, or treatment with albumin, recombinant 
human thrombopoietin or colony-stimulating factor (CSF) within 14 days 
prior to the first dose in this study): 
Hematologic system 
Absolute neutrophil count (ANC) 
≥ 1.5×109/L  
Lymphocyte 
≥ 0.5×109/L 
Platelet (PLT) 
≥ 100×109/L 
Haemoglobin (Hb) 
≥ 90 g/L 
Liver function 
Total bilirubin (TBIL) 
≤ 1.5×upper limit of normal (ULN) 
For patients with Gilbert's syndrome, 
total bilirubin ≤ 3 × ULN is acceptable 
Alanine transaminase (ALT) 
≤ 2.5×ULN; 
≤ 5.0 × ULN for patients with liver 
metastases 
Aspartic transaminase (AST) 
≤ 2.5×ULN; 
≤ 5.0 × ULN for patients with liver 
metastases 
Alkaline phosphatase (ALP) 
≤ 2.5×ULN; 
≤ 5.0 × ULN for patients with liver or 
bone metastases 
Renal function 
Creatinine (Cr) 
≤ 1.5×ULN; 
In case of > 1.5 × ULN, creatinine 
clearance ≥ 50 mL/min 

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(calculated 
from 
Cockcroft-Gault 
formula) 
Coagulation function 
Activated partial prothrombin time 
(APTT) 
≤ 1.5×ULN 
International normalized ratio (INR) 
≤ 1.5×ULN 
The above requirements apply only to subjects who are not receiving anticoagulant 
therapy; subjects who are receiving anticoagulant therapy must maintain a stable 
dose of anticoagulants. 
13. Female patients must meet one of the following conditions: 
① Menopause (defined as no menses for at least 1 year and no confirmed 
cause other than menopause), or 
② Surgically sterilized (removal of the ovaries and/or uterus), or 
③ With child-bearing potential, but must: 
• have a negative serum pregnancy test within 7 days prior to the first dose 
of study drug, and 
• agree to use contraception with an annual failure rate of < 1% or to remain 
abstinent (avoid heterosexual intercourse) from obtaining informed 
consent to at least 120 days after the last dose of trial medication and at 
least 150 days after the last dose of chemotherapy medication 
(Contraception methods with an annual failure rate of < 1% include 
bilateral tubal ligation, male sterilization, correct use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper-containing intrauterine devices), and  
• not breastfeeding 
14. Male patients must: agree to abstinence (avoid heterosexual intercourse) 
or take contraception measures as follows: male patients with a pregnant 
partner or a partner with childbearing potential must remain abstinent or 
use a condom to prevent embryonic exposure during chemotherapy 
treatment (carboplatin or etoposide) and for at least 150 days after the last 
dose of chemotherapy. Periodic abstinence (e.g., contraceptive methods 
based on calendar day, ovulation, basal body temperature or post-

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ovulation) and external ejaculation are ineligible methods of 
contraception. 
Exclusion Criteria 
1. Histologically or cytologically confirmed mixed-type SCLC. 
2. Other active malignancies within 5 years or at the same time. Localized 
tumors that have been cured, such as basal cell carcinoma, squamous-cell 
skin cancer, superficial bladder cancer, prostate carcinoma in situ, cervical 
cancer in situ and breast cancer in situ are acceptable. 
3. Patients who are preparing for or have received an organ or bone marrow 
transplant. 
4. Pleural or pericardial effusion requiring clinical intervention, or ascites. 
5. Patients with known or documented active central nervous system (CNS) 
metastases and/or carcinomatous meningitis at screening. However, the 
following subjects are allowed to be enrolled: ① Subjects with 
asymptomatic brain metastases (i.e., no progressive central nervous 
system symptoms caused by brain metastases, no requirement for 
corticosteroids, and lesion size ≤ 1.5 cm) may be included, but are required 
to receive regular brain imaging as a site of lesion. ② Subjects with 
treated brain metastases which have been stable for at least 2 months (as 
confirmed by 2 radiological examinations at least 4 weeks apart after 
treatment of brain metastases), with no evidence of new or enlarging brain 
metastases, and with discontinued steroids 3 days prior to study drug 
administration. (Stable brain metastases here should be confirmed before 
the first dose of the study drug.) 
6. Subjects with spinal cord compression that has not been radically treated 
with surgery and/or radiotherapy. 
7. Patients with myocardial infarction within half a year before the first dose 
of the study drug, poorly controlled arrhythmia (including QTc intervals ≥ 
450 ms for males and ≥ 470 ms for females) (QTc intervals are calculated 

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by Fridericia's formula). 
8. Class III to IV cardiac insufficiency according to NYHA classification or 
an LVEF (left ventricular ejection fraction) < 50% by cardiac color 
Doppler. 
9. Subject has uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L 
ionized calcium or calcium > 12 mg/dL or corrected serum calcium > 
ULN). 
10. Subject with peripheral neuropathy ≥ Grade 2 by CTCAE. 
11. Human immunodeficiency virus (HIV) infection, , positive test for HIV 
antibody. 
12. Active pulmonary tuberculosis. 
13. Subjects 
with 
previous 
and 
concurrent 
interstitial 
pneumonia, 
pneumoconiosis, radiation pneumonitis, drug-related pneumonitis and 
severe impaired pulmonary function that may interfere with the detection 
and management of suspected drug-related pulmonary toxicity as judged 
by the investigator. 
14. Hepatitis B (positive test for HBsAg or HBcAb and positive test for HBV-
DNA) or Hepatitis C (positive tests for HCV antibody and HCV-RNA). 
Hepatitis B and C co-infection (positive test for HBsAg or HBcAb and 
positive test for HCV antibody); 
15. Known active or suspected autoimmune or interstital lung diseases. 
Subjects in a stable state with no need for systemic immunosuppressant 
therapy are allowed to enroll.  
16. Treatment with live vaccines within 28 days prior to study drug 
administration; inactivated viral vaccines for seasonal influenza are 
allowed. 
17. Patients requiring treatment with systemic corticosteroids (> 10 mg/day 
prednisone efficacy dose) or other immunosuppressive drugs within 14 
days prior to the first dose or during the study. However, in the absence of 

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active autoimmune disease, subjects are allowed to use topical or inhaled 
steroids and adrenal hormone replacement therapy at doses equivalent to 
≤ 10 mg/day of prednisone efficacy. 
18. Any active infection requiring systemic anti-infective therapy within 14 
days prior to study drug administration. 
19. Major surgery within 28 days prior to the first dose of the study drug, 
defined as: surgeries requiring at least 3 weeks of recovery to be able to 
receive treatment in this study. 
20. Radical radiation therapy within 3 months prior to study medications. 
Note: Palliative radiotherapy to bone or palliative radiotherapy to 
superficial lesions is allowed according to local standards 14 days 
prior to the first dose. Radiotherapy covering more than 30% of the 
bone marrow area within 28 days prior to the first dose is not allowed. 
21. The subject has previously received other antibodies/drugs against 
immune checkpoints, such as PD-1, PD-L1, CTLA4, etc. 
22. Participation in any other ongoing clinical studies, or less than 14 days 
from the end of the previous clinical study treatment to the start of this 
trial. 
23. Known history of severe allergy to any monoclonal antibody. 
24. Known hypersensitivity to carboplatin or etoposide. 
25. Pregnant or lactating women. 
26. Known history of psychotropics abuse or drug abuse. 
27. In the judgment of the investigator, the subject has any other factors that 
may lead to a premature discontinuation. 
Statistics 
Sample Size Estimation 
The allocation ratio is 2:1 in this study. The sample size is estimated based on 
an assumption that the median progression-free survival (PFS) for placebo + 
chemotherapy (carboplatin-etoposide) is 5 months, and the hazard ratio (HR) 
for the HLX10 + chemotherapy arm versus the control arm is 0.7. At an overall 
significance level of α = 0.05 (two-sided), and assuming an treatment period 

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of 24 months and an entire study period of 29 months, at least 336 PFS events 
are to be observed for an 85% power. Considering a dropout rate of 20%, a 
total of 489 subjects (326 in investigational arm and 163 in the control arm) 
need to be enrolled in the 2 arms. 
Estimation of Blinded Sample Size 
In this study, when 320 subjects are enrolled (accounting for about 2/3 of the 
planned enrollments), the sponsor will consider conducting a blinded sample 
size assessment. If the overall median PFS under the blind condition is lower 
than expected, the sponsor should communicate with the PI and regulatory 
authorities to increase the sample size (number of PFS events) as necessary. 
Statistical Analysis Sets: 
 Intent-to-Treat Set (ITT): defined as all subjects randomized into the trial. 
The ITT population will be the primary analysis population for the 
efficacy analysis in this study. ITT population will be analyzed based on 
treatment arms. 
 Per Protocol Set (PPS): a subset of ITT, in which all randomized subjects 
who have received at least one post-treatment tumor assessment and have 
no major protocol deviation that significantly affects the primary efficacy 
are included. The analysis based on the PPS will serve as a support of ITT 
analyses. 
 Safety Set (SS): defined as all subjects who received at least one dose of 
study drugs. The safety set is the primary population for safety endpoint 
analysis and will be analyzed based on treatment arms. 
 Pharmacokinetic Set (PKS): including all subjects who have received at 
least one dose of HLX10, had at least one post-dose concentration 
measurement at scheduled PK time points, without any major protocol 
violation that could significantly affect the PK assessment. PKS will be 
used for PK analysis. 
Efiicacy Analysis 
• Primary Efficacy Endpoint 

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Progression-free survival (PFS): assessed by IRRC according to RECIST v1.1 
criteria. PFS will be compared between the two arms using the stratified log-
rank test with PD-L1 expression level (negative, positive, or not available), 
brain metastasis (yes versus no) and age (≥ 65 years versus < 65 years); HR 
and its 95% confidence interval are estimated by stratified COX proportional 
hazards model; medias is estimated using Kaplan Meier method and Kaplan-
Meier curves are plotted. 
• Secondary Efficacy Endpoints 
➢ Overall survival (OS): using the same statistical method as the primary 
efficacy endpoint; 
➢ Progression-free survival (PFS): as assessed by the investigator according 
to RECIST v1.1 and modified RECIST criteria and analyzed using the 
same method as the primary efficacy endpoint; 
➢ Objective response rate (ORR): The stratified Cochran-Mantel-Haenszel 
(CMH) test is used for the difference in ORR between the two arms, and 
the odds ratio and its 95% confidence interval are estimated; 
➢ Duration of response (DOR): the median is estimated using the Kaplan 
Meier method and Kaplan-Meier curves are plotted. 
Interim Analysis: 
An Independent Data Monitoring Committee (IDMC) will be established for 
this study to conduct the interim analysis. One interim analysis of PFS will be 
performed in this study. An α-spending function of O'Brien-Fleming type 
(approximated by the Lan-DeMets method) is used to control the overall type 
I error rate. 
⚫ The interim analysis of PFS is planned when 66% (approximately 222) 
of planned PFS events are observed, in which the safety and efficacy 
of the investigational product will be evaluated. The first interim 
analysis of PFS based on the O'Brien-Fleming alpha spending function 
had an alpha of 0.012 (two-sided). 
⚫ The final analysis of PFS will be performed when a target number of 
PFS events (approximately 336) are observed, and for final analysis the 

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α is 0.046 (two-sided) based on the O'Brien-Fleming alpha spending 
function. 
Safety Analysis 
AEs will be described according to MedDRA terms and graded according to 
CTCAE v4.03. Adverse events occurring during or after the first dose of the 
study drug will be summarized by CTCAE grade. Treatment-emergent adverse 
events (TEAEs) and concomitant medications in the trial will be summarized 
separately by treatment arm. Laboratory measurements, ECOG, vital signs, 
physical examination and ECG will be summarized by treatment arm and visit. 
Values observed and changes from baseline will be descriptively reported by 
visit in this trial. 
Pharmacokinetics and Immunogenicity  
Serum drug concentration, pharmacokinetics, and ADA positive rates are 
descriptively summarized by visit.Biomarker Analysis 
At screening, the subjects' tumor tissues will be collected for determining PD-
L1 expression level, microsatellite instability (MSI) and tumor mutation 
burden (TMB); the subjects' blood samples are collected for the detection of 
MSI and TMB. The primary objective is to assess the relationships between 
PD-L1 expression and MSI, TMB and efficacy. 
Analysis of Subject-Reported Outcome Variables 
Subjects' quality of life will be assessed by EQ-5D-5L scale, EORTC QLQ-
C30 and EORTC QLQ-LC13 scale. Descriptive statistics are based on the 
allocation for the scale scores, subscale scores, and individual scores at each 
visit and their changes from baseline. 

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ICF 
Arm A (HLX-10): HLX10 + etoposide/carboplatin 
Screening 
Treatment period 
(21-day cycles) 
Follow-Up Period 
Randomiza
tion 
Day 1 
(Week 1) 
Arm B (control): placebo + etoposide/carboplatin 
Discontinuation 
One treatment visit every 3 weeks ± 3 days 
Assessed once every 6 weeks (± 7 days) for 48 weeks, then every 9 weeks (± 7 days) 
thereafter 
Survival follow-up 
period 
 
Safety follow-up 
period 
For study treatment schedule, please refer to Figure 2. Schematic of study treatment. 
Stratification factors: 

Gender (male versus female) 

PD-L1 expression level (negative, positive, not available) 

Brain metastasis (yes versus no) 

Age (≥ 65 years versus < 65 years) 
Screening period: At least 28 days 
Safety follow-up period: 90 days after last dose. Safety visit is required at the site 30 days (±7 
days) after the last dose, and telephone follow-up is required 90 days (±7 days) after the 
last dose. 
Survival follow-up period: every 12 weeks ± 7 days 
Figure 1. Overall study design 

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Study Procedures（1） 
Periods 
Screening Period 
Treatment Period (three-week cycles) 
End-of-Treatment 
(EOT) visit1 
Follow-Up Period2 
Treatment Cycles/Visits 
Screening Period 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-ups 
Survival follow-up3 
Time of Visit 
-28 to -8 
-7 to -1 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days 
after last dose (by 
telephone calls) 
Every 12 weeks 
Time Window4 
 
 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
Management Procedures 
 
 
 
 
 
 
 
 
 
Informed consent form 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Dispensing of subject ID card 
X 
 
 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
 
 
Prior and concomitant therapies5 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Operations/Assessments 
 
 
 
 
 
 
 
 
 
Adverse events6 
X  
X 
X 
X 
X 
X 
X 
X 
 
Quality of life7 
 
X 
X 
 
X 
 
X 
X 
X 
 
Echocardiography 
X 
 
 
 
 
 
 
 
 
12-lead ECG 
X  
X 
X 
X 
X 
X 
X 
X 
 
Complete physical examination 
X 
 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
X 
X 
X 
X 
X 
X 
X 
 
Height, weight and vital signs8 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG scores 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Subsequent antineoplastic therapy 
 
 
 
 
 
 
 
X 
X 
Survival status 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

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Study Procedures（2） 
Periods 
Screening Period 
Treatment Period (three-week cycles) 
End-of-Treatment 
(EOT) visit1 
Follow-Up Period2 
Study Treatment 
 
 
 
 
 
 
 
 
 
Randomization9 
 
X 
 
 
 
 
 
 
 
HLX10 or placebo9 
 
X 
X 
X 
X 
X 
 
 
 
Etoposide + carboplatin 
 
X 
X 
X 
X 
 
 
 
 
Clinical Operations/Assessments: by study site 
 
 
 
 
 
 
 
 
 
Pregnancy test10 
 
X 
 
 
X 
 
X 
X 
X 
 
Routine blood test, biochemistry, coagulation, 
urinalysis11 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
T3 or FT3, T4 or FT4, TSH12 
   
X 
 
 
X 
 
X 
X 
X 
 
HBV antibody, HBV DNA13 
X 
 
 
 
 
 
 
 
 
⚫ In case of HBV DNA (-) and: 1) HBsAg (+), 
or 2) HBcAb (+) and HBsAg (-) at baseline, 
HBV antibody and HBV DNA should be 
examined during the treatment period. 
 
 
 
X 
 
X 
X 
X 
 
HCV antibody, HCV RNA13 
X 
 
 
 
 
 
 
 
 
⚫ In case of HCV antibody (+) and HCV RNA 
(-)at baseline, HCV antibody and HCV RNA 
should be examined during the treatment 
period. 
 
 
 
X 
 
X 
X 
X 
 
HIV  
X 
 
 
 
 
 
 
 
 
Clinical Operations/Assessments: by central 
laboratory 
 
 
 
 
 
 
 
 
 
HLX10-PK, ADA14 
 
X 
X 
 
X 
X 
X 
X 
 
Efficacy Assessment 
 
 
 
 
 
 
 
 
 
Radiological Examination15 
X 
 
 
X 
 
X 
X 
 
 
Biomarker Sample Collection 
 
 
 
 
 
 
 
 
 
Tumor tissue16 
X 
 
 
 
 
 
 
 
 
Blood 
X 
 
 
 
 
 
 
 
 
1. 
If a subject discontinues study treatment for any reason, an end-of-treatment (EOT) visit should be performed whenever possible and should be completed within 7 days after informed or 
discontinuation confirmed (and should be completed before the subject starts a new anti-tumor therapy); 
2. 
All subjects are required to visit the study site for safety follow-up 30 days (± 7 days) after the last dose; if the end-of-treatment visit is delayed for any reasons and occurs after the time window of 
30 days (± 7 days), no further safety follow-up visit is required. All subjects are required to receive a follow-up telephone call for safety follow-up 90 days (± 7 days) after the last administration. 
Only the information of AEs and AE-related concomitant drugs is collected. For subjects who discontinued for reasons other than disease progression, radiological assessments are to be continued 
as scheduled as far as possible, until disease progression, initiation of new antineoplastic therapy, withdrawal of ICF, death, or end of study, whichever occurs first. 

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Periods 
Screening Period 
Treatment Period (three-week cycles) 
End-of-Treatment 
(EOT) visit1 
Follow-Up Period2 
3. 
Subjects should be followed for survival by telephone every 12 weeks ± 7 days after starting a new antineoplastic therapy or treatment termination criteria are met ; the frequency of survival 
follow-up may be increased as appropriate. 
4. 
The maximum screening period is 28 days; the time windows are ± 3 days for treatment, ± 7 days for tumor assessment, + 7 days for EOT visit, and ± 7 days for follow-up. ECOG performance 
status, pregnancy test, blood routine, biochemistry, coagulation, urinalysis and thyroid function (T3 or FT3, T4 or FT4, TSH) should be completed within 7 days before randomization, and the 
subjects should meet the corresponding inclusion/exclusion criteria for enrollment. 
5. 
All prior and concomitant medications are recorded from 30 days prior to signing the ICF through the safety follow-up visit; concomitant medications associated with AEs are recorded up to 90 
days after the last study treatment. 
6. 
All AEs and treatment emergent AEs are recorded from the time of signing the ICF until 90 days after the last study treatment. If a subject starts a new antineoplastic therapy during the AE collection 
period, only information on AEs related to study treatment are collected after the new antineoplastic therapy. 
7. 
Quality of life scales including the EQ-5D-5L, the European Organization for Research and Treatment of Cancer Quality of Life Scale (EORTC QLQ-C30), and the European Organization for 
Research and Treatment of Cancer lung cancer questionnaire module (EORTC QLQ-LC13). Such scales are evaluated prior to the first dose and every other subsequent dosing cycle (i.e., pre-dose 
in Cycles 1, 3, 5, 7, etc.) until EOT. A quality of life assessment is required at the EOT visit if no assessment has been performed within the past 3 weeks. Re-assessments prior to dosing in Cycle 1 
are not required for subjects who had a quality of life assessment on Day -7 to Day -1 of the screening period. 
8. 
The height measurement is performed only at screening; vital signs include body temperature, pulse, respiratory rate, and blood pressure. Body weight is measured before each dose, and no 
dose adjustment of the study drug is required if the subject's body weight differs ≤ 10% from the reference value of the current dose during the study, otherwise the dose should be recalculated. 
This new body weight will serve as the baseline value for subsequent body weight measurements. 
9. 
Study drug is administered on Day 1 of each 3-week cycle after all clinical and laboratory operations/assessments are completed. No more than 3 days must have elapsed between the date of 
randomization and the date of the first study dose. 
10. 
Women of childbearing potential must have a serum pregnancy test. This is also performed within 3 days prior to dosing every other cycle during the treatment period. 
11. 
Routine laboratory tests include routine blood test, coagulation, biochemistry and urinalysis. Routine blood test items include red blood cell count, hemoglobin, platelet, white blood cell count, 
white blood cell differential counts and percentages (including: basophils, eosinophils, lymphocytes, monocytes, neutrophils); biochemistry items include blood urea/urea nitrogen, creatinine, 
sodium, potassium, magnesium, chloride, carbon dioxide binding capacity or bicarbonate or total carbon dioxide, calcium, phosphorus, blood glucose, total bilirubin, direct bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase, total cholesterol, total protein, albumin; urinalysis items include specific gravity, pH, urine 
glucose, urine protein, ketone body and blood cells. These are performed within 3 days before dose in each cycle; for aforementioned laboratory tests scheduled on the same day as study 
treatment, the study treatment can be arranged only after the test results are obtained. For combined chemotherapy, routine blood tests should be performed on Day 8 (± 3 days) of each treatment 
cycle to closely monitor bone marrow suppression. 
12. 
Thyroid function tests include triiodothyronine (T3 or FT3), thyroxine (T4 or FT4) and thyroid stimulating hormone (TSH) assays. This is also performed within 3 days prior to dosing every other 
cycle during the treatment period. 
13. 
All subjects are tested for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody at screening; HBsAg positive subjects should be further tested for hepatitis B virus (HBV) 
DNA titer; and HCV antibody positive subjects should be further tested for HCV RNA. In case of HBV DNA (-) and: 1) HBsAg (+), or 2) HBcAb (+) and HBsAg (-) at baseline, HBV antibody 
and HBV DNA should be tested every 2 cycles during the treatment period. In case of HCV antibody (+) and HCV RNA (-) at baseline, HCV antibody and HCV RNA should be tested every 2 
cycles during the treatment period. 
14. 
PK and ADA sampling: (Note: ADA samples will only be collected pre-dose and procedures are described in the laboratory manual) 
➢ 
PK and ADA samples for HLX10 or placebo will be collected at the following time points: within 7 days pre-dose in Cycle 1, within 3 days pre-dose in Cycles 2, 4, 6, 8 and every 4 
cycles thereafter, within 2 hours after the end of dosing in Cycles 1 and 8 of treatment period (for PK only), at EOT visit and safety follow-up. 
15. 
CT or MRI should be performed at screening, every 6 weeks (± 7 days) during the first 48 weeks after the start of study treatment, and every 9 weeks (± 7 days) after week 48 on sites including 
brain, chest, abdomen, pelvic cavity and any other sites suspected to have tumor lesions, in which brain MRI or CT (preferably MRI) and bone scans are required for all subjects at screening, 
and are performed in treatment period as determined by the investigator according to clinical needs; examination methods at the same site should be consistent as much as possible throughout the 

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Periods 
Screening Period 
Treatment Period (three-week cycles) 
End-of-Treatment 
(EOT) visit1 
Follow-Up Period2 
study; if there are no contraindications, contrast agent should be used. The investigator and IRRC respectively assess the tumor images according to RECIST v1.1 (the tumor assessment can be 
performed by the investigator according to clinical needs), and the investigator should make subsequent treatment judgment according to the results of their own efficacy evaluation. If tumor 
assessment has been performed within 28 days prior to the first dose by the same methods and devices in the same hospital, it may serve as the baseline tumor assessment. At the EOT visit, if 
tumor imaging has been performed within the last 4 weeks, a re-test is not required. For subjects who discontinued for reasons other than disease progression, radiological assessments are to be 
continued as scheduled, until disease progression, initiation of new antineoplastic therapy, withdrawal of ICF, death, or end of study, whichever occurs first. 
16. 
To the extent possible, formalin-fixed paraffin-embedded (FFPE) tumor samples (paraffin blocks or unstained sections) collected at or after the diagnosis of ES-SCLC and within 6 months prior 
to the start of study medication or pathological reports of such specimens should be provided. In case of no archived tumor tissue samples available, it is recommended to conduct a fresh tumor 
lesion biopsy at screening to obtain the corresponding tumor sample (the number of specimens required is based on the biopsy result). Tumor tissue sections will be used for immunohistochemical 
analysis to evaluate the expression level of PD-L1 in tumor cells and tumor-infiltrating immune cells and other purposes. Freshly collected specimens, radical resections, core needle biopsy, 
excisions, incisions, punch or clamp biopsies are acceptable. Fine-needle aspirations (i.e., samples that lack a complete tissue structure and provide only cell suspension and/or cell smear), brush 
biopsies, and cell pellet samples from pleural or peritoneal effusions are unacceptable. For detailed requirements for tissue samples, see the laboratory manual. 

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1 INTRODUCTION 
1.1 Disease Background and Treatment Status 
The global cancer statistics show that lung cancer is the most common cancer (11.6% of total cancer 
cases) and cause of death (18.4% of total cancer deaths) in the world. It is estimated that by 2018, 2.1 
million new cases of lung cancer and 1.8 million new cases of lung cancer deaths will occur 
worldwide[1]. According to the data released by the National Cancer Center of China in 2018, there are 
about 781,000 new cases of lung cancer and 626,000 deaths from lung cancer each year in China, with 
the occurrence and mortality ranking first among malignant tumors[2]. 
Small cell lung cancer (SCLC) is derived from epithelial cells with neuroendocrine differentiation, 
accounting for 15%-20% of the total number of lung cancers[3]. The SCLC is staged using the US 
Veterans Administration (VA) staging system and is divided into a limited stage and an extensive stage. 
Most patients present with tumor metastases as the first symptom[4], and only 30% to 40% of patients 
are in the limited stage at the time of initial diagnosis[5]. Patients with extensive disease have shorter 
survival due to extensive tumor metastasis and poor physical status only with supportive care. The 
median survival time of untreated extensive small-cell lung cancer (ES-SCLC) is reported to be 2-4 
months[6]. With a combination of surgery, radiotherapy and chemotherapy, the median survival of ES-
SCLC patients can reach 8 to 13 months, with a 2-year survival rate of 5%[7]. 
Currently, systemic chemotherapy is still the primary treatment for ES-SCLC. The first-line platinum-
based treatment recommended are the EP treatment (etoposide plus cisplatin), the EC treatment 
(etoposide plus carboplatin), the IP treatment (irinotecan plus cisplatin), and the IC treatment 
(irinotecan plus carboplatin). First-line treatment of SCLC is highly effective, but 80% of patients with 
limited-stage disease and almost all patients with extensive-stage disease relapse within one year, with 
a median survival of only 4 to 5 months after relapse[8]. Due to the limited understanding of SCLC 
genetic changes and the significant heterogeneity of SCLC at the genetic level, the success of some 
new treatment methods, such as intensive chemotherapy, supportive treatment, and molecular targeted 
therapy, did not benefit patients with extensive-stage SCLC. Therefore, there is an urgent need to 
explore more effective first-line treatments for extensive-stage SCLC. 

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1.2 Research Development and Basis for Dose Selection 
1.2.1 
Introduction to HLX10 
HLX10 is an innovative monoclonal antibody targeting PD-1 independently developed by Shanghai 
Henlius Biotech, Inc. HLX10 is the IgG4 humanized monoclonal antibody. The gene sequence is 
screened using the hybridoma technique and genetically engineered to complete humanization. CHO 
were used as host cells to construct a stable cell line. The protein generated is composed of two 
identical heavy chains and two identical light chains linked by interchain disulfide bonds to form a 
typical human immunoglobulin IgG4 structure of a Y shape. 
1.2.2 
Non-clinical studies on HLX10 
1.2.2.1 In vitro pharmacodynamic studies on HLX10 
A series of in vitro pharmacodynamic studies comparing HLX10 with the positive control Nivolumab 
showed: HLX10 can bind to the surface of activated T cells expressing PD-1 and has the ability to 
block the binding of PD-1 to PD-L1 or PD-L2 on the cell surface. The binding and blocking ability of 
HLX10 present dose-dependence. The HLX10 in vitro mixed leukocyte reaction (MLR) assay showed 
that HLX10 blocks immunosuppression depending on the binding of PD-1 to its ligand, thereby 
stimulating activated CD4+ T cells, increasing T cell proliferation and producing more IL-2 cytokine. 
This phenomenon was dose-dependent in both the investigational product HLX10 and the positive 
control Nivolumab. 
In addition, to investigate the occupancy ratio of HLX10 to PD-1 receptor on human T cells, different 
doses of HLX10 were used (50.0, 10.0, 2.0, 4.0 × 10-1, 8.0 × 10-2, 1.6 × 10-2, 3.2 × 10-3 and 6.4 × 10-4 
μg/mL) were pre-incubated with whole blood of six healthy subjects to simulate the injection of 
HLX10 into human blood. The results showed that with an increasing dose of HLX10 during pre-
incubation, the PD-L1 receptor occupancy (RO) on CD3+ T cells increased. In six healthy subjects, 
once the blood concentration of HLX10 in four of the subjects reached 2 μg/mL, the PD-1 receptor 
occupancy on CD3+ T cells reached more than 80%. 

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1.2.2.2 In vivo pharmacodynamic studies of HLX10 
The results of anti-tumor efficacy and safety evaluation in NOD/SCID mice model subcutaneously 
xenografted with HT-29 human colon cancer cells showed that HLX10 had no adverse effects on the 
health status and body weight of mice in each dose group, indicating that HLX10 has a high level of 
safety. In terms of tumor suppressive effect, 30 mg/kg of HLX10 was able to effectively inhibit the 
growth of subcutaneously xenografted HT-29 human colon cancer cells in NOD/SCID mice in the 
presence of human peripheral blood mononuclear cells (P < 0.0001). 
The anti-tumor effect and safety evaluation of human non-small cell lung cancer cells NCI-H292 in 
subcutaneous xenograft NOD/SCID mice showed that the higher dose of HLX10 did not cause adverse 
effects on the health status and body weight of mice, indicating that the investigational product HLX10 
has a high level of safety. In terms of tumor suppression, HLX10 at a dose of 30 mg/kg significantly 
inhibited the growth of NCI-H292 tumor tissues in the presence of human peripheral blood 
mononuclear cells (P < 0.001), as compared with the placebo group in both tumor volume observation 
and statistical data. 
In the dose exploration test (P16-106-TS), pharmacokinetic test (P16-106-YD) and chronic toxicity 
test (P16-106-CD), different doses of HLX10 were administered to cynomolgus monkeys to study the 
receptor occupancy (RO) at different time points before and after intravenous injection, which 
provided a basis for the selection of clinical effective dose and first dose. 
The final results showed that the results of in vivo test were consistent with that of in vitro test in terms 
of the PD-1 receptor occupancy (RO) in human peripheral blood, i.e., once the HLX10 concentration 
in the blood of subjects reached 2 μg/mL, the occupancy rate of PD-1 receptor on CD3+ T cells reached 
more than 80%. In cynomolgus monkeys, when the blood concentrations of both test animals in the 3 
mg/kg group were below the lower limit of detection (2 μg/mL), the corresponding RO values were 
still 79% and 97%, respectively. Taking all the results into consideration, it can be concluded that when 
a single dose of 3 mg/kg HLX10 was administered to cynomolgus monkeys, the RO saturation can be 
maintained for more than 4 weeks; when a dose of 5 mg/kg was administered continuously to 
cynomolgus monkeys for 13 weeks (once weekly), 100% RO saturation rate can be still achieved in 
some animals after the end of the 6-week recovery period. It can be inferred that HLX10 with lower 
clinical dose (less than 1 mg/kg) can reach RO saturation and show good curative effect. 

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1.2.2.3 Tissue cross reactivity of HLX10 
The results of human tissue cross-reactivity study of HLX10 showed that HLX10-Biotin (2.0 μg/mL 
and 0.5 μg/mL) specifically bound to normal human lymphocytes, including lymphocytes in lymph 
node, lung, ileum, stomach, spleen, fallopian tube, colon and thymus tissues. 
The results of cynomolgus monkey tissue cross-reactivity study of HLX10 showed that HLX10-Biotin 
(2.0 μg/mL and 0.5 μg/mL) specifically bound to normal cynomolgus monkey lymphocytes, including 
lymphocytes in stomach, jejunum, colon, spleen, thymus and mesenteric lymph nodes. 
1.2.2.4 General pharmacology studies of HLX10 
The general pharmacology evaluation test on central nervous system, cardiovascular system and 
respiratory system was conducted in cynomolgus monkeys. This test was conducted concomitantly 
with the chronic toxicity test. During the test, no test-related abnormalities were found in clinical 
symptoms of animals in each group, and no obvious abnormalities were found in their behaviors, 
breathing, etc. The abnormal findings of dying female animals in high-dose group euthanized on D55 
were related to amoeba infection, while the abnormal findings of dead female animals on D64 were 
related to allergic reaction caused by drug administration. Surviving animals showed no regular 
changes in ECG parameters such as body temperature, systolic blood pressure, diastolic blood 
pressure, mean arterial blood pressure, blood oxygen saturation, heart rate, P-R, Q-T, and QTc 
intervals, and QRS duration. Therefore, when 5, 50, and 100 mg/kg of HLX10 were continuously 
given to cynomolgus monkeys via intravenous infusion for 13 weeks (once weekly), no significant 
effect on the central nervous system, cardiovascular system and respiratory system of cynomolgus 
monkeys was observed. 
1.2.2.5 Acute toxicity study of HLX10 
A 4-week dose exploration toxicity study was conducted in cynomolgus monkeys with repeated 
intravenous infusions of HLX10 at 5 mg/kg, 50 mg/kg, and 100 mg/kg, respectively. Administration 
was carried out on D1, D8, D15 and D22, and all animals were euthanized on D29 and subjected to 
gross anatomy. No dead or dying animal was seen during the test. One male animal in medium-dose 

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group had loose and soft stools on D15-20 and D21-29, respectively, and one female animal in 
medium-dose group also had loose stools on D11-13, D15-20 and D29, which was considered possibly 
related to the test sample. No abnormal symptoms related to the test sample was observed in the low-
dose group and the high-dose group. No abnormal changes in body weight, food consumption, body 
temperature, ECG parameters, coagulation function indicators, blood biochemistry, or gross anatomy 
observations were observed in the animals in each dose group. The anti-drug antibodies (ADA) 
positive rates in 5, 50, and 100 mg/kg groups were 4/4, 3/4, and 4/4, respectively. The time of first 
appearance of antibodies was D8, and antibody titers ranged from < 1 to 128. Based on the results of 
this study, HLX10 was administered to cynomolgus monkeys for 4 weeks, and the animals were well 
tolerated to 100 mg/kg of HLX10. A dose of 100 mg/kg can be chosen for repeated-dose study with 
longer term. 
1.2.2.6 Chronic toxicity study of HLX10 
Toxicity and toxicokinetic studies were performed in cynomolgus monkeys with repeated intravenous 
infusions of HLX10 for 13 weeks and a recovery period of 6 weeks. Intravenous infusion of placebo 
and 5 mg/kg, 50 mg/kg, 100 mg/kg, respectively, of HLX10 were given once a week for a total of 13 
weeks. During the study, no test sample-related death or dying situation was observed in animals in 
the low-dose and medium-dose groups. At the dose of 100 mg/kg, one female animal was found dead 
from a drug-related allergic reaction; one dying female animal was euthanized on D55 due to amoebic 
infection. The symptoms of loose stools and/or soft stools were observed in each dose group, and the 
occurrence in female animals of high-dose group (100 mg/kg) was slightly higher with slightly longer 
duration. The above gastrointestinal symptoms may be related to drug administration and are 
consistent with the adverse reactions of PD-1 reported. Except for two dead animals in the high-dose 
group, the gastrointestinal reactions (loose/soft stools) of the other animals recovered completely after 
the 6-week recovery period. Surviving animals in the treatment groups did not show any other 
abnormal symptoms related to the test sample during the study. Except for the female animal of high-
dose group euthanized on D55, ADA positive state was observed in all animals of treatment groups, 
and ADA response was the highest in the low-dose group. Antibody titers increased with the increasing 
dose frequency and continued to increase until the end of the recovery period (D134). In combination 

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with toxicokinetic (TK) results, the presence of ADA significantly reduced systemic exposure in all 
dose groups. HLX10 at 5 and 50 mg/kg were repeatedly administered to cynomolgus monkeys via 
intravenous injection once weekly. No significant toxicity was observed after continuous 
administration for 13 weeks and no irritative reaction was seen at the infusion sites. No significant 
effect on major functional systems such as the cardiovascular system, central nervous system and 
respiratory system was observed. The maximum non-observed-adverse-effect level (NOAEL) of 
HLX10 was 50 mg/kg under the conditions of this experiment. The AUClast and Cmax of males on D85 
were 597.60 h*mg/mL and 4909.72 μg/mL, respectively, and the AUClast and Cmax of females were 
403.64 h*mg/mL and 3726.17 μg/mL, respectively. 
1.2.2.7 Preclinical pharmacokinetic study of HLX10 
The results of a pharmacokinetic study of HLX10 in cynomolgus monkeys by single intravenous 
infusion showed that after HLX10 was intravenously infused at 3, 10 and 30 mg/kg in animals, blood 
drug concentrations all increased with increasing dose. The systemic exposure (Cmax and AUClast) 
increased with the increasing dose. The median resorting time (MRT) was between 153.02-231.28 h. 
The elimination half life (t1/2) was between 137.97-256.99 h. The results showed that in the dose range 
of 3-30 mg/kg, the test sample basically showed linear pharmacokinetic profile in cynomolgus 
monkeys. The clearance rate among groups and volume of distribution (Vz) of HLX10 among groups 
were similar, which ranged in 0.13-0.23 mL/h/kg and 38.05-53.52 mL/kg, respectively. All animals in 
HLX10 dose groups at 3, 10 and 30 mg/kg on D8, D15, D22 and D29 were positive for anti-drug 
antibody (ADA), the time of first appearance of antibody was on D8, and the antibody titer ranged 
from < 1 to 512. Except that the area under the concentration-time curve (AUClast, AUCinf) of female 
animals in 10 mg/kg group was lower than that of male animals with statistical difference (p < 0.05), 
there was no significant difference in pharmacokinetic parameters between genders in other dose 
groups. According to the analysis results of antibody generation, it can be concluded that 2/3 female 
animals in 10 mg/kg group developed strong antibody on D22, with antibody titers of 8-128, resulting 
in female animals having slightly faster elimination and lower area under curve (AUClast, AUCinf) than 
male animals. 

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1.2.2.8 Toxicokinetics study of HLX10 
The toxicokinetic study was conducted concomitantly with the 4-week dose exploration toxicity test 
of repeated HLX10 intravenous infusions to cynomolgus monkeys. The results showed that, on D1 
and D22, the systemic exposure of HLX10 (Cmax and AUClast) increased with the increasing dose. The 
generation of anti-drug antibodies in some animals on D22 accelerated the elimination of blood 
HLX10 concentration. In ADA-negative animals, the mean Cmax and mean AUClast in each dose group 
on D22 were higher than those on D1, indicating that the drug accumulated to some extent. The blood 
HLX10 concentration in the D22 pre-dose samples also showed this feature. The accumulation factor 
was between 2.24-2.41. Compared with those on D1, the ADA negative group showed a smaller 
volume of distribution of HLX10 and a slower clearance rate on D22. In the ADA-positive group, the 
clearance increased significantly. 
The toxicity and toxicokinetic studies of repeated HLX10 intravenous infusions in cynomolgus 
monkeys for 13 weeks and a 6-week recovery period were conducted concomitantly with a 
toxicokinetic study. The results showed that on D1 and D85, the systemic exposure of HLX10 (Cmax 
and AUClast) increased with the increasing dose, and dose-dependent toxicokinetic characteristics were 
presented. Some of the animals generated anti-drug antibodies after repeated administration. In ADA-
negative animals, the mean Cmax and mean AUClast in each dose group on D85 were higher than those 
on D1, indicating that drug accumulation was present. The blood HLX10 concentration in the D85 
pre-dose samples also showed this feature. The accumulation factor was between 2.34–4.32. 
Compared with those on D1, the ADA negative group showed a smaller volume of distribution of 
HLX10 and a slower clearance rate on D85. In the ADA-positive group, the clearance increased 
significantly. On D1, male animals in the 100 mg/kg group had slightly higher systemic exposure 
(AUClast, AUCinf) and slightly lower clearance (CL) than female animals. There was no significant 
gender difference in the pharmacokinetic parameters on D1 and D85 in other groups. 
1.2.2.9 HLX10 immunogenicity and immunotoxicity 
Evaluation tests for immunogenicity and immunotoxicity were carried out in cynomolgus monkeys, 
and this test was conducted concomitantly with the chronic toxicity study. The results showed that 
when 5, 50, and 100 mg/kg of HLX10 were administered intravenously to cynomolgus monkeys once 

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a week for 13 weeks, no immunotoxicity was observed at dose of 5 and 50 mg/kg. At the dose of 100 
mg/kg, one female died from an allergic reaction, the anti-drug antibody was positive, and IL-6 
increased after the drug administered. The CD3+, CD4+ and CD4+/CD8+ ratio decreased in male 
animals at 100 mg/kg, while CD8+ increased and the increase was associated with the pharmacological 
activity of the test sample. Anti-drug antibodies could be seen after HLX10 was administered to 
animals. The occurrence of anti-drug antibodies in the low-dose group was higher than that in the 
medium- and the high-dose group. Antibody titer increased with the increase of administration time, 
and could lead to significant reduction of system exposure. As a humanized antibody, HLX10 is an 
exogenous substance to cynomolgus monkeys. Therefore, immunogenicity in the animals is reasonable. 
For immunogenicity evaluation of antibody-based drugs, human clinical trial is a preferred method. 
1.2.2.10 Other preclinical studies of HLX10 
The hemolysis study of HLX10 showed that HLX10 at a concentration of 10 mg/mL had no hemolytic 
effect on human red blood cells in vitro and did not cause red blood cell aggregation. 
The local irritation study was conducted concomitantly with the chronic toxicity test. The test results 
showed that when HLX10 at doses of 5, 50 and 100 mg/kg were administered to cynomolgus monkeys 
by repeated intravenous infusion once weekly for 13 weeks, no obvious irritative injury was seen in 
blood vessels and surrounding tissues in infusion sites in the dose range of 0.5-10.0 mg/mL. 
No genotoxicity study of HLX10 has been conducted yet. 
1.2.3 
Clinical studies of HLX10 
HLX10 has been approved by the US FDA, China Taiwan FDA and China NMPA for a dose escalation 
phase I clinical trial. There are four dose groups (0.3, 1, 3 and 10 mg/kg, once two weeks) in the trial, 
with a maximum enrollment of about 30 subjects. At present, three patients in the fourth dose group 
have completed the enrollment, and no dose-limiting toxicity was observed in all dose groups during 
the dose-limiting toxicity observation period. 

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1.2.4 
Basis for selection of chemotherapy as a control group 
The platinum-based chemotherapy provided in this study is EC regimen (etoposide plus carboplatin), 
which is the first-line chemotherapy regimen for ES-SCLC recommended by NCCN and Chinese 
Expert Consensus on the Diagnosis and Treatment of Advanced Primary Lung Cancer (2016 Edition), 
allowing investigators and subjects to have more flexibility in conducting study and treatment 
according to the standard clinical practice of drugs. 
1.2.5 
Basis for combined treatment 
With the deepening of the study on the molecular pathogenesis of cancer, the immunological 
mechanism of tumorigenesis and development has gradually become a study hotspot. It is becoming 
increasingly clear that cancer can be recognized by the immune system, and in some cases, the immune 
system can control or even eliminate tumors. PD-1 was originally cloned by Ishida et al.[9] as a member 
of the CD28 superfamily in murine T cell hybridomas. It is a monomeric glycoprotein that is mainly 
expressed on the surface of activated macrophages, T lymphocytes, B lymphocytes, NK cells, and 
some myeloid cells. Its ligands, PD-L1 (programmed death ligand 1) and PD-L2, are mainly expressed 
on tumor cells and antigen-presenting cells[10][11][12]. Because activation of the PD-1 gene may be 
involved in the classical type of programmed cell death, it is named programmed death receptor 1 (PD-
L1). PD-L1 is highly expressed in a variety of cancers, and is as high as 88% in some cancers. In these 
cancers (including lung cancer), PD-1 binds to PD-L1 in tumor tissues, weakens the body's immune 
response, protects tumor tissues from cytotoxic T cells, and leads to tumor immune tolerance[13][14]. 
Therefore, T cell anti-tumor response can be enhanced by blocking the binding of PD-1 to its ligand 
PD-L1[15][16][17][18][19]. 
In recent years, with the rapid development of tumor immunotherapy, the focus of first-line treatment 
for advanced NSCLC with no driver gene has gradually turned to immunotherapy, and multiple PD-1 
inhibitors have been approved by the FDA for NSCLC treatment; The National Comprehensive Cancer 
Network (NCCN) Guidelines have also included PD-1 inhibitors as one of the recommended protocols 
for the treatment of relapsed SCLC. In the absence of breakthrough of targeted drug treatment for 
SCLC in the past 30 years, a new drug has been discovered for SCLC. In 2018, the FDA approved 
Nivolumab for the treatment of relapsed SCLC. In addition, a number of clinical trials of PD-1 

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antibody combined with chemotherapy for SCLC are currently underway. Preliminary results show 
that PD-1 inhibitor plus chemotherapy can significantly improve overall survival and progression-free 
survival, and is expected to become the new standard of first-line treatment for SCLC. 
The survival of cytotoxic chemotherapy in patients with ES-SCLC reaches a plateau, leaving much 
room for improving the prognosis of such patients. Exposure of the immune system to high levels of 
tumor antigens can reasonably be expected to result in cytotoxicity effects on tumor cell (TC) by 
cytotoxic chemotherapy, and restoration of tumor-specific T cell immunity in this setting may produce 
deeper and durable responses than standard chemotherapy alone by inhibiting the PD-L1/PD-1 
signaling pathway[20][21]. Therefore, it is reasonable to assume that the combination of 
immunosuppressive and cytotoxic chemotherapy drugs may have a stronger synergistic anti-tumor 
effect. 
1.2.6 
Basis for HLX10 dose selection 
Based on the results of the HLX10 preclinical and phase I clinical trials, the currently available PK 
and ADA data support an average body weight dose of HLX10 of 4.5 mg/kg administered every 21 
days as the recommended dose for phase III clinical studies. 
1.3 Assessment for Risks and Benefits 
1.3.1 
Potential benefits 
Atezolizumab (trade name Tecentriq), a PD-L1 inhibitor developed by Roche in September 2018, has 
achieved landmark results in the first-line treatment of SCLC:  
IMpower 133, a randomized, controlled phase III study evaluating atezolizumab plus carboplatin-
etoposide versus placebo plus carboplatin-etoposide in the treatment of untreated extensive SCLC, 
enrolled 403 patients and randomized at 1:1 with a median follow-up of 13.9 months. Median overall 
survival were 12.3 months (95% confidence interval (CI), 10.8-15.9) in the atezolizumab plus 
chemotherapy group and 10.3 months (95% CI, 9.3-11.3) in the placebo plus chemotherapy group 
(HR = 0.70, 95% CI 0.54-0.91, P = 0.007). Median progression-free survival was 5.2 months (95% 
CI, 4.4-5.6) in the atezolizumab plus chemotherapy group and 4.3 months (95% CI, 4.2-4.5) in the 

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placebo plus chemotherapy group (HR = 0.77, 95% CI 0.62-0.96, P = 0.02). At the same time, in 
terms of safety, the safety of Atezolizumab plus chemotherapy was consistent with that in the 
previous reports and no new toxicity was found. 
Based on the above study results, Henlius plans to study the anti-tumor activity of HLX10 plus 
chemotherapy as first-line treatment of ES-SCLC. The preliminary efficacy, safety and tolerability 
data of PD-L1 plus chemotherapy in the IMpower 133 study supports the use of this treatment in ES-
SCLC. The primary objective of this phase III study is to determine the clinical efficacy and safety of 
HLX10 plus chemotherapy in previously untreated ES-SCLC patients. 
1.3.2 
Identified and potential risks 
PD-1/PD-L1 inhibitors not only enhance the anti-tumor effect of cellular immunity, but could also 
enhance the normal immune response, leading to immune tolerance imbalance and immune-related 
adverse reactions (irAEs). IrAEs can affect any organ in the human body, and nearly two-thirds of 
patients currently treated with immune checkpoint inhibitors experience irAEs of varying 
degrees[20,21]. In February 2018, NCCN and ASCO jointly issued the Guidelines for the Management 
of Toxicity Related to Immunotherapy (Version 1, 2018), which states that the immune-related 
adverse events of the skin, intestine, endocrine, lung and musculoskeletal systems are relatively 
common, while the immune-related adverse events of the cardiovascular, hematological, renal, 
neurological and ophthalmic systems are rare. Most immune-related adverse events were mild-
moderate in severity; common irAEs known in patients currently treated with PD-1/PD-L1 inhibitors 
were as follows: skin toxicity (mainly maculopapular rash and pruritus; 30% to 40%), diarrhea 
and/or colitis (8% to 19%), fatigue (16% to 24%), immune-related hepatitis (5%), hypothyroidism 
(4% to 10%), hyperthyroidism (4%), hypophysitis (< 1%), type 1 diabetes, immune-related 
pneumonia, sarcoidosis, inflammatory arthritis, etc. Others such as cardiovascular adverse events, 
anemia, thrombocytopenia, nephritis, encephalopathy, leukoencephalopathy, post-reversible 
encephalopathy syndrome (PRES), peripheral motor and sensory neuropathy, uveitis, episcleritis, 
blepharitis, and acute pancreatitis occurred less frequently. 
The safety evaluation of IMpower 133 in ES-SCLC also showed that the occurrences of AEs in the 
atezolizumab + EC group and placebo + EC group were comparable, with the occurrences of AEs of 

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any grade being 100% and 96.4% in the two groups, respectively; the occurrences of grade 3-4 AEs 
were 67.2% and 63.8% in the two groups, respectively. The occurrences of treatment-related AEs 
were 94.9% and 92.3%, respectively. The occurrences of SAEs were 37.4% and 34.7%, respectively; 
the occurrences of immune-related AEs were 39.9% and 24.5%, respectively. The comparisons for 
occurrences of most common grade 3-4 AEs: Neutropenia (22.7% and 24.5%), anemia (14.1% and 
12.2%), neutrophil count decrease (14.1% and 16.8%), thrombocytopenia (10.1% and 7.7%), 
leukopenia (5.1% and 4.1%). The occurrences of immune-related grade 3-4 AEs in the atezolizumab 
+ EP group were 2% for rash, 1.5% for hepatitis, 2% for infusion-related reactions, and 0.5% for 
pneumonia. 
1.3.3 
Overall benefits: risk and ethical assessment 
At present, chemotherapy for advanced SCLC has encountered the bottleneck of efficacy, and it is 
urgent to explore more effective first-line treatment for SCLC. With the progress of various studies, 
immune checkpoint combination therapy has become a new treatment option for SCLC, which is likely 
to greatly improve the prognosis of SCLC patients. At the same time, the adverse events of the 
atezolizumab combination protocol were consistent with the known toxicity of monotherapy, and no 
new safety signals were found. No DLT was observed based on the current first-in-human study data 
for HLX10, and the available safety data and pharmacokinetic data demonstrate that the safety of 
HLX10 in patients is acceptable enough to support the implementation of this phase of the clinical 
study. 
2 OBJECTIVES 
2.1 Primary Objective 
To evaluate the clinical efficacy of HLX10 combining with chemotherapy versus placebo combining 
with chemotherapy in previously untreated patients with ES-SCLC. 
2.2 Secondary Objective 
To evaluate the safety and tolerability of HLX10 combining with chemotherapy versus placebo 

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combining with chemotherapy in previously untreated patients with ES-SCLC. 
3 STUDY PROTOCOL 
3.1 Overall Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, clinical Phase III study to 
evaluate the clinical efficacy, safety and tolerability of recombinant humanized anti-PD-1 
monoclonal antibody injection (HLX10) or placebo in combination with chemotherapy in patients 
with previously untreated ES-SCLC, to collect PK parameters and to investigate the biomarker 
related to efficacy. For details, please refer to Figure 1 "Overall study design" and study events flow 
chart. 
3.2 Endpoints 
3.2.1 
Primary endpoint 
• Progression free survival (PFS, assessed by IRRC according to RECIST v1.1) 
3.2.2 
Secondary endpoints 
• Overall survival (OS) 
• PFS (assessed by the investigator according to RECIST v1.1 and modified RECIST criteria) 
• Objective response rate (ORR, assessed by IRRC and the investigator according to RECIST 
v1.1 criteria) 
• Duration of response (DOR, assessed by IRRC and the investigator according to RECIST 
v1.1 criteria) 
• Incidence rates of AEs and SAEs 
• Pharmacokinetics (PK): serum HLX10 concentration 
• Immunogenicity evaluation: positive anti-drug antibody (ADA) rate 
• Relationship between PD-L1 expression level, MSI, TMB in tumor tissues and efficacy 
• Quality of life assessment 

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3.3 Randomization, Blinding, and Unblinding 
A randomized, double-blind design is employed in this trial. Eligible subjects are randomly allocated 
to the following two arms using an interactive web/voice response system (IWRS/IVRS)  at 2:1 ratio: 
• 
Arm A (HLX10): HLX10 + chemotherapy (carboplatin-etoposide) 
• 
Arm B (control): placebo + chemotherapy (carboplatin-etoposide) 
Randomization are stratified by: PD-L1 expression level (negative, positive, not available), brain 
metastasis (yes versus no), and age (≥ 65 years versus < 65 years). During the study, the subjects, the 
investigator, the sponsor, and the designees are not aware of the randomized allocation, except in the 
event of emergency unblinding. 
During the course of treatment with the study drug, if the investigator determines that the study drug 
is related to a life-threatening situation of the subject, and the investigator considers that knowing the 
medication of the subject is conducive to the handling of adverse events, an emergency unblinding is 
allowed. The decision to unblind in an emergency is the responsibility of the investigator and will not 
be delayed or declined by the sponsor; however, the investigator may contact the sponsor or its 
designees to discuss the unblinding and the protocol that is in the best interest of the subject prior to 
unblinding. The investigator shall ensure that unblinding is performed in strict accordance with the 
protocol. The investigator shall inform the sponsor of the circumstances of and reasons for emergency 
unblinding as soon as possible, and record these details clearly on the subject’s source document. The 
unblinding process is completed on the IWRS using individual emergency unblinding identification 
numbers. If deemed necessary, the unblinding shall only apply to the affected subject. 
The study will be unblinded overall after the last subject completed the study visit. The study shall 
remain blinded unless there is an emergency medical condition (emergency treatment is only possible 
when being informed of the randomized medication) or unblinding is requested by the regulatory 
authorities. Only when all data have been input into the database, all data queries have been resolved 
and subjects have been allocated into analysis sets, can the random codes be unblinded. 
3.4 Number of Subjects 
489 subjects are to be enrolled in study in a randomization ratio of 2:1, with 326 in the HLX10 arm 

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and 163 in the placebo arm. 
3.5 Eligibility 
3.5.1 
Inclusion criteria 
1. Voluntary participation in clinical studies; fully understand, be informed about the study and have 
signed the informed consent form (ICF); willingness to follow and ability to complete all trial 
procedures. 
2. Aged ≥ 18 years and ≤ 75 years at the time of signing the ICF. 
3. Histologically or cytologically diagnosed with ES-SCLC (according to the Veterans 
Administration Lung Study Group (VALG) staging system). 
4. No prior systemic therapy for ES-SCLC (including systemic chemotherapy, molecular targeted 
therapy, biological therapy, and other investigational therapies, etc.). 
5. Patients who have received chemoradiotherapy for previous limited stage SCLC must be treated 
with curative intent and have a treatment-free interval of at least 6 months from the last course of 
chemotherapy, radiotherapy, or chemoradiotherapy to the diagnosis of extensive stage SCLC. 
6. At least one measurable lesion as assessed by the IRRC according to RECIST v1.1 within 4 weeks 
prior to randomization. 
Note: Measurable lesions are not from previously irradiated sites. If the lesion at the 
previously irradiated site is the only selectable target lesion, anteroposterior images showing 
significant progression of the lesion should be provided by the investigator. 
7. Every effort should be made to provide tumor tissues that meet the requirements for the 
determination of PD-L1 expression levels. Subjects are assessed for an evaluable PD-L1 
expression category (negative, positive, or not available) by the central laboratory for 
randomization. 
Note: It is recommended to provide formalin-fixed tumor tissue samples, paraffin-
embedded tumor specimens (preferred), FFPE tumor specimens or newly prepared 
unstained serial tissue sections (preferably adhesive slides) within 6 months prior to the first 
dose of study medication. A relevant pathology report must also be provided for the above 

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specimens. Freshly collected specimens, radical resections, core needle biopsy, excisions, 
incisions, punch or clamp biopsies are acceptable (newly obtained tissues are preferred). 
Fine-needle aspirations (i.e., samples that lack a complete tissue structure and provide only 
cell suspension and/or cell smear), brush biopsies, and cell pellet samples from pleural or 
peritoneal effusions are unacceptable. For detailed requirements for tissue samples, see the 
laboratory manual. 
8. Prior antineoplastic therapy must have been ≥ 2 weeks from the first dose in this study with 
treatment-related AEs resolved to NCI-CTCAE Grade ≤ 1 (except for Grade 2 alopecia). 
9. An ECOG PS score of 0 or 1  
10. An expected survival ≥ 12 weeks. 
11. Subjects with prior denosumab use that can and agree to switch to bisphosphonate therapy 
for bone metastases starting prior to randomization and throughout treatment; 
12. Normal major organ functions as defined by the following criteria (no blood transfusions, or 
treatment with albumin, recombinant human thrombopoietin or colony-stimulating factor 
(CSF) within 14 days prior to the first dose in this study): 
Hematologic system 
Absolute neutrophil count 
(ANC) 
≥ 1.5×109/L  
Lymphocyte 
≥ 0.5×109/L 
Platelet (PLT) 
≥ 100×109/L 
Haemoglobin (Hb) 
≥ 90 g/L 
Liver function 
Total bilirubin (TBIL) 
≤ 1.5×upper limit of normal (ULN) 
For patients with Gilbert's syndrome, total bilirubin ≤ 3 × 
ULN is acceptable 
Alanine transaminase (ALT) 
≤ 2.5×ULN; 
≤ 5 × ULN for patients with liver metastases 
 
Aspartic transaminase (AST) 
≤ 2.5×ULN; 
≤ 5 × ULN for patients with liver metastases 
 
Alkaline phosphatase (ALP) 
≤ 2.5×ULN; 
≤ 5.0 × ULN for patients with liver or bone metastases 
Renal function 
Creatinine (Cr) 
≤ 1.5×ULN; 
In case of > 1.5 × ULN, creatinine clearance ≥ 50 mL/min 
(calculated from Cockcroft-Gault formula) 

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Coagulation function 
Activated partial prothrombin 
time (APTT) 
≤ 1.5×ULN 
International normalized ratio 
(INR) 
≤ 1.5×ULN 
The above requirements apply only to subjects who are not receiving anticoagulant therapy; 
subjects who are receiving anticoagulant therapy must maintain a stable dose of 
anticoagulants. 
13. Female patients must meet one of the following conditions: 
① Menopause (defined as no menses for at least 1 year and no confirmed cause other than 
menopause), or 
② Surgically sterilized (removal of the ovaries and/or uterus), or 
③ With child-bearing potential, but must: 
• have a negative serum pregnancy test within 7 days prior to first dose, and 
• agree to use contraception with an annual failure rate of < 1% or to remain abstinent 
(avoid heterosexual intercourse) from obtaining informed consent to at least 120 days after 
the last dose of trial medication and at least 150 days after the last dose of chemotherapy 
medication (Contraception methods with an annual failure rate of < 1% include bilateral 
tubal ligation, male sterilization, correct use of hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper-containing intrauterine 
devices), and 
• not breastfeed 
14. Male patients must: agree to abstinence (avoid heterosexual intercourse) or take 
contraception measures as follows: male patients with a pregnant partner or a partner with 
childbearing potential must remain abstinent or use a condom to prevent embryonic exposure 
during chemotherapy treatment (carboplatin or etoposide) and for at least 150 days after the 
last dose of chemotherapy. Periodic abstinence (e.g., contraceptive methods based on 
calendar day, ovulation, basal body temperature or post-ovulation) and external ejaculation 
are ineligible methods of contraception. 
3.5.2 
Exclusion criteria 
1. Histologically or cytologically confirmed mixed SCLC. 

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2. Other active malignancies within 5 years or at the same time. Localized tumors that have 
been cured, such as basal cell carcinoma, squamous-cell skin cancer, superficial bladder 
cancer, prostate carcinoma in situ, cervical cancer in situ and breast cancer in situ are 
acceptable. 
3. Patients who are preparing for or have received an organ or bone marrow transplant. 
4. Pleural or pericardial effusion requiring clinical intervention, or ascites. 
5. Patients with known or documented active central nervous system (CNS) metastases and/or 
carcinomatous meningitis at screening. However, the following subjects are allowed to be 
enrolled: 1) Subjects with asymptomatic brain metastases (i.e., no progressive central 
nervous system symptoms caused by brain metastases, no requirement for corticosteroids, 
and lesion size ≤ 1.5 cm) may be included, but are required to receive regular brain imaging 
as a site of lesion. 2) Subjects with treated brain metastases which have been stable for at 
least 2 months (as confirmed by 2 radiological examinations at least 4 weeks apart after 
treatment of brain metastases), with no evidence of new or enlarging brain metastases, and 
with discontinued steroids 3 days prior to study drug administration. (Stable brain metastases 
here should be confirmed before the first dose of the study drug.) 
6. Subjects with spinal cord compression that has not been radically treated with surgery and/or 
radiotherapy. 
7. Patients with myocardial infarction within half a year before the first dose of the study drug, 
poorly controlled arrhythmia (including QTc intervals ≥ 450 ms for males and ≥ 470 ms for 
females) (QTc intervals are calculated by Fridericia's formula). 
8. Class III to IV cardiac insufficiency according to NYHA classification or an LVEF (left 
ventricular ejection fraction) < 50% by cardiac color Doppler. 
9. Subject has uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or 
calcium > 12 mg/dL or corrected serum calcium > ULN). 
10. Subject with peripheral neuropathy ≥ Grade 2 by CTCAE. 
11. Human immunodeficiency virus (HIV) infection, positive test for HIV antibody. 
12. Active pulmonary tuberculosis. 
13. Subjects with previous and concurrent interstitial pneumonia, pneumoconiosis, radiation 
pneumonitis, drug-related pneumonitis and severe impaired pulmonary function that may 

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interfere with the detection and management of suspected drug-related pulmonary toxicity as 
judged by the investigator. 
14. Hepatitis B (positive test for HBsAg or HBcAb and positive test for HBV-DNA) or Hepatitis 
C (positive tests for HCV antibody and HCV-RNA). Hepatitis B and C co-infection (positive 
test for HBsAg or HBcAb and positive test for HCV antibody); 
15. Known active or suspected autoimmune diseases. Subjects in a stable state with no need for 
systemic immunosuppressant therapy are allowed to enroll. 
16. Treatment with live vaccines within 28 days prior to study drug administration; inactivated 
viral vaccines for seasonal influenza are allowed. 
17. Subjects requiring treatment with systemic corticosteroids (> 10 mg/day prednisone efficacy 
dose) or other immunosuppressive drugs within 14 days prior to the first dose or during the 
study. However, in the absence of active autoimmune disease, subjects are allowed to use 
topical or inhaled steroids and adrenal hormone replacement therapy at doses equivalent to 
≤ 10 mg/day of prednisone efficacy. 
18. Any active infection requiring systemic anti-infective therapy within 14 days prior to study 
drug administration. 
19. Major surgery within 28 days prior to the first dose of the study drug, defined as: surgeries 
requiring at least 3 weeks of recovery to be able to receive treatment in this study. 
20. Radical radiation therapy within 3 months prior to study medications. 
Note: Palliative radiotherapy to bone or palliative radiotherapy to superficial lesions is 
allowed according to local standards 14 days prior to the first dose. Radiotherapy covering 
more than 30% of the bone marrow area within 28 days prior to the first dose is not allowed. 
21. The subject has previously received other antibodies/drugs against immune checkpoints, 
such as PD-1, PD-L1, CTLA4, etc. 
22. Participation in any other ongoing clinical studies, or less than 14 days from the end of the 
previous clinical study treatment to the start of this trial. 
23. Known history of severe allergy to any monoclonal antibody. 
24. Known hypersensitivity to carboplatin or etoposide. 
25. Pregnant or lactating women. 
26. Known history of psychotropics abuse or drug abuse. 

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27. In the judgment of the investigator, the subject has any other factors that may lead to a 
premature discontinuation. 
3.5.3 
Criteria for discontinuation 
3.5.3.1 Reasons for premature discontinuation 
A discontinuation of treatment means that the subject will no longer receive a study medication of this 
trial. Reasons for the discontinuation of treatment may include: 
1. 
Poor compliance that has affected the efficacy and safety evaluation; 
2. 
AEs or SAEs that are inappropriate to continue the study treatment as judged by the 
investigator; 
3. 
Evidence of unequivocal progression or worsening of the disease;  
4. 
A delayed dosing of the study drug meeting the criteria in Section 3.6.3; 
5. 
Loss to follow-up or death; 
6. 
Withdrawal of informed consent; 
7. 
Other reasons of discontinuation as determined by the investigator in the best interest of the 
subject. 
3.5.3.2 Management of premature discontinuations 
The reasons for premature discontinuations shall be documented in the eCRF. 
All subjects who discontinue the trial prematurely shall undergo an EOT visit and be followed up for 
safety. 
Subjects who discontinue the trial for reasons other than disease progression should be radiologically 
followed up until disease progression, withdrawal of informed consent, death or start of a new 
antineoplastic therapy. 
All AEs present at the time of discontinuation must be followed up until the outcomes of such adverse 
events.  
In case of an enrolled subject's withdrawal for any reasons, no subject replacement is permitted. 

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3.6 Early Termination of Study/Closure of Study Site 
The study may be terminated prematurely due to the following reasons. Written permissions of both 
the principal investigator and the sponsor are required for the early termination of the study, and results 
of the study shall be reported in accordance with the requirements of the protocol. 
1. The study is unlikely to be completed within an acceptable time frame due to difficulties in 
subject enrollment; 
2. The investigator questions the safety of the drug during the study and concludes that further 
study would pose serious risks to the subjects;  
3. The principal investigator and the sponsor believe that the number and severity of adverse 
events suggest a premature termination; 
4. The efficacy fails to meet expectations and it is not necessary to continue the clinical trial; 
5. The study is revoked by regulatory authorities; 
6. The sponsor has the right to terminate the study at a certain study site in the event of: 
 
serious violations of ICH-GCP by the study site; 
 
repeated serious protocol violations by the study site; 
Upon the termination of the study, all related records shall be kept for future reference. 
3.7 Study Treatment 
3.7.1 
Information on study drugs 
Investigational product HLX10 
Name 
Recombinant humanized anti-PD-1 monoclonal antibody injection 
(HLX10) 
Specification 
HLX10 100 mg/10 mL/vial 
Storage condition 
2–8 °C 
Manufacturer 
Shanghai Henlius Biotech, Inc. 
Supplier 
Shanghai Henlius Biotech, Inc. 
Placebo control 
A visually indistinguishable injection without active ingredient of HLX10. 

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Other study medications 
Commercially available carboplatin and etoposide supplied by Shanghai Henlius Biotech, Inc. 
Kindly refer to the currently approved prescribing information for information on formulation, 
preparation, storage and administration of carboplatin and etoposide. 
3.7.2 
Route of administration and dosage 
Study drugs are administered as follows with a 3-week cycle (every 21 days). 
Investigational/reference product: 
HLX10 or placebo, 4.5 mg/kg, once every 3 weeks (21 days) 
Other study drugs: chemotherapy 
• Etoposide: 100 mg/m2, IV, on Days 1, 2, and 3 of each cycle. 
• Carboplatin: AUC = 5, up to a dose of 800 mg, IV, on Day 1 of each cycle. 
Dose of carboplatin shall be calculated according to the following Calvert formula:  
➢ Dose of carboplatin (mg) = target AUC x [(CrCl (mL/min) + 25)]  
➢ Creatinine clearance (CrCl) is calculated according to the Corkroft-Gault formula 
(Appendix 6) on the basis of the subject’s most recent serum creatinine and body weight. 
Note: If CrCl calculated by the Corkroft-Gault formula is > 125 mL/min, CrCl shall be 
calculated using an alternative formula in accordance to the standards of the study site, 
or capped at 125 mL/min. 
A combination of HLX10 or placebo + carboplatin + etoposide shall be administered in a 3-week 
treatment cycle; carboplatin and etoposide are administered for a maximum of 4 cycles. 
Refer to Figure 2 "Schematic of study treatment" for the regimen of each treatment arm. In each 3-
week cycle, the subjects shall receive an intravenous infusion of HLX10 or placebo, followed by 
intravenous infusion of carboplatin + etoposide on the first day of dosing with close monitoring of 
vital signs. Administration of HLX10/placebo shall be blinded, while carboplatin + etoposide are 
openly administered. Subjects will continue to receive etoposide on Days 2 and 3. The treatment will 
continue until disease progression, intolerable toxicity, discontinuation decided by the subject or the 
investigator, death, withdrawal of informed consent, pregnancy, incompliance with protocol or 

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procedure requirements, administrative reasons, or other reasons specified in the protocol, whichever 
occurs first. The dosing window is ±3 days from the scheduled date of administration (from the date 
of the first dose). Drugs administered outside the dosing window is considered a delayed dose, and 
subsequent doses shall be administered according to the actual date of last administration. If 
chemotherapy is not used due to toxicity or other reasons in a certain cycle, it is not counted as the 
number of combined chemotherapy cycles. After completing 4 cycles of chemotherapy, even if the 
subject does not meet the above criteria, the chemotherapy will not be continued. 
3.7.3 
Dose modification 
Starting from the beginning of HLX10 or placebo infusion, subjects shall be closely monitored for 
allergic reactions that may occur within a few minutes. In case of mild symptoms (such as flushing or 
local skin reactions), drugs may be administered at a slower speed. For serious hypotension, 
bronchospasm, or generalized rash/erythema, the administration should be stopped immediately and 
appropriate therapies should be given. For a life-threatening reaction, including allergic reactions, 
hypersensitivity reactions, renal failure, severe cardiopulmonary events, and severe skin reactions, etc., 
the medications shall be discontinued permanently. 
The dosing window is ± 3 days from the scheduled date of administration (from the date of the first 
dose). Drugs administered outside the dosing window is considered a delayed dose, and subsequent 
doses shall be administered according to the actual date of last administration. During the course of 
combined treatment, if a delay of more than 2 weeks is expected due to the toxicity of chemotherapy, 
only HLX10 or placebo will be administered until the toxicity returns to the standard of chemotherapy 
administration. Chemotherapy may be continuously suspended for a maximum of 6 weeks, otherwise 
the chemotherapy should be discontinued. If a delay of more than 2 weeks is expected due to the 
toxicity of HLX10 or placebo, only chemotherapy will be administered until the toxicity recovers to 
the HLX10 or placebo dosing criteria. HLX10 or placebo therapy may be continuously suspended for 
a maximum of 12 weeks, otherwise the HLX10 or placebo will be discontinued. In case of a delay due 
to toxicity with equivocal association, all the study drugs shall be synchronously delayed if the event 
is expected to return to re-dosing standards within 2 weeks. 

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3.7.3.1 General principles for dose modification  
Any modified or delayed doses or adopted supportive therapies should be recorded in the source 
documents and eCRFs. Adverse events are assessed for severity according to CTCAE v4.03. 
• 
For concomitant conditions already present at baseline, dose modifications may be 
determined by the investigator based on changes in severity of toxicity. For example, if the 
subject already has a Grade 1 weakness at baseline, and the severity increases to Grade 2 
during treatment, it may be considered to make dose modification according to Grade 1 
toxicity due to 1-grade increase in toxicity. 
• 
If multiple toxicities of different severities occur at the same time, the dose should be 
adjusted according to the most severe toxicity. 
• 
If the toxicity is related to one of the study drugs only (for example, HLX10, carboplatin 
or etoposide) as assessed by the investigator, dose modification of that study drug only with 
reference to the corresponding dose modification principle is acceptable, and the subject 
can continue receiving the other study treatment in the absence of other contraindications. 
• 
If the toxicity is associated with only one of the chemotherapy medications as assessed by 
the investigator, the dose of the other chemotherapy medication may not be adjusted. 
• 
In the event that a delay is required for reasons of toxicity (not definitively related to which 
drug), similar delays of all study drugs at the same time are required if recovery to a re-
dosing level is expected within 2 weeks. 
• 
If HLX10/placebo, carboplatin, or etoposide is interrupted due to toxicity, study treatment 
must be restarted, keeping HLX10/placebo in sync with the chemotherapy treatment cycles. 
3.7.3.2 Principles for HLX10 or placebo dose modifications 
In the event of HLX10- or placebo-related toxicity, a delay in HLX10 or placebo is allowed rather than 
dose adjustment. Subjects who miss a scheduled infusion should be actively contacted to arrange 
another visit as soon as possible for administration. Administration of HLX10 or placebo may be 
delayed, but a dosing interval of up to 12 weeks is considered intolerable, where HLX10 or placebo 
will be permanently discontinued and the subject should withdraw from the trial. For a treatment delay 

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due to intolerance to HLX10 or placebo, chemotherapy should be administered as scheduled, and 
HLX10 or placebo may be postponed to the next cycle with no more than 12 weeks between doses; 
similarly, for a treatment delay due to intolerance to chemotherapy, chemotherapy may be postponed 
to the next cycle with an interval no more than 6 weeks. 
3.7.3.3 Principles for chemotherapy dose modifications 
In the event of intolerance to etoposide/carboplatin, doses may be adjusted twice in accordance with 
the prescribing information of carboplatin and etoposide and local treatment standards. 
 
 

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Table 1. Principles for chemotherapy dose modifications 
Dose Level 
Etoposide Dosing Regimen 
Carboplatin Dosing Regimen 
Starting Dose 
100 mg/m2, 
Intravenous infusion (IV) on Day 1, 2 and 3 
of each 3-week (21-day) cycle. 
AUC = 5, up to a dose of 800 mg, 
intravenous infusion (IV) on Day 1 of 
each 3-week (21-day) cycle. 
First Dose 
Reduction 
75% of starting dose 
75% of starting dose 
Second Dose 
Reduction 
50% of starting dose 
50% of starting dose 
 
 If treatment is delayed due to intolerance to chemotherapy, chemotherapy may be delayed to the 
next cycle of administration, with the maximum permissible interval for chemotherapy not exceeding 
6 weeks. 
The following are recommended carboplatin dose modifications for hematological and non-
hematological toxicities. 
Hematological toxicities 
At the start of each cycle, neutrophil count (ANC) must be ≥ 1.5 × 109/L and platelet count (PLT) 
must be ≥ 100 × 109/L. Otherwise the treatment should be postponed for up to 42 days to provide a 
sufficient period for recovery. According to the guidelines of the American Society of Clinical 
Oncology (ASCO) and National Comprehensive Cancer Network (NCCN), growth factors can be 
given to subjects with reduced ANC and/or PLT. At the beginning of subsequent cycles after 
recovery, dosage shall be adjusted based on the PLT and ANC nadirs of the last cycle (refer to Table 
2). 
Table 2. Carboplatin dose modifications for hematological toxicities 
Toxicitya 
Dose of carboplatin 
ANC < 0.5 ×109/L and PLT ≥ 50 ×109/L 
75% of the previous dose 
PLT < 50 ×109/L, ANC not considered 
75% of the previous dose 
PLT < 50 ×109/L with Grade 2 hemorrhage, ANC not considered 
50% of the previous dose 
ANC < 1×109/L with fever ≥ 38.5 °C 
75% of the previous dose 
a 
Nadir of the last cycle 
Doses shall be permanently reduced at the first onset of neutropenic fever or thrombocytopenia (PLT 
< 25 × 109/L or < 50 × 109/L with signs of bleeding or need for blood transfusion). For the need for 

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dose reduction at the second onset of neutropenic fever or thrombocytopenia, dose of carboplatin 
shall be reduced in accordance with the physician’s judgement and local standard medical practices. 
In case of neutropenic fever or Grade 4 neutropenia, colony-stimulating factors (such as granulocyte 
colony-stimulating factor) may be administered in place of reduced doses in accordance with local 
standard medical practices and ASCO guidelines. For subjects who require a third dose reduction, 
the chemotherapy shall be discontinued immediately. 
Subjects who require dosing modification due to both ANC and platelet count shall receive a lower 
dose. 
Treatments may be postponed for up to 42 days until the first day when ANC is ≥ 1.5 × 109/ L and PLT 
is ≥ 100 × 109/L. However, if the counts fail to recover within 3 weeks, the chemotherapy shall be 
reduced or suspended in accordance with the physician's judgement and local standard medical 
practices before ANC recovery. 
The investigator shall pay attention and remain alert to early and significant signs of myelosuppression, 
infections and neutropenic fever, to ensure a prompt and appropriate management of such 
complications. The investigator shall remind the subjects of the signs of such complications and 
encourage them to seek medical attention as soon as possible. 
If chemotherapy is to be suspended due to hematological toxicities, a complete blood count (including 
WBC differential counts) shall be performed once a week until such counts return to the lower limit 
specified for the treatment. The treatment shall be completed as planned thereafter. 
No dose reduction is required for anemia. Subjects shall be given supportive care in accordance with 
the guidelines of the institution where the attending physician is located. 
Non-hematological toxicities 
In the event of Grade 3 or 4 gastrointestinal toxicities, treatment shall be delayed until the measurement 
falls below or is equivalent to the subject’s baseline value. At the beginning of the subsequent cycles, 
the dose shall be reduced based on the dose of the last cycle leading to gastrointestinal toxicities. The 
following table includes related recommendations for dosing modifications for non-hematological 
toxicities. 
Table 3. Carboplatin dose modifications based on non-hematological toxicities in previous 
treatments 
Toxicities 
Modified carboplatin dose by % of 
previous dosea 
Diarrhea 
Grade 3 or 4b 
100% 
Oral mucositis 
Grade 3 or 4 
75% 
Nausea/vomiting 
Grade 3 or 4 
75% 

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Neurotoxicity (motor or sensory) 
Grade 2 
100% 
Grade 3 or 4 
75% 
Transaminitis 
Grade 3 
75% 
Grade 4 
Discontinuation 
Others 
Grade 3 or 4 
75% 
AUC = Area under the concentration-time curve. 
a 
Modify carboplatin dose to a specific percentage of the previous AUC, if deemed appropriate by the 
attending physician 
b 
Or any severity of diarrhea that requires hospitalization. 
Nausea and/or vomiting shall be treated with an appropriate antiemetics. If Grade 3 or 4 
nausea/vomiting continues despite the use of antiemetic, reduce subsequent dose by 25%. If the next 
dose is tolerated, restore the dose to 100% as soon as possible. 
If a subject develops oral mucositis on day 1 of any cycle, suspend the treatment until the oral 
mucositis subsides. If oral mucositis/stomatitis does not subside within 3 weeks, discontinue 
carboplatin. For the subject developing Grade 3 acute oral mucositis at any time, doses are 
administered at 75% after the oral mucositis has completely subsided. This shall be a permanent dose 
reduction. 
Other toxicities 
If a subject experiences any Grade 3 or 4 toxicities that are not mentioned above (except alopecia), 
discontinue carboplatin until the subject has fully recovered or the toxicity has been relieved to 
Grade 1. Treatment should then be restarted at a 50% dose and this shall mark a permanent dose 
reduction. If the toxicity does not recover to Grade 1 within 3 weeks, carboplatin shall be 
discontinued. For Grade 1 and 2 toxicities, no dose reduction is needed. 
Recommended etoposide dosing modifications are as follows. The investigator may adhere to the 
following or to his/her clinical practice during the study. 
Table 4. Etoposide dose modification for subjects with renal impairment 
Creatinine clearance rate (mL/min) 
Dose of etoposide 
>50 
100% 
15–50 
75% of the dose 
Modification of etoposide dose based on the prescribing information for etoposide and the local 
medical standard is permitted. Once reduced, the current dose will never return to 100%. 
3.7.4 
Packaging and labeling 
HLX10, placebo and carboplatin-etoposide vials shall be labeled by a third party designated by the 
sponsor. 

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The label shall include: drug name, drug number, protocol number, specifications, usage and dosage, 
batch number, expiration date, storage requirements and other specific information required by local 
regulations and the Good Manufacturing Practices (GMP). 
3.7.5 
Storage, management, and dispensing 
The study drugs shall be delivered by the sponsor or a designated third party. The study site shall 
establish a comprehensive procedure for study drug reception. A designee is required to receive the 
study drugs and sign for the receipt. Study drugs are only used in trials specified in this study protocol. 
Only authorized personnel may have access to these drugs. 
The study site shall establish a strict and designated drug management system for the storage and 
dispensing of study drugs, as well as a registration system. The site should ensure that the storage 
conditions of the study drugs are in compliance with the regulations, and shall document such 
conditions and keep the records. 
Only the investigator or assigned personnel may administer the medications to the subject and manage 
such medications. The dispensing and retrieval of every dose shall be documented on a specified log 
in a timely manner. Any loss, missing or misuse of study drugs shall be documented in detail. 
The retrieval and disposition of study drugs shall be undertaken by the sponsor or its designated third 
party to prevent the drugs from entering the market. 
For details, please refer to the drug management and operating procedure. 
3.7.6 
Concomitant medication 
The investigator may, at his/her discretion, administer any drugs that he/she deems necessary for the 
treatment of subjects and are not expected to interfere with the evaluation of the study drugs (i.e., the 
best supportive care). Prophylactic and other supportive treatment for nausea and vomiting may be 
given to subjects according to local medical practice before and after carboplatin and etoposide 
administration. 
All concomitant medications (including start/end dates, total daily doses, and indications) must be 
documented in the subject's source document and in the corresponding section in the electronic case 
report form (eCRF). 

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Prohibited medications/therapies 
Medications and therapies which are prohibited during the study include: 
• Any other therapy with anti-tumor effects, including systemic chemotherapy, radiotherapy, 
immunotherapy, biotherapy, molecular targeted therapy, or NMPA-approved anti-tumor 
modern Chinese medical formulations for marketing (refer to Appendix 9), immunomodulating 
adjuvants with anti-tumor effects (such as thymosin, lentinan, interleukin-12), etc.; localized 
treatment of isolated lesions (other than the target lesion) may be accepted (e.g., local surgery 
or radiotherapy for bone metastases); 
• Any other clinical investigational drugs; 
• Immunosuppressants include, but are not limited to, prednisone of over 10 mg/day, or 
equivalent systemic corticosteroids, methotrexate, azathioprine, and TNF-α blockers, with the 
exceptions of: 
✓ management of study treatment-related AEs with immunosuppressants; 
✓ short-term prophylactic use in a subject who is scheduled to receive chemotherapy, when 
the prescribing information requests for corticosteroids to be administered to patients with 
known hypersensitivity; 
✓ use in subjects who are allergic to contrast agents; 
✓ use of inhaled, topical and intranasal corticosteroids; 
✓ short-term use of corticosteroids when clinical indications are present and when deemed 
necessary by the investigator for disease management (e.g., for chronic obstructive 
pulmonary disease, radiation therapy, nausea, etc.). 
• Live vaccines within 4 weeks prior to the first study dose and throughout the trial, including 
but not limited to: measles, mumps, rubella, chickenpox, yellow fever, rabies, Bacillus 
Calmette-Guérin, and typhoid vaccines. Subjects may receive live attenuated influenza 
vaccines for seasonal flu, provided that they are not administered via the intranasal route. 
Permitted medications/therapies 
Medications and therapies which are permitted during the study include: 
• Treatment for complications, adverse events or symptoms (including blood products, blood 
transfusions, infusions, antibiotics, anti-diarrheal medications, etc.), with the exception of 
medications/therapies which are expected to interfere (or interact) with the evaluation of the study; 

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• Antiemetics; 
• Nutritional support; 
• Medication or therapy necessary for previous disease. 
3.7.7 
Medication compliance 
During the study and follow-up periods, details of study medications shall be recorded in the eCRF. 
Any deviations from the protocol shall be recorded in the eCRF, including the date of and reason for 
such deviations. The Clinical Research Associate (CRA) shall review the medication compliance 
during visits to the study site and at the end of the study. 
4 STUDY PROCEDURES AND VISITS 
For an overview of the study procedures, see the study events flow chart. All study results will be 
recorded in eCRF. Each scheduled visit must be completed within the specified time window (see 
study flow chart). 
4.1 Study Procedures 
4.1.1 
Demographics and medical history 
Demographics contain information on date of birth, gender, ethnicity, etc. 
At screening, lung cancer history of subjects must be collected, including: clinical phase, pathological 
diagnosis, 
diagnosis method, diagnosis 
date and prior medications 
(surgical 
history, 
radiotherapy/chemotherapy history, etc.). Subjects' personal histories are also collected, including 
allergy history, drug dependence history, smoking and drinking; in addition, histories of other 
important diseases within one year prior to signing the informed consent form must be collected. 
4.1.2 
Prior and concomitant medications 
All prior and concomitant medications are recorded from 30 days prior to signing the informed consent 
through the safety follow-up visit should be recorded. Concomitant medications associated with AEs 
are recorded up to 90 days after the last study treatment. Prior and concomitant medications (including 

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traditional Chinese medicine) are collected and recorded in the eCRF. 
4.1.3 
Adverse Events 
All AEs and treatment emergent AEs are recorded from the time of signing the ICF until 90 days after 
the last study treatment. If a subject started a new antineoplastic therapy during the AE collection 
period, only information on AEs related to study treatment are collected after the new antineoplastic 
therapy.  
4.1.4 
Quality of life assessment 
In this study, subjects will be assessed for quality of life, including by EQ-5D-5L, EORTC QLQ-C30 
and EORTC QLQ-LC13. 
4.1.4.1 EQ-5D-5L 
The EQ-5D is a standardized measure of health status developed by the EuroQol group that allows a 
simple and general rating of health status from a clinical and economic evaluation perspective 
(EuroQol Group 1990). The scale is applicable to a variety of health conditions and treatments. It lists 
simple descriptive features, gives single index values for health state, and can be used for clinical and 
economic evaluation of health treatments as well as population health surveys. This questionnaire 
contains 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
Each dimension has 5 response options (no problems, slight problems, moderate problems, severe 
problems, and extreme problems) that reflect an increased degree of severity (EuroQol Group, 2013). 
Since 2009, the EuroQol group has developed a more sensitive EQ-5D version (EQ-5D-5L) in which 
the range of responses for each dimension is expanded, i.e., from three levels of increasing severity to 
five (Herdman et al, 2011). Preliminary studies have shown that, compared to the nature of the 3-level 
version of the measured parameters, the 5-level version improved in the following aspects: reduced 
ceiling effects, increased robustness, and enhanced ability to distinguish between different health 
levels. 
During the study, subjects are asked to select the most appropriate level from the five dimensions 
described above, indicating their current health status. The questionnaire also includes a visual analog 

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scale in which subjects will be asked to rate their current health state on a scale from 0 to 100, with 0 
indicating the worst health state (see Appendix 3). 
4.1.4.2 EORTC QLQ-C30 
The EORTC QLQ-C30 v3 questionnaire is an established measure of health-related quality of life 
(HRQoL) and is commonly used as an endpoint in oncology clinical trials. The questionnaire assesses 
HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, 
emotional, and social), 3 symptom scales (fatigue, pain, nausea and vomiting), and 1 global health and 
QoL (quality of life) scale. The 6 individual symptom measures include: dyspnea, insomnia, loss of 
appetite, constipation, diarrhea, and financial difficulties (see Appendix 3). For the 15 domains 
described above, the total score is standardized to a range from 0 to 100, where higher scores indicate 
stronger functioning, higher HRQoL or higher symptom levels. 
4.1.4.3 EORTC QLQ-LC13 
The QLQ-LC13 is a 13-item self-administered questionnaire for lung cancer disease that will be used 
along with the EORTC QLQ-C30. The scale includes both multiple and single lung cancer-related 
symptom parameters (i.e., cough, hemoptysis, dyspnea and pain), as well as side effects of 
conventional chemotherapy and radiotherapy (i.e., alopecia, neurological disorders, oral pain and 
dysphagia). Similar to the EORTC QLQ-C30, all questions (except one) are on a 4-point scale: "not at 
all", "a little", "quite a bit", and "very much". Only 1 question (43rd question "Did you take any 
medicine for pain?") is with response options of "yes" or "no". The QLQ-LC13 are scored similarly to 
the EORTC QLQ-C30. 
4.1.5 
Echocardiography 
Echocardiography must be performed for all subjects at screening, and the results of left ventricular 
ejection fraction are recorded. 
During the study treatment, if the subject has clinical symptoms such as shortness of breath, 
tachycardia, cough, jugular vein distention and hepatomegaly, relevant examinations must be timely 
performed after assessed by the investigator. 

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4.1.6 
12-lead ECG; 
Subjects will rest for 5 minutes before each 12-lead ECG. In case of clinically significant ECG 
abnormalities at a visit, a re-examination is recommended within 24 hours.  
4.1.7 
Complete physical examination 
At screening, the subjects shall have a complete physical examination including head and neck 
(including thyroid gland), chest (including heart and lung), abdomen (liver, gallbladder, spleen and 
kidney), limbs, skin, lymph nodes, nervous system as well as the general conditions of subjects, with 
the examination results recorded; special attention should be paid to the symptoms and signs in 
respiratory system. 
4.1.8 
Symptom-directed physical examination 
A symptom-directed physical examination will be performed by the investigator during study 
treatment based on clinical observations and symptoms. Clinically significant physical examination 
abnormalities that are judged by the investigator to be significantly worse than the screening period or 
newly developed should be recorded as adverse events. 
4.1.9 
Height, weight and vital signs 
Height is measured only at screening. 
Vital signs should be assessed after the subject has rested for at least 5 minutes, including blood 
pressure (mmHg), pulse (beats/min), respiratory rate (breaths/min) and body temperature (°C), and 
body weight should be recorded. 
Body weight and vital signs are to be measured prior to each dose during study treatment. No dose 
adjustment of the study drug is required if the subject's body weight differs ≤ 10% from the reference 
value of the current dose, otherwise the dose should be recalculated. 
4.1.10 ECOG scores 
Evaluation of ECOG performance status by the investigator is recommended throughout the study. 
The first ECOG score should be completed within 7 days prior to randomization. 

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4.1.11 Local laboratory tests 
Local laboratory tests performed at study sites include routine blood test, biochemistry, coagulation, 
urinalysis, thyroid function, virology and pregnancy test. Routine blood test, biochemistry, coagulation 
and urinalysis should be performed within 3 days pre-dose in each treatment cycle; for combined 
chemotherapy, routine blood tests should be performed on Day 8 (± 3 days) of each treatment cycle to 
closely monitor bone marrow suppression. For aforementioned laboratory tests scheduled on the same 
day as study treatment, the study treatment can be arranged only after the test results are obtained. 
During the treatment period, thyroid function and blood pregnancy (for females of childbearing age 
only) tests are performed 3 days pre-dose every 2 cycles 
Table 5. Local laboratory tests 
Routine blood test 
Biochemistry 
Urinalysisb 
Others 
Red blood cells 
Haemoglobin 
Platelet 
White blood cells 
WBC differential counts 
and percentages 
• 
Basophils 
• 
Eosinophils 
• 
Lymphocyte 
• 
Monocytes 
• 
Neutrophils 
 
Urea/urea nitrogen 
Creatinine 
Bicarbonatea 
Blood glucose 
Total bilirubin 
Direct bilirubin 
ALT 
AST 
ALP 
Lactate 
dehydrogenase 
Total cholesterol 
Total protein 
Albumin 
Sodium 
Potassium 
Magnesium 
Chlorine 
Calcium 
Urine specific gravity 
Urine pH 
Urine protein 
Urine glucose 
Urine ketones 
Urine occult blood 
Urine white blood cells 
In case of 
abnormalities, 
microscopically 
examine: 
white blood cells 
red blood cells 
Coagulation function 
International normalized ratio 
(INR) 
Activated partial prothrombin 
time (APTT) 
Thyroid function tests 
Triiodothyronine (T3 or FT3) 
Thyroxine (T4 or FT4) 
Thyroid stimulating hormone 
(TSH) 
VirologyC 
Hepatitis B surface antigen 
(HBsAg) 
HBs antibody (HBsAb) 
Hepatitis B E-antigen 
(HBeAg) 
HBe antibody (HBeAb) 
HBc antibody (HBcAb) 
Hepatitis C virus (HCV) 

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Phosphorus 
antibody 
HBV-DNA (optional) 
HCV-RNA (optional) 
Anti-HIV 
Pregnancy testd 
a. 
Bicarbonate/carbon dioxide binding capacity/total carbon dioxide (TCO2) 
b. 
If a subject has two consecutive 2++ urine protein or one ≥ 3+++, urine protein should be tested at 24 hours; 
c. 
All subjects are tested for HBsAg or HCV antibody at screening; HBsAg positive subjects should be further 
tested for HBV DNA titer; and HCV antibody positive subjects should be further tested for HCV RNA. In 
case of HBV DNA (-) and: 1) HBsAg (+), or 2) HBcAb (+) and HBsAg (-) at baseline, HBV antibody and 
HBV DNA should be tested every 2 cycles during the treatment period. In case of HCV antibody (+) and HCV 
RNA (-) at baseline, HCV antibody and HCV RNA should be tested every 2 cycles during the treatment period. 
d. 
Women of childbearing potential should have a blood pregnancy test within 7 days prior to randomization and 
must have a negative result for enrollment; this is also tested within 3 days pre-dose every 2 cycles. 
 
4.1.12 Central laboratory assessments 
PK and ADA samples of HLX10 or placebo are collected and sent to the central laboratory for 
evaluation. PK and ADA samples for HLX10 or placebo will be collected at the following time points: 
Within 7 days pre-dose in Cycle 1, within 3 days pre-dose in Cycles 2, 4, 6, 8 and every 4 cycles 
thereafter, within 2 hours after the end of dosing in Cycles 1 and 8 of treatment period (for PK only), 
and at EOT visit and safety follow-up. 
 
 

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Table 6. PK and ADA blood sampling 
Study visits 
Blood sampling 
PKa 
ADAb 
Treatment period 
Cycle 1 
Within 7 days pre-dose 
X 
X 
Within 2 hours post-dose 
X 
- 
Cycle 2 
Within 3 days pre-dose 
X 
X 
Cycle 4 
Within 3 days pre-dose 
X 
X 
Cycle 6 
Within 3 days pre-dose 
X 
X 
Cycle 8 
Within 3 days pre-dose 
X 
X 
Within 2 hours post-dose 
X 
- 
Every 4 cycles 
thereafter 
Within 3 days pre-dose 
X 
X 
Discontinuation 
- 
X 
X 
Safety follow-up 
- 
X 
X 
a. Blood samples for HLX10 PK are collected within 2 hours after the end of HLX10 or placebo 
administration in Cycles 1 and 8 of the treatment period. 
b. ADA samples will only be collected pre-dose and procedures are described in the laboratory manual. 
4.1.13 Tumor imaging 
Imaging studies in this trial include computed tomography or magnetic resonance imaging (CT/MRI). 
Images will be assessed by the IRRC according to RECIST v1.1 (see Appendix 2-1) and modified 
RECIST criteria (see Appendix 2-2). The parameters (such as slice thickness and field of view) used 
for all follow-up imaging should be consistent with those at baseline. CT/MRI scans must meet the 
criteria for imaging lesions in the corresponding organ system. 
Subjects should undergo CT or MRI (including brain, chest, abdomen, pelvic cavity and any other sites 
suspected of having tumor lesions) at screening (within 4 weeks pre-dose), every 6 weeks (± 7 days) 
during the first 48 weeks after the start of study treatment, and every 9 weeks (± 7 days) after week 48. 
Wherein, 
At screening, bone scans are required for all subjects. Positive scans should be confirmed by CT/MRI, 
and re-examinations are determined by the investigator according to clinical needs during the treatment 

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period. Brain MRI is also required at screening, but for subjects with contraindication, brain CTs are 
acceptable. The investigator and IRRC respectively assess the tumor images according to RECIST 
v1.1 (the tumor assessment can be performed by the investigator according to clinical needs), and the 
investigator should make subsequent treatment judgment according to the results of their own efficacy 
evaluation. If tumor assessment has been performed within 28 days prior to the first dose by the same 
methods and devices in the same hospital, it may serve as the baseline tumor assessment. 
Tumor imaging studies are conducted every 6 weeks (± 7 days) for the first 48 weeks after the start 
of study treatment and every 9 weeks (± 7 days) after week 48, regardless of dose delay. 
At the EOT visit, if tumor imaging has been performed within the last 4 weeks, a re-test is not required. 
For subjects who discontinued for reasons other than disease progression, imaging assessments are to 
be continued as scheduled (at the same frequency as if the subject have remained on study treatment , 
i.e., every 6 weeks (± 7 days) for the first 48 weeks and every 9 weeks (± 7 days) after 48 weeks), until 
disease progression, initiation of new antineoplastic therapy, withdrawal of ICF, death, or end of study, 
whichever occurs first. 
4.1.14 Biomarker sample collection 
At screening, blood samples must be collected for biomarkers detecting. To the extent possible, 
formalin-fixed paraffin-embedded (FFPE) tumor samples (paraffin blocks or 10 unstained 3–4 μm 
sections) collected at or after the diagnosis of ES-SCLC and within 6 months prior to the start of study 
medication or pathological reports of such specimens should also be provided. In case of no archived 
tumor tissue samples available, it is recommended to conduct a fresh tumor lesion biopsy at screening 
to obtain the corresponding tumor sample (the number of specimens required is based on the biopsy 
result). Tumor tissue sections will be used for immunohistochemical analysis to evaluate the 
expression level of PD-L1 in tumor cells and tumor-infiltrating immune cells. Freshly collected 
specimens, radical resections, core needle biopsy, excisions, incisions, punch or clamp biopsies are 
acceptable. Fine-needle aspirations (i.e., samples that lack a complete tissue structure and provide only 
cell suspension and/or cell smear), brush biopsies, cell pellet samples from pleural effusions and 
bronchoalveolar lavage fluid samples are unacceptable. For detailed requirements for tissue samples, 
see the laboratory manual. 

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4.2 Screening Period (Day -28 to -1) 
The Informed Consent Form (ICF) must be signed and dated by the subject or legal representative 
prior to conducting study-related procedures. 
The screening period should not exceed 28 days, beginning from the subject signing and dating the 
informed consent form and ending when the subject is randomized or fails screening. In this study, one 
re-screening is allowed for ineligible subjects: in case of unqualified laboratory tests, one re-test can 
be performed within the screening time window, without giving a new screening number; for other 
conditions incompliant with the inclusion/exclusion criteria, subjects should be re-screened with a new 
screening number. 
Subjects must complete the following study procedures or assessments at screening: 
1) Signing informed consent form 
2) Demographics and medical history 
3) Prior and concomitant medications 
4) Adverse events 
5) Quality of life assessment (Day -7 to -1) 
6) Echocardiography 
7) 12-lead ECG; 
8) Complete physical examination 
9) Height, weight and vital signs 
10) ECOG scores (Day -7 to -1) 
11) Local laboratory tests: routine blood test, biochemistry, coagulation, urinalysis, thyroid 
function, pregnancy test (for females of childbearing age only) and virology. Tests other than 
virology should be completed within 7 days before randomization. 
12) Tumor imaging: 
CT or MRI should be performed at screening (on sites including brain, chest, abdomen, pelvic 
cavity and any other sites suspected to have tumor lesions). At screening, bone scans are required 
for all subjects. Positive scans should be confirmed by CT/MRI. Brain MRI is also required at 
screening, but for subjects with contraindication, brain CTs are acceptable. If tumor assessment 
has been performed within 28 days prior to the first dose by the same methods and devices in 

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the same hospital, it may serve as the baseline tumor assessment. 
13) Biomarker sample collection: Tumor tissue and blood samples are collected for biomarker 
detection. 
4.3 Treatment period 
The treatment period begins with the subject's enrollment, and the first dose should be administered 
within 3 days after randomization. Study drugs are given every 3 weeks until disease progression, 
intolerable toxicity, discontinuation decided by the subject or the investigator, death, withdrawal of 
informed consent, pregnancy, incompliance with protocol or procedure requirements, administrative 
reasons, or other reasons specified in the protocol, whichever occurs first. See Figure 2 "Schematic of 
study treatment" for details. 
Subjects will be closely monitored for safety and tolerability throughout the study. All assessments 
must be performed and documented for each subject. Also, subjects are assessed for toxicity prior to 
each dose; doses are only given when clinical assessments and local laboratory tests are acceptable. 
Treatment should be discontinued when they have evidence of disease progression as assessed by 
RECIST v1.1. However, considering the limited availability and efficacy or greater toxicity of 
treatment options after withdrawal, and for better adaptation to standard clinical practice, the subject 
who meets all the following conditions may continue the treatment as determined by the investigator 
and after appropriate discussion with the subject and obtaining the informed consent. 
(1) With no clinical signs and symptoms (including worsening of laboratory findings) indicating a 
significant disease progression.  
(2) A stable Eastern Cooperative Oncology Group (ECOG) performance status score.  
(3) No rapid disease progression or tumor progression requiring urgent alternative medical intervention 
at critical anatomical sites (e.g., spinal cord compression). 
(4) The major organ function meets the inclusion and exclusion criteria of this study.  
(5) The subject should sign an informed consent form again. 
Such subjects should be closely monitored with imaging assessments within 6 weeks or as soon as 
possible if symptoms worsen. Treatment should be discontinued at any time if clinical worsening due 
to disease progression is noted or if continuous disease progression is confirmed by subsequent 

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imaging assessments. In addition, treatment is to be discontinued if, in the judgment of investigator, 
the subject experiences intolerable toxicities or worsening of symptoms or has other evidence of 
disease progression based on imaging assessments and a global assessment of clinical condition. 
Subjects who re-consent after disease progression should complete the screening assessment for 
continuation of treatment within 28 days after confirmation of disease progression (in case of a need 
for recovery due to AEs, a maximum of 42 days from the end of previous study treatment is allowed). 
The imaging test confirming the subject's disease progression (first PD) can serve as the baseline for 
further treatment if the following two conditions are met: (1) an interval of no more than 28 days from 
the imaging test to the start of further treatment; (2) no study treatment has been done after that imaging 
test; otherwise the baseline imaging assessments should be performed again before further treatment. 
The study treatment visit will be continued every 3 weeks after the start of further treatment, and the 
visits will be scheduled as those in the treatment period. 
 
 

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Figure 2. Schematic of study treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following study procedures must be completed at each visit during treatment period: 
1) Concomitant medications; 
Randomization 
(2:1) 
Placebo (D1) + 
Carboplatin (D1) + etoposide  
(D1 to 3) 
Once every 3-week cycle for 4 
cycles 
HLX10 (D1) + 
Carboplatin (D1) + etoposide 
 (D1 to 3) 
Once every 3-week cycle for 4 
cycles 
HLX10 
Once every 3 weeks 
Placebo 
Once every 3 weeks 
Progressive Disease 
Follow-Up Period 
Arm A (HLX10) 
Arm B (control) 
Starting dose: 
HLX10, 4.5 mg/kg, once every 3 weeks. 
Etoposide: 100 mg/m2; once every 3-week cycle for up to 4 cycles. 
Carboplatin: AUC = 5, up to a dose of 800 mg. Once every 3-week cycle for up to 4 cycles 
The subject should re-consent and meet the following conditions: 
(1) With no clinical signs and symptoms (including worsening of laboratory findings) indicating 
a significant disease progression.  
(2) A stable Eastern Cooperative Oncology Group (ECOG) performance status score.  
(3) No rapid disease progression or tumor progression requiring urgent alternative medical 
intervention at critical anatomical sites (e.g., spinal cord compression).  
(4) The major organ function meets the inclusion and exclusion criteria of this study.  
(5) The subject should sign an informed consent form again. 
Continue the treatment until persistent disease progression, worsening 
of symptoms due to disease progression, or intolerant toxicities 

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2) Adverse events 
3) Quality of life assessment: prior to the first dose and every other subsequent dosing cycle (i.e., 
pre-dose in Cycles 1, 3, 5, 7, etc.) until EOT. Re-assessments are not required for subjects who 
had a quality of life assessment on Day -7 to Day -1 of the screening period. 
4) 12-lead ECG;  
5) Symptom-directed physical examination; 
6) Weight and vital signs; 
7) ECOG scores 
8) Survival status; 
9) Local laboratory tests: routine blood test, biochemistry, coagulation, urinalysis, thyroid function, 
pregnancy test (for females of childbearing age only) and virology (if necessary); 
− 
Routine blood test, biochemistry, coagulation and urinalysis should be performed within 3 
days pre-dose in each treatment cycle; for combined chemotherapy, routine blood tests should 
be performed on Day 8 (± 3 days) of each treatment cycle. 
− 
Thyroid function must be tested at the local site within 3 days pre-dose every 2 cycles. 
− 
Serum pregnancy test must be performed for women of childbearing age at the local site 
within 3 days pre-dose every 2 cycles during the treatment period. 
− 
In case of HBV DNA (-) and: 1) HBsAg (+), or 2) HBcAb (+) and HBsAg (-) at baseline, 
HBV antibody and HBV DNA should be tested every 2 cycles during the treatment period. In 
case ofHCV antibody (+) and HCV RNA (-) at baseline, HCV antibody and HCV RNA should 
be tested every 2 cycles during the treatment period. 
For aforementioned laboratory tests scheduled on the same day as study treatment, the study 
treatment can be arranged only after the test results are obtained 
10) Central laboratory assessments: including HLX10 or placebo-PK, HLX10 or placebo-ADA 
sample collections 
11) Study treatment 
Study drugs, including HLX10/placebo, carboplatin and etoposide, are administered on Day 1 of each 
cycle after all clinical and laboratory operations/assessments are completed. 
12) Tumor imaging assessments 
CT or MRI should be performed every 6 weeks (± 7 days) during the first 48 weeks after the start 

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of study treatment, and every 9 weeks (± 7 days) after week 48 on sites including brain, chest, 
abdomen, pelvic cavity and any other sites suspected to have tumor lesions; examination methods 
at the same site should be consistent as much as possible throughout the study; if there are no 
contraindications, contrast agent should be used. The investigator and IRRC should assess the 
tumor images according to RECIST v1.1 (the tumor assessment can be performed by the 
investigator according to clinical needs), and the investigator should make subsequent treatment 
judgment according to the results of their own efficacy evaluation. 
4.4 End-of-Treatment Visit 
For any subject withdrawing from the study or terminating the study regardless of causality, a end-of-
treatment (EOT) visit should be performed, where possible, in 7 days after the end of treatment is 
learned of or confirmed (and should be done prior to initiation of any new anti-tumor treatment in the 
subject). During the visit, the investigator shall collect the following information. 
1) Concomitant therapy  
2) Adverse events 
3) Quality-of-life assessment: One quality-of-life assessment should be performed at this visit if 
such assessment has never been done in the past 3 weeks. 
4) 12-lead ECG 
5) Symptom-oriented physical examination 
6) Body weight and vital signs 
7) ECOG score 
8) Survival status 
9) Local laboratory tests: including routine blood test, blood chemistry test, coagulation test, 
routine urine test, thyroid function test, pregnancy test (in women of child-bearing age only), 
and virological test (when necessary); 
− 
Retest may be waived if it is not more than 3 weeks from the last thyroid function test. 
− 
If, 1. HBV DNA(-) and HBsAg(+) or 2. HBcAb(+) and HBsAg(-) during screening period 
(baseline), and it is more than 3 weeks from the last test, then HBV antibody assay and 
HBV DNA assay should be performed at the study termination visit. If HCV antibody(+) 

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and HCV RNA(-)  at baseline, and it is more than 3 weeks from the last test, then HCV 
antibody assay and HCV RNA assay should be performed at the study termination visit. 
10) Central laboratory assessment: including HLX10 or placebo-PK blood sampling and HLX10 
or placebo-ADA blood sampling 
11) Radiologic tumor assessment: If any radiologic tumor assessment has been done in the first 4 
weeks, then it may be unnecessary to repeat radiologic tumor assessment at the termination 
visit. 
4.5 Follow-Up Period 
After the EOT visit, subjects will be followed up. If a subject terminates the study not because of 
progressive disease (PD), then radiologic assessment should be further performed according to an 
established schedule, where possible, until PD, initiation of a new anti-tumor therapy, ICF withdrawal, 
death or study completion (whichever occurs first). 
4.5.1 
Safety follow-up period 
Subjects should be subjected to safety follow-up in 90 days after the final dose, and AEs in subjects 
will be collected. Each subject shall come to the study center for safety follow-up 30 (±7) days after 
the final dose; if the EOT visit is delayed regardless of causality 30 (±7) days after the final study 
treatment, then the safety follow-up visit will no longer be performed. One safety follow-up should be 
performed by phone 90 (±7) days after the final dose in each subject, in which information of the 
subject about AEs and AE-related concomitant therapy only will be collected. If the patient starts a 
new anti-tumor therapy during AE collection period, only AE information related to the study 
treatment need be collected after the initiation of the new anti-tumor therapy. Safety information should 
be acquired by phone with a window period of ±7 days. Safety follow-up assessment 30 (±7) days 
after the final dose includes: 
1) Concomitant therapy 
2) Adverse events 
3) Quality-of-life assessment 
4) 12-lead ECG 

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5) Symptom-oriented physical examination 
6) Body weight and vital signs 
7) ECOG score 
8) Documenting subsequent anti-tumor therapies 
9) Documenting survival status 
10) Local laboratory tests: including routine blood test, blood chemistry test, coagulation test, 
routine urine test, thyroid function test, pregnancy test (in females of child-bearing age only), 
and virological test (when necessary); 
− 
Retest may be waived if it is not more than 3 weeks from the last thyroid function test. 
− 
If, 1. HBV DNA(-) and HBsAg(+) or 2. HBcAb(+) and HBsAg(-) during screening period 
(baseline), and it is more than 3 weeks from the last test, then HBV antibody assay and 
HBV DNA assay should be performed at the safety follow-up visit. If HCV antibody(+) 
and HCV RNA(-)at baseline, and it is more than 3 weeks from the last test, then HCV 
antibody assay and HCV RNA assay should be performed at the safety visit. 
11) Central laboratory assessment: including HLX10 or placebo-PK blood sampling and HLX10 or 
placebo-ADA blood sampling 
4.5.2 
Survival follow-up 
During the survival follow-up period, subjects without PD and not receiving any other anti-tumor 
therapy should return to the hospital according to the established schedule for radiologic assessment 
follow-up, until PD, initiation of a new anti-tumor therapy, ICF withdrawal, death or study completion 
(whichever occurs first); while subjects experiencing PD or undergoing any other anti-tumor therapy 
just need to be followed up for survival status by telephone call (TC) once every 12 weeks (±7 days). 
The following assessments shall be done at each follow-up visit: 
1) Documenting survival status. 
2) Documenting subsequent anti-tumor therapies. 

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4.6 Study Assessments 
4.6.1 
Efficacy assessment 
Except overall survival, other efficacy endpoints are evaluated based on tumor response as per RECIST 
1.1. Tumor assessment will be performed by qualified personnel in each study center and independent 
radiologic review committee (IRRC). Therapeutic decision will be made based on tumor response 
assessment verified by the investigator. These results will be reported in eCRF. 
Tumor assessment schedule is not influenced by treatment interruption or any other event leading to 
imbalance in disease assessment time between treatment groups. 
Progression-free survival (PFS) is defined as a period from randomization initiation through the first 
objective PD or death (on account of any cause without PD). PFS will be always obtained based on 
scan/assessment date instead of visit date. 
Overall survival (OS) is defined as a period from randomization through death regardless of causality. 
Objective response rate (ORR) is defined as the percentage of subjects whose best overall responses 
are evaluated as CR or PR. 
Duration of response (DOR) is defined as a period from the first documentation of response (CR or 
PR) through the first documentation of PD or death (whichever occurs first). Response termination 
date should be consistent with the date of PD or death regardless of causality for evaluation of PFS 
endpoint as per RECIST 1.1. 
4.6.2 
Safety assessment 
Safety assessment consists of monitoring and documenting all adverse events (including serious 
adverse events), laboratory tests (routine blood test, blood chemistry test, coagulation test, routine 
urine test, and thyroid function test), 12-lead ECG, vital signs, and physical examination. 
4.7 Adverse Events 
4.7.1 
Definition of AE 
Adverse event (AE) is defined as any adverse medical event occurring in a subject after receiving a 

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drug in a clinical trial, not definitely having causality to treatment. Therefore, an AE can be any 
clinically significant manifestation (e.g., a clinically significant outlier in laboratory findings), 
symptom or disease, regardless of relevance to the study drug. 
In the event of any outlier, it should be determined according to the following criteria whether the 
objective outlier should be reported as an AE or not: 
 
The finding is associated with a symptom, and (or)  
 
The finding necessitates further diagnostic examination or drug/surgery intervention, and (or)  
 
The finding leads to dose adjustment (out-of-protocol-specification dose adjustment) or  
 
The finding constitutes an AE in the opinion of the investigator or the sponsor. 
If none of the above criteria is satisfied, then repeated outliers alone will not constitute an AE. It is 
unnecessary to report any incorrectly reported finding as an AE. 
Any concomitant disease, which is manifested upon signing Informed Consent Form and does not 
worsen in either severity or onset frequency during the study, is defined as a baseline medical condition, 
rather than an AE/SAE. However, if such concomitant disease in a subject is exacerbated, resulting in 
any complication or increased onset frequency, then such exacerbation or complication should be 
documented as an AE correspondingly. The investigator shall ensure that any documented event term 
is able to reflect the change of this condition (e.g., “exacerbation of ...”). 
4.7.1.1 Progressive disease 
Progression of any underlying disease, i.e., underlying tumor, should not be reported as an AE, and if 
its explicit manifestation is consistent with suspected progression of the underlying tumor defined in 
RECIST v1.1 and a subject is admitted just because of progression of the underlying tumor, then this 
PD should not be reported as an SAE. If it cannot be verified that a symptom is completely due to 
progression of underlying tumor, or a symptom does not conform to expected manifestation of PD in 
this study, then the progressing clinical symptom can be reported as an AE. If it cannot be verified that 
an AE is caused by underlying tumor only, then this AE should be reported as an AE/SAE. 
4.7.1.2 New tumor 
Onset of any new tumor should be regarded as an SAE. New primary tumor refers to a cancer that is 

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not a dominant cause of study drug treatment and is discovered after subject enrollment. 
4.7.1.3 Death 
All deaths occurring during the study or during follow-up period following the final dose of the study 
drug as specified in the study protocol have to be reported according to the following requirements: 
• 
Any death confirmed to be PD-induced should be reported to the sponsor at the next 
monitoring visit. It should be documented but not reported as an SAE. 
• 
When a death is not (or not explicitly) due to PD, the AE resulting in this death has to be 
deemed as an SAE and reported to the clinical research associate (CRA), the sponsor, or a 
representative of the sponsor in 24 h. The report should include comments regarding whether 
the death is concurrently complicated by PD or not (if applicable), and provide main cause of 
the death. 
• 
Any death from unknown cause should be reported as an SAE with the comment "death from 
unknown cause". The cause of death should be further explained during follow-up. An 
autopsy may help assess the cause of death. If an autopsy is performed, the autopsy report 
should be submitted to the sponsor's pharmacovigilance team or its representative as soon as 
possible. 
4.7.1.4 Overdose 
Drug overdose means that a subject receive (intentionally or accidentally) a drug dose in excess of the 
dose specified in the protocol. In the event of drug overdose, appropriate symptomatic and supportive 
therapies may be performed in the subject. Any overdose-induced adverse reaction should be reported 
to CRA and included in a standard AE report. 
Any drug overdose complicated by SAE will be reported in the form and the time frame pursuant to 
the standard SAE report. 
4.7.1.5 Immune-related adverse event (irAE) 
Immune-related adverse event (irAE) refers to an AE that is related to drug exposure and in conformity 
with immune-mediated mechanism of action without any other definitive pathological factor. 

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Serological, immunological and histological (biopsy) data should be used to support diagnosis of irAE 
when appropriate. Appropriate methods should be used to exclude pathological factors of irAE such 
as tumor, infection, metabolism, toxin, etc. More detailed guidance on its assessment and treatment is 
described in Appendix 8. 
For any suspected irAE, related system functions need to be closely observed and adequate assessment 
shall be carried out to identify etiology and exclude other potential causes. In general, depending on 
severity of an AE, HLX10 (or placebo) should be suspended or permanently terminated, and/or 
symptomatic treatment (e.g., glucocorticoids) may be given. If the AE is not improved or is worsened 
after glucocorticoid therapy, one can consider increasing the dose of glucocorticoid and/or using any 
other systemic immunosuppressant. When grade of an AE is <1, dose of glucocorticoid can be reduced 
gradually and the treatment has to persist for at least 1 month. When an AE is recovered to < grade 1 
and dose of glucocorticoid is reduced to prednisone (or another drug with equal potency) with a daily 
dose <10 mg, HLX10 or placebo transfusion may continue. In the event of recurrence of any grade 3 
or above irAE (except for endocrine system disorders), permanent discontinuation and study 
withdrawal have to be done immediately. 
4.7.2 
Definition of SAE 
Serious adverse event (SAE): AEs occurring during a clinical trial in conformity with any or more of 
the following circumstances should be deemed as SAEs: 
1) Leading to death 
2) Life-threatening (AE occurrence leads to an immediate risk of subject death, not including those 
AEs that may lead to death after PD, e.g., drug-induced hepatitis without liver failure) 
3) Necessitating hospitalization or prolonged length of stay; if a subject develops a discomfort or 
disease prior to study enrollment and is planned to be admitted for treatment and/or surgery before 
or during the study but does not present with exacerbation in an unexpected manner during the 
study, then this event will not be classified as an SAE 
4) Leading to permanent or serious disability/insufficiency 
5) Leading to congenital malformation/birth defect 
6) Other significant medical events: Based on scientific medical judgment, it has to be decided 

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whether reporting is to be expedited or not, and if the significant medical event might not 
immediately threaten the life, lead to death or hospitalization but some medical measures have to 
be taken to prevent any of the aforesaid circumstances from occurring, then this event will be 
normally deemed serious. For example, important treatment in A&E or domestic anaphylactic 
bronchospasm, non-nosocomial cachexia or convulsion, drug dependence or addiction, etc. 
Note: Hospitalization or prolonged hospitalization on account of any non-AE cause/convenience (for 
purpose of health insurance reimbursement, etc.) or simply for clinical trial purpose does not meet the 
criteria for medical event and thus should not be considered as an SAE. However, each event leading 
to unexpected hospitalization or prolonged selective length of stay (e.g., any unexpected results of 
drug treatment) has to be documented and reported as an AE/SAE. 
Hospitalization also includes nosocomial transfers to emergency/ICU ward (such as transfer from 
pediatrics to internal medicine, transfer from internal medicine to ICU ward for patients with coronary 
heart disease, transfer from neurology to TB ward, etc.). 
Hospitalization in the following institutions are excluded: 
 
Rehabilitation facilities; 
 
Hospice care centers; 
 
Short-term care facilities (e.g., care provided by nursing assistants); 
 
Specialized nursing facilities; 
 
Nursing home; 
 
Routine observation in A&E department; 
 
Day surgery (outpatient treatment/diurnal surgery/diurnal operation). 
Hospitalization or prolonged hospitalization due to any of the following causes is not classified as an 
SAE: 
 
Hospitalization for treatment of any original disease unrelated to any new AE or worsening 
of any original adverse disease (for example, inspection of persistent laboratory outliers 
existing prior to treatment); 
 
Hospitalization due to any non-medical cause (e.g., homelessness); 
 
Transactional hospitalization (e.g., routine checkup); 
 
Hospitalization specified in the study protocol (e.g., operation required for implementation of 
the study protocol); 

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 
Voluntary hospitalization that will not give rise to any clinical AE (e.g., for elective plastic 
surgery); 
 
Treatment or surgery planned in the study protocol and (or) for individual subjects should be 
documented in baseline documents; 
 
Hospitalization specifically for use of the study drug. 
Diagnostic and therapeutic non-invasive/invasive operations, such as surgeries, should not be reported 
as AEs. Nonetheless, if diseases that such operations are intended to treat meet the definition of AE, 
then such operations should be reported as AEs. For example, acute appendicitis occurring during AE 
reporting should be reported as an AE, and appendectomy for treating the disease should be 
documented as treatment for this AE. 
4.7.3 
Documentation of AEs 
All AEs occurring in a period from signing Informed Consent Form through 90 days after the final 
administration of the study drug (including chemotherapy drugs) should be documented in 
corresponding AE pages in EDC. The investigator shall provide all detailed information required to be 
completed, including date of onset, severity, action, outcome, and causality to the study drug. When 
collecting AE data, one has better recording diagnosis information (if possible), rather than recording 
a number of signs and symptoms. However, if a diagnosis is known but the patient still has other 
symptoms or signs not contributing to such diagnosis, then each symptom or sign should be 
documented separately. 
All AEs/SAEs occurring in a period from signing Informed Consent Form through 90 days after the 
final dose of the study drug should be documented, and the following information has to be collected: 
 
AE 
 
Onset date and end date of the AE 
 
CTCAE grade 
 
SAE or not 
 
Causality between the AE and the study drug as assessed by the investigator 
 
Actions against the study drug 
 
Therapeutic actions against the AE 

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 
Outcome 
 
irAE or not 
 
In addition, the following information will be collected for each SAE: 
 
Date when the AE meets SAE criteria 
 
Date when the investigator learns of the SAE 
 
Justification of SAE  
 
Date of discharge (if applicable) 
 
Potential cause of death (if applicable) 
 
Date of death (if applicable) 
 
Autopsy findings (if applicable) 
 
Assessment of causality between the AE and study operation 
 
Assessment of causality between the AE and other drugs 
 
Description of the AE 
Note: If the investigator learns, after a subject has completed safety follow-up or withdrawn from the 
study, that the subject experienced any SAE (including death) and reasonably considers that this event 
is possibly related to the study drug, then the investigator should report it to the sponsor’s 
pharmacovigilance team or representative. 
4.7.3.1 Severity of AEs 
National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) V4.03 is used 
to document severity of AEs, classified in grades 1–5. 
 
Grade 
CTCAE Description 
1 
Mild: No or mild symptom; only clinical or diagnostic observation is required; action is not 
needed. 
2 
Moderate: Small-scope, local or non-invasive action is needed; instrumental Activities of 
Daily Living (ADL) are restricted to appropriate ages*. 
3 
Serious or medically significant but not immediately life-threatening; necessitating 
hospitalization or prolonged hospitalization; incapacity; self-care ADL are restricted**. 

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4 
Fatal result: Urgent action is to be taken. 
5 
AE-related death 
CTCAE = Common Terminology Criteria for Adverse Events 
*: Instrumental ADL are activities such as cooking, grocery shopping, making/receiving phone 
calls, and financial management. 
**: Self-care ADL are activities such as bathing, dressing and undressing, feeding yourself, going 
to the restroom, taking pills, and leaving the bed. 
Attention must be paid to distinguish severity from intensity of an AE. "Severe" is used to describe 
intensity, so a severe AE is not definitely an SAE. For example, headache may appear severe in 
intensity but cannot be classified as an SAE, unless it meets the criteria for SAE. 
4.7.3.2 Causality between the AE and the study drug 
The investigator will evaluate whether causality between the study drug and the AE is "definitely 
related", "possibly related", "unlikely related", "definitely unrelated", or "not evaluable". Any AE 
without given causality to the study drug will be deemed as "possibly related" to the study drug. 
• 
Definitely related: 
 
Reasonable time relation+ 
 
In conformity with a known type of adverse reactions+ 
 
AE is absent or attenuated after interruption or dose reduction+ 
 
AE reoccurs after repeated medication+ 
5 Other reasonable interpretation-  
• 
Possibly related: 
 
Reasonable time relation+ 
 
In conformity with a known type of adverse reactions±? 
 
AE is absent or attenuated after interruption or dose reduction±? 
 
AE reoccurs after repeated medication±? 
 
There is a probability of any other cause leading to this AE±? 
• 
Unlikely related: 

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 
Reasonable time relation- 
 
In conformity with a known type of adverse reactions- 
 
AE is absent or attenuated after interruption or dose reduction±? 
 
AE reoccurs after repeated medication±? 
 
There is a probability of any other cause leading to this AE±? 
• 
Definitely unrelated: 
 
-Reasonable time relation- 
 
In conformity with a known type of adverse reactions- 
 
AE is absent or attenuated after interruption or dose reduction- 
 
AE reoccurs after repeated medication- 
 
There is a probability of any other cause leading to this AE+ 
• 
Not evaluable: Essential data for evaluation is unavailable 
Table 7. Evaluation of causality between AE and study drug 
 
Definitely 
Related 
Possibly 
Related 
Unlikely 
Related 
Definitely 
Unrelated 
Not 
Evaluable 
Reasonable time relation with 
the study drug 
＋ 
＋ 
－ 
－ 
 
Essential 
data for 
evaluation is 
unavailable 
Known type of drug reactions 
＋ 
±? 
－ 
－ 
Reaction is attenuated or absent 
after interruption 
＋ 
±? 
±? 
－ 
Reaction reoccurs after repeated 
medication 
＋ 
? 
? 
－ 
There is a probability of any 
other cause leading to this AE 
－ 
±? 
±? 
+ 
Note: ＋Yes   －No    ± Likely    ? Unknown 
5.1.1 
Determination of predictability 
An unexpected AE refers to an event not in conformity with corresponding reference safety 
information (RSI) of the drug in nature or severity. For investigational medicinal products, the 
predictability of an AE will be assessed based on whether the event is listed in the Investigator’s 
Brochure. For comparators that are already approved for marketing, the predictability of an AE will 
be assessed based on whether the event is listed in the drug instructions. 

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5.1.2 
Reporting of SAEs 
All SAEs occurring during the clinical study should be reported immediately (or in 24 h after being 
informed) by the investigator to the sponsor or a representative designated by the sponsor. This time 
frame applies to additional information (follow-up information) of previously released SAE report, 
and initial report and follow-up report of pregnant cases, too. The sponsor’s representative and the 
investigator share the responsibility of ensuring that all essential information is submitted within the 
above time frame. 
For all SAEs, the investigator is obliged to acquire relevant information and submit it to the sponsor 
within the above-mentioned time frame of reporting. In addition, the sponsor may request the 
investigator to acquire more follow-up information quickly. Such information may be more detailed 
than the information shown in the AE report. In general, such information shall include sufficiently 
detailed description of AEs so as to facilitate comprehensive medical assessment of the cases and 
independent assessment of causality. Moreover, the investigator must provide information about other 
potential causes of AEs, such as concomitant medications and complications. 
In the event of subject death, a summary of autopsy findings (if any biopsy finding is available) has to 
be submitted to the sponsor or the representative designated by the sponsor as soon as possible. 
Once the investigator or any other staff of the study site reports an AE as an SAE in the EDC system, 
an email will be automatically sent to alert the sponsor or the representative designated by the sponsor. 
In the event of any fault occurring in EDC, a hard copy of completed and signed SAE report should 
be sent to the sponsor and the designated representative, and the study contact by fax/mail. In rare 
cases when no facsimile device is available, the event may be notified by phone, then a hard copy of 
SAE report can be sent by mail. After the investigator sends a notification by phone, it is still necessary 
for the investigator to complete and sign a hard copy of SAE report in 24 h after being aware of the 
event. 
Information concerning contact among study sites for SAE reporting is detailed in investigator files 
provided to each study site. Each study site needs to keep original and fax confirmation pages (if a 
facsimile is used) of the SAE report along with the case report form. 
Refer to the study-related Safety Management Plan (SMP) for details. 
The sponsor is legally liable to inform local regulatory authority and other regulatory bodies of safety 

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information of the study drug. The investigator is legally obliged and ethically responsible to report 
promptly SAEs to relevant regulatory bodies and health authority, the ethics committee, and the study 
contact specifically in charge of receiving SAE reports, and make sure safety of other subjects is 
guaranteed. 
The investigator or any person-in-charge required by local authority shall abide by local regulatory 
regulations on SAE reporting and report SAEs to regulatory bodies, Institutional Review Board (IRB) 
or Independent Ethics Committee (IEC). 
Refer to the study-related SMP for more details. 
5.1.3 
Follow-up of AEs 
All AEs occurring in a period from signing Informed Consent Form through 90 days after the final 
dose of the study drug should be followed up until any of the following circumstances occurs: 
1) 
The event is recovered (or returns to the baseline level); 
2) 
The event is stable (as predicted by the investigator, the AE will not be further improved or 
exacerbated); 
3) 
Failing to acquiring more information (the subject refuses to provide more information, or it is 
evidenced that the subject is lost to follow-up even after the maximum effort has been made). 
The sponsor reserves a right to request (if necessary) more information of current AE/SAEs from any 
subject at the end of the study. After the subject withdraws from the study, the investigator has no 
longer any obligation of proactively collecting and reporting any new AE or SAE after the 90-day 
safety follow-up period. Nonetheless, if the investigator learns, after a subject has withdrawn from the 
study, that the subject experienced any SAE (including death) and reasonably considers that this event 
is possibly related to the study drug, then the investigator should report it to the sponsor’s 
pharmacovigilance team or representative. 
5.1.4 
Pregnancy 
Each fertile subject shall take appropriate contraceptive measures in a period from signing Informed 
Consent Form through at least 120 days after the final dose of the study drug and in at least 150 days 
after the final dose of chemotherapy drug. 

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Once becoming pregnant during the study, female subjects shall immediately discontinue the study 
drug and notify the investigator. The investigator shall report any pregnancy event to the sponsor (or 
an authorized representative) in 24 h after becoming aware of the pregnancy. Monitoring of the subject 
will persist until the end of pregnancy. Any pregnancy that occurs within 6 months after the final dose 
of the study drug should be reported to the investigator. 
If any female subject or the spouse of any male subject gets pregnant during the treatment and within 
6 months after the final dose of the study drug (whichever occurs first), the investigator should 
complete a Pregnancy Report in 24 h after becoming aware of the pregnancy, report to the sponsor (or 
an authorized representative), and record in eCRF to facilitate outcome follow-up. Any pregnancy 
event should be followed up until 30 days after the end of pregnancy. 
Any AE/SAE occurring in a mother or newborn during pregnancy, such as natural abortion or induced 
abortion, birth defects or congenital malformation of newborns, malformation and anomalies of death 
fetuses, complications of mothers and newborns, etc., should be documented and reported according 
to "4.7.3 Documentation of AEs" and "4.7.5 Reporting of SAEs". 
6 STATISTICAL METHODOLOGY 
6.1 Sample Size Estimation 
The randomization ratio for this study is 2:1. The sample size is estimated based on the assumption 
that the median progression-free survival (PFS) for treatment with placebo + chemotherapy 
(Carboplatin–Etoposide) is 5 months and the hazard ratio (HR) of (HLX10 + chemotherapy) group 
versus the control group is 0.7, and it is further assumed that when the enrollment period is 24 months 
and the whole study period is 29 months, to achieve a confidence level of 85% at an overall 
significance level α = 0.05 (two-sided), at least 336 PFS events have to be observed. Considering a 
dropout rate of 20%, a total of 489 subjects (326 in treatment arm and 163 in control arm) need to be 
enrolled in the 2 arms. 
6.2 Blinded Sample Size Re-estimation 
It is planned in this study that, when the 320 subjects (about 2/3 of the number of subjects planned to 

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be enrolled) was enrolled under supervision of the Independent Data Monitoring Committee (IDMC), 
the sponsor will consider performing a blinded sample size estimation, and if the blinded overall 
median PFS is lower than the expected value, then the sponsor will communicate with PI and 
regulatory authorities about the necessary increase in the sample size (number of PFS events). 
6.3 Statistical Analysis Sets 
6.3.1 
Intent-to-treat (ITT) set 
The ITT set is defined as a set of all subjects randomized in this trial, and the ITT population will 
serve as the primary population of efficacy assessment in this study. ITT population will be analyzed 
based on treatment arms. 
6.3.2 
Per protocol set (PPS) 
As a subset of the ITT set, the PPS consists of all randomized subjects undergoing at least one post-
treatment tumor assessment without any major protocol deviation that impacts the primary efficacy 
significantly. The analysis based on the PPS will serve as a support of ITT analyses. 
6.3.3 
Safety set (SS) 
The SS is defined as a set of all subjects receiving at least one dose of the study drug. The safety set 
is the primary population for safety endpoint analysis and will be analyzed based on treatment arms. 
6.3.4 
Pharmacokinetic set (PKS) 
All subjects receiving at least one dose of HLX10 and having at least one post-dose concentration 
measurement at scheduled PK time points without any major protocol violation that may impact the 
PK assessment significantly. PKS will be used for PK analysis. 
6.4 Interim Analysis and Final Analysis 
An Independent Data Monitoring Committee (IDMC) will be formed for this study to conduct the 
interim analysis. In this study, one interim analysis is planned, in which O'Brien–Fleming-like α-
spending function (Lan–DeMets approximation) is used to control the overall Type I error rate. 

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• 
The interim analysis of PFS is planned when 66% (approximately 222) of planned PFS events are 
observed, in which the safety and efficacy of the investigational drug will be evaluated. Based on 
the first interim analysis using O'Brien-Fleming α-spending function, α = 0.012 (two-sided). 
• 
The final analysis of PFS will be performed when a target number of PFS events (approximately 
336) are observed, and for final analysis the α is 0.046 (two-sided) based on the O'Brien-Fleming 
alpha spending function. 
6.5 Statistical Analysis Methods 
All statistical analyses will be performed using SAS9.2 (or later) statistical analysis software. For 
continuous variables, standard descriptive statistics include median, mean, standard deviation (SD), 
minimum, and maximum, while categorical variables include the quantity and percentage. 
The detailed statistical analysis plan and methodology shall be elaborated in the Statistical Analysis 
Plan (SAP). 
6.5.1 
Demographics, medical history, and baseline characteristics 
Demographic information, baseline profile data, medical history, and concomitant medications of all 
randomized subjects will be summarized using descriptive statistics depending on the randomization 
approach. 
6.5.2 
Medication compliance 
The medication compliance data of the investigational product (HLX10 or placebo combined with 
Carboplatin–Etoposide) will be summarized using descriptive statistics in groups. 
6.5.3 
Efiicacy analysis 
6.5.3.1 Analysis of primary efficacy endpoints 
PFS (assessed by the IRRC as per RECIST v1.1): PFS is defined as a period from randomization 
initiation to the first documentation of PD or death regardless of causality (whichever occurs first). 
Data of subjects with neither PD nor death will be censored on the day of the final valid tumor 
evaluation. Data of surviving subjects not undergoing any tumor assessment during the study will be 

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censored on the day of randomization. Data of subjects who have no PD reported and initiate any 
antitumor therapy not specified in the protocol will be censored on the day of the last evaluable tumor 
assessment prior to the initiation of subsequent antitumor treatment. The between-group comparison 
of PFS is performed by a stratified log-rank test with the following stratification factors: Sex (male 
versus female), PD-L1 expression level (negative, positive, or unidentified), brain metastasis (yes 
versus no), and age (≥ 65 years versus < 65 years); stratified COX proportional risk model will be used 
to estimate HR and its 95% CI; the Kaplan Meier method will be used to estimate the median, and the 
Kaplan–Meier curve will be plotted. 
6.5.3.2 Analysis of secondary efficacy endpoints 
Overall survival (OS): Defined as a period from randomization through death regardless of causality. 
Data of patients without death record will be censored on the last known survival date. Data of patients 
not providing any follow-up information will be censored on the randomization day. The OS will be 
analyzed using the same method as that for primary efficacy endpoints. 
PFS assessed by the investigator as per RECIST v1.1: Its statistical method is the same as that for 
primary efficacy endpoints; 
Objective response rate (ORR) assessed by the IRRC and the investigator as per RECIST v1.1 
separately: Defined as the percentage of subjects whose best overall responses are evaluated as complete 
response (CR) or partial response (PR). The stratified Cochran-Mantel-Haenszel (CMH) method is used 
to test the between-group variation in the ORR and to estimate the odds ratio and its 95% CI. 
Duration of response (DOR): Defined as a period from the first documentation of response (CR or PR) 
through the first documentation of PD or death (whichever occurs first). The DOR will be analyzed 
only for patients whose best overall responses are evaluated as CR or PR. Data of patients not 
experiencing PD or death after achieving response will be censored on the day of the final tumor 
assessment; if no tumor assessment is performed after response achievement, then data of such patients 
will be censored on the day of tumor assessment when response is achieved. The Kaplan-Meier method 
is used to estimate the median and plot the Kaplan-Meier curve; 

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6.5.4 
Safety analysis 
AEs will be described according to MedDRA terms and graded according to CTCAE v4.03. Adverse 
events occurring during or after the first dose of study drug will be summarized by CTCAE grade. 
Treatment-emergent adverse events (TEAEs) and concomitant medications in the trial will be 
summarized separately by treatment arm. The clinical laboratory parameters, ECOG PS scores, vital 
signs, physical examination, and ECG will be summarized by the treatment group and study visit. 
Values observed and changes from baseline will be descriptively reported by visit in this trial. 
6.5.5 
Pharmacokinetic analysis and immunogenicity analysis 
6.5.6 
Serum drug concentration will be descriptively summarized by scheduled collection 
time, at the same time as samples collection to assess for the presence of ADA. The schedule of 
blood sampleing for PK and immunogenicity assessment is summarized in Table 6 The 
statistical method will be detailed in the SAP.Biomarker analysis 
During the screening for this study, tumor tissues of subjects will be collected for assay of the PD-L1 
expression level, MSI and TMB; blood samples of subjects will be collected for assay of the MSI and 
TMB. The primary objective is to assess the relations among the PD-L1 expression and MSI, TMB 
and efficacy. 
6.5.7 
Analysis of subject-reported outcome variables 
The health status and self-perceived health of each patient will be documented in the form of EQ-5D-
5L scale, EORTC QLQ-C30 scale, and EORTC QLQ-LC13 scale. 
Descriptive statistics are based on the allocation for the scale scores, subscale scores, and individual 
scores at each visit and their changes from baseline. The analytical methods will be detailed in the SAP. 
Unless otherwise specified, PRO analysis of all data will be performed based on the ITT set. 

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7 ETHICS 
7.1 Ethical Requirements 
This trial shall be implemented in accordance with the GCP, Declaration of Helsinki, relevant 
regulations, and review comments of the Institutional Review Board. 
The investigator shall ensure that this trial is reviewed and approved by a qualified institutional review 
board in compliance with GCP. Prior to the trial, the investigator shall submit the trial protocol, 
informed consent forms, and other essential documents to the Institutional Review Board for review 
and approval. The sponsor shall provide the study drug after receiving the approval from the 
Institutional Review Board. Meanwhile, the Institutional Review Board shall be informed of 
subsequent protocol amendments and SAEs occurring during the study that may impact the safety of 
subjects in the trial and preclude the subjects from study continuation. The investigator is obligated to 
report the trial progress to the Institutional Review Board. In addition, the investigator must timely 
submit copies of all correspondences with the Institutional Review Board to the sponsor. When 
reviewing and approving the trial protocol, the Institutional Review Board must verify the protocol 
title and number, indicate and date the reviewed protocol documents. In the event of any additional 
amendment to the trial protocol and the informed consent forms during the trial, an additional written 
approval shall be obtained from relevant authorities according to relevant regulations. 
7.2 Informed Consent 
The investigator must inform information about this trial in both oral and written manners. The subject 
has the right to know detailed information about this trial. 
The informed consent forms (along with the trial protocol) must be reviewed and approved by the 
Institutional Review Board. If necessary, the investigator is obligated to explain the content of the 
informed consent form to each subject in a manner and wording understandable to the subject. The 
subject shall have enough time to read through before duly signing the informed consent form. 
The final text of the informed consent form shall contain: the trial objective, processes and time frame 
of the trial, operational check, expected potential benefits and risks of the subject, informing the subject 

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of being probably assigned to any other group in the trial; treatment and corresponding compensation 
obtained by the subject in the event of any trial-related damage; principle of confidentiality for personal 
data of the subject, etc. 
The informed consent form must be signed and dated by the subject, and the investigator implementing 
the informed consent process shall also sign and date the informed consent form. The informed consent 
form shall be made in duplicates, with the investigator and the subject holding one copy. Should any 
important new information related to the study drug be found, the informed consent form has to be 
revised in writing and submitted to the Institutional Review Board for approval before being approved 
by the subject again. 
7.3 Confidentiality for the Subject 
The investigator is obligated to keep the subject anonymous. In the Case Report Form or other 
documents, the subjects can be only identified with capitalized letters, numbers and/or codes, instead 
of names. The investigator must properly keep the Subject Enrollment Log documenting the codes, 
names, and residential addresses of the subjects. The investigator must keep strictly confidential any 
document that may reveal the identity of the subject. 
8 DATA MANAGEMENT 
8.1 Database Setup 
Data of this clinical trial will be collected through remote data entry in the eCRF. The data 
administrator shall design a database and test it with simulation data or real eCRF data to ensure that 
the database is accurate and correct. 
8.2 Data Checks 
During data management, data checks include the edit check, manual check, medical check, and 
statistical pre-analysis check. All the data query will be displayed in the EDC system in the form of 
electronic query for the study site to answer. The query will be closed if the answer is acceptable. If 
any data query is not resolved or a new query arises after the database is updated based on the answer 

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to the previous data query, then the investigator or CRC shall answer again. The above process will be 
repeated until all data in the database is checked to be correct. 
8.3 Database Lock 
The data administrator shall draft a data review report pursuant to the trial protocol, data review criteria, 
and the database. The project manager shall convene a data review meeting attended by the sponsor, 
principal investigator, statistician, and data administrator to review the data, and a data review 
resolution shall be jointly signed by the representatives of the participants. The data administrator shall 
implement data locking upon approval by all the participants. The locked data will be submitted to the 
statistician for statistical analysis. 
The data can be locked when the following conditions are satisfied. 
1) All data has been collected and entered into the database. 
2) All codes have been checked and verified. 
3) All data queries have been resolved (including queries proposed in data review). 
4) Data review has been completed. 
5) Source data verification has been completed. 
6) Verification of SAEs has been completed. 
7) Signatures of all investigators have been obtained. 
8) Analyzable cases have been defined and stored in the final analysis database. 
9) The SAP has been signed. 
9 STUDY MANAGEMENT 
9.1 Quality Control and Quality Assurance 
Prior to the formal initiation of the trial, the sponsor (or CRO authorized by the sponsor) and the 
investigator shall discuss and develop a clinical study plan to guarantee the trial quality. The study 
personnel involved in this trial shall be trained on GCP. 
Study drugs must be managed in each study site as per relevant SOPs, which involve the receipt, 
retention, distribution, and recovery of the drugs. 
In accordance with the GCP guideline, necessary steps must be taken during the design and 

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implementation of this study to ensure the accuracy, consistency, integrity, and credibility of the 
collected data. All observations and outliers in the clinical trial shall be promptly and carefully verified 
and recorded to ensure data reliability. Ensure that various instruments, devices, reagents, and 
reference standards in this clinical trial are in strict compliance with corresponding quality 
specifications and operate in the normal state. 
The investigator will enter information required by the protocol into the Case Report Form, and the 
monitor shall check if it is completely and accurately filled out and instruct the personnel in the study 
site to make amendments and supplements if necessary. 
The drug regulatory authorities and the sponsor may authorize auditors to conduct systematic 
examination of activities and documents in connection with the clinical trial, so as to evaluate if the 
trial is carried out in accordance with the trial protocol, SOPs and relevant regulatory requirements, 
and if the trial data is documented in a timely, authentic, accurate, and complete manner. The audit 
shall be performed by personnel not directly involved in this clinical trial. 
9.1.1 
Training 
According to the GCP guideline, the CRA shall have the qualification accepted by the sponsor; before 
the clinical trial, the person in charge of the study site shall train the investigator on the trial protocol, 
so as to enable the investigator to become fairly familiar with this clinical trial protocol, master the 
GCP guideline, unify the documentation approach and evaluation criteria, and perform the trial in strict 
accordance with the protocol. 
9.1.2 
Clinical monitoring 
The CRA is a primary liaison between the sponsor and the investigator. The CRA will fulfill all 
monitoring responsibilities to monitor this clinical study in accordance with GCP. The CRA will 
establish and maintain regular contact between the investigator and the sponsor. 
The CRA will conduct regular clinical monitoring according to all relevant regulatory requirements 
and standards, or visit the study site depending on actual situation, push the progress of the clinical 
trial, check and verify if all data records and reports, and eCRF entries are correct and complete, and 

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consistent with the source data, and ensure that the clinical trial is performed according to the clinical 
trial protocol; the investigator shall actively assist the CRA in these processes. 
9.1.3 
Audit 
During the study, the sponsor may conduct a QA audit for the study site, the study database, and the 
study documentation. The audit includes drug supply, required trial documents, documentation of the 
informed consent process, and consistency between the Case Report Form and source documents, and 
so on. The content and scope of the audit can be added when needed. After being reasonably notified, 
the investigator shall accept the study-related audit by the auditors authorized by the sponsor, as well 
as the inspection by regulatory authorities. 
In addition, the regulatory authorities may inspect the study as well. 
9.1.4 
Data management 
The departments of data management and biostatistics will process data generated in this clinical study 
according to relevant SOPs. 
Data acquisition is performed by the personnel from a study site designated and authorized by the 
investigator. Before the study is initiated and any data of any subject in the study is entered into the 
EDC system, the investigator and all the personnel from the authorized study site must be trained 
properly, and appropriate safety measures shall be taken. 
The monitor will compare the eCRF with source documents to ensure that there is no deviation 
between crucial data. All items, corrections, and changes have to be completed by the investigator or 
the personnel designated by the investigator. Relevant personnel of the study will raise queries and 
send to the investigator. In this regard, the EDC will be audited and tracked, which means the names 
of the study personnel, time, and date will be documented. 
The investigator is responsible for maintaining source documents. These documents shall be checked 
by the monitor of the study during each monitoring visit. The investigator must submit one copy of 
complete eCRF including data of every subject receiving study medication, regardless of the treatment 
duration of the subject. The study and subject numbers shall be used to indicate explicitly all supporting 
documents submitted along with the eCRF, e.g., laboratory or hospital records. Any personal 

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information including subject names shall be deleted or made illegible so as to keep the subject 
information confidential. 
9.1.5 
Missing and useless data 
The processing procedures for missing and useless data are detailed in the SAP. 
9.2 Documentation and Retention of Study Data 
The investigator is obligated to maintain essential documents of the study (the protocol and protocol 
amendment, completed eCRFs, signed informed consent forms, important correspondence files, and 
all other supportive documents). The study site shall establish a plan to retain these documents for 5 
years after study completion. The study site shall always retain these documents until at least 2 years 
after the investigational product is finally approved for marketing, and until at least 5 years after there 
is no pending approval or marketing authorization application for the investigational product, or after 
clinical development of this investigational product is formally terminated. These documents shall be 
retained for a longer time upon the request of any corresponding regulatory authority, or any hospital, 
institution, or private clinic involved in this study. Subject codes (subject names and corresponding 
study numbers) should also be retained for the same time period. As agreed by the sponsor, these 
documents can be transferred to another responsible party who must observe the document retention 
policy. The sponsor must be notified in writing of any transfer of documents. The investigator must 
contact the sponsor before disposing of any study record. 
9.3 Follow-ups and Medical Measures After Study Completion 
Unresolved AEs/SAEs (including laboratory outliers) when the study is completed or any subject 
withdraws from the study prematurely have to be followed up, as detailed in "4. AEs and SAEs". 
After study medication is completed, the investigator shall take necessary and reasonable medical 
measures for the subjects to safeguard the safety, rights and interests of the subjects. 

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10 RESPONSIBILITIES 
10.1 
Responsibilities of the Investigator 
The investigator's responsibilities mainly include but are not limited to: 
1) Designing and signing a trial protocol with the sponsor through discussion, and reporting the 
protocol to the Institutional Review Board for approval before implementation. 
2) Scrutinizing, understanding, and strictly implementing the protocol. 
3) Being knowledgeable about and familiar with the nature, function, efficacy, and safety of the 
investigational product (including information about the preclinical study for the product), as well 
as all new information related to the product discovered during the clinical trial. 
4) Conducting the clinical trial in medical institutions equipped with adequate medical facilities, 
laboratory equipment, and staffing, as well as all facilities needed to handle emergencies to ensure 
the safety of the subjects. Ensuring the laboratory results are accurate and reliable. 
5) Obtaining the consent of the medical institution or the competent authority, and ensuring that 
sufficient time is left to complete the clinical trial within the time limit set by the protocol. 
Explaining the data, regulations, and responsibilities concerning the trial to all staff participating 
in the clinical trial to ensure that a sufficient number of subjects meeting the requirements of the 
protocol are enrolled in the clinical trial. 
6) Explaining to the subjects the details of the trial approved by the Institutional Review Board and 
obtaining the Informed Consent Form from the subjects. 
7) Making medical decisions related to the clinical trial to ensure that the subjects receive appropriate 
treatment in case of adverse events during the trial. 
8) Taking necessary measures to ensure the safety of the subjects and putting on record such 
measures. Taking immediate and appropriate treatment measures for the subjects in case of any 
serious adverse events during the clinical trial, reporting the serious adverse event to the drug 
regulatory authorities, health administrative departments, the sponsor and the Institutional Review 
Board, and making sure to sign and date the report before submission. 
9) Ensuring that data is recorded in the case history and the Case Report Form in a true, accurate, 
complete, timely, and legitimate manner. 

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10) Accepting the monitoring and audit by the monitors and auditors dispatched by the sponsor, as 
well as the audit and inspection by the drug regulatory authorities to ensure the quality of the 
clinical trial. 
11) Discussing with the sponsor the cost of the clinical trial and including it in the contract. Refraining 
from charging the subjects for the cost of the investigational product during the clinical trial. 
12) Writing, signing, and dating a final report after the clinical trial is complete, and sending it to the 
sponsor. 
10.2 
Responsibilities of the Sponsor 
The sponsor's responsibilities mainly include but are not limited to: 
1) Obtaining approval from the China Food and Drug Administration (CFDA). 
2) Initiating and applying for a clinical trial, as well as funding the trial. 
3) Providing an Investigator's Brochure covering the chemical, pharmaceutical, toxicological, 
pharmacological, and clinical (including previous and ongoing trials) information and data for 
the investigational product. 
4) Designing a clinical trial protocol jointly with the investigator. Signing the trial protocol and 
contract agreed upon by both parties. 
5) Providing the investigator with an investigational product and a comparator that are easy to 
identify, correctly coded, and specially labeled, while guaranteeing the quality of the 
investigational product and the comparator. Packaging and storing the investigational product 
properly as required by the trial protocol. Establishing a management system and recording system 
for the investigational product. 
6) Appointing qualified monitors who are accepted by the investigator. 
7) Establishing a quality control and quality assurance system for the clinical trial, and organizing 
audits for the clinical trial to ensure its quality. 
8) Working with the investigator to promptly study the serious adverse events that have occurred and 
taking necessary measures to ensure the safety and rights of the subjects. Reporting the serious 
adverse events to the drug regulatory authorities and health administrative departments in a timely 
manner. 

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9) Submitting a final report of the trial to the China Food and Drug Administration (CFDA). 
10) Purchasing the liability insurance for this drug clinical trial. Providing comprehensive medical 
coverage for the subjects of the clinical trial, and bearing the cost of the treatment and 
corresponding financial compensation for the subjects experiencing injuries or deaths associated 
with the trial. Providing the investigator with legal and economic guarantees, except for those 
caused by medical malpractice. 
11 CONFIDENTIALITY AND PUBLICATION OF TRIAL RESULTS 
All information about the trial (including but not limited to the following documents: the protocol, and 
the Investigator's Brochure) is the intellectual property of the sponsor and may not be disclosed to any 
third party not related to the trial. The investigator must recognize that the scientific or medical 
information obtained from this trial may be of commercial value to the sponsor. The investigator shall 
keep the information and data related to this trial confidential. If the investigator intends to publish the 
information related to this trial or the conclusions drawn from the trial, the investigator shall negotiate 
with the sponsor in advance and obtain the written consent of the sponsor. In order to protect its rights, 
the sponsor may request the investigator not to publish information related to the trial before the trial 
product is approved for marketing. 
The sponsor has the right to publish or release information or data related to the trial or to report it to 
the drug administrative departments. If the sponsor needs to display the name of the investigator in the 
content published, released, or advertised, the sponsor shall obtain the consent of the investigator.
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vivo and in vitro study[J] .PLOSONE, 2013, 8(1) :e54824. 
[12] Chen S, Liu H, Su N, et al. Myeloid-derived suppressor cells promote age-related increase of lung 
cancer growth via B7-H1[J]. Experimental Gerontology, 2015, 61:84-91. 
[13] Keir, M. E. Tissue expression of PD-L1 mediates peripheral T cell tolerance[J]. Journal of 
Experimental Medicine, 2006, 203(4):883-895. 
[14] Dong H, Strome S E, Salomao D R, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A 
potential mechanism of immune evasion[J]. Nature Medicine, 2002, 8(8):793-800. 
[15] Nishizumi H . Development of lupus-like autoimmune diseases by disruption of the PD-1 gene 
encoding an ITIM motif-carrying immunoreceptor[J]. Immunity, 1999, 11(2):141-151. 
[16] Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application[J]. 
International Immunology, 2007, 19(7):813-824. 
[17] Yokosuka T, Takamatsu M, Kobayashiimanishi W, et al. Programmed cell death 1 forms negative 
costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting 
phosphatase SHP2[J]. Journal of Experimental Medicine, 2012, 209(6):1201-1217. 

Shanghai Henlius Biotech, Inc. 
Protocol Number: HLX10-005-SCLC301 
Version: V1.0 
Investigational Product: HLX10 
Version Date: Mar. 04, 2019 
100 
[18] Sheppard K A , Fitz L J , Lee J M , et al. PD-1 inhibits T-cell receptor induced phosphorylation of 
the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ[J]. Febs Letters, 2004, 574(1-
3):0-41. 
[19] Patsoukis N, Brown J, Petkova V, et al. Selective Effects of PD-1 on Akt and Ras Pathways 
Regulate Molecular Components of the Cell Cycle and Inhibit T Cell Proliferation[J]. Science 
Signaling, 2012, 5(230):ra46. 
[20] Merritt RE, Mahtabifard A, Yamada RE, et al. Cisplatin augments cytotoxic T-lymphocyte-
mediated antitumor immunity in poorly immunogenic murine lung cancer[J]. The Journal of 
Thoracic and Cardiovascular Surgery, 2003; 126:1609-17. 
[21] Apetoh L , Ghiringhelli F , Tesniere A , et al. Toll-like receptor 4-dependent contribution of the 
immune system to anticancer chemotherapy and radiotherapy.[J]. Nature Medicine, 2007, 
13(9):1050-1059. 
 
 
 
 
 

Shanghai Henlius Biotech, Inc. 
Protocol Number: HLX10-005-SCLC301 
Version: V1.0 
Investigational Product: HLX10 
Version Date: Mar. 04, 2019 
101 
13 APPENDICES 
Appendix 1: Common Terminology Criteria for Adverse Events 
This study will report AE using CTCAE v4.03. CTCAE v4.03 can be downloaded from the home page 
of the Cancer Therapy Evaluation Program (CTEP). CTCAE v4.03 shall be used in all relevant study 
sites. The URL is as follows: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 2-1: Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
The following is the Response Evaluation Criteria in Solid Tumors RECIST Version 1.1. For more details, 
please refer to the English version at http://ctep.cancer.gov/protocolDevelopment/docs/ recist_guideline.pdf. 
Method 
• 
Currently, CT and MRI are the best reproducible methods used for assessing the response of selected 
target lesions. The lesion on the CT scan is measured according to the following assumption: CT slice 
thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size for 
a measurable lesion should be at least twice the slice thickness. The use of MRI to assess diseases 
throughout the entire study is acceptable. 
• 
Through the entire trial, the same assessment method and the same technique are used to characterize each 
identified and reported lesion. 
• 
Ultrasound diagnosis (US) shall not be used to measure objective tumor response or progressive disease. 
For this study protocol, cross sectional imaging techniques (CT or MRI) are used to assess complete 
responses, partial response, or stable disease. FDG-PET examination is not suitable for assessing tumor 
response. It is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progressive disease. To determine progressive disease (PD), new lesions on the 
basis of FDG-PET imaging can be identified according to the following algorithm: 
1) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
2) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-
up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at 
follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed 
to determine if there is truly progression occurring at that site (if so, the date of PD will be the date 
of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-
existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
If the investigator decides to use combined PET-CT, the CT portions of PET-CT shall not be substituted for 
dedicated CT examination required by this study protocol to complete the RECIST measurement, unless the 
research institute may confirm that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast). 
Cytology and histology can be used to differentiate between PR and CR in rare cases if required by protocol 
(for example, residual lesions in tumor types such as germ cell tumors, where known residual benign tumors 

ENGLISH 
 
103 
can remain). When effusions are known to be a potential adverse effect of treatment (e.g. with certain taxane 
compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment can be considered if the measurable tumor has met criteria for 
response or stable disease in order to differentiate between response (or stable disease) and progressive disease. 
The definitions of "measurable" and "non-measurable" tumors: 
All measurements should be recorded in metric notation, using rulers or calipers. Measurement results shall 
be recorded in a single dimension. At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows: 
• 
Measurable: The tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of 10 mm by CT scan (CT scan slice 
thickness no greater than 5 mm). When the CT scan slice thickness is greater than 5 mm, the longest 
diameter of the measurable lesion shall be at least 10 mm or twice the slice thickness. Malignant lymph 
nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in short 
axis when assessed by CT scan. 
• 
Non-measurable: All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly non-measurable lesions, that are 
characterized as non-target lesions. Lesions considered truly non-measurable include: bone lesions, 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that 
is not measurable by reproducible imaging techniques. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm diameter as 
assessed using calipers (e.g. skin nodules and tangible lymph nodes). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is suggested. 
Lesions which cannot be accurately measured with calipers should be recorded as non-measurable. 
Special considerations regarding lesion measurability: 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components (that can be evaluated 
by cross sectional imaging techniques such as CT or MRI) can be considered as measurable lesions if the soft 
tissue component meets the definition of measurability described above. Blastic bone lesions are non-
measurable. 
Cystic lesions: Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions. "Cystic lesions" is thought to represent cystic metastases that can be considered as 
measurable lesions, if they meet the definition of measurability described above. However, if noncystic lesions 
are present in the same patient, these are preferred for selection as target lesions. 

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104 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, 
are usually not considered measurable unless there has been demonstrated progression in the lesion. 
Baseline (i.e., before treatment) documentation of "target" and "non-target" lesions 
During treatment, a maximum of five 5 target lesions are selected for measurement (a maximum of two lesions 
per organ). Target lesions shall be selected according to their size and the appropriateness of reproducible 
repeated measurements using imaging techniques or clinical means. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 
be calculated and reported as the baseline sum diameters. The baseline sum diameters will be used as reference 
to further characterize any objective tumor regression in the measurable dimension of the disease. 
• 
All other lesions (or affected sites; including any measurable lesions or pathological lymph nodes not 
selected as target lesions) shall be identified as non-target lesions. Non-target lesions shall be recorded 
and qualitatively assessed during treatment. Measurements are not required and these lesions should be 
followed as "present", "absent", or in rare cases "unequivocal progression". 
• 
Bone lesions: Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. If a sign or symptom indicative of bone metastases is present, a bone scan, MRI, 
CT, PET, PET/CT, or X-ray scan shall be performed. For subjects who are positive for bone scans or PET 
scans, another imaging technique (e.g., X-ray, CT, or MRI) must be used to confirm bone metastasis. 
Response criteria 
A subject's tumor response is assessed based on the response for target and non-target lesions, as well as the 
appearance of new lesions and disappearance of old lesions. 
Evaluation of target lesions 
*Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have a reduction in short axis to < 
10 mm. 
*Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
*Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study. In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression). 
*Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while in 

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105 
study. 
Not Applicable (NA): 
No target lesions are identified at baseline. 
Not Evaluable (NE): 
The scan is not completed, the scan result is incomplete, or the scan is 
not evaluated due to poor quality of the scan at the time point chosen 
for the evaluation of target lesions. 
*Diameter to be used: 
For lymph node lesions: the shortest axis 
For non-lymph node lesions: the sum of longest diameters 
Once the study is started, the following rule will be adopted: If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned. If the size of the lesion increases 
to 5 mm or more in one direction, their actual diameter shall be recorded. Lymph nodes identified as target 
lesions should always have the actual short axis measurement recorded even if the nodes regress to below 10 
mm in study. This means that when lymph nodes are included as target lesions, the "sum" of lesions may not 
be zero even if complete response criteria are met, since a normal lymph node is defined as having a short axis 
of < 10 mm. In order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD, and PD, 
the actual short axis measurement of the nodes is to be included in the sum of target lesions. 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (< 10 mm short axis) 
Non-CR/non-PD: 
Persistence of one or more non-target lesion(s) 
Progressive Disease (PD): 
Appearance of one or more new lesions, or if the original non-target 
lesions show suspicious progression. 
Not Applicable (NA): 
No non-target lesions are identified at baseline. 
Not Evaluable (NE): 
The scan is not completed, the scan result is incomplete, or the scan is 
not evaluated due to poor quality of the scan at the time point chosen 
for the evaluation of non-target lesions. 
When the patient also has measurable disease, in this setting, to achieve "unequivocal progression" on the 
basis of the non-target disease, there must be an overall level of substantial worsening in non-target disease. 
Even in presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. When the patient has only non-measurable disease, the increase in overall disease 
burden based on the change in non-measurable disease is comparable in magnitude to the increase that would 
be required to declare PD for measurable disease (which is equivalent to a 20% increase in the sum of 
diameters in all measurable lesions). 

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106 
Evaluation of best overall response 
The status of the overall response of subjects at various time points is calculated as follows: 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable 
Time point response of patients with non-target disease only. 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
NE 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
A "Non-CR/Non-PD" is preferred over "stable disease" for non-target disease since SD is increasingly 
used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised. 
Special notes on response assessment 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as "symptomatic deterioration". In this case, it 
is not possible at this time to use "progressive disease" as an overall objective response of the tumor. Every 
effort should be made to document objective progression even after discontinuation of treatment. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the residual lesion 
be investigated (fine needle aspirate/biopsy) before assigning a status of complete response. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or necrosis 
in existing lesions), treatment may continue until the next scheduled assessment. If at the next scheduled 

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107 
assessment, progression is confirmed, the date of progression should be the earlier date when progression was 
suspected. 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurement recorded in study). 
 
 

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108 
Appendix 2-2: Modified Response Evaluation Criteria in Solid Tumors 
Modified Response Evaluation Criteria in Solid Tumors 
Conventional response criteria may not be adequate to characterize the anti-tumor activity of 
immunotherapeutic agents like atezolizumab, which can produce delayed responses that may be preceded by 
initial apparent radiological progression, including the appearance of new lesions. Therefore, modified 
response criteria have been developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment. 
Modified Response Evaluation Criteria in Solid Tumors (RECIST) is derived from RECIST version 1.1 
conventions1,2,3 and immune-related response criteria3,4,5 (irRC). The provisions of RECIST v1.1 are adopted 
unless otherwise specified. 
Modified RECIST and RECIST, Version 1.1: Summary of Changes 
 
RECIST v1.1 
Modified RECIST 
New Lesions After Baseline 
Define progression 
New measurable lesions are added into 
the total tumor burden and followed. 
Non-Target Lesions 
May contribute to the 
designation of overall 
progression 
Only contribute to the assessment of a 
complete response 
Radiographic Progression 
First instance of ≥20% 
increase in the sum of 
diameters or unequivocal 
progression in non-target 
disease 
Determined only on the basis of 
measurable disease 
RECIST = Response Evaluation Criteria in Solid Tumors. 
A. Definitions of Measurable/non-Measurable Lesions 
All measurable and non-measurable lesions should be assessed at screening and at the protocol-specified tumor 
assessment time points. Additional assessments may be performed, as clinically indicated for suspicion of 
progression. 
A.1 Measurable Lesions 
Tumor Lesions. Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size as follows: 
● 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan (CT/MRI scan slice 
thickness/interval no greater than 5 mm) 
● 
10-mm caliper measurement by clinical examination (lesions that cannot be accurately measured with 
calipers should be recorded as non-measurable) 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph node must be ≥ 

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109 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and follow-up, only the short axis will be measured and followed. 
A.2 Non-Measurable Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter <10 mm or pathological lymph 
nodes with short axis ≥10 but <15 mm), as well as truly non-measurable lesions. Lesions considered truly non-
measurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal mass/abdominal 
organomegaly identified by physical examination that is not measurable by reproducible imaging techniques. 
A.3 Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular comment, as 
outlined below. 
Bone Lesions 
Bone scan, positron emission tomography (PET) scan, or plain films are not considered adequate imaging 
techniques for measuring bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
Lytic bone lesions or mixed lytic-osteogenic lesions, with identifiable soft tissue components, that can be 
evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as measurable lesions 
if the soft tissue component meets the definition of measurability described above. 
Osteogenic bone lesions are non-measurable. 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant 
lesions (neither measurable nor non-measurable) because they are, by definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, if they meet the 
definition of measurability described above. However, if non-cystic lesions are present in the same patient, 
these are preferred for selection as target lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previously irradiated area or in an area subjected to other loco-regional therapy are 
usually not considered measurable unless there has been demonstrated progression in the lesion. Study 
protocols should detail the conditions under which such lesions would be considered measurable. 
B. Tumor Response Evaluation 
B.1 Definition of Target/Non-Target Lesions 
Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of five lesions total 
(and a maximum of two lesions per organ) representative of all involved organs should be identified as target 
lesions and will be recorded and measured at baseline. This means that, for instances in which patients have 
only one or two organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), 

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110 
respectively, will be recorded. Other lesions in those organs will be recorded as non-measurable lesions (even 
if the size is >10 mm by CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and be 
representative of all involved organs, but in addition, should lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance, the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention because they are normal anatomical structures that may be visible by 
imaging even if not involved by tumor. As noted above, pathological nodes that are defined as measurable and 
may be identified as target lesions must meet the criterion of a short axis of ≥15 mm by CT scan. Only the 
short axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT, this is almost always the axial plane; for MRI, 
the plane of acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node that is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node. In this example, 20 mm should be recorded as the node measurement. All 
other pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered non-target lesions. 
Nodes that have a short axis of <10 mm are considered non-pathological and need not to be recorded or 
followed. 
Lesions irradiated within 3 weeks prior to Cycle 1, Day 1 may not be counted as target lesions. 
Non-Target Lesions 
All other lesions (or sites of disease), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline. Measurements are not required. 
It is possible to record multiple non-target lesions involving the same organ as a single item on the Case Report 
Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). 
After baseline, changes in non-target lesions will contribute only to the assessment of complete response (i.e., 
a complete response is attained only with the complete disappearance of all tumor lesions, including non-target 
lesions) and will not be used to assess progressive disease. 
New Lesions 
During the study, all new lesions identified and recorded after baseline must be evaluated at all tumor 
assessment time points. The measurability of new lesions must also be assessed in the same manner with the 
prospective evaluation criteria for target lesions (according to RECIST) used at baseline (e.g., non-lymph node 
lesions must be ≥10 mm; see note for new lymph node lesions). A maximum of five lesions total (and a 
maximum of two lesions per organ) are measured at all time points and are included in the tumor response 
evaluation. According to RECIST criteria, new-type lesions that are not target lesions are not included in the 
tumor response evaluation. 

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111 
Thereafter, if there are less than five new measurable lesions, new lesions that are not measurable in the first 
instance but meet the measurability criteria at subsequent follow-up time points can be included in the sum of 
longest diameters (SLD). 
B.2 Calculation of Sum of the Diameters 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will 
be calculated as a measure of tumor burden. 
The sum of the diameters is calculated at baseline and at each tumor assessment for the purpose of 
classification of tumor responses. 
Sum of the Diameters at Baseline: The sum of the diameters for all target lesions identified at baseline prior 
to treatment on Day 1. 
Sum of the Diameters at Tumor Assessment: For every on-study tumor assessment collected per protocol or 
as clinically indicated, the sum of the diameters at tumor assessment will be calculated using tumor imaging 
scans. All target lesions and all new measurable lesions (a maximum of five lesions total and a maximum of 
two lesions per organ) that have emerged after baseline will contribute to the sum of the diameters at tumor 
assessment. Hence, each net percentage change in tumor burden per assessment with use of modified RECIST 
accounts for the size and growth kinetics of both old and new lesions as they appear. 
Note: If new lymph nodes appear, its evaluation must be carried out following RECIST v1.1 for measurable 
lesions (equivalent to the selection of baseline target lesions). If the short diameter of a newly appeared lymph 
node lesion is ≥15 mm, it is considered as a new measurable lesion, and is followed up and included in the 
SLD. Thereafter, lymph node lesions are measured at subsequent time points and the results are included in 
the SLD, even if the short diameter shrinks to <15 mm (or even to <10 mm). However, if the diameter shrinks 
to <10 mm at subsequent time points and all other lesions cannot be detected (or if the short diameter of the 
lymph nodes shrinks to <10 mm), the result of response evaluation is CR. 
If the short diameter of a newly appeared lymph node lesion is ≥10 mm and <15 mm, the lymph node is not 
measurable but is still considered as a new lesion. This lesion will not be included in the SLD unless it becomes 
measurable later (short diameter ≥15 mm). 
If the new lymph node is <10 mm in diameter, it is not considered as a pathological lesion and is not considered 
as a new lesion. 
B.3 Response Criteria 
Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs. Table 1 provides a 
summary of the overall response status calculation at each time point for patients who have measurable disease 
at baseline. 
Complete response (CR): Disappearance of all target lesions. Lymph nodes that shrink to <10 mm short axis 
are considered normal. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of all target and all non-target 

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112 
measurable lesions, taking as reference the baseline sum of diameters, in the absence of CR. 
Note: The appearance of new measurable lesions is factored into the overall tumor burden but does not 
automatically qualify as progressive disease until the sum of the diameters increases by ≥20% when compared 
with the sum of the diameters at nadir. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum of the diameters while in the study. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of all target and all new measurable 
lesions, taking as reference the smallest sum in study (minimum SLD; this includes the baseline sum if that is 
the smallest in study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. 
Impact of New Lesions on Modified RECIST 
New lesions alone do not qualify as progressive disease. However, their contribution to total tumor burden is 
included in the sum of the diameters, which is used to determine the overall modified RECIST tumor response. 
Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point. If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that time point, unless a convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned time point response. This would be most likely to 
happen in the case of PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions 
and at follow-up only two lesions were assessed but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
Table 1. Modified RECIST Time Point Response Definitions 
% Change in Sum of the Diametersa 
Response Evaluation of 
Non-Target Lesions 
Overall Modified RECIST 
Time Point Response 
Compared with the baseline period: –100%b 
CR 
CR 
Compared with the baseline period: –100%b 
Non-CR or not all 
evaluated 
PR 
Compared with the baseline period: ≤ –30% 
Any 
PR 
> –30% to < +20% 
Any 
SD 
Not all evaluated 
Any 
NE 
Compared with minimum SLD: ≥ +20% 
Any 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; RECIST = 
Response Evaluation Criteria in Solid Tumors; SD = stable disease; SLD = sum of longest diameters. 
a 
% change in sum of the diameters (including measurable new lesions when present) 

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113 
b 
When lymph nodes are included as target lesions, the % change in the sum of the 
diameters may not be 100% even if complete response criteria are met because a normal 
lymph node is defined as having a short axis of = 10 mm. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm in order to 
meet the definition of CR.Appendix 3:Quality of Life Scale EORTC QLQ-C30, EQ-5D-
5L, EORTC QLQ-LC13 
EORTC QLQ-C30 (3rd Edition) 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the 
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year): 
 
Today's date (Day, Month, Year): 
31  
 
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
 

ENGLISH 
 
114 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
Please go on to the next page 

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During the past week: 
Not at All 
A 
Little 
Quite a 
Bit 
Very 
Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
For the following questions please circle the number between 1 and 7 that best 
applies to you 
 
29. How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
Very poor 
Excellent 

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EQ-5D-5L Health Questionnaire 
Under each heading, please tick the ONE box that best describes your health TODAY. 
14 MOBILITY 
I have no problems in walking about 
❑ 
I have slight problems in walking about 
❑ 
I have moderate problems in walking about 
❑ 
I have severe problems in walking about 
❑ 
I am unable to walk about 
❑ 
15 SELF-CARE 
I have no problems washing or dressing myself 
❑ 
I have slight problems washing or dressing myself 
❑ 
I have moderate problems washing or dressing myself 
❑ 
I have severe problems washing or dressing myself 
❑ 
I am unable to wash or dress myself 
❑ 
USUAL ACTIVITIES (e.g. work, study, housework, family 
or leisure activities) 
I have no problems doing my usual activities 
❑ 
I have slight problems doing my usual activities 
❑ 
I have moderate problems doing my usual activities 
❑ 
I have severe problems doing my usual activities 
❑ 
I am unable to do my usual activities 
❑ 
16 PAIN / DISCOMFORT 
I have no pain or discomfort 
❑ 
I have slight pain or discomfort 
❑ 
I have moderate pain or discomfort 
❑ 
I have severe pain or discomfort 
❑ 
I have extreme pain or discomfort 
❑ 

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17 ANXIETY / DEPRESSION 
I am not anxious or depressed 
❑ 
I am slightly anxious or depressed 
❑ 
I am moderately anxious or depressed 
❑ 
I am severely anxious or depressed 
❑ 
I am extremely anxious or depressed 
❑ 
 
 
 
• 
We would like to know how good or bad your health is TODAY. 
 
• 
This scale is numbered from 0 to 100. 
 
• 
100 means the best health you can imagine. 0 means the worst health you 
can imagine. 
 
• 
Mark an X on the scale to indicate how your health is TODAY. 
 
• 
Now, please write the number you marked on the scale in the box below. 
The best health you can imagine 
 
 
 
 
 
 
The worst health 
you can imagine 
The best health you 
can imagine 
YOUR HEALTH TODAY = 
 

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EORTC QLQ- LC13 
 
Patients sometimes report that they have the following symptoms or problems. Please indicate the 
extent to which you have experienced these symptoms or problems during the past week. Please 
answer by circling the number that best applies to you. 
During the past week : 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
31. 
How much did you cough? 
1 
2 
3 
4 
32. 
Did you cough up blood? 
1 
2 
3 
4 
33. 
Were you short of breath when you rested? 
1 
2 
3 
4 
34. 
Were you short of breath when you walked? 
1 
2 
3 
4 
35. 
Were you short of breath when you climbed stairs? 
1 
2 
3 
4 
36. 
Have you had a sore mouth or tongue? 
1 
2 
3 
4 
37. 
Have you had trouble swallowing? 
1 
2 
3 
4 
38. 
Have you had tingling hands or feet? 
1 
2 
3 
4 
39. 
Have you had hair loss? 
1 
2 
3 
4 
40. 
Have you had pain in your chest? 
1 
2 
3 
4 
41. 
Have you had pain in your arm or shoulder? 
1 
2 
3 
4 
42. 
Have you had pain in other parts of your body? 
1 
2 
3 
4 
If yes, where  
 
43. 
Did you take any medicine for pain? 
1 
No 
2 
Yes 
If yes, how much did it help? 
1 
2 
3 
4 
 
 
 
 
 
 
 
 

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Annex 4: Eastern Cooperative Oncology Group (ECOG) - Performance Status 
Scale 
Score 
ECOG Status 
0 
Mobility is completely normal, and there is no difference before and after the onset of the 
disease. 
1 
Free to walk and engage in light physical activities, including general housework or office 
work, but not heavy physical activities. 
2 
Able to walk and independently take care of oneself, but cannot do any work. Able to get 
up and move around for at least half of the time during the day. 
3 
Able to only finish some of self-care activities and spend more than half of the time during 
the day in bed or in a wheelchair. 
4 
Complete disability. Cannot take care of oneself at all. Totally confined to bed or in a 
wheelchair. 
5 
Death 
ECOG = Eastern Cooperative Oncology Group 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 5: Fridericia Correction Formula 
Fridericia formula: QTc=QT/RR0.33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 6: Cockcroft and Gault Formula 
The creatinine clearance rate is calculated using the measured value of serum creatinine (unit: mL): 
Male: 
(140－age) × weight (kg)
 serum creatinine (mg/dL)× 72   
Female: 
(140－age) × weight (kg)
 serum creatinine (mg/dL)× 72 × 0.85 
 
Cited from Cockcroft DW et al. Nephron. 1976; 16(1): 31-41. 
 
The creatinine clearance rate is calculated using the measured value of serum creatinine (unit: μmol/L): 
Male: (140－age)× weight (kg) × 1.23
 creatinine (µmol/L)
  
Female: (140－age) × weight (kg) × 1.23 × 0.85
 creatinine (µmol/L)
  
 
Cited from Cockcroft DW et al. Nephron. 1976;16(1):31-41. 
 
 
 
 
 
 
 

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Appendix 7: Heart Functional Classification of New York Heart Association 
Grade 
Behavioral Status 
Grade I 
Physical activities are not restricted. Normal physical activities do not 
cause excessive fatigue, palpitations or breathing difficulties 
Grade II 
Physical activities are slightly restricted and the patient feels comfortable 
at rest. However, normal physical activities can cause fatigue, 
palpitations or difficulty breathing 
Grade III 
Physical activities are significantly restricted. The patient feels 
comfortable at rest. However, activities lighter than normal physical 
activities can cause fatigue, palpitations or difficult breathing 
Grade IV 
Unable to perform any physical activity comfortably. Symptoms of 
cardiac insufficiency can occur even at rest. Any physical activity can 
aggravate discomfort. 
 
 

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Appendix 8: Guidelines for Dose Modification and Treatment for Immune-Related Toxicity 
Dose Modification 
Toxicity Treatment 
Based on the severity of the toxicity caused by drug administration (according to NCI 
CTCAE v4.03 classification), adjustment will be made to the administration of the study 
drug/study protocol to manage potential immune-related AEs. 
In addition to the criteria for permanently discontinuation of the study drug/study protocol 
based on CTC grade/severity (listed below), the study drug/study protocol is permanently 
discontinued if: 
• 
After the last dose of study drug/study protocol, the dose of corticosteroids cannot be 
reduced to prednisone ≤10 mg/day (or an equivalent dose of other medications) within 
12 weeks 
•  Recurrence of pre-existing grade 3 TEAE after the resumption of treatment 
It is recommended that the treatment of irAE shall follow 
the guidelines described in this table. 
− Subjects shall be fully evaluated to rule out any other 
possible causes (e.g., progressive disease, 
concomitant medication, and infection). 
− In the absence of a clear cause other than immune-
related causes, all events shall be considered as 
potentially immune-related. 
− For low-grade (grade 1 or 2, unless otherwise stated) 
events, symptomatic and topical treatments shall be 
considered. 
− For sustained (>3-5 days) low-grade (grade 2) or 
severe (≥3) adverse events, patients shall be 
immediately treated with prednisone PO 1-2 
mg/kg/day or IV administration of an equivalent dose 
of other medications 
− If the symptoms recur or worsen during the gradual 
dose reduction of corticosteroids (during a 28-day 
period of dose reduction), the dose of corticosteroids 
shall be increased (the dose of prednisone (e.g., up to 
2-4 mg/kg/day or IV administration of an equivalent 
dose of other medications)) until the symptoms 
Grade 1 
No dose adjustment is required 
Grade 2 
Suspend the administration of study drug/study protocol until 
grade 2 response is relieved to ≤ grade 1.  
If the toxicity is aggravated, treatment is performed according 
to those suitable for grade 3 or grade 4 responses. 
Once the dose of steroids is gradually reduced and the event is 
stabilized to ≤ grade 1, the study drug/study protocol can be 
resumed. 
For patients with endocrine disorders who may require long-
term or sustained steroid replacement therapy, they may 
resume the treatment of the study drug/study protocol under 
the following conditions:  

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1. The event has become stabilized and controlled.  
2. The subject is clinically stable according to the judgment of 
the investigator or attending physician. 
3. The dose of prednisone or an equivalent dose of other 
medications is ≤ 10 mg/day. 
stabilize or improve, then the dose of corticosteroids 
shall be decreased at a slower rate (> 28 days).  
− For events that did not response to systemic steroids, 
a more potent immunosuppressive agent shall be 
considered, such as a TNF inhibitor (e.g., infliximab) 
(for specific types of immunosuppressive agents, 
please refer to various sections of irAE).  
− For grade 3/4 inflammatory responses (e.g., 
inflammatory responses to metastatic lesions and 
lymph nodes) caused by local tumor responses, there 
is no need for compulsory discontinuation of study 
drug/study treatment. Whether or not to continue the 
use of the study drug in this case shall be determined 
based on the patient's benefit/risk analysis. 
Grade 3 
Based on individual toxicity, the study drug/study protocol may 
be permanently discontinued. Please refer to the guideline 
below. 
Grade 4 
Permanent discontinuation of the study drug/study protocol. 
Note: The study drug/study protocol is suspended for asymptomatic amylase or lipase 
elevation at grade 3 and above. If a complete examination does not suggest evidence of 
pancreatitis, the study drug/study protocol can be resumed or restarted. 
Immune-Mediated Response 
Adverse Events 
Seriousness of 
Adverse Events (NCI 
CTCAE Version 4.03) 
Administration Adjustment 
Toxicity Management 
Pneumonia/ILD 
All grades 
General guidelines 
For immune-mediated response of all grades: 
− Subjects are monitored for signs and symptoms of 
pneumonia or ILD (new or aggravated episodes of 
shortness of breath or cough). Subjects shall be 
assessed using imaging and pulmonary function 
examinations, including other diagnostic procedures 
described below. 
− Initial examinations may include clinical evaluation, 
monitoring of oxygenation (oxygenation during rest 

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and activity) by a pulse oximeter, laboratory 
examinations, and high-resolution CT scans. 
Grade 1 
(asymptomatic, only 
with results of clinical 
or diagnostic 
observations, no 
indication for 
intervention) 
No administration adjustment is 
required. However, during the 
etiological diagnosis, it may be 
necessary to suspend the 
administration of the study 
drug/study protocol depending on 
the clinical situation. 
For grade 1 (with changes in imaging results only): 
− Clinical symptoms, pulse oximetry (oxygenation 
during rest and activity) and laboratory tests shall be 
monitored and closely followed within 2 to 4 days, 
followed by further monitoring and follow-up based 
on clinical indications. 
− A consultation with the departments of respiration 
and infectious diseases can be considered. 
Grade 2 
(With symptoms, 
indications for 
medical intervention, 
and limited instrument 
activities of daily 
living) 
Suspend the administration of study 
drug/study protocol until grade 2 
response is relieved to ≤ grade 1. 
• 
If the toxicity is aggravated, 
treatment is performed according to 
those suitable for grade 3 or grade 4 
responses. 
• 
If the toxicity is improved to ≤ 
grade 1, the resumption of the study 
drug/study protocol will be 
determined based on the clinical 
judgment of the attending physician 
after the dose reduction of steroids is 
completed. 
For grade 2 (mild to moderate new symptoms): 
− Monitor symptoms daily and consider 
hospitalization. 
− Immediately start the treatment with systemic 
steroids (e.g., prednisone 1-2 mg/kg/day PO or IV 
administration of an equivalent dose of other 
medications). 
− Imaging examinations are performed again according 
to clinical indications. 
− If there is no improvement within 3-5 days, 
additional examination shall be considered along 
with an immediate treatment with IV 
methylprednisolone 2-4 mg/kg/day. 
− If there is still no improvement within 3-5 days after 
the treatment with IV methylprednisolone 2-4 
mg/kg/day, an immunosuppressive treatment, such as 
the use of a TNF inhibitor (for example, infliximab 

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5mg/kg, once every 2 weeks), shall be started 
immediately. Note: It is important to rule out sepsis 
and refer to the general instructions of infliximab for 
use. 
− Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal or anti-PCP agents shall be 
considered (refer to current NCCN guidelines for the 
treatment of cancer-related infections (category 2B 
recommendations))a. 
− A consultation with the departments of respiration 
and infectious diseases can be considered. 
− Consider to discuss with the physician if necessary. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limited 
self-care ability in 
activities of daily 
living; indication for 
oxygen inhalation) 
 
(Grade 4: life-
threatening respiratory 
failure requiring 
urgent intervention 
(e.g., tracheotomy or 
intubation)) 
Permanent discontinuation of the 
study drug/study protocol. 
For grade 3 or 4 (severe or new symptoms, new 
hypoxia/aggravated hypoxia, life-threatening): 
− Immediately start the empiric treatment with 
methylprednisolone 1-4 mg/kg/day or IV 
administration of an equivalent dose of other 
medications. 
− A consultation with the departments of respiration 
and infectious diseases. 
− Subject hospitalization. 
− Supportive treatment (oxygen inhalation, etc.). 
− If there is no improvement within 3-5 days, 
additional tests shall be considered along with an 
additional immunosuppressive treatment, such as the 
use of a TNF inhibitor (for example, infliximab 

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5mg/kg, once every 2 weeks). Note: It is important to 
rule out sepsis and refer to the general instructions of 
infliximab for use. 
− Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal, and especially anti-PCP 
agents shall be considered (refer to current NCCN 
guidelines for the treatment of cancer-related 
infections (category 2B recommendations))a. 
Diarrhoea/Enterocolitis 
All grades 
General guidelines 
For immune-mediated response of all grades: 
− 
Symptoms that may be associated with 
diarrhoea/enterocolitis (abdominal pain, spasm, or 
change in bowel habits such as increased bowel 
frequency or blood stools compared to baseline), or 
symptoms associated with intestinal perforation 
(such as sepsis, peritoneal irritation sign, and bowel 
obstruction) shall be monitored. 
− Subjects shall be fully evaluated to rule out any other 
cause (e.g., progressive disease, other medications or 
infections), including tests for Clostridium difficile 
toxins. 
− In order to prevent progression to higher-grade 
adverse events, steroids shall be considered in the 
absence of other clear causes, even in the case of 
low-grade adverse events. 

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− Analgesics shall be used with caution; such drugs 
may mask the symptoms of peritoneal inflammation 
and perforation. 
Grade 1 
(Defecation frequency 
is increased by <4 
times/day compared to 
baseline) 
No administration adjustment is 
required. 
For grade 1: 
− Symptomatic deterioration shall be closely 
monitored. 
− Symptomatic treatment shall be considered, 
including fluid and electrolyte replacement, dietary 
changes (e.g., colitis diet recommended by the 
American Dietetic Association), and loperamide 
treatment. Probiotics can be used according to the 
clinical judgment of the attending physician. 
Grade 2 
(Defecation frequency 
is increased by 4-6 
times/day compared to 
baseline) 
Suspend the administration of study 
drug/study protocol until the toxicity 
is relieved to ≤ grade 1. 
• 
If the toxicity is aggravated, 
treatment is performed according to 
those suitable for grade 3 or grade 4 
responses. 
• 
If the toxicity is improved to ≤ 
grade 1, the study drug/study 
protocol can be resumed after the 
dose reduction of steroid is 
completed. 
For grade 2: 
− Symptomatic treatment shall be considered, 
including fluid and electrolyte replacement, dietary 
changes (e.g., colitis diet recommended by the 
American Dietetic Association), and loperamide 
and/or budesonide treatment. 
− Immediately start the treatment with prednisone 1-2 
mg/kg/day PO or IV administration of an equivalent 
dose of other medications. 
− If there is no improvement or worsening of the AE 
within 3-5 days after the treatment with prednisone 
1-2 mg/kg/day PO or IV administration of an 
equivalent dose of other medications, the 
consultation with the department of gastroenterology 
shall be considered along with further examinations, 

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such as an imaging examination and/or colonoscopy, 
to confirm colitis and exclude the possibility of 
perforation. In addition, IV administration of 2-4 
mg/kg/day methylprednisolone shall be started 
immediately. 
− If there is still no improvement within 3-5 days after 
the treatment with IV administration of 2-4 
mg/kg/day methylprednisolone, an 
immunosuppressive treatment, such as the use of a 
TNF inhibitor (for example, infliximab 5mg/kg, once 
every 2 weeks), shall be started immediately. Note: It 
is important to rule out sepsis and refer to the general 
instructions of infliximab for use. 
− If there is still no improvement to ≤ grade 1 in 3-4 
days, consult with the physician. 
− Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal or anti-PCP agents shall be 
considered (refer to current NCCN guidelines for the 
treatment of cancer-related infections (category 2B 
recommendations))a. 
Grade 3 or 4 
(Grade 3: Defecation 
frequency is increased 
by ≥7 times/day 
compared to baseline; 
 
Permanent discontinuation of the 
study drug/study protocol. 
For grade 3 or 4: 
- Immediately start the empiric treatment with 
methylprednisolone 2-4 mg/kg/day or IV 
administration of an equivalent dose of other 
medications. 
- The frequency of bowel movements and stool 

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Grade 4: Life-
threatening 
consequences) 
volume shall be monitored along with sufficient fluid 
replacement. 
- When applicable, consult the department of 
gastroenterology for imaging or/and colonoscopy 
examinations. If there is still no improvement within 
3-5 days after the treatment with IV administration of 
2-4 mg/kg/day methylprednisolone or an equivalent 
dose of other medications, an immunosuppressive 
treatment (for example, infliximab 5 mg/kg, once 
every 2 weeks) shall be started immediately. Note: It 
is important to consult with department of 
gastroenterology to rule out intestinal perforation and 
refer to the general instructions of infliximab for use. 
- Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal or anti-PCP agents shall be 
considered (refer to current NCCN guidelines for the 
treatment of cancer-related infections (category 2B 
recommendations))a. 
Hepatitis (elevated LFT) 
Infliximab shall not be 
used to treat immune-
related hepatitis.  
All grades 
General guidelines 
For immune-mediated response of all grades: 
- Monitor and assess liver functions: AST, ALT, ALP, 
and total bilirubin.  
- Assess other possible causes (e.g., viral hepatitis, 
progressive disease, concomitant medication). 
Grade 1 
No dose adjustment is required. 
• 
If the AE is aggravated, it will 
be treated as a grade 2 event. 
For grade 1: 
- Continue to monitor the LFT according to the 
protocol. 

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AST or ALT ≥ 3x 
ULN and/or TB ≥ 1.5x 
ULN 
Grade 2 
(AST or ALT > 3-5x 
ULN and/or TB > 1.5-
3.0x ULN) 
Suspend the administration of study 
drug/study protocol until grade 2 
response is relieved to ≤ grade 1 
• 
If the toxicity is aggravated, 
treatment is performed according to 
those suitable for grade 3 or grade 4 
responses. 
• 
If the toxicity is improved to ≤ 
grade 1 or baseline, the study 
drug/study protocol can be resumed 
after the dose reduction of steroid is 
completed. 
For grade 2: 
- Regularly and frequently check the level of LFT (for 
example, every 1-2 days) until the elevated indicator 
improves or recovers.  
- If there is still no improvement to ≤ grade 1 in 1-2 
days, consult with the physician. 
- Immediately start the treatment with prednisone 1-2 
mg/kg/day PO or IV administration of an equivalent 
dose of other medications if the event persists (> 3-5 
days) or worsens. 
- If there is still no improvement within 3-5 days after 
the treatment with 1-2 mg/kg/day prednisone PO or 
IV administration of an equivalent dose of other 
medications, additional examination shall be 
considered along with an immediate treatment with 
IV administration of 2-4 mg/kg/day of 
methylprednisolone. 
- If there is still no improvement within 3-5 days after 
the treatment with IV administration of 2-4 
mg/kg/day methylprednisolone, an 
immunosuppressant (mycophenolate mofetil) shall be 
used immediately. If mycophenolate mofetil is not 
accessible, discuss the issue with the physician. 
Infliximab shall not be used. 

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- Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal or anti-PCP agents shall be 
considered (refer to current NCCN guidelines for the 
treatment of cancer-related infections (category 2B 
recommendations))a. 
Grade 3 or 4 
(Grade 3: AST or 
ALT > 5-20x ULN 
and/or TB > 3.0-10x 
ULN) 
 
(Grade 4: AST or 
ALT > 20x ULN 
and/or TB > 10x 
ULN) 
For grade 3: 
If transaminase is increased by ≤ 8x 
ULN or bilirubin is increased by ≤ 
5x ULN: 
• 
Suspend the administration of 
study drug/study protocol until it is 
relieved to ≤ grade 1 or baseline. 
• 
If the elevated indicator is 
reduced to ≤ grade 1 or baseline 
within 14 days, the study drug/study 
protocol is resumed at the next 
scheduled dose. 
• 
If the elevated indicator dose not 
reduce to ≤ grade 1 or baseline 
within 14 days, the study drug/study 
protocol is permanently 
discontinued. 
If transaminase is increased by > 8x 
ULN or bilirubin is increased by > 
5x ULN, the study drug/study 
protocol is discontinued. 
For grade 3 or 4: 
- Immediately start the empiric treatment with 
methylprednisolone 1-4 mg/kg/day or IV 
administration of an equivalent dose of other 
medications.  
- If there is still no improvement within 3-5 days after 
the treatment with IV administration of 1-4 
mg/kg/day methylprednisolone or an equivalent dose 
of other medications, an immunosuppressant 
(mycophenolate mofetil) shall be used immediately. 
If mycophenolate mofetil is not accessible, discuss 
the issue with the physician. Infliximab shall not be 
used. 
- Consultation with liver specialists, abdominal 
examination and imaging examination (if applicable) 
- Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal or anti-PCP agents shall be 
considered (refer to current NCCN guidelines for the 
treatment of cancer-related infections (category 2B 
recommendations))a. 

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For the initial finding that meets the 
criteria of the Hy's Law (ALT > 3x 
ULN + bilirubin > 2x ULN) without 
cholestasis (i.e., increased ALP), if 
no other cause can be determined, 
the study drug/study protocol is 
permanently discontinued.  
For grade 4: 
Permanent discontinuation of the 
study drug/study protocol. 
Nephritis or renal 
insufficiency 
(increased serum 
creatinine) 
All grades 
General guidelines 
For immune-mediated response of all grades: 
- Consult with nephrology specialists. 
- Signs and symptoms that may be associated with 
changes in renal function (e.g., urine routine, 
increased blood BUN and creatinine, decreased 
creatinine clearance, electrolyte imbalance, decreased 
urine volume, proteinuria, etc.) shall be monitored.  
- Subjects shall be fully evaluated to rule out any other 
possible causes (e.g., progressive disease or 
infection). 
- In order to prevent potential progression to higher-
grade adverse events, steroids shall be considered in 
the absence of other clear causes, even in the case of 
low-grade (grade 2) adverse events. 
Grade 1 
No administration adjustment is 
required. 
For grade 1: 
- Blood creatinine and any accompanying symptoms 

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(serum creatinine > 1-
1.5x baseline value; > 
1-1.5x ULN) 
shall be monitored once a week. 
• If the creatinine level returns to baseline, resume its 
periodic testing. 
• If creatinine is abnormally aggravated, it shall be 
treated as grade 2, grade 3 or grade 4 adverse events 
depending on its severity. 
− Symptomatic treatments shall be considered, 
including fluid and electrolyte replacement, and the 
use of diuretics. 
Grade 2 
(serum creatinine > 
1.5-3.0x baseline; > 
1.5-3.0x ULN) 
Suspend the administration of study 
drug/study protocol until it is relieved 
to ≤ grade 1 or baseline.  
• 
If the toxicity is aggravated, 
treatment is performed according to 
those suitable for grade 3 or grade 4 
responses. 
• 
If the toxicity is improved to ≤ 
grade 1 or baseline, the study 
drug/study protocol can be resumed 
after the dose reduction of steroid is 
completed. 
For grade 2: 
− Symptomatic treatments shall be considered, 
including fluid and electrolyte replacement, and the 
use of diuretics.  
− Blood creatinine is carefully monitored once every 2-
3 days, as well as when its monitoring is clinically 
needed. 
− Consult with nephrology specialists and consider 
kidney biopsy if there is clinical indication. 
− Immediately start the treatment with prednisone 1-2 
mg/kg/day PO or IV administration of an equivalent 
dose of other medications if the event persists (> 3-5 
days) or worsens. 
− Within 3-5 days after the treatment with 1-2 
mg/kg/day prednisone PO or IV administration of an 
equivalent dose of other medications, if there is still 
no improvement or if the event worsens, additional 
examinations shall be considered along with an 

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immediate treatment with IV administration of 2-4 
mg/kg/day of methylprednisolone.  
− Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal or anti-PCP agents shall be 
considered (refer to current NCCN guidelines for the 
treatment of cancer-related infections (category 2B 
recommendations))a. 
− After the event returns to baseline, the study 
drug/study protocol is resumed along with routine 
monitoring of serum creatinine carried out according 
to the study protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine > 3.0x 
baseline; > 3.0-6.0 x 
ULN; 
 
Grade 4: serum 
creatinine > 6.0x 
ULN) 
Permanent discontinuation of the 
study drug/study protocol. 
For grade 3 or 4: 
− Level of serum creatinine is closely monitored daily. 
− Consult with nephrology specialists and consider 
kidney biopsy if there is clinical indication. 
− Immediately start the treatment with prednisone 1-2 
mg/kg/day PO or IV administration of an equivalent 
dose of other medications. 
− Within 3-5 days after the treatment with 1-2 
mg/kg/day prednisone PO or IV administration of an 
equivalent dose of other medications, if there is still 
no improvement or if the event worsens, additional 
examinations shall be considered along with an 
immediate treatment with IV administration of 2-4 
mg/kg/day of methylprednisolone. 

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− Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal or anti-PCP agents shall be 
considered (refer to current NCCN guidelines for the 
treatment of cancer-related infections (category 2B 
recommendations))a. 
Rash 
(Except for skin bulla) 
All grades 
(For definitions of 
severity/grade, refer to 
NCI CTCAE Version 
4.03, based on the 
type of rash) 
General guidelines 
For immune-mediated response of all grades: 
− Signs and symptoms of dermatitis (rash and pruritus) 
shall be monitored. 
− ** If any skin bulla forms, contact the physician and 
discontinue the study drug**.  
Grade 1 
No administration adjustment is 
required. 
For grade 1: 
− Consider symptomatic treatments, including oral 
anti-pruritic drugs (e.g., diphenhydramine or 
hydroxyzine) and topical treatments (e.g., urea 
cream). 
Grade 2 
For a sustained (> 1-2 weeks) grade 2 
event, suspend the administration of 
study drug/study protocol until it is 
relieved to ≤ grade 1 or baseline. 
• 
If the toxicity is aggravated, 
treatment is performed according to 
those suitable for grade 3 responses. 
• 
If the toxicity is improved to ≤ 
grade 1 or baseline, the study 
drug/study protocol can be resumed 
For grade 2: 
− Consult with dermatologists. 
− Consider symptomatic treatments, including oral 
anti-pruritic drugs (e.g., diphenhydramine or 
hydroxyzine) and topical treatments (e.g., urea 
cream). 
− Consider taking moderate-strength topical steroid 
treatment. 
− Within 3-5 days after the symptomatic treatment 
and/or the use of a moderate-strength topical steroids, 

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after the dose reduction of steroid is 
completed. 
if there is still no improvement or if the event 
worsens, discuss with the physician and immediately 
start the systemic steroid treatment (prednisone 1-2 
mg/kg/day PO or IV administration of an equivalent 
dose of other medications) if the event persists (>3-5 
days) or worsens. 
− If the AE persists for > 1-2 weeks or recurs, consider 
a skin biopsy. 
Grade 3 or 4 
For grade 3: 
Suspend the administration of study 
drug/study protocol until it is 
relieved to ≤ grade 1 or baseline. 
If the grade 3 rash cannot be 
improved to ≤ grade 1 or baseline 
within 30 days after the study 
drug/study protocol is suspended, the 
study drug/study protocol shall be 
permanently discontinued. 
 
For grade 4: 
Permanent discontinuation of the 
study drug/study protocol. 
For grade 3 or 4: 
− 
Consult with dermatologists. 
− Immediately start the empiric treatment with 1-4 
mg/kg/day methylprednisolone or IV administration 
of an equivalent dose of other medications. 
− Hospitalization is considered. 
− Monitor the extent of the rash (rule of nine)]. 
− If clinically feasible, consider a skin biopsy 
(preferably more than 1 site is examined). 
− Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal or anti-PCP agents shall be 
considered (refer to current NCCN guidelines for the 
treatment of cancer-related infections (category 2B 
recommendations))a.  
− Discuss with the physician. 
Endocrine disorders 
(hyperthyroidism, 
hypothyroidism, 
All grades 
(For definitions of 
CTC grade/severity 
General guidelines 
For immune-mediated response of all grades: 
− Consult with endocrinologists. 

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hypopituitarism, adrenal 
insufficiency, etc.) 
based on the type of 
endocrine disorders, 
refer to NCI CTCAE 
Version 4.03) 
− Subjects are monitored for signs and symptoms of 
endocrine disorders. Non-specific symptoms include 
headache, fatigue, behavioral changes, mental state 
changes, vertigo, abdominal pain, abnormal bowel 
habit, hypotension, and weakness. 
− Subjects shall be fully evaluated to rule out any other 
possible causes (e.g., progressive disease including 
brain metastases or infection). 
− Monitoring and evaluation of thyroid functions: TSH, 
free T3 and free T4 and other relevant endocrine 
laboratory tests based on the suspected endocrine 
disease. 
− If a subject's AE is considered to be caused by 
autoimmune factors (e.g., thyroiditis, pancreatitis, 
pituitary inflammation, diabetes insipidus), the 
investigator shall send a blood sample for the test of 
corresponding autoimmune antibodies. 
Grade 1 
No administration adjustment is 
required. 
For grade 1 (including asymptomatic TSH elevation): 
− Appropriate endocrine function tests are performed 
to monitor subjects. 
− If TSH < 0.5x LLN or TSH > 2x ULN, or if TSH is 
outside its normal range in two consecutive 
measurements, free T4 shall be monitored in the 
following cycles according to clinical indications. In 
addition, consultation with department of 
endocrinology shall be considered. 

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Grade 2 
In addition to hypothyroidism, the 
administration of study drug/study 
protocol shall be suspended for 
grade 2 endocrine disorders until the 
patient becomes clinically stable. 
• 
If the toxicity is aggravated, 
treatment is performed according to 
those suitable for grade 3 or grade 4 
responses. 
Once the dose of steroids is 
gradually reduced and the event is 
stabilized, the study drug/study 
protocol can be resumed. 
For subjects with endocrine 
disorders who may require long-term 
or sustained steroid replacement 
therapy, they may resume the 
treatment of the study drug/study 
protocol under the following 
conditions: 
1. The event has become stabilized 
and controlled. 
2. The patient is clinically stable 
according to the judgment of the 
investigator or attending physician. 
For grade 2 (including symptomatic endocrine 
disorders): 
− Simple hypothyroidism can be treated with a 
replacement therapy without treatment interruption 
and without a corticosteroid treatment. 
− Hormone replacement therapy can be initiated 
according to the needs of clinical demands. 
− Endocrine functions are assessed. In addition, 
pituitary scans can be considered based on clinical 
indications. 
− For subjects with abnormal results of endocrine 
examinations other than subjects with simple 
hypothyroidism, short-term corticosteroids shall be 
considered (e.g., 1-2 mg/kg/day methylprednisolone 
or IV administration of an equivalent dose of other 
medications) along with an immediate replacement 
therapy using related hormones (e.g., levothyroxine, 
hydrocortisone, or sex hormones).  
− Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal or anti-PCP agents shall be 
considered (refer to current NCCN guidelines for the 
treatment of cancer-related infections (category 2B 
recommendations))a. 
− For subjects with normal results of endocrine 
examinations (laboratory or MRI results), laboratory 

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1. The dose of prednisone or an 
equivalent dose of other medications 
is ≤ 10 mg/day. 
tests/MRI scans shall be repeated according to 
clinical indications. 
Grade 3 or 4 
For grade 3 or 4 endocrine disorders 
(except for hypothyroidism), 
suspend the administration of study 
drug/study protocol until the 
symptoms of endocrine disorders are 
under control. 
Once the dose of steroids is 
gradually reduced and the event is 
stabilized, the study drug/study 
protocol can be resumed. 
For grade 3 or 4: 
− Consult with endocrinologists. 
− Simple hypothyroidism can be treated with a 
replacement therapy without treatment interruption 
and without a corticosteroid treatment. 
− Immediately start the empiric treatment with 
methylprednisolone 1-2 mg/kg/day or IV 
administration of an equivalent dose of other 
medications. 
− Hormone replacement therapy can be initiated if 
needed. 
− For adrenal crisis, severe dehydration, hypotension or 
shock: Immediately start the intravenous injection of 
corticosteroids with mineralocorticoid activity. 
− Once there is improvement, steroids are gradually 
reduced for ≥ 28 days. In addition, prophylactic use 
of antibiotics, anti-fungal or anti-PCP agents shall be 
considered (refer to current NCCN guidelines for the 
treatment of cancer-related infections (category 2B 
recommendations))a. 
− Discuss with the physician. 
Neurotoxicity 
(Including but not 
limited to marginal 
All grades 
(For definitions of 
CTC grade/severity 
General guidelines 
For immune-mediated response of all grades: 

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encephalitis and 
autonomic neuropathy, 
excluding myasthenia 
gravis and Guillain-
Barre syndrome) 
based on the grading 
of neurotoxicity, refer 
to NCI CTCAE 
Version 4.03) 
− Subjects shall be fully evaluated to rule out any other 
possible causes (e.g., progressive disease, infection, 
metabolic syndrome, or drug treatment). 
− The systemic symptoms of the subjects shall be 
monitored (headache, nausea, vertigo, behavioral 
changes, or weakness). 
− Appropriate diagnostic tests shall be considered (e.g., 
electromyography and nerve conduction tests). 
− If appropriate, conduct a consultation with the 
department of neurology and carry out a 
symptomatic treatment. 
Grade 1 
No administration adjustment is 
required. 
For grade 1: 
− See the recommendation for "all grades" shown 
above. 
Grade 2 
For acute motor neuropathy or 
neurotoxicity, suspend the 
administration of study drug/study 
protocol until the event is relieved to 
≤ grade 1. 
For sensory neuropathy/neuropathic 
pain, consider to suspend the 
administration of study drug/study 
protocol until the event is relieved to 
≤ grade 1. 
• 
If the toxicity is aggravated, 
treatment is performed according to 
For grade 2: 
− Discuss with the physician.  
− Consultation with the department of neurology. 
− Sensory neuropathy/neuropathic pain can be treated 
with a suitable drug (e.g., gabapentin or duloxetine). 
− Immediately start the treatment with systemic 
steroids (prednisone 1-2 mg/kg/day PO or IV 
administration of an equivalent dose of other 
medications). 
− If there is still no improvement within 3-5 days after 
the treatment with 1-2 mg/kg/day prednisone PO or 
IV administration of an equivalent dose of other 
medications, additional examination shall be 

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those suitable for grade 3 or grade 4 
responses. 
Once the dose of steroids is 
gradually reduced and the event is 
stabilized to ≤ grade 1, the study 
drug/study protocol can be resumed. 
considered along with an immediate treatment with 
other immunosuppressive treatment (such as IVIG). 
Grade 3 or 4 
For grade 3: 
Suspend the administration of study 
drug/study protocol until it is 
relieved to ≤ grade 1. 
If the grade 3 irAE has not been 
alleviated to ≤ grade 1 within 30 
days, the dosing of the study 
drug/study protocol shall be 
permanently discontinued. 
 
For grade 4: 
Permanent discontinuation of the 
study drug/study protocol. 
For grade 3 or 4: 
− Discuss with the physician. 
− Consultation with the department of neurology. 
− Hospitalization is considered. 
− Immediately start the empiric treatment with 
methylprednisolone 1-2 mg/kg/day or IV 
administration of an equivalent dose of other 
medications. 
− If there is still no improvement within 3-5 days after 
the IV administration of corticosteroids, additional 
examinations shall be considered along with an 
immediate treatment with other immunosuppressive 
treatment (such as IVIG). 
− Once the event becomes stable, gradually reduce the 
steroid dose for ≥ 28 days. 
Peripheral Motor 
Syndrome 
(such as Guillain-Barre 
syndrome and 
myasthenia gravis) 
All grades 
General guidelines 
For immune-mediated response of all grades: 
− The timely diagnosis of immune-mediated peripheral 
motor syndrome is important because some subjects 
may experience unanticipated acute decompensation, 
leading to possible disability or, in the worst case, 
death. Special attention shall be paid to certain 

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precursor symptoms that may indicate serious 
consequences, such as significant dysphagia, rapid 
progression of weakness, respiratory insufficiency, or 
signs of autonomic disorders. 
− Subjects shall be fully evaluated to rule out any other 
possible causes (e.g., progressive disease, infection, 
metabolic syndrome, or drug treatment). It shall be 
noted that the diagnosis of immune-mediated 
peripheral motor syndrome is particularly 
challenging in subjects with cancer due to the 
multiple confusing effects exerted by cancer (and its 
treatment) on the nerve axis. Given the importance of 
timely and accurate diagnosis, it is crucial to lower 
the threshold for neurology consultation. 
− If such a condition is suspected, a neurophysiological 
diagnosis shall be performed (e.g., if muscle 
weakness is suspected, EMG and nerve conduction 
tests as well as “repetitive stimulation” can be 
performed), and it is best to assist the examination 
via a neurology consultation. 
− It is important to consider that the use of steroids as 
the primary treatment for Guillain-Barre syndrome is 
generally ineffective. For subjects in need of 
treatment, an IVIG treatment shall be initiated, 
followed by a plasma treatment if the IVIG therapy is 
ineffective. 

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Grade 1 
No administration adjustment is 
required. 
For grade 1: 
− Discuss with the physician. 
− Special attention shall be paid to certain precursor 
symptoms that may indicate serious consequences 
(such as those mentioned above). 
− Neurology consultation is required unless the 
symptoms are extremely mild and stable. 
Grade 2 
Suspend the administration of study 
drug/study protocol until it is 
relieved to ≤ grade 1. 
If the event has not been alleviated 
to ≤ grade 1 within 30 days, or if 
there are signs of respiratory 
insufficiency or autonomic disorders, 
the dosing of the study drug/study 
protocol shall be permanently 
discontinued. 
For grade 2: 
− Discuss with the physician. 
− Special attention shall be paid to certain precursor 
symptoms that may indicate serious consequences 
(such as those mentioned above). 
− Consultation with the department of neurology. 
− Sensory neuropathy/neuropathic pain can be treated 
with a suitable drug (e.g., gabapentin or duloxetine). 
Myasthenia gravis: 
o Steroids can be used to successfully treat 
myasthenia gravis. It is important to consider 
that a steroid treatment (especially at high 
doses) may lead to a transient exacerbation of 
muscle weakness, so the administration of 
steroids shall be monitored under the guidance 
of a neurologist.  
o Subjects who are unable to tolerate steroids 
may be considered for a plasma exchange or 
IVIG treatment. Given the unique needs of 

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each patient, it is best to consult a neurologist 
when the decision is made. 
o In the presence of myasthenia gravis-like 
neurotoxicity, a treatment using 
acetylcholinesterase (AChE) inhibitors can be 
considered in addition to steroids. If the 
treatment is successful, it can also help with the 
diagnosis. 
Guillain-Barre syndrome: 
o It is important to recognize that steroids are 
generally not considered as the main effective 
treatment for Guillain-Barre syndrome. 
o For subjects in need of treatment, an IVIG 
treatment shall be initiated first, followed by 
plasma exchange if the IVIG treatment is 
ineffective. 
Grade 3 or 4 
For grade 3: 
Suspend the administration of study 
drug/study protocol until it is 
relieved to ≤ grade 1. 
If the event has not been alleviated 
to ≤ grade 1 within 30 days, or if 
there are signs of respiratory 
insufficiency or autonomic disorders, 
the dosing of the study drug/study 
protocol shall be permanently 
discontinued. 
For grade 3 or 4 (severe or life-threatening events): 
− Discuss with the physician. 
− Hospitalization is recommended. 
− The symptoms shall be monitored along with a 
consultation with the department of neurology. 
Myasthenia gravis: 
o Steroids can be used to successfully treat 
myasthenia gravis. The administration of 
steroid shall be monitored under the guidance 
of a neurologist. 

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Appendix 9: Prohibited Traditional Chinese Medicines 
 
Prohibited Traditional Chinese Medicines 
 
For grade 4: 
Permanent discontinuation of the 
study drug/study protocol. 
o Subjects who are unable to tolerate steroids 
may be considered for a plasma exchange or 
IVIG treatment. 
o In the presence of myasthenia gravis-like 
neurotoxicity, a treatment using AChE 
inhibitors can be considered in addition to 
steroids. If the treatment is successful, it can 
also help with the diagnosis. 
Guillain-Barre syndrome: 
o It is important to recognize that steroids are 
generally not considered as the main effective 
treatment for Guillain-Barre syndrome. 
o For subjects in need of treatment, an IVIG treatment 
shall be initiated first, followed by plasma exchange 
if the IVIG treatment is ineffective. 

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Hua Zheng Hui Sheng Tablet 
Anticancer Ping Pill 
Brucea Javanica Oil Soft Capsule/Brucea Javanica Oil Injection 
Fu Kang Capsule 
Zhe Mu Syrup 
Xiao Ai Ping 
Cantharidin/Cantharidin Injection/Cantharidin Capsule 
Ping Xiao Capsule 
Hua Chan Su 
Ping Xiao Tablet 
Toad Venom 
Shen Dan San Jie Capsule 
Kang Ai Injection 
An Kang Xin Capsule 
Kang Lai Te 
Bo Sheng Ai Ning 
Herba Sarcandrae Injection 
Zedoary Turmeric Oil Glucose Injection 
Ai Di Injection 
Kang Li Xin Capsule 
A Wei Hua Pi Cream 
Ci Dan Capsule 
Shenmai 
Lightyellow Sophora Root 
Placental Polypeptide 
 
Note: Traditional Chinese medicines prohibited during the trial include but not limited to the above drugs. 
 

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Title Page 
Protocol Title: A Randomized, Double-Blind, Multicenter, Phase III Study to Compare Clinical Efficacy and 
Safety of HLX10 (Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection) in Combination with 
Chemotherapy (Carboplatin-Etoposide) in Previously Untreated Patients with Extensive Stage Small Cell 
Lung Cancer (ES-SCLC) 
Protocol Number: HLX10-005-SCLC301 
Amendment Number: Not applicable 
Compound Number: HLX10 
Short Title: A Randomized, Double-blind, Placebo-Controlled Phase III Study to Investigate Efficacy and 
Safety of HLX10 + Chemotherapy (Carboplatin- Etoposide) in Patients with Extensive Stage Small Cell Lung 
Cancer (ES-SCLC) 
Sponsor Name and Legal Registered Address: Shanghai Henlius Biotech, Inc. Room 303 & 304, Block 7, No. 
1999, Zhangheng Road, China (Shanghai) Pilot Free Trade Zone. 
Regulatory Agency Identifying Number(s): NMPA Approval Document Number: 2018L02201, EudraCT 
Number: 2019-003063-21 
Approval Date: 05 February 2021 
 
 

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05 February 2021 
 
Investigator Agreement Page 
Declaration of the Global Coordinating Investigator 
Title: A Randomized, Double-Blind, Multicenter, Phase III Study to Compare Clinical 
Efficacy and Safety of HLX10 (Recombinant Humanized Anti-PD-1 Monoclonal Antibody 
Injection) in Combination with Chemotherapy (Carboplatin-Etoposide) in Previously 
Untreated Patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC) 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
product as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, and the guidelines on Good Clinical Practice. 
 
Global Coordinating Investigator 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 
 
 
 

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Investigator Agreement Page 
Declaration of the Principal Investigator 
Title: A Randomized, Double-Blind, Multicenter, Phase III Study to Compare Clinical 
Efficacy and Safety of HLX10 (Recombinant Humanized Anti-PD-1 Monoclonal Antibody 
Injection) in Combination with Chemotherapy (Carboplatin-Etoposide) in Previously 
Untreated Patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC) 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
product as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, and the guidelines on Good Clinical Practice. 
 
Principal Investigator 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 
 
 

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Sponsor Signatory 
 
 
Wenying Kang, 
Medical Director of Global Clinical Medical Affairs 
Shanghai Henlius Biotech, Inc. 
 
Date 

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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Version 
Date 
Notes 
Version 4.0 
05 February 2021 
This document 
Global level 
Version 3.0 
08 April 2020 
This document 
Version 2.0 
27 Sep 2019 
Global Level 
Version 1.0 
04 Mar 2019 
Applicable for China only 
 
 
 

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Overall Rationale for the Amendment 3: 
Protocol version 3.0 was updated to Version 4.0, based on comments from the European Medicines Agency as part of a Scientific 
Advice procedure, comments from the Bulgarian Drug Agency, and from the Office for Registration of Medicinal Products, Medical 
Devices and Biocidal Products (Poland Regulatory Agency), additional clarifications, and correction of minor inconsistencies between 
sections. In addition, minor corrections, including typographical/grammatical errors, have been made. Changes made during 
development of Version 4.0 are clarified as follows: 
Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
1.1 Synopsis 
3 Objectives and Endpoints 
8.3 Study Assessments 
9.4.1.2 Analysis of secondary 
efficacy endpoints 
Section 1.1 
PFS2 (assessed by the investigator based on RECIST 1.1) 
 
Section 3 
PFS2 (assessed by the investigator based on RECIST 1.1) 
 
Section 8.3 
Progression-free survival 2 (PFS2) is defined as time from 
randomization to second/subsequent objective tumor progression 
on next-line treatment or death from any cause. 
 
Section 9.4.1.2 
Progression-free survival 2 (assessed by the investigator based on 
RECIST 1.1). PFS2 is defined as time from randomization to 
second/subsequent objective tumor progression on next-line 
treatment or death from any cause. It will be analyzed using the 
same method as that for PFS. 
Revision based on 
comments from the 
European Medicines 
Agency 
1.3 Schedule of Activities 
(SoA) 
Section 1.3 
Schedule of activities table footnote #12 (initial treatment period and 
Removal of myoglobin 
testing. It is recommended 

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8.1 Tests and Evaluations 
during the Study 
post-PD treatment period): …myocardial function detection includes 
troponin-I (TnI)/ or troponin-T (TnT), creatine kinase isoenzyme (CK-
MB)/creatine kinase (CK), and Brain Natriuretic Peptide (BNP)/N-
terminal pro-Brain Natriuretic Peptide (NT-pro BNP)and 
myoglobin; 
 
Section 8.1, Table 5 
Myocardial function: Troponin-I (TnI)/or Troponin-T (TnT), 
Creatine kinase isoenzyme (CK-MB)/creatine kinase (CK), 
myoglobin Brain Natriuretic Peptide (BNP)/N-terminal pro-Brain 
Natriuretic Peptide (NT-pro BNP), Myoglobin 
Footnote: **Routine blood test, blood chemistry, coagulation function, 
myocardial function and urinalysis 
that the biomarker used 
for diagnosis of acute 
myocardial infarction is 
cardiac troponin due to its 
sensitivity and accuracy. 
Myoglobin remains a 
biomarker of secondary 
relevance as compared to 
troponin-assessments, 
hence it was removed. 
 
1.3 Schedule of Activities 
(SoA) 
5.2 Exclusion Criteria 
8.1 Tests and Evaluations 
during the study 
8.2.1 Screening Period (day -
28 to day -1) 
Section 1.3 
Schedule of activities table: Tuberculosis screening 
Footnote#15 (initial treatment period) 
 
Section 5.2 
Active or latent pulmonary tuberculosis. 
 
Section 8.1 and Table 5 
Local laboratory tests performed at study sites include routine blood 
test, serum biochemistry, coagulation, myocardial enzymogram, 
urinalysis, thyroid function, virology, tuberculosis screening (as 
requested by the Bulgarian Drug Agency for Bulgarian subjects) 
and pregnancy test. 
 
Section 8.2.1 
Local laboratory tests: routine blood test, serum biochemistry, 
coagulation, myocardial enzymogram, urinalysis, thyroid function, 
Addition of tuberculosis 
testing at Screening and 
addition of latent 
tuberculosis in exclusion 
criteria as requested by the 
Bulgarian Drug Agency 
for Bulgarian subjects 

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pregnancy test (for females of childbearing age only), and virology and 
tuberculosis screening (as requested by the Bulgarian Drug Agency 
for Bulgarian subjects). 
2.3.2 Identified and potential 
risks 
In the phase Ⅱ study of HLX10 in patients with previously treated 
HCC, 1 subject received HLX10 (3 mg/kg) combined with HLX04 (5 
mg/kg) once every 2 weeks experienced DLT at safety run in stage 
(increased total bilirubin is 39.4 mµmol/L which is >2 mg/dL and 
considered to be caused by hepatocellular cancer progression) 
Correction of 
typographical error for 
total bilirubin unit 
Sponsor Signatory 
Xin ZhangWenying Kang 
Vice president Medical Director of Global Clinical Medical Affairs 
To update the Sponsor 
signatory information. 
1.3 Schedule of Activities 
(SoA) 
1.1 Synopsis 
3 Objectives and Endpoints 
8.1 Tests and Evaluations 
during the Study 
8.2.2 Treatment Period 
8.4 Safety Assessment 
Section 1.3 
Footnote 4# (Initial Treatment Period) 
ECOG performance status, serum pregnancy test, blood routine, 
biochemistry, coagulation, myocardial function, urinalysis and thyroid 
function (T3 or FT3, T4 or FT4, TSH) should be completed within 7 
days before randomization, and the subjects should meet the 
corresponding inclusion/exclusion criteria for enrollment. 
 
Section 1.1 and Section 3: 
Safety Endpoints 
 Adverse events (AEs) (including serious adverse events 
[SAEs]), laboratory tests (routine blood test, blood chemistry, 
coagulation function, urinalysis, myocardial function and 
thyroid function), 12-lead electrocardiogram (12-lead ECG), 
vital signs, and physical examination, etc. 
 
Section 8.1 Table 5 
Add “myocardial 
function” in laboratory 
tests to be consistent with 
Table 5. 

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Routine blood test, blood chemistry, coagulation function, myocardial 
function and urinalysis must be performed at screening and within 3 
days prior to drug administration every treatment cycle. 
 
Section 8.2.2 (Initial treatment visit and Post-PD treatment visit) 
Routine blood test, biochemistry, coagulation, myocardial function 
and urinalysis should be performed within 3 days pre-dose in each 
treatment cycle; for combined chemotherapy, routine blood tests should 
be performed on Day 8 (± 3 days) of each treatment cycle. 
 
Section 8.4 
Safety assessments variables include AEs (including SAEs), laboratory 
tests (routine blood test, blood chemistry test, coagulation test, routine 
urine test, myocardial function and thyroid function test), 12-lead 
ECG, vital signs, and physical examination. 
1.3 Schedule of Activities 
(SoA) 
8.1 Tests and Evaluations 
during the Study 
8.2.2. Treatment Period 
Section 1.3 
Footnote 16# (Initial Treatment Period and Post-PD Treatment Period) 
Computerized tomography (CT) or magnetic resonance imaging (MRI) 
should be performed at screening, every 6 weeks (± 7 days) during the 
first 48 weeks after the start of study treatment, and every 9 weeks (± 7 
days) after week 48 on sites including brain, chest, abdomen, pelvic 
cavity and any other sites suspected to have tumor lesions, in which 
brain MRI or CT (preferably MRI) and bone scans are required for all 
subjects at screening, and are performed in the treatment period as 
determined by the investigator according to clinical needs (if baseline 
brain CT/MRI shows that brain metastasis is not present, the 
subject should have follow up brain imaging only if clinically 
indicated at the discretion of the investigator. If baseline brain 
CT/MRI has confirmed central nervous system (CNS) metastasis, 
continuous brain imaging test should be carried out as part of the 
Revision based on NTF 
clarification. 

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regular RECIST evaluation assessments); examination methods at 
the same site should be consistent as much as possible throughout the 
study; if there are no contraindications, contrast agent should be used. 
The investigator and IRRC respectively assess the tumor images 
according to RECIST 1.1 (the tumor assessment can be performed by 
the investigator according to clinical needs), and the investigator 
should make subsequent treatment judgment according to the results of 
their own efficacy evaluation. If tumor assessment has been performed 
within 28 days prior to the first dose by the same methods and devices 
in the same hospital, it may serve as the baseline tumor assessment. At 
the EOT visit, if tumor imaging has been performed within the last 4 
weeks, a re-test is not required. For subjects who discontinued for 
reasons other than disease progression, radiological assessments are to 
be continued as scheduled, until disease progression, initiation of new 
antineoplastic therapy, withdrawal of ICF, death, or end of studyEOT, 
whichever occurs first. 
 
Section 8.1 
Subjects should undergo CT or MRI (including brain, chest, abdomen, 
pelvic cavity and any other sites suspected of having tumor lesions) at 
screening (within 4 weeks pre-dose), every 6 weeks (± 7 days) during 
the first 48 weeks after the start of study treatment, and every 9 weeks 
(± 7 days) after week 48 (if baseline brain CT/MRI shows that brain 
metastasis is not present, the subject should have follow up brain 
imaging only if clinically indicated at the discretion of the 
investigator. If baseline brain CT/MRI has confirmed CNS 
metastasis, continuous brain imaging test should be carried out as 
part of the regular RECIST evaluation assessments). 
 
Section 8.2.2 

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Initial treatment visit and Post-PD treatment visit (Optional) 
(if the baseline brain CT/MRI shows that brain metastasis is not 
present, the subject should have follow-up brain imaging only if 
clinically indicated at the discretion of the investigator. If the 
baseline brain CT/MRI confirms CNS metastasis, a continuous 
brain imaging test should be carried out as part of the regular 
RECIST evaluation assessments); 
2.1 Background 
Anti-PD-1 monoclonal antibodies have been approved for 
melanoma, non-small cell lung cancer (NSCLC), SCLC, head and 
neck squamous cell cancer, urothelial carcinoma, microsatellite 
instability-high or mismatch repair deficient solid tumors and 
colorectal cancer, gastric cancer, esophageal cancer, cervical cancer, 
hepatocellular carcinoma (HCC), Merkel cell carcinoma, renal cell 
carcinoma, endometrial carcinoma, bladder cancer, primary 
mediastinal large B-cell lymphoma and classical Hodgkin’s 
lymphoma. Numerous clinical studies are ongoing with anti-PD-1 
antibodies, either as monotherapy or in combination with various 
agents. 
Add the approved 
indication of anti-PD-1 
antibodies in background. 
2.2 Study Rationale 
Based on the results of the HLX10 preclinical and phase I clinical 
trials, the currently available pharmacokinetic (PK) and anti-drug 
antibody (ADA) data support an average body weight dose of HLX10 
of 4.5 mg/kg administered every 21 days as the recommended dose for 
phase III clinical studies. 
The available clinical data demonstrated that HLX10 is safe and 
tolerable in the phase I, first-in-human study in patients with 
advanced solid tumors, and in other clinical studies in patients with 
malignant solid tumors. And preliminary efficacy has been 
observed in some patients with advanced solid tumors in the 
Add available clinical 
studies information to 
support the study 
rationale. 

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first-in-human phase I clinical study (HLX10-001). The safety and 
efficacy of HLX10 will be further evaluated in clinical studies. 
2.2 Study Rationale 
Based on the results of preclinical and clinical studies, Shanghai 
Henlius Biotech, Inc. planned to conduct a phase III clinical study in 
previously untreated patients with ES-SCLC worldwide to compare the 
clinical efficacy and safety of HLX10 (recombinant anti-PD-1 
humanized monoclonal antibody injection) in combination with 
chemotherapy (Carboplatin Etoposide). 
Correcting a minor typo 
noted to ensure 
consistency and was 
updated in POL PA V2.1. 
2.2.1 Preclinical Studies of 
HLX10 
In the dose-finding trial (P16-106-TS), pharmacokinetic (PK) test 
(P16-106-YD), and long-term toxicity test (P16-106-CD) in 
cynomolgus monkeys; receptor occupancy (RO) at different time points 
was also investigated before and after intravenous injection of different 
doses of HLX10 to provide a basis for selection of the clinical effective 
dose and the initial dose. 
Correcting a minor typo 
noted after PA V3.0 was 
finalized. 
2.2.1 Preclinical Studies of 
HLX10 
Genetic Toxicology Studies 
The genotoxicity isn’t required to be evaluated for monoclonal 
antibodies like HLX10 according to ICHS6 (R1). 
No genotoxicity study of HLX10 has been conducted. 
Re-organized to clarify the 
genetic toxicology studies 
information. 
2.2.1 Preclinical Studies of 
HLX10 
Tissue cross-reactivity of HLX10 
The results of tissue cross-reactivity test of HLX10 in frozen normal 
human showed that HLX10-Biotin (2.0 μg/mL and 0.5 μg/mL) 
specifically binds to normal human lymphocytes from including the 
lymph nodes, the lungs, ileum, stomach, spleen, fallopian tubes, colon 
and thymus tissues. 
Minor update to wording 
for tissue cross-reactivity 
study 
2.2.2 Clinical Study of 
HLX10 
A clinical study of HLX10 had been approved by US FDA, Taiwan 
Food and Drug Administration (TFDA) and China NMPA. 
The most up-to-date 
clinical studies are added 
in this protocol. 

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Phase I clinical trial of HLX10: A prospective, open-label, dose-
escalation study of HLX10 in patients with metastatic or recurrent solid 
tumors who had failed standard therapy. Bayesian optimal interval 
design (BOIN) was used to determine the maximum tolerated dose 
(MTD) of HLX10. The objective of this study was to evaluate the 
safety, PK characteristics, biomarkers, PD markers, immunogenicity 
and preliminary efficacy of the study drug. Eligible subjects who meet 
the inclusion criteria in the screening period will receive infusion of 
HLX10 at a dose level specified in the protocol once every 2 weeks 
until disease progression, or up to one year, withdrawal from study, or 
death, whichever occurs first. Each treatment cycle consists of two 
doses of study drug, once every 2 weeks. The trial is currently ongoing. 
The enrollment of patients into the 0.3, 1, and 3 mg/kg groups has been 
completed, and the safety evaluation is ongoing. 
 
To date, HLX10 has been administered to human subjects in 
14 ongoing clinical studies. Clinical studies of HLX10, given as 
monotherapy or in combination with chemotherapy or other 
antibodies (anti-VEGF antibody HLX04), are being conducted in 
patients with advanced solid tumors, previously untreated 
metastatic non-squamous NSCLC, previously treated unresectable 
or metastatic MSI-high or mismatch repair deficiency solid tumors, 
previously treated advanced HCC, gastric cancer, metastatic 
esophageal squamous cell carcinoma (ESCC), metastatic colorectal 
cancer (mCRC), relapsed and/or advanced cervical cancer, and 
advanced head and neck cancer. 
The clinical efficacy and safety results from these studies, as well as 
the nonclinical toxicology and safety data, provide evidence to 
support continued clinical development for HLX10. 

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2.3.1 Potential Benefits 
Atezolizumab (trade name Tecentriq®), a PD-L1 inhibitor developed by 
Roche in September 2018, has achieved landmark results in the first-
line treatment of SCLC: 
IMpower 133, a randomized, controlled phase III study evaluating 
atezolizumab plus carboplatin-etoposide versus placebo plus 
carboplatin-etoposide in the treatment of untreated extensive SCLC, 
enrolled 403 patients and randomized at 1:1 with a median follow-up of 
13.9 months. Median overall survival was 12.3 months (95% 
confidence interval [CI], 10.8-15.9) in the atezolizumab plus 
chemotherapy group and 10.3 months (95% CI, 9.3-11.3) in the 
placebo plus chemotherapy group (HR = 0.70, 95% CI 0.54-0.91, P = 
0.007). Median progression-free survival was 5.2 months (95% CI, 4.4-
5.6) in the atezolizumab plus chemotherapy group and 4.3 months 
(95% CI, 4.2-4.5) in the placebo plus chemotherapy group (HR = 0.77, 
95% CI 0.62-0.96, P = 0.02). At the same time, in terms of safety, the 
safety of Atezolizumab plus chemotherapy was consistent with that in 
the previous reports and no new toxicity was found. 
Based on the above study results, Henlius plans to study the anti-tumor 
activity of HLX10 plus chemotherapy as first-line treatment of ES-
SCLC. The preliminary efficacy, safety and tolerability data of PD-L1 
plus chemotherapy in the IMpower 133 study supports the use of this 
treatment in ES-SCLC. The primary objective of this phase III study is 
to determine the clinical efficacy and safety of HLX10 plus 
chemotherapy in previously untreated ES-SCLC patients. 
Available clinical data for HLX10 include that collected from 
clinical studies of HLX10, which was given as monotherapy and/or 
in combination with chemotherapy or other antibody (anti-VEGF 
antibody HLX04), in patients with advanced solid tumors, 
previously untreated metastatic non-squamous NSCLC, previously 
treated unresectable or metastatic MSI-H or dMMR solid tumors, 
The study results of 
atezolizumab (IMpower 
133) in this protocol will 
be replaced by the interim 
analysis results of phase I 
first-in-human study 
(HLX10-001). 

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previously treated advanced HCC, gastric cancer, metastatic 
ESCC, mCRC, relapsed and/or advanced cervical cancer, and 
advanced head and neck cancer. 
The available clinical data shows that HLX10 monotherapy or 
combined with other therapies was safe and tolerable in patients 
with malignant tumors. 
Only 1 subject in the 3 mg/kg dose cohort (n=6) experienced DLT 
during the first cycle in the HLX10 first-in-human phase I study in 
patients with advanced solid tumors with four dose levels (0.3, 1, 3 
and 10 mg/kg). The maximum tolerated dose (MTD) was not 
reached until 10 mg/kg of HLX10 was given every two weeks. 
Accumulation of HLX10 was observed following multiple dose 
administration. The 0.3 mg/kg of HLX10 was enough to saturate 
the PD-1 binding and induce the functional blockade. The efficacy 
results demonstrated anti-tumor activity of HLX10 in this first-in-
human phase I study with DCR of 68.8%, ORR of 6.3%, and 
median PFS of 107.0 days.  
In the phase II study of HLX10 in patients with previously treated 
HCC, 1 subject in the dose level A (n=7) of safety run-in stage 
experienced DLT (increased total bilirubin is 39.4 µmol/L which is 
>2 mg/dL and considered to be caused by hepatocellular cancer 
progression). 
The study showed the anti-tumor activity of HLX10 and patients 
with advanced solid tumors can benefit from HLX10. 
2.3.2 Identified and Potential 
Risks 
The safety evaluation of IMpower 133 in ES-SCLC also showed that 
the occurrences of AEs in the atezolizumab + EC group and placebo + 
EC group were comparable, with the occurrences of AEs of any grade 
being 100% and 96.4% in the two groups, respectively; the occurrences 
of grade 3-4 AEs were 67.2% and 63.8% in the two groups, 
respectively. The occurrences of treatment-related AEs were 94.9% and 
The safety information of 
atezolizumab (IMpower 
133) in this protocol will 
be replaced by the up-to-
date risk information 

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92.3%, respectively. The occurrences of SAEs were 37.4% and 34.7%, 
respectively; the occurrences of immune-related AEs were 39.9% and 
24.5%, respectively. The comparisons for occurrences of most common 
grade 3-4 AEs: Neutropenia (22.7% and 24.5%), anemia (14.1% and 
12.2%), neutrophil count decrease (14.1% and 16.8%), 
thrombocytopenia (10.1% and 7.7%), leukopenia (5.1% and 4.1%). The 
occurrences of immune-related grade 3-4 AEs in the atezolizumab + EP 
group were 2% for rash, 1.5% for hepatitis, 2% for infusion-related 
reactions, and 0.5% for pneumonia. 
HLX10 is currently being studied with limited safety information 
available. The available clinical data from the first-in-human phase 
I clinical study, shows that the most frequently reported study drug 
related adverse events were nausea, fatigue and decreased appetite, 
constipation, vomiting and pyrexia. The severity was mainly grade 
1-2. The most frequently reported serious adverse event (SAE) that 
was greater or equal than grade 3 was pyrexia. 
In another phase I clinical study (HLX10HLX04-001) of the study 
drug combined with another antibody, no DLT was observed in the 
18 subjects when the study drug was administered from 1 mg/kg to 
10 mg/kg. 
In the phase Ⅱ study (HLX10-008-HCC201) of HLX10 in patients 
with previously treated HCC, 1 subject received HLX10 (3 mg/kg) 
combined with HLX04 (5 mg/kg) once every 2 weeks experienced 
DLT at safety run in stage (increased total bilirubin is 39.4 µmol/L 
which is >2 mg/dL and considered to be caused by hepatocellular 
cancer progression).  
In the ongoing phase III study (HLX10-002-NSCLC301) of HLX10 
in patients with previously untreated non-squamous non-small cell 
lung cancer (NSCLC), 6 subjects have received HLX10 (4.5 mg/kg) 
+ HLX04 (15 mg/kg) + carboplatin (AUC=5) + pemetrexed 
reported in the 
Investigator’s Brochure. 

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(500 mg/m2) once every 3 weeks with no major safety concerns. No 
grade ≥4 hematologic toxicity and grade ≥3 non-hematologic 
toxicity-safety events and grade ≥2 pneumonia (and no recovery to 
grade 1 in 3 days) occurred after the treatment of the first cycles. 
No serious adverse drug reactions (ADRs) were observed in the 
first stage of the study (safety run-in period). The most common 
ADRs included platelet count decreased, white blood cell count 
decreased, neutrophil count decreased and hypertriglyceridaemia.  
Several other phase II and III clinical studies of the study drug are 
ongoing, where HLX10 has been administered as monotherapy 
and/or in combination with chemotherapy or other antibody, in 
patients with advanced solid tumors, previously untreated 
metastatic non-squamous non-small cell lung cancer and 
previously treated unresectable or metastatic MSI-H (microsatellite 
instability-high) or dMMR (deficiency in mismatch repair) solid 
tumors. The available clinical data showed that the study drug 
given as a monotherapy or combined with other therapies was safe 
and tolerable in patients with malignant tumors. 
The most commonly reported side effects with probability greater 
than 5% include: rash, pyrexia, anemia, diarrhea, nausea, 
decreased appetite, platelet count decreased, white blood cell count 
decreased, neutrophil count decreased, nephritis, hepatic function 
abnormal, and hypothyroidism. 
Adverse events related to the study drug reported in these studies 
which are serious, fatal and life-threatening include: pyrexia, 
myocarditis, platelet count decreased, neutrophil count decreased, 
white blood cell count decreased, pneumonitis, hepatic function 
abnormal, colitis, pancreatitis, and renal impairment. 
More detailed information about the known and expected risks of 
HLX10 can be referred to in the Investigator’s Brochure. 

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2.3.3 Overall benefits: risk 
and ethical assessment 
Based on the current study data of HLX10, only 2 subjects 
experienced DLTs (1 subject received HLX10 monotherapy [3 
mg/kg] once every 2 weeks, and 1 subject received HLX10 [3 
mg/kg] combined with HLX04 [5 mg/kg] once every 2 weeks), the 
MTD was not reached yet. No dose-limiting toxicity was observed 
based on the current first-in-human study data for HLX10, and tThe 
available safety data and pharmacokineticPK data demonstrated that 
the safety of HLX10 in patients is acceptable and adequate enough to 
support the implementation of this phase III of the clinical study. 
Add the latest reported 
clinical study results. 
4.3 Justification for Dose 
Based on the results of the HLX10 preclinical and clinical phase I 
clinical trials of HLX10, the currently available PK and ADA data 
support HLX10 4.5 mg/kg based on mean body weight, an average 
body weight dose of HLX10 of 4.5 mg/kg administered every 21 days 
as the recommended dose for phase III clinical studyies. Results of 
Dose Exposure Response analysis demonstrated both 4.5 mg/kg every 
three weeks and 3.0 mg/kg every two weeks were oversaturated doses. 
Given the fact that no maximum tolerated dose (MTD) was observed in 
anti-PD-1 antibodies and the European Medicines AgencyEMA and 
FDA approved oversaturated doses for nivolumab (nivo) and 
pembrolizumab (pembro) in clinical practice across multiple tumor 
types, Henlius believes that 4.5 mg/kg every three weeks or 3.0 mg/kg 
every two weeks is justified and safe. 
Updates based on POL PA 
V2.1. 
8.1 Tests and Evaluations 
during the Study 
8.2.2 Treatment Period 
8.3 Study Assessments 
Section 8.1 Tumor imaging 
Images will be assessed by the IRRC according to RECIST v1.1 (see 
Appendix 2-1: Response Evaluation Criteria in Solid Tumors (RECIST 
1.1)) and iRECIST criteria (see Appendix 2-2: iRECIST: Guidelines for 
response criteria for use in trials testing immunotherapeutics 
immunotherapeutics). 
 
To clarify that IRRC will 
only be assessing based on 
RECIST 1.1 and 
investigator will assess 
based on RECIST 1.1 and 
iRECIST. 

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The investigator and IRRC respectively assesses the tumor images 
according to RECIST 1.1 and iRECIST (the tumor assessment can be 
performed by the investigator according to clinical needs), and the 
investigator should make subsequent treatment judgment according to 
the results of their own efficacy evaluation. The IRRC assess the 
tumor images according to RECIST 1.1. 
 
At the EOT visit, if tumor imaging has been performed within the last 4 
weeks, a re-test is not required. Note: For all tumor imaging 
timepoints, investigator must assess all the tumor images according 
to RECIST 1.1 and iRECIST. 
 
Section 8.2.2 
Initial treatment visit 
The investigator and IRRC should assess the tumor images according 
to RECIST 1.1 and iRECIST (the tumor assessment can be performed 
by the investigator according to clinical needs), and the investigator 
should make subsequent treatment judgment according to the results of 
their own efficacy evaluation. The IRRC should assess the tumor 
images according to RECIST 1.1. 
 
Post-PD treatment visit 
The investigator should assess the tumor images according to RECIST 
1.1 and iRECIST (the tumor assessment can be performed by the 
investigator according to clinical needs), and the investigator should 
make subsequent treatment judgment according to the results of their 
own efficacy evaluation. 
 
Section 8.3 

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Except overall survival, other efficacy endpoints are evaluated based on 
tumor response as per RECIST 1.1 and iRECIST. 
8.2.1 Screening Period (day -
28 to day -1) 
Note: All reports from diagnostic procedures, which were 
performed before the ICF is signed and as part of the standard of 
care in the region and the examination methods/devices meet the 
study requirements might be used for the eligibility evaluation 
during the screening. This option restricted to those cases only, 
where the patient has given written confirmation that he/she 
consent to use his/her diagnostic reports of performed procedures 
before the date of ICF signature for eligibility evaluation of the 
actual study. 
Updates per NtF for PA 
V3.0. 
6.2 Dosing Regimen 
Preparation/Handling/Storage/ 
Accountability 
The infusion of investigational product is completed between 30 mins 
and 90 mins if there is not any infusion reaction. The diluted drug 
solution is recommended to be used within 6 hours of preparation 
and has been shown to be stable for up at 24 hours. The diluted 
drug solution needs to be stored at approximately 2-8 °C for no 
longer than 24 hours and be kept from light if not used within 6 
hours. 
Updates per IB 4.0 
following stability testing. 
1.1 Synopsis 
6.6 Dose Modification 
Section 1.1 
In the event of intolerance to etoposide/carboplatin, the dose can be 
modified twice according to the etoposide/carboplatin prescribing 
information and local standard-of-care. Once reduced, the dose 
cannot be increased back to 100%. 
If treatment is delayed due to intolerance to chemotherapy, 
chemotherapy may be delayed to the next cycle of administration, with 
the maximum permissible interval for chemotherapy not exceeding 6 
weeks. 
 
Section 6.6 
Alignment of ‘principles 
for chemotherapy 
modification’ text between 
sections and removal of 
dose modification table 
for chemotherapy as in 
practice, the dose of 
carboplatin would be re-
calculated before each 
dose. 

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Principles for chemotherapy dose modifications 
In the event of intolerance to etoposide/carboplatin, doses may be 
adjusted twice in accordance with the prescribing information of 
carboplatin and etoposide, the investigator’s decision based on the 
subject’s safety, and local treatment standards practice. Once reduced, 
the dose cannot be increased back to 100%. 
 
 
 
5.1 Inclusion Criteria #12 
≤ 1.5×ULN; 
In case of > 1.5 × ULN, creatinine clearance ≥ 5060 mL/min 
Decrease the value of 
creatinine clearance as per 
a request from the EMA 
8.2.2 Treatment Period 
The tumor image used to determine disease progression can be used as 
the new baseline image for the post-PD treatment period if 1) within 
28 days prior to receiving the first dose of HLX10 or placebo therapy 
and 2) No study treatment between the image and first dose of HLX10 
or placebo therapy, otherwise a new baseline image must be performed 
prior to HLX10 or placebo treatment. 
Clarification that the 
tumor image can be used 
within 28 days 

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8.4.7. Pregnancy 
Each fertile subject shall take appropriate contraceptive measures in a 
period from signing ICF through at least 6 months after the final dose 
of the study drug, and in at least 6 months after the final dose of 
chemotherapy drug. 
Update of information 
regarding contraceptive 
measures 
6.6 Dose Modifications 
Hematological toxicities 
Table 1 
ANC < 0.5 ×109/L and PLT ≥ 50 ×109/L: 75% of the planned previous 
dose 
PLT < 50 ×109/L, regardless of ANC: 75% of the planned previous 
dose 
PLT < 50 ×109/L with Grade 2 hemorrhage, regardless of ANC: 50% of 
the planned previous dose 
ANC < 1×109/L with fever ≥ 38.5 °C: 75% of the planned previous 
dose 
 
Non-hematological toxicities 
Table 2 
Modified carboplatin dose by % of planned previous dosea 
To add flexibility for 
investigational sites to 
apply dose reduction 
based on their standard 
clinical practice 
8.4.1.4 Death 
• Any death (confirmed to be PD-induced or non-PD-induced) 
should be reported as an SAE and the death should not be 
reported as a separate event. The SAE report needs to be 
submitted and reported to the clinical research associate 
(CRA)/clinical site manager (CSM), the sponsor, or a representative 
of the sponsor within 24 hrs. 
• When a death is not (or not explicitly) due to PD, the AE resulting in 
this death has to be deemed as an SAE and reported to the 
CRA/CSM, the sponsor, or a representative of the sponsor in 24 h. 
The primary cause of death should be provided. 
Rewording to avoid 
possible misunderstanding 

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8.4.2 Serious Adverse Events 
2) Life-threatening (AE occurrence leads to an immediate risk of 
subject death, not including those AEs that may lead to death after PD, 
e.g., drug-induced hepatitis without liver failure) 
Update as per ICH-E2A 
8.4.4 Reporting of SAEs 
The sponsor is legally liable to inform has a legal responsibility to 
notify both the local regulatory authority and other regulatory bodies 
agencies about the of safety information of the study drug of a study 
intervention under clinical investigation. The investigator sponsor is 
legally obliged and ethically responsible to report promptly SAEs to 
relevant regulatory bodies and health authority, the ethics committee, 
and the study contact specifically in charge of receiving SAE reports, 
and make sure safety of other subjects is guaranteed will comply with 
country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and Investigators. 
 
The investigator or any person-in-charge required by local authority 
shall abide by local regulatory regulations on SAE reporting and report 
SAEs to regulatory bodies, Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC), as per request. 
Updated to meet cross-
countries’ requirement 
9.5.1 Independent Data 
Monitoring Committee 
(IDMC) 
The IDMC will be established to independently oversee the blinded 
sample size re-estimation procedure; 
Correction of 
typographical error 
9.5 Interim Analyses 
An IDMC will be established for this study for blinded interim 
analysis. This study plans to carry out an interim analysis.  
Correction of text as the 
interim analysis will not 
be blinded 
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding 
The blinding will be performed by the Data Management and 
Statistical Unit during study treatment. 
Deletion of Data 
Management, as blinding 
process is not created by 

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the Data Management 
function. 
7. Discontinuation of Study 
Intervention and Participant 
Discontinuation 
7 Discontinuation of Study Intervention, and Participant 
Discontinuation, and Study Termination 
 
Section 7.1.1 Reasons for Premature Discontinuation 
1. Poor subject compliance that has affected the efficacy and safety 
evaluation; 
2. The occurrence of AEs or SAEs in the subjects, who are deemed 
unsuitable to that are inappropriate to continue receiving the study 
drug treatment as judged by the investigator; 
3. Evidence of clear disease unequivocal progression or worsening of 
the disease;  
4. A delayed dosing of the study drug administration meeting the 
criteria specified in the protocol; 
5. Subject lost loss to follow-up or death during treatment; 
6. Subject decided to Wwithdrawal of informed consent; 
7. Subject decides to discontinue treatment; 
8. Other reasons of discontinuation as determined by the investigator 
in the best interest of the subject. 
 
Section 7.1.2 Management of premature discontinuations 
The reasons for premature discontinuations shall be documented in the 
eCRF by the investigator. 
 
Updates for clarity of 
language and provide 
further detail for subjects 
discontinuing treatment 

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All subjects who discontinue the trial prematurely (except patients who 
withdraw informed consent) and agree to continued follow-up of 
associate clinical outcome information, shall undergo an EOT visit 
and be followed up for safety and survival. See Section 8.2.4 for 
assessments during the follow-up period. 
 
Subjects who discontinue the trial for reasons other than disease 
progression and agree to continue follow-up of associated clinical 
outcome information should be radiologically followed up until 
disease progression, withdrawal of informed consent, death or start of a 
new antineoplastic therapy. 
 
All AEs present at the time of discontinuation must be followed up 
until the outcomes of such AEs. 
 
In case of an enrolled subject’s withdrawal for any reasons, no subject 
replacement is permitted. 
 
7.4 
Premature Termination of Study and Site Closure 
The study may be terminated prematurely for the reasons 
described below, and the premature termination of the study must 
be approved in writing by both the principal investigator and the 
Sponsor, and the results of the study should be reported as 
required by the protocol. 
 
1. The study is unlikely to be completed within an acceptable time 
frame due to difficult enrollment of subjects; 
2. The investigator doubts the safety of the drug during the study, 
and believes that continuing the study will bring serious risks to 
the subjects;  

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3. The principal investigator and the Sponsor believe that it is 
necessary to terminate the study prematurely based on the 
number of AEs and their severity; 
4. The expected efficacy cannot be reached, and it is not necessary 
to continue the clinical study; 
5. Withdrawal of the study by the drug regulatory authority; 
6. The Sponsor has the right to decide to terminate the study in a 
study site if the following occurs: 
• Serious violation of International Conference on 
Harmonization Good Clinical Practice (ICH-GCP) by the 
study site 
• Multiple serious protocol violations by the study site 
 
After termination of the study, all study-related records should be 
retained for reference. 
Section 5.2 Exclusion criteria 
Section 7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
Section 5.2 
16. Treatment with live vaccines and all COVID-19 vaccines (fully 
administered to the required number of doses) within 28 days prior 
to study drug administration; inactivated viral vaccines for seasonal 
influenza are allowed. 
 
18. 
Any active infection requiring systemic anti-infective therapy 
within 14 days prior to study drug administration or subjects with a 
positive RT-PCR test for SARS-CoV-2 infection at randomization. 
Subjects with a history of COVID-19 infection must have a 
negative RT-PCR test prior to the first dose of the study drug. 
 
Section 7.2 
If a subject develops fever or symptoms suspected of being a result 
of COVID-19 during the study, they will be instructed to follow-up 
Addition of information 
relating to subjects with or 
a history of COVID-19 
infection 

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with their regular healthcare provider or follow the instructions for 
suspected COVID-19 cases per their local health authority. A 
subject will discontinue treatment based on discussion with the 
Sponsor and Medical Monitor under the following circumstances: 
any suspected or confirmed COVID-19 case will be immediately 
discontinued from study treatment for up to 12 weeks after the last 
study drug administration; subjects who recover from the infection 
within 12 weeks from the last study drug administration, can 
continue treatment following Sponsor’s confirmation. 
 
Overall Rationale for the Amendment 2: 
Protocol Version 2.0 was updated to Version 3.0 based on the comments from the European Medicines Agency and the United States 
Food and Drug Administration as part of Scientific Advice procedures. 
Section # and Name 
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Brief Rationale 
1.1 Synopsis 
3 Objective and Endpoint 
Primary Efficacy Endpoint 
• 
Progression-free survival (PFS) (assessed by the independent 
radiology review committee [IRRC] based on Response Evaluation 
Criteria in Solid Tumors [RECIST] 1.1) 
• 
Overall survival (OS)  
OS is the recommended 
primary endpoint as 2-year 
survival for ES-SCLC is less 
than 5% and there is a limited 
activity in second-line 
therapies.  
1.1 Synopsis 
3 Objective and Endpoint 
Secondary Efficacy 
Endpoint  
• 
Overall survival (OS) 
• 
Progression-free survival (PFS) (assessed by the independent 
radiology review committee [IRRC] based on Response Evaluation 
Criteria in Solid Tumors [RECIST] 1.1) 
Change PFS to a secondary 
endpoint 
 

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1.1 Synopsis 
4.1 Overall Design 
Initial tTreatment should be discontinued when they have evidence of 
disease progression as assessed by RECIST v1.1. However, considering 
the limited availability and efficacy or greater toxicity of treatment 
options after withdrawal, and for better adaptation to standard clinical 
practice, 
If a subject has 1st disease progression and is clinically stable, and 
tends to receive 2nd line chemotherapy treatment subsequently (the 
selection of 2nd line chemotherapy may refer to the NCCN 
guidelines or the ESMO guidelines), it is at the discretion of the 
investigator to continue treating the subject with blinded HLX10 or 
placebo assignment per protocol in addition to the 2nd line 
chemotherapy, until the 2nd disease progression lost clinical benefit, 
intolerable toxicity, death, withdrawal of consent, or lost to follow-
up. Subjects who permanently discontinue initial treatment due to 
an adverse event, withdrawal of consent, or for any reason other 
than disease progression, will not be eligible for the post-PD 
treatment. 
the sSubjects who meets all the following conditions may continue 
the treatment and after appropriate discussion with the subject and 
obtaining the supplementary informed consent. 
1. Subjects who had received HLX10 or placebo in combination 
with chemotherapy, who may benefit from continuing 
HLX10/placebo treatment despite progression, will be able to 
receive HLX10 or placebo therapy in the post-PD treatment. 
1. With no clinical signs and symptoms (including worsening of 
laboratory findings) indicating a significant disease progression. 
2. Subjects eligible for continued treatment in the post-PD 
treatment period, as judged by the investigator. 
2. A stable Eastern Cooperative Oncology Group (ECOG) performance 
status score. 
In combination with second-
line chemotherapy in the post-
PD treatment period, subjects 
are prevented from being 
exposed to placebo alone. 

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3. The subject should sign the supplementary informed consent 
form to receive investigational product with 2nd line chemotherapy. 
4.The subject is clinically stable, defined as: 
a) With no clinical signs and/or symptoms (including worsening of 
laboratory findings) that might indicate disease progression. 
b) A stable Eastern Cooperative Oncology Group (ECOG) 
performance status score. 
c) No rapid disease progression or tumor progression requiring 
urgent alternative medical intervention at critical anatomical sites 
(e.g., spinal cord compression). 
3. No rapid disease progression or tumor progression requiring urgent 
alternative medical intervention at critical anatomical sites (e.g., spinal 
cord compression). 
4. The major organ function meets the inclusion and exclusion criteria 
of this study. 
5. The subject should sign the supplementary informed consent form to 
continue treatment. 
 The primary objective of this study is to compare the PFSs of HLX10 
in combination with chemotherapy versus placebo in combination with 
chemotherapy, as assessed by an Independent Radiology Review 
Committee (IRRC) using RECIST v1.1. 
1.1 Synopsis 
Treatment Groups and 
Duration: 
8.2.2 Treatment Period 
This study is divided into three periods: Screening period (28 days), 
treatment period (initial treatment and post-PD treatment 
[Optional], until disease progression loss of clinical benefit, death, 
intolerable toxicity, withdrawal of informed consent, or occurrence of 
other reasons specified in the protocol, whichever occurs first), and 
Follow-up period (including safety follow-up and survival follow-up). 
Adjustment of treatment 
periods because of the 
addition of post-PD treatment. 

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1.1 Synopsis Other study 
drugs: combined 
chemotherapy 
4.1 Overall Design 
6.2 Dosing Regimen 
Preparation/Handling/Storag
e/Accountability 
6.6 Dose Modification 
Carboplatin: Area under the concentration-time curve (AUC) = 5, IV 
infusion, on Day 1 of each cycle up to a dose of 800750 mg. On Day 1, 
etoposide shall be administered following infusion of carboplatin. 
To adjust the maximum 
dosage of carboplatin 
according to the NCCN 
Chemotherapy Order 
Templates about Maximum 
Carboplatin Dose Calculation. 
To clarify the order of drug 
administration. 
1.2 Schema 
Screening period: The maximum screening period is 28 days. At least 
28 days. 
Treatment period: Including initial treatment and post-PD treatment 
(optional) 
After finishing the initial treatment period, patients in both arms 
who had 1st disease progression per RECIST 1.1 and might benefit 
from their assigned treatment in addition to 2nd line chemotherapy, 
may be eligible to continue to receive their assigned treatment in the 
post-PD treatment period (Optional) until the 2nd disease 
progression, intolerable toxicity, death, withdrawal of consent, or 
lost to follow-up. 
Safety follow-up period: 90 days after the last study drug 
administration dose. Safety visit is required at the site 30 days (±7 
days) after the last study drug administration dose, and telephone 
follow-up is required 90 days (±7 days) after the last study drug 
administration dose. 
Survival follow-up period: Every 12 weeks ± 7 days 
To keep the study periods 
consistent throughout the 
protocol. 
1.3 Schedule of Activities 
(SoA) 
Study Procedures Initial Treatment Period and Post-PD Treatment 
Period (Optional) 
To keep the study periods 
consistent throughout the 
protocol. 

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1.3 Schedule of Activities 
(SoA) Initial Treatment 
Period footnote #7 
Re-assessments Quality of life assessment could be performed either 
on Day -7 to Day -1 of the screening period or prior to dosing in 
Cycle 1 are not required for subjects who had a quality of life 
assessment on Day -7 to Day -1 of the screening period. 
To clarify the acceptable time 
window for performing 
quality of life assessment 
during the screening period. 
1.3 Schedule of Activities 
(SoA) Initial Treatment 
Period footnote #8 
Adding footnote #8: Re-assessments prior to dosing in Cycle 1 are 
not required for subjects who had 12-lead ECG and ECOG scores 
assessment on Day -7 to Day -1 of the screening period 
To clarify the acceptable time 
window for performing 12-
lead ECG and ECOG scores 
assessment during the 
screening period. 
1.3 Schedule of Activities 
(SoA) Initial Treatment 
Period footnote #9 
8.1 Tests and Evaluations 
during the Study 
If the change in the subject’s body weight from baseline during the 
study is ≤10%, dose adjustment of investigational product study drug 
will not be required, and if the weight change is >10%, the dose of 
study drug must be recalculated. If the subject’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the dose 
of investigational product, the dose of investigational product must 
be recalculated. All doses should be rounded to the nearest 
milligram. 
To substitute “study drug” 
with “investigational product” 
as investigational product 
stands for HLX 10/placebo 
only and does not include 
chemotherapy drugs. 
Language has been edited to 
make the dose modifications 
of investigational product 
clearer. 
1.3 Schedule of Activities 
(SoA) Initial Treatment 
Period footnote #12 
8.1 Tests and Evaluations 
during the Study 
Laboratory Tests 
12.serum biochemistry items include blood urea/urea nitrogen, 
creatinine, sodium, potassium, magnesium, chloride, carbon dioxide 
binding capacity or bicarbonate or total carbon dioxide, calcium, 
phosphorus, blood glucose, total bilirubin, direct bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase, lactate dehydrogenase, total cholesterol, total protein, 
albumin; coagulation test consist of prothrombin time (PT), 
activated partial thromboplastin time (APTT) and international 
normalized ratio (INR); myocardial enzymogram detection includes 
troponin-I, creatine kinase isoenzyme (CK-MB) and myoglobin; 
To delete “carbon dioxide 
binding capacity or 
bicarbonate or total carbon 
dioxide” from the serum 
biochemistry test as these 
items are not required but can 
be performed if considered 
standard of care in the region.  

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urinalysis items include specific gravity, urine leukocytes, pH, urine 
glucose, urine protein, ketone body and blood cellsurine occult blood, 
microscopic examination of white blood cells and red blood cells 
should be collected if urine leukocytes and urine occult blood are 
out of normal range. Can be performed within 3 days before dosing in 
each cycle; for aforementioned laboratory tests scheduled on the same 
day as study treatment, the study treatment can be arranged only after 
the test results are obtained. For laboratory tests from the screening 
period completed on Day -7 ~ Day -1, it is not necessary to repeat 
the test again before the first administration (C1D1). For combined 
chemotherapy, routine blood tests should be performed on Day 8 (± 3 
days) of each treatment cycle to closely monitor bone marrow 
suppression. 
To include myocardial 
enzymogram detection to 
address safety concern. 
Language has been added to 
clarify the urinalysis items. 
To clarify time window of 
local lab test at screening 
period. 
1.3 Schedule of Activities 
(SoA) Initial Treatment 
Period footnote #14 
8.1 Tests and Evaluations 
during the Study 
Laboratory Tests  
Patients with HBsAg (+) and/or HBcAb (+) HBsAg positive subjects 
should be further tested for hepatitis B virus (HBV) DNA titer; and 
HCV antibody positive subjects should be further tested for HCV RNA. 
Language has been edited to 
clarify the HBV testing 
requirements. 
1.1 Synopsis 
9.2 Sample Size 
Determination 
9.5 Interim Analyses 
Number of Participants: 
Approximately 489567 (326 378 for HLX10 and 163189 for placebo). 
Corresponding wording and recalculation were applied to section 9.2 
and 9.5 
Sample size was recalculated 
due to change of primary 
endpoint to OS. 
2.2.2 Clinical Study of 
HLX10 
Phase I clinical trial of HLX10: A prospective, open-label, dose-
escalation study of HLX10 in patients with metastatic or recurrent 
solid tumors who had failed standard therapy. Bayesian optimal 
interval design (BOIN) was used to determine the maximum 
tolerated dose (MTD) of HLX10. The objective of this study was to 
evaluate the safety, PK characteristics, biomarkers, PD markers, 
To make the description of 
phase I study clearer. 

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immunogenicity and preliminary efficacy of the study drug. Eligible 
subjects who meet the inclusion criteria in the screening period will 
receive infusion of HLX10 at a dose level specified in the protocol 
once every 2 weeks until disease progression, or up to one year, 
withdrawal from study, or death, whichever occurs first. Each 
treatment cycle consists of two doses of study drug, once every 2 
weeks. The trial is currently ongoing. The enrollment of patients 
into the 0.3, 1, and 3 mg/kg groups has been completed, and the 
safety evaluation is ongoing. 
for a dose escalation phase I clinical trial. There are four dose groups 
(0.3, 1, 3 and 10 mg/kg, once two weeks) in the trial, with a maximum 
enrollment of about 30 subjects. At present, three patients in the fourth 
dose group have completed the enrollment, and no dose-limiting 
toxicity was observed in all dose groups during the dose-limiting 
toxicity observation period. 
4.1 Overall Design 
The primary endpoint of this study is to compare the OS PFSs of 
HLX10 in combination with chemotherapy versus placebo in 
combination with chemotherapy, as assessed by an IRRC using RECIST 
v1.1 as evaluation criteria. 
Change OS to primary 
efficacy endpoint. 
4.1 Overall Design  
Figure 1: Schematic of 
study treatment 
1st Disease Progression  
The subject should re-consent and meet the following conditions: The 
subject (tending to receive 2nd line chemotherapy treatment 
subsequently) should re-consent and meet the following conditions: 
(1) Subjects who had received HLX10 or placebo in combination 
with chemotherapy, who may benefit from continuing 
HLX10/placebo treatment despite progression, will be able to 
receive HLX10 or placebo therapy in the post-PD treatment period 
With no clinical signs and symptoms (including worsening of laboratory 
findings) indicating a significant disease progression.  
To keep the study design 
consistent throughout the 
document. 

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(2) Subjects eligible for continued treatment in the post-PD 
treatment period, as judged by the investigator. A stable ECOG 
performance status score.  
(3) The subject should sign the supplementary informed consent 
form to receive investigational product with 2nd line chemotherapy. 
(4) The subject is clinically stable. No rapid disease progression or 
tumor progression requiring urgent alternative medical intervention at 
critical anatomical sites (e.g., spinal cord compression).  
(4) The major organ function meets the inclusion and exclusion criteria 
of this study.  
(5) The subject should sign an informed consent form again. 
Continue the treatment until persistent disease progression, worsening 
of symptoms due to disease progression, or intolerant toxicities 
Continue the treatment until the 2nd disease progression, intolerant 
toxicities, death, withdrawal of consent, or lost to follow-up. 
Continue the treatment until persistent disease progression, worsening 
of symptoms due to disease progression, or intolerant toxicities 
* Follow-Up Period includes safety follow-up and survival follow-
up. Patients who are not eligible for post-PD treatment will be 
followed up for safety and survival status. 
4.2 Scientific Rationale for 
Study Design 
Rationale for Post-PD 
Treatment 
Patients with ES-SCLC experience rapid tumor growth, fast clinical 
deterioration, and have an overall poor prognosis. First-line 
therapy with a platinum agent and etoposide has consistently 
demonstrated high response rates and significant clinical benefit. 
However, considering the limited availability and efficacy or greater 
toxicity of treatment options after withdrawal, and for better 
adaptation to standard clinical practice, subjects may be considered 
for subsequent treatment assignment blinded beyond radiographic 
disease progression per RECIST 1.1, at the discretion of the 
To clarity the rationale for 
post-PD treatment. 

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investigator, after appropriate discussion with the patient and 
obtaining informed consent. 
In addition, conventional response criteria may not adequately 
assess the activity of immunotherapeutic agents because disease 
progression (by initial radiographic evaluation) does not necessarily 
reflect therapeutic failure. Related research shows that shorter 
treatment increases the risk of relapse or progression, and there are 
potential benefits to patients receiving longer IO (Immunotherapy) 
treatment21. Because of the potential for pseudoprogression/tumor-
immune infiltration, this study will allow patients to remain on 
treatment after apparent radiographic disease progression per 
RECIST 1.1, provided all criteria meet post-PD treatment 
conditions. 
4.4 End of Study Definition 
“The end of the study, defined as the final analysis of PFS OS, will be 
performed when a target number of PFS OS events (approximately 
336342) are observed...” 
To redefine End of Study due 
to change of primary endpoint  
5.1 Inclusion Criteria #2 
Male or female aged ≥ 18 between 18 to 75 (inclusive) years at the time 
of signing the ICF. 
Remove upper age limit as 
patients older than 75 years 
represent a substantial 
proportion of patients with 
ES-SCLC. 
5.1 Inclusion Criteria #6 
Note: Measurable lesions are not from previously irradiated sites. If the 
lesion at the previously irradiated site is the only selectable target lesion, 
a radiological assessment showing significant progression of the 
irradiated lesion should be provided by the investigator. 
anteroposterior images showing significant progression of the lesion 
should be provided by the investigator. 
Wording re-edit. 

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Brief Rationale 
5.1 Inclusion Criteria #12 
≤ 1.5×ULN; 
In case of > 1.5 × ULN, creatinine clearance ≥ 6050 mL/min 
Increase the value of 
creatinine clearance to take 
into account the renal toxicity 
of carboplatin. 
5.1 Inclusion Criteria #13 
Agree to use birth control methods with an annual failure rate of <1% or 
maintain abstinence (avoid heterosexual intercourse) (from the signing 
of informed consent form (ICF) to at least 6 months 120 days after the 
final dose of study drug or at least 150 days after the final dose of 
chemotherapy drug) (birth control methods with an annual failure rate 
of <1% include bilateral tubal ligation, male sterilization, proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine contraceptive devices and copper containing intrauterine 
contraceptive devices or condoms) 
Extending of time limits of 
using birth control methods or 
maintain abstinence after the 
final dose of study drug 
5.1 Inclusion Criteria #14 
Male patients must: agree to abstinence (avoid heterosexual intercourse) 
or take contraception measures as follows: male patients with a pregnant 
partner or a partner with of childbearing potential must remain abstinent 
or use a condom to prevent embryonic exposure during study 
treatment chemotherapy treatment (carboplatin or etoposide) and for at 
least 150 days6 months after the last dose of study drug chemotherapy. 
Periodic abstinence (e.g., contraceptive methods based on calendar day, 
ovulation, basal body temperature or post-ovulation) and external 
ejaculation are ineligible methods of contraception. 
Extending of time limits of 
abstinence or use a condom to 
prevent embryonic exposure 
after the last dose of study 
drug. 
 
 6.2 Dosing Regimen 
Preparation/Handling/Storag
e/Accountability 
Other study drugs: chemotherapy 
• Etoposide: 100 mg/m2, IV infusion, on Days 1, 2, and 3 of each 
cycle. On Day 1, etoposide shall be administered following infusion 
of carboplatin. 
To clarify the order of 
adminstration of study drugs 
6.5 Concomitant Therapy 
6.5.3 Subsequent Anti-Cancer Therapy Status 
Adding subsequent anti-
cancer therapy status, to 

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The investigator or his/her qualified designee will review all new 
anti-cancer therapy initiated after the discontinuation of trial 
treatment. If the subject continues the post-PD treatment, he/she 
must choose to receive 2nd line chemotherapy. The preferred 2nd line 
chemotherapy was determined by the investigators following the 
NCCN /or ESMO guidelines and communicated as such to the 
subjects who chose to continue the Post-PD treatment. Any other 
anti-PD1 and anti-PD-L1 therapy are not allowed.  
clarify the concomitant 
therapy in post-PD treatment 
6.6 Dose modification  
In the event of intolerance to etoposide/carboplatin, doses may be 
adjusted twice in accordance with the prescribing information of 
carboplatin and etoposide and local treatment standards. Once reduced, 
the dose cannot be increased back to 100%. 
Make adjustment in” Non-hematological toxicities” in both text and 
table for recommended carboplatin dose modification 
To make adjustment to 
recommended dose 
modification. 
7.1.2 Management of 
premature discontinuations 
All subjects who discontinue the trial prematurely (except patients who 
withdraw informed consent) shall undergo an EOT visit and be 
followed up for safety. 
To exclude subjects who 
withdraw their informed 
consent from the EOT visit 
and safety follow-up. 
8.2.4 Follow-Up period 
During the survival follow-up period, subjects without PD and not 
receiving any other anti-tumor therapy should return to the hospital 
according to the established schedule for radiologic assessment should 
be followed up until PD, initiation of a new anti-tumor therapy, ICF 
withdrawal, death, the patient is lost to follow-up, study termination 
by the sponsor, or study completion, whichever occurs first.; while 
subjects experiencing PD or undergoing any other anti-tumor therapy 
just need to be followed up for survival status by telephone call once 
every 12 weeks (±7 days). 
To update the condition of 
survival follow up  

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Brief Rationale 
8.4 Safety Assessment 
The structure and wording were re-edited, changes are listed below： 
1. Any death confirmed to be PD-induced should be reported as an SAE 
and reported to the clinical research associate (CRA)/clinical site 
manager (CSM), the sponsor, or a representative of the sponsor 
within 24 hrs. to the sponsor at the next monitoring visit. It should be 
documented but not reported as an SAE. 
2. Insert a section “8.4.2. 1 Drug-induced liver injury, (DILI)” 
 
3. 8.4.3. Documentation of AEs. All AEs occurring in a period from 
signing ICF (either main or supplementary) through 90 days after the 
final administration of the study drug should be documented in 
corresponding AE pages in EDC. If a subject starts a new 
antineoplastic therapy during the AE collection period, only 
information on AEs related to study treatment are documented 
after the new antineoplastic therapy. The investigator shall provide all 
detailed information required to be completed, including date of onset, 
severity, action, outcome, and causality to the study drug. When 
collecting AE data, one has better recording diagnosis information (if 
possible), rather than recording a number of signs and symptoms. 
However, if a diagnosis is known but the patient still has other 
symptoms or signs not contributing to such diagnosis, then each 
symptom or sign should be documented separately. 
 
4. Add AESI as follows: AESIs are events of scientific and medical 
concern related to use of the investigate drug that may need to be 
closely monitored and communicated to sponsors by investigators. 
AESI can be a serious or non-serious event. The AESI expedited 
To rearrange this section 
according to the updated 
Pharmacovigilance rules. 
 

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Brief Rationale 
report enables continuous monitoring of these events in order to 
describe and understand their association with the drug used in the 
study.  
In this study, AESI include infusion reaction (infusion-related 
adverse reactions, IRR) and immune-related adverse events (irAE). 
5. Each fertile subject shall take appropriate contraceptive measures in a 
period from signing ICF through at least120 days 6 months after the 
final dose of the study drug and in at least 150 days 6 months after the 
final dose of chemotherapy drug. 
6. The investigator will evaluate whether causality between the study 
drug and the AE is "definitely related", "possibly related", "unlikely 
related", "definitely unrelated", or "not evaluable unknown". AEs other 
than "unlikely related" and "not related" are recorded as adverse 
reactions. Any AE without given causality to the study drug will be 
deemed as "possibly related" to the study drug. 
7. All AEs and SAEs that occur in each subject throughout the 
study should be actively followed up. Even if such events persist 
after discontinuation or study termination, the investigator should 
follow them up until all events meet any of the following criteria: 
All AEs occurring in a period from signing ICF through 90 days after 
the final dose of the study drug should be followed up until any of the 
following circumstances occurs: 
9.4.1 Efficacy Analyses 
Analyses of the primary efficacy endpoint and the secondary efficacy 
endpoints will be performed for both the ITT and PPS, mainly on the 
ITT. analyses of the secondary and exploratory efficacy endpoints will 
be performed for the ITT only. 
To correct population for 
analyses due to changing of 
endpoints. 
9.4.1.1 Analysis of primary 
efficacy endpoint 
9.4.1.1 Analysis of primary efficacy endpoint 
Overall survival (OS): Defined as a period from randomization 
through death regardless of causality. Data of patients without a 
To keep consistency in the 
document text after changing 
of endpoints. 

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Section # and Name 
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Brief Rationale 
9.4.1.2 Analysis of 
secondary efficacy 
endpoints 
death record will be censored on the last known survival date. 
Progression free survival (assessed by the IRRC as per RECIST v1.1): 
PFS is defined as a period from randomization initiation to the first 
documentation of PD or death regardless of causality (whichever occurs 
first). Data of subjects with neither PD nor death will be censored on the 
day of the final valid tumor evaluation. Data of surviving subjects not 
undergoing any tumor assessment during the study will be censored on 
the day of randomization. Data of subjects who have no PD reported 
and initiate any antitumor therapy not specified in the protocol will be 
censored on the day of the last evaluable tumor assessment prior to the 
initiation of subsequent antitumor treatment. The between-group 
comparison of OS PFS is performed by a stratified log-rank test with 
the following stratification factors: PD-L1 expression level (negative: 
TPS <1%, positive: TPS ≥1%, or not evaluable/not available), brain 
metastasis (yes versus no), and age (≥ 65 years versus < 65 years); a 
stratified COX proportional risk model will be used to estimate HR and 
its 95% CI; the Kaplan-Meier method will be used to estimate the 
median, and the Kaplan–Meier curve will be plotted. 
9.4.1.2 Analysis of secondary efficacy endpoints 
Progression free survival (assessed by the IRRC as per RECIST 
1.1): PFS is defined as a period from randomization initiation to the 
first documentation of PD or death regardless of causality 
(whichever occurs first). Censor rules will be defined in SAP. 
Overall survival (OS): Defined as a period from randomization through 
death regardless of causality. Data of patients without death record will 
be censored on the last known survival date. Data of patients not 
providing any follow-up information will be censored on the 
randomization day. The PFSOS will be analyzed using the same method 
as that for primary efficacy endpoints. 
 
 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
 
9.4.1.3 Subgroup analyses 
Add the new section as 9.4.1.3 “Subgroup analyses” 
To assess the consistency of 
the study PFS and OS, results 
in subgroups will be 
examined. 
9.5 Interim Analyses 
Add the stopping boundary for OS interim and final analyses 
To add description per ICH-
E9  
10.10 Appendix 8 
Replaced Appendix 8 with NCCN Guidelines®: Management of 
Immunotherapy-Related Toxicities (2019 V2) 
To update the guidelines  
Throughout the protocol 
Some editorial changes were made. 
To keep the consistency 
throughout protocol. 
 
Overall Rationale for the Amendment 1: 
The structure of protocol Version 2.0 was updated and rearranged based on Version 1.0 in accordance with ICH guidance. Additional 
changes made during development of Version 2.0 are clarified as follows. 
Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
Title page  
A Randomized, Double-Blind, Multicenter, Phase III Study to Evaluate 
Compare Clinical Efficacy and Safety of HLX10 (Recombinant 
Humanized Anti-PD-1 Monoclonal Antibody Injection) in Combination 
with Chemotherapy (Carboplatin-Etoposide) in Previously Untreated 
Patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC) 
A short title was added. 
To include the objective in 
the title for clarifying the 
purpose and objective of 
the study. 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
Title Page, Regulatory 
Agency Identifying 
Number(s) 
NMPA Approval Document Number: 2018L02201, EudraCT 
Number: 2019-003063-21 
To add the NMPA approval 
document Number and 
EudraCT Number for this 
protocol. 
Investigator Agreement 
Page 
Updated the Agreement pages, one page for Principal Investigator, the 
other page for Global Coordinating Investigator. 
To provide agreement 
pages for Principal 
Investigator and the Global 
Coordinating Investigator. 
1. Protocol Summary 
Inserted a header of section 1: protocol summary 
To give an overview of the 
protocol. 
1.3 Schedule of Activities 
(SoA) footnote #11 
8.1 Tests and Evaluations 
during the Study 
Laboratory Tests 
total cholesterol, total protein, albumin; urinalysis items include specific 
gravity, urine leukocytes, pH, urine glucose, urine protein, ketone body 
and blood cells. 
To include urine leukocytes 
for urinalysis to monitor the 
subject’s immune response.  
1.1 Synopsis 
3 Secondary Efficacy 
Objective 
Progression-free survival (PFS) assessed by the investigator based on 
RECIST v1.1 and modified RECIST criteria a modified RECIST 1.1 
for immune-based therapeutics (termed iRECIST). 
To add consensus guideline 
(iRECIST) developed for 
the use in cancer 
immunotherapy trials for 
the evaluation of PFS. 
9.4.1.2 Analysis of 
Secondary Efficacy 
Endpoints 
PFS assessed by the investigator as per RECIST v1.1 and iRECIST: Its 
statistical method is the same as that for primary efficacy endpoints. 
10.4 Appendix 2-2 
“Modified Response Evaluation Criteria in Solid Tumors” was replaced 
with “iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics”. 
1.1 Synopsis 
3 Objectives and Endpoints 
Exploratory 
• Exploratory population pharmacokinetic (PopPK) analysis  
To delete the secondary 
objective of “Exploratory”. 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
1.1 Synopsis 
1.2 Shema 
4.1 Overall Design 
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding 
9.4.1.1 Analysis of primary 
efficacy endpoint 
Randomization are stratified by PD-L1 expression level (negative: 
tumor proportion scores [TPS] <1%, positive: TPS ≥1%, or not 
evaluable/not available), brain metastasis (yes versus no), and age (≥ 
65 years versus < 65 years) 
To define the limits for 
PD-L1 expression levels 
specifically. 
1.3 SoA footnote #8 
The height measurement is performed only at screening; vital signs 
include body temperature, pulse, respiratory rate, and blood pressure. 
Body weight is measured before each dose, and no dose adjustment of 
the study drug is required if the subject's body weight differs ≤ 10% 
from the reference value of the current dose during the study, otherwise 
the dose should be recalculated. This new body weight will serve as the 
baseline value for subsequent body weight measurements. Body weight 
will be measured prior to drug administration at each treatment 
cycle. If the change in the subject’s body weight from baseline 
during the study is ≤10%, dose adjustment of study drug will not be 
required, and if the weight change is >10%, the dose of study drug 
must be recalculated. 
To clarify the timing of 
bodyweight measurement 
to allow an adjustment of 
the administration dose. 
1.3 SoA footnote #16 
Patients must provide tumor tissues that meet the requirements for 
the determination of PD-L1 expression levels. It is recommended to 
provide formalin-fixed tumor tissue samples, paraffin-embedded 
tumor specimens (preferred), formalin-fixed paraffin embedded 
(FFPE), tumor specimens or newly prepared unstained serial tissue 
sections (preferably adhesive slides) within 6 months prior to the 
first dose of study medication. A relevant pathology report must 
also be provided for the above specimens. To the extent possible, 
formalin-fixed paraffin-embedded (FFPE) tumor samples (paraffin 
To clarify the tumor tissue 
assessment procedure and 
purpose. 

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blocks or unstained sections) collected at or after the diagnosis of ES-
SCLC and within 6 months prior to the start of study medication or 
pathological reports of such specimens should be provided. In case of 
no archived tumor tissue samples available, it is recommended to 
conduct a fresh tumor lesion biopsy at screening to obtain the 
corresponding tumor sample (the number of specimens required is 
based on the biopsy result). Tumor tissue sections will be used for 
immunohistochemical analysis to evaluate the expression level of PD-
L1 in tumor cells and tumor-infiltrating immune cells and other 
purposes. Freshly collected specimens, radical resections, core needle 
biopsy, excisions, incisions, punch or clamp biopsies are acceptable 
(newly obtained tissues are preferred). Fine-needle aspirations (i.e., 
samples that lack a complete tissue structure and provide only cell 
suspension and/or cell smear), brush biopsies, and cell pellet samples 
from pleural or peritoneal effusions are unacceptable. For detailed 
requirements for tissue samples, see the laboratory manual. 
3 Objectives and Endpoints 
Primary endpoint Primary Efficacy Endpoint 
Secondary endpoint Secondary Efficacy Endpoint 
• Incidence rates of AEs and SAEs 
• Pharmacokinetics (PK): serum HLX10 concentration 
• Immunogenicity evaluation: positive anti-drug antibody (ADA) rate 
• Relationship between PD-L1 expression level, MSI, TMB in tumor 
tissues and efficacy 
• Quality of life assessment 
Safety Endpoints 
• 
Adverse events (AEs) (including serious adverse events 
[SAEs]), laboratory tests (routine blood test, blood chemistry, 
coagulation function, urinalysis, thyroid function), 12-lead 
Endpoints classification 
were re-organized for better 
readability and to ensure the 
clarification of the 
endpoints.  

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Section # and Name 
Description of Change(s) 
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Brief Rationale 
electrocardiogram (12 lead ECG), vital signs, and physical 
examination, etc. 
 
PK Endpoint 
• 
Concentration of HLX10 in serum 
Immunogenicity Endpoint 
• 
HLX10 anti-drug antibody (ADA) positive rate 
 
Biomarker Endpoint 
• 
Relationship between PD-L1 expression, microsatellite 
instability (MSI), tumor mutation burden (TMB) in tumor 
tissue and efficacy. 
 
Quality of life assessment 
4.Study Design  
Inserted section 4.4 End of study definition, and description started 
from “The end of the study is defined as the final analysis of PFS 
will be performed when a target number of PFS events 
(approximately 336)…etc.” 
To clarify the definition of 
the end of the study. 
5.1 Inclusion Criteria # 2  
2. Male or female between 18 to 75 (inclusive) years at the time of 
signing the ICF. 
To clarify the gender 
requirement of the subjects. 
5.1 Inclusion Criteria # 7 
Patients must provide tumor tissues that meet the requirements for the 
determination of PD-L1 expression levels. Subjects are assessed for an 
evaluable PD-L1 expression category (negative: TPS <1%, positive: 
TPS ≥1%, or not evaluable/not available) by the central laboratory for 
randomization. 
To define the limits for 
PD-L1 expression levels 
specifically. 
5. study population  
1. Inserted section 5.3 Lifestyle Consideration and description of “No 
restrictions are required.” 
1. To clarify the concerns to 
the subject’s lifestyle and to 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
2. Inserted section 5.4 Screen failures and description started from 
“Screen failures are defined as participants who consent to 
participate in the clinical study but are not subsequently entered in 
the study. A minimal set of screen failure…etc.” 
follow the common 
protocol template structure. 
2. To clarify the definition 
of screen failures and the 
information required. 
6. Study Intervention  
Inserted the new header of Section 6 Study Intervention and 
description started from “Study drug is defined as any investigational 
interventions, marketed products…etc.” 
To clarify the definition of 
the study drug and to 
follow the common 
protocol template structure. 
6.1 Study Interventions 
Administered 
Name : Recombinant anti-PD-1 humanized monoclonal antibody 
injection (HLX10) 
Formulations: Liquid 
Specifications: 100 mg (10 mL)/vial 
To clarify the formulation 
of the study drug. 
6.2 Dosing Regimen 
Preparation/Handling/Stora
ge/Accountability 
Investigational/reference product: 
• HLX10: 4.5 mg/kg, IV infusion for 30 to 90 minutes, administered 
on Day 1 of each cycle, once every 3 weeks (21 days). 
• Placebo: IV infusion, administered on Day 1 of each cycle, once 
every 3 weeks (21 days). 
The infusion of study drug is completed between 30 mins and 90 
mins if there is not any infusion reaction. 
To define the completion of 
study drug infusion 
duration.  
6.3 Measure to Minimize 
Bias: Randomization and 
Blinding 
1.Inserted the new header of Section 6.3 Measure to Minimize Bias: 
Randomization and Blinding and description started from “All 
subjects will be centrally randomized the IWRS/IVRS. Each subject 
will be assigned a unique number (randomization number)…etc.’ 
 
2. Inserted subtitle of Blinding and the description started from. “ 
The blinding will be performed by the Data Management and 
Statistical Unit during study treatment…etc.” 
To clarify the randomizing 
and blinding procedure to 
minimize bias. 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
6.7 Intervention After the 
End of the Study 
Inserted the new header of Section 6.7: Intervention After the End of 
the Study and description started from “Subjects will receive 
standard of care…etc.” 
To clarify the treatment 
subject will receive after 
the completion of the study 
and to follow the common 
protocol template structure.  
7. Discontinuation of Study 
Intervention and Participant 
Discontinuation 
Inserted the section 7.2 and 7.3. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
7.3 
Loss of Participants to Follow-Up 
To clarify the 
discontinuation/ 
withdrawal, and lost to 
follow- up from the Study. 
8.1 Tests and Evaluations 
during the Study 
Table 5 and footnotes 
Routine blood test 
 
Basophils (BAS&BAS%) 
 
Eosinophils (EOS&EOS%) 
 
Lymphocytes (LYM&LYM%) 
 
Monocytes (MON&MONO%) 
 
Neutrophils (NEU&NEUT%) 
Biochemistry 
 
Fasting blood glucose (GLU) 
Urinalysis 
 
Urine Specific gravity (SG) 
 
Urine leukocytes 
 
Urine pH value 
 
Urine protein (U PRO) 
 
Urinary glucose (U GLU) 
 
Ketones (KET) 
 
Urine occult blood (BLO) 
 
Microscopic examination of white blood cells (U-WBC) 
 
Microscopic examination of red blood cells (U-RBC) 
Coagulation function 
 
Prothrombin time (PT) or international normalized ratio (INR) 
To update Table 5 and 
footnotes to clarify the 
variables to be collected 
during laboratory 
examination.  

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Brief Rationale 
 
Activated Partial thromboplastin time (APTT) 
 
Footnote  
c. Thyroid function tests will be performed during screening and 
within 3 days prior to drug administration every 2 treatment cycles 
during the treatment period 
 
**Routine blood test, blood chemistry, coagulation function and 
urinalysis must be performed at screening and within 3 days prior 
to drug administration every treatment cycle. When the 
aforementioned laboratory tests and study drug administration are 
scheduled on the same day, the study drug administration must be 
scheduled only after the test results are obtained. Routine blood 
tests will be performed on Day 8 (±3 days) of each treatment cycle 
during treatment with carboplatin, and close attention should be 
paid to bone marrow suppression. 
8.1 Tests and Evaluations 
during the Study  
Tumor imaging 
Imaging studies in this trial include computed tomography or magnetic 
resonance imaging (CT/MRI). Images will be assessed by the IRRC 
according to RECIST v1.1 (see Appendix 2-1 Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1)) and modified RECIST 
iRECIST criteria (see Appendix 2-2: iRECIST: guidelines for 
response criteria for use in trials testing immunotherapeutics). 
To keep consistent with the 
study endpoint assessment 
criteria, changed from 
“RECIST V1.1 and 
modified RECIST” to 
“RECIST V1.1 and 
iRECIST”. 
8.1 Tests and Evaluations 
during the Study 
Biomarker sample 
collection 
At screening, blood samples and tumor tissue samples must be 
collected for biomarkers detecting.  
Inserted the description started from: “Patients must provide tumor 
tissues that meet the requirements for the determination of PD-L1 
expression levels...etc.” 
To update the requirement 
of tissue collection 
according to inclusion 
criteria #7. 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
Deleted the description started from: “As far as possible, FFPE tumor 
samples…etc.” 
9.3 Populations for 
Analyses 
The definition of the enrolled population was added. 
Definition wordings of other populations including ITT set, PPS, SS and 
PKS were re-organized. 
To clarify and define the 
populations to be analyzed 
in the study.  
9.5 Interim Analysis 
Wordings were re-organized. 
To clarify the definition of 
the interim analysis.  
9.5.1 Independent Data 
Monitoring Committee 
(IDMC) 
10.1.3 Financial Disclosure 
10.1.11 Source Documents 
10.1.14 Protocol Approval 
and Amendment 
Several sections were added. 
To adhere to the ICH 
guidance. 
10.2 Appendix 1 
The version of Common Terminology Criteria for Adverse Events 
(CTCAE) is updated from v4.03 to v5. 
To update the version of 
CTCAE. 
10.5 Appendix 3 
Quality of Life Scale EORTC QLQ-C30, EQ-5D-5L and EORTC QLQ-
LC13 are updated. 
To update the Quality of 
Life Scale. 
Throughout the protocol 
Some editorial changes were made. 
To keep the consistency 
throughout protocol. 

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Table of Contents 
 
Investigator Agreement Page ......................................................................................................................................... 2 
Investigator Agreement Page ......................................................................................................................................... 3 
Sponsor Signatory ......................................................................................................................................................... 4 
Protocol Amendment Summary of Changes Table ....................................................................................................... 5 
Table of Contents ........................................................................................................................................................ 50 
1 
Protocol Summary ................................................................................................................................................ 55 
1.1 Synopsis ............................................................................................................................................................... 55 
1.2 Schema  ............................................................................................................................................................... 61 
1.3 Schedule of Activities (SoA) ............................................................................................................................... 62 
2 
Introduction .......................................................................................................................................................... 74 
2.1 Background .......................................................................................................................................................... 74 
2.2 Study Rationale .................................................................................................................................................... 75 
2.2.1 
Preclinical Study of HLX10 ................................................................................................................... 76 
2.2.2 
Clinical Study of HLX10 ....................................................................................................................... 82 
2.3 Benefit/Risk Assessment ...................................................................................................................................... 82 
2.3.1 
Potential benefits .................................................................................................................................... 82 
2.3.2 
Identified and potential risks .................................................................................................................. 83 
2.3.3 
Overall benefits: risk and ethical assessment ......................................................................................... 85 
3 
Objectives and Endpoints ..................................................................................................................................... 86 
4 
Study Design ........................................................................................................................................................ 87 
4.1 Overall Design ..................................................................................................................................................... 87 
4.2 Scientific Rationale for Study Design .................................................................................................................. 90 
4.3 Justification for Dose ........................................................................................................................................... 91 
4.4 End of Study Definition ....................................................................................................................................... 92 
4.5 Unblinding ........................................................................................................................................................... 92 

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5 
Study Population .................................................................................................................................................. 92 
5.1 Inclusion Criteria .................................................................................................................................................. 92 
5.2 Exclusion Criteria ................................................................................................................................................ 95 
5.3 Lifestyle Considerations....................................................................................................................................... 97 
5.4 Screen Failures ..................................................................................................................................................... 97 
6 
Study Drug ........................................................................................................................................................... 98 
6.1 Study Interventions Administered ........................................................................................................................ 98 
6.2 Dosing Regimen Preparation/Handling/Storage/Accountability .......................................................................... 99 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................ 101 
6.4 Study Treatment Compliance ............................................................................................................................. 101 
6.5 Concomitant Therapy ......................................................................................................................................... 102 
6.5.1 
Prohibited Concomitant Therapies ....................................................................................................... 102 
6.5.2 
Permitted Medications/Treatments ...................................................................................................... 103 
6.5.3 
Subsequent Anti-Cancer Therapy Status ............................................................................................. 103 
6.6 Dose Modification .............................................................................................................................................. 103 
6.7 Intervention after the End of the Study .............................................................................................................. 107 
7 
Discontinuation of Study Intervention, Participant Discontinuation, and Study Termination ........................... 108 
7.1 Discontinuation of Study Intervention ............................................................................................................... 108 
7.1.1 
Reasons for Premature Discontinuation ............................................................................................... 108 
7.1.2 
Management of premature discontinuations ........................................................................................ 108 
7.2 Participant Discontinuation/Withdrawal from the Study ................................................................................... 109 
7.3 Loss of Participants to Follow-Up ..................................................................................................................... 109 
7.4 Premature Termination of Study and Site Closure ............................................................................................. 110 
8 
Study Assessments and Procedures .................................................................................................................... 110 
8.1 Tests and Evaluations during the Study ............................................................................................................. 110 
8.2 Visit schedule ..................................................................................................................................................... 119 
8.2.1 
Screening Period (day -28 to day -1) ................................................................................................... 119 
8.2.2 
Treatment Period .................................................................................................................................. 120 

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8.2.3 
End-of-Treatment Visit ........................................................................................................................ 123 
8.2.4 
Follow-up Period ................................................................................................................................. 124 
8.3 Study Assessments ............................................................................................................................................. 126 
8.4 Safety Assessment .............................................................................................................................................. 127 
8.4.1 
Adverse Events .................................................................................................................................... 127 
8.4.2 
Serious Adverse Events ....................................................................................................................... 128 
8.4.3 
Documentation of AEs ......................................................................................................................... 131 
8.4.4 
Reporting of SAEs ............................................................................................................................... 134 
8.4.5 
Follow-up of AEs ................................................................................................................................. 135 
8.4.6 
Adverse event of special interest (AESI) ............................................................................................. 135 
8.4.7 
Pregnancy ............................................................................................................................................. 136 
9 
Statistical Considerations ................................................................................................................................... 137 
9.1 Statistical Hypotheses ........................................................................................................................................ 137 
9.2 Sample Size Determination ................................................................................................................................ 137 
9.3 Populations for Analyses.................................................................................................................................... 138 
9.4 Statistical Analyses ............................................................................................................................................ 139 
9.4.1 
Efficacy Analyses ................................................................................................................................ 139 
9.4.2 
Safety Analyses .................................................................................................................................... 141 
9.4.3 
Pharmacokinetic Analyses ................................................................................................................... 141 
9.4.4 
Immunogenicity Analyses.................................................................................................................... 141 
9.4.5 
Biomarker Analyses ............................................................................................................................. 141 
9.4.6 
Analysis of Subject-reported Outcome Variables ................................................................................ 142 
9.5 Interim Analyses ................................................................................................................................................ 142 
9.5.1 
Independent Data Monitoring Committee (IDMC) ............................................................................. 142 
10 Supporting Documentation and Operational Considerations ............................................................................. 143 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................. 143 
10.1.1 
Data Management ................................................................................................................................ 143 
10.1.2 
Regulatory and Ethical Considerations ................................................................................................ 144 

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10.1.3 
Financial Disclosure ............................................................................................................................. 144 
10.1.4 
Informed Consent Process ................................................................................................................... 144 
10.1.5 
Data Protection .................................................................................................................................... 145 
10.1.6 
GCP training ........................................................................................................................................ 145 
10.1.7 
Data Quality Assurance ....................................................................................................................... 145 
10.1.8 
Audit .................................................................................................................................................... 146 
10.1.9 
Data Management/Coding ................................................................................................................... 146 
10.1.10 
Documentation and Retention of Study Data ....................................................................................... 147 
10.1.11 
Source Documents ............................................................................................................................... 147 
10.1.12 
Premature Termination of Study and Site Closure ............................................................................... 147 
10.1.13 
Confidentiality and Publication Policy ................................................................................................ 148 
10.1.14 
Protocol Approval and Amendment..................................................................................................... 148 
10.1.15 
Liability and Insurance ........................................................................................................................ 149 
10.2 Appendix 1: Common Terminology Criteria for Adverse Events ..................................................................... 152 
10.3 Appendix 2-1: Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ................................................... 153 
10.4 Appendix 2-2: iRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics ........... 160 
10.5 Appendix 3: Quality of Life Scale EORTC QLQ-C30, EQ-5D-5L, EORTC QLQ-LC13 ................................. 183 
10.6 Appendix 4: Eastern Cooperative Oncology Group (ECOG) - Performance Status Scale ................................ 190 
10.7 Appendix 5: Fridericia Correction Formula ....................................................................................................... 191 
10.8 Appendix 6: Cockcroft and Gault Formula ........................................................................................................ 192 
10.9 Appendix 7: Heart Functional Classification of New York Heart Association .................................................. 193 
10.10 
Appendix 8: Guidelines for Dose Modification and Treatment for Immune-Related Toxicity ........... 194 
10.11 
Appendix 9: Prohibited Traditional Chinese Medicines ...................................................................... 218 
10.12 
Appendix 10: Abbreviations ................................................................................................................ 219 
11 References .......................................................................................................................................................... 221 
 
 
 

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List of Tables 
Table 1: Carboplatin Dose Modifications for Hematological Toxicities ................................................................... 106 
Table 2: Carboplatin Dose Modifications Based on Non-Hematological Toxicities in Previous Treatments ........... 107 
Table 3: Etoposide Dose Modification for Subjects with Renal Impairment ............................................................ 107 
Table 4: Laboratory Tests .......................................................................................................................................... 115 
Table 5: Blood Sample Collection Time Points ........................................................................................................ 117 
Table 6: The abnormal liver function test (LFT) needed to be reported as an SAE .................................................. 130 
Table 7: CTCAE Description .................................................................................................................................... 132 
Table 8: Evaluation of Causality Between AE and Study Drug ................................................................................ 134 
Table 9 Analysis Timing and Stopping Boundary of Overall Survival ..................................................................... 142 
Table 10: Evaluation of Target Lesions ..................................................................................................................... 156 
Table 11: Evaluation of Non-Target Lesions ............................................................................................................. 157 
List of Figures 
Figure 1: Schematic of study treatment ....................................................................................................................... 89 
 

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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A Randomized, Double-Blind, Multicenter, Phase III Study to Compare Clinical 
Efficacy and Safety of HLX10 (Recombinant Humanized Anti-PD-1 Monoclonal Antibody 
Injection) in Combination with Chemotherapy (Carboplatin-Etoposide) in Previously Untreated 
Patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC) 
Sponsor Study No.: HLX10-005-SCLC301 
Phase: Phase III 
Sponsor: Shanghai Henlius Biotech, Inc. 
Rationale: 
Based on the considerable benefits of PD-1/PD-L1 inhibitors in patients with tumors, Shanghai 
Henlius Biotech, Inc. has developed an innovative monoclonal antibody HLX10 targeting PD-1. 
Based on preclinical animal studies of HLX10, it has the potential to treat a variety of different 
tumor types, either as monotherapy or in combination with chemotherapy. The present study is 
planned in previously untreated patients with ES-SCLC worldwide to compare clinical efficacy 
and safety of HLX10 (recombinant anti-PD-1 humanized monoclonal antibody injection) in 
combination with chemotherapy (Carboplatin-Etoposide). 

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Objectives and Endpoints 
Objective 
Endpoint 
Primary  
To compare the clinical 
efficacy of HLX10 in 
combination with 
chemotherapy versus 
placebo in combination 
with chemotherapy in 
previously untreated 
patients with ES-SCLC. 
Primary Efficacy Endpoint 
 Overall survival (OS) 
Secondary Efficacy Endpoints 
 Progression-free survival (PFS) (assessed by the 
independent radiology review committee [IRRC] based on 
Response Evaluation Criteria in Solid Tumors [RECIST] 
1.1) 
 PFS (assessed by the investigator based on RECIST 1.1 
and a modified RECIST 1.1 for immune-based 
therapeutics [termed iRECIST])  
 PFS2 (assessed by the investigator based on RECIST 1.1) 
 Objective response rate (ORR) (assessed by the IRRC and 
investigator based on RECIST 1.1) 
 Duration of response (DOR) (assessed by the IRRC and 
the investigator based on RECIST 1.1) 
Secondary 
To compare the safety and 
tolerability of HLX10 in 
combination with 
chemotherapy versus 
placebo in combination 
with chemotherapy in 
previously untreated 
patients with ES-SCLC. 
 
To measure the exposure 
following HLX10 
administration. 
Safety Endpoints 
• 
Adverse events (AEs) (including serious adverse events 
[SAEs]), laboratory tests (routine blood test, blood chemistry, 
coagulation function, urinalysis, myocardial function and 
thyroid function), 12-lead electrocardiogram (12-lead ECG), 
vital signs, and physical examination, etc. 
Pharmacokinetic (PK) Endpoint 
• 
Concentration of HLX10 in serum 
Immunogenicity Endpoint 
• 
HLX10 anti-drug antibody (ADA) positive rate 
Biomarker Endpoint 
• 
Relationship between PD-L1 expression, microsatellite 
instability (MSI), tumor mutation burden (TMB) in tumor 
tissue and efficacy. 
Quality of life assessment 

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Overall Design: 
This is a randomized, double-blind, placebo controlled, clinical phase III study to compare the 
clinical efficacy, safety and tolerability of HLX10 or placebo in combination with chemotherapy 
in patients with previously untreated ES-SCLC, to collect PK parameters and to investigate the 
biomarker related to efficacy. 
Subjects in this study will be randomized to arm A or B at 2:1 ratio as follows: 
• Arm A (HLX10): HLX10 + chemotherapy (carboplatin-etoposide) 
• Arm B (control): placebo + chemotherapy (carboplatin-etoposide) 
Randomization is stratified by PD-L1 expression level (negative: tumor proportion scores [TPS] 
<1%, positive: TPS ≥1%, or not evaluable/not available), brain metastasis (yes versus no), and 
age (≥ 65 years versus < 65 years). 
After screening, subjects meeting the inclusion criteria and none of the exclusion criteria will be 
enrolled. Included subjects will be treated with HLX10 or placebo in combination with 
chemotherapy once every 3 weeks, until disease progression, death, intolerable toxicity, 
withdrawal of informed consent, or occurrence of other reasons specified in the protocol 
(whichever occurs first). 
Initial treatment should be discontinued when they have evidence of disease progression as 
assessed per RECIST 1.1. If a subject has 1st disease progression and is clinically stable, and 
tends to receive 2nd line chemotherapy treatment subsequently (the selection of 2nd line 
chemotherapy may refer to the NCCN guidelines or the ESMO guidelines), it is at the discretion 
of the investigator to continue treating the subject with blinded HLX10 or placebo assignment 
per protocol in addition to the 2nd line chemotherapy, until the 2nd disease progression, intolerable 
toxicity, death, withdrawal of consent, or lost to follow-up. Subjects who permanently 
discontinue initial treatment due to an adverse event, withdrawal of consent, or for any reason 
other than disease progression, will not be eligible for the Post-Progressive Disease treatment.  
Subjects who meet the following conditions may continue the treatment after appropriate 
discussion with the subject and obtaining the supplementary informed consent. 
1. Subjects who had received HLX10 or placebo in combination with chemotherapy, and 
who may benefit from continuing HLX10/placebo treatment despite progression, will be 
able to receive HLX10 or placebo therapy in the post-PD treatment. 

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2. Subjects eligible for continued treatment in the post-PD treatment period, as judged by the 
investigator. 
3. The subject should sign the supplementary informed consent form to receive 
investigational product with 2nd line chemotherapy. 
4. The subject is clinically stable, defined as: 
a) With no clinical signs and/or symptoms (including worsening of laboratory findings) 
that might indicate disease progression. 
b) A stable Eastern Cooperative Oncology Group (ECOG) performance status score. 
c) No rapid disease progression or tumor progression requiring urgent alternative 
medical intervention at critical anatomical sites (e.g., spinal cord compression). 
Number of Participants: 
Approximately 567 (378 for HLX10 and 189 for placebo). 
Treatment Groups and Duration: 
This study is divided into three periods: Screening period (28 days), treatment period (initial 
treatment and post-PD treatment [Optional] until disease progression, death, intolerable toxicity, 
withdrawal of informed consent, or occurrence of other reasons specified in the protocol, 
whichever occurs first), and Follow-up period (including safety follow-up and survival follow-
up). 
The study drugs including HLX10/placebo and chemotherapy drugs are administered every 3-
week (21-day) cycle as follows: 
Investigational product: HLX10 or placebo 
• HLX10, intravenous (IV) infusion, 4.5 mg/kg, administered on Day 1 of each 3-week 
(21 day) cycle. 
The infusion of investigational product is completed between 30 mins and 90 mins if there is no 
any infusion reaction. 
Other study drugs: combined chemotherapy 
The following regimen will be given every 21-day (3-week) cycle for a maximum of 4 cycles. 
• Etoposide: 100 mg/m2, IV infusion, on Days 1, 2, and 3 of each cycle. 

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• 
Carboplatin: Area under the concentration-time curve (AUC) = 5, IV infusion, on Day 1 of 
each cycle up to a dose of 750 mg. On Day 1, etoposide shall be administered following 
infusion of carboplatin. 
Refer to Figure 1 "Schematic of study treatment" for the regimen of each treatment arm. On 
Day 1 of dosing in each treatment cycle, subjects will be given HLX10 or placebo intravenously 
first, followed by intravenous carboplatin + etoposide. Vital signs will be closely monitored 
during the administration. HLX10 or placebo is administered via a blinded infusion, carboplatin 
+ etoposide (up to 4 cycles) via an open-label infusion, and subjects will continue receiving 
etoposide on Days 2 and 3. Treatment with study drug will continue until disease progression, 
intolerable toxicity, discontinuation decided by subject or investigator, death, withdrawal of 
informed consent, pregnancy, noncompliance with protocol or procedure requirements, 
administrative reasons, or other reasons specified in the protocol, whichever occurs first.  
If chemotherapy is not used due to toxicity or other reasons in a certain cycle, it is not counted as 
the number of chemotherapy cycles. After completing 4 cycles of chemotherapy, even if the 
subject does not meet the above criteria, the chemotherapy will not be continued. 
General Principles for Dose Modification 
Any modified or delayed doses should be recorded in the source document and electronic case 
report form (eCRF). Adverse events are assessed for severity according to Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0. 
• For concomitant conditions already present at baseline, dose modifications may be 
determined by the investigator based on changes in severity of toxicity. For example, if the 
subject already has a Grade 1 weakness at baseline, and the severity increases to Grade 2 
during treatment, it may be considered to make dose modification according to Grade 1 
toxicity due to 1-grade increase in toxicity. 
• If multiple toxicities of different severities occur at the same time, the dose should be 
adjusted according to the most severe toxicity. 
• If the toxicity is related to one of the study drugs only (for example, HLX10, carboplatin or 
etoposide) as assessed by the investigator, dose modification of that study drug only with 
reference to the corresponding dose modification principle is acceptable, and the subject can 
continue receiving the other study treatment in the absence of other contraindications. 
• If the toxicity is associated with only one of the chemotherapy medications as assessed by the 
investigator, the dose of the other chemotherapy medication may not be adjusted. 

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• In the event that a delay is required for reasons of toxicity (not definitively related to which 
drug), similar delays of all study drugs at the same time are required if recovery to a 
re-dosing level is expected within 2 weeks. 
• If HLX10/placebo, carboplatin, or etoposide is interrupted due to toxicity, study treatment 
must be restarted, keeping HLX10/placebo in sync with the chemotherapy treatment cycles. 
Principles for Chemotherapy Modification 
In the event of intolerance to etoposide/carboplatin, the dose can be modified twice according to 
the etoposide/carboplatin prescribing information and local standard-of-care. Once reduced, the 
dose cannot be increased back to 100%. 
If treatment is delayed due to intolerance to chemotherapy, chemotherapy may be delayed to the 
next cycle of administration, with the maximum permissible interval for chemotherapy not 
exceeding 6 weeks. 
Principles for HLX10 or Placebo Modification 
In the event of HLX10- or placebo-related toxicity, a delay in HLX10 or placebo is allowed 
rather than dose adjustment. Subjects who miss a scheduled infusion should be actively 
contacted to arrange another visit as soon as possible for administration. Administration of 
HLX10 or placebo may be delayed, but a dosing interval of up to 12 weeks is considered 
intolerable of HLX10 or placebo, where HLX10 or placebo will be permanently discontinued 
and the subject should withdraw from the trial. For a treatment delay due to intolerance to 
HLX10 or placebo, chemotherapy should be administered as scheduled, and HLX10 or placebo 
may be postponed to the next cycle with no more than 12 weeks between doses; for a treatment 
delay due to intolerance to chemotherapy, chemotherapy may be postponed to the next cycle 
with an interval no more than 6 weeks. 

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1.2 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall study design 
Arm A (HLX-10): HLX10 + etoposide/carboplatin 
Screening 
Period 
Treatment Period  
(21-day cycles) 
Follow-up Period  
Day 1 
(Week 1) 
Arm B (control): placebo + etoposide/carboplatin 
Discontinuation 
One treatment visit every 3 weeks ± 3 days 
Assessed once every 6 weeks (± 7 days) for 48 weeks,  
then every 9 weeks (± 7 days) thereafter 
Survival 
follow-up  
Safety 
follow-up  
For study treatment schedule, please refer to Figure 1. Schematic of study treatment. 
Stratification factors: 

PD-L1 expression level (negative: TPS <1%, positive: 
 TPS ≥1%, or not evaluable/not available) 

Brain metastasis (yes versus no) 

Age (≥ 65 years versus < 65 years) 
Screening period: The maximum screening period is 28 days. 
Treatment period: Including initial treatment and post-PD treatment (optional) 
After finishing the initial treatment period, patients in both arms who had 1stdisease 
progression per RECIST 1.1 and might benefit from their assigned treatment in addition to 
2nd line chemotherapy, may be eligible to continue to receive their assigned treatment in the 
post-PD treatment period (Optional) until the 2nd disease progression, intolerable toxicity, 
death, withdrawal of consent, or lost to follow-up.  
Safety follow-up period: 90 days after the last study drug administration. Safety visit is 
required at the site 30 days (±7 days) after the last study drug administration, and telephone 
follow-up is required 90 days (±7 days) after the last study drug administration. 
Survival follow-up period: Every 12 weeks ± 7 days. 
ICF 
Randomization 
(≤ 28 days) 
TPS = Tumor Proportion Scores. 

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1.3 Schedule of Activities (SoA) 
Initial Treatment Period 
Periods 
Screening Period 
Treatment Period (three-week 
cycles) 
End-of-
Treatment 
(EOT) visit1 
Follow-up Period2 
Treatment Cycles/Visits 
Screening Period 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up3 
Time of Visit 
-28 to -8 
-7 to -1 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days 
after the last study 
drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window4 
 
 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
Management Procedures 
 
 
 
 
 
 
 
 
 
Informed consent form 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Dispensing of subject ID card 
X 
 
 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
 
 
Prior and concomitant therapies5 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Operations/Assessments 
 
 
 
 
 
 
 
 
 
Adverse events6 
X  
X 
X 
X 
X 
X 
X 
X 
 
Quality of life7 
 
X 
X 
 
X 
 
X 
X 
X 
 
Echocardiography 
X 
 
 
 
 
 
 
 
 
12-lead ECG8 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG scores8 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete physical examination 
X 
 
 
 
 
 
 
 
 
Symptom-oriented physical 
examination 
 
X 
X 
X 
X 
X 
X 
X 
 
Height, weight and vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
 
Subsequent antineoplastic therapy 
 
 
 
 
 
 
 
X 
X 
Survival status 
 
X 
X 
X 
X 
X 
X 
X 
X 
Study Treatment 
 
 
 
 
 
 
 
 
 

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Periods 
Screening Period 
Treatment Period (three-week 
cycles) 
End-of-
Treatment 
(EOT) visit1 
Follow-up Period2 
Treatment Cycles/Visits 
Screening Period 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up3 
Time of Visit 
-28 to -8 
-7 to -1 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days 
after the last study 
drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window4 
 
 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
Randomization10 
 
X 
 
 
 
 
 
 
 
HLX10 or placebo10 
 
X 
X 
X 
X 
X 
 
 
 
Etoposide + carboplatin 
 
X 
X 
X 
X 
 
 
 
 
Clinical Operations/Assessments: by 
study site 
 
 
 
 
 
 
 
 
 
 
Pregnancy test11 
 
X 
 
 
X 
 
X 
X 
X 
 
Routine blood test, serum biochemistry, 
coagulation test, myocardial function 
(CK, CKMB, TnI/TnT) and BNP (or 
NT pro BNP), urinalysis12 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
T3 or FT3, T4 or FT4, TSH13 
   
X 
 
 
X 
 
X 
X 
X 
 
HBV antibody, HBV DNA14 
X 
 
 
 
 
 
 
 
 
 In case of HBV DNA (-) and: 1) 
HBsAg (+), or 2) HBcAb (+) and 
HBsAg (-) at baseline, HBV 
antibody and HBV DNA should be 
examined during the treatment 
period. 
 
 
 
X 
 
X 
X 
X 
 
HCV antibody, HCV RNA14 
X 
 
 
 
 
 
 
 
 
 In case of HCV antibody (+) and 
HCV RNA (-) at baseline, HCV 
antibody and HCV RNA should be 
 
 
 
X 
 
X 
X 
X 
 

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Periods 
Screening Period 
Treatment Period (three-week 
cycles) 
End-of-
Treatment 
(EOT) visit1 
Follow-up Period2 
Treatment Cycles/Visits 
Screening Period 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up3 
Time of Visit 
-28 to -8 
-7 to -1 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days 
after the last study 
drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window4 
 
 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
examined during the treatment 
period. 
HIV  
X 
 
 
 
 
 
 
 
 
Tuberculosis15 
X 
 
 
 
 
 
 
 
 
Clinical Operations/Assessments: by 
central laboratory 
 
 
 
 
 
 
 
 
 
HLX10-PK, ADA16 
 
X 
X 
 
X 
X 
X 
X 
 
Efficacy Assessment 
 
 
 
 
 
 
 
 
 
Radiological Examination17 
X 
 
 
X 
 
X 
X 
 
 
Biomarker Sample Collection 
 
 
 
 
 
 
 
 
 
Tumor tissue18 
X 
 
 
 
 
 
 
 
 
Blood 
X 
 
 
 
 
 
 
 
 
ADA=anti-drug antibody, DNA=deoxyribonucleic acid, ECOG=Eastern Cooperative Oncology Group, HBcAb=hepatitis B core antibody, HBsAg=hepatitis 
B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, PK=pharmacokinetics, RNA=ribonucleic acid. 
1. 
If a subject discontinues study treatment for any reason, an end-of-treatment (EOT) visit should be performed whenever possible and should be completed within 7 days 
after informed or discontinuation confirmed (and should be completed before the subject starts a new anti-tumor therapy); 
2. 
All subjects are required to visit the study site for safety follow-up 30 days (± 7 days) after the last study drug administration; if the end-of-treatment visit is delayed for 
any reasons and occurs after the time window of 30 days (± 7 days), no further safety follow-up visit is required. All subjects are required to receive a follow-up 
telephone call for safety follow-up 90 days (± 7 days) after the last study drug administration. Only the information of AEs and AE-related concomitant drugs is 
collected.  
3. 
Subjects should be followed for survival by telephone every 12 weeks ± 7 days after starting a new antineoplastic therapy or treatment termination criteria are met; the 
frequency of survival follow-up may be increased as appropriate. 

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Periods 
Screening Period 
Treatment Period (three-week 
cycles) 
End-of-
Treatment 
(EOT) visit1 
Follow-up Period2 
Treatment Cycles/Visits 
Screening Period 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up3 
Time of Visit 
-28 to -8 
-7 to -1 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days 
after the last study 
drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window4 
 
 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
4. 
The maximum screening period is 28 days; the time windows are ± 3 days for treatment, ± 7 days for tumor assessment, + 7 days for EOT visit, and ± 7 days for follow-
up. ECOG performance status, serum pregnancy test, blood routine, biochemistry, coagulation, myocardial function, urinalysis and thyroid function (T3 or FT3, T4 or 
FT4, TSH) should be completed within 7 days before randomization, and the subjects should meet the corresponding inclusion/exclusion criteria for enrollment. 
5. 
All prior and concomitant medications are recorded from 30 days prior to signing the informed consent form (ICF) through the safety follow-up visit; concomitant 
medications associated with AEs are recorded up to 90 days after the last study treatment. 
6. 
All AEs and treatment emergent AEs are recorded from the time of signing the ICF until 90 days after the last study treatment. If a subject starts a new antineoplastic 
therapy during the AE collection period, only information on AEs related to study treatment are collected after the new antineoplastic therapy. 
7. 
Quality of life scales including the EQ-5D-5L, the European Organization for Research and Treatment of Cancer Quality of Life Scale (EORTC QLQ-C30), and the 
European Organization for Research and Treatment of Cancer lung cancer questionnaire module (EORTC QLQ-LC13). Such scales are evaluated prior to the first dose 
and every other subsequent dosing cycle (i.e., pre-dose in Cycles 1, 3, 5, 7, etc.) until EOT. A quality of life assessment is required at the EOT visit if no assessment has 
been performed within the past 3 weeks. Quality of life assessment could be performed either on Day -7 to Day -1 of the screening period or prior to dosing in Cycle 1. 
8. 
Re-assessments prior to dosing in Cycle 1 are not required for subjects who had 12-lead ECG and ECOG scores assessment on Day -7 to Day -1 of the screening period. 
9. 
The height measurement is performed only at screening; vital signs include body temperature, pulse, respiratory rate, and blood pressure. Body weight will be 
measured prior to drug administration at each treatment cycle. If the subject’s weight on the day of dosing differs by > 10% from the weight used to calculate the dose of 
investigational product, the dose of investigational product must be recalculated. All doses should be rounded to the nearest milligram. 
10. 
Study drug is administered on Day 1 of each 3-week cycle after all clinical and laboratory operations/assessments are completed. No more than 3 days must have elapsed 
between the date of randomization and the date of the first study dose.  
11. 
Women of childbearing potential must have a serum pregnancy test. This is also performed within 3 days prior to dosing every other cycle during the treatment period. 
12. 
 Routine blood test items include red blood cell count, hemoglobin, platelet, white blood cell count, white blood cell differential counts and percentages (including: 
basophils, eosinophils, lymphocytes, monocytes, neutrophils); serum biochemistry items include blood urea/urea nitrogen, creatinine, sodium, potassium, magnesium, 
chloride, calcium, phosphorus, blood glucose, total bilirubin, direct bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, 
lactate dehydrogenase, total cholesterol, total protein, albumin; coagulation test consist of prothrombin time (PT), activated partial thromboplastin time (APTT) and 

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Periods 
Screening Period 
Treatment Period (three-week 
cycles) 
End-of-
Treatment 
(EOT) visit1 
Follow-up Period2 
Treatment Cycles/Visits 
Screening Period 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up3 
Time of Visit 
-28 to -8 
-7 to -1 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days 
after the last study 
drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window4 
 
 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
international normalized ratio (INR); myocardial function detection includes troponin-I (TnI)/troponin-T (TnT), creatine kinase isoenzyme (CK-MB)/ and creatine kinase 
(CK), Brain Natriuretic Peptide (BNP)/N-terminal pro-Brain Natriuretic Peptide (NT-pro BNP); urinalysis items include specific gravity, urine leukocytes, pH, urine 
glucose, urine protein, ketone body and urine occult blood, microscopic examination of white blood cells and red blood cells should be collected if urine leukocytes and 
urine occult blood are out of normal range. These tests should be performed within 3 days before dosing in each cycle; for aforementioned laboratory tests scheduled on 
the same day as study treatment, the study treatment can be arranged only after the test results are obtained. For laboratory tests from the screening period completed on 
Day -7 ~ Day -1, it is not necessary to repeat the test again before the first administration (C1D1). For combined chemotherapy, routine blood tests should be performed 
on Day 8 (± 3 days) of each treatment cycle to closely monitor bone marrow suppression. 
13. 
Thyroid function tests include triiodothyronine (T3 or FT3), thyroxine (T4 or FT4) and thyroid stimulating hormone (TSH) assays. This is also performed within 3 days 
prior to dosing every other cycle during the treatment period. 
14. 
All subjects are tested for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody at screening. Patients with HBsAg (+) and/or HBcAb (+) should be 
further tested for hepatitis B virus (HBV) DNA titer; and HCV antibody positive subjects should be further tested for HCV RNA. In case of HBV DNA (-) and: 1) 
HBsAg (+), or 2) HBcAb (+) and HBsAg (-) at baseline, HBV antibody and HBV DNA should be tested every 2 cycles during the treatment period. In case of HCV 
antibody (+) and HCV RNA (-) at baseline, HCV antibody and HCV RNA should be tested every 2 cycles during the treatment period. 
15. 
Bulgarian subjects should be tested for active and latent tuberculosis using a method as per standard local practice (as requested by the Bulgarian Drug Agency for 
Bulgarian subjects). 
16. 
PK and ADA sampling: (Note: ADA samples will only be collected pre-dose and procedures are described in the laboratory manual) 
 
PK and ADA samples for HLX10 or placebo will be collected at the following time points: within 7 days pre-dose in Cycle 1, within 3 days pre-dose in 
Cycles 2, 4, 6, 8 and every 4 cycles thereafter, within 2 hours after the end of dosing in Cycles 1 and 8 of treatment period (for PK only), at EOT visit and 
safety follow-up. 
17. 
Computerized tomography (CT) or magnetic resonance imaging (MRI) should be performed at screening, every 6 weeks (± 7 days) during the first 48 weeks after the 
start of study treatment, and every 9 weeks (± 7 days) after week 48 on sites including brain, chest, abdomen, pelvic cavity and any other sites suspected to have tumor 
lesions, in which brain MRI or CT (preferably MRI) and bone scans are required for all subjects at screening, and are performed in the treatment period as determined 
by the investigator according to clinical needs (if baseline brain CT/MRI shows that brain metastasis is not present, the subject should have follow up brain imaging only 

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Periods 
Screening Period 
Treatment Period (three-week 
cycles) 
End-of-
Treatment 
(EOT) visit1 
Follow-up Period2 
Treatment Cycles/Visits 
Screening Period 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up3 
Time of Visit 
-28 to -8 
-7 to -1 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days 
after the last study 
drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window4 
 
 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
if clinically indicated at the discretion of the investigator. If baseline brain CT/MRI has confirmed central nervous system (CNS) metastasis, continuous brain imaging 
test should be carried out as part of the regular RECIST evaluation assessments); examination methods at the same site should be consistent as much as possible 
throughout the study; if there are no contraindications, contrast agent should be used. The investigator and IRRC respectively assess the tumor images according to 
RECIST 1.1 (the tumor assessment can be performed by the investigator according to clinical needs), and the investigator should make subsequent treatment judgment 
according to the results of their own efficacy evaluation. If tumor assessment has been performed within 28 days prior to the first dose by the same methods and devices 
in the same hospital, it may serve as the baseline tumor assessment. At the EOT visit, if tumor imaging has been performed within the last 4 weeks, a re-test is not 
required. For subjects who discontinued for reasons other than disease progression, radiological assessments are to be continued as scheduled, until disease progression, 
initiation of new antineoplastic therapy, withdrawal of ICF, death, or end of study, whichever occurs first. 
18. 
Patients must provide tumor tissues that meet the requirements for the determination of PD-L1 expression levels. It is recommended to provide formalin-fixed tumor 
tissue samples, paraffin-embedded tumor specimens (preferred), formalin-fixed paraffin embedded (FFPE), tumor specimens or newly prepared unstained serial tissue 
sections (preferably adhesive slides) within 6 months prior to the first dose of study medication. A relevant pathology report must also be provided for the above 
specimens. Freshly collected specimens, radical resections, core needle biopsy, excisions, incisions, punch or clamp biopsies are acceptable (newly obtained tissues are 
preferred). Fine-needle aspirations (i.e., samples that lack a complete tissue structure and provide only cell suspension and/or cell smear), brush biopsies, and cell pellet 
samples from pleural or peritoneal effusions are unacceptable. For detailed requirements for tissue samples, see the laboratory manual. 

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Post-PD Treatment Period (Optional) 
Periods 
Post-PD Treatment Period (three-
week cycles)1 
End-of-Treatment 
(EOT) visit2 
Follow-up Period3 
Treatment Cycles/Visits 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up4 
Time of Visit 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days after 
the last study drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window5 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
Management Procedures 
 
 
 
 
 
 
 
 
Supplementary informed consent form 
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
Concomitant therapies6 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Operations/Assessments 
 
 
 
 
 
 
 
 
Adverse events7 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
 
Symptom-oriented physical examination 
X 
X 
X 
X 
X 
X 
X 
 
Weight and vital signs8 
X 
X 
X 
X 
X 
X 
X 
 
ECOG scores 
X 
X 
X 
X 
X 
X 
X 
 
Subsequent antineoplastic therapy 
X9 
 
X 
X 

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Periods 
Post-PD Treatment Period (three-
week cycles)1 
End-of-Treatment 
(EOT) visit2 
Follow-up Period3 
Treatment Cycles/Visits 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up4 
Time of Visit 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days after 
the last study drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window5 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
Survival status 
X 
X 
X 
X 
X 
X 
X 
X 
Study Treatment 
 
 
 
 
 
 
 
 
HLX10 or placebo10 
X 
X 
X 
X 
X 
 
 
 
Clinical Operations/Assessments: by study site 
 
 
 
 
 
 
 
 
Pregnancy test11 
X 
 
X 
 
X 
X 
X 
 
Routine blood test, serum biochemistry, 
coagulation test, myocardial function, urinalysis12 
X 
X 
X 
X 
X 
X 
X 
 
T3 or FT3, T4 or FT4, TSH13 
X 
 
X 
 
X 
X 
X 
 
HBV antibody, HBV DNA14 
 
 
 
 
 
 
 
 
 In case of HBV DNA (-) and: 1) HBsAg (+), 
or 2) HBcAb (+) and HBsAg (-) at baseline, 
HBV antibody and HBV DNA should be 
examined during the treatment period. 
X 
 
X 
 
X 
X 
X 
 
HCV antibody, HCV RNA14 
 
 
 
 
 
 
 
 

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Periods 
Post-PD Treatment Period (three-
week cycles)1 
End-of-Treatment 
(EOT) visit2 
Follow-up Period3 
Treatment Cycles/Visits 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up4 
Time of Visit 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days after 
the last study drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window5 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
 In case of HCV antibody (+) and HCV RNA 
(-) at baseline, HCV antibody and HCV RNA 
should be examined during the treatment 
period. 
X 
 
X 
 
X 
X 
X 
 
HLX10-PK, ADA15 
X 
 
 
 
X 
X 
X 
 
Efficacy Assessment 
 
 
 
 
 
 
 
 
Radiological Examination16 
X 
 
X 
 
X 
X 
 
 

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Periods 
Post-PD Treatment Period (three-
week cycles)1 
End-of-Treatment 
(EOT) visit2 
Follow-up Period3 
Treatment Cycles/Visits 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up4 
Time of Visit 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days after 
the last study drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window5 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
1. 
After finishing the initial treatment period, patients in both arms who had 1st disease progression per RECIST 1.1 who, in the investigator’s opinion, would continue to 
receive benefit from their assigned treatment in addition to 2nd line chemotherapy may be eligible to continue to receive their assigned treatment in the post-PD treatment 
period (Optional) until the 2nd disease progression, intolerable toxicity, death, withdrawal of consent, or lost to follow-up. The following visits and assessments are 
recommended for post-PD treatment period.  
2. 
If a subject discontinues study treatment for any reason, an end-of-treatment (EOT) visit should be performed whenever possible and should be completed within 7 days 
after informed or discontinuation confirmed (and should be completed before the subject starts a new anti-tumor therapy). 
3. 
All subjects are required to visit the study site for safety follow-up 30 days (± 7 days) after the last study drug administration; if the EOT visit is delayed for any reason and 
occurs after the time window of 30 days (± 7 days), no further safety follow-up visit is required. All subjects are required to receive a follow-up telephone call for safety 
follow-up 90 days (± 7 days) after the last study drug administration. Only the information of AEs and AE-related concomitant drugs is collected. 
4. 
Subjects should be followed for survival by telephone every 12 weeks ± 7 days after starting a new antineoplastic therapy or treatment termination criteria are met; the 
frequency of survival follow-up may be increased as appropriate. 
5. 
The time windows are ± 3 days for treatment, ± 7 days for tumor assessment, + 7 days for EOT visit, and ± 7 days for follow-up. The subjects should meet the 
corresponding eligibility criteria for enrollment.  
6. 
All concomitant medications are recorded up to the safety follow-up visit, and concomitant medications associated with AEs are recorded up to 90 days after the last study 
treatment. 
7. 
All AEs and treatment emergent AEs are recorded up to 90 days after the last study treatment. If a subject starts a new antineoplastic therapy during the AE collection 
period, only information on AEs related to study treatment are collected after the new antineoplastic therapy. 
8. 
Vital signs include body temperature, pulse, respiratory rate, and blood pressure. Body weight will be measured prior to drug administration at each treatment cycle. If the 
subject’s weight on the day of dosing differs by > 10% from the weight used to calculate the dose of investigational product, the dose of investigational product must be 
recalculated. All doses should be rounded to the nearest milligram. 

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Periods 
Post-PD Treatment Period (three-
week cycles)1 
End-of-Treatment 
(EOT) visit2 
Follow-up Period3 
Treatment Cycles/Visits 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up4 
Time of Visit 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days after 
the last study drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window5 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
9. 
Subsequent antineoplastic therapy in post-PD treatment period must be 2nd line chemotherapy. 2nd line chemotherapy (anti-PD1 and anti-PD-L1 therapy are not included) 
was determined by investigators after communicating with the subjects, NCCN guidelines or ESMO guidelines are the preferred reference.  
10. Subjects must not initiate treatment with HLX10 or placebo in post-PD treatment any earlier than 21 days and no more than 12 weeks after their last dose of initial 
treatment (including chemotherapy) regardless of the time of progression. HLX10 or placebo is administered on Day 1 of each 3-week cycle after all clinical and 
laboratory operations/assessments are completed. 
11. Women of childbearing potential must have a serum pregnancy test. This is also performed within 3 days prior to dosing every other cycle during the treatment period. If 
the test is done within 3 days before the first dose of investigational drug, it is not necessary to perform the test again. 
12. Routine blood test items include red blood cell count, hemoglobin, platelet, white blood cell count, white blood cell differential counts and percentages (including: 
basophils, eosinophils, lymphocytes, monocytes, neutrophils); serum biochemistry items include blood urea/urea nitrogen, creatinine, sodium, potassium, magnesium, 
chloride, calcium, phosphorus, blood glucose, total bilirubin, direct bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, 
lactate dehydrogenase, total cholesterol, total protein, albumin; coagulation test consist of prothrombin time (PT), activated partial thromboplastin time (APTT) and 
international normalized ratio (INR); myocardial function detection (TnI/TnT, CK-MB/CK) and BNP/NT-pro BNP; urinalysis items include specific gravity, urine 
leukocytes, pH, urine glucose, urine protein, ketone body and urine occult blood, microscopic examination of white blood cells and red blood cells should be collected if 
urine leukocytes and urine occult blood are out of normal range. These are performed within 3 days before dose in each cycle; for aforementioned laboratory tests 
scheduled on the same day as study treatment, the study treatment can be arranged only after the test results are obtained. If concomitant chemotherapy requires additional 
laboratory tests, follow local clinical guidelines. If the test is done within 3 days before the first dose of investigational drug, it is not necessary to perform the test again. 
13. Thyroid function tests include triiodothyronine (T3 or FT3), thyroxine (T4 or FT4) and thyroid stimulating hormone (TSH) assays. This is also performed within 3 days 
prior to dosing every other cycle during the treatment period. If the test is done within 3 days before the first dose of investigational drug, it is not necessary to perform the 
test again. 

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Periods 
Post-PD Treatment Period (three-
week cycles)1 
End-of-Treatment 
(EOT) visit2 
Follow-up Period3 
Treatment Cycles/Visits 
1 
2 
3 
4 
n 
Discontinuation 
Safety follow-up 
Survival follow-up4 
Time of Visit 
Every 21 days 
After informed or 
discontinuation 
confirmed 
30 days, 90 days after 
the last study drug 
administration (by 
telephone calls) 
Every 12 weeks 
Time Window5 
 
± 3 
± 3 
± 3 
± 3 
+7 
± 7 
± 7 
14. Patients with HBsAg (+) and/or HBcAb (+) should be further tested for hepatitis B virus (HBV) DNA titer; and HCV antibody positive subjects should be further tested for 
HCV RNA. In case of HBV DNA (-) and: 1) HBsAg (+), or 2) HBcAb (+) and HBsAg (-) at baseline, HBV antibody and HBV DNA should be tested every 2 cycles during 
the treatment period. In case of HCV antibody (+) and HCV RNA (-) at baseline, HCV antibody and HCV RNA should be tested every 2 cycles during the treatment 
period. If the test is done within 3 days before the first dose of investigational drug, it is not necessary to perform the test again. 
15. PK and ADA sampling: PK and ADA samples for HLX10 or placebo will be collected at the following time points: within 3 days pre-dose in cycle 1 and thereafter every 4 
cycles, at EOT visit and safety follow-up. 
16. The tumor image used to determine disease progression can be used as the new baseline image for the post-PD treatment period if 1) the this is done within 28 days prior to 
receiving the first dose of HLX10 or placebo therapy and 2) there is no study treatment between the image and first dose of HLX10 or placebo therapy, otherwise a new 
baseline image must be performed prior to HLX10 or placebo treatment. Computerized tomography (CT) or magnetic resonance imaging (MRI) performed every 6 weeks 
(± 7 days) during the first 48 weeks after the start of study treatment, and every 9 weeks (± 7 days) after week 48 on sites including brain, chest, abdomen, pelvic cavity 
and any other sites suspected to have tumor lesions, in which brain MRI or CT (preferably MRI) and bone scans are performed in the treatment period as determined by the 
investigator according to clinical needs (if baseline brain CT/MRI shows that brain metastasis is not present, the subject should have follow up brain imaging only if 
clinically indicated at the discretion of the investigator. If baseline brain CT/MRI has confirmed central nervous system (CNS) metastasis, continuous brain imaging test 
should be carried out as part of the regular RECIST evaluation assessments); examination methods at the same site should be consistent as much as possible throughout the 
study; if there are no contraindications, contrast agent should be used. The investigator will assess the tumor images according to RECIST 1.1 (the tumor assessment can 
be performed by the investigator according to clinical needs), and the investigator should make subsequent treatment judgment according to the results of their own 
efficacy evaluation. At the EOT visit, if tumor imaging has been performed within the last 4 weeks, a re-test is not required. For subjects who discontinued for reasons 
other than disease progression, radiological assessments are to be continued as scheduled, until disease progression, initiation of new antineoplastic therapy, withdrawal of 
ICF, death, or end of study, whichever occurs first. 
 

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2 Introduction 
2.1 Background 
The global cancer statistics show that lung cancer is the most common cancer (11.6% of total 
cancer cases) and cause of death (18.4% of total cancer deaths) in the world. It is estimated that 
by 2018, 2.1 million new cases of lung cancer and 1.8 million new cases of lung cancer deaths 
will occur worldwide1. According to the data released by the National Cancer Center of China in 
2018, there are about 781,000 new cases of lung cancer and 626,000 deaths from lung cancer 
each year in China, with the occurrence and mortality ranking first among malignant tumors2. 
Small cell lung cancer (SCLC) is derived from epithelial cells with neuroendocrine 
differentiation, accounting for 15%-20% of the total number of lung cancers3. The SCLC is 
staged using the United States (US) Veterans Administration staging system and is divided into a 
limited stage and an extensive stage. Most patients present with tumor metastases as the first 
symptom4, and only 30% to 40% of patients are in the limited stage at the time of initial 
diagnosis5. Patients with extensive disease have shorter survival due to extensive tumor 
metastasis and poor physical status only with supportive care. The median survival time of 
untreated extensive small-cell lung cancer (ES-SCLC) is reported to be 2-4 months6. With a 
combination of surgery, radiotherapy and chemotherapy, the median survival of ES-SCLC 
patients can reach 8 to 13 months, with a 2-year survival rate of 5%7. 
Currently, systemic chemotherapy is still the primary treatment for ES-SCLC. The first-line 
platinum-based treatment recommended are the EP treatment (etoposide plus cisplatin), the EC 
treatment (etoposide plus carboplatin), the IP treatment (irinotecan plus cisplatin), and the IC 
treatment (irinotecan plus carboplatin). First-line treatment of SCLC is highly effective, but 80% 
of patients with limited-stage disease and almost all patients with extensive-stage disease relapse 
within one year, with a median survival of only 4 to 5 months after relapse7. Due to the limited 
understanding of SCLC genetic changes and the significant heterogeneity of SCLC at the genetic 
level, the success of some new treatment methods, such as intensive chemotherapy, supportive 
treatment, and molecular targeted therapy, did not benefit patients with extensive-stage SCLC. 
Therefore, there is an urgent need to explore more effective first-line treatments for 
extensive-stage SCLC.  
Anti-PD-1 monoclonal antibodies have been approved for melanoma, non-small cell lung cancer 
(NSCLC), SCLC, head and neck squamous cell cancer, urothelial carcinoma, microsatellite 
instability-high or mismatch repair deficient solid tumors and colorectal cancer, gastric cancer, 
esophageal cancer, cervical cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma, 
renal cell carcinoma, endometrial carcinoma, bladder cancer, primary mediastinal large B-cell 

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lymphoma and classical Hodgkin’s lymphoma. Numerous clinical studies are ongoing with 
anti-PD-1 antibodies, either as monotherapy or in combination with various agents. 
2.2 Study Rationale 
With the deepening of the study on the molecular pathogenesis of cancer, the immunological 
mechanism of tumorigenesis and development has gradually become a study hotspot. It is 
becoming increasingly clear that cancer can be recognized by the immune system, and in some 
cases, the immune system can control or even eliminate tumors. PD-1 was originally cloned by 
Ishida et al.8 as a member of the CD28 superfamily in murine T cell hybridomas. It is a 
monomeric glycoprotein that is mainly expressed on the surface of activated macrophages, 
T lymphocytes, B lymphocytes, natural killer (NK) cells, and some myeloid cells. Its ligands, 
PD-L1 (programmed death ligand 1) and PD-L2, are mainly expressed on tumor cells and 
antigen-presenting cells9,10,11. Because activation of the PD-1 gene may be involved in the 
classical type of programmed cell death, it is named programmed death receptor 1 (PD-L1). 
PD-L1 is highly expressed in a variety of cancers and is as high as 88% in some cancers. In these 
cancers (including lung cancer), PD-1 binds to PD-L1 in tumor tissues, weakens the body's 
immune response, protects tumor tissues from cytotoxic T cells, and leads to tumor immune 
tolerance12,13. Therefore, T cell anti-tumor response can be enhanced by blocking the binding of 
PD-1 to its ligand PD-L114,15,16,17,18. 
In recent years, with the rapid development of tumor immunotherapy, the focus of first-line 
treatment for advanced NSCLC with no driver gene has gradually turned to immunotherapy, and 
multiple PD-1 inhibitors have been approved by the Food and Drug Administration (FDA) for 
NSCLC treatment; The National Comprehensive Cancer Network (NCCN) Guidelines have also 
included PD-1 inhibitors as one of the recommended protocols for the treatment of relapsed 
SCLC. In the absence of breakthrough of targeted drug treatment for SCLC in the past 30 years, 
a new drug has been discovered for SCLC. In 2018, the FDA approved Nivolumab for the 
treatment of relapsed SCLC. In addition, a number of clinical trials of PD-1 antibody combined 
with chemotherapy for SCLC are currently underway. Preliminary results show that PD-1 
inhibitor plus chemotherapy can significantly improve overall survival and progression-free 
survival and is expected to become the new standard of first-line treatment for SCLC. 
The survival of cytotoxic chemotherapy in patients with ES-SCLC reaches a plateau, leaving 
much room for improving the prognosis of such patients. Exposure of the immune system to high 
levels of tumor antigens can reasonably be expected to result in cytotoxicity effects on tumor 
cells by cytotoxic chemotherapy, and restoration of tumor-specific T cell immunity in this setting 
may produce deeper and durable responses than standard chemotherapy alone by inhibiting the 
PD-L1/PD-1 signaling pathway19,20. Therefore, it is reasonable to assume that the combination of 

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immunosuppressive and cytotoxic chemotherapy drugs may have a stronger synergistic 
anti-tumor effect. 
Based on the considerable benefits of PD-1/PD-L1 inhibitors in patients with tumors, Shanghai 
Henlius Biotech, Inc. has developed an innovative monoclonal antibody HLX10 targeting PD-1. 
HLX10 is an IgG4-type humanized monoclonal antibody, where the gene sequence was obtained 
by screening using the hybridization technique and humanized modification was completed by 
genetic engineering, stable cell strains was constructed by using Chinese hamster ovary as a host 
cell, and the produced protein was connected to two identical heavy chains and two identical 
light chains by interchain disulfide bonds to form the “Y”-shaped typical human 
immunoglobulin IgG4 structure. 
The available clinical data demonstrated that HLX10 is safe and tolerable in the phase I, 
first-in-human study in patients with advanced solid tumors, and in other clinical studies in 
patients with malignant solid tumors. And preliminary efficacy has been observed in some 
patients with advanced solid tumors in the first-in-human phase I clinical study (HLX10-001). 
The safety and efficacy of HLX10 will be further evaluated in clinical studies. 
The platinum-based chemotherapy provided in this study is EC regimen (etoposide plus 
carboplatin), which is the first-line chemotherapy regimen for ES-SCLC recommended by 
NCCN and Chinese Expert Consensus on the Diagnosis and Treatment of Advanced Primary 
Lung Cancer (2016 Edition), allowing investigators and subjects to have more flexibility in 
conducting study and treatment according to the standard clinical practice of drugs. 
Based on the results of preclinical and clinical studies, Shanghai Henlius Biotech, Inc. planned to 
conduct a phase III clinical study in previously untreated patients with ES-SCLC worldwide to 
compare the clinical efficacy and safety of HLX10 (recombinant anti-PD-1 humanized 
monoclonal antibody injection) in combination with chemotherapy (Carboplatin-Etoposide). 
2.2.1 Preclinical Study of HLX10 
In vitro pharmacodynamic studies of HLX10 
A series of in vitro pharmacodynamic studies of HLX10 versus the positive control nivolumab 
showed that: HLX10 can bind to the surface of activated T cells expressing PD-1 and has the 
ability to block the binding of PD-1 and PD-L1 or PD-L2 ligand on the cell surface. The binding 
and blocking ability of HLX10 showed dose-dependency. The analysis of in vitro mixed 
leukocyte reaction of HLX10 has shown that HLX10 can block the immunosuppression that is 
dependent on PD-1 and its ligand binding pathway, thereby stimulating activated CD4+ T cells to 

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increase the T cell proliferative potential and produce more IL-2 cytokines. This phenomenon 
showed dose-dependency in both the study drug HLX10 and the positive control nivolumab. 
In addition, to study the occupying ratio of HLX10 in PD-1 receptor on human T cells, different 
doses of HLX10 (50.0, 10.0, 2.0, 4.0×10-1, 8.0×10-2, 1.6×10-2, 3.2×10-3 and 6.4×10-4 μg/mL) 
were pre-incubated in the whole blood of six healthy subjects to simulate the condition of 
HLX10 injected into human blood. The experiment results showed that; as the pre-incubated 
dose of HLX10 increased, the PD-1 receptor occupancy on CD3+ T cells also increased. Out of 
the six healthy subjects, once the HLX10 concentration in the blood of four of the subjects 
reached 2 μg/mL, the PD-1 receptor occupancy on CD3+ T cells would have reached above 80%. 
In vivo pharmacodynamic studies of HLX10 
The results of the evaluation of anti-tumor effect and safety in the subcutaneous xenograft tumor 
model of HT-29 human colon cancer cell NOD/SCID immunodeficient mice showed that 
HLX10 did not cause adverse effects on the health and weight of the mice in each dose group, 
indicating that HLX10 is relatively safe. In terms of tumor inhibition, 30 mg/kg of HLX10 can 
effectively inhibit the growth of the subcutaneous xenograft tumor in HT-29 human colon cancer 
cell NOD/SCID immunodeficient mice in the presence of human peripheral blood mononuclear 
cells (P<0.0001). 
The results of the evaluation of anti-tumor effect and safety in the subcutaneous xenograft tumor 
model of NCI-H292 human NSCLC cell NOD/SCID immunodeficient mice showed that HLX10 
did not cause adverse effects on the health and weight of the mice at a higher dose, indicating 
that HLX10 is very safe. In terms of tumor inhibition, both the tumor volume observation and 
data statistics results in the HLX10 high-dose group versus the placebo group showed that 
30 mg/kg of HLX10 had significant inhibitory effect on the growth of NCI-H292 tumor tissues 
in the presence of human peripheral blood mononuclear cells (P<0.001). 
In the dose-finding trial (P16-106-TS), pharmacokinetic (PK) test (P16-106-YD), and long-term 
toxicity test (P16-106-CD) in cynomolgus monkeys; receptor occupancy (RO) at different time 
points was also investigated before and after intravenous injection of different doses of HLX10 
to provide a basis for selection of the clinical effective dose and the initial dose. 
Final results showed that the in vivo experiment result was consistent with the in vitro human 
peripheral blood PD-1 receptor occupancy (RO), i.e., once the HLX10 concentration in the blood 
of the subjects/experimental animals reached 2 μg/mL, the PD-1 receptor occupancy on CD3+ T 
cells would have reached above 80%. In cynomolgus monkeys, when the blood concentration of 
two test animals in the 3 mg/kg group was below the lower detection limit (that is, 2 μg/mL), the 

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corresponding RO was still 79% and 97%, respectively. Combining all results, it was concluded 
that when a single dose of 3 mg/kg of HLX10 was given to cynomolgus monkeys, the RO 
saturation rate could be maintained for more than 4 weeks; when doses of 5 mg/kg were given to 
cynomolgus monkeys for 13 consecutive weeks (once a week), the RO saturation rate of 100% 
could still be achieved after the end of the recovery period of 6 weeks in some animals. It can 
thus be inferred that a relatively low dose of HLX10 (lower than 1mg/kg) in clinical practice can 
potentially achieve RO saturation, showing relatively good efficacy. 
Tissue cross-reactivity of HLX10 
The results of tissue cross-reactivity test of HLX10 in frozen normal human showed that 
HLX10-Biotin (2.0 μg/mL and 0.5 μg/mL) specifically binds to normal human lymphocytes 
from the lymph node, lung, ileum, stomach, spleen, fallopian tube, colon and thymus. 
The results of tissue cross-reactivity test of HLX10 in cynomolgus monkeys showed that 
HLX10-Biotin (2.0 μg/mL and 0.5 μg/mL) specifically binds to normal cynomolgus monkey 
lymphocytes, including stomach, jejunum, colon, spleen, thymus and mesenteric lymph nodes. 
General pharmacology study of HLX10 
A general pharmacological evaluation of the central nervous system (CNS), cardiovascular 
system and respiratory system was conducted in cynomolgus monkeys, and this trial was a 
companion test of the long-term toxicity trial. During the trial, no test substance-related 
abnormalities were found in the clinical symptoms in each group of animals, and no obvious 
abnormalities were found in the activity and respiration of the animals. The abnormalities in a 
moribund female animal undergoing euthanasia on Day 55 in the high-dose group were found to 
be related to amoebic infection, and the abnormalities in a dead female animal on Day 64 were 
found to be related to the allergic reaction induced by drug administration. No 
toxicologically-significant regular changes in body temperature, systolic blood pressure, diastolic 
blood pressure, mean arterial pressure, oxygen saturation, heart rate, P-R interval, Q-T interval, 
QTc interval, QRS duration and other ECG parameters were found in surviving animals. 
Therefore, intravenous infusion of 5, 50 and 100 mg/kg of HLX10 once a week in cynomolgus 
monkeys for 13 consecutive weeks had no significant effects on the CNS, cardiovascular system 
and respiratory system of cynomolgus monkeys. 
Acute toxicity test of HLX10 
A dose-finding toxicity test of repeated intravenous infusion of HLX10 was conducted in 
cynomolgus monkeys for 4 weeks, and they were given intravenous infusion of 5 mg/kg, 
50 mg/kg and 100 mg/kg of HLX10. The drug was administered on Day 1, Day 8, Day 15 and 
Day22, and all animals were euthanized on Day 29. Gross anatomy was performed for 

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observation. No animals died or were moribund during the trial. One male animal in the 
medium-dose group developed loose stools and soft stools on Day 15-20 and Day 21-29 
respectively. One female animal in the medium-dose group also developed loose stools on 
Day 11-13, Day 15-20 and Day 29, which were considered to be possibly related to the test 
substance (male and female animal findings). No test substance-related abnormalities were 
observed in the clinical observations of animals in the low-dose group and the high-dose group. 
No dosing-related abnormal changes in body weight, food intake, body temperature, 
electrocardiography (ECG) parameters, coagulation parameters, blood biochemistry or gross 
anatomic observation were observed in the animals of each dose group. 4/4, 3/4 and 4/4 animals 
in the 5, 50 and 100 mg/kg groups tested positive for anti-drug antibodies/neutralizing antibodies 
(ADA/NAb) respectively. The first occurrence of ADA/NAb was on Day 8, and the antibody 
titer range was <1-128. Based on the results of this trial, after HLX10 was given to cynomolgus 
monkeys for 4 weeks, the animals could tolerate 100 mg/kg of HLX10 very well. The dose of 
100 mg/kg can be used for longer-term repeat-dose trials. 
Long-term toxicity test of HLX10 
A toxicity and toxicokinetic trial of repeated intravenous infusion of HLX10 for 13 weeks 
followed by a 6-week recovery period was conducted in cynomolgus monkeys, in which placebo 
and 5, 50 and 100 mg/kg of HLX10 were given once a week for 13 consecutive weeks. No test 
substance-related deaths or moribund animals were found in the low- and medium-dose groups 
during the trial. At the dose of 100 mg/kg, one female animal died of drug-related allergic 
reaction and another moribund female animal was euthanized on Day 55 due to amoebic 
infection. Loose stools and/or soft stools were observed in each dose group. Of which, female 
animals in the high-dose group (100 mg/kg) had a slightly higher incidence with slightly longer 
duration. The gastrointestinal symptoms described above were possibly related to drug 
administration, which was consistent with the reported adverse reactions of PD-1 monoclonal 
antibody. With the exception of the two deaths in the high-dose group, the gastrointestinal 
reactions of the remaining animals (loose stools/soft stools) were completely recovered after the 
6-week recovery period. No other test substance-related abnormalities were observed in the 
surviving animals of the dose group during the trial. With the exception of the female animal in 
the high-dose group that was euthanized on Day 55, all animals in the dose groups tested positive 
for ADA/NAb, and the ADA/NAb response was the highest in the low-dose group. The antibody 
titer also increased as the number of doses increased, and it lasted until the end of the recovery 
period (Day 134). In combination with toxicokinetic (TK) results, the occurrence of ADA/NAb 
significantly reduced systemic exposure in all dose groups. After repeated intravenous infusion 
of 5 and 50 mg/kg of HLX10 in cynomolgus monkeys once a week for 13 consecutive weeks, no 
significant toxicity was observed, and no reactions were observed at the site of drug 

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administration. There were no significant effects on the major functional systems such as the 
cardiovascular system, CNS or respiratory system. Under the conditions of this trial, the 
maximum no observed adverse effect level (NOAEL) of HLX10 was 50 mg/kg. The AUClast and 
maximum (or peak) serum concentration (Cmax) in male animals were 597.60 h*mg/mL and 
4,909.72 μg/mL respectively, and the AUClast and Cmax in female animals were 403.64 h*mg/mL 
and 3,726.17 μg/mL respectively at this dose on Day 85. 
Preclinical pharmacokinetics study of HLX10 
The results of the PK study in cynomolgus monkeys receiving a single intravenous infusion of 
HLX10 showed that after intravenous infusion of HLX10 at 3, 10 and 30 mg/kg, the serum drug 
concentration increased with the increase in dose. The systemic exposure (Cmax and AUClast) 
increased with the increase in dose. The mean retention time (MRT) was between 153.02-
231.28 h. The elimination half-life (t1/2) was between 137.97-256.99 h. The results showed that 
the test substance generally showed linear PK characteristics in cynomolgus monkeys in the dose 
range of 3-30 mg/kg. The clearance rate and volume of distribution (Vz) of HLX10 were similar 
in all dose groups, and they were between 0.13-0.23 mL/h/kg and 38.05-53.52 mL/kg. All 
animals in the 3, 10 and 30 mg/kg HLX10 dose groups tested positive for ADA/NAb on Day 8, 
Day 15, Day 22 and Day 29. The first occurrence of ADA/NAb was on Day 8, and the antibody 
titer range was between <1-512. Other than the statistical difference (P<0.05) in the 10 mg/kg 
group where in the area under the concentration-time curve (AUClast and AUCinf) for female 
animals was lower than that for male animals, there were no statistically significant differences 
in the PK parameters between genders in other dose groups. Analysis of the impact of ADA/NAb 
status on PK showed that 2/3 of female animals in the 10 mg/kg group produced relatively strong 
antibodies on D22 with an antibody titer of 8-128, resulting in a slightly faster elimination in 
female animals than male animals and a smaller area under the curve (AUClast and AUCinf).  
Toxicokinetic study of HLX10 
A toxicokinetic study was performed along with the dose-finding toxicity test of repeated 
intravenous infusion of HLX10 in cynomolgus monkeys for 4 weeks. The results showed that: on 
Day 1 and Day 22, the systemic exposure of HLX10 (Cmax and AUClast) increased with the 
increase in dose. On Day 22, the production of anti-drug antibodies in some animals resulted in a 
faster elimination of serum HLX10 concentration. In ADA-negative animals, the mean values of 
Cmax and AUClast in each dose group were higher on Day 22 than on Day 1, indicating that there 
was accumulation of the drug to some extent. This characteristic was also shown in the serum 
HLX10 concentration in pre-dose samples on Day 22. The accumulation factor was between 
2.24-2.41. Compared to Day 1, the volume of distribution of HLX10 decreased and the clearance 
rate decreased in the ADA-negative group on Day 22. In the ADA-positive group, the clearance 
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Another toxicokinetic study was performed along with the toxicity and toxicokinetic trial of 
repeated intravenous infusion of HLX10 for 13 weeks followed by a 6-week recovery period in 
cynomolgus monkeys. The results showed that, on Day 1 and Day 85, the systemic exposure of 
HLX10 (Cmax and AUClast) increased with an increase in dose, showing dose-dependent 
toxicokinetic characteristics. Some animals produced ADA after repeated dosing. In 
ADA-negative animals, the mean values of Cmax and AUClast in each dose group were higher on 
Day 85 than on Day 1, indicating that there was accumulation of the drug. This characteristic 
was also shown in the serum HLX10 concentration in pre-dose samples on Day 85. The 
accumulation factor was between 2.34-4.32. Compared to Day 1, the volume of distribution of 
HLX10 decreased and the clearance rate decreased in the ADA-negative group on Day 85. In the 
ADA-positive group, the clearance rate increased significantly. On Day 1, the systemic exposure 
(AUClast and AUCinf) was slightly higher in male animals than in female animals and the 
clearance rate was slightly lower in male animals than in female animals in the 100 mg/kg dose 
group, but there were no significant differences in PK parameters between genders on Day 1 and 
Day 85 in the remaining animals. 
Immunogenicity and immunotoxicity of HLX10 
An evaluation test of immunogenicity and immunotoxicity were carried out in cynomolgus 
monkeys, and this trial was a companion test of the long-term toxicity trial. The results showed 
that, after repeated intravenous infusion of 5, 50 and 100 mg/kg of HLX10 in cynomolgus 
monkeys once a week for 13 consecutive weeks, no immunotoxicity was observed at doses of 
5 and 50 mg/kg. At the dose of 100 mg/kg, one female animal died of an allergic reaction, the 
ADA was positive, and IL-6 increased after dosing. At the dose of 100 mg/kg, the ratios of 
CD3+, CD4+ and CD4+/CD8+ of male animals decreased, and the increase in CD8+ was related to 
the pharmacologic effects of the test substance. Anti-drug antibodies were found after HLX10 
dosing in the animals, and the incidence of ADA in the low-dose group was higher than that in 
the medium- and high-dose groups. Antibody titer increased with an increase in duration of drug 
administration and may result in a significant decrease in systemic exposure. HLX10 is a 
humanized antibody and is an exogenous substance to cynomolgus monkeys. Hence, the 
production of immunogenicity is a reasonable phenomenon in the animals. The evaluation of 
immunogenicity of antibody drugs is suitable in human clinical trials.  
Genetic Toxicology Studies 
The genotoxicity isn’t required to be evaluated for monoclonal antibodies like HLX10 according 
to ICHS6 (R1). 
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The results of the hemolytic study of HLX10 showed that HLX10 with a concentration of 
10 mg/mL had no hemolytic effect on human erythrocytes in vitro and did not cause erythrocyte 
coagulation. 
Local irritability study was conducted along with the long-term toxicity test, and the results 
showed that after repeated intravenous infusion of 5, 50 and 100 mg/kg of HLX10 in cynomolgus 
monkeys once a week for 13 weeks, there was no significant irritative damage to local blood 
vessels and surrounding tissues within the concentration range of 0.5-10.0 mg/mL. 
2.2.2 Clinical Study of HLX10 
To date, HLX10 has been administered to human subjects in 14 ongoing clinical studies. Clinical 
studies of HLX10, given as monotherapy or in combination with chemotherapy or other 
antibodies (anti-VEGF antibody HLX04), are being conducted in patients with advanced solid 
tumors, previously untreated metastatic non-squamous NSCLC, previously treated unresectable 
or metastatic MSI-high or mismatch repair deficiency solid tumors, previously treated advanced 
HCC, gastric cancer, metastatic esophageal squamous cell carcinoma (ESCC), metastatic 
colorectal cancer (mCRC), relapsed and/or advanced cervical cancer, and advanced head and 
neck cancer. 
The clinical efficacy and safety results from these studies, as well as the nonclinical toxicology 
and safety data, provide evidence to support continued clinical development for HLX10. 
 
2.3 Benefit/Risk Assessment 
2.3.1 
Potential benefits 
 Available clinical data for HLX10 include that collected from clinical studies of HLX10, which 
was given as monotherapy and/or in combination with chemotherapy or other antibody (anti-
VEGF antibody HLX04), in patients with advanced solid tumors, previously untreated metastatic 
non-squamous NSCLC, previously treated unresectable or metastatic MSI-H or dMMR solid 
tumors, previously treated advanced HCC, gastric cancer, metastatic ESCC, mCRC, relapsed 
and/or advanced cervical cancer, and advanced head and neck cancer.  
The available clinical data shows that HLX10 monotherapy or combined with other therapies 
was safe and tolerable in patients with malignant tumors. 
Only 1 subject in the 3 mg/kg dose cohort (n=6) experienced DLT during the first cycle in the 
HLX10 first-in-human phase I study in patients with advanced solid tumors with four dose levels 

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(0.3, 1, 3 and 10 mg/kg). The maximum tolerated dose (MTD) was not reached until 10 mg/kg of 
HLX10 was given every two weeks. Accumulation of HLX10 was observed following multiple 
dose administration. The 0.3 mg/kg of HLX10 was enough to saturate the PD-1 binding and 
induce the functional blockade. The efficacy results demonstrated anti-tumor activity of HLX10 
in this first-in-human phase I study with DCR of 68.8%, ORR of 6.3%, and median PFS of 107.0 
days.  
In the phase II study of HLX10 in patients with previously treated HCC, 1 subject in the dose 
level A (n=7) of safety run-in stage experienced DLT (increased total bilirubin is 39.4 µmol/L 
which is >2 mg/dL and considered to be caused by hepatocellular cancer progression). 
The study showed the anti-tumor activity of HLX10 and patients with advanced solid tumors can 
benefit from HLX10. 
2.3.2 
Identified and potential risks 
PD-1/PD-L1 inhibitors not only enhance the anti-tumor effect of cellular immunity, but could 
also enhance the normal immune response, leading to immune tolerance imbalance and 
immune-related adverse reactions (irAEs). Immune-related adverse reactions can affect any 
organ in the human body, and nearly two-thirds of patients currently treated with immune 
checkpoint inhibitors experience irAEs of varying degrees19,20. In February 2018, NCCN and 
American Society of Clinical Oncology (ASCO) jointly issued the Guidelines for the 
Management of Toxicity Related to Immunotherapy (Version 1, 2018), which states that the 
immune-related AEs of the skin, intestine, endocrine, lung and musculoskeletal systems are 
relatively common, while the immune-related AEs of the cardiovascular, hematological, renal, 
neurological and ophthalmic systems are rare. Most immune-related AEs were mild-moderate in 
severity; common irAEs known in patients currently treated with PD-1/PD-L1 inhibitors were as 
follows: skin toxicity (mainly maculopapular rash and pruritus; 30% to 40%), diarrhea and/or 
colitis (8% to 19%), fatigue (16% to 24%), immune-related hepatitis (5%), hypothyroidism (4% 
to 10%), hyperthyroidism (4%), hypophysitis (< 1%), type 1 diabetes, immune-related 
pneumonia, sarcoidosis, inflammatory arthritis, etc. Others such as cardiovascular AEs, anemia, 
thrombocytopenia, nephritis, encephalopathy, leukoencephalopathy, post-reversible 
encephalopathy syndrome, peripheral motor and sensory neuropathy, uveitis, episcleritis, 
blepharitis, and acute pancreatitis occurred less frequently. 
 HLX10 is currently being studied with limited safety information available. The available 
clinical data from the first-in-human phase I clinical study (HLX10-001), shows that the most 
frequently reported study drug related adverse events were nausea, fatigue and decreased 
appetite, constipation, vomiting and pyrexia. The severity was mainly grade 1-2. The most 

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frequently reported serious adverse event (SAE) that was greater or equal than grade 3 was 
pyrexia. 
In another phase I clinical study (HLX10HLX04-001) of the study drug combined with another 
antibody, no DLT was observed in the 18 subjects when the study drug was administered from 
1 mg/kg to 10 mg/kg. 
In the phase Ⅱ study (HLX10-008-HCC201) of HLX10 in patients with previously treated HCC, 
1 subject received HLX10 (3 mg/kg) combined with HLX04 (5 mg/kg) once every 2 weeks 
experienced DLT at safety run in stage (increased total bilirubin is 39.4 µmol/L which 
is >2 mg/dL and considered to be caused by hepatocellular cancer progression).  
In the ongoing phase III study (HLX10-002-NSCLC301) of HLX10 in patients with previously 
untreated non-squamous non-small cell lung cancer (NSCLC), 6 subjects have received HLX10 
(4.5 mg/kg) + HLX04 (15 mg/kg) + carboplatin (AUC=5) + pemetrexed (500 mg/m2) once every 
3 weeks with no major safety concerns. No grade ≥4 hematologic toxicity and grade ≥3 non-
hematologic toxicity-safety events and grade ≥2 pneumonia (and no recovery to grade 1 in 3 
days) occurred after the treatment of the first cycles. No serious adverse drug reactions (ADRs) 
were observed in the first stage of the study (safety run-in period). The most common ADRs 
included platelet count decreased, white blood cell count decreased, neutrophil count decreased 
and hypertriglyceridaemia. 
Several other phase II and III clinical studies of the study drug are ongoing, where HLX10 has 
been administered as monotherapy and/or in combination with chemotherapy or other antibody, 
in patients with advanced solid tumors, previously untreated metastatic NSCLC and previously 
treated unresectable or metastatic MSI-H (microsatellite instability-high) or dMMR (deficiency 
in mismatch repair) solid tumors. The available clinical data showed that the study drug given as 
a monotherapy or combined with other therapies was safe and tolerable in patients with 
malignant tumors. 
The most commonly reported side effects with probability greater than 5% include: rash, pyrexia, 
anemia, diarrhea, nausea, decreased appetite, platelet count decreased, white blood cell count 
decreased, neutrophil count decreased, nephritis, hepatic function abnormal, and hypothyroidism. 
Adverse events related to the study drug reported in these studies which are serious, fatal and 
life-threatening include: pyrexia, myocarditis, platelet count decreased, neutrophil count 
decreased, white blood cell count decreased, pneumonitis, hepatic function abnormal, colitis, 
pancreatitis, and renal impairment. 

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More detailed information about the known and expected risks of HLX10 can be referred to in 
the Investigator’s Brochure. 
2.3.3 
Overall benefits: risk and ethical assessment 
At present, chemotherapy for advanced SCLC has encountered the bottleneck of efficacy, and 
there is an urgency to explore to explore more effective first-line treatment for SCLC. With the 
progress of various studies, immune checkpoint combination therapy has become a new 
treatment option for SCLC, which is likely to greatly improve the prognosis of SCLC patients. 
At the same time, the AEs of the atezolizumab combination protocol were consistent with the 
known toxicity of monotherapy, and no new safety signals were found. Based on the current 
study data of HLX10, only 2 subjects experienced DLTs (1 subject received HLX10 
monotherapy [3 mg/kg] once every 2 weeks, and 1 subject received HLX10 [3 mg/kg] combined 
with HLX04 [5 mg/kg] once every 2 weeks), the MTD was not reached yet. The available safety 
data and PK data demonstrated that the safety of HLX10 in patients is acceptable and adequate to 
support the implementation of this phase III clinical study. 

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3 Objectives and Endpoints 
Objectives 
Endpoints 
Primary  
To compare the clinical efficacy of 
HLX10 in combination with 
chemotherapy versus placebo in 
combination with chemotherapy in 
previously untreated patients with 
ES-SCLC. 
Primary Efficacy Endpoint 
 Overall survival (OS) 
Secondary Efficacy Endpoints 
 Progression-free survival (PFS) (assessed by 
the independent radiology review committee 
[IRRC] based on Response Evaluation Criteria 
in Solid Tumors [RECIST] 1.1) 
 PFS (assessed by the investigator based on 
RECIST 1.1 and a modified RECIST 1.1 for 
immune-based therapeutics [termed iRECIST])  
 PFS2 (assessed by the investigator based on 
RECIST 1.1) 
 Objective response rate (ORR) (assessed by the 
IRRC and investigator based on RECIST 1.1) 
 Duration of response (DOR) (assessed by the 
IRRC and the investigator based on RECIST 
1.1) 
Secondary 
To compare the safety and 
tolerability of HLX10 in 
combination with chemotherapy 
versus placebo in combination with 
chemotherapy in previously 
untreated patients with ES-SCLC. 
 
To measure the exposure following 
HLX10 administration.  
 
Safety Endpoints 
 Adverse events (AEs) (including serious 
adverse events [SAEs]), laboratory tests 
(routine blood test, blood chemistry, 
coagulation function, urinalysis, myocardial 
function and thyroid function), 12-lead 
electrocardiogram (12-lead ECG), vital signs, 
and physical examination, etc. 
PK Endpoint 
 Concentration of HLX10 in serum 
Immunogenicity Endpoint 
 HLX10 anti-drug antibody (ADA) positive rate 
Biomarker Endpoint 
 Relationship between PD-L1 expression, 
microsatellite instability (MSI), tumor mutation 
burden (TMB) in tumor tissue and efficacy. 
Quality of life assessment 
 

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4 Study Design 
4.1 Overall Design 
This is a randomized, double-blind, placebo-controlled, multicenter, clinical phase III study to 
compare the clinical efficacy, safety and tolerability of recombinant humanized anti-PD-1 
monoclonal antibody injection (HLX10) or placebo in combination with chemotherapy in 
patients with previously untreated ES-SCLC, to collect PK parameters and to investigate the 
biomarker related to efficacy. See Section 1.2 for study schema and Section 1.3 for SoA. 
Subjects in this study will be randomized to arm A or B at 2:1 ratio as follows: 
• Arm A (HLX10): HLX10 + chemotherapy (carboplatin-etoposide) 
• Arm B (control): placebo + chemotherapy (carboplatin-etoposide) 
Randomization is stratified by PD-L1 expression level (negative: tumor proportion scores [TPS] 
<1%, positive: TPS ≥1%, or not evaluable/not available), brain metastasis (yes versus no), and 
age (≥ 65 years versus < 65 years). 
After screening, subjects meeting the inclusion criteria and none of the exclusion criteria will be 
enrolled. Included subjects will be treated with HLX10 or placebo in combination with 
chemotherapy once every 3 weeks, until disease progression, death, intolerable toxicity, 
withdrawal of informed consent, or occurrence of other reasons specified in the protocol 
(whichever occurs first). 
Initial treatment should be discontinued when they have evidence of disease progression as 
assessed per RECIST 1.1. If a subject has 1st disease progression and is clinically stable, and 
tends to receive 2nd line chemotherapy treatment subsequently (the selection of 2nd line 
chemotherapy may refer to the NCCN guidelines or the ESMO guidelines), it is at the discretion 
of the investigator to continue treating the subject with blinded HLX10 or placebo assignment 
per protocol in addition to the 2nd line chemotherapy, until the 2nd disease progression, intolerable 
toxicity, death, withdrawal of consent, or lost to follow-up. Subjects who permanently 
discontinue initial treatment due to an adverse event, withdrawal of consent, or for any reason 
other than disease progression, will not be eligible for the post-PD treatment. 
Subjects who meet the following conditions may continue the treatment after appropriate 
discussion with the subject and obtaining the supplementary informed consent. 

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1. Subjects who had received HLX10 or placebo in combination with chemotherapy, who 
may benefit from continuing HLX10/placebo treatment despite progression, will be able 
to receive HLX10 or placebo therapy in the post-PD treatment. 
2. Subjects eligible for continued treatment in the post-PD treatment period, as judged by the 
investigator. 
3. The subject should sign the supplementary informed consent form to receive 
investigational product with 2nd line chemotherapy. 
4. The subject is clinically stable, defined as: 
a) With no clinical signs and/or symptoms (including worsening of laboratory findings) 
that might indicate disease progression. 
b) A stable Eastern Cooperative Oncology Group (ECOG) performance status score. 
c) No rapid disease progression or tumor progression requiring urgent alternative 
medical intervention at critical anatomical sites (e.g., spinal cord compression). 
The primary endpoint of this study is to compare the OS of HLX10 in combination with 
chemotherapy versus placebo in combination with chemotherapy. 
 

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Figure 1: Schematic of study treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (2:1) 
Placebo (Day 1) + 
Carboplatin (Day 1) + etoposide  
(Day 1 to 3) 
Once every 3-week cycle for 4 cycles 
HLX10 (Day 1) + 
Carboplatin (Day 1) + etoposide 
(Day1 to 3) 
Once every 3-week cycle for 4 cycles 
HLX10 
Once every 3 weeks 
Placebo 
Once every 3 weeks 
1st Disease Progression  
Follow-Up Period* 
Arm A (HLX10) 
Arm B (control) 
The subject (tending to receive 2nd line chemotherapy treatment subsequently) should re-
consent and meet the following conditions: 
(1) Subjects who had received HLX10 or placebo in combination with chemotherapy, who may 
benefit from continuing HLX10/placebo treatment despite progression, will be able to receive 
HLX10 or placebo therapy in the post-PD treatment period.  
(2) Subjects eligible for continued treatment in the post-PD treatment period, as judged by the 
investigator.  
(3) The subject should sign the supplementary informed consent form to receive investigational 
product with 2nd chemotherapy. 
(4) The subject is clinically stable. 
Continue the treatment until the 2nd disease progression, intolerable 
toxicity, death, withdrawal of consent, or lost to follow-up. 
Starting dose: 
HLX10, 4.5 mg/kg, once every 3 weeks. 
Etoposide: 100 mg/m2; once every 3-week cycle for up to 4 cycles. 
Carboplatin: AUC = 5, up to a dose of 750 mg. Once every 3-week cycle for up to 4 cycles 
* Follow-Up Period includes safety follow-up and survival follow-up. Patients who are not eligible for post-PD 
treatment will be followed up for safety and survival status. 
Post-PD Treatment (Optional) 

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4.2 Scientific Rationale for Study Design 
Rationale for Control Drug Selection 
The platinum-based chemotherapy provided in this study is EC regimen (etoposide plus 
carboplatin), which is the first-line chemotherapy regimen for ES-SCLC recommended by 
NCCN and Chinese Expert Consensus on the Diagnosis and Treatment of Advanced Primary 
Lung Cancer (2016 Edition), allowing investigators and subjects to have more flexibility in 
conducting study and treatment according to the standard clinical practice of drugs. 
Basis for Combination Therapy 
With more insight on the molecular pathogenesis of cancer, the immunological mechanism of 
tumorigenesis and development has gradually become a study hotspot. It is becoming 
increasingly clear that cancer can be recognized by the immune system, and in some cases, the 
immune system can control or even eliminate tumors. PD-1 was originally cloned by Ishida et 
al.8 as a member of the CD28 superfamily in murine T cell hybridomas. It is a monomeric 
glycoprotein that is mainly expressed on the surface of activated macrophages, T lymphocytes, B 
lymphocytes, NK cells, and some myeloid cells. Its ligands, PD-L1 (programmed death ligand 1) 
and PD-L2, are mainly expressed on tumor cells and antigen-presenting cells9,10,11. Because 
activation of the PD-1 gene may be involved in the classical type of programmed cell death, it is 
named programmed death ligand 1 (PD-L1). PD-L1 is highly expressed in a variety of cancers 
and is as high as 88% in some cancers. In these cancers (including lung cancer), PD-1 binds to 
PD-L1 in tumor tissues, weakens the body's immune response, protects tumor tissues from 
cytotoxic T cells, and leads to tumor immune tolerance12,13. Therefore, T cell anti-tumor response 
can be enhanced by blocking the binding of PD-1 to its ligand PD-L114,15,16,17,18. 
In recent years, with the rapid development of tumor immunotherapy, the focus of first-line 
treatment for advanced NSCLC with no driver gene has gradually turned to immunotherapy, and 
multiple PD-1 inhibitors have been approved by the FDA for NSCLC treatment; The NCCN 
Guidelines have also included PD-1 inhibitors as one of the recommended protocols for the 
treatment of relapsed SCLC. In the absence of breakthrough of targeted drug treatment for SCLC 
in the past 30 years, a new drug has been discovered for SCLC. In 2018, the FDA approved 
Nivolumab for the treatment of relapsed SCLC. In addition, a number of clinical trials of PD-1 
antibody combined with chemotherapy for SCLC are currently underway. Preliminary results 
show that PD-1 inhibitor plus chemotherapy can significantly improve overall survival and 
progression-free survival and is expected to become the new standard of first-line treatment for 
SCLC. 

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The survival of cytotoxic chemotherapy in patients with ES-SCLC reaches a plateau, leaving 
much room for improving the prognosis of such patients. Exposure of the immune system to high 
levels of tumor antigens can reasonably be expected to result in cytotoxicity effects on tumor cell 
(TC) by cytotoxic chemotherapy, and restoration of tumor-specific T cell immunity in this setting 
may produce deeper and durable responses than standard chemotherapy alone by inhibiting the 
PD-L1/PD-1 signaling pathway19,20. Therefore, it is reasonable to assume that the combination of 
immunosuppressive and cytotoxic chemotherapy drugs may have a stronger synergistic anti-
tumor effect. 
Rationale for Post-PD Treatment 
Patients with ES-SCLC experience rapid tumor growth, fast clinical deterioration, and have an 
overall poor prognosis. First-line therapy with a platinum agent and etoposide has consistently 
demonstrated high response rates and significant clinical benefit. However, considering the 
limited availability and efficacy or greater toxicity of treatment options after withdrawal, and for 
better adaptation to standard clinical practice, subjects may be considered for subsequent 
treatment assignment blinded beyond radiographic disease progression per RECIST 1.1, at the 
discretion of the investigator, after appropriate discussion with the patient and obtaining 
informed consent. 
In addition, conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because disease progression (by initial radiographic evaluation) does 
not necessarily reflect therapeutic failure. Related research shows that shorter treatment increases 
the risk of relapse or progression, and there are potential benefits to patients receiving longer IO 
(Immunotherapy) treatment21. Because of the potential for pseudoprogression/tumor-immune 
infiltration, this study will allow patients to remain on treatment after apparent radiographic 
disease progression per RECIST 1.1, provided all criteria meet post-PD treatment conditions. 
4.3 Justification for Dose 
Based on the results of the preclinical and clinical trials of HLX10, the currently available PK 
and ADA data support HLX10 4.5 mg/kg based on mean body weight, administered every 
21 days as the recommended dose for phase III clinical study. Results of Dose Exposure 
Response analysis demonstrated both 4.5 mg/kg every three weeks and 3.0 mg/kg every two 
weeks were oversaturated doses. Given the fact that no MTD was observed in anti-PD-1 
antibodies and the European Medicines Agency (EMA) and FDA approved oversaturated doses 
for nivolumab (nivo) and pembrolizumab (pembro) in clinical practice across multiple tumor 
types, Henlius believes that 4.5 mg/kg every three weeks or 3.0 mg/kg every two weeks is 
justified and safe.  

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See Sections 2.2.1 and 2.2.2 for details. 
4.4 End of Study Definition 
The end of the study, defined as the final analysis of OS, will be performed when a target number 
of OS events (approximately 342) are observed, and for final analysis the α is 0.046 (two-sided) 
based on the O'Brien-Fleming alpha spending function. 
Or 
The end of the study is defined as the date when all subjects enrolled completed the safety 
follow-up 90 days after the end of treatment visit. 
Whichever occurs last. Additionally, the sponsor may decide to terminate the study at any time. 
4.5 Unblinding 
Emergency Unblinding 
During study drug treatment, if a life-threatening condition determined by the investigator to be 
related to the use of the study drug, or if the investigator considers the knowledge of the subject’s 
drug is helpful for management of the adverse event, emergency unblinding may be used. The 
decision to unblind in emergency situations shall be the responsibility of the investigator, and the 
sponsor will not delay or reject it. However, the investigator may contact the sponsor or its 
designated personnel to discuss the unblinding and the most favorable option for the subject. The 
investigator should ensure that emergency unblinding is performed only during events stipulated 
in the protocol. The investigator should immediately notify the sponsor of the emergency 
unblinding and the reason for the unblinding, and record these clearly on the subject’s source 
documents. The unblinding process will be completed on Interactive Web/Voice Response 
System (IWRS/IVRS) using the emergency unblinding personal identification number. 
Unblinding can only occur in an affected subject if unblinding is required. 
5 Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The study population will consist of participants with ES-SCLC. Participants must be able to 
provide written consent and meet all the inclusion criteria and none of the exclusion criteria. 
5.1 Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 

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1. Voluntary participation in clinical studies; fully understand, be informed about the study 
and have signed the informed consent form (ICF); willingness to follow and ability to 
complete all trial procedures. 
2. Male or female aged ≥ 18 years at the time of signing the ICF. 
3. Histologically or cytologically diagnosed with ES-SCLC (according to the Veterans 
Administration Lung Study Group staging system). 
4. No prior systemic therapy for ES-SCLC (including systemic chemotherapy, molecular 
targeted therapy, biological therapy, and other investigational therapies, etc.). 
5. Patients who have received chemoradiotherapy for previous limited stage SCLC must be 
treated with curative intent and have a treatment-free interval of at least 6 months from the 
last course of chemotherapy, radiotherapy, or chemoradiotherapy to the diagnosis of 
extensive stage SCLC. 
6. At least one measurable lesion as assessed by the IRRC according to RECIST 1.1 within 4 
weeks prior to randomization. 
Note: Measurable lesions are not from previously irradiated sites. If the lesion at the 
previously irradiated site is the only selectable target lesion, a radiological 
assessment showing significant progression of the irradiated lesion should be 
provided by the investigator. 
7. Patients must provide tumor tissues that meet the requirements for the determination of 
PD-L1 expression levels. Patients are assessed for an evaluable PD-L1 expression 
category (negative: TPS <1%, positive: TPS ≥1%, or not evaluable/not available) by the 
central laboratory for randomization. 
Note: It is recommended to provide formalin-fixed tumor tissue samples, paraffin-
embedded tumor specimens (preferred), formalin-fixed paraffin-embedded (FFPE), 
tumor specimens or newly prepared unstained serial tissue sections (preferably 
adhesive slides) within 6 months prior to the first dose of study medication. A 
relevant pathology report must also be provided for the above specimens. Freshly 
collected specimens, radical resections, core needle biopsy, excisions, incisions, punch 
or clamp biopsies are acceptable (newly obtained tissues are preferred). Fine-needle 
aspirations (i.e., samples that lack a complete tissue structure and provide only cell 
suspension and/or cell smear), brush biopsies, and cell pellet samples from pleural or 
peritoneal effusions are unacceptable. For detailed requirements for tissue samples, 
see the laboratory manual. 

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8. Prior antineoplastic therapy must have been ≥ 2 weeks from the first dose in this study 
with treatment-related AEs resolved to NCI-CTCAE Grade ≤ 1 (except for Grade 2 
alopecia). 
9. An ECOG PS score of 0 or 1. 
10. An expected survival ≥ 12 weeks. 
11. Subjects with prior denosumab use that can and agree to switch to bisphosphonate therapy 
for bone metastases starting prior to randomization and throughout treatment. 
12. Normal major organ functions as defined by the following criteria (no blood transfusions, 
or treatment with albumin, recombinant human thrombopoietin or colony-stimulating 
factor within 14 days prior to the first dose in this study): 
Hematologic system 
Absolute neutrophil count 
(ANC) 
≥ 1.5×109/L  
Lymphocyte 
≥ 0.5×109/L 
Platelet (PLT) 
≥ 100×109/L 
Hemoglobin (Hb) 
≥ 90 g/L 
Hepatic functions 
Total bilirubin (TB) 
≤ 1.5×upper limit of normal (ULN) 
For patients with Gilbert's syndrome, total bilirubin ≤ 3 × 
ULN is acceptable 
Alanine transaminase (ALT) 
≤ 2.5×ULN; 
≤ 5 × ULN for patients with liver metastases 
Aspartic transaminase (AST) 
≤ 2.5×ULN; 
≤ 5 × ULN for patients with liver metastases 
Alkaline phosphatase (ALP) 
≤ 2.5×ULN;  
≤ 5.0 × ULN for patients with liver or bone metastases 
Renal functions 
Creatinine (Cr) 
≤ 1.5×ULN; 
In case of > 1.5 × ULN, creatinine clearance ≥ 50 mL/min  
(calculated from Cockcroft-Gault formula) 

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Coagulation functions 
Activated partial prothrombin 
time (APTT) 
≤ 1.5×ULN 
Prothrombin time (PT) or 
International normalized ratio 
(INR) 
≤ 1.5×ULN 
The above requirements apply only to subjects who are not receiving anticoagulant therapy; 
subjects who are receiving anticoagulant therapy must maintain a stable dose of 
anticoagulants. 
13. Female patients must meet one of the following conditions: 
a. Menopause (defined as no menses for at least 1 year and no confirmed cause other 
than menopause), or 
b. Surgically sterilized (removal of the ovaries and/or uterus), or 
c. Of child-bearing potential, but must meet the following: 
o 
Serum pregnancy test must be negative within 7 days prior to randomization, and 
o 
Agree to use birth control methods with an annual failure rate of <1% or maintain 
abstinence (avoid heterosexual intercourse) (from the signing of ICF to at least 6 
months after the final dose of study drug) (birth control methods with an annual 
failure rate of <1% include bilateral tubal ligation, male sterilization, proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
contraceptive devices and copper-containing intrauterine contraceptive devices or 
condoms), and 
o 
Must not be breast-feeding. 
14. Male patients must: agree to abstinence (avoid heterosexual intercourse) or take 
contraception measures as follows: male patients with a pregnant partner or a partner of 
childbearing potential must remain abstinent or use a condom to prevent embryonic 
exposure during study treatment and for at least 6 months after the last dose of study drug. 
Periodic abstinence (e.g., contraceptive methods based on calendar day, ovulation, basal 
body temperature or post-ovulation) and external ejaculation are ineligible methods of 
contraception. 
5.2 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Histologically or cytologically confirmed mixed SCLC. 
2. Other active malignancies within 5 years or at the same time. Localized tumors that have 
been cured, such as basal cell carcinoma, squamous-cell skin cancer, superficial bladder 

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cancer, prostate carcinoma in situ, cervical cancer in situ and breast cancer in situ are 
acceptable. 
3. Patients who are preparing for or have received an organ or bone marrow transplant. 
4. Pleural or pericardial effusion requiring clinical intervention, or ascites. 
5. Patients with known or documented active CNS metastases and/or carcinomatous 
meningitis at screening. However, the following subjects are allowed to be enrolled: 1) 
Subjects with asymptomatic brain metastases (i.e., no progressive central nervous 
system symptoms caused by brain metastases, no requirement for corticosteroids, and 
lesion size ≤ 1.5 cm) may be included, but are required to receive regular brain imaging 
as a site of lesion. 2) Subjects with treated brain metastases which have been stable for 
at least 2 months (as confirmed by 2 radiological examinations at least 4 weeks apart 
after treatment of brain metastases), with no evidence of new or enlarging brain 
metastases, and with discontinued steroids 3 days prior to study drug administration. 
(Stable brain metastases here should be confirmed before the first dose of the study 
drug.). 
6. Subjects with spinal cord compression that has not been radically treated with surgery 
and/or radiotherapy. 
7. Patients with myocardial infarction within half a year before the first dose of the study 
drug, poorly controlled arrhythmia (including QTc intervals ≥ 450 ms for males and ≥ 
470 ms for females) (QTc intervals are calculated by Fridericia's formula). 
8. Class III to IV cardiac insufficiency according to NYHA classification or a left 
ventricular ejection fraction < 50% by cardiac color Doppler. 
9. Subject has uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium 
or calcium > 12 mg/dL or corrected serum calcium > ULN). 
10. Subject with peripheral neuropathy ≥ Grade 2 by CTCAE. 
11. Human immunodeficiency virus (HIV) infection, positive test for HIV antibody. 
12. Active or latent pulmonary tuberculosis. 
13. Subjects with previous and concurrent interstitial pneumonia, pneumoconiosis, radiation 
pneumonitis, drug-related pneumonitis and severe impaired pulmonary function that 
may interfere with the detection and management of suspected drug-related pulmonary 
toxicity, as judged by the investigator. 
14. Hepatitis B (positive test for HBsAg or HBcAb and positive test for HBV-DNA) or 
Hepatitis C (positive tests for HCV antibody and HCV-RNA). Hepatitis B and C co-
infection (positive test for HBsAg or HBcAb and positive test for HCV antibody). 
15. Known active or suspected autoimmune diseases. Subjects in a stable state with no need 
for systemic immunosuppressant therapy are allowed to enroll. 
16. Treatment with live vaccines and all COVID-19 vaccines (fully administered to the 

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required number of doses) within 28 days prior to study drug administration; inactivated 
viral vaccines for seasonal influenza are allowed. 
17. Subjects requiring treatment with systemic corticosteroids (> 10 mg/day prednisone 
efficacy dose) or other immunosuppressive drugs within 14 days prior to the first dose 
or during the study. However, in the absence of active autoimmune disease, subjects are 
allowed to use topical or inhaled steroids and adrenal hormone replacement therapy at 
doses equivalent to ≤ 10 mg/day of prednisone efficacy. 
18. Any active infection requiring systemic anti-infective therapy within 14 days prior to 
study drug administration or subjects with a positive RT-PCR test for SARS-CoV-2 
infection at randomization. Subjects with a history of COVID-19 infection must have a 
negative RT-PCR test prior to the first dose of the study drug. 
19. Major surgery within 28 days prior to the first dose of the study drug, defined as: 
surgeries requiring at least 3 weeks of recovery to be able to receive treatment in this 
study. 
20. Radical radiation therapy within 3 months prior to study medications. 
Note: Palliative radiotherapy to bone or palliative radiotherapy to superficial lesions is 
allowed according to local standards 14 days prior to the first dose. Radiotherapy 
covering more than 30% of the bone marrow area within 28 days prior to the first dose 
is not allowed. 
21. The subject has previously received other antibodies/drugs against immune checkpoints, 
such as PD-1, PD-L1, CTLA4, etc. 
22. Participation in any other ongoing clinical studies, or less than 14 days from the end of 
the previous clinical study treatment to the start of this trial. 
23. Known history of severe allergy to any monoclonal antibody. 
24. Known hypersensitivity to carboplatin or etoposide. 
25. Pregnant or lactating women. 
26. Known history of psychotropics abuse or drug abuse. 
27. In the judgment of the investigator, the subject has any other factors that may lead to a 
premature discontinuation. 
5.3 Lifestyle Considerations 
No restrictions are required. 
5.4 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 

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ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. In this study, one re-screening is allowed for ineligible subjects: in case of 
unqualified laboratory tests, one re-test can be performed within the screening time window, 
without giving a new screening number; for other conditions noncompliant with the 
inclusion/exclusion criteria, subjects should be re-screened with a new screening number. 
6 Study Drug 
Study drug is defined as any investigational interventions, marketed products, or placebo 
intended to be administered to a study subject according to the study protocol. 
Investigational product is defined as HLX10/placebo. 
Study drugs will be administered IV. 
6.1 Study Interventions Administered 
HLX10 
Name 
Recombinant anti-PD-1 humanized monoclonal antibody injection 
(HLX10) 
Formulations 
Liquid 
Specifications 
100 mg (10 mL)/vial 
Storage conditions 
2-8°C 
Manufacturer 
Shanghai Henlius Biopharmaceuticals Co., Ltd 
Drug supplier 
Shanghai Henlius Biotech, Inc. 
Placebo 
Injection that is not externally recognizable and contains no HLX10 active ingredient, 
manufactured by Shanghai Henlius Biopharmaceuticals Co., Ltd, and provided by Shanghai 
Henlius Biotech, Inc. 
Chemotherapy Drug 
Commercially available carboplatin and etoposide consolidated and provided by Shanghai 
Henlius Biotech, Inc. For information regarding the formulation, preparation, storage, and dosing 
information, please refer to currently-approved information on prescription of carboplatin and 
etoposide. 

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6.2 Dosing Regimen Preparation/Handling/Storage/Accountability 
Dosing Regimen and Preparation 
Study drugs are administered as follows, each treatment cycle is 3-weeks (every 21 days). 
Investigational/reference product: 
• HLX10: 4.5 mg/kg, IV infusion for 30 to 90 minutes, administered on Day 1 of each cycle, 
once every 3 weeks (21 days). 
• Placebo: IV infusion, administered on Day 1 of each cycle, once every 3 weeks (21 days). 
The infusion of investigational product is completed between 30 mins and 90 mins if there is not 
any infusion reaction. The diluted drug solution is recommended to be used within 6 hours of 
preparation and has been shown to be stable for up at 24 hours. The diluted drug solution needs 
to be stored at approximately 2-8 °C for no longer than 24 hours and be kept from light if not 
used within 6 hours. 
Other study drugs: chemotherapy 
• Etoposide: 100 mg/m2, IV infusion, on Days 1, 2, and 3 of each cycle. On Day 1, etoposide 
shall be administered following infusion of carboplatin.  
• Carboplatin: AUC = 5, up to a dose of 750 mg, IV infusion, on Day 1 of each cycle. 
Dose of carboplatin shall be calculated according to the following Calvert formula:  
 Dose of carboplatin (mg) = target AUC x [(CrCl (mL/min) + 25)] 
 Creatinine clearance (CrCl) is calculated according to the Cockroft-Gault formula 
(Appendix 6: Cockcroft and Gault Formula) on the basis of the subject’s most recent serum 
creatinine and body weight. Note: If CrCl calculated by the Cockroft-Gault formula 
is > 125 mL/min, CrCl shall be calculated using an alternative formula in accordance 
to the standards of the study site, or capped at 125 mL/min. 
A combination of HLX10 or placebo + carboplatin + etoposide shall be administered in a 3-week 
treatment cycle; carboplatin and etoposide are administered for a maximum of 4 cycles. 
Refer to Figure 1 "Schematic of study treatment" for the regimen of each treatment arm. In each 
3-week cycle, the subjects shall receive an IV infusion of HLX10 or placebo, followed by 
intravenous infusion of carboplatin, then etoposide on the first day of dosing with close 
monitoring of vital signs. Administration of HLX10/placebo shall be blinded, while carboplatin 
+ etoposide are openly administered. Subjects will continue to receive etoposide on Days 2 and 
3. The treatment will continue until disease progression, intolerable toxicity, discontinuation 

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decided by the subject or the investigator, death, withdrawal of informed consent, pregnancy, 
noncompliance with protocol or procedure requirements, administrative reasons, or other reasons 
specified in the protocol, whichever occurs first. The dosing window is ±3 days from the 
scheduled date of administration (from the date of the first dose). Drugs administered outside the 
dosing window is considered a delayed dose, and subsequent doses shall be administered 
according to the actual date of last administration. If chemotherapy is not used due to toxicity or 
other reasons in a certain cycle, it is not counted as the number of combined chemotherapy 
cycles. After completing 4 cycles of chemotherapy, even if the subject does not meet the above 
criteria, the chemotherapy will not be continued. 
Handling, Storage, Management, and Distribution 
The study drug will be dispatched by the sponsor or a third-party designated by the sponsor. The 
study sites should establish a good drug receipt procedure and require a specialized personnel to 
receive the study drug and sign the drug receipt form. The study drug can only be used in the 
trial specified by this protocol and only authorized staff will be able to access these drugs. 
The study site should establish a strict drug management system with a specialized personnel 
responsible for the safekeeping and distribution of the study drug and establish a registration 
system. The study site should ensure that the storage conditions of the study drug are in 
compliance with the requirements and are recorded and stored. 
Only the study personnel or his/her designee will be able to provide the drug to the subjects and 
manage the drug. The dispensing and returning of each drug should be recorded on the 
specialized record sheet in a timely manner. If the study drug is lost, dispersed, or misused, it 
should be recorded in detail. 
The study drug will be returned and destroyed by the sponsor or the third-party designated by the 
sponsor, and must not be released into the market. 
Refer to the drug management and operating procedure for detailed operation. 
Packaging and labeling 
Vials of HLX10/placebo, carboplatin, and etoposide are labeled by a third-party designated by 
the sponsor. 
The content of the label includes: drug name, drug number, protocol number, specifications, 
dosage and administration, batch number, expiration date, storage requirements, and other 
specific information required by the local regulatory authority and Good Manufacturing Practice. 

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6.3 Measures to Minimize Bias: Randomization and Blinding 
All subjects will be centrally randomized the IWRS/IVRS. Each subject will be assigned a 
unique number (randomization number) that encodes the subject’s assignment to one of the two 
arms of the study, according to the randomization schedule generated by Medidata using a 
validated computer program. Details of the procedure are described in the IWRS/IVRS Manual 
provided to all sites. 
Randomization 
This study adopts a randomized, double-blind study design. The eligible subjects will be 
randomly assigned to the following two groups using the IWRS/IVRS at 2:1 ratio: 
• 
Arm A (HLX10): HLX10 + chemotherapy (carboplatin-etoposide) 
• 
Arm B (control): placebo + chemotherapy (carboplatin-etoposide) 
Stratification factors for randomization include: PD-L1 expression level (negative: TPS <1%, 
positive: TPS ≥1%, or not evaluable/not available), brain metastasis (yes versus no), and age (≥ 
65 years versus < 65 years). 
Blinding 
The blinding will be performed by the Statistical Unit during study treatment. The subjects, 
investigator, sponsor, and designated personnel will not be aware of the randomization and 
treatment allocation. This study will perform overall unblinding after the last subject completes 
the end of study visit. Unblinding will be performed only in case of emergency (emergency 
rescue can only be conducted if the type of randomized drug received by the subject is known) or 
as required by regulatory authorities. Otherwise, blinding should be maintained. All 
randomization numbers will be unblinded only after all data are entered into the database, all 
data queries are resolved, and subjects are included in analysis sets. 
6.4 Study Treatment Compliance 
During the study and during the follow-up period, the situation of drug use during the study 
treatment will be recorded in the eCRF. Any deviations from the medications stipulated in the 
study protocol will be recorded in the eCRF, including the date and reason for the use of 
medication. The clinical research associate (CRA) will review treatment compliance during the 
study site visits and at the end of the study. 

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6.5 Concomitant Therapy 
The investigator may, at his/her discretion, administer any drugs that he/she deems necessary for 
the treatment of subjects and are not expected to interfere with the evaluation of the study drugs 
(i.e., the best supportive care). Prophylactic and other supportive treatment for nausea and 
vomiting may be given to subjects according to local medical practice before and after 
carboplatin and etoposide administration. 
All concomitant medications (including start/end dates, total daily doses, and indications) must 
be documented in the subject's source document and in the corresponding section in the eCRF. 
6.5.1 Prohibited Concomitant Therapies 
Medications or treatments prohibited during the study treatment period include: 
• Any other systemic chemotherapy, radiotherapy, immunotherapy, biological therapy, 
molecular targeted therapy with anti-tumor effects or modern Chinese medicine preparations 
in anti-tumor therapy approved for marketing by National Medical Products Administration 
(NMPA) (see Appendix 9) during initial treatment period, immunomodulators with adjuvant 
anti-tumor effects (e.g., thymosin, lentinan, interleukin-12, etc.) that has anti-tumor effect; 
local remission of an isolated lesion (other than the target lesion) is acceptable (e.g., local 
surgery or radiotherapy for bone metastasis) 
• Any other clinical trial drugs; 
• Other immunosuppressive drugs, including but not limited to: systemic glucocorticoids with 
a dose of more than 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
tumor necrosis factor (TNF)-inhibitors. Except for the following situations: 
o 
The use of immunosuppressive drugs to treat study treatment-related AEs; 
o 
Where they are used for short-term prophylaxis in subjects who are expected to 
receive chemotherapy, and the use of glucocorticoids in subjects who have 
hypersensitivity reactions required by the prescription information on the drug; 
o 
Used in subjects allergic to contrast agents; 
o 
The use of inhaled, topical, and intranasal glucocorticoids is permitted; 
o 
If clinical indications are present and the investigator considers it necessary to 
carry out disease management for the subject, the use of short-term glucocorticoids 
(e.g., to control chronic obstructive pulmonary disease, radiotherapy, nausea, etc.) 
is permitted; 

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• Live vaccine administration within 4 weeks prior to the first dose of study drug and during 
the study. Live vaccines include but are not limited to: measles, epidemic parotitis, rubella, 
varicella, yellow fever, rabies, Bacillus Calmette-Guerin, typhoid fever vaccines. Injectable 
inactivated seasonal influenza vaccines are allowed, but intranasal live attenuated influenza 
vaccines are not allowed. 
6.5.2 Permitted Medications/Treatments 
Medications and therapies which are permitted during the study include: 
• Treatment for complications, AEs or symptoms (including blood products, blood 
transfusions, infusions, antibiotics, anti-diarrheal medications, etc.), with the exception of 
medications/therapies which are expected to interfere (or interact) with the evaluation of the 
study; 
• Antiemetics; 
• Nutritional support; 
• Medication or therapy necessary for previous disease. 
6.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or his/her qualified designee will review all new anti-cancer therapy initiated 
after the discontinuation of trial treatment. If the subject continues the post-PD treatment, he/she 
must choose to receive 2nd line chemotherapy. The preferred 2nd line chemotherapy was 
determined by the investigators following the NCCN /or ESMO guidelines and communicated as 
such to the subjects who chose to continue the post-PD treatment. Any other anti-PD1 and anti-
PD-L1 therapy are not allowed. 
6.6 Dose Modification 
Starting from the beginning of HLX10 or placebo infusion, subjects shall be closely monitored 
for allergic reactions that may occur within a few minutes. In case of mild symptoms (such as 
flushing or local skin reactions), drugs may be administered at a slower speed. For serious 
hypotension, bronchospasm, or generalized rash/erythema, the administration should be stopped 
immediately, and appropriate therapies should be given. For a life-threatening reaction, including 
allergic reactions, hypersensitivity reactions, renal failure, severe cardiopulmonary events, and 
severe skin reactions, etc., the medications shall be discontinued permanently. 
The dosing window is ± 3 days from the scheduled date of administration (from the date of the 
first dose). Drugs administered outside the dosing window is considered a delayed dose, and 
subsequent doses shall be administered according to the actual date of last administration. During 
the course of combined treatment, if a delay of more than 2 weeks is expected due to the toxicity 

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of chemotherapy, only HLX10 or placebo will be administered until the toxicity returns to the 
standard of chemotherapy administration. Chemotherapy may be continuously suspended for a 
maximum of 6 weeks, otherwise the chemotherapy should be discontinued. If a delay of more 
than 2 weeks is expected due to the toxicity of HLX10 or placebo, only chemotherapy will be 
administered until the toxicity recovers to the HLX10 or placebo dosing criteria. HLX10 or 
placebo therapy may be continuously suspended for a maximum of 12 weeks, otherwise the 
HLX10 or placebo will be discontinued. In case of a delay due to toxicity with equivocal 
association, all the study drugs shall be synchronously delayed if the event is expected to return 
to re-dosing standards within 2 weeks. 
General principles for dose modification 
Any modified or delayed doses or adopted supportive therapies should be recorded in the source 
documents and eCRFs. Adverse events are assessed for severity according to CTCAE v5.0. 
• For concomitant conditions already present at baseline, dose modifications may be 
determined by the investigator based on changes in severity of toxicity. For example, if the 
subject already has a Grade 1 weakness at baseline, and the severity increases to Grade 2 
during treatment, it may be considered to make dose modification according to Grade 1 
toxicity due to 1-grade increase in toxicity. 
• If multiple toxicities of different severities occur at the same time, the dose should be 
adjusted according to the most severe toxicity. 
• If the toxicity is related to one of the study drugs only (for example, HLX10, carboplatin or 
etoposide) as assessed by the investigator, dose modification of that study drug only with 
reference to the corresponding dose modification principle is acceptable, and the subject can 
continue receiving the other study treatment in the absence of other contraindications. 
• If the toxicity is associated with only one of the chemotherapy medications as assessed by the 
investigator, the dose of the other chemotherapy medication may not be adjusted. 
• In the event that a delay is required for reasons of toxicity (not definitively related to which 
drug), similar delays of all study drugs at the same time are required if recovery to a re-
dosing level is expected within 2 weeks. 
• If HLX10/placebo, carboplatin, or etoposide is interrupted due to toxicity, study treatment 
must be restarted, keeping HLX10/placebo in sync with the chemotherapy treatment cycles. 
Principles for HLX10 or placebo dose modifications 

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In the event of HLX10- or placebo-related toxicity, a delay in HLX10 or placebo is allowed 
rather than dose adjustment. Subjects who miss a scheduled infusion should be actively 
contacted to arrange another visit as soon as possible for administration. Administration of 
HLX10 or placebo may be delayed, but a dosing interval of up to 12 weeks is considered 
intolerable of HLX10/placebo where HLX10 or placebo will be permanently discontinued, and 
the subject should withdraw from the trial. For a treatment delay due to intolerance to HLX10 or 
placebo, chemotherapy should be administered as scheduled, and HLX10 or placebo may be 
postponed to the next cycle with no more than 12 weeks between doses.  
Principles for chemotherapy dose modifications 
In the event of intolerance to etoposide/carboplatin, doses may be adjusted twice in accordance 
with the prescribing information of carboplatin and etoposide, the investigator’s decision based 
on the subject’s safety, and local treatment standard practice. Once reduced, the dose cannot be 
increased back to 100%. 
If treatment is delayed due to intolerance to chemotherapy, chemotherapy may be delayed to the 
next cycle of administration, with the maximum permissible interval for chemotherapy not 
exceeding 6 weeks. 
The following are recommended carboplatin dose modifications for hematological and non-
hematological toxicities. 
Hematological toxicities 
At the start of each cycle, ANC must be ≥ 1.5 × 109/L and PLT count must be ≥ 100 × 109/L. 
Otherwise the treatment should be postponed for up to 42 days to provide a sufficient period for 
recovery. According to the guidelines of the ASCO and NCCN, growth factors can be given to 
subjects with reduced ANC and/or PLT. At the beginning of subsequent cycles after recovery, 
dosage shall be adjusted based on the PLT and ANC nadirs of the last cycle (refer to Table 1).

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Table 1: Carboplatin Dose Modifications for Hematological Toxicities 
Toxicitya 
Dose of carboplatin 
ANC < 0.5 ×109/L and PLT ≥ 50 ×109/L 
75% of the planned dose 
PLT < 50 ×109/L, regardless of ANC 
75% of the planned dose 
PLT < 50 ×109/L with Grade 2 hemorrhage, regardless of ANC 
50% of the planned dose 
ANC < 1×109/L with fever ≥ 38.5 °C 
75% of the planned dose 
ANC = Absolute neutrophil count, PLT = Platelets. 
aNadir of the last cycle 
Doses shall be permanently reduced at the first onset of neutropenic fever or thrombocytopenia 
(PLT < 25 × 109/L or < 50 × 109/L with signs of bleeding or need for blood transfusion). For the 
need for dose reduction at the second onset of neutropenic fever or thrombocytopenia, dose of 
carboplatin shall be reduced in accordance with the physician’s judgement and local standard 
medical practices. In case of neutropenic fever or Grade 4 neutropenia, colony-stimulating 
factors (such as granulocyte colony-stimulating factor) may be administered in place of reduced 
doses in accordance with local standard medical practices and ASCO guidelines. For subjects 
who require a third dose reduction, the chemotherapy shall be discontinued immediately. 
Subjects who require dosing modification due to both ANC and platelet count shall receive a 
lower dose. 
Treatments may be postponed for up to 42 days until the first day when ANC is ≥ 1.5 × 109/ L 
and PLT is ≥ 100 × 109/L. However, if the counts fail to recover within 3 weeks, the 
chemotherapy shall be reduced or suspended in accordance with the physician's judgement and 
local standard medical practices before ANC recovery. 
The investigator shall pay attention and remain alert to early and significant signs of 
myelosuppression, infections and neutropenic fever, to ensure a prompt and appropriate 
management of such complications. The investigator shall remind the subjects of the signs of 
such complications and encourage them to seek medical attention as soon as possible. 
If chemotherapy is to be suspended due to hematological toxicities, a complete blood count 
(including white blood cell (WBC) differential counts) shall be performed once a week until such 
counts return to the lower limit specified for the treatment. The treatment shall be completed as 
planned thereafter. 
No dose reduction is required for anemia. Subjects shall be given supportive care in accordance 
with the guidelines of the institution where the attending physician is located. 

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Non-hematological toxicities 
In the event of non-hematologic toxicities, treatment shall be delayed for up to 6 weeks until the 
measurement falls below or is equivalent to the subject’s baseline value (or Grade ≤1 if the 
patient did not have the toxicity at baseline). At the beginning of the subsequent cycles, the dose 
shall be reduced based on the dose of the last cycle leading to non-hematologic toxicities. The 
following table includes related recommendations for dosing modifications for non-
hematological toxicities. 
Table 2: Carboplatin Dose Modifications Based on Non-Hematological Toxicities in Previous Treatments 
Toxicities 
Modified carboplatin dose by % of 
planned dosea 
Diarrhea 
Grade 3 or 4b 
75% 
Nausea/vomiting 
Grade 3 or 4c 
75% 
Neurotoxicity 
Grade 2 
75% 
Grade 3 or 4 
50% or permanent discontinuation 
Transaminitis 
Grade 3 
75% 
Grade 4 
Discontinuation 
Others 
Grade 3 or 4 
75% 
AUC = Area under the concentration-time curve. 
a 
Modify carboplatin dose to a specific percentage of the previous AUC, if deemed appropriate by the attending physician 
b 
Grade 3 or 4 diarrhea requiring adequate antidiarrheal medication or any severity of diarrhea that requires hospitalization. 
c       Despite the use of anti-emetics. 
Recommended etoposide dosing modifications are as follows. The investigator may adhere to 
the following or to his/her clinical practice during the study. 
Table 3: Etoposide Dose Modification for Subjects with Renal Impairment 
Creatinine clearance rate (mL/min) 
Dose of etoposide 
>50 
100% 
15–50 
75% of the dose 
Modification of etoposide dose based on the prescribing information for etoposide and the local 
medical standard is permitted. Once reduced, the current dose will never return to 100%. 
6.7 Intervention after the End of the Study 
Subjects will receive standard of care treatment as determined by their healthcare provider after 
completion of the study. 

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7 Discontinuation of Study Intervention, Participant Discontinuation, and 
Study Termination 
7.1 Discontinuation of Study Intervention 
7.1.1 Reasons for Premature Discontinuation 
A discontinuation of treatment means that the subject will no longer receive a study medication 
of this trial. Reasons for the discontinuation of treatment may include: 
1. Poor subject compliance that has affected the efficacy and safety evaluation; 
2. 
The occurrence of AEs or SAEs in the subjects, who are deemed unsuitable to continue 
receiving the study drug treatment as judged by the investigator; 
3. 
Evidence of clear disease progression or worsening of the disease;  
4. 
A delayed study drug administration meeting the criteria specified in the protocol; 
5. 
Subject lost to follow-up or death during treatment; 
6. 
Subject decides to withdraw informed consent; 
7. 
Subject decides to discontinue treatment; 
8. 
Other reasons of discontinuation as determined by the investigator in the best interest of 
the subject. 
7.1.2 Management of premature discontinuations 
The reasons for premature discontinuations shall be documented in the eCRF by the investigator. 
All subjects who discontinue the trial prematurely (except patients who withdraw informed 
consent) and agree to continued follow-up of associated clinical outcome information, shall 
undergo an EOT visit and be followed up for safety and survival. See Section 8.2.4 for 
assessments during the follow-up period. 
Subjects who discontinue the trial for reasons other than disease progression and agree to 
continue follow-up of associated clinical outcome information should be radiologically followed 
up until disease progression, withdrawal of informed consent, death or start of a new 
antineoplastic therapy. 
All AEs present at the time of discontinuation must be followed up until the outcomes of such 
AEs. 
In case of an enrolled subject's withdrawal for any reason, no subject replacement is permitted.  

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7.2 Participant Discontinuation/Withdrawal from the Study 
A subject may withdraw from the study at any time at his/her own request, or may be withdrawn 
at any time at the discretion of the investigator for safety, behavioral, or administrative reasons. 
If the subject withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records. 
If a subject develops fever or symptoms suspected of being a result of COVID-19 during the 
study, they will be instructed to follow-up with their regular healthcare provider or follow the 
instructions for suspected COVID-19 cases per their local health authority. A subject will 
discontinue treatment based on discussion with the Sponsor and Medical Monitor under the 
following circumstances: any suspected or confirmed COVID-19 case will be immediately 
discontinued from study treatment for up to 12 weeks after the last study drug administration; 
subjects who recover from the infection within 12 weeks from the last study drug administration, 
can continue treatment following Sponsor’s confirmation. 
Refer to Section 1.3, the SoA, for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.3 Loss of Participants to Follow-Up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined) and counsel the subject on the 
importance of maintaining the assigned visit schedule and ascertain whether or not the 
subject wishes to and/or should continue in the study. 
• In cases in which the subject is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the subject (where possible, three telephone calls 
and, if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s medical 
record/CRF. 

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Should the subject continue to be unreachable, he/she will be considered to have withdrawn from 
the study. 
7.4 Premature Termination of Study and Site Closure 
The study may be terminated prematurely for the reasons described below, and the premature 
termination of the study must be approved in writing by both the principal investigator and the 
Sponsor, and the results of the study should be reported as required by the protocol. 
1. The study is unlikely to be completed within an acceptable time frame due to difficult 
enrollment of subjects; 
2. The investigator doubts the safety of the drug during the study, and believes that 
continuing the study will bring serious risks to the subjects;  
3. The principal investigator and the Sponsor believe that it is necessary to terminate the 
study prematurely based on the number of AEs and their severity; 
4. The expected efficacy cannot be reached, and it is not necessary to continue the clinical 
study; 
5. Withdrawal of the study by the drug regulatory authority; 
6. The Sponsor has the right to decide to terminate the study in a study site if the following 
occurs: 
• Serious violation of International Conference on Harmonization Good Clinical 
Practice (ICH-GCP) by the study site 
• Multiple serious protocol violations by the study site 
After termination of the study, all study-related records should be retained for reference. 
 
8 Study Assessments and Procedures 
8.1 Tests and Evaluations during the Study 
See Section 1.3 for SoA of tests and evaluations during the study. 
Demographics and Medical History 

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Demographics contain information on date of birth, gender, ethnicity, etc. 
At screening, lung cancer history of subjects must be collected, including: clinical phase, 
pathological diagnosis, diagnosis method, diagnosis date and prior medications (surgical history, 
radiotherapy/chemotherapy history, etc.). Subjects' personal histories are also collected, 
including allergy history, drug dependence history, smoking and drinking; in addition, histories 
of other important diseases within one year prior to signing the informed consent form must be 
collected. 
Prior Treatment and Concomitant Treatment 
All prior and concomitant medications are recorded from 30 days prior to signing the informed 
consent through the safety follow-up visit should be recorded. Concomitant medications 
associated with AEs are recorded up to 90 days after the last study treatment. Prior and 
concomitant medications (including traditional Chinese medicine) are collected and recorded in 
the eCRF. 
Adverse Event Assessment 
All AEs and treatment emergent AEs are recorded from the time of signing the ICF until 90 days 
after the last study treatment. If a subject started a new antineoplastic therapy during the AE 
collection period, only information on AEs related to study treatment are collected after the new 
antineoplastic therapy. 
Quality of Life Assessment 
In this study, subjects will be assessed for quality of life, including by EQ-5D-5L, EORTC QLQ-
C30 and EORTC QLQ-LC13. 
EQ-5D-5L: The EQ-5D is a standardized measure of health status developed by the EuroQol 
group that allows a simple and general rating of health status from a clinical and economic 
evaluation perspective. The scale is applicable to a variety of health conditions and treatments. It 
lists simple descriptive features, gives single index values for health state, and can be used for 
clinical and economic evaluation of health treatments as well as population health surveys. This 
questionnaire contains 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has 5 response options (no problems, slight problems, 
moderate problems, severe problems, and extreme problems) that reflect an increased degree of 
severity. 

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Since 2009, the EuroQol group has developed a more sensitive EQ-5D version (EQ-5D-5L) in 
which the range of responses for each dimension is expanded, i.e., from three levels of increasing 
severity to five. Preliminary studies have shown that, compared to the nature of the 3-level 
version of the measured parameters, the 5-level version improved in the following aspects: 
reduced ceiling effects, increased robustness, and enhanced ability to distinguish between 
different health levels. 
During the study, subjects are asked to select the most appropriate level from the five dimensions 
described above, indicating their current health status. The questionnaire also includes a visual 
analog scale in which subjects will be asked to rate their current health state on a scale from 0 to 
100, with 0 indicating the worst health state (see Appendix 3: Quality of Life Scale EORTC 
QLQ-C30, EQ-5D-5L, EORTC QLQ-LC13). 
EORTC QLQ-C30: The EORTC QLQ-C30 v3 questionnaire is an established measure of 
health-related quality of life (HRQoL) and is commonly used as an endpoint in oncology clinical 
trials. The questionnaire assesses HRQoL/health status through 9 multi-item scales: 5 functional 
scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, nausea 
and vomiting), and 1 global health and QoL (quality of life) scale. The 6 individual symptom 
measures include: dyspnea, insomnia, loss of appetite, constipation, diarrhea, and financial 
difficulties (see Appendix 3: Quality of Life Scale EORTC QLQ-C30, EQ-5D-5L, EORTC QLQ-
LC13). For the 15 domains described above, the total score is standardized to a range from 0 to 
100, where higher scores indicate stronger functioning, higher HRQoL or higher symptom levels. 
EORTC QLQ-LC13: The QLQ-LC13 is a 13-item self-administered questionnaire for lung 
cancer disease that will be used along with the EORTC QLQ-C30. The scale includes both 
multiple and single lung cancer-related symptom parameters (i.e., cough, hemoptysis, dyspnea 
and pain), as well as side effects of conventional chemotherapy and radiotherapy (i.e., alopecia, 
neurological disorders, oral pain and dysphagia). Similar to the EORTC QLQ-C30, all questions 
(except one) are on a 4-point scale: "not at all", "a little", "quite a bit", and "very much". Only 1 
question (43rd question "Did you take any medicine for pain?") is with response options of "yes" 
or "no". The QLQ-LC13 are scored similarly to the EORTC QLQ-C30. 
Echocardiogram 
Echocardiography must be performed for all subjects at screening, and the results of left 
ventricular ejection fraction are recorded. 

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During the study treatment, if the subject has clinical symptoms such as shortness of breath, 
tachycardia, cough, jugular vein distention and hepatomegaly, relevant examinations must be 
timely performed after assessed by the investigator. 
12-Lead Electrocardiogram (ECG) 
Subjects will rest for 5 minutes before each 12-lead ECG. In case of clinically significant ECG 
abnormalities at a visit, a re-examination is recommended within 24 hours. 
Complete Physical Examination 
At screening, the subjects shall have a complete physical examination including head and neck 
(including thyroid gland), chest (including heart and lung), abdomen (liver, gallbladder, spleen 
and kidney), limbs, skin, lymph nodes, nervous system as well as the general conditions of 
subjects, with the examination results recorded; special attention should be paid to the symptoms 
and signs in respiratory system. 
Symptom-Directed Physical Examination 
A symptom-directed physical examination will be performed by the investigator during study 
treatment based on clinical observations and symptoms. Clinically significant physical 
examination abnormalities that are judged by the investigator to be significantly worse than the 
screening period or newly developed should be recorded as AEs. 
Height, Body Weight and Vital Signs 
Height is measured only at screening. 
Vital signs should be assessed after the subject has rested for at least 5 minutes, including 
blood pressure (mmHg), pulse (beats/min), respiratory rate (breaths/min) and body 
temperature (°C), and body weight should be recorded. 
Body weight and vital signs are to be measured prior to each dose during study treatment. If the 
subject’s weight on the day of dosing differs by > 10% from the weight used to calculate the dose 
of investigational product, the dose of investigational product must be recalculated. All doses 
should be rounded to the nearest milligram. 
ECOG Score 
Evaluation of ECOG performance status by the investigator is recommended throughout the 
study. The first ECOG score should be completed within 7 days prior to randomization. 

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Local Laboratory Tests 
Local laboratory tests performed at study sites include routine blood test, serum biochemistry, 
coagulation, myocardial function, urinalysis, thyroid function, virology, tuberculosis screening 
(as requested by the Bulgarian Drug Agency for Bulgarian subjects) and pregnancy test. Routine 
blood test, biochemistry, coagulation, myocardial function and urinalysis should be performed 
within 3 days pre-dose in each treatment cycle; For laboratory tests from the screening period 
completed on Day -7 ~ Day -1, it is not necessary to repeat the test again before the first 
administration (C1D1). For chemotherapy, routine blood tests should be performed on Day 8 (± 
3 days) of each treatment cycle to closely monitor bone marrow suppression. For aforementioned 
laboratory tests scheduled on the same day as study treatment, the study treatment can be 
arranged only after the test results are obtained. During the treatment period, thyroid function 
and blood pregnancy (for females of childbearing age only) tests are performed 3 days pre-dose 
every 2 cycles. 
 
 

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Table 4: Laboratory Tests 
Routine blood test 
Biochemistry 
Urinalysisa 
Others 
Red blood cell count 
(RBC) 
Hemoglobin (HGB) 
Platelet (PLT) 
White blood cell count 
(WBC) 
White blood cell 
differential count and 
percentage 
 
Basophils 
(BAS&BAS%) 
 
Eosinophils 
(EOS&EOS%) 
 
Lymphocytes 
(LYM&LYM%) 
 
Monocytes 
(MON&MONO%) 
 
Neutrophils 
(NEU&NEUT%) 
 
Urea (UREA)/Blood 
urea nitrogen (BUN) 
Creatinine (CR) 
Fasting blood 
glucose (GLU) 
Total bilirubin (TB) 
Direct bilirubin (TB) 
Alanine 
aminotransferase 
(ALT) 
Aspartate 
aminotransferase 
(AST) 
Alkaline phosphatase 
(ALP) 
Lactate 
dehydrogenase 
(LDH) 
Total cholesterol 
(CHOL) 
Total protein (TP) 
Albumin (ALB) 
Sodium (Na) 
Potassium (K) 
Magnesium (Mg) 
Chloride (Cl) 
Calcium (Ca) 
Phosphorus (P) 
Specific gravity (SG) 
Urine leukocytes 
Urine pH value 
Urine protein (U-PRO) 
Urinary glucose 
(U-GLU) 
Ketones (KET) 
Urine occult blood 
(BLO) 
Microscopic 
examination of white 
blood cells (U-WBC) 
Microscopic 
examination of red 
blood cells (U-RBC) 
Coagulation function 
Prothrombin Time（PT） 
Activated Partial 
Thromboplastin Time 
(APTT) 
International Normalized 
Ratio (INR) 
Myocardial function 
Troponin-I (TnI)/troponin-T 
(TnT), creatine kinase 
isoenzyme (CK-
MB)/creatine kinase (CK), 
myoglobin Brain Natriuretic 
Peptide (BNP)/N-terminal 
pro-Brain Natriuretic Peptide 
(NT-pro BNP) 
Thyroid function testsb 
Triiodothyronine (T3 or FT3) 
Thyroxine (T4 or FT4) 
Thyroid-stimulating hormone 
(TSH) 
Virologyc 
Hepatitis B Surface Antigen 
(HBsAg) 
Anti-HBs (HBsAb) 
Anti-HBc (HBcAb) 
Anti-Hepatitis C (HCV) 
Antibody 
HBV DNA (optional) 
HCV RNA (optional) 
Anti-HIV 

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Routine blood test 
Biochemistry 
Urinalysisa 
Others 
Pregnancy testd 
Tuberculosis teste 
a. 
If a subject has two consecutive 2++ urine protein or one ≥ 3+++, urine protein should be tested at 24 
hours; 
Microscopic examination of white blood cells (U-WBC) should be collected if urine leukocytes is out 
of normal range. Microscopic examination of red blood cells (U-RBC) should be collected if urine 
occult blood is out of normal range. 
b. 
Thyroid function tests will be performed during screening and within 3 days prior to drug 
administration every 2 treatment cycles during the treatment period; 
c. 
All subjects are tested for HBsAg or HCV antibody at screening; Patients with HBsAg (+) and/or 
HBcAb (+) should be further tested for HBV DNA titer; and HCV antibody positive subjects should be 
further tested for HCV RNA. In case of HBV DNA (-) and: 1) HBsAg (+), or 2) HBcAb (+) and 
HBsAg (-) at baseline, HBV antibody and HBV DNA should be tested every 2 cycles during the 
treatment period. In case of HCV antibody (+) and HCV RNA (-) at baseline, HCV antibody and HCV 
RNA should be tested every 2 cycles during the treatment period. 
d. 
Women of childbearing potential should have a blood pregnancy test within 7 days prior to 
randomization and must have a negative result for enrollment; this is also tested within 3 days pre-dose 
every 2 cycles. 
**Routine blood test, blood chemistry, coagulation function, myocardial function and urinalysis must be 
performed at screening and within 3 days prior to drug administration every treatment cycle. When the 
aforementioned laboratory tests and study drug administration are scheduled on the same day, the study 
drug administration must be scheduled only after the test results are obtained. Data from screening period 
should be completed on Day -7 ~ Day -1, and it is not necessary to perform the test again before the first 
administration (C1D1). Routine blood tests will be performed on Day 8 (±3 days) of each treatment cycle 
during treatment with carboplatin, and close attention should be paid to bone marrow suppression. 
e. 
Bulgarian subjects must undergo tuberculosis testing for active and latent tuberculosis using a testing 
method as per local standard practice (as requested by the Bulgarian Drug Agency for Bulgarian 
subjects). 
 
Central Laboratory Tests 
PK and ADA samples of HLX10 or placebo are collected and sent to the central laboratory for 
evaluation. PK and ADA samples for HLX10 or placebo will be collected at the following time 
points: 

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Within 7 days pre-dose in Cycle 1, within 3 days pre-dose in Cycles 2, 4, 6, 8 and every 4 cycles 
thereafter, within 2 hours after the end of dosing in Cycles 1 and 8 of treatment period (for PK 
only), and at EOT visit and safety follow-up. 
Table 5: Blood Sample Collection Time Points 
Study visits 
Blood sampling 
Pharmacokineticsa 
Anti-drug 
antibodyb 
Treatment period 
Cycle 1 
Within 7 days pre-dose 
X 
X 
Within 2 hours post-dose 
X 
- 
Cycle 2 
Within 3 days pre-dose 
X 
X 
Cycle 4 
Within 3 days pre-dose 
X 
X 
Cycle 6 
Within 3 days pre-dose 
X 
X 
Cycle 8 
Within 3 days pre-dose 
X 
X 
Within 2 hours post-dose 
X 
- 
Every 4 cycles 
thereafter 
Within 3 days pre-dose 
X 
X 
Discontinuation 
- 
X 
X 
Safety follow-up 
- 
X 
X 
a. Blood samples for HLX10 PK are collected within 2 hours after the end of HLX10 or placebo 
administration in Cycles 1 and 8 of the treatment period. 
b. ADA samples will only be collected pre-dose and procedures are described in the laboratory manual. 
 
Tumor imaging: 
Imaging studies in this trial include CT or MRI. Images will be assessed by the IRRC according 
to RECIST 1.1 (see Appendix 2-1: Response Evaluation Criteria in Solid Tumors (RECIST 1.1)). 
The parameters (such as slice thickness and field of view) used for all follow-up imaging should 
be consistent with those at baseline. CT/MRI scans must meet the criteria for imaging lesions in 
the corresponding organ system. 
Subjects should undergo CT or MRI (including brain, chest, abdomen, pelvic cavity and any 
other sites suspected of having tumor lesions) at screening (within 4 weeks pre-dose), every 6 
weeks (± 7 days) during the first 48 weeks after the start of study treatment, and every 9 weeks 
(± 7 days) after week 48 (if baseline brain CT/MRI shows that brain metastasis is not present, the 
subject should have follow up brain imaging only if clinically indicated at the discretion of the 
investigator. If baseline brain CT/MRI has confirmed CNS metastasis, continuous brain imaging 
test should be carried out as part of the regular RECIST evaluation assessments).  

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At screening, bone scans are required for all subjects. Positive scans should be confirmed by 
CT/MRI, and re-examinations are determined by the investigator according to clinical needs 
during the treatment period. Brain MRI is also required at screening, but for subjects with 
contraindication, brain CTs are acceptable. The investigator assesses the tumor images according 
to RECIST 1.1 and iRECIST (the tumor assessment can be performed by the investigator 
according to clinical needs), and the investigator should make subsequent treatment judgment 
according to the results of their own efficacy evaluation. The IRRC assess the tumor images 
according to RECIST 1.1. If tumor assessment has been performed within 28 days prior to the 
first dose by the same methods and devices in the same hospital, it may serve as the baseline 
tumor assessment. 
Tumor imaging studies are conducted every 6 weeks (± 7 days) for the first 48 weeks after the 
start of study treatment and every 9 weeks (± 7 days) after week 48, regardless of dose delay. 
At the EOT visit, if tumor imaging has been performed within the last 4 weeks, a re-test is not 
required. Note: For all tumor imaging timepoints, investigator must assess all the tumor images 
according to RECIST 1.1 and iRECIST. 
For subjects who discontinued for reasons other than disease progression, imaging assessments 
are to be continued as scheduled (at the same frequency as if the subject have remained on study 
treatment, i.e., every 6 weeks (± 7 days) for the first 48 weeks and every 9 weeks (± 7 days) after 
48 weeks), until disease progression, initiation of new antineoplastic therapy, withdrawal of ICF, 
death, or end of study, whichever occurs first. 
Biomarker sample collection: 
At screening, blood samples and tumor tissue samples must be collected for biomarkers 
detecting. Patients must provide tumor tissues that meet the requirements for the determination 
of PD-L1 expression levels. The patients are recommended to provide formalin-fixed tumor 
tissue samples, paraffin-embedded tumor specimens (preferred), formalin-fixed 
paraffin-embedded (FFPE), tumor specimens or newly prepared unstained serial tissue sections 
(preferably adhesive slides) within 6 months prior to the first dose of study medication. A 
relevant pathology report must also be provided for the above specimens. Freshly collected 
specimens, radical resections, core needle biopsy, excisions, incisions, punch or clamp biopsies 
are acceptable (newly obtained tissues are preferred). Fine-needle aspirations (i.e., samples that 
lack a complete tissue structure and provide only cell suspension and/or cell smear), brush 
biopsies, and cell pellet samples from pleural or peritoneal effusions are unacceptable. For 
detailed requirements for tissue samples, see the laboratory manual. 

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8.2 Visit schedule 
8.2.1 Screening Period (day -28 to day -1) 
The ICF must be signed and dated by the subject or legal representative prior to conducting 
study-related procedures. 
The screening period should not exceed 28 days, beginning from the subject signing and dating 
the ICF and ending when the subject is randomized or fails screening. In this study, one re-
screening is allowed for ineligible subjects: in case of unqualified laboratory tests, one re-test can 
be performed within the screening time window, without giving a new screening number; for 
other conditions incompliant with the inclusion/exclusion criteria, subjects should be re-screened 
with a new screening number. 
Subjects must complete the following study procedures or assessments at screening: 
1) Signing ICF 
2) Demographics and medical history 
3) Prior and concomitant medications 
4) Adverse events 
5) Quality of life assessment (Day -7 to -1) 
6) Echocardiography 
7) 12-lead ECG 
8) Complete physical examination 
9) Height, weight and vital signs 
10) ECOG scores (Day -7 to -1) 
11) Local laboratory tests: routine blood test, serum biochemistry, coagulation, myocardial 
function, urinalysis, thyroid function, pregnancy test (for females of childbearing age only), 
virology and tuberculosis screening (as requested by the Bulgarian Drug Agency for 
Bulgarian subjects). Tests other than virology should be completed within 7 days before 
randomization 
12) Tumor imaging: 
CT or MRI should be performed at screening (on sites including brain, chest, abdomen, 
pelvic cavity and any other sites suspected to have tumor lesions). At screening, bone scans 
are required for all subjects. Positive scans should be confirmed by CT/MRI. Brain MRI is 
also required at screening, but for subjects with contraindication, brain CTs are acceptable. 
If tumor assessment has been performed within 28 days prior to the first dose by the same 
methods and devices in the same hospital, it may serve as the baseline tumor assessment 
13) Biomarker sample collection: Tumor tissue and blood samples are collected for biomarker 

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detection 
Note: All reports from diagnostic procedures, which were performed before the ICF is 
signed and as part of the standard of care in the region and the examination 
methods/devices meet the study requirements might be used for the eligibility evaluation 
during the screening. This option restricted to those cases only, where the patient has 
given written confirmation that he/she consent to use his/her diagnostic reports of 
performed procedures before the date of ICF signature for eligibility evaluation of the 
actual study. 
8.2.2 Treatment Period 
Initial treatment visit 
The initial treatment period begins with the subject's enrollment, and the first dose should be 
administered within 3 days after randomization. Study drugs are given every 3 weeks until 
disease progression, intolerable toxicity, discontinuation decided by the subject or the 
investigator, death, withdrawal of informed consent, pregnancy, noncompliance with protocol or 
procedure requirements, administrative reasons, or other reasons specified in the protocol, 
whichever occurs first. See Figure 1 "Schematic of study treatment" for details. 
Subjects will be closely monitored for safety and tolerability throughout the study. All 
assessments must be performed and documented for each subject. Also, subjects are assessed for 
toxicity prior to each dose; doses are only given when clinical assessments and local laboratory 
tests are acceptable. 
The following study procedures must be completed at each visit during initial treatment period: 
1) Concomitant medications 
2) Adverse events 
3) Quality of life assessment: prior to the first dose and every other subsequent dosing cycle 
(i.e., pre-dose in Cycles 1, 3, 5, 7, etc.) until EOT. Re-assessments are not required for 
subjects who had a quality of life assessment on Day -7 to Day -1 of the screening period 
4) 12-lead ECG 
5) Symptom-oriented physical examination 
6) Weight and vital signs 
7) ECOG scores 
8) Survival status 
9) Local laboratory tests: routine blood test, serum biochemistry, coagulation, myocardial 
function, urinalysis, thyroid function, pregnancy test (for females of childbearing age only) 

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and virology (if necessary) 
− 
Routine blood test, biochemistry, coagulation, myocardial function and urinalysis 
should be performed within 3 days pre-dose in each treatment cycle; for combined 
chemotherapy, routine blood tests should be performed on Day 8 (± 3 days) of each 
treatment cycle. 
− 
Thyroid function must be tested at the local site within 3 days pre-dose every 2 cycles. 
− 
Serum pregnancy test must be performed for women of childbearing age at the local site 
within 3 days pre-dose every 2 cycles during the treatment period. 
− 
In case of HBV DNA (-) and: 1) HBsAg (+), or 2) HBcAb (+) and HBsAg (-) at 
baseline, HBV antibody and HBV DNA should be tested every 2 cycles during the 
treatment period. In case of HCV antibody (+) and HCV RNA (-) at baseline, HCV 
antibody and HCV RNA should be tested every 2 cycles during the treatment period. 
For aforementioned laboratory tests scheduled on the same day as study treatment, the study 
treatment can be arranged only after the test results are obtained 
10) Central laboratory assessments: including HLX10 or placebo-PK, HLX10 or placebo-ADA 
sample collections 
11) Study treatment 
Study drugs, including HLX10/placebo, carboplatin and etoposide, are administered on Day 
1 of each cycle after all clinical and laboratory operations/assessments are completed. 
12) Tumor imaging assessments 
CT or MRI should be performed every 6 weeks (± 7 days) during the first 48 weeks after the 
start of study treatment, and every 9 weeks (± 7 days) after week 48 on sites including brain, 
chest, abdomen, pelvic cavity and any other sites suspected to have tumor lesions (if the 
baseline brain CT/MRI shows that brain metastasis is not present, the subject should have 
follow-up brain imaging only if clinically indicated at the discretion of the investigator. If 
the baseline brain CT/MRI confirms CNS metastasis, a continuous brain imaging test should 
be carried out as part of the regular RECIST evaluation assessments); examination methods 
at the same site should be consistent as much as possible throughout the study; if there are 
no contraindications, contrast agent should be used. The investigator should assess the tumor 
images according to RECIST 1.1 and iRECIST (the tumor assessment can be performed by 
the investigator according to clinical needs), and the investigator should make subsequent 
treatment judgment according to the results of their own efficacy evaluation. The IRRC 
should assess the tumor images according to RECIST 1.1. 
Post-PD treatment visit (Optional) 
Initial treatment should be discontinued when they have evidence of disease progression as 
assessed by RECIST 1.1., if a subject has 1st disease progression, and is clinically stable, and 

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tends to receive 2nd line chemotherapy treatment subsequently (The selection of 2nd line 
chemotherapy may refer to the NCCN guidelines or the ESMO guidelines), he/she may continue 
the post-PD treatment assignment blinded at the discretion of the investigator and after 
appropriate discussion with the patient and obtaining the supplementary informed consent.  
After comprehensive assessment by investigator, subjects would continue to receive benefit from 
their assigned treatment in addition to 2nd line chemotherapy may be eligible to continue to 
receive their assigned treatment in the post-PD treatment period (Optional) until the 2nd disease 
progression, intolerant toxicities, death, withdraw consent, or lost to follow-up. Subjects must 
not initiate treatment with HLX10 or placebo in post-PD treatment any earlier than 21 days and 
more than 12 weeks after their last dose of initial treatment (including chemotherapy) regardless 
of the time of progression.   
The tumor image used to determine disease progression can be used as the new baseline image 
for the post-PD treatment period if 1) within 28 days prior to receiving the first dose of HLX10 
or placebo therapy and 2) No study treatment between the image and first dose of HLX10 or 
placebo therapy, otherwise a new baseline image must be performed prior to HLX10 or placebo 
treatment. Subjects will be also monitored for safety and tolerability during the post-PD 
treatment period. All assessments must be performed and documented for each subject as the 
same as initial treatment period. 
An objective response or progression of disease that occurs during the post-PD Treatment Period 
for a subject will not be counted as an event for the efficacy analysis of either endpoint in this 
trial. 
The visits and following assessments are recommended for post-PD treatment period at each 
follow-up visit: 
1) Concomitant medications 
2) Adverse events 
3) 12-lead ECG 
4) Symptom-oriented physical examination 
5) Weight and vital signs 
6) Documenting subsequent anti-tumor therapies 
7) ECOG scores 
8) Survival status 
9) Local laboratory tests: routine blood test, serum biochemistry, coagulation, myocardial 
function, urinalysis, thyroid function, pregnancy test (for females of childbearing age only) 
and virology (if necessary) 

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− 
Routine blood test, biochemistry, coagulation, myocardial function and urinalysis 
should be performed within 3 days pre-dose in each treatment cycle; for combined 
chemotherapy, routine blood tests should be performed on Day 8 (± 3 days) of each 
treatment cycle. 
− 
Thyroid function must be tested at the local site within 3 days pre-dose every 2 cycles. 
− 
Serum pregnancy test must be performed for women of childbearing age at the local site 
within 3 days pre-dose every 2 cycles during the treatment period. 
− 
In case of HBV DNA (-) and: 1) HBsAg (+), or 2) HBcAb (+) and HBsAg (-) at 
baseline, HBV antibody and HBV DNA should be tested every 2 cycles during the 
treatment period. In case of HCV antibody (+) and HCV RNA (-) at baseline, HCV 
antibody and HCV RNA should be tested every 2 cycles during the treatment period. 
For aforementioned laboratory tests scheduled on the same day as study treatment, the study 
treatment can be arranged only after the test results are obtained 
10) Central laboratory assessments: including HLX10 or placebo-PK, HLX10 or placebo-ADA 
sample collections 
11) Study treatment 
Investigational product (HLX10/placebo) are administered on Day 1 of each cycle after all 
clinical and laboratory operations/assessments are completed. 
12) Tumor imaging assessments 
CT or MRI should be performed every 6 weeks (± 7 days) during the first 48 weeks after the 
start of study treatment, and every 9 weeks (± 7 days) after week 48 on sites including brain, 
chest, abdomen, pelvic cavity and any other sites suspected to have tumor lesions; (if the 
baseline brain CT/MRI shows that brain metastasis is not present, the subject should have 
follow-up brain imaging only if clinically indicated at the discretion of the investigator. If 
the baseline brain CT/MRI confirms CNS metastasis, a continuous brain imaging test should 
be carried out as part of the regular RECIST evaluation assessments); examination methods 
at the same site should be consistent as much as possible throughout the study; if there are 
no contraindications, contrast agent should be used. The investigator should assess the tumor 
images according to RECIST 1.1 and iRECIST (the tumor assessment can be performed by 
the investigator according to clinical needs), and the investigator should make subsequent 
treatment judgment according to the results of their own efficacy evaluation. 
8.2.3 End-of-Treatment Visit 
For any subject withdrawing from the study or terminating the study regardless of causality, an 
EOT visit should be performed, where possible, in 7 days after the end of the treatment is learned 
of or confirmed (and should be done prior to initiation of any new anti-tumor treatment in the 
subject). During the visit, the investigator shall collect the following information. 

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1) Concomitant therapy 
2) Adverse events 
3) Quality-of-life assessment: One quality-of-life assessment should be performed at this 
visit if such assessment has never been done in the past 3 weeks 
4) 12-lead ECG 
5) Symptom-oriented physical examination 
6) Body weight and vital signs 
7) ECOG score 
8) Survival status 
9) Local laboratory tests: including routine blood test, serum chemistry test, coagulation test, 
myocardial function, routine urine test, thyroid function test, pregnancy test (in women of 
child-bearing age only), and virological test (when necessary) 
Note: 
Thyroid function: If no more than 3 weeks have elapsed since the last thyroid function 
test, a repeat test is not required. 
HBV/HCV:  
o If at screening (baseline): HBV DNA (-), and 1. HBsAg (+), or 2. HBcAb (+), 
HBsAg (-), and it has been more than 3 weeks since the last test, then HBV DNA 
should be tested at treatment termination visit.  
o If at baseline: 1. HCV antibody (+), and HCV RNA (-), or 2. HCV RNA (+), and 
it has been more than 3 weeks since the last test, then HCV antibody and HCV 
RNA should be tested at treatment termination visit. 
10) Central laboratory assessment: including HLX10 or placebo-PK blood sampling and 
HLX10 or placebo-ADA blood sampling 
11) Radiologic tumor assessment: If any radiologic tumor assessment has been conducted 
during the first 4 weeks, then it may be unnecessary to repeat radiologic tumor assessment 
at the termination visit. 
8.2.4 Follow-up Period 
After the EOT visit, subjects will be followed up. If a subject terminates the study not because of 
PD, then radiologic assessment should be further performed according to an established 
schedule, where possible, until disease progression, initiation of a new anti-tumor therapy, ICF 
withdrawal, death or study completion (whichever occurs first). 
Safety follow-up period 
Subjects should be subjected to safety follow-up in 90 days after the last study drug 
administration, and AEs in subjects will be collected. Each subject shall come to the study center 

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for safety follow-up 30 (±7) days after the last study drug administration; if the EOT visit is 
delayed regardless of causality 30 (±7) days after the final study treatment, then the safety 
follow-up visit will no longer be performed. One safety follow-up should be performed by phone 
90 (±7) days after discontinuation in each subject, in which information of the subject about AEs 
and AE-related concomitant therapy only will be collected. If the patient starts a new anti-tumor 
therapy during AE collection period, only AE information related to the study treatment need be 
collected after the initiation of the new anti-tumor therapy. Safety information should be acquired 
by phone with a window period of ±7 days. Safety follow-up assessment 30 (±7) days after 
discontinuation includes: 
1) Concomitant therapy 
2) Adverse events 
3) Quality-of-life assessment 
4) 12-lead ECG 
5) Symptom-oriented physical examination 
6) Body weight and vital signs 
7) ECOG score 
8) Documenting subsequent anti-tumor therapies 
9) Documenting survival status 
10) Local laboratory tests: including routine blood test, serum chemistry test, coagulation test, 
myocardial function, routine urine test, thyroid function test, pregnancy test (in females of 
child-bearing age only), and virological test (when necessary) 
Note: 
Thyroid function: If no more than 3 weeks have elapsed since the last thyroid function 
test, a repeat test is not required. 
HBV/HCV: 
o If at screening (baseline): HBV DNA (-), and 1. HBsAg (+), or 2. HBcAb (+), 
HBsAg (-), and it has been more than 3 weeks since the last test, then HBV DNA 
should be tested at safety follow-up.  
o If at baseline: 1. HCV antibody (+), and HCV RNA (-), or 2. HCV RNA (+), and 
it has been more than 3 weeks since the last test, then HCV antibody and HCV 
RNA should be tested at safety follow-up. 
11) Central laboratory assessment: including HLX10 or placebo-PK blood sampling and HLX10 
or placebo-ADA blood sampling. 
 
Survival follow-up period 

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During the survival follow-up period, subjects should be followed up until ICF withdrawal, 
death, the patient is lost to follow-up, study termination by the sponsor, or study completion, 
whichever occurs first. 
The following assessments shall be done at each follow-up visit: 
1) 
Documenting survival status. 
2) 
Documenting subsequent anti-tumor therapies. 
8.3 Study Assessments 
Efficacy assessment 
Except overall survival, other efficacy endpoints are evaluated based on tumor response as per 
RECIST 1.1 and iRECIST. Tumor assessment will be performed by qualified personnel in each 
study center and IRRC. Therapeutic decision will be made based on tumor response assessment 
verified by the investigator. These results will be reported in eCRF. 
Tumor assessment schedule is not influenced by treatment interruption or any other event leading 
to imbalance in disease assessment time between treatment groups. 
Progression-free survival (PFS) is defined as a period from randomization initiation through the 
first objective PD or death (on account of any cause without PD). Progression-free survival will 
be always obtained based on scan/assessment date instead of visit date.  
Progression-free survival 2 (PFS2) is defined as time from randomization to second/subsequent 
objective tumor progression on next-line treatment or death from any cause. 
Overall survival (OS) is defined as a period from randomization through death regardless of 
causality. 
Objective response rate (ORR) is defined as the percentage of subjects whose best overall 
responses are evaluated as complete response (CR) or partial response (PR). 
Duration of response (DOR) is defined as a period from the first documentation of response (CR 
or PR) through the first documentation of PD or death (whichever occurs first). Response 
termination date should be consistent with the date of PD or death regardless of causality for 
evaluation of PFS endpoint as per RECIST 1.1. 

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8.4 Safety Assessment 
Safety assessments variables include AEs (including SAEs), laboratory tests (routine blood test, 
blood chemistry test, coagulation test, routine urine test, myocardial enzymogram, BNP/NT-
proBNP and thyroid function test), 12-lead ECG, vital signs, and physical examination. 
8.4.1 Adverse Events 
8.4.1.1 Definition of AE 
Adverse event (AE) is defined as any adverse medical event occurring in a subject after 
receiving a drug in a clinical trial, not definitely having causality to treatment. Therefore, an AE 
can be any clinically significant manifestation (e.g., a clinically significant outlier in laboratory 
findings), symptom or disease, regardless of relevance to the study drug. 
In the event of any outlier, it should be determined according to the following criteria whether 
the objective outlier should be reported as an AE or not: 
 
The finding is associated with a symptom, and (or) 
 
The finding necessitates drug/surgery intervention, and (or) 
 
The finding leads to dose adjustment (out-of-protocol-specification dose adjustment) or 
 
The finding constitutes an AE in the opinion of the investigator or the sponsor 
If none of the above criteria is satisfied, then repeated outliers alone will not constitute an AE. It 
is unnecessary to report any incorrectly reported finding as an AE. 
Any concomitant disease, which is manifested upon signing ICF and does not worsen in either 
severity or onset frequency during the study, is defined as a baseline medical condition, rather 
than an AE/SAE. However, if such concomitant disease in a subject is exacerbated, resulting in 
any complication or increased onset frequency, then such exacerbation or complication should be 
documented as an AE correspondingly. The investigator shall ensure that any documented event 
term is able to reflect the change of this condition (e.g., “exacerbation of ...”). 
8.4.1.2 Disease Progression  
Progression of any underlying disease, i.e., underlying tumor, should not be reported as an AE, 
and if its explicit manifestation is consistent with suspected progression of the underlying tumor 
defined in RECIST 1.1 and a subject is admitted just because of progression of the underlying 
tumor, then this PD should not be reported as an SAE. If it cannot be verified that a symptom is 
completely due to progression of underlying tumor, or a symptom does not conform to expected 
manifestation of PD in this study, then the progressing clinical symptom can be reported as an 

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AE. If it cannot be verified that an AE is caused by underlying tumor only, then this AE should 
be reported as an AE/SAE. 
8.4.1.3 New tumor 
Onset of any new tumor should be regarded as an SAE. New primary tumor refers to a cancer 
that is not a dominant cause of study drug treatment and is discovered after subject enrollment. 
8.4.1.4 Death 
All deaths occurring during the study or during follow-up period following the final dose of the 
study drug as specified in the study protocol have to be reported according to the following 
requirements: 
• 
The cause of death (confirmed to be PD-induced or non-PD-induced) should be reported 
as an SAE and the death should be recorded as event outcome. The SAE report needs to 
be submitted to the clinical research associate (CRA)/clinical site manager (CSM), the 
sponsor, or a representative of the sponsor within 24 hrs. 
• 
Any death from unknown cause should be reported as an SAE with the comment "death 
from unknown cause". The cause of death should be further explained during follow-up. 
An autopsy may help assess the cause of death. If an autopsy is performed, the autopsy 
report should be submitted to the sponsor's pharmacovigilance team or its representative 
as soon as possible. 
8.4.1.5 Drug Overdose 
Drug overdose means that a subject receives (intentionally or accidentally) a drug dose in excess 
of the dose specified in the protocol. In the event of drug overdose, appropriate symptomatic and 
supportive therapies may be performed in the subject. Any overdose-induced adverse reaction 
should be reported to CRA/CSM and included in a standard AE report. 
Any overdose 3 times of the prescribed dose should be reported along with any AE and 
laboratory data  
8.4.2 Serious Adverse Events 
Serious adverse event: AEs occurring during a clinical trial in conformity with any or more of the 
following circumstances should be deemed as SAEs: 
1) Leading to death 

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2) Life-threatening (AE occurrence leads to an immediate risk of subject death, not including 
those AEs that may lead to death after PD, e.g., drug-induced hepatitis without liver failure) 
3) Necessitating hospitalization or prolonged length of stay; if a subject develops a discomfort 
or disease prior to study enrollment and is planned to be admitted for treatment and/or 
surgery before or during the study but does not present with exacerbation in an unexpected 
manner during the study, then this event will not be classified as an SAE 
4) Leading to permanent or serious disability/insufficiency 
5) Leading to congenital malformation/birth defect 
6) Other significant medical events: Based on scientific medical judgment, it has to be decided 
whether reporting is to be expedited or not, and if the significant medical event might not 
immediately threaten the life, lead to death or hospitalization but some medical measures 
have to be taken to prevent any of the aforesaid circumstances from occurring, then this 
event will be normally deemed serious. For example, important treatment in A&E or 
domestic anaphylactic bronchospasm, non-nosocomial cachexia or convulsion, drug 
dependence or addiction, etc. 
Note: Hospitalization or prolonged hospitalization on account of any non-AE cause/convenience 
(for purpose of health insurance reimbursement, etc.) or simply for clinical trial purpose does not 
meet the criteria for medical event and thus should not be considered as an SAE. However, each 
event leading to unexpected hospitalization or prolonged selective length of stay (e.g., any 
unexpected results of drug treatment) has to be documented and reported as an AE/SAE. 
Hospitalization also includes nosocomial transfers to emergency/ intensive care unit (ICU) ward 
(such as transfer from pediatrics to internal medicine, transfer from internal medicine to ICU 
ward for patients with coronary heart disease, transfer from neurology to tuberculosis ward, etc.). 
Hospitalization in the following institutions are excluded: 
 
Rehabilitation facilities 
 
Hospice care centers 
 
Short-term care facilities (e.g., care provided by nursing assistants) 
 
Specialized nursing facilities 
 
Nursing home 
 
Routine observation in A&E department 
 
Day surgery (outpatient treatment/diurnal surgery/diurnal operation) 
Hospitalization or prolonged hospitalization due to any of the following causes is not classified 
as an SAE: 
 
Hospitalization for treatment of any original disease unrelated to any new AE or 

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worsening of any original adverse disease (for example, inspection of persistent 
laboratory outliers existing prior to treatment); 
 
Hospitalization due to any non-medical cause (e.g., homelessness); 
 
Transactional hospitalization (e.g., routine checkup); 
 
Hospitalization specified in the study protocol (e.g., operation required for 
implementation of the study protocol); 
 
Voluntary hospitalization that will not give rise to any clinical AE (e.g., for elective 
plastic surgery); 
 
Treatment or surgery planned in the study protocol and (or) for individual subjects 
should be documented in baseline documents; 
 
Hospitalization specifically for use of the study drug. 
Diagnostic and therapeutic non-invasive/invasive procedures, such as surgeries, should not be 
reported as AEs. Nonetheless, if diseases that such operations are intended to treat meet the 
definition of AE, diseases should be reported as AEs. For example, acute appendicitis occurring 
during AE reporting should be reported as an AE, and appendectomy for treating the disease 
should be documented as treatment for this AE. 
8.4.2.1 Drug-induced liver injury (DILI) 
All cases confirmed on repeat testing as meeting the criteria, as described below, with no other 
cause for liver function test (LFT) abnormalities identified at the time should be considered 
potential Hy’s Law cases irrespective of availability of all the results of the investigations 
performed to determine etiology of the abnormal LFTs. The event meeting the below criteria 
should be reported as serious adverse event. 
Table 6: The abnormal liver function test (LFT) needed to be reported as an SAE 
Baseline 
AST or ALT and total bilirubin 
baseline values within the normal 
range 
ALT or AST or total bilirubin values above the 
upper limit of normal 
Treatment 
time 
 
 
ALT or AST≥ 3×ULN (upper 
limit of normal) 
 
Concurrent 
with 
a 
total 
bilirubin≥ 2×ULN  
 
And 
alkaline 
phosphatase≤ 
2×ULN or not available 
 
And no evidence of hemolysis 
 
AST or ALT≥ 2 times the baseline values，
and ≥ 3× ULN；or AST or ALT≥ 8× ULN 
(whichever is smaller)   
 
Concurrent with a total bilirubin≥ 2×ULN and 
increased by one upper limit of normal over 
baseline or > 3×ULN (whichever is smaller) 
 
And alkaline phosphatase≤ 2×ULN or not 
available 
 
And no evidence of hemolysis 
 
 

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8.4.3 Documentation of AEs 
All AEs occurring in a period from signing ICF (either main or supplementary) through 90 days 
after the final administration of the study drug should be documented in corresponding AE pages 
in EDC. If a subject starts a new antineoplastic therapy during the AE collection period, only 
information on AEs related to study treatment are documented after the new antineoplastic 
therapy. The investigator shall provide all detailed information required to be completed, 
including date of onset, severity, action, outcome, and causality to the study drug. When 
collecting AE data, one has better recording diagnosis information (if possible), rather than 
recording a number of signs and symptoms. However, if a diagnosis is known but the patient still 
has other symptoms or signs not contributing to such diagnosis, then each symptom or sign 
should be documented separately. 
All AEs/SAEs occurring in a period from signing ICF through 90 days after the final dose of the 
study drug (including chemotherapy drugs) or the start of a new anti-tumor treatment (whichever 
occurs first) should be documented, and the following information has to be collected: 
 
AE 
 
Onset date and end date of the AE 
 
CTCAE grade 
 
SAE or not 
 
Causality between the AE and the study drug as assessed by the investigator 
 
Actions taken with the study drug 
 
Therapeutic actions against the AE 
 
Outcome 
 
AESI or not 
In addition, the following information will be collected for each SAE: 
 
Date when the AE meets SAE criteria 
 
Date when the investigator learns of the SAE 
 
Justification of SAE  
 
Date of discharge (if applicable) 
 
Potential cause of death (if applicable) 
 
Date of death (if applicable) 
 
Autopsy findings (if applicable) 
 
Assessment of causality between the AE and study operation 
 
Assessment of causality between the AE and other drugs 
 
Description of the AE 

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Note: If the investigator learns, after a subject has completed safety follow-up or withdrawn from 
the study, that the subject experienced any SAE (including death) and reasonably considers that 
this event is possibly related to the study drug, then the investigator should report it to the 
sponsor’s pharmacovigilance team or representative. 
8.4.3.1 Severity of AEs 
National Cancer Institute’s CTCAE V5.0 is used to document severity of AEs, classified in 
grades 1–5. 
Table 7: CTCAE Description 
Grade 
CTCAE Description 
1 
Mild: No or mild symptom; only clinical or diagnostic observation is required; action is not 
needed. 
2 
Moderate: Small-scope, local or non-invasive action is needed; instrumental Activities of Daily 
Living (ADL) are restricted to appropriate ages*. 
3 
Serious or medically significant but not immediately life-threatening; necessitating hospitalization 
or prolonged hospitalization; incapacity; self-care ADL are restricted**. 
4 
Fatal result: Urgent action is to be taken. 
5 
AE-related death 
ADL= Activities of Daily Living; AE=Adverse Event; CTCAE = Common Terminology Criteria for 
Adverse Events 
*: 
Instrumental ADL are activities such as cooking, grocery shopping, making/receiving phone calls, 
and financial management. 
**: 
Self-care ADL are activities such as bathing, dressing and undressing, feeding yourself, going to 
the restroom, taking pills, and leaving the bed. 
Attention must be paid to distinguish severity from intensity of an AE. "Severe" is used to describe 
intensity, so a severe AE is not definitely an SAE. For example, headache may appear severe in intensity but 
cannot be classified as an SAE, unless it meets the criteria for SAE. 

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8.4.3.2 Causality between the AE and the study drug 
The investigator will evaluate whether causality between the study drug and the AE is "related", 
"possibly related", "unlikely related", "unrelated", or "unknown". AEs other than "unlikely 
related" and "unrelated" are recorded as adverse reactions. 
• 
related: 
 
Reasonable time relation+ 
 
In conformity with a known type of adverse reactions+ 
 
AE is absent or attenuated after interruption or dose reduction+ 
 
AE reoccurs after repeated medication+ 
 
Other reasonable interpretations –  
 
• 
Possibly related: 
 
Reasonable time relation+ 
 
In conformity with a known type of adverse reactions±? 
 
AE is absent or attenuated after interruption or dose reduction±? 
 
AE reoccurs after repeated medication±? 
 
There is a probability of any other cause leading to this AE±? 
• 
Unlikely related: 
 
Reasonable time relation- 
 
In conformity with a known type of adverse reactions- 
 
AE is absent or attenuated after interruption or dose reduction±? 
 
AE reoccurs after repeated medication±? 
 
There is a probability of any other cause leading to this AE±? 
• 
unrelated: 
 
Reasonable time relation- 
 
In conformity with a known type of adverse reactions- 
 
AE is absent or attenuated after interruption or dose reduction- 
 
AE reoccurs after repeated medication- 
 
There is a probability of any other cause leading to this AE+ 
• 
Unknown: Essential data for evaluation is unavailable 

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Table 8: Evaluation of Causality Between AE and Study Drug 
 
related Possibly 
related 
Unlikely 
related 
unrelated Unknown 
Reasonable time relation with the 
study drug 
+ 
+ 
- 
－ 
Essential data 
for evaluation 
is unavailable 
Known type of drug reactions 
+ 
±? 
－ 
－ 
Reaction is attenuated or absent 
after discontinuation 
+ 
±? 
±? 
－ 
Positive Rechallenge 
+ 
? 
? 
－ 
There is a probability of any other 
cause leading to this AE 
- 
±? 
±? 
+ 
Note: + Yes   – No    ± Likely    ? Unknown 
 
8.4.3.3 Determination of Expectedness 
An unexpected AE refers to an event not in conformity with corresponding reference safety 
information of the drug in nature or severity. For investigational medicinal products, the 
predictability of an AE will be assessed based on whether the event is listed in the Investigator’s 
Brochure. For comparators that are already approved for marketing, the predictability of an AE 
will be assessed based on whether the event is listed in the drug instructions. 
8.4.4 Reporting of SAEs 
All SAEs occurring during the clinical study should be reported immediately (or in 24 h after 
being informed) by the investigator to the sponsor or a representative designated by the sponsor. 
This time frame applies to additional information (follow-up information) of previously released 
SAE report, and initial report and follow-up report of pregnant cases, too. The sponsor’s 
representative and the investigator share the responsibility of ensuring that all essential 
information is submitted within the above time frame. 
For all SAEs, the investigator is obliged to acquire relevant information and submit it to the 
sponsor within the above-mentioned time frame of reporting. In addition, the sponsor may 
request the investigator to acquire more follow-up information quickly. Such information may be 
more detailed than the information shown in the AE report. In general, such information shall 

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include sufficiently detailed description of AEs so as to facilitate comprehensive medical 
assessment of the cases and independent assessment of causality. Moreover, the investigator must 
provide information about other potential causes of AEs, such as concomitant medications and 
complications. 
In the event of subject death, a summary of autopsy findings (if any autopsy finding is available) 
has to be submitted to the sponsor or the representative designated by the sponsor as soon as 
possible. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators. 
The investigator or any person-in-charge required by local authority shall abide by local 
regulatory regulations on SAE reporting and report SAEs to regulatory bodies, Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC), as per request. 
8.4.5 Follow-up of AEs 
All AEs and SAEs that occur in each subject throughout the study should be actively followed 
up. Even if such events persist after discontinuation or study termination, the investigator should 
follow them up until all events meet any of the following criteria: 
1) 
The event is recovered (or returns to the baseline level); 
2) 
The event is stable (as predicted by the investigator, the AE will not be further improved or 
exacerbated); 
3) 
Failing to acquire more information (the subject refuses to provide more information, or it 
is evidenced that the subject is lost to follow-up even after the maximum effort has been 
made). 
The sponsor reserves a right to request (if necessary) more information of current AE/SAEs from 
any subject at the end of the study.  
8.4.6 Adverse event of special interest (AESI)  
AESIs are events of scientific and medical concern related to use of the investigational product 
that may need to be closely monitored and communicated to sponsors by investigators. AESI can 
be a serious or non-serious event. The AESI expedited report enables continuous monitoring of 
these events in order to describe and understand their association with the drug used in the study.  

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In this study, AESI include infusion reaction (infusion-related adverse reactions, IRR) and 
immune-related adverse events (irAE). 
Immune-related adverse event (irAE) refers to an AE that is related to drug exposure and in 
conformity with immune-mediated mechanism of action without any other definitive 
pathological factor. Serological, immunological and histological (biopsy) data should be used to 
support diagnosis of irAE when appropriate. Appropriate methods should be used to exclude 
pathological factors of irAE such as tumor, infection, metabolism, toxin, etc.  
More detailed guidance on its assessment and treatment please refer to Appendix 8:NCCN 
Guidelines®: Management of Immunotherapy-Related Toxicities (2019 V2). 
For any suspected irAE, related system functions need to be closely observed and adequate 
assessment shall be carried out to identify etiology and exclude other potential causes. In general, 
depending on severity of an AE, HLX10 (or placebo) should be suspended or permanently 
terminated, and/or symptomatic treatment (e.g., glucocorticoids) may be given. If the AE is not 
improved or is worsened after glucocorticoid therapy, one can consider increasing the dose of 
glucocorticoid and/or using any other systemic immunosuppressant. When grade of an AE is <1, 
dose of glucocorticoid can be reduced gradually, and the treatment has to persist for at least 1 
month. When an AE is recovered to < grade 1 and dose of glucocorticoid is reduced to 
prednisone (or another drug with equal potency) with a daily dose <10 mg, HLX10 or placebo 
transfusion may continue. In the event of recurrence of any grade 3 or above irAE (except for 
endocrine system disorders), permanent discontinuation and study withdrawal have to be done 
immediately. 
If an irAE meets the SAE criteria, it should be handled in accordance with the relevant 
procedures of SAE reporting. For the following AEs, they should be reported to the sponsor 
within 24 hrs (adverse event of special interest) even if they do not meet the SAE criteria  
(with no need to report to the relevant regulatory and Ethics Committee): 
≥ Grade 3 of infusion-related reaction 
≥Grade 2 of colitis, uveitis, interstitial pneumonia, myocarditis 
≥3 Other immune-related adverse events. 
8.4.7 Pregnancy 
Each fertile subject shall take appropriate contraceptive measures in a period from signing ICF 
through at least 6 months after the final dose of the study drug. 

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Once becoming pregnant during the study, female subjects shall immediately discontinue the 
study drug and notify the investigator. The investigator shall report any pregnancy event to the 
sponsor (or an authorized representative) in 24 hours after becoming aware of the pregnancy. 
Monitoring of the subject will persist until the end of pregnancy. Any pregnancy that occurs 
within 6 months after the final dose of the study drug should be reported to the investigator. 
If any female subject or the spouse of any male subject gets pregnant during the treatment and 
within 6 months after the final dose of the study drug (whichever occurs first), the investigator 
should complete a Pregnancy Report in 24 h after becoming aware of the pregnancy, report to the 
sponsor (or an authorized representative), and record in eCRF to facilitate outcome follow-up. 
Any pregnancy event should be followed up until 30 days after the end of pregnancy. 
Any AE/SAE occurring in a mother or newborn during pregnancy, such as natural abortion or 
termination of pregnancy for medical reasons, birth defects or congenital malformation of 
newborns, malformation and anomalies of death fetuses, complications of mothers and newborns, 
etc., should be documented and reported according to "Documentation of AEs" and "Reporting of SAEs". 
9 Statistical Considerations 
9.1 Statistical Hypotheses 
See statistical analysis plan for further details. 
9.2 Sample Size Determination 
The randomization ratio for this study is 2:1. The sample size is estimated based on the 
assumption that the median OS for treatment with placebo + chemotherapy (Carboplatin–
Etoposide) is 10 months and the hazard ratio (HR) of (HLX10 + chemotherapy) group versus the 
control group is 0.7, and it is further assumed that when the enrollment period is 24 months and 
the whole study period is 34 months, to achieve a confidence level of 85% at an overall 
significance level α = 0.05 (two-sided), at least 342 OS events have to be observed. Considering 
a dropout rate of 20%, a total of 567 subjects (378 in treatment arm and 189 in control arm) need 
to be enrolled in the 2 arms. 
It is planned in this study that, when the 378 subjects (about 2/3 of the number of subjects 
planned to be enrolled) was enrolled under supervision of the Independent Data Monitoring 
Committee (IDMC), the sponsor will consider performing a blinded sample size estimation, and 
if the blinded overall median OS is lower than the expected value, then the sponsor will 
communicate with principal investigator and regulatory authorities about the necessary increase 
in the sample size (number of OS events). 

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9.3 Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 
Population 
Description 
Enrolled 
All participants who signed the ICF (including 
screening failures). 
Intent-to-treat (ITT) set 
The ITT comprises all participants to whom study 
intervention has been randomized. Statistical 
analyses will be based on study intervention groups 
as per randomization, irrespective of the study 
intervention actually received. The ITT population 
will serve as the primary population of efficacy 
assessment in this study. ITT population will be 
analyzed based on treatment arms. 
Per Protocol Analysis Set (PPS) 
The PPS comprises a subset of the ITT. The PPS 
consists of all randomized subjects undergoing at 
least one post-treatment tumor assessment without 
any major protocol deviation that impacts the 
primary efficacy significantly. The PPS will be used 
to demonstrate robustness of results for the efficacy 
endpoint. 
Safety Set 
The Safety Set consists of all participants who 
received at least one dose of study intervention. 
Participants will be analyzed according to the study 
intervention they actually received. The safety set is 
the primary population for safety endpoint analysis. 
A precise definition of “as actually received” will 
be added in the Statistical Analysis Plan (SAP). 
PK Analysis Set (PKS) 
The PKS consists of all participants who received at 
least one dose of study intervention with at least 
one post-dose concentration measurement at 
scheduled PK time points without any major 
protocol violation that may impact the PK 
assessment significantly. The PK analysis set will 
be used for PK analysis. 

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9.4 Statistical Analyses 
All statistical analyses will be performed using SAS version 9.2 (or later) statistical analysis 
software. For continuous variables, standard descriptive statistics include median, mean, standard 
deviation, minimum, and maximum, while categorical variables include the quantity and 
percentage. 
Demographic information, baseline profile data, medical history, and concomitant medications of 
all randomized subjects will be summarized using descriptive statistics depending on the 
randomization approach. 
The medication compliance data of the investigational product (HLX10 or placebo combined 
with Carboplatin–Etoposide) will be summarized using descriptive statistics in groups. 
The detailed statistical analysis plan and methodology shall be elaborated in the Statistical 
Analysis Plan (SAP). 
Demographic information, baseline profile data, medical history, and concomitant medications of 
all randomized subjects will be summarized using descriptive statistics depending on the 
randomization approach. 
The medication compliance data of the investigational product (HLX10 or placebo combined 
with Carboplatin–Etoposide) will be summarized using descriptive statistics in groups. 
Below is a summary of planned statistical analyses of the primary and secondary endpoints. 
Further details are presented in the SAP. 
9.4.1 Efficacy Analyses 
Analyses of the primary efficacy endpoint and the secondary efficacy endpoints will be 
performed for both the ITT and PPS, mainly on the ITT.  
9.4.1.1 Analysis of primary efficacy endpoint 
Overall survival (OS): Defined as a period from randomization through death regardless of 
causality. Data of patients without a death record will be censored on the last known survival 
date. The between-group comparison of OS is performed by a stratified log-rank test with the 
following stratification factors: PD-L1 expression level (negative: TPS <1%, positive: TPS ≥1%, 
or not evaluable/not available), brain metastasis (yes versus no), and age (≥ 65 years versus < 65 
years); a stratified COX proportional risk model will be used to estimate HR and its 95% 

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confidence interval (CI); the Kaplan-Meier method will be used to estimate the median, and the 
Kaplan–Meier curve will be plotted. 
9.4.1.2 Analysis of secondary efficacy endpoints 
Progression free survival (assessed by the IRRC as per RECIST 1.1): PFS is defined as a period 
from randomization initiation to the first documentation of PD or death regardless of causality 
(whichever occurs first). Censor rules will be defined in SAP. The PFS will be analyzed using the 
same method as that for primary endpoints. 
Progression-free survival assessed by the investigator as per RECIST 1.1 and iRECIST. Its 
statistical method is the same as that for primary efficacy endpoints.  
Progression-free survival 2 (assessed by the investigator based on RECIST 1.1). PFS2 is 
defined as time from randomization to second/subsequent objective tumor progression on next-
line treatment or death from any cause. It will be analyzed using the same method as that for 
PFS. 
Objective response rate (ORR) assessed by the IRRC and the investigator as per RECIST 1.1 
separately: Defined as the percentage of subjects whose best overall responses are evaluated as CR 
or PR. The stratified Cochran-Mantel-Haenszel method is used to test the between-group variation 
in the ORR and to estimate the odds ratio and its 95% CI. 
Duration of response (DOR): Defined as a period from the first documentation of response (CR 
or PR) through the first documentation of PD or death (whichever occurs first). The DOR will be 
analyzed only for patients whose best overall responses are evaluated as CR or PR. Data of 
patients not experiencing PD or death after achieving response will be censored on the day of the 
final tumor assessment; if no tumor assessment is performed after response achievement, then 
data of such patients will be censored on the day of tumor assessment when response is achieved. 
The Kaplan-Meier method is used to estimate the median and plot the Kaplan-Meier curve. 
9.4.1.3 Subgroup Analyses 
To assess the consistency of the study PFS and OS, results in subgroups will be examined. The 
following subgroups will be considered: 
• 
Demographics (e.g., age, sex, and region/race/ethnicity, etc.) 
• 
Baseline prognostic characteristics (e.g., ECOG performance status, smoking status, 
presence of brain metastases, etc.) 

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To explore the efficacy under different PD-L1 expression level, the following subgroups will be 
examined. 
• 
PD-L1 expression level based on tumor proportion scores (positive TPS ≥1% vs. negative 
TPS <1%) 
• 
PD-L1 expression level based on combined positive score (positive CPS ≥1% vs. negative 
CPS < 1%) 
Summaries of PFS and OS, including unstratified HRs estimated from Cox proportional hazards 
models will be displayed in a forest plot. Kaplan-Meier estimates of median PFS and OS will be 
produced separately for each level of the categorical variables for the comparisons between 
treatment arms. 
9.4.2 Safety Analyses 
All safety analyses will be performed on the Safety Set. 
AEs will be described according to Medical Dictionary for Regulatory Activities (MedDRA) 
terms and graded according to CTCAE v5.0. Adverse events occurring during or after the first 
dose of study drug will be summarized by CTCAE grade. Treatment-emergent adverse events 
(TEAEs) and concomitant medications in the trial will be summarized separately by treatment 
arm. The clinical laboratory parameters, ECOG PS scores, vital signs, physical examination, and 
ECG will be summarized by the treatment group and study visit. Values observed and changes 
from baseline will be descriptively reported by visit in this trial. 
9.4.3 Pharmacokinetic Analyses 
The statistical method will be detailed in the SAP. 
9.4.4 Immunogenicity Analyses 
The statistical method will be detailed in the SAP. 
9.4.5 Biomarker Analyses 
During the screening for this study, tumor tissues of subjects will be collected for assay of the 
PD-L1 expression level, MSI and TMB; blood samples of subjects will be collected for assay of 
the MSI and TMB. The primary objective is to assess the relations among the PD-L1 expression 
and MSI, TMB and efficacy. 

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9.4.6 Analysis of Subject-reported Outcome Variables 
The health status and self-perceived health of each patient will be documented in the form of 
EQ-5D-5L scale, EORTC QLQ-C30 scale, and EORTC QLQ-LC13 scale. 
Descriptive statistics are based on the allocation for the scale scores, subscale scores, and 
individual scores at each visit and their changes from baseline. The analytical methods will be 
detailed in the SAP. Unless otherwise specified, PRO analysis of all data will be performed based 
on the ITT set. 
9.5 Interim Analyses 
An IDMC will be established for this study for interim analysis. This study plans to carry out an 
interim analysis. The O’Brien-Fleming type alpha-spending function (using the Lan-DeMets 
method to approximate) shall be used to control overall type I error rate. The stopping boundary 
for OS interim and final analyses are shown in Table 9. 
• 
The first interim analysis is scheduled to be conducted when 66% (approximately 226) of 
OS events are observed, and the interim analysis will assess the safety and efficacy of the 
trial group. The α for the first interim analysis will be 0.012 (two-tailed) based on the 
O’Brien-Fleming type alpha-spending function. 
• 
The final analysis of OS will be performed when a target number of OS events 
(approximately 342) are observed, and the α for the final analysis will be 0.046 (two-tailed) 
based on the O’Brien-Fleming type alpha-spending function. 
Table 9 Analysis Timing and Stopping Boundary of Overall Survival 
Analysis Timing 
Information Fraction  
(Number of Events) 
Estimated Time  
(month) 
Stopping 
Boundary 
(p-value) 
OS interim analysis 
66% (226) 
19 
<0.012 
OS final analysis 
100% (342) 
34 
<0.046 
 
The SAP will describe the planned interim analyses in greater detail. 
9.5.1 Independent Data Monitoring Committee (IDMC) 
The IDMC will be established to independently oversee the blinded sample size re-estimation 
procedure; to review safety data at regular intervals in order to safeguard the interests of study 

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participants; and to monitor the overall conduct of the study. Responsibilities of the IDMC will 
be fully documented in the IDMC Charter.  
10 Supporting Documentation and Operational Considerations 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Data Management 
Establishment of Database 
Data from this clinical trial will be collected through remote data entry in the eCRF. The data 
administrator shall design a database and test it with simulation data or real eCRF data to ensure 
that the database is accurate and correct. 
Data Checks 
During data management, data checks include the edit check, manual check, medical check, and 
statistical pre-analysis check. All the data query will be displayed in the EDC system in the form 
of electronic query for the study site to answer. The query will be closed if the answer is 
acceptable. If any data query is not resolved or a new query arises after the database is updated 
based on the answer to the previous data query, then the investigator or clinical research 
coordinator shall answer again. The above process will be repeated until all data in the database 
is checked to be correct. 
Database Lock 
The data administrator shall draft a data review report pursuant to the trial protocol, data review 
criteria, and the database. The project manager shall convene a data review meeting attended by 
the sponsor, principal investigator, statistician, and data administrator to review the data, and a 
data review resolution shall be jointly signed by the representatives of the participants. The data 
administrator shall implement data locking upon approval by all the participants. The locked data 
will be submitted to the statistician for statistical analysis. 
The data can be locked when the following conditions are satisfied. 
1) All data has been collected and entered into the database 
2) All codes have been checked and verified 
3) All data queries have been resolved (including queries proposed in data review) 
4) Data review has been completed 
5) Source data verification has been completed 
6) Verification of SAEs has been completed 

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7) Signatures of all investigators have been obtained 
8) Analyzable cases have been defined and stored in the final analysis database 
9) The SAP has been signed 
10.1.2 Regulatory and Ethical Considerations 
This trial shall be implemented in accordance with the good clinical practice (GCP), Declaration 
of Helsinki, relevant regulations, and review comments of the Institutional Review Board. 
The investigator shall ensure that this trial is reviewed and approved by a qualified institutional 
review board in compliance with GCP. Prior to the trial, the investigator shall submit the trial 
protocol, informed consent forms, and other essential documents to the IRB for review and 
approval. The sponsor shall provide the study drug after receiving the approval from the IRB. 
Meanwhile, the IRB shall be informed of subsequent protocol amendments and SAEs occurring 
during the study that may impact the safety of subjects in the trial and preclude the subjects from 
study continuation. The investigator is obligated to report the trial progress to the IRB. In 
addition, the investigator must timely submit copies of all correspondences with the IRB to the 
sponsor. When reviewing and approving the trial protocol, the IRB must verify the protocol title 
and number, indicate and date the reviewed protocol documents. In the event of any additional 
amendment to the trial protocol and the ICFs during the trial, an additional written approval shall 
be obtained from relevant authorities according to relevant regulations. 
10.1.3 Financial Disclosure 
Investigators and sub-Investigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
10.1.4 Informed Consent Process 
Information related to this trial must be informed by the investigator both verbally and in writing. 
The subject has the right to know detailed information about the trial. 
The ICF (together with the trial protocol) must be reviewed and approved by the Ethics 
Committee. If needed, the investigator shall be responsible for explaining the content of the ICF 
to the subject in a manner and wording that is understood by the subject. The subject should have 
sufficient time to read the informed consent before signing the informed consent officially.  

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The text in the final ICF should include the following content: The objectives of trial, the course 
and duration of the trial, the examination procedures, the expected benefits and risks of the 
subjects, and the subjects shall be informed that they may be assigned to the different groups in 
the trial; in the event of trial-related damages, the subjects may receive treatment and 
corresponding compensation; confidentiality principle of subject personal data, etc. 
The ICF must be signed and dated by the subject, and the investigator who executed the 
informed consent process must also sign and date the ICF. One copy each of the ICF should be 
kept by the investigator and the subject. If important new information related to the study drug is 
found, a written amendment to the ICF must be submitted to the Ethics Committee for approval 
before obtaining consent from the subjects again. 
10.1.5 Data Protection 
The investigator is obligated to keep the subject anonymous. In the CRF or other documents, the 
subjects can be only identified with capitalized letters, numbers and/or codes, instead of names. 
The investigator must properly keep the Subject Enrollment Log documenting the codes, names, 
and residential addresses of the subjects. The investigator must keep strictly confidential any 
document that may reveal the identity of the subject. 
10.1.6 GCP training 
According to the GCP guideline, the CRA shall have the qualification accepted by the sponsor; 
before the clinical trial, the person in charge of the study site shall train the investigator on the 
trial protocol, so as to enable the investigator to become fairly familiar with this clinical trial 
protocol, master the GCP guideline, unify the documentation approach and evaluation criteria, 
and perform the trial in strict accordance with the protocol. 
10.1.7 Data Quality Assurance 
Prior to the formal initiation of the trial, the sponsor (or Contract research organization 
authorized by the sponsor) and the investigator shall discuss and develop a clinical study plan to 
guarantee the trial quality. The study personnel involved in this trial shall be trained on GCP. 
Study drugs must be managed in each study site as per relevant standard operating procedures 
(SOP)s, which involve the receipt, retention, distribution, and recovery of the drugs. 
In accordance with the GCP guideline, necessary steps must be taken during the design and 
implementation of this study to ensure the accuracy, consistency, integrity, and credibility of the 
collected data. All observations and outliers in the clinical trial shall be promptly and carefully 

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verified and recorded to ensure data reliability. Ensure that various instruments, devices, 
reagents, and reference standards in this clinical trial are in strict compliance with corresponding 
quality specifications and operate in the normal state. 
The investigator will enter information required by the protocol into the CRF, and the monitor 
shall check if it is completely and accurately filled out and instruct the personnel in the study site 
to make amendments and supplements if necessary. 
The drug regulatory authorities and the sponsor may authorize auditors to conduct systematic 
examination of activities and documents in connection with the clinical trial, so as to evaluate if 
the trial is carried out in accordance with the trial protocol, SOPs and relevant regulatory 
requirements, and if the trial data is documented in a timely, authentic, accurate, and complete 
manner. The audit shall be performed by personnel not directly involved in this clinical trial. 
10.1.8 Audit 
During the study, the sponsor may conduct a quality assurance audit for the study site, the study 
database, and the study documentation. The audit includes drug supply, required trial documents, 
documentation of the informed consent process, and consistency between the CRF and source 
documents, and so on. The content and scope of the audit can be added when needed. After being 
reasonably notified, the investigator shall accept the study-related audit by the auditors 
authorized by the sponsor, as well as the inspection by regulatory authorities. 
In addition, the regulatory authorities may inspect the study as well. 
10.1.9 Data Management/Coding 
The departments of data management and biostatistics will process data generated in this clinical 
study according to relevant SOPs. 
Data acquisition is performed by the personnel from a study site designated and authorized by 
the investigator. Before the study is initiated and any data of any subject in the study is entered 
into the EDC system, the investigator and all the personnel from the authorized study site must 
be trained properly, and appropriate safety measures shall be taken. 
The monitor will compare the eCRF with source documents to ensure that there is no deviation 
between crucial data. All items, corrections, and changes have to be completed by the 
investigator or the personnel designated by the investigator. Relevant personnel of the study will 
raise queries and send to the investigator. In this regard, the EDC will be audited and tracked, 
which means the names of the study personnel, time, and date will be documented. 

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The investigator is responsible for maintaining source documents. These documents shall be 
checked by the monitor of the study during each monitoring visit. The investigator must submit 
one copy of complete eCRF including data of every subject receiving study medication, 
regardless of the treatment duration of the subject. The study and subject numbers shall be used 
to indicate explicitly all supporting documents submitted along with the eCRF, e.g., laboratory or 
hospital records. Any personal information including subject names shall be deleted or made 
illegible so as to keep the subject information confidential. 
10.1.10 Documentation and Retention of Study Data 
The investigator is obligated to maintain essential documents of the study (the protocol and 
protocol amendment, completed eCRFs, signed informed consent forms, important 
correspondence files, and all other supportive documents). The study site shall establish a plan to 
retain these documents for 5 years after study completion. The study site shall always retain 
these documents until at least 2 years after the investigational product is finally approved for 
marketing, and until at least 5 years after there is no pending approval or marketing authorization 
application for the investigational product, or after clinical development of this investigational 
product is formally terminated. These documents shall be retained for a longer time upon the 
request of any corresponding regulatory authority, or any hospital, institution, or private clinic 
involved in this study. Subject codes (subject names and corresponding study numbers) should 
also be retained for the same time period. As agreed by the sponsor, these documents can be 
transferred to another responsible party who must observe the document retention policy. The 
sponsor must be notified in writing of any transfer of documents. The investigator must contact 
the sponsor before disposing of any study record. 
10.1.11 Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
10.1.12 Premature Termination of Study and Site Closure 
The study may be terminated prematurely due to the following reasons. Written permissions of 
both the principal investigator and the sponsor are required for the early termination of the study, 
and results of the study shall be reported in accordance with the requirements of the protocol. 

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1. The study is unlikely to be completed within an acceptable time frame due to difficulties 
in subject enrollment; 
2. The investigator questions the safety of the drug during the study and concludes that 
further study would pose serious risks to the subjects;  
3. The principal investigator and the sponsor believe that the number and severity of AEs 
suggest a premature termination; 
4. The efficacy fails to meet expectations and it is not necessary to continue the clinical 
trial; 
5. The study is revoked by regulatory authorities; 
6. The sponsor has the right to terminate the study at a certain study site in the event of: 
 
serious violations of GCP by the study site; 
 
repeated serious protocol violations by the study site; 
Upon the termination of the study, all related records shall be kept for future reference. 
10.1.13 Confidentiality and Publication Policy 
All information about the trial (including but not limited to the following documents: the 
protocol, and the Investigator's Brochure) is the intellectual property of the sponsor and may not 
be disclosed to any third party not related to the trial. The investigator must recognize that the 
scientific or medical information obtained from this trial may be of commercial value to the 
sponsor. The investigator shall keep the information and data related to this trial confidential. If 
the investigator intends to publish the information related to this trial or the conclusions drawn 
from the trial, the investigator shall negotiate with the sponsor in advance and obtain the written 
consent of the sponsor. In order to protect its rights, the sponsor may request the investigator not 
to publish information related to the trial before the trial product is approved for marketing. 
The sponsor has the right to publish or release information or data related to the trial or to report 
it to the drug administrative departments. If the sponsor needs to display the name of the 
investigator in the content published, released, or advertised, the sponsor shall obtain the consent 
of the investigator. 
10.1.14 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The sponsor 
must ensure that all ethical and legal requirements have been met before the first patient is 
enrolled in the study. 

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This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate). In the US: Following approval, the protocol 
amendment(s) will be submitted to the Investigational New Drug (IND) under which the study is 
being conducted. 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.15 Liability and Insurance 
10.1.15.1 
Responsibilities of the Investigator 
The investigator's responsibilities mainly include but are not limited to: 
1) Designing and signing a trial protocol with the sponsor through discussion, and reporting the 
protocol to the IRB for approval before implementation. 
2) Scrutinizing, understanding, and strictly implementing the protocol. 
3) Being knowledgeable about and familiar with the nature, function, efficacy, and safety of the 
investigational product (including information about the preclinical study for the product), as 
well as all new information related to the product discovered during the clinical trial. 
4) Conducting the clinical trial in medical institutions equipped with adequate medical 
facilities, laboratory equipment, and staffing, as well as all facilities needed to handle 
emergencies to ensure the safety of the subjects. Ensuring the laboratory results are accurate 
and reliable. 
5) Obtaining the consent of the medical institution or the competent authority, and ensuring that 
sufficient time is left to complete the clinical trial within the time limit set by the protocol. 
Explaining the data, regulations, and responsibilities concerning the trial to all staff 
participating in the clinical trial to ensure that a sufficient number of subjects meeting the 
requirements of the protocol are enrolled in the clinical trial. 
6) Explaining to the subjects the details of the trial approved by the IRB and obtaining the ICF 
from the subjects. 
7) Making medical decisions related to the clinical trial to ensure that the subjects receive 
appropriate treatment in case of AEs during the trial. 
8) Taking necessary measures to ensure the safety of the subjects and putting on record such 
measures. Taking immediate and appropriate treatment measures for the subjects in case of 
any SAEs during the clinical trial, reporting the serious adverse event to the drug regulatory 
authorities, health administrative departments, the sponsor and the IRB, and making sure to 

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sign and date the report before submission. 
9) Ensuring that data is recorded in the case history and the CRF in a true, accurate, complete, 
timely, and legitimate manner. 
10) Accepting the monitoring and audit by the monitors and auditors dispatched by the sponsor, 
as well as the audit and inspection by the drug regulatory authorities to ensure the quality of 
the clinical trial. 
11) Discussing with the sponsor the cost of the clinical trial and including it in the contract. 
Refraining from charging the subjects for the cost of the investigational product during the 
clinical trial. 
12) Writing, signing, and dating a final report after the clinical trial is complete, and sending it to 
the sponsor. 
10.1.15.2 
Responsibilities of the Sponsor 
The sponsor's responsibilities mainly include but are not limited to: 
1) Obtaining approval from the China Food and Drug Administration (CFDA). 
2) Initiating and applying for a clinical trial, as well as funding the trial. 
3) Providing an Investigator's Brochure covering the chemical, pharmaceutical, toxicological, 
pharmacological, and clinical (including previous and ongoing trials) information and data 
for the investigational product. 
4) Designing a clinical trial protocol jointly with the investigator. Signing the trial protocol and 
contract agreed upon by both parties. 
5) Providing the investigator with an investigational product and a comparator that are easy to 
identify, correctly coded, and specially labeled, while guaranteeing the quality of the 
investigational product and the comparator. Packaging and storing the investigational 
product properly as required by the trial protocol. Establishing a management system and 
recording system for the investigational product. 
6) Appointing qualified monitors who are accepted by the investigator. 
7) Establishing a quality control and quality assurance system for the clinical trial, and 
organizing audits for the clinical trial to ensure its quality. 
8) Working with the investigator to promptly study the SAEs that have occurred and taking 
necessary measures to ensure the safety and rights of the subjects. Reporting the SAEs to the 
drug regulatory authorities and health administrative departments in a timely manner. 
9) Submitting a final report of the trial to the CFDA. 
10) Purchasing the liability insurance for this drug clinical trial. Providing comprehensive 
medical coverage for the subjects of the clinical trial, and bearing the cost of the treatment 
and corresponding financial compensation for the subjects experiencing injuries or deaths 

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associated with the trial. Providing the investigator with legal and economic guarantees, 
except for those caused by medical malpractice. 
10.1.15.3 Access to Source Data 
The CRA is a primary liaison between the sponsor and the investigator. The CRA will fulfill all 
monitoring responsibilities to monitor this clinical study in accordance with GCP. The CRA will 
establish and maintain regular contact between the investigator and the sponsor. 
The CRA will conduct regular clinical monitoring according to all relevant regulatory 
requirements and standards, or visit the study site depending on actual situation, push the 
progress of the clinical trial, check and verify if all data records and reports, and eCRF entries 
are correct and complete, and consistent with the source data, and ensure that the clinical trial is 
performed according to the clinical trial protocol; the investigator shall actively assist the CRA in 
these processes. 
 

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10.2 Appendix 1: Common Terminology Criteria for Adverse Events 
This study will report AE using CTCAE v5.0 can be downloaded from the home page of the Cancer Therapy 
Evaluation Program (CTEP). CTCAE v5.0 shall be used in all relevant study sites. The URL is as follows: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf 
 
 

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10.3 Appendix 2-1: Response Evaluation Criteria in Solid Tumors (RECIST 
1.1) 
The following is the Response Evaluation Criteria in Solid Tumors RECIST Version 1.1. For 
more details, please refer to the English version at 
http://ctep.cancer.gov/protocolDevelopment/docs/ recist_guideline.pdf. 
Method 
• 
Currently, CT and MRI are the best reproducible methods used for assessing the response of 
selected target lesions. The lesion on the CT scan is measured according to the following 
assumption: CT slice thickness is 5 mm or less. When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be at least twice the slice 
thickness. The use of MRI to assess diseases throughout the entire study is acceptable. 
• 
Through the entire trial, the same assessment method and the same technique are used to 
characterize each identified and reported lesion. 
• 
An ultrasound diagnosis shall not be used to measure objective tumor response or 
disease progression. For this study protocol, cross sectional imaging techniques (CT or 
MRI) are used to assess complete responses, partial response, or stable disease. 
18F-fluorodeoxyglucose positron emission tomography (FDG-PET) examination is not 
suitable for assessing tumor response. It is sometimes reasonable to incorporate the use 
of FDG-PET scanning to complement CT scanning in assessment of disease 
progression. To determine progressive disease (PD), new lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm: 
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that 
site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
If the investigator decides to use combined PET-CT, the CT portions of PET-CT shall not be 
substituted for dedicated CT examination required by this study protocol to complete the 
RECIST measurement, unless the research institute may confirm that the CT performed as part 
of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast). 

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Cytology and histology can be used to differentiate between PR and CR in rare cases if required 
by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain). When effusions are known to be a potential adverse effect of 
treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment 
can be considered if the measurable tumor has met criteria for response or stable disease in order 
to differentiate between response (or stable disease) and disease progression. 
The definitions of "measurable" and "non-measurable" tumors: 
All measurements should be recorded in metric notation, using rulers or calipers. Measurement 
results shall be recorded in a single dimension. At baseline, tumor lesions/lymph nodes will be 
categorized measurable or non-measurable as follows: 
• 
Measurable: The tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of 10 
mm by CT scan (CT scan slice thickness no greater than 5 mm). When the CT scan slice 
thickness is greater than 5 mm, the longest diameter of the measurable lesion shall be at least 
10 mm or twice the slice thickness. Malignant lymph nodes: To be considered pathologically 
enlarged and measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT 
scan. 
• 
Non-measurable: All other lesions, including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly non-measurable 
lesions, that are characterized as non-target lesions. Lesions considered truly non-
measurable include: bone lesions, leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed. 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm 
diameter as assessed using calipers (e.g. skin nodules and tangible lymph nodes). For the case of 
skin lesions, documentation by color photography including a ruler to estimate the size of the 
lesion is suggested. Lesions which cannot be accurately measured with calipers should be 
recorded as non-measurable. 
Special considerations regarding lesion measurability: 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components (that 
can be evaluated by cross sectional imaging techniques such as CT or MRI) can be considered as 

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measurable lesions if the soft tissue component meets the definition of measurability described 
above. Blastic bone lesions are non-measurable. 
Cystic lesions: Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions. "Cystic lesions" is thought to represent cystic metastases that 
can be considered as measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. 
Baseline (i.e., before treatment) documentation of "target" and "non-target" lesions. 
During treatment, a maximum of five 5 target lesions are selected for measurement (a maximum 
of two lesions per organ). Target lesions shall be selected according to their size and the 
appropriateness of reproducible repeated measurements using imaging techniques or clinical 
means. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
• 
All other lesions (or affected sites; including any measurable lesions or pathological lymph 
nodes not selected as target lesions) shall be identified as non-target lesions. Non-target 
lesions shall be recorded and qualitatively assessed during treatment. Measurements are not 
required, and these lesions should be followed as "present", "absent", or in rare cases 
"unequivocal progression". 
• 
Bone lesions: Bone scan, PET scan, or plain films are not considered adequate imaging 
techniques to measure bone lesions. If a sign or symptom indicative of bone metastases is 
present, a bone scan, MRI, CT, PET, PET/CT, or X-ray scan shall be performed. For 
subjects who are positive for bone scans or PET scans, another imaging technique (e.g., X-
ray, CT, or MRI) must be used to confirm bone metastasis. 
Response criteria 
A subject's tumor response is assessed based on the response for target and non-target lesions, as 
well as the appearance of new lesions and disappearance of old lesions. 
 
 

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Table 10: Evaluation of Target Lesions 
*Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have a reduction in short axis to < 10 
mm. 
*Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
*Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study. In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
(Note: the appearance of one or more new lesions is also considered 
progression). 
*Stable Disease 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while in 
study. 
Not Applicable (NA): 
No target lesions are identified at baseline. 
Not Evaluable (NE): 
The scan is not completed, the scan result is incomplete, or the scan is not 
evaluated due to poor quality of the scan at the time point chosen for the 
evaluation of target lesions. 
*Diameter to be used: 
For lymph node lesions: the shortest axis 
For non-lymph node lesions: the sum of longest diameters 
Once the study is started, the following rule will be adopted: If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned. 
If the size of the lesion increases to 5 mm or more in one direction, their actual diameter shall be 
recorded. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm in study. This means that when 
lymph nodes are included as target lesions, the "sum" of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short axis 
of < 10 mm. In order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, 
SD, and PD, the actual short axis measurement of the nodes is to be included in the sum of target 
lesions. 
 
 

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Table 11: Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (< 10 mm short axis) 
Non-CR/non-PD: 
Persistence of one or more non-target lesion(s) 
Progressive Disease (PD): 
Appearance of one or more new lesions, or if the original non-target lesions show 
suspicious progression. 
Not Applicable (NA): 
No non-target lesions are identified at baseline. 
Not Evaluable (NE): 
The scan is not completed, the scan result is incomplete, or the scan is not 
evaluated due to poor quality of the scan at the time point chosen for the 
evaluation of non-target lesions. 
When the patient also has measurable disease, in this setting, to achieve "unequivocal 
progression" on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease. Even in presence of SD or PR in target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation of therapy. When the patient has 
only non-measurable disease, the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease (which is equivalent to a 20% increase in the sum of diameters in all 
measurable lesions). 
 
 

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Evaluation of best overall response 
The status of the overall response of subjects at various time points is calculated as follows: 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = in 
evaluable 
 

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Time point response of patients with non-target disease only. 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
NE 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = in 
evaluable  
A "Non-CR/Non-PD" is preferred over "stable disease" for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not 
advised. 
Special notes on response assessment 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration". In this case, it is not possible at this time to use " disease 
progression" as an overall objective response of the tumor. Every effort should be made to 
document objective progression even after discontinuation of treatment. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or disease progression is 
objectively documented (taking as reference for disease progression the smallest measurement 
recorded in study). 
 

Shanghai Henlius Biotech, Inc. 
Clinical Study Protocol 
Protocol HLX10-005-SCLC301 
CONFIDENTIAL 
 
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10.4 Appendix 2-2: iRECIST: Guidelines for response criteria for use in trials 
testing immunotherapeutics 
 
 

iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics
Prof Lesley Seymour, MD,
Canadian Cancer Trials Group, Queen’s University, Kingston, ON, Canada
Jan Bogaerts, PhD,
EORTC Headquarters, Brussels, Belgium
Andrea Perrone, MD,
Translational Medicine, Merck & Co, Kenilworth, NJ, USA
Robert Ford, MD,
Clinical Trials Imaging Consulting, LLC, Belle Mead, NJ, USA
Prof Lawrence H Schwartz, MD,
Department of Radiology, Columbia University Medical Center, New York, NY, USA
New York Presbyterian Hospital, New York, NY, USA
Prof Sumithra Mandrekar, PhD,
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
Nancy U Lin, MD,
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
MA, USA
Saskia Litière, PhD,
EORTC Headquarters, Brussels, Belgium
Correspondence to: Prof Lesley Seymour, Canadian Cancer Trials Group, Queen’s University, Kingston, ON K7L 3N6, Canada 
lseymour@ctg.queensu.ca. 
Contributors
All authors contributed to the literature search and writing of the report.
Declaration of interests
LS reports grants from AstraZeneca and Merck, outside the submitted work. AP owns stocks in Merck & Co. RF reports personal fees 
from Amgen, Abbvie, Aptiv, Aragon, BMS, Bioclinica, Celldex, Celsion, Clovis, Covance, Biomedical systems, ACR Image Metrix, 
Exelixis, Genentech, Janssen, Kyowa, Loxo, ICON Medical Imaging, Eisai, EMD Serono, Imaging Endpoints, Mlrati, Celgene, 
Merck, Novartis, Novocure, Roche, Pfizer, Quintile, Tokai, ONO, Red Hill, Radiant Sage, Orbimed Advisors, Cinven, Virtualscopics, 
Sun Advanced Pharma Research Company, Median Therapeutics, Optimer Biotechnology Inc, Vascular Biogenics, Ignyta, 
Immunocellular CBT Pharmaceuticals, Tracon, DNAtrix, CytRx, Kolltan, and Samsung Bioepsis, outside the submitted work. LHS 
reports grants and consulting fees from Novartis, grants from Astellas, Eli Lilly, Merck, Pfizer, consulting fees from GSK, outside the 
submitted work. JD reports grants from Merck, AstraZeneca, Pfizer, Ottawa Hospital Research Institute, Novartis, outside the 
submitted work. FSH reports grants from Bristol-Myers Squibb, and personal fees from Merck, Novartis, Genentech, and EMD 
Serono, outside the submitted work. Additionally, FSH has a patent MICA Related Disorders with royalties paid, and a patent Tumor 
Antigens and Uses Thereof issued. JDW reports grants from Bristol Myers Squibb, Merck, and Genentech during the conduct of the 
study; consulting fees from Bristol Myers Squibb and Merck, and is on the scientific advisory board for Medimmune, outside the 
submitted work. MB reports personal fees from Genentech outside the submitted work, and owns stocks in Roche. CC reports 
personal fees from Roche, BMS, and AstraZeneca, outside the submitted work. EGEdV reports consulting fees from Synthon, 
Medivation, and Merck; and grants from Novartis, Amgen, Roche/Genentech, Servier, Chugai, Synthon, AstraZeneca, and Radius 
Health, outside the submitted work. JB, SM, NUL, SL, AC, PT, OSH, and LKS declare no competing interests.
For the EORTC RECIST data warehouse see www.eortc.org/RECIST
HHS Public Access
Author manuscript
Lancet Oncol. Author manuscript; available in PMC 2017 October 19.
Published in final edited form as:
Lancet Oncol. 2017 March ; 18(3): e143–e152. doi:10.1016/S1470-2045(17)30074-8.
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Prof Janet Dancey, MD,
Canadian Cancer Trials Group, Queen’s University, Kingston, ON, Canada
Alice Chen, MD,
Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National 
Cancer Institute, Bethesda, MD, USA
Prof F Stephen Hodi, MD,
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
MA, USA
Patrick Therasse, MD,
Institut de Recherche International Servier, Paris, France
Prof Otto S Hoekstra, MD,
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, 
Netherlands
Lalitha K Shankar, MD,
Diagnostic Imaging Branch, National Cancer Institute, Bethesda, MD, USA
Jedd D Wolchok, MD,
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Marcus Ballinger, PhD,
Weill Cornell Medical and Graduate Colleges, New York, NY, USA
Ludwig Institute for Cancer Research, New York, NY, USA
Genentech Inc, San Francisco, CA, USA
Caroline Caramella, MD, and
Department of Radiology, Gustav Roussy Cancer Campus, Villejuif, France
Prof Elisabeth G E de Vries, MD
Department of Medical Oncology, University Medical Center Groningen, Groningen, Netherlands
on behalf of the RECIST working group
Abstract
Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising 
questions about the assessment of changes in tumour burden—a mainstay of evaluation of cancer 
therapeutics that provides key information about objective response and disease progression. A 
consensus guideline—iRECIST—was developed by the RECIST working group for the use of 
modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer 
immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing 
collection of trial data, and ultimate validation of the guideline. This guideline describes a standard 
approach to solid tumour measurements and definitions for objective change in tumour size for use 
in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints 
required from future trials and those currently in development to facilitate the compilation of a 
data warehouse to use to later validate iRECIST. An unprecedented number of trials have been 
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done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of 
modified response criteria. This guideline will allow consistent conduct, interpretation, and 
analysis of trials of immunotherapies.
Introduction
Changes in tumour burden (termed response) are often used as surrogates of survival or 
quality of life;1 consequently, validated and consistent criteria for defining response to 
treatment are crucial. In 2000, the Response Evaluation Criteria in Solid Tumours (RECIST) 
working group simplified the 1981 WHO response criteria2 after validation in a large data 
warehouse.3 In 2009, RECIST was refined to RECIST version 1.1.4 The RECIST working 
group ensures that RECIST undergoes continuous testing, validation, and updates.5–7
Immune modulators are one of the most important classes of new anticancer 
therapeutics.8–10 Cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 
(PD-1), and programmed death ligand-1 (PD-L1) pathways are the most intensively 
studied,11–17 and drugs that are active in these pathways have, since 2011, received 
marketing authorisation (for some drugs the authorisation is conditional, pending the 
completion of other studies) for melanoma, lung, bladder, renal, and head and neck 
cancer.18–23 The novel mechanism of action of these drugs, with immune and T-cell 
activation, is postulated to lead to unusual patterns of response that resemble tumour flare 
but are more pronounced and more frequent than previously described responses. In early 
trials of immune-based therapeutics in melanoma, investigators described unique response 
patterns, termed pseudoprogression. Some patients whose disease met the criteria for disease 
progression based on traditional response criteria such as RECIST (an increase in the sum of 
measures of target lesions, unequivocal increase in non-target disease, or the appearance of 
new lesions) were noted to have late but deep and durable responses.24–28 In 2009, modified 
response criteria based on WHO criteria (which include the collection of bidimensional 
measurements of target lesions) were proposed—the immune-related response criteria 
(irRC).29 The major modification involved the inclusion of the measurements of new target 
lesions (each must be at least 5 × 5 mm in size; with a maximum of ten visceral lesions in 
total, up to five new lesions per organ, and five new cutaneous lesions) into disease 
assessments. In 2013, researchers published revised irRC using unidimensional 
measurements based on the original RECIST.30 Subsequent recommendations, some 
published in abstract form, seem to incorporate RECIST 1.1 recommendations.31–33 These 
recommendations are often referred to as irRECIST, but have not always been consistently 
applied, leading to concerns about the comparability of data and results across trials, 
difficulty with pooling databases, and poor clarity regarding whether new lesions were 
measured, and if so, how many were captured, and whether measures were incorporated into 
tumour burden. Recent trials (since 2010) have generally used RECIST-based immune 
criteria to assess responses to immunotherapies.
Because of the need to standardise and validate response criteria, the RECIST working 
group prospectively planned to create a warehouse of data from trials of immunotherapeutics 
to test and validate RECIST 1.1 and suggest modifications if required. During the planning 
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and initial collection of the immunotherapeutic warehouse, it was apparent that most trials 
testing these drugs have typically used RECIST 1.1 to define the primary and secondary 
efficacy-based endpoints, and reserved irRC or their modified definition of RECIST for 
exploratory endpoints.31,32 Additionally, substantial variability in which criteria were used 
was seen across clinical trials within pharmaceutical companies and cooperative groups, 
leading to serious concerns about interpretation of pooled datasets. Finally, most trials that 
used immune-modified criteria used independent imaging review by a commercial entity for 
those criteria, rather than investigator assessments. We think that response criteria should be 
applicable across all cancer clinical trials, including those done in the academic sector, 
where costly independent review is not feasible.
On the basis of these observations, the RECIST working group decided to develop a 
guideline for the use of a modified RECIST to ensure consistent design and data collection 
that would facilitate the ongoing collection of clinical trial data and ultimate validation, if 
indicated, of a modified RECIST 1.1 for immune-based therapeutics (termed iRECIST). 
These guidelines are not intended to define or guide clinical practice or treatment decisions, 
but rather to provide a consistent framework for the management of data collected in clinical 
trials of immune-based therapies. Treatment decisions rest with the patient and their health-
care team.
Terminology
iRECIST is based on RECIST 1.1. Responses assigned using iRECIST have a prefix of “i” 
(ie, immune)—eg, “immune” complete response (iCR) or partial response (iPR), and 
unconfirmed progressive disease (iUPD) or confirmed progressive disease (iCPD) to 
differentiate them from responses assigned using RECIST 1.1. Similar nomenclature is used 
for stable disease (iSD). New lesions are assessed and subcategorised into those that qualify 
as target lesions (new lesion, target) or non-target lesions (new lesion, non-target).
Development of the guideline
The RECIST working group formed a subcommittee and held a series of conference calls 
and face-to-face meetings in 2015 and 2016 to discuss plans for the development and 
validation of iRECIST (figure 1) and to review existing approaches to assess response in 
immune modulator trials, and also to identify points of consensus and items that needed 
further discussion. Members of the subcommittee included clinical, statistical, and imaging 
experts in methodology and immunotherapy, representatives from the pharmaceutical 
companies developing immunotherapeutics, and key regulatory authorities (appendix p 1). 
On June 2, 2016, a formal meeting was held in Chicago (IL, USA), with invited 
presentations from regulatory authorities, pharmaceutical companies with immune 
modulator drugs in development, and academic groups, followed by a structured discussion. 
Before the meeting, the 52 invited participants were polled to enable the identification of 
questions that needed to be addressed, as well as the response criteria routinely used by 
participants. Ten respondents provided responses before the meeting (including some pooled 
responses) and all eight presenters identified additional areas of interest in their 
presentations. After review and discussion during the meeting, the group identified a list of 
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important questions to be addressed by iRECIST (panel 1). Notably, all participants 
confirmed that RECIST 1.1 was used for primary endpoints, with immune-modified 
response criteria being used in an exploratory manner, with very few exceptions; in one 
instance, immune-modified criteria were used as a coprimary endpoint. The most commonly 
used immune-modified criteria were variations of irRECIST. There was more variability in 
independent imaging review and the period of time during which response data were 
collected after RECIST 1.1 progression or cessation of protocol therapy. Further calls and 
meetings were held to develop and plan the full validation of iRECIST (figure 1).
iRECIST
The continued use of RECIST 1.1 is recommended to define whether tumour lesions, 
including lymph nodes, are measurable or non-measurable, as well as for the management of 
bone lesions, cystic lesions, and lesions with previous local treatment (eg, radiotherapy; 
table 1). Similarly, no changes have been made to the recommendations regarding the 
method of measurement, although clinical examination and chest radiograph are rarely used, 
with the availability of more modern imaging techniques (eg, CT scans and MRI). The 
principles used to establish objective tumour response are largely unchanged from RECIST 
1.1, but the major change for iRECIST is the concept of resetting the bar if RECIST 1.1 
progression is followed at the next assessment by tumour shrinkage.
iRECIST defines iUPD on the basis of RECIST 1.1 principles; however, iUPD requires 
confirmation, which is done on the basis of observing either a further increase in size (or in 
the number of new lesions) in the lesion category in which progression was first identified in 
(ie, target or non-target disease), or progression (defined by RECIST 1.1) in lesion 
categories that had not previously met RECIST 1.1 progression criteria. However, if 
progression is not confirmed, but instead tumour shrinkage occurs (compared with baseline), 
which meets the criteria of iCR, iPR, or iSD, then the bar is reset so that iUPD needs to 
occur again (compared with nadir values) and then be confirmed (by further growth) at the 
next assessment for iCPD to be assigned. If no change in tumour size or extent from iUPD 
occurs, then the timepoint response would again be iUPD. This approach allows atypical 
responses, such as delayed responses that occur after pseudoprogression, to be identified, 
further understood, and better characterised (tables 1–3, figure 2, appendix pp 2–4). Sample 
case record forms and protocol sections are included in the appendix pp 5–19. In the next 
few paragraphs, we only briefly summarise sections of RECIST 1.1 that are unchanged; 
readers should refer to RECIST 1.1 for full descriptions.4
Assessment of target, non-target, and new lesions
Most RECIST 1.1 recommendations are unchanged for timepoint response, including the 
management of lymph nodes, lesions that become too small to measure, lesions that split or 
coalesce, and the definition of complete response, partial response, stable disease, and 
progressive disease. Each timepoint response is based on the assessment of target lesions, 
non-target lesions, and new lesions.
For target lesions, iCR, iPR, and iSD can all be assigned after iUPD has been documented, 
as long as iCPD was not confirmed. iUPD is defined by RECIST 1.1 criteria for progressive 
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disease; iUPD can be assigned multiple times as long as iCPD is not confirmed at the next 
assessment. Progression is confirmed in the target lesion category if the next imaging 
assessment after iUPD (4–8 weeks later) confirms a further increase in sum of measures of 
target disease from iUPD, with an increase of at least 5 mm. However, the criteria for iCPD 
(after iUPD) are not considered to have been met if complete response, partial response, or 
stable disease criteria (compared with baseline and as defined by RECIST 1.1) are met at the 
next assessment after iUPD. The status is reset (unlike RECIST 1.1, in which any 
progression precludes later complete response, partial response, or stable disease). iCR, iPR, 
or iSD should then be assigned; and if no change is detected, then the timepoint response is 
iUPD.
The assessment of non-target lesions at each timepoint follows similar principles. iUPD (but 
not iCPD) can have been documented before iCR or when the criteria for neither CR nor PD 
have been met (referred to as non-iCPD/non-iUPD) and can be assigned several times, as 
long as iCPD was not confirmed. iUPD is defined by RECIST 1.1 criteria; however, iUPD 
can be assigned multiple times as long as iCPD is not confirmed at the next assessment. 
Progressive disease in the non-target lesion category is confirmed if subsequent imaging, 
done 4–8 weeks after iUPD, shows a further increase from iUPD. The criteria for iCPD are 
not judged to have been met if RECIST 1.1 criteria for complete response or non-iCR/non-
iUPD are met after a previous iUPD. The status is reset (unlike RECIST 1.1) and iCR, or 
non-iCR/non-iUPD is assigned; if no change is detected, the timepoint response is iUPD.
RECIST 1.1 defines the appearance of new malignant lesions as denoting true disease 
progression, providing that other lesions (artefacts or benign intercurrent disease) are 
appropriately assessed and discounted if not malignant. These principles of RECIST 1.1 
remain useful and clearly identify the management of new lesions that are considered to be 
potentially artefactual: “If a new lesion is equivocal, for example because of its small size, 
continued therapy and follow-up assessment will clarify whether it represents truly new 
disease. If repeat scans confirm there is definitely a new lesion, then progression should be 
declared using the date of the initial scan”.4
However, many aspects of new lesion assessment are unique to iRECIST. If a new lesion is 
identified (thus meeting the criteria for iUPD) and the patient is clinically stable, treatment 
should be continued. New lesions should be assessed and categorised as measurable or non-
measurable using RECIST 1.1 principles. Five lesions (no more than two per organ) should 
be measured and recorded as a new lesion target, but should not be included in the sum of 
measures of the original target lesions identified at baseline (appendix p 17). Other 
measurable and non-measurable lesions are recorded as new lesion non-target. Trialists 
might choose to measure and record more than five new lesions for research purposes, but 
this method is not believed to be practical for general use. New lesions do not need to meet 
the criteria for new lesion target to result in iUPD (or iCPD); new lesion non-target can also 
drive iUPD or iCPD. Progressive disease is confirmed (iCPD) in the new lesion category if 
the next imaging assessment, done at 4–8 weeks after iUPD, confirms additional new lesions 
or a further increase in new lesion size from iUPD (sum of measures increase in new lesion 
target ≥5 mm, any increase for new lesion non-target).
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Notably, if iUPD criteria were met on the basis of progression in the target or non-target 
disease, or the appearance of new lesions, then RECIST 1.1-assigned progression in another 
lesion category in the confirmatory scan also confirms iCPD.
Continued treatment after iUPD
The existing literature describes pseudoprogression as an increase in the size of lesions, or 
the visualisation of new lesions, followed by a response, which might be durable. Although 
well described, differentiating transient pseudoprogression from true progression, potentially 
requiring a change in therapy, can be challenging. Although early discontinuation of an 
effective drug is not desirable, continued long-term treatment with a non-effective drug past 
true progression might delay the initiation of potentially effective salvage therapy.
We recommend that clinical trials in which treatment beyond initial RECIST 1.1-defined 
progression (ie, iUPD) is permitted should only allow patients who are clinically stable to 
continue on treatment until the next assessment (≥4 weeks later); this next imaging 
assessment should be no longer than 8 weeks later, to ensure that patients remain fit for 
salvage therapies. A longer timeframe before the next assessment might be reasonable if 
pseudoprogression is well described in the tumour type (eg, melanoma treated with a 
CTLA4 inhibitor), especially if no effective salvage therapies are available (eg, BRAF wild-
type melanoma) but should be justified in the trial protocol. All decisions regarding 
continuation or discontinuation of therapy should be made by the patient and their health-
care provider; iRECIST describes what data are to be collected, submitted, and analysed in 
clinical trials of immune-based therapies.
An assignment of clinical stability requires that no worsening of performance status has 
occurred, that no clinically relevant increases in disease-related symptoms such as pain or 
dyspnoea occur that are thought to be associated with disease progression (these symptoms 
are generally understood to mean a requirement for increased palliative intervention), and 
that no requirement for intensified management of disease-related symptoms exists, 
including increased analgesia, radiotherapy, or other palliative care.
The imaging findings and the recommendation to continue with treatment despite iUPD 
should be discussed with the patient before a decision is made about whether or not to 
continue therapy. Patients who have iUPD and are not clinically stable should be designated 
as not clinically stable in the case report form. This designation will allow the best overall 
response to be calculated and the date of iUPD to be used in estimates of progression-free 
survival.
If the confirmatory scan confirms iCPD, but the investigator or patient believes that 
continued treatment is appropriate, imaging should continue and data should be collected to 
allow further elucidation of tumour growth dynamics with immune modulators. For the same 
reason, and if feasible, even patients who discontinue therapy for iCPD are recommended to 
continue to have disease assessments until they start other systemic or local therapies.
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Timepoint and best overall response
Although the principles of the assignment of the timepoint response and best overall 
response closely follow RECIST 1.1, and reflect assessment of target and non-target lesions 
as well as the presence of new lesions, the possibility of pseudoprogression adds complexity 
(tables 1–3, panel 2, appendix pp 2–4). The timepoint response is calculated using the 
response assigned for each category of lesion (as for RECIST 1.1), but takes into account the 
last timepoint response.
The algorithm for patients with no previous iUPD is identical to RECIST 1.1. For patients 
with iUPD at the last timepoint response, the next timepoint response is dependent on the 
status of all lesions, including target, non-target, new lesion target, and new lesion non-
target; on whether any increase in size has occurred (either a further increase in size or a 
sufficient increase to assign a new iUPD if the criteria were not previously met); or the 
appearance of additional new lesions.
For iRECIST, the best overall response (iBOR) is the best timepoint response recorded from 
the start of the study treatment until the end of treatment, taking into account any 
requirement for confirmation. iUPD will not override a subsequent best overall response of 
iSD, iPR, or iCR (tables 1–3, appendix pp 2–4), meaning that iPR or iSD can be assigned 
(timepoint response or iBOR) even if new lesions have not regressed, or if unequivocal 
progression (non-target lesions) remains unchanged, providing that the criteria for iCPD are 
not met.
Confirmation of response is not required when using RECIST 1.1, except in non-randomised 
trials, and this approach is also recommended for iRECIST. The duration of iCR and iPR is 
from the timepoint when the criteria for iCR or iPR are first met, whereas the duration of 
iSD is still calculated from baseline.
The protocol should establish how missing response assessments will be handled. 
Assessments that are not done or are not evaluable should be disregarded. For example, an 
iUPD followed by an assessment that was not done or not evaluable, and then another 
unconfirmed progressive disease, would be indicative of iCPD. Protocols should clearly 
specify whether assessments done after protocol therapy is discontinued can be considered 
in identification of iBOR; it might be reasonable to include assessments done several weeks 
or months after protocol treatment has been discontinued if late responses are anticipated 
(such as with a CTLA4 inhibitor) and patients have not received other systemic or local 
therapies. Protocols should also specify how any new therapy introduced before progression 
(eg, radiotherapy or surgery) will affect iBOR designation. Other RECIST 1.1 
recommendations, including the management of missing assessments, remain unchanged, 
including requiring that the statistical analysis plan should indicate how missing data or 
assessments will be addressed in the determination of response and progression.
Frequency of tumour reassessment
In general, follow-up response assessment every 6–12 weeks is recommended for iRECIST, 
depending on the frequency of treatment visits, as recommended for RECIST 1.1. The 
protocol should specify which anatomical locations are assessed at baseline and follow-up, 
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and whether bone scans should be repeated at each response assessment, only to confirm 
iPR or iCR, or when clinically indicated. For all trials, especially comparative ones, response 
assessments should be done on a calendar schedule and not be affected by delays in therapy 
or the requirement for earlier confirmatory scans, which might be done to confirm iUPD or 
in some trials, to confirm complete or partial response.
Tumour reassessment can be done earlier than originally planned (but only between 4 and 8 
weeks after iUPD) to confirm iUPD (or, in non-randomised trials, to confirm iCR or iPR ≥4 
weeks after the scan showing complete or partial response). If progression is not confirmed, 
reassessment should continue as originally planned (ie, if scans were to be done at 8, 16, and 
24 weeks, and a scan was done at 12 weeks to confirm response, then the next scans should 
be done at 16 weeks and 24 weeks, as planned). If patients continue on treatment per 
protocol after iCPD, assessments should continue to be done, at the same planned schedule, 
until protocol treatment is discontinued.
Ideally, all imaging done after protocol treatment has been discontinued should continue to 
be recorded on the case report form until subsequent therapies are initiated, as the protocol 
and informed consent document permit. These data will allow further refinement of 
iRECIST.
Statistical and protocol considerations
The event date to be used for calculation of progression-free survival (iPFS) should be the 
first date at which progression criteria are met (ie, the date of iUPD) provided that iCPD is 
confirmed at the next assessment (appendix pp 2–4 and 19). If iUPD occurs, but is 
disregarded because of later iSD, iPR, or iCR, that iUPD date should not be used as the 
progression event date.
If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, then the iUPD 
date should still be used in the following scenarios: if the patient stops protocol treatment 
because they were not judged to be clinically stable, or no further response assessments are 
done (because of patient refusal, protocol noncompliance, or patient death); the next 
timepoint responses are all iUPD, and iCPD never occurs; or the patient dies from their 
cancer. The case report form collects the reason why confirmatory response assessment was 
not done at any timepoint, such as not clinically stable, centre error, patient refusal, or 
patient death.
For protocols that permit crossover, or if intermittent schedules are being tested, the protocol 
should clearly specify whether iUPD or iCPD would be used for a treatment decision 
leading to crossover and how data subsequent to crossover will be managed and analysed. In 
general, we suggest that iCPD be used especially for scenarios with immunotherapy in both 
treatment groups and when pseudoprogression is anticipated.
Adjuvant trials of immune modulators given after curative surgery for melanoma or lung 
cancer are ongoing (NCT 02437279, 02388906, 02595944, 02504372, and 02273375) but 
have yet to report their results. Suspected new lesions in the curative setting should always 
be investigated thoroughly and preferably have a biopsy taken before the designation of 
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relapse is assigned. If taking a biopsy sample is not technically feasible, then it would seem 
to be reasonable to follow the principles of iRECIST, with a follow-up scan to confirm 
relapse in patients who are clinically stable.
The collection of anonymised imaging (even if centralised blinded review of imaging studies 
is not planned) is recommended for all studies using an imaging-based endpoint (ie, 
response or progression-free survival) if feasible. Although the iRECIST guideline requires 
the recording of the measurements of up to five new lesions, it might eventually be 
necessary to record additional lesions to obtain a more precise estimate of progression. 
Central collection of images will allow further assessment by an independent radiologist if 
necessary. If real-time central review is planned, the protocol should clearly explain how 
treatment decisions will be made.
We recommend that phase 3 clinical trials continue to incorporate both RECIST 1.1 and 
iRECIST (table 1) and that RECIST 1.1 should continue to be used to define the primary 
efficacy outcomes (progression-free survival, disease progression, and best overall 
response). Exploratory analyses using the iPD date (ie, the first date of iUPD that is 
subsequently confirmed) can be defined in the statistical analysis plan. Early-phase trials can 
consider using iRECIST as the primary criteria. The protocol should carefully explain which 
will be the primary criteria used to assess response, and which would be exploratory. This 
information is especially important for trials that compare an immune modulator treatment 
with a non-immune modulator treatment.
Discussion: next steps and validation
Immunotherapeutics are a major advance in the treatment of an escalating number of 
cancers. The increasing testing and use of these drugs in multiple clinical settings, including 
adjuvant, first, second, and subsequent lines of therapy will require the use of progression-
based endpoints. RECIST 1.1 might not always adequately capture the unique patterns of 
response that have been well described in clinical trials of these drugs in a low proportion of 
patients, typically reported as 10% or less, mainly in melanoma studies.32–34 The true 
frequency in trials of other malignancies (including non-small-cell lung cancer) is unclear 
because most trials have reported RECIST 1.1-based response rates,35 but might be less 
common based on anecdotal reports. Similarly, whether this pattern is unique to drugs active 
in the CTLA4–PD-1–PD-L1 pathway is currently unknown. Trials testing 
immunotherapeutics in combination with standard therapies, especially when they are 
compared with these standard therapies alone, further confound the assessment of 
progression-based endpoints.
RECIST 1.1 already addresses the management of equivocal progression, including 
suspected new lesions, which might explain, at least in part, the continued use of RECIST 
1.1 to define response-based primary endpoints. RECIST 1.1 deals with mainly technical 
differences in scans that give the appearance that new lesions might have developed, or the 
concept of the isodense lesion at baseline that becomes more visible after the start of therapy 
since it becomes internally more necrotic as opposed to a true new lesion. However, the 
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intention was never to use those recommendations to manage pseudoprogression described 
with immune modulators.
Although modified response criteria have been used, a formal guideline is clearly needed, 
with robust plans for prospective testing and consistent data collection and validation. Trials 
have not always been consistent in the definition of the response criteria to be used, have 
used trial-specific modifications of response criteria in which new lesion measurements can 
or cannot be included in the assessment of response, and response assessments after 
progression defined by RECIST 1·1 are not always done. Those data are crucial to 
understand the dynamics of tumour response to immunotherapeutics, including whether 
immunotherapeutics with different mechanisms of action have varying effects.
Although some progress has been made in understanding tumour dynamics with 
immunotherapeutics, progress in this area has undoubtedly been limited by reluctancy 
toward data sharing across trials, companies, and immunotherapeutics. Publications have 
been based on trials done by individual pharmaceutical companies or commercial 
organisations. In the development of this guideline, virtually all major pharmaceutical 
companies developing immunotherapeutics participated and have shared their experiences, 
protocols, response criteria, and, most importantly, their data. The iRECIST team also 
included members of the European Medicines Agency and the US Food and Drug 
Administration.
Although this guideline is consensus based, it is not yet validated because the data 
warehouse is still being created with initial trial data already in place. The guideline includes 
all available knowledge on response dynamics, allowing appropriate management of true 
pseudoprogression, but importantly, it also safeguards patients: although pseudoprogression 
is now well described, it still only occurs in fewer than one in ten patients. Treatment past 
radiographic progression might be appropriate only in a small number of patients, and the 
continuation of treatment past true progression could reduce subsequent effective therapies if 
the patient is no longer fit enough to tolerate any further treatment.
iRECIST requires the confirmation of progression to rule out or confirm pseudoprogression. 
Although this recommendation is in keeping with that of RECIST 1.1 to continue treatment 
and repeat imaging in the case of a mixed response or equivocal findings, if 
pseudoprogression is common, patients might be exposed to a higher risk (of continuing 
ineffective therapy or increasing exposure to radiotherapy) or cost (for the potentially 
ineffective therapy or the costs of imaging). We recommend that these criteria are used for 
clinical trial protocols rather than to guide clinical practice. Treatment beyond RECIST 1.1-
based progression should be considered only in carefully selected scenarios in which the 
patient is stable (or improving) symptomatically and if there is just a short period remaining 
before reassessment.
Although at first glance the recommendation to collect measurements of new lesions as 
defined in this guideline seems onerous, the collection of these measurements and the 
recording of both RECIST 1.1 and iRECIST for timepoint response and best overall 
response have several benefits. The association between the site of the new lesion and 
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progression-free survival and the value of adding new lesion measurements to the sum of 
measures can be explored. Continuing to record RECIST 1.1 allows comparison with 
reported immunotherapy trials that have used RECIST 1.1, as well as chemotherapy trials, 
while also allowing treatment past progression and collecting data that will allow further 
testing and validation of iRECIST. Differences in trial outcomes using RECIST 1.1 versus 
iRECIST could occur, and the interpretation will be informative. Our proposed plan will 
enable identification of such situations, and hopefully clarification of the underlying 
mechanisms. Additionally, in the future, quantification of the differences in outcome 
estimation between RECIST 1.1 and iRECIST will be possible, enabling better informed 
decisions for future changes to RECIST guidelines.
This strategy will also be useful for trials comparing immunotherapy-based with non-
immunotherapy-based therapeutics. RECIST 1.1 and iRECIST should yield almost identical 
results for non-immunotherapy treatments, based on the RECIST warehouses; whereas an 
immune modulator warehouse and associated sensitivity analysis of endpoints will enable 
the quantification of potential added benefit for the immunotherapy component. Although 
comparison of iRECIST in such situations incorporates an element of bias by construction, 
confirmation and validation of the guideline by overall survival results might gain additional 
importance.
Our recommendation for the design of randomised studies planned for licensing applications 
is to continue to use RECIST 1.1 as the primary criteria for response-based endpoints. 
iRECIST should be regarded as exploratory in such trials, although earlier phase trials might 
consider using primarily iRECIST.
The creation of a data warehouse is underway and updates are available from EORTC where 
the warehouse is held. Meanwhile the implementation of this guideline, and the continued 
sharing of anonymised, patient-level data will allow the formal validation of iRECIST, 
ensuring that response-based guidelines remain robust and enable the rapid and robust future 
development of new cancer therapeutics to improve treatments for patients.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
AC and LKS are employees of the National Institutes of Health/National Cancer Institute. This publication was 
supported by the Canadian Cancer Society Research Institute (grant #021039), the EORTC Cancer Research Fund, 
and the National Cancer Institute (grant number 5U10-CA11488-45). The contents of this paper were presented in 
part at the EORTC-NCI-AACR 2016 Meeting (Munich, Germany; Nov 29–Dec 2, 2016). We gratefully 
acknowledge the thoughtful participation of the following in this initiative: Patricia Keegan (US Food and Drug 
Administration, Silver Spring, MD, USA); Francesco Pignatti (European Medicine Agency, London, UK); Wendy 
Hayes (Bristol-Myers Squibb, Princeton, NJ, USA); Eric Rubin (Merck & Co, Kenilworth, NJ, USA). We also 
received written comments from Darragh Halpenny, Jean-Yves Blay, Florian Lordick, Silke Gillessen, Hirokazu 
Watanabe, Jose Pablo Maroto Rey, Pietro Quaglino, Howard Kaufman, Denis Lacombe, Corneel Coens, Catherine 
Fortpied, Jessica Menis, Francisco Vera-Badillo, Jean Powers, Michail Ignatiadis, Eric Gauthier, Michael O’Neal, 
Caroline Malhaire, Laure Fournier, and Glen Laird. We thank Anouk Funke for her assistance with this manuscript.
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Panel 1: Key questions identified by the RECIST working group
•
How to define the date of progression in scenarios in which initial progression 
by RECIST 1.1 is followed by response and later progression
•
How to define best overall response when initial progression is established 
with RECIST 1.1
•
How to manage response and progression in trials comparing standard non-
immunotherapy drugs against immunotherapeutics
•
Whether or not progression should be confirmed with a second scan; and if 
so, which timepoint denotes the date of progression?
•
New lesions: when to measure, how many to measure, and whether all should 
be measured at each subsequent assessment
•
Optimal timing of frequency of response assessment
•
How to manage therapeutic interventions such as surgery or radiotherapy after 
response
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Panel 2: Key principles to be considered
•
If the criteria for iUPD have never been met, principles follow RECIST 1.1
•
However, if the criteria for iUPD have been met, the next timepoint response 
could be:
•
iUPD: no change noted in any category of lesion
•
iSD, iPR, or iCR. Here, iUPD (followed by iCPD) should occur again
•
iCPD, if the category in which iUPD was met at the last timepoint response 
shows a further increase in tumour burden as evidenced (as applicable) by a 
≥5 mm increase in sum of measures of target or new target lesions, further 
increase in non-target or new non-target lesions, or an increase in the number 
of new lesions
iCPD of a category which did not meet criteria for iUPD now meets the criteria for 
RECIST 1.1 progression Prefix “i” indicates immune responses assigned using iRECIST. 
RECIST=Response Evaluation Criteria in Solid Tumours. iCR=complete response. 
iCPD=complete progression. iPR=partial response. iSD=stable disease. 
iUPD=unconfirmed progression.
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Search strategy and selection criteria
This paper describes a consensus guideline, rather than a formal literature review. 
However, a database search was done using PubMed in August, 2016, with the following 
search terms: “immune response criteria” (limited to cancer, clinical trials, and 
publications in English language; 234 citations), “irRC” (23 citations), and 
“pseudoprogression” (limited to cancer, clinical trials, and pubications in English 
language; 39 citations).
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Figure 1. Process for developing and validating iRECIST consensus guidelines
Blue shaded boxes represent steps still in progress. RECIST=Response Evaluation Criteria 
in Solid Tumours.
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Figure 2. RECIST 1.1 and iRECIST: an example of assessment
Prefix “i” indicates immune responses assigned using iRECIST; others without “i” are 
confirmed by RECIST 1.1. RECIST=Response Evaluation Criteria in Solid Tumours. 
iCR=complete response. iCPD=complete progression. iPR=partial response. iSD=stable 
disease. iUPD=unconfirmed progression. TP=timepoint.
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Table 1
Comparison of RECIST 1.1 and iRECIST
RECIST 1.1
iRECIST
Definitions of measurable and non-
measurable disease; numbers and site of 
target disease
Measurable lesions are ≥10 mm in 
diameter (≥15 mm for nodal lesions); 
maximum of five lesions (two per 
organ); all other disease is considered 
non-target (must be ≥10 mm in short 
axis for nodal disease)
No change from RECIST 1.1; however, new lesions are 
assessed as per RECIST 1.1 but are recorded separately 
on the case report form (but not included in the sum of 
lesions for target lesions identified at baseline)
Complete response, partial response, or 
stable disease
Cannot have met criteria for 
progression before complete response, 
partial response, or stable disease
Can have had iUPD (one or more instances), but not 
iCPD, before iCR, iPR, or iSD
Confirmation of complete response or 
partial response
Only required for non-randomised trials
As per RECIST 1.1
Confirmation of stable disease
Not required
As per RECIST 1.1
New lesions
Result in progression; recorded but not 
measured
Results in iUPD but iCPD is only assigned on the basis 
of this category if at next assessment additional new 
lesions appear or an increase in size of new lesions is 
seen (≥5 mm for sum of new lesion target or any 
increase in new lesion non-target); the appearance of 
new lesions when none have previously been recorded, 
can also confirm iCPD
Independent blinded review and central 
collection of scans
Recommended in some circumstances
—eg, in some trials with progression-
based endpoints planned for marketing 
approval
Collection of scans (but not independent review) 
recommended for all trials
Confirmation of progression
Not required (unless equivocal)
Required
Consideration of clinical status
Not included in assessment
Clinical stability is considered when deciding whether 
treatment is continued after iUPD
“i” indicates immune responses assigned using iRECIST. RECIST=Response Evaluation Criteria in Solid Tumours. iUPD=unconfirmed 
progression. iCPD=confirmed progression. iCR=complete response. iPR=partial response. iSD=stable disease.
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Table 2
Assignment of timepoint response using iRECIST
Timepoint 
response with no 
previous iUPD in 
any category
Timepoint response with previous iUPD in any category*
Target lesions: i CR; non-target lesions: iCR; 
new lesions: no
iCR
iCR
Target lesions: iCR; non-target lesions: non-
iCR/non-iUPD; new lesions: no
iPR
iPR
Target lesions: iPR; non-target lesions: non-
iCR/non-iUPD; new lesions: no
iPR
iPR
Target lesions: iSD; non-target lesions: non-
iCR/non-iUPD; new lesions: no
iSD
iSD
Target lesions: iUPD with no change, or with a 
decrease from last timepoint; non-target 
lesions: iUPD with no change, or decrease 
from last timepoint; new lesions: yes
Not applicable
New lesions confirm iCPD if new lesions were previously identified 
and they have increased in size (≥5 mm in sum of measures for new 
lesion target or any increase for new lesion non-target) or number; if 
no change is seen in new lesions (size or number) from last timepoint, 
assignment remains iUPD
Target lesions: iSD, iPR, iCR; non-target 
lesions: iUPD; new lesions: no
iUPD
Remains iUPD unless iCPD is confirmed on the basis of a further 
increase in the size of non-target disease (does not need to meet 
RECIST 1.1 criteria for unequivocal progression)
Target lesions: iUPD; non-target lesions: non-
iCR/non-iUPD, or iCR; new lesions: no
iUPD
Remains iUPD unless iCPD is confirmed on the basis of a further 
increase in sum of measures ≥5 mm; otherwise, assignment remains 
iUPD
Target lesions: iUPD; non-target lesions: iUPD; 
new lesions: no
iUPD
Remains iUPD unless iCPD is confirmed based on a further increase 
in previously identified target lesion iUPD in sum of measures >5 mm 
or non-target lesion iUPD (previous assessment need not have shown 
unequivocal progression)
Target lesions: iUPD; non-target lesions: iUPD; 
new lesions: yes
iUPD
Remains iUPD unless iCPD is confirmed on the basis of a further 
increase in previously identified target lesion iUPD sum of measures 
≥5 mm, previously identified non-target lesion iUPD (does not need 
to be unequivocal), or an increase in the size or number of new lesions 
previously identified
Target lesions: non-iUPD or progression; non-
target lesions: non-iUPD or progression; new 
lesions: yes
iUPD
Remains iUPD unless iCPD is confirmed on the basis of an increase 
in the size or number of new lesions previously identified
Target lesions, non-target lesions, and new lesions defined according to RECIST 1.1 principles; if no pseudoprogression occurs, RECIST 1.1 and 
iRECIST categories for complete response, partial response, and stable disease would be the same.
*Previously identified in assessment immediately before this timepoint. “i” indicates immune responses assigned using iRECIST. iCR=complete 
response. iPR=partial response. iSD=stable disease. iUPD=unconfirmed progression. non-iCR/non-iUPD=criteria for neither CR nor PD have been 
met. iCPD=confirmed progression. RECIST=Response Evaluation Criteria in Solid Tumours.
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Table 3
Scenarios of assignments of best overall response using iRECIST
Timepoint response 1
Timepoint response 2
Timepoint response 3
Timepoint response 4
Timepoint response 5
iBOR
Example 1
iCR
iCR, iPR, iUPD, or NE
iCR, iPR, iUPD, or NE
iUPD
iCPD
iCR
Example 2
iUPD
iPR, iSD, or NE
iCR
iCR, iUPD, or NE
iCR, iPR, iSD, iUPD, iCPD, or NE
iCR
Example 3
iUPD
iPR
iPR, iSD, iUPD, or NE
iPR, iSD, iUPD, NE, or iCPD
iPR, iSD, iUPD, NE, or iCPD
iPR
Example 4
iUPD
iSD or NE
iPR
iPR, iSD, iUPD, or NE
iPR, iSD, iUPD, iCPD, or NE
iPR
Example 5
iUPD
iSD
iSD, iUPD, or NE
iSD, iUPD, iCPD, or NE
iSD, iUPD, iCPD, or NE
iSD
Example 6
iUPD
iCPD
Any
Any
Any
iCPD
Example 7
iUPD
iUPD (no iCPD)
iCPD
Any
Any
iCPD
Example 8
iUPD
NE
NE
NE
NE
iUPD
Eight examples are presented for patients with target disease at baseline, but many more scenarios exist following the same principles. Table assumes a randomised study in which confirmation of complete 
response or partial response is not required. For patients with non-target disease only at baseline, only iCR or non-complete response or non-progression of disease can be assigned at each timepoint (not 
shown in the table for ease of presentation). “i” indicates immune responses assigned using iRECIST. iBOR=best overall response. iCR=complete response. iPR=partial response. NE=not evaluable. 
iUPD=unconfirmed progression. iCPD=confirmed progression. iSD=stable disease. RECIST=Response Evaluation Criteria in Solid Tumours.
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10.5 Appendix 3: Quality of Life Scale EORTC QLQ-C30, EQ-5D-5L, 
EORTC QLQ-LC13 
EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" 
answers. The information that you provide will remain strictly confidential. 
 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year): 
 
Today's date (Day, Month, Year): 
31  
 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside 
of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other daily 
activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other leisure 
time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 

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11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
Please go on to the next page 

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During the past week: 
Not at All A 
Little 
Quite a 
Bit 
Very 
Much 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
 
1 
 
2 
 
3 
 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
 
1 
 
2 
 
3 
 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
 
1 
 
2 
 
3 
 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
 
1 
 
2 
 
3 
 
4 
 
For the following questions please circle the number between 1 and 7 that best 
applies to you 
29. 
How would you rate your overall health during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
 
Very poor 
Excellent 
 
30. 
How would you rate your overall quality of life during the past week? 
 
1 
2 
3 
4 
5 
6 
7 
Very poor 
Excellent 

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EQ-5D-5L Health Questionnaire 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure 
activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 

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I am extremely anxious or depressed 
 
 
 

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The worst health 
you can imagine 
 
• 
We would like to know how good or bad your health is 
TODAY. 
• 
This scale is numbered from 0 to 100. 
• 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TODAY. 
• 
Now, please write the number you marked on the scale in the 
box below. 
 
 
 
 
 
  
The best health 
you can imagine 
YOUR HEALTH TODAY = 
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100 
5
15 
25 
35 
45 
55 
75 
65 
85 
95 

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EORTC QLQ- LC13 
 
Patients sometimes report that they have the following symptoms or problems. Please indicate the 
extent to which you have experienced these symptoms or problems during the past week. Please 
answer by circling the number that best applies to you. 
During the past week: 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
31. 
How much did you cough? 
1 
2 
3 
4 
32. 
Did you cough up blood? 
1 
2 
3 
4 
33. 
Were you short of breath when you rested? 
1 
2 
3 
4 
34. 
Were you short of breath when you walked? 
1 
2 
3 
4 
35. 
Were you short of breath when you climbed stairs? 
1 
2 
3 
4 
36. 
Have you had a sore mouth or tongue? 
1 
2 
3 
4 
37. 
Have you had trouble swallowing? 
1 
2 
3 
4 
38. 
Have you had tingling hands or feet? 
1 
2 
3 
4 
39. 
Have you had hair loss? 
1 
2 
3 
4 
40. 
Have you had pain in your chest? 
1 
2 
3 
4 
41. 
Have you had pain in your arm or shoulder? 
1 
2 
3 
4 
42. 
Have you had pain in other parts of your body? 
1 
2 
3 
4 
 
If yes, where   
 
43. 
Did you take any medicine for pain?  
 
1 
No 
2 
Yes 
 
If yes, how much did it help? 
1 
2 
3 
4 
 
 
 

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10.6 Appendix 4: Eastern Cooperative Oncology Group (ECOG) - 
Performance Status Scale 
Score 
ECOG Status 
0 
Mobility is completely normal, and there is no difference before and after the onset of the disease. 
1 
Free to walk and engage in light physical activities, including general housework or office work, 
but not heavy physical activities. 
2 
Able to walk and independently take care of oneself, but cannot do any work. Able to get up and 
move around for at least half of the time during the day. 
3 
Able to only finish some of self-care activities and spend more than half of the time during the day 
in bed or in a wheelchair. 
4 
Complete disability. Cannot take care of oneself at all. Totally confined to bed or in a wheelchair. 
5 
Death 
ECOG = Eastern Cooperative Oncology Group 

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10.7 Appendix 5: Fridericia Correction Formula 
Fridericia formula: QTc=QT/RR0.33 
 
 

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10.8 Appendix 6: Cockcroft and Gault Formula 
The creatinine clearance rate is calculated using the measured value of serum creatinine (unit: 
mg/dL): 
Male: 
(140－age) × weight (kg)
 serum creatinine (mg/dL)× 72   
Female: 
(140－age) × weight (kg)
 serum creatinine (mg/dL)× 72 × 0.85 
 
Cited from Cockcroft DW et al. Nephron. 1976; 16(1): 31-41. 
 
The creatinine clearance rate is calculated using the measured value of serum creatinine (unit: 
μmol/L): 
Male: (140－age)× weight (kg) × 1.23
 creatinine (µmol/L)
  
Female: (140－age) × weight (kg) × 1.23 × 0.85
 creatinine (µmol/L)
  
 
Cited from Cockcroft DW et al. Nephron. 1976;16(1):31-41. 
 
 

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10.9 Appendix 7: Heart Functional Classification of New York Heart 
Association 
Grade 
Behavioral Status 
Grade I 
Physical activities are not restricted. Normal physical activities do not 
cause excessive fatigue, palpitations or breathing difficulties 
Grade II 
Physical activities are slightly restricted, and the patient feels 
comfortable at rest. However, normal physical activities can cause 
fatigue, palpitations or difficulty breathing 
Grade III 
Physical activities are significantly restricted. The patient feels 
comfortable at rest. However, activities lighter than normal physical 
activities can cause fatigue, palpitations or difficult breathing 
Grade IV 
Unable to perform any physical activity comfortably. Symptoms of 
cardiac insufficiency can occur even at rest. Any physical activity can 
aggravate discomfort. 

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10.10 Appendix 8: Guidelines for Dose Modification and Treatment for Immune-Related Toxicity 
The following is the "NCCN Guidelines for Management of Immunotherapy-Related Toxicities" (2019, v2). For more details, please 
refer to the original document at https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf 
AE 
Assessment 
Grading 
Management 
Infusion-related reactions 
 
 
Physical exam  
 
Vital signs  
 
Pulse oximetry  
 
ECG (if chest pain  
 
or sustained tachycardia) 
 
Mild (G1) 
or 
Moderate (G2) 
 
Treat per institutional guidelines  
 
Consider hold or slow the rate of infusion  
 
Continue immunotherapy  
 
Consider premedication with acetaminophen and 
diphenhydramine with future infusions 
Severe (G3–4) 
 
 
Treat per institutional guidelines  
 
Permanently discontinue immunotherapy  
 
There are no data to guide the use of alternate 
immune checkpoint inhibitors 
Dermatologic Adverse Event(s) 
Maculopapular rash 
 
 
Total body skin exam, 
including mucosa  
 
Assess for history of prior 
inflammatory dermatologic 
diseases  
 
Consider biopsy if unusual 
features 
 
Mild (G1) 
 
 
Continue immunotherapy  
 
Topical emollient  
 
Oral antihistamine  
 
Treatment with moderate potency topical steroids 
to affected areas  
Moderate (G2) 
 
 
Consider holding immunotherapy 
 
Topical emollient  
 
Oral antihistamine  
 
Treatment with high potency topical steroids to 
affected areas and/or  
 
Prednisone 0.5–1 mg/kg/day 

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AE 
Assessment 
Grading 
Management 
Severe (G3–4) 
 
 
Hold immunotherapy 
 
Treatment with high potency topical steroids to 
affected areas  
 
Prednisone 0.5–1 mg/kg/day (increase dose up to 
2 mg/kg/day if no improvement)  
 
Urgent dermatology consultation  
 
Consider inpatient care  
Pruritus 
 
 
Total body skin exam, 
including mucosa  
 
Assess for history of prior 
inflammatory dermatologic 
diseases 
 
Mild (G1) 
 
 
Continue immunotherapy  
 
Oral antihistamine  
 
Treatment with moderate potency topical steroids 
to affected areas 
Moderate (G2) 
 
 
Continue immunotherapy with intensified 
antipruritic therapy  
 
Oral antihistamine  
 
Treatment with high potency topical steroids to 
affected areas 
 
Dermatology consultation 
Severe (G3) 
 
 
Hold immunotherapy 
 
Oral antihistamine  
 
Prednisone/methylprednisolone 0.5–1 mg/kg/day 
 
Consider GABA agonists (gabapentin, 
pregabalin)  
 
Consider aprepitant or omalizumab for refractory 
cases  
 
Urgent dermatology consultation  
Bullous dermatitis 
 
Urgent dermatology consultation 
 
 
Mild (G1) 
 
Hold immunotherapy 
 
Treatment with high potency topical steroids to 
affected areas 

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AE 
Assessment 
Grading 
Management 
Moderate (G2) 
 
Hold immunotherapy until < G1 
 
Prednisone/methylprednisolone 0.5–1 mg/kg/day 
Severe (G3) or life-
threatening 
 
 
Permanently discontinue immunotherapy  
 
Prednisone/methylprednisolone 1–2 mg/kg/day g  
Inpatient care required  
 
Urgent dermatology, ophthalmology, and urology 
consultation 
Stevens-Johnson 
Syndrome (SJS) 
Toxic epidermal 
necrolysis 
(TEN) 
Urgent dermatology consultation 
 
Severe (G3) or life-
threatening 
 
 
Permanently discontinue immunotherapy  
 
Prednisone/methylprednisolone 1–2 mg/kg/day 
 
 Inpatient care required  
 
Urgent dermatology, ophthalmology, and urology 
consultation 
Gastrointestinal Adverse Event(s) 
Diarrhoea  
Colitis 
 
 
Stool evaluation to rule out 
infectious aetiology  
 
Nucleic acid amplification 
tests (NAATs) for GI 
pathogens/bacterial culture 
 
C. difficile  
 
Ova & parasites; molecular 
testing for Giardia and 
Cryptosporidium spp and E. 
histolytica; consider 
microsporidia, 
Cyclosporal/isospora spp 
 
Viral pathogens testing when 
available 
Mild (G1) 
 
 
Consider holding immunotherapy  
 
Loperamide or diphenoxylate/atropine  
 
Hydration  
 
Close monitoring 
Moderate (G2) 
 
Hold immunotherapy 
 
Methylprednisolone 1 mg/kg/day i.v. 
 
No response in 2–3 days:  
 
Increase dose to 2 mg/kg/day 
 
Consider adding infliximab 
Severe (G3–4) 
 
 
G3: Discontinue anti-CTLA-4; consider resuming 
anti-PD-1/PD-L1 after resolution of toxicity 
 
G4: Permanently discontinue immunotherapy 
agent responsible for toxicity 

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AE 
Assessment 
Grading 
Management 
 
Based on institutional 
availability, consider 
lactoferrin/calprotectin 
 
Consider abdominal/pelvic 
CT with contrast  
 
Consider GI consultation  
 
Colonoscopy or flexible 
sigmoidoscopy ± 
esophagogastroduodenoscopy 
(EGD) with biopsy  
 
Consider inpatient care for provision of 
supportive care 
 
Methylprednisolone 2 mg/kg/day i.v. 
 
No response in 2 days: 
 
Continue steroids, consider adding infliximab 
 
If infliximab-refractory, consider vedolizumab 
Hepatic Adverse Event(s) 
 
 
Transaminitis without 
elevated bilirubin 
 
 
Rule out viral aetiology, 
disease-related hepatic 
dysfunction, other drug-
induced transaminase 
elevations  
 
Consider GI evaluation 
 
Ultrasound 
 
If normal ultrasound, 
consider magnetic resonance 
cholangiopancreatography 
(MRCP)  
 
Limit/discontinue 
hepatotoxic medications 
(assess acetaminophen, 
dietary supplement, and 
alcohol use) 
 
Mild (G1) <  
3 × ULN 
 
 
Continue immunotherapy, consider holding 
immunotherapy for concerning lab value trend 
 
Assess transaminases and bilirubin with 
increased frequency 
Moderate (G2) 3–5 × ULN 
 
Hold immunotherapy 
 
Monitor liver function tests (LFTs) every 3–5 
days  
 
Consider prednisone 0.5–1 mg/kg/day 
Severe (G3) > 5–20 × ULN 
 
 
Permanently discontinue immunotherapy  
 
Initiate prednisone 1–2 mg/kg/day 
 
Consider inpatient care  
 
Monitor liver enzymes every 1–2 days  
 
Hepatology consultation  
 
If steroid refractory or no improvement after  
3 days, consider adding mycophenolate  
 
Infliximab should not be used for hepatitis 
Life-threatening (G4) 
 
Permanently discontinue immunotherapy  

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AE 
Assessment 
Grading 
Management 
> 20 × ULN 
 
 
Initiate prednisone/methylprednisolone 2 
mg/kg/day  
 
Inpatient care  
 
Monitor liver enzymes daily  
 
Hepatology consultation  
 
Liver biopsy if no contraindications 
 
If steroid refractory or no improvement after  
3 days, consider adding mycophenolate 
 
Infliximab should not be used for hepatitis  
Grade > 1 transaminitis 
with bilirubin > 1.5 × 
ULN (unless Gilbert's 
syndrome) 
 
 
Rule out viral aetiology, 
disease-related hepatic 
dysfunction, other drug-
induced transaminase 
elevations  
 
Consider GI evaluation 
 
Limit/discontinue 
hepatotoxic medications 
(assess acetaminophen, 
dietary supplement, and 
alcohol use) 
 
 
Permanently discontinue immunotherapy  
 
Initiate prednisone/methylprednisolone 2 
mg/kg/day  
 
Inpatient care  
 
Monitor liver enzymes daily  
 
Hepatology consultation  
 
If steroid refractory or no improvement after 3 
days, consider adding mycophenolate 
 
Infliximab should not be used for hepatitis 
Pancreatic Adverse Event(s) 
Elevation in 
amylase/lipase  
(asymptomatic) 
 
 
Assess for signs/symptoms of 
pancreatitis  
 
If clinical concern for 
pancreatitis, see acute 
pancreatitis 
 
Mild 
Amylase ≤ 3 × ULN 
and/or 
Lipase ≤ 3 × ULN 
 
 
If isolated elevation of enzymes without evidence 
of pancreatitis, continue immunotherapy  
 
Evaluate for pancreatitis  
 
Clinical assessment cc  
 
Consider abdominal CT with contrast  
 
Consider magnetic resonance 
cholangiopancreatography (MRCP)  

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AE 
Assessment 
Grading 
Management 
 
If evidence of pancreatitis, manage according to 
pancreatitis algorithm  
 
Consider other causes for elevated amylase/lipase 
Moderate 
Amylase > 3–5 × ULN 
and/or 
Lipase > 3 × ULN 
 
 
If isolated elevation of enzymes without evidence 
of pancreatitis, consider continuing 
immunotherapy 
 
Evaluate for pancreatitis  
 
Clinical assessment 
 
If persistent moderate to severe amylase and/or 
lipase elevation, abdominal CT with contrast or 
MRCP  
 
Consider other causes for elevated amylase/lipase 
 
If evidence of pancreatitis, manage according to 
pancreatitis algorithm 
Severe 
Amylase >  
5 × ULN 
and/or 
Lipase >  
5 × ULN 
 
 
If isolated elevation of enzymes without evidence 
of pancreatitis, consider continuing 
immunotherapy 
 
Evaluate for pancreatitis  
 
Clinical assessment 
 
If persistent moderate to severe amylase and/or 
lipase elevation, abdominal CT with contrast or 
MRCP  
 
Consider other causes for elevated amylase/lipase 
 
If evidence of pancreatitis, manage according to 
pancreatitis algorithm 
Acute pancreatitis 
 
Assess for signs/symptoms of 
pancreatitis  
 
Abdominal CT with contrast  
Mild (G1) 
 
 
Consider gastroenterology referral  
 
Manage as per elevation in amylase/lipase  
Moderate (G2) 
 
Hold immunotherapy 

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AE 
Assessment 
Grading 
Management 
 
Consider MRCP if clinical 
suspicion of pancreatitis and 
no radiologic evidence on CT  
 
Prednisone/methylprednisolone 0.5–1 mg/kg/day 
Severe (G3–4) 
 
Permanently discontinue immunotherapy  
 
Prednisone/methylprednisolone 1–2 mg/kg/day 
Endocrine Adverse Event(s) 
Hyperglycaemia 
Fasting glucose preferred 
 
New-onset hyperglycaemia < 
200 mg/dL and/or 
 
History of type II DM with 
low suspicion for DKA 
 
Steroid-related 
hyperglycaemia or 
 
Preexisting type II 
DM 
 
Continue immunotherapy 
 
Monitor serial blood glucose with each dose 
 
Diet and lifestyle modification if needed, medical 
therapy per institutional guidelines 
 
Consider endocrine consultation if patient is 
symptomatic and/or glucose is persistently 
uncontrolled 
 
 
New-onset fasting glucose > 
200 mg/dL or 
 
Random blood glucose > 250 
mg/dL or 
 
History of type II DM with 
fasting/random glucose >  
250 mg/dL 
 
Consider new-onset 
type I DM 
 
Evaluate for DKA if 
clinically appropriate 
as per institutional 
guidelines 
 
Blood pH, basic 
metabolic panel, urine 
or serum ketones, beta 
hydroxybutyrate 
 
C-peptide, if urine or 
serum ketones/anion 
gap positive 
 
Consider anti-GAD, 
anti-islet cell 
antibodies 
Workup negative for DKA 
 
Continue immunotherapy 
 
Monitor serial blood glucose with each dose 
 
Diet and lifestyle modification if needed, medical 
therapy per institutional guidelines 
 
Consider endocrine consultation if patient is 
symptomatic and/or glucose is persistently 
uncontrolled 
Workup positive for DKA 
 
Hold immunotherapy 
 
Inpatient care 
 
Endocrine consultation 
 
Management of DKA as per institutional 
guidelines 
 
Insulin as directed by inpatient team and/or 
endocrinologist 
 
4 ≤ TSH < 10  
 
Continue immunotherapy 

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AE 
Assessment 
Grading 
Management 
Asymptomatic/subclinical 
hypothyroidism 
 
Monitor thyroid-stimulating 
hormone (TSH), free T4 
every 4–6 weeks 
 
If TSH elevated, 
proceed based on TSH levels as 
follows or repeat TSH, free T4 in 
4–6 weeks 
 
Patient asymptomatic 
 
Normal free T4 
 
Continue to monitor thyroid function tests (TFTs) 
 
Elevated TSH (> 10) 
 
Normal free T4 
 
Continue immunotherapy 
 
Consider levothyroxine 
 
Normal or low TSH 
 
Low free T4 
 
See Central hypothyroidism 
Clinical, 
primary 
hypothyroidism 
 
 
Monitor thyroid-stimulating 
hormone (TSH), free T4 
every 4–6 weeks 
 
 
Continue immunotherapy 
 
Consider endocrine consultation 
 
Thyroid hormone supplementation 
 
Exclude concomitant adrenal insufficiency (AM 
cortisol level) 
Thyrotoxicosis 
 
Low or suppressed TSH with 
high free T4/total T3, 
consider thyroid peroxidase 
(TPO) antibody and thyroid-
stimulating hormone receptor 
antibody (TRAb) 
 
Consider endocrine 
consultation 
 
 
Continue immunotherapy if asymptomatic 
 
Consider propranolol (10–20 mg every 4–6 h as 
needed) or atenolol or metoprolol as needed for 
symptoms until thyrotoxicosis resolves 
 
 Repeat TFTs in 4–6 weeks. 
 
If resolved, no further therapy. 
 
If remains with suppressed TSH, high free 
T4/total T3, then 4- or 24-h I-123 thyroid 
uptake/scan to determine if true hyperthyroidism 
and Graves-like aetiology 
 
Thyrotoxicosis often evolves to hypothyroidism 
 
If TSH is > 10, initiate levothyroxine therapy, 
oral daily ~1.6 mcg/ kg or 75–100 mcg with goal 
of getting TSH to reference range or age-
appropriate range. 
Primary adrenal 
 
Evaluate cortisol level (AM) 
 
 
Endocrine consultation 

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AE 
Assessment 
Grading 
Management 
insufficiency 
 
Comprehensive metabolic 
panel (Na, K, CO2, glucose), 
renin level 
 
Endocrine evaluation prior to surgery or any 
procedure 
 
Hold immunotherapy 
 
Start corticosteroid first before other hormone 
replacement to avoid adrenal crisis 
 
Steroid replacement 
 
Hydrocortisone 20 mg in AM, 10 mg in PM, then 
slowly titrating doses down according to 
symptoms 
or 
 
Prednisone 7.5 mg or 10 mg starting dose, then 
reduce to 5 mg daily as appropriate 
and 
 
Fludrocortisone can be started 0.1 mg every other 
day; then titrated up or down based on blood 
pressure, symptoms, lower-extremity oedema, 
and labs 
 
If hemodynamically unstable, inpatient care and 
initiate high-dose/stress-dose steroids 
 
Patients with severe symptoms (hypotension) 
may require additional fluids (e.g., normal saline 
often > 2 L required) 
 
Patient education regarding stress doses of 
hydrocortisone for infection, trauma, etc. 
 
Alert bracelet is recommended 
Central 
hypothyroidism 
 
Evaluate cortisol (AM), FSH, 
LH, TSH, free T4, DHEA-S 
 
Estradiol testing in women 
 
 
Continue immunotherapy 
 
Treat as hypophysitis 

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Grading 
Management 
 
Testosterone testing in men 
 
Consider MRI of pituitary if 
confirmed central 
thyroid/adrenal insufficiency 
Hypophysitis 
 
Evaluate cortisol (AM), FSH, 
LH, TSH, 
 
free T4, testosterone in men, 
oestrogen in premenopausal 
women 
 
MRI brain ± contrast with 
pituitary/sellar cuts, if 
symptomatic 
 
 
Consider endocrine consultation 
 
Hold immunotherapy until acute symptoms 
resolve 
 
If symptomatic, prednisone/methylprednisolone 
1–2 mg/kg/day 
 
Hormone replacement as indicated 
 
Patient education regarding stress doses of 
hydrocortisone for infection, trauma, etc. 
 
Alert bracelet is recommended 
Pulmonary Adverse Event(s) 
Pneumonitis 
 
Mild (G1) 
 
Hold immunotherapy 
 
Reassess in 1–2 weeks 
 
H&P 
 
Pulse oximetry (resting and with ambulation) 
 
Consider chest CT with contrast 
 
Consider repeat chest CT in 3–4 weeks or as 
clinically indicated for worsening symptoms 
Moderate (G2) 
 
Hold immunotherapy 
 
Consider infectious workup: 
 
Nasal swab for potential viral pathogens 
 
Sputum culture, blood culture, and urine culture 
 
Consider bronchoscopy with bronchoalveolar 
lavage (BAL) to rule out infection and malignant 
lung infiltration 

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Grading 
Management 
 
Consider chest CT with contrast 
 
Repeat chest CT in 3–4 weeks 
 
Recommend infectious evaluation with 
institutional immunocompromised panel 
 
Consider empiric antibiotics if infection has not 
yet been fully excluded 
 
Prednisone/methylprednisolone 1–2 mg/kg/day 
 
Monitor every 3–7 days with: 
 
H&P 
 
Pulse oximetry (resting and with ambulation) 
 
If no improvement after 48–72 h of 
corticosteroids, treat as Grade 3 
Severe (G3–4) 
 
Permanently discontinue immunotherapy 
 
Inpatient care 
 
Infectious workup: 
 
Consider that patient may be 
immunocompromised 
 
Nasal swab for potential viral pathogens 
 
Sputum culture, blood culture, and urine culture 
 
Pulmonary and infectious disease consultation, 
consider PFT 
 
Bronchoscopy with BAL to rule out infection and 
malignant lung infiltration 
 
Consider empiric antibiotics if infection has not 
yet been fully excluded 
 
Methylprednisolone 1–2 mg/kg/day. Assess 
response within 48 h and plan taper over ≥ 6 
weeks 

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Grading 
Management 
 
Consider adding any of the following if no 
improvement after 48 h: 
 
Infliximab 5 mg/kg IV, a second dose may be 
repeated 14 days later at the discretion of the 
treating provider  
 
Mycophenolate mofetil 1–1.5 g BID then taper in 
consultation with pulmonary service 
 
Intravenous immunoglobulin (IVIG) 2 g/kg 
Renal Adverse Event(s) 
Elevated serum 
creatinine/ 
acute renal failure 
 
Limit/discontinue 
nephrotoxic medications and 
dose adjust to creatinine 
clearance 
 
Evaluate potential alternative 
aetiologies (recent IV 
contrast, medications, fluid 
status, UTI) 
 
Spot urine protein/creatinine 
ratio 
Mild (G1) (Creatinine 1.5–
2x above baseline; increase 
of ≥ 0.3 mg/dL) 
 
Consider holding immunotherapy 
 
Follow creatinine and urine protein every  
3–7 days 
Moderate (G2) (Creatinine 
2–3x above baseline) 
 
Hold immunotherapy 
 
Follow creatinine and urine protein every 3–7 
days 
 
Nephrology consultation 
 
Start prednisone 0.5–1 mg/kg/day if other causes 
are ruled out 
 
For persistent G2 beyond 1 week, 
prednisone/methylprednisolone 1–2 mg/kg/day 
Severe (G3) (Creatinine > 
3x baseline or >  
4.0 mg/dL) 
Life-threatening (G4) 
(Creatinine > 6x baseline; 
dialysis indicated) 
 
Permanently discontinue immunotherapy 
 
Consider inpatient care 
 
Prednisone/methylprednisolone 1–2 mg/kg/day 
 
Nephrology consultation 
 
Consider renal biopsy 
 
Consider adding one of the following if > G2 
after 1 week of steroids: 
 
Azathioprine 

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Assessment 
Grading 
Management 
 
Cyclophosphamide (monthly) 
 
Cyclosporine 
 
Infliximab 
 
Mycophenolate 
Ocular Adverse Event(s) 
Vision changes 
Vision testing 
by or under the guidance of 
ophthalmology 
to include: 
 
Visual acuity in each eye 
 
Colour vision 
 
Pupil size, shape, and 
reactivity 
 
Red reflex 
 
Fundoscopic examination 
Uveitis 
Mild (G1) 
 
Continue immunotherapy 
 
Artificial tears 
 
Refer to ophthalmology 
Anterior 
uveitis (G2) 
 
Hold immunotherapy 
 
Urgent ophthalmology consultation 
 
Treatment guided by ophthalmology to include 
ophthalmic and systemic 
prednisone/methylprednisolone 
Posterior or 
Pan-uveitis 
(G3) 
•
 
20/20
0 vision (G4) 
 
Permanently discontinue immunotherapy 
 
Urgent ophthalmology consultation 
 
Treatment guided by ophthalmology to include 
ophthalmic and systemic 
prednisone/methylprednisolone 
Episcleitis 
Mild (G1) 
 
Continue immunotherapy 
 
Artificial tears 
 
Refer to ophthalmology 
20/40 vision 
or better 
(G2) 
 
Hold immunotherapy 
 
Urgent ophthalmology consultation 
 
Treatment guided by ophthalmology to include 
ophthalmic and systemic 
prednisone/methylprednisolone 

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Management 
•
 
Wors
e than 20/40 
(G3) 
•
 
20/20
0 vision (G4) 
 
Permanently discontinue immunotherapy 
 
Urgent ophthalmology consultation 
 
Treatment guided by ophthalmology to include 
ophthalmic and systemic 
prednisone/methylprednisolone 
Nervous System Adverse Event(s) 
Myasthenia gravis 
 
Acetylcholine receptor 
(AChR) antibodies and anti-
muscle-specific tyrosine 
kinase antibodies in blood 
(not needed for diagnosis) 
 
Pulmonary function 
assessment with negative 
inspiratory force (NIF) and 
vital capacity (VC) 
 
Erythrocyte sedimentation 
rate (ESR), C-reactive protein 
(CRP), creatine 
phosphokinase (CPK), 
aldolase for possible 
superimposed myositis 
 
If respiratory insufficiency or 
elevated CPK, perform 
cardiac exam, ECG, troponin, 
and TTE for possible 
concomitant myocarditis 
Moderate 
(G2) 
 
Hold immunotherapy 
 
Pyridostigmine 30 mg TID and gradually 
increase to maximum of 120 mg orally four times 
a day as tolerated and based on symptoms.  
 
Consider low-dose oral prednisone 20 mg daily. 
Increase by 5 mg every 3–5 days to a target dose 
of 1 mg/kg/day but not more than 100 mg daily 
(steroid taper based on symptom improvement) 
 
Severe (G3–4) 
 
Permanently discontinue immunotherapy 
 
Inpatient care (may need intensive care unit 
[ICU]-level monitoring) 
 
Methylprednisolone 1–2 mg/kg/day (steroid taper 
based on symptom improvement) 
 
Initiate plasmapheresis or IVIG (2 g/kg) if no 
improvement/worsening on steroids or severe 
symptoms 
 
Frequent pulmonary function assessment 
 
Daily neurologic evaluation 
 
Avoid medications that can worsen myasthenia 

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Assessment 
Grading 
Management 
 
Electromyography (EMG) 
with repetitive stimulation 
and nerve conduction study 
(NCS) 
 
Neurology consultation 
 
Consider MRI brain and/or 
spine depending on 
symptoms to rule out CNS 
involvement by disease 
Guillain-Barré syndrome 
(GBS) 
 
Inpatient care with access to 
ICU-level monitoring 
 
Neurology consultation 
 
MRI of spine with or without 
contrast (rule out 
compressive lesion) 
 
Lumbar puncture 
 
Serum antibody tests for GBS 
variants (GQ1b for Miller 
Fisher variant associated with 
ataxia and ophthalmoplegia) 
 
Pulmonary function testing 
(negative inspiratory force 
[NIF]/vital capacity [VC]) 
Moderate (G2) 
or 
Severe (G3–4) 
 
Permanently discontinue immunotherapy 
 
Inpatient care with capability of rapid transfer to 
ICU-level monitoring 
 
Start IVIG (2 g/kg) or plasmapheresis in addition 
to pulse-dose methylprednisolone 1 gram daily 
for  
5 days 
 
Frequent neurologic evaluation and pulmonary 
function monitoring 
 
Monitor for concurrent autonomic dysfunction 
 
Non-opioid management of neuropathic pain 
Peripheral neuropathy 
 
Evaluate for other causes of 
neuropathy such as: 
medication, infection, 
metabolic/endocrine 
disorders, environmental 
Mild (G1) 
 
Consider holding immunotherapy 
 
Monitor symptoms for a week 

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Management 
exposures, vascular or 
autoimmune disease, trauma, 
etc. 
 
Consider neuraxial imaging 
as per neurology 
 
Evaluate for other causes of 
neuropathy such as: 
medication, infection, 
metabolic/endocrine 
disorders, environmental 
exposures, vascular or 
autoimmune disease, trauma, 
etc. 
 
Neuraxial imaging as per 
neurology 
 
Consider EMG/NCS 
 
Consider neurology 
consultation 
Moderate (G2) 
 
Hold immunotherapy 
 
Initial observation or initiate prednisone 0.5–1 
mg/kg orally (if progressing from mild) 
 
If progression, initiate methylprednisolone 2–4 
mg/kg/day and see Guillain-Barré Syndrome 
 
Gabapentin, pregabalin, or duloxetine for pain 
 
 
See Guillain-Barré Syndrome 
Severe (G3–4) 
 
See Guillain-Barré Syndrome 
Aseptic meningitis 
 
MRI brain with and without 
contrast + pituitary protocol 
 
AM cortisol, to rule out 
adrenal insufficiency 
 
Consider lumbar puncture 
 
Consider neurology 
consultation 
 
 
Hold immunotherapy if mild/moderate 
 
Permanently discontinue immunotherapy if 
severe 
 
Inpatient care (G3–4) 
 
Consider IV acyclovir until polymerase chain 
reaction (PCR) results obtained 
 
Rule out bacterial and viral infection, then may 
closely monitor off steroids or consider 
prednisone 0.5–1 mg/kg/day or 

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Management 
methylprednisolone 1–2 mg/kg/day if 
moderate/severe symptoms 
Encephalitis 
 
Neurology consultation 
 
MRI brain with and without 
contrast 
 
Lumbar puncture 
 
EEG to evaluate for 
subclinical seizures 
 
Comprehensive metabolic 
panel, CBC, ESR, CRP, 
antineutrophil cytoplasmic 
antibody (ANCA) (if 
vasculitic process suspected), 
thyroid panel including TPO 
and thyroglobulin 
 
Autoimmune encephalopathy 
and paraneoplastic panel in 
CSF and serum 
 
 
Hold immunotherapy if mild 
 
Permanently discontinue immunotherapy if 
moderate/severe 
 
Inpatient care (G3–4) 
 
Consider IV acyclovir until PCR results obtained 
 
Trial of methylprednisolone 1–2 mg/kg/day 
 
If severe or progressing symptoms or oligoclonal 
bands present, consider pulse steroids 
methylprednisolone 1 g IV daily for 3–5 days 
plus IVIG  
 
If positive for autoimmune encephalopathy 
antibody or limited or no improvement, consider 
rituximab 
 
Transverse myelitis 
 
Neurology consultation 
 
MRI of spine and brain 
 
Lumbar puncture 
 
B-12, HIV, rapid plasma 
reagin (RPR), ANA, anti-
Ro/La antibodies, TSH, 
aquaporin-4 IgG, 
paraneoplastic panel for anti-
Hu and anti-CRMP5/CV2 
Severe (G3–4) 
 
Permanently discontinue immunotherapy 
 
Inpatient care 
 
Methylprednisolone pulse dosing 1 g/day for 3–5 
days 
 
Strongly consider IVIG or plasmapheresis 

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Assessment 
Grading 
Management 
 
Evaluation for urinary 
retention, constipation 
Cardiovascular Adverse Event(s) 
• Myocarditis 
• Pericarditis 
• Arrhythmias 
• Impaired ventricular 
function 
 
Immediate cardiology 
consultation 
 
ECG 
 
Telemetry monitoring 
 
Cardiac biomarkers (creatine 
kinase and troponin) 
 
Inflammatory biomarkers 
 
ESR 
 
CRP 
 
WBC count 
 
Cardiac MRI 
 
Evaluate for other causes: 
 
Viral titres  
 
Echocardiography 
 
Biopsy if severe symptoms 
Severe (G3) 
 
Permanently discontinue immunotherapy 
 
Consider methylprednisolone pulse dosing 1 
g/day for 3–5 days 
 
Treat until cardiac function returns to baseline, 
then taper over 4–6 weeks 
 
Inpatient care 
Life-threatening (G4) 
 
Permanently discontinue immunotherapy 
 
Consider methylprednisolone pulse dosing 1 
g/day for 3–5 days 
 
Treat until cardiac function returns to baseline, 
then taper over 4–6 weeks 
 
If no improvement within 24 h on steroids, 
consider adding anti-thymocyte globulin (ATG). 
May also consider adding infliximab 
 
Inpatient care 
Musculoskeletal Adverse Event(s) 
Inflammatory arthritis 
 
Number of joints involved 
 
Functional assessment 
 
X-ray, joint ultrasound, or 
joint MRI 
Mild 
 
Continue immunotherapy 
 
NSAIDs 
 
If NSAIDs ineffective, consider 
low-dose prednisone 10–20 mg 
daily × 4 weeks; if not 
improving, treat as moderate 
 
Consider intra-articular steroids 
in affected joint(s), depending 
Monitor with 
serial 
rheumatologic 
examinations 
± ESR, CRP  
every 4–6 
weeks after 
treatment 

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Assessment 
Grading 
Management 
on joint location and number 
involved 
 
 
 
Moderate 
 
Consider holding 
immunotherapy i 
 
Prednisone 0.5 mg/kg/day × 4–6 
weeks, treat as severe if no 
improvement 
 
If no improvement by week 4 
strongly recommend 
rheumatology consultation 
Severe 
 
Hold or permanently discontinue 
immunotherapy 
 
Prednisone/methylprednisolone  
1 mg/kg/day 
 
If no improvement by week 2, 
rheumatology consultation for 
consideration of additional 
disease modifying anti-
rheumatic drugs depending on 
clinical phenotype of 
inflammatory arthritis. Options 
include: infliximab, 
methotrexate, tocilizumab, 
sulfasalazine, azathioprine, 
leflunomide, IVIG 
Myalgias 
or 
Myositis 
 
Comprehensive metabolic 
panel 
Mild pain 
 
Continue immunotherapy 
 
Monitor serial aldolase/creatine kinase 
 
Pain treatment as indicated 

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Assessment 
Grading 
Management 
 
Check creatine 
kinase/aldolase levels 
Moderate or severe or life-
threatening 
 
Hold immunotherapy if levels elevated 
 
Muscle MRI and EMG 
 
Prednisone 1–2 mg/kg/day 
 
Consider muscle biopsy, especially in severe or 
refractory cases. Consider concomitant 
myasthenia gravis. 
 
Monitor serial aldolase/creatine kinase until 
symptoms resolve or steroids discontinued 
 
Pain treatment as indicated 
 
Principles of Immunosuppression 
 
These immunosuppression recommendations are for patients receiving immune checkpoint inhibitor immunotherapy. 
 
Close consultation with disease-specific subspecialties is encouraged. 
 
Referral to a tertiary care centre may be required for management of complex cases or multi-system irAE. 
 
Corticosteroids are the mainstay of treatment of the majority of irAE related to immunotherapy. 
 
Early intervention with corticosteroids is a key goal in the general management of immune-related toxicity. 
 
Use of corticosteroids to treat irAE has not been shown to reduce anti-tumour efficacy. 
 
In the absence of specific indications such as prior infusion reaction and nausea, routine premedication with corticosteroids is not 
recommended given the potential mitigation of immunotherapeutic effectiveness in the prophylactic setting. 
 
Longer steroid tapers (> 4 weeks, sometimes 6–8 weeks or longer) may be required to prevent recurrent irAE events, particularly pneumonitis 
and hepatitis. 
 
See individual toxicity pages for specific recommendations on steroid dose by grade. Where immunotherapy rechallenge is indicated, see 
"Principles of Immunotherapy Rechallenge" (IMMUNO-C) for guidance by organ site. 
 
Prophylaxis against pneumocystis jiroveci pneumonia (PJP) can be considered in patients receiving a prednisone equivalent of 20 mg or more 
daily for 4 or more weeks. 
 
Prophylaxis against fungal infections (e.g., fluconazole) can be considered in patients receiving a prednisone equivalent of 20 mg or more 
daily for 6–8 or more weeks. 
 
Proton pump inhibitor therapy or H2 blockers can be considered for patients at higher risk of gastritis (e.g., NSAID use, anticoagulation) for 
the duration of corticosteroid therapy. 
 
Higher potency (e.g., Class 2 or Class 3) topical corticosteroids are preferred for short-term use for immune-related dermatitis, compared to 
longer term use of lower potency steroids. 

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 
For neurologic, or Grade 3 or Grade 4 irAE, higher dose steroids (e.g., methylprednisolone or prednisone 1–2 mg/kg/day) should be given. 
 
If patients need to be on long-term steroids, they are at risk of developing osteoporosis. Vitamin D and calcium supplementation should be 
provided to prevent osteoporosis. 
 
Selected irAE including hypothyroidism and other endocrine irAE may be treated with hormonal supplementation, without the need for 
corticosteroid therapy. See Endocrine Toxicities section. 
 
Anti-TNFα agents should be avoided in patients with immune-related hepatitis. Anti-TNFα agents (e.g., infliximab) are particularly effective 
in the management of immune-related colitis and inflammatory arthritis. 
 
There is a risk for hepatitis B virus reactivation with infliximab. Test for viral hepatitis B and hepatitis C prior to TNF inhibition and monitor 
HBV/HCV carriers during and for several months after therapy 
 
There is a risk for tuberculosis (TB) activation. Test for latent/active TB prior to TNF inhibition. TB testing should not delay initiation of anti-
TNFα agents for the management of irAE. 
 
Results of TB testing need not be finalised prior to dosing anti-TNFα agents in the acute setting. 
 
Interferon-gamma release assays for TB testing are preferred. 
 
For patients with severe irAE not responsive to steroids within 48–72 h, early (~72 h) initiation of anti-TNFα therapy (e.g., infliximab 5 
mg/kg) may be warranted in consultation with the relevant medical specialist. 
 
A second dose of anti-TNFα therapy may be required and can be administered 2 weeks after the initial dose of infliximab. 
 
Anti-TNFα agents should be avoided in patients with immune-related hepatitis. 
 
Alpha-4 beta-7 integrin inhibitors (e.g., vedolizumab) may be considered in these cases for management of concomitant hepatitis and 
immune-related colitis. 
 
Other immunosuppressive agents may be of use in certain irAE; see individual toxicity pages. 
 
Patients with pre-existing autoimmune conditions or organ transplant recipients may be candidates for immune checkpoint blockade. 
 
Anti-CTLA-4-based therapy has a higher incidence of exacerbating baseline autoimmune conditions relative to anti-PD-1/PD-L1-based 
approaches. 
 
Optimisation of immunosuppression for pre-existing autoimmune conditions, including close follow-up with pertinent subspecialists, is 
recommended. 
 
Goal of immunosuppressive regimen allowing for a dose of prednisone < 10 mg daily or equivalent prior to initiating cancer immunotherapy. 
 
Patients with solid organ transplantation may be candidates for immunotherapy, particularly if no prior evidence of graft rejection and if on 
maintenance immunosuppression. Graft failure while on cancer immunotherapy has been reported. Transplant organ loss may be an outcome 
of treatment with cancer immunotherapy and should be discussed with patient and organ transplant team. 
 
Patients with autoimmune neurologic conditions or life-threatening autoimmune disorders, particularly if not controlled with 
immunosuppressive medications or requiring high doses of immunosuppression, are unlikely to be suitable candidates for cancer 
immunotherapy. 
 
Patients with prior allogeneic stem cell transplant may be candidates for immunotherapy. 
 
There is an increased risk of transplant-related complications, including potentially fatal graft-versus-host disease (GVHD). 
 
Careful discussion with patient and stem cell transplant physicians should precede the initiation of immunotherapy. 
 
Patients with a history of HIV or viral hepatitis may be candidates for immunotherapy. 
 
Vaccines that are inactivated or killed preparations are permissible during a course of immunotherapy. There is less clarity regarding live 
vaccine use and there should be an educated discussion with the patient prior to the administration of live vaccine. 

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Principles of Immunotherapy Rechallenge 
General Principles: 
 
Exercise caution when considering resumption of immunotherapy after significant irAE. Close follow-up should be performed when resuming 
immunotherapy to monitor for recurrent symptoms. 
 
If re-challenged and toxicity returns, permanently discontinue class of immunotherapy. 
 
Permanent discontinuation of a given class of immunotherapy is typically warranted in the setting of severe irAE induced by that class of 
immunotherapy and may be warranted in the setting of moderate irAE. For example, if a patient experiences Grade 3 or Grade 4 toxicity from 
an ipilimumab-containing regimen, consideration may be given to later therapy with a PD-1 or PD-L1 monotherapy after the resolution of 
earlier toxicity. 
 
With some exceptions, resumption of immunotherapy following Grade 2 irAE can be considered upon resolution to ≤ Grade 1. 
 
Consult with organ-specific specialists prior to the resumption of immunotherapy as appropriate following an immunotherapy hold due to 
irAE. 
Organ-Specific Considerations for Immunotherapy Rechallenge After a Hold 
Skin 
 
Maculopapular rash and/or pruritus: Consider resuming after symptoms have resolved to ≤ 
Grade 1 (i.e., once skin condition is mild/localised with only topical intervention indicated). 
 
Permanent discontinuation of immunotherapy in the setting of severe or life-threatening bullous 
disease (Grade 3 and Grade 4), including all cases of SJS and TEN. 
GI 
 
PD-1/PD-L1 agents: After Grade 2 and Grade 3 colitis, consider resumption of immunotherapy 
after symptoms have resolved to ≤ Grade 1. In rare circumstances in which the patient cannot 
completely taper off steroids, immunotherapy may be resumed while the patient is still on ≤ 10 
mg prednisone equivalent daily. 
Liver 
 
Transaminitis without elevated bilirubin: following a Grade 2 irAE, consider resumption of 
immunotherapy after ALT/AST return to baseline and steroids, if used, have been tapered to ≤ 
10 mg prednisone equivalent daily. 
 
Permanent discontinuation is warranted in the setting of severe or life-threatening (Grade 3 and 
Grade 4) hepatitis. 
Pancreas 
 
Symptomatic Grade 2 pancreatitis: Consider resumption of immunotherapy if no 
clinical/radiologic evidence of pancreatitis ± improvement in amylase/lipase. Consider 
consultation with a pancreatic-related specialist regarding resumption. 
 
Permanent discontinuation is warranted for severe (Grade 3 and Grade 4) pancreatitis. 

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Endocrine 
 
Thyroid: No discontinuation required for hypothyroidism. For symptomatic hyperthyroidism 
resembling Graves-like disease, consider holding immunotherapy and resuming after workup is 
complete and there is evidence for improvement in symptoms and TFTs. 
 
Primary adrenal insufficiency: After appropriate replacement endocrine therapy is instituted, 
immunotherapy may continue. 
 
Hypophysitis manifested by the deficiency of TSH/ACTH and/or gonad-stimulating hormones, 
but without symptomatic pituitary swelling: Immunotherapy may continue while replacement 
endocrine therapy is regulated. 
 
Hypophysitis accompanied by symptoms of pituitary swelling (e.g., headache, vision 
disturbance, and/or neurologic dysfunction): Hold immunotherapy until resolution of symptoms 
after steroid therapy; consider resumption of immunotherapy after symptoms are controlled on < 
10 mg daily steroid dose. 
 
T1DM with DKA: Consider resuming once DKA has been corrected and glucose level has 
stabilised. 
 
 
Progressive Grade 1 pneumonitis requiring a hold: Consider resuming upon radiographic 
evidence of improvement. 
 
Grade 2: Resume once pneumonitis has resolved to ≤ Grade 1. 
 
Permanent discontinuation is warranted in the setting of severe (Grade 3 and Grade 4) 
pneumonitis 
Kidney 
 
Grade 1 and Grade 2 renal irAE: Hold immunotherapy per guidelines; upon resolution to ≤ 
Grade 1, consider resuming concomitant with steroid if creatinine is stable. 
 
Permanent discontinuation is warranted in the setting of severe (Grade 3 and Grade 4) 
proteinuria. 
Eye 
 
Grade 2 irAE: Hold immunotherapy per guideline; consider resumption of immunotherapy in 
consultation with ophthalmology upon resolution to ≤ Grade 1. 
 
Permanent discontinuation of immunotherapy is warranted in the setting of severe (Grade 3 and 
Grade 4) uveitis or episcleritis. 
Nervous System 
 
Myasthenia gravis: Consider resuming immunotherapy after moderate (Grade 2) AE based on 
steroid responsiveness. Permanently discontinue immunotherapy after Grade 3 and Grade 4 AE. 
 
GBS: Permanently discontinue immunotherapy for any-grade GBS. 
 
Peripheral neuropathy: Following hold for Grade 1 and Grade 2 AE, consider resuming if 
symptoms resolve to ≤ Grade 1 or if a patient has well-controlled isolated painful sensory 
neuropathy. 
 
Aseptic meningitis: Consider resuming following mild to moderate AE if symptoms resolve to 
Grade 0. 
 
Encephalitis: Permanent discontinuation is warranted in the setting of moderate to severe 
encephalitis (Grade 2 to Grade 4). 

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 
Transverse myelitis: Discontinuation of immunotherapy following any-grade transverse 
myelitis. 
Cardiovascular 
 
Grade 1 myocarditis: Consider resuming upon resolution of symptoms. 
 
Permanent discontinuation is warranted in the setting of myocarditis (Grade 2 to Grade 4) 
Musculoskeletal 
 
Inflammatory arthritis (moderate to severe irAE requiring hold): Resume upon stabilisation or 
adequate management of symptoms. 
 
Permanent discontinuation may be warranted for severe inflammatory arthritis that significantly 
impairs ADLs and quality of life. 
 
 
 

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10.11 Appendix 9: Prohibited Traditional Chinese Medicines 
Prohibited Traditional Chinese Medicines 
Hua Zheng Hui Sheng Tablet 
Anticancer Ping Pill 
Brucea Javanica Oil Soft Capsule/Brucea Javanica 
Oil Injection 
Fu Kang Capsule 
Zhe Mu Syrup 
Xiao Ai Ping 
Cantharidin/Cantharidin Injection/Cantharidin 
Capsule 
Ping Xiao Capsule 
Hua Chan Su 
Ping Xiao Tablet 
Toad Venom 
Shen Dan San Jie Capsule 
Kang Ai Injection 
An Kang Xin Capsule 
Kang Lai Te 
Bo Sheng Ai Ning 
Herba Sarcandrae Injection 
Zedoary Turmeric Oil Glucose Injection 
Ai Di Injection 
Kang Li Xin Capsule 
A Wei Hua Pi Cream 
Ci Dan Capsule 
Shenmai 
Lightyellow Sophora Root 
Placental Polypeptide 
 
Note: Traditional Chinese medicines prohibited during the trial include but not limited to the above drugs.

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10.12 Appendix 10: Abbreviations 
Abbreviation 
Explanation 
ADA 
Anti-drug antibody 
ADL 
Activities of Daily Living 
AE 
Adverse events 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial prothrombin time 
ASCO  
American Society of Clinical Oncology 
AST 
Aspartic transaminase 
AUC 
Area under the concentration-time curve 
BUN 
Blood urea nitrogen 
CFDA 
China Food and Drug Administration 
CI 
Confidence interval 
CNS 
central nervous system 
Cmax 
maximum (or peak) serum concentration 
COVID-19 
Coronavirus disease 2019 
CR 
Complete response 
Cr 
Creatinine 
CrCl 
Creatinine clearance 
CRA 
Clinical research associate 
CSM 
Clinical site manager 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
ECG 
12 lead electrocardiography 
ECOG  
Eastern Cooperative Oncology Group 
eCRF  
Electronic case report form 
EDC 
Electronic data capture system 
EOT 
End-of-Treatment 
ESCC 
Esophageal squamous cell carcinoma  
ES-SCLC 
Extensive stage small cell lung cancer 
EQ-5D-5L 
5-level EQ-5D version 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life Scale 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
FFPE 
Formalin-fixed paraffin embedded 

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Abbreviation 
Explanation 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
Hb 
Hemoglobin 
HbcAb 
Hepatitis B core antibody 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV  
Hepatitis C virus 
HR 
Hazard Ratio 
HRQoL 
Health-related quality of life 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICU 
intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IO 
Immunotherapy 
INR 
International normalized ratio 
IRB  
Institutional Review Board 
IRRC 
Independent Radiology Review Committee 
irAEs 
Immune-related adverse events 
ITT  
Intent-to-treatment set 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
IWRS 
Interactive web response system 
IO 
Immunotherapy 
LFT 
Liver function test 
mCRC 
Metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite instability 
MTD 
Maximum tolerated dose 
NA 
Not applicable 
NCCN 
National Comprehensive Cancer Network 
NMPA 
National Medical Products Administration 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PCP 
Pneumocystis pneumonia 

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Abbreviation 
Explanation 
PD 
Progressive disease 
PD-L1 
Programmed cell death-ligand 1 
PET-CT 
Positron emission tomography – computerized tomography 
PD-1 
Programmed cell death 1 
PFS  
Progression-free survival 
PK 
Pharmacokinetics 
PKS 
PK analysis set 
PLT 
Platelet 
PPS 
Per protocol set 
PR  
Partial response 
PT 
Prothrombin time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RO 
Receptor occupancy 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SoA 
Schedule of Activities 
SMP 
Safety Management Plan 
SOP 
Standard operating procedure 
T3 
Triiodothyronine 
T4 
Thyroxine 
TB 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
TMB 
Tumor mutation burden 
TNF 
Tumor necrosis factor  
TPS 
Tumor proportion scores 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
Ultrasound 
 
 
11 References 
1 
Siegel R L , Miller K D , Jemal A . Cancer statistics, 2018.[J]. Ca A Cancer Journal for 
Clinicians, 2018, 60(5):277-300. 
 
 

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2 
Chen Wan-qing, Sun Ke-xin, Zheng Rong-shou, et al.Report of Cancer Incidence and 
Mortality in Different Areas of China，2014 [J]. China cancer, 2018, 27(1): 1-14. 
3 
Eskandar A, Ahmed A, Daughtey M, et al. Racial and sex differences in presentation and 
outcomes of small cell lung cancer in the United States: 1973 to 2010[J]. Chest, 2015,147(4): 
e164-e165 
4  Klautke G , Sauer R , Fietkau R . Combined Treatment Modality in Small Cell Lung Cancer[J]. 
Strahlentherapie Und Onkologie, 2008, 184(2):61-66. 
5 
Kurup A, Hanna NH. Treatment of small cell lung cancer[J]. Crit Rev Oncol Hematol, 2004, 
52: 117-126. 
6 
彭红. 肺癌住院病例的流行病学特征及预后随访研究[D]. 上海: 复旦大学, 2010. 
7 
Puglisi M , Dolly S , Faria A , et al. Treatment options for small cell lung cancer – do we have 
more choice?[J]. Br J Cancer, 2010, 102(4):629-638. 
8 
Ishida Y , Agata Y , Shibahara K , et al. Induced expression of PD-1, a novel member of the 
immunoglobulin gene superfamily, upon programmed cell death[J]. Embo Journal, 1992, 
11(11):3887-3895. 
9 
Stadler S, Weina K, Gebhardt C, et al. New therapeutic options for advanced non-resectable 
malignant melanoma[J]. Adv Med Sci, 2015, 60(1):83-88. 
10 Basso D,Fogar P,Falconi M,et al.Pancreatic tumors and immature immunosuppressive 
myeloid cells in blood and spleen：role of inhibitorv co-stimulatorv molecules PDLl and 
CTLA4.An in vivo and in vitro study[J] .PLOSONE, 2013, 8(1) :e54824. 
11 Chen S, Liu H, Su N, et al. Myeloid-derived suppressor cells promote age-related increase of 
lung cancer growth via B7-H1[J]. Experimental Gerontology, 2015, 61:84-91. 
12 Keir, M. E. Tissue expression of PD-L1 mediates peripheral T cell tolerance[J]. Journal of 
Experimental Medicine, 2006, 203(4):883-895. 
13 Dong H, Strome S E, Salomao D R, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: 
A potential mechanism of immune evasion[J]. Nature Medicine, 2002, 8(8):793-800. 
14 Nishizumi H . Development of lupus-like autoimmune diseases by disruption of the PD-1 gene 
encoding an ITIM motif-carrying immunoreceptor[J]. Immunity, 1999, 11(2):141-151. 
15 Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application[J]. 
International Immunology, 2007, 19(7):813-824. 
16 Yokosuka T, Takamatsu M, Kobayashiimanishi W, et al. Programmed cell death 1 forms 
negative costimulatory microclusters that directly inhibit T cell receptor signaling by 
recruiting phosphatase SHP2[J]. Journal of Experimental Medicine, 2012, 209(6):1201-1217. 
17 Sheppard K A , Fitz L J , Lee J M , et al. PD-1 inhibits T-cell receptor induced phosphorylation 
of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ[J]. Febs Letters, 2004, 
574(1-3):0-41. 
18 Patsoukis N, Brown J, Petkova V, et al. Selective Effects of PD-1 on Akt and Ras Pathways 
 

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Regulate Molecular Components of the Cell Cycle and Inhibit T Cell Proliferation[J]. Science 
Signaling, 2012, 5(230):ra46. 
19 Merritt RE, Mahtabifard A, Yamada RE, et al. Cisplatin augments cytotoxic 
T-lymphocyte-mediated antitumor immunity in poorly immunogenic murine lung cancer[J]. 
The Journal of Thoracic and Cardiovascular Surgery, 2003; 126:1609-17. 
20 Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the 
immune system to anticancer chemotherapy and radiotherapy. [J]. Nature Medicine, 2007, 
13(9):1050-1059. 
21   Remon J, Menis J, Aspeslagh S, et al. Treatment duration of checkpoint inhibitors for NSCLC. 
Lancet Respir Med. 2019;7 (10):835–837. doi:10.1016/S2213-2600(19)30192-4. 

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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Version 
Date 
Notes 
Version 4.0 
05 February 2021 
This document 
Global level 
Version 3.0 
08 April 2020 
This document 
Version 2.0 
27 Sep 2019 
Global Level 
Version 1.0 
04 Mar 2019 
Applicable for China only 
 
 
 

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Overall Rationale for the Amendment 3: 
Protocol version 3.0 was updated to Version 4.0, based on comments from the European Medicines Agency as part of a Scientific 
Advice procedure, comments from the Bulgarian Drug Agency, and from the Office for Registration of Medicinal Products, Medical 
Devices and Biocidal Products (Poland Regulatory Agency), additional clarifications, and correction of minor inconsistencies between 
sections. In addition, minor corrections, including typographical/grammatical errors, have been made. Changes made during 
development of Version 4.0 are clarified as follows: 
Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
1.1 Synopsis 
3 Objectives and Endpoints 
8.3 Study Assessments 
9.4.1.2 Analysis of secondary 
efficacy endpoints 
Section 1.1 
PFS2 (assessed by the investigator based on RECIST 1.1) 
 
Section 3 
PFS2 (assessed by the investigator based on RECIST 1.1) 
 
Section 8.3 
Progression-free survival 2 (PFS2) is defined as time from 
randomization to second/subsequent objective tumor progression 
on next-line treatment or death from any cause. 
 
Section 9.4.1.2 
Progression-free survival 2 (assessed by the investigator based on 
RECIST 1.1). PFS2 is defined as time from randomization to 
second/subsequent objective tumor progression on next-line 
treatment or death from any cause. It will be analyzed using the 
same method as that for PFS. 
Revision based on 
comments from the 
European Medicines 
Agency 
1.3 Schedule of Activities 
(SoA) 
Section 1.3 
Schedule of activities table footnote #12 (initial treatment period and 
Removal of myoglobin 
testing. It is recommended 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
8.1 Tests and Evaluations 
during the Study 
post-PD treatment period): …myocardial function detection includes 
troponin-I (TnI)/ or troponin-T (TnT), creatine kinase isoenzyme (CK-
MB)/creatine kinase (CK), and Brain Natriuretic Peptide (BNP)/N-
terminal pro-Brain Natriuretic Peptide (NT-pro BNP)and 
myoglobin; 
 
Section 8.1, Table 5 
Myocardial function: Troponin-I (TnI)/or Troponin-T (TnT), 
Creatine kinase isoenzyme (CK-MB)/creatine kinase (CK), 
myoglobin Brain Natriuretic Peptide (BNP)/N-terminal pro-Brain 
Natriuretic Peptide (NT-pro BNP), Myoglobin 
Footnote: **Routine blood test, blood chemistry, coagulation function, 
myocardial function and urinalysis 
that the biomarker used 
for diagnosis of acute 
myocardial infarction is 
cardiac troponin due to its 
sensitivity and accuracy. 
Myoglobin remains a 
biomarker of secondary 
relevance as compared to 
troponin-assessments, 
hence it was removed. 
 
1.3 Schedule of Activities 
(SoA) 
5.2 Exclusion Criteria 
8.1 Tests and Evaluations 
during the study 
8.2.1 Screening Period (day -
28 to day -1) 
Section 1.3 
Schedule of activities table: Tuberculosis screening 
Footnote#15 (initial treatment period) 
 
Section 5.2 
Active or latent pulmonary tuberculosis. 
 
Section 8.1 and Table 5 
Local laboratory tests performed at study sites include routine blood 
test, serum biochemistry, coagulation, myocardial enzymogram, 
urinalysis, thyroid function, virology, tuberculosis screening (as 
requested by the Bulgarian Drug Agency for Bulgarian subjects) 
and pregnancy test. 
 
Section 8.2.1 
Local laboratory tests: routine blood test, serum biochemistry, 
coagulation, myocardial enzymogram, urinalysis, thyroid function, 
Addition of tuberculosis 
testing at Screening and 
addition of latent 
tuberculosis in exclusion 
criteria as requested by the 
Bulgarian Drug Agency 
for Bulgarian subjects 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
pregnancy test (for females of childbearing age only), and virology and 
tuberculosis screening (as requested by the Bulgarian Drug Agency 
for Bulgarian subjects). 
2.3.2 Identified and potential 
risks 
In the phase Ⅱ study of HLX10 in patients with previously treated 
HCC, 1 subject received HLX10 (3 mg/kg) combined with HLX04 (5 
mg/kg) once every 2 weeks experienced DLT at safety run in stage 
(increased total bilirubin is 39.4 mµmol/L which is >2 mg/dL and 
considered to be caused by hepatocellular cancer progression) 
Correction of 
typographical error for 
total bilirubin unit 
Sponsor Signatory 
Xin ZhangWenying Kang 
Vice president Medical Director of Global Clinical Medical Affairs 
To update the Sponsor 
signatory information. 
1.3 Schedule of Activities 
(SoA) 
1.1 Synopsis 
3 Objectives and Endpoints 
8.1 Tests and Evaluations 
during the Study 
8.2.2 Treatment Period 
8.4 Safety Assessment 
Section 1.3 
Footnote 4# (Initial Treatment Period) 
ECOG performance status, serum pregnancy test, blood routine, 
biochemistry, coagulation, myocardial function, urinalysis and thyroid 
function (T3 or FT3, T4 or FT4, TSH) should be completed within 7 
days before randomization, and the subjects should meet the 
corresponding inclusion/exclusion criteria for enrollment. 
 
Section 1.1 and Section 3: 
Safety Endpoints 
 Adverse events (AEs) (including serious adverse events 
[SAEs]), laboratory tests (routine blood test, blood chemistry, 
coagulation function, urinalysis, myocardial function and 
thyroid function), 12-lead electrocardiogram (12-lead ECG), 
vital signs, and physical examination, etc. 
 
Section 8.1 Table 5 
Add “myocardial 
function” in laboratory 
tests to be consistent with 
Table 5. 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
Routine blood test, blood chemistry, coagulation function, myocardial 
function and urinalysis must be performed at screening and within 3 
days prior to drug administration every treatment cycle. 
 
Section 8.2.2 (Initial treatment visit and Post-PD treatment visit) 
Routine blood test, biochemistry, coagulation, myocardial function 
and urinalysis should be performed within 3 days pre-dose in each 
treatment cycle; for combined chemotherapy, routine blood tests should 
be performed on Day 8 (± 3 days) of each treatment cycle. 
 
Section 8.4 
Safety assessments variables include AEs (including SAEs), laboratory 
tests (routine blood test, blood chemistry test, coagulation test, routine 
urine test, myocardial function and thyroid function test), 12-lead 
ECG, vital signs, and physical examination. 
1.3 Schedule of Activities 
(SoA) 
8.1 Tests and Evaluations 
during the Study 
8.2.2. Treatment Period 
Section 1.3 
Footnote 16# (Initial Treatment Period and Post-PD Treatment Period) 
Computerized tomography (CT) or magnetic resonance imaging (MRI) 
should be performed at screening, every 6 weeks (± 7 days) during the 
first 48 weeks after the start of study treatment, and every 9 weeks (± 7 
days) after week 48 on sites including brain, chest, abdomen, pelvic 
cavity and any other sites suspected to have tumor lesions, in which 
brain MRI or CT (preferably MRI) and bone scans are required for all 
subjects at screening, and are performed in the treatment period as 
determined by the investigator according to clinical needs (if baseline 
brain CT/MRI shows that brain metastasis is not present, the 
subject should have follow up brain imaging only if clinically 
indicated at the discretion of the investigator. If baseline brain 
CT/MRI has confirmed central nervous system (CNS) metastasis, 
continuous brain imaging test should be carried out as part of the 
Revision based on NTF 
clarification. 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
regular RECIST evaluation assessments); examination methods at 
the same site should be consistent as much as possible throughout the 
study; if there are no contraindications, contrast agent should be used. 
The investigator and IRRC respectively assess the tumor images 
according to RECIST 1.1 (the tumor assessment can be performed by 
the investigator according to clinical needs), and the investigator 
should make subsequent treatment judgment according to the results of 
their own efficacy evaluation. If tumor assessment has been performed 
within 28 days prior to the first dose by the same methods and devices 
in the same hospital, it may serve as the baseline tumor assessment. At 
the EOT visit, if tumor imaging has been performed within the last 4 
weeks, a re-test is not required. For subjects who discontinued for 
reasons other than disease progression, radiological assessments are to 
be continued as scheduled, until disease progression, initiation of new 
antineoplastic therapy, withdrawal of ICF, death, or end of studyEOT, 
whichever occurs first. 
 
Section 8.1 
Subjects should undergo CT or MRI (including brain, chest, abdomen, 
pelvic cavity and any other sites suspected of having tumor lesions) at 
screening (within 4 weeks pre-dose), every 6 weeks (± 7 days) during 
the first 48 weeks after the start of study treatment, and every 9 weeks 
(± 7 days) after week 48 (if baseline brain CT/MRI shows that brain 
metastasis is not present, the subject should have follow up brain 
imaging only if clinically indicated at the discretion of the 
investigator. If baseline brain CT/MRI has confirmed CNS 
metastasis, continuous brain imaging test should be carried out as 
part of the regular RECIST evaluation assessments). 
 
Section 8.2.2 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
Initial treatment visit and Post-PD treatment visit (Optional) 
(if the baseline brain CT/MRI shows that brain metastasis is not 
present, the subject should have follow-up brain imaging only if 
clinically indicated at the discretion of the investigator. If the 
baseline brain CT/MRI confirms CNS metastasis, a continuous 
brain imaging test should be carried out as part of the regular 
RECIST evaluation assessments); 
2.1 Background 
Anti-PD-1 monoclonal antibodies have been approved for 
melanoma, non-small cell lung cancer (NSCLC), SCLC, head and 
neck squamous cell cancer, urothelial carcinoma, microsatellite 
instability-high or mismatch repair deficient solid tumors and 
colorectal cancer, gastric cancer, esophageal cancer, cervical cancer, 
hepatocellular carcinoma (HCC), Merkel cell carcinoma, renal cell 
carcinoma, endometrial carcinoma, bladder cancer, primary 
mediastinal large B-cell lymphoma and classical Hodgkin’s 
lymphoma. Numerous clinical studies are ongoing with anti-PD-1 
antibodies, either as monotherapy or in combination with various 
agents. 
Add the approved 
indication of anti-PD-1 
antibodies in background. 
2.2 Study Rationale 
Based on the results of the HLX10 preclinical and phase I clinical 
trials, the currently available pharmacokinetic (PK) and anti-drug 
antibody (ADA) data support an average body weight dose of HLX10 
of 4.5 mg/kg administered every 21 days as the recommended dose for 
phase III clinical studies. 
The available clinical data demonstrated that HLX10 is safe and 
tolerable in the phase I, first-in-human study in patients with 
advanced solid tumors, and in other clinical studies in patients with 
malignant solid tumors. And preliminary efficacy has been 
observed in some patients with advanced solid tumors in the 
Add available clinical 
studies information to 
support the study 
rationale. 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
first-in-human phase I clinical study (HLX10-001). The safety and 
efficacy of HLX10 will be further evaluated in clinical studies. 
2.2 Study Rationale 
Based on the results of preclinical and clinical studies, Shanghai 
Henlius Biotech, Inc. planned to conduct a phase III clinical study in 
previously untreated patients with ES-SCLC worldwide to compare the 
clinical efficacy and safety of HLX10 (recombinant anti-PD-1 
humanized monoclonal antibody injection) in combination with 
chemotherapy (Carboplatin Etoposide). 
Correcting a minor typo 
noted to ensure 
consistency and was 
updated in POL PA V2.1. 
2.2.1 Preclinical Studies of 
HLX10 
In the dose-finding trial (P16-106-TS), pharmacokinetic (PK) test 
(P16-106-YD), and long-term toxicity test (P16-106-CD) in 
cynomolgus monkeys; receptor occupancy (RO) at different time points 
was also investigated before and after intravenous injection of different 
doses of HLX10 to provide a basis for selection of the clinical effective 
dose and the initial dose. 
Correcting a minor typo 
noted after PA V3.0 was 
finalized. 
2.2.1 Preclinical Studies of 
HLX10 
Genetic Toxicology Studies 
The genotoxicity isn’t required to be evaluated for monoclonal 
antibodies like HLX10 according to ICHS6 (R1). 
No genotoxicity study of HLX10 has been conducted. 
Re-organized to clarify the 
genetic toxicology studies 
information. 
2.2.1 Preclinical Studies of 
HLX10 
Tissue cross-reactivity of HLX10 
The results of tissue cross-reactivity test of HLX10 in frozen normal 
human showed that HLX10-Biotin (2.0 μg/mL and 0.5 μg/mL) 
specifically binds to normal human lymphocytes from including the 
lymph nodes, the lungs, ileum, stomach, spleen, fallopian tubes, colon 
and thymus tissues. 
Minor update to wording 
for tissue cross-reactivity 
study 
2.2.2 Clinical Study of 
HLX10 
A clinical study of HLX10 had been approved by US FDA, Taiwan 
Food and Drug Administration (TFDA) and China NMPA. 
The most up-to-date 
clinical studies are added 
in this protocol. 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
Phase I clinical trial of HLX10: A prospective, open-label, dose-
escalation study of HLX10 in patients with metastatic or recurrent solid 
tumors who had failed standard therapy. Bayesian optimal interval 
design (BOIN) was used to determine the maximum tolerated dose 
(MTD) of HLX10. The objective of this study was to evaluate the 
safety, PK characteristics, biomarkers, PD markers, immunogenicity 
and preliminary efficacy of the study drug. Eligible subjects who meet 
the inclusion criteria in the screening period will receive infusion of 
HLX10 at a dose level specified in the protocol once every 2 weeks 
until disease progression, or up to one year, withdrawal from study, or 
death, whichever occurs first. Each treatment cycle consists of two 
doses of study drug, once every 2 weeks. The trial is currently ongoing. 
The enrollment of patients into the 0.3, 1, and 3 mg/kg groups has been 
completed, and the safety evaluation is ongoing. 
 
To date, HLX10 has been administered to human subjects in 
14 ongoing clinical studies. Clinical studies of HLX10, given as 
monotherapy or in combination with chemotherapy or other 
antibodies (anti-VEGF antibody HLX04), are being conducted in 
patients with advanced solid tumors, previously untreated 
metastatic non-squamous NSCLC, previously treated unresectable 
or metastatic MSI-high or mismatch repair deficiency solid tumors, 
previously treated advanced HCC, gastric cancer, metastatic 
esophageal squamous cell carcinoma (ESCC), metastatic colorectal 
cancer (mCRC), relapsed and/or advanced cervical cancer, and 
advanced head and neck cancer. 
The clinical efficacy and safety results from these studies, as well as 
the nonclinical toxicology and safety data, provide evidence to 
support continued clinical development for HLX10. 

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2.3.1 Potential Benefits 
Atezolizumab (trade name Tecentriq®), a PD-L1 inhibitor developed by 
Roche in September 2018, has achieved landmark results in the first-
line treatment of SCLC: 
IMpower 133, a randomized, controlled phase III study evaluating 
atezolizumab plus carboplatin-etoposide versus placebo plus 
carboplatin-etoposide in the treatment of untreated extensive SCLC, 
enrolled 403 patients and randomized at 1:1 with a median follow-up of 
13.9 months. Median overall survival was 12.3 months (95% 
confidence interval [CI], 10.8-15.9) in the atezolizumab plus 
chemotherapy group and 10.3 months (95% CI, 9.3-11.3) in the 
placebo plus chemotherapy group (HR = 0.70, 95% CI 0.54-0.91, P = 
0.007). Median progression-free survival was 5.2 months (95% CI, 4.4-
5.6) in the atezolizumab plus chemotherapy group and 4.3 months 
(95% CI, 4.2-4.5) in the placebo plus chemotherapy group (HR = 0.77, 
95% CI 0.62-0.96, P = 0.02). At the same time, in terms of safety, the 
safety of Atezolizumab plus chemotherapy was consistent with that in 
the previous reports and no new toxicity was found. 
Based on the above study results, Henlius plans to study the anti-tumor 
activity of HLX10 plus chemotherapy as first-line treatment of ES-
SCLC. The preliminary efficacy, safety and tolerability data of PD-L1 
plus chemotherapy in the IMpower 133 study supports the use of this 
treatment in ES-SCLC. The primary objective of this phase III study is 
to determine the clinical efficacy and safety of HLX10 plus 
chemotherapy in previously untreated ES-SCLC patients. 
Available clinical data for HLX10 include that collected from 
clinical studies of HLX10, which was given as monotherapy and/or 
in combination with chemotherapy or other antibody (anti-VEGF 
antibody HLX04), in patients with advanced solid tumors, 
previously untreated metastatic non-squamous NSCLC, previously 
treated unresectable or metastatic MSI-H or dMMR solid tumors, 
The study results of 
atezolizumab (IMpower 
133) in this protocol will 
be replaced by the interim 
analysis results of phase I 
first-in-human study 
(HLX10-001). 

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previously treated advanced HCC, gastric cancer, metastatic 
ESCC, mCRC, relapsed and/or advanced cervical cancer, and 
advanced head and neck cancer. 
The available clinical data shows that HLX10 monotherapy or 
combined with other therapies was safe and tolerable in patients 
with malignant tumors. 
Only 1 subject in the 3 mg/kg dose cohort (n=6) experienced DLT 
during the first cycle in the HLX10 first-in-human phase I study in 
patients with advanced solid tumors with four dose levels (0.3, 1, 3 
and 10 mg/kg). The maximum tolerated dose (MTD) was not 
reached until 10 mg/kg of HLX10 was given every two weeks. 
Accumulation of HLX10 was observed following multiple dose 
administration. The 0.3 mg/kg of HLX10 was enough to saturate 
the PD-1 binding and induce the functional blockade. The efficacy 
results demonstrated anti-tumor activity of HLX10 in this first-in-
human phase I study with DCR of 68.8%, ORR of 6.3%, and 
median PFS of 107.0 days.  
In the phase II study of HLX10 in patients with previously treated 
HCC, 1 subject in the dose level A (n=7) of safety run-in stage 
experienced DLT (increased total bilirubin is 39.4 µmol/L which is 
>2 mg/dL and considered to be caused by hepatocellular cancer 
progression). 
The study showed the anti-tumor activity of HLX10 and patients 
with advanced solid tumors can benefit from HLX10. 
2.3.2 Identified and Potential 
Risks 
The safety evaluation of IMpower 133 in ES-SCLC also showed that 
the occurrences of AEs in the atezolizumab + EC group and placebo + 
EC group were comparable, with the occurrences of AEs of any grade 
being 100% and 96.4% in the two groups, respectively; the occurrences 
of grade 3-4 AEs were 67.2% and 63.8% in the two groups, 
respectively. The occurrences of treatment-related AEs were 94.9% and 
The safety information of 
atezolizumab (IMpower 
133) in this protocol will 
be replaced by the up-to-
date risk information 

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92.3%, respectively. The occurrences of SAEs were 37.4% and 34.7%, 
respectively; the occurrences of immune-related AEs were 39.9% and 
24.5%, respectively. The comparisons for occurrences of most common 
grade 3-4 AEs: Neutropenia (22.7% and 24.5%), anemia (14.1% and 
12.2%), neutrophil count decrease (14.1% and 16.8%), 
thrombocytopenia (10.1% and 7.7%), leukopenia (5.1% and 4.1%). The 
occurrences of immune-related grade 3-4 AEs in the atezolizumab + EP 
group were 2% for rash, 1.5% for hepatitis, 2% for infusion-related 
reactions, and 0.5% for pneumonia. 
HLX10 is currently being studied with limited safety information 
available. The available clinical data from the first-in-human phase 
I clinical study, shows that the most frequently reported study drug 
related adverse events were nausea, fatigue and decreased appetite, 
constipation, vomiting and pyrexia. The severity was mainly grade 
1-2. The most frequently reported serious adverse event (SAE) that 
was greater or equal than grade 3 was pyrexia. 
In another phase I clinical study (HLX10HLX04-001) of the study 
drug combined with another antibody, no DLT was observed in the 
18 subjects when the study drug was administered from 1 mg/kg to 
10 mg/kg. 
In the phase Ⅱ study (HLX10-008-HCC201) of HLX10 in patients 
with previously treated HCC, 1 subject received HLX10 (3 mg/kg) 
combined with HLX04 (5 mg/kg) once every 2 weeks experienced 
DLT at safety run in stage (increased total bilirubin is 39.4 µmol/L 
which is >2 mg/dL and considered to be caused by hepatocellular 
cancer progression).  
In the ongoing phase III study (HLX10-002-NSCLC301) of HLX10 
in patients with previously untreated non-squamous non-small cell 
lung cancer (NSCLC), 6 subjects have received HLX10 (4.5 mg/kg) 
+ HLX04 (15 mg/kg) + carboplatin (AUC=5) + pemetrexed 
reported in the 
Investigator’s Brochure. 

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(500 mg/m2) once every 3 weeks with no major safety concerns. No 
grade ≥4 hematologic toxicity and grade ≥3 non-hematologic 
toxicity-safety events and grade ≥2 pneumonia (and no recovery to 
grade 1 in 3 days) occurred after the treatment of the first cycles. 
No serious adverse drug reactions (ADRs) were observed in the 
first stage of the study (safety run-in period). The most common 
ADRs included platelet count decreased, white blood cell count 
decreased, neutrophil count decreased and hypertriglyceridaemia.  
Several other phase II and III clinical studies of the study drug are 
ongoing, where HLX10 has been administered as monotherapy 
and/or in combination with chemotherapy or other antibody, in 
patients with advanced solid tumors, previously untreated 
metastatic non-squamous non-small cell lung cancer and 
previously treated unresectable or metastatic MSI-H (microsatellite 
instability-high) or dMMR (deficiency in mismatch repair) solid 
tumors. The available clinical data showed that the study drug 
given as a monotherapy or combined with other therapies was safe 
and tolerable in patients with malignant tumors. 
The most commonly reported side effects with probability greater 
than 5% include: rash, pyrexia, anemia, diarrhea, nausea, 
decreased appetite, platelet count decreased, white blood cell count 
decreased, neutrophil count decreased, nephritis, hepatic function 
abnormal, and hypothyroidism. 
Adverse events related to the study drug reported in these studies 
which are serious, fatal and life-threatening include: pyrexia, 
myocarditis, platelet count decreased, neutrophil count decreased, 
white blood cell count decreased, pneumonitis, hepatic function 
abnormal, colitis, pancreatitis, and renal impairment. 
More detailed information about the known and expected risks of 
HLX10 can be referred to in the Investigator’s Brochure. 

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2.3.3 Overall benefits: risk 
and ethical assessment 
Based on the current study data of HLX10, only 2 subjects 
experienced DLTs (1 subject received HLX10 monotherapy [3 
mg/kg] once every 2 weeks, and 1 subject received HLX10 [3 
mg/kg] combined with HLX04 [5 mg/kg] once every 2 weeks), the 
MTD was not reached yet. No dose-limiting toxicity was observed 
based on the current first-in-human study data for HLX10, and tThe 
available safety data and pharmacokineticPK data demonstrated that 
the safety of HLX10 in patients is acceptable and adequate enough to 
support the implementation of this phase III of the clinical study. 
Add the latest reported 
clinical study results. 
4.3 Justification for Dose 
Based on the results of the HLX10 preclinical and clinical phase I 
clinical trials of HLX10, the currently available PK and ADA data 
support HLX10 4.5 mg/kg based on mean body weight, an average 
body weight dose of HLX10 of 4.5 mg/kg administered every 21 days 
as the recommended dose for phase III clinical studyies. Results of 
Dose Exposure Response analysis demonstrated both 4.5 mg/kg every 
three weeks and 3.0 mg/kg every two weeks were oversaturated doses. 
Given the fact that no maximum tolerated dose (MTD) was observed in 
anti-PD-1 antibodies and the European Medicines AgencyEMA and 
FDA approved oversaturated doses for nivolumab (nivo) and 
pembrolizumab (pembro) in clinical practice across multiple tumor 
types, Henlius believes that 4.5 mg/kg every three weeks or 3.0 mg/kg 
every two weeks is justified and safe. 
Updates based on POL PA 
V2.1. 
8.1 Tests and Evaluations 
during the Study 
8.2.2 Treatment Period 
8.3 Study Assessments 
Section 8.1 Tumor imaging 
Images will be assessed by the IRRC according to RECIST v1.1 (see 
Appendix 2-1: Response Evaluation Criteria in Solid Tumors (RECIST 
1.1)) and iRECIST criteria (see Appendix 2-2: iRECIST: Guidelines for 
response criteria for use in trials testing immunotherapeutics 
immunotherapeutics). 
 
To clarify that IRRC will 
only be assessing based on 
RECIST 1.1 and 
investigator will assess 
based on RECIST 1.1 and 
iRECIST. 

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The investigator and IRRC respectively assesses the tumor images 
according to RECIST 1.1 and iRECIST (the tumor assessment can be 
performed by the investigator according to clinical needs), and the 
investigator should make subsequent treatment judgment according to 
the results of their own efficacy evaluation. The IRRC assess the 
tumor images according to RECIST 1.1. 
 
At the EOT visit, if tumor imaging has been performed within the last 4 
weeks, a re-test is not required. Note: For all tumor imaging 
timepoints, investigator must assess all the tumor images according 
to RECIST 1.1 and iRECIST. 
 
Section 8.2.2 
Initial treatment visit 
The investigator and IRRC should assess the tumor images according 
to RECIST 1.1 and iRECIST (the tumor assessment can be performed 
by the investigator according to clinical needs), and the investigator 
should make subsequent treatment judgment according to the results of 
their own efficacy evaluation. The IRRC should assess the tumor 
images according to RECIST 1.1. 
 
Post-PD treatment visit 
The investigator should assess the tumor images according to RECIST 
1.1 and iRECIST (the tumor assessment can be performed by the 
investigator according to clinical needs), and the investigator should 
make subsequent treatment judgment according to the results of their 
own efficacy evaluation. 
 
Section 8.3 

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Except overall survival, other efficacy endpoints are evaluated based on 
tumor response as per RECIST 1.1 and iRECIST. 
8.2.1 Screening Period (day -
28 to day -1) 
Note: All reports from diagnostic procedures, which were 
performed before the ICF is signed and as part of the standard of 
care in the region and the examination methods/devices meet the 
study requirements might be used for the eligibility evaluation 
during the screening. This option restricted to those cases only, 
where the patient has given written confirmation that he/she 
consent to use his/her diagnostic reports of performed procedures 
before the date of ICF signature for eligibility evaluation of the 
actual study. 
Updates per NtF for PA 
V3.0. 
6.2 Dosing Regimen 
Preparation/Handling/Storage/ 
Accountability 
The infusion of investigational product is completed between 30 mins 
and 90 mins if there is not any infusion reaction. The diluted drug 
solution is recommended to be used within 6 hours of preparation 
and has been shown to be stable for up at 24 hours. The diluted 
drug solution needs to be stored at approximately 2-8 °C for no 
longer than 24 hours and be kept from light if not used within 6 
hours. 
Updates per IB 4.0 
following stability testing. 
1.1 Synopsis 
6.6 Dose Modification 
Section 1.1 
In the event of intolerance to etoposide/carboplatin, the dose can be 
modified twice according to the etoposide/carboplatin prescribing 
information and local standard-of-care. Once reduced, the dose 
cannot be increased back to 100%. 
If treatment is delayed due to intolerance to chemotherapy, 
chemotherapy may be delayed to the next cycle of administration, with 
the maximum permissible interval for chemotherapy not exceeding 6 
weeks. 
 
Section 6.6 
Alignment of ‘principles 
for chemotherapy 
modification’ text between 
sections and removal of 
dose modification table 
for chemotherapy as in 
practice, the dose of 
carboplatin would be re-
calculated before each 
dose. 

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Principles for chemotherapy dose modifications 
In the event of intolerance to etoposide/carboplatin, doses may be 
adjusted twice in accordance with the prescribing information of 
carboplatin and etoposide, the investigator’s decision based on the 
subject’s safety, and local treatment standards practice. Once reduced, 
the dose cannot be increased back to 100%. 
 
 
 
5.1 Inclusion Criteria #12 
≤ 1.5×ULN; 
In case of > 1.5 × ULN, creatinine clearance ≥ 5060 mL/min 
Decrease the value of 
creatinine clearance as per 
a request from the EMA 
8.2.2 Treatment Period 
The tumor image used to determine disease progression can be used as 
the new baseline image for the post-PD treatment period if 1) within 
28 days prior to receiving the first dose of HLX10 or placebo therapy 
and 2) No study treatment between the image and first dose of HLX10 
or placebo therapy, otherwise a new baseline image must be performed 
prior to HLX10 or placebo treatment. 
Clarification that the 
tumor image can be used 
within 28 days 

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8.4.7. Pregnancy 
Each fertile subject shall take appropriate contraceptive measures in a 
period from signing ICF through at least 6 months after the final dose 
of the study drug, and in at least 6 months after the final dose of 
chemotherapy drug. 
Update of information 
regarding contraceptive 
measures 
6.6 Dose Modifications 
Hematological toxicities 
Table 1 
ANC < 0.5 ×109/L and PLT ≥ 50 ×109/L: 75% of the planned previous 
dose 
PLT < 50 ×109/L, regardless of ANC: 75% of the planned previous 
dose 
PLT < 50 ×109/L with Grade 2 hemorrhage, regardless of ANC: 50% of 
the planned previous dose 
ANC < 1×109/L with fever ≥ 38.5 °C: 75% of the planned previous 
dose 
 
Non-hematological toxicities 
Table 2 
Modified carboplatin dose by % of planned previous dosea 
To add flexibility for 
investigational sites to 
apply dose reduction 
based on their standard 
clinical practice 
8.4.1.4 Death 
• Any death (confirmed to be PD-induced or non-PD-induced) 
should be reported as an SAE and the death should not be 
reported as a separate event. The SAE report needs to be 
submitted and reported to the clinical research associate 
(CRA)/clinical site manager (CSM), the sponsor, or a representative 
of the sponsor within 24 hrs. 
• When a death is not (or not explicitly) due to PD, the AE resulting in 
this death has to be deemed as an SAE and reported to the 
CRA/CSM, the sponsor, or a representative of the sponsor in 24 h. 
The primary cause of death should be provided. 
Rewording to avoid 
possible misunderstanding 

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8.4.2 Serious Adverse Events 
2) Life-threatening (AE occurrence leads to an immediate risk of 
subject death, not including those AEs that may lead to death after PD, 
e.g., drug-induced hepatitis without liver failure) 
Update as per ICH-E2A 
8.4.4 Reporting of SAEs 
The sponsor is legally liable to inform has a legal responsibility to 
notify both the local regulatory authority and other regulatory bodies 
agencies about the of safety information of the study drug of a study 
intervention under clinical investigation. The investigator sponsor is 
legally obliged and ethically responsible to report promptly SAEs to 
relevant regulatory bodies and health authority, the ethics committee, 
and the study contact specifically in charge of receiving SAE reports, 
and make sure safety of other subjects is guaranteed will comply with 
country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and Investigators. 
 
The investigator or any person-in-charge required by local authority 
shall abide by local regulatory regulations on SAE reporting and report 
SAEs to regulatory bodies, Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC), as per request. 
Updated to meet cross-
countries’ requirement 
9.5.1 Independent Data 
Monitoring Committee 
(IDMC) 
The IDMC will be established to independently oversee the blinded 
sample size re-estimation procedure; 
Correction of 
typographical error 
9.5 Interim Analyses 
An IDMC will be established for this study for blinded interim 
analysis. This study plans to carry out an interim analysis.  
Correction of text as the 
interim analysis will not 
be blinded 
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding 
The blinding will be performed by the Data Management and 
Statistical Unit during study treatment. 
Deletion of Data 
Management, as blinding 
process is not created by 

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the Data Management 
function. 
7. Discontinuation of Study 
Intervention and Participant 
Discontinuation 
7 Discontinuation of Study Intervention, and Participant 
Discontinuation, and Study Termination 
 
Section 7.1.1 Reasons for Premature Discontinuation 
1. Poor subject compliance that has affected the efficacy and safety 
evaluation; 
2. The occurrence of AEs or SAEs in the subjects, who are deemed 
unsuitable to that are inappropriate to continue receiving the study 
drug treatment as judged by the investigator; 
3. Evidence of clear disease unequivocal progression or worsening of 
the disease;  
4. A delayed dosing of the study drug administration meeting the 
criteria specified in the protocol; 
5. Subject lost loss to follow-up or death during treatment; 
6. Subject decided to Wwithdrawal of informed consent; 
7. Subject decides to discontinue treatment; 
8. Other reasons of discontinuation as determined by the investigator 
in the best interest of the subject. 
 
Section 7.1.2 Management of premature discontinuations 
The reasons for premature discontinuations shall be documented in the 
eCRF by the investigator. 
 
Updates for clarity of 
language and provide 
further detail for subjects 
discontinuing treatment 

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All subjects who discontinue the trial prematurely (except patients who 
withdraw informed consent) and agree to continued follow-up of 
associate clinical outcome information, shall undergo an EOT visit 
and be followed up for safety and survival. See Section 8.2.4 for 
assessments during the follow-up period. 
 
Subjects who discontinue the trial for reasons other than disease 
progression and agree to continue follow-up of associated clinical 
outcome information should be radiologically followed up until 
disease progression, withdrawal of informed consent, death or start of a 
new antineoplastic therapy. 
 
All AEs present at the time of discontinuation must be followed up 
until the outcomes of such AEs. 
 
In case of an enrolled subject’s withdrawal for any reasons, no subject 
replacement is permitted. 
 
7.4 
Premature Termination of Study and Site Closure 
The study may be terminated prematurely for the reasons 
described below, and the premature termination of the study must 
be approved in writing by both the principal investigator and the 
Sponsor, and the results of the study should be reported as 
required by the protocol. 
 
1. The study is unlikely to be completed within an acceptable time 
frame due to difficult enrollment of subjects; 
2. The investigator doubts the safety of the drug during the study, 
and believes that continuing the study will bring serious risks to 
the subjects;  

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3. The principal investigator and the Sponsor believe that it is 
necessary to terminate the study prematurely based on the 
number of AEs and their severity; 
4. The expected efficacy cannot be reached, and it is not necessary 
to continue the clinical study; 
5. Withdrawal of the study by the drug regulatory authority; 
6. The Sponsor has the right to decide to terminate the study in a 
study site if the following occurs: 
• Serious violation of International Conference on 
Harmonization Good Clinical Practice (ICH-GCP) by the 
study site 
• Multiple serious protocol violations by the study site 
 
After termination of the study, all study-related records should be 
retained for reference. 
Section 5.2 Exclusion criteria 
Section 7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
Section 5.2 
16. Treatment with live vaccines and all COVID-19 vaccines (fully 
administered to the required number of doses) within 28 days prior 
to study drug administration; inactivated viral vaccines for seasonal 
influenza are allowed. 
 
18. 
Any active infection requiring systemic anti-infective therapy 
within 14 days prior to study drug administration or subjects with a 
positive RT-PCR test for SARS-CoV-2 infection at randomization. 
Subjects with a history of COVID-19 infection must have a 
negative RT-PCR test prior to the first dose of the study drug. 
 
Section 7.2 
If a subject develops fever or symptoms suspected of being a result 
of COVID-19 during the study, they will be instructed to follow-up 
Addition of information 
relating to subjects with or 
a history of COVID-19 
infection 

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with their regular healthcare provider or follow the instructions for 
suspected COVID-19 cases per their local health authority. A 
subject will discontinue treatment based on discussion with the 
Sponsor and Medical Monitor under the following circumstances: 
any suspected or confirmed COVID-19 case will be immediately 
discontinued from study treatment for up to 12 weeks after the last 
study drug administration; subjects who recover from the infection 
within 12 weeks from the last study drug administration, can 
continue treatment following Sponsor’s confirmation. 
 
Overall Rationale for the Amendment 2: 
Protocol Version 2.0 was updated to Version 3.0 based on the comments from the European Medicines Agency and the United States 
Food and Drug Administration as part of Scientific Advice procedures. 
Section # and Name 
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Brief Rationale 
1.1 Synopsis 
3 Objective and Endpoint 
Primary Efficacy Endpoint 
• 
Progression-free survival (PFS) (assessed by the independent 
radiology review committee [IRRC] based on Response Evaluation 
Criteria in Solid Tumors [RECIST] 1.1) 
• 
Overall survival (OS)  
OS is the recommended 
primary endpoint as 2-year 
survival for ES-SCLC is less 
than 5% and there is a limited 
activity in second-line 
therapies.  
1.1 Synopsis 
3 Objective and Endpoint 
Secondary Efficacy 
Endpoint  
• 
Overall survival (OS) 
• 
Progression-free survival (PFS) (assessed by the independent 
radiology review committee [IRRC] based on Response Evaluation 
Criteria in Solid Tumors [RECIST] 1.1) 
Change PFS to a secondary 
endpoint 
 

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1.1 Synopsis 
4.1 Overall Design 
Initial tTreatment should be discontinued when they have evidence of 
disease progression as assessed by RECIST v1.1. However, considering 
the limited availability and efficacy or greater toxicity of treatment 
options after withdrawal, and for better adaptation to standard clinical 
practice, 
If a subject has 1st disease progression and is clinically stable, and 
tends to receive 2nd line chemotherapy treatment subsequently (the 
selection of 2nd line chemotherapy may refer to the NCCN 
guidelines or the ESMO guidelines), it is at the discretion of the 
investigator to continue treating the subject with blinded HLX10 or 
placebo assignment per protocol in addition to the 2nd line 
chemotherapy, until the 2nd disease progression lost clinical benefit, 
intolerable toxicity, death, withdrawal of consent, or lost to follow-
up. Subjects who permanently discontinue initial treatment due to 
an adverse event, withdrawal of consent, or for any reason other 
than disease progression, will not be eligible for the post-PD 
treatment. 
the sSubjects who meets all the following conditions may continue 
the treatment and after appropriate discussion with the subject and 
obtaining the supplementary informed consent. 
1. Subjects who had received HLX10 or placebo in combination 
with chemotherapy, who may benefit from continuing 
HLX10/placebo treatment despite progression, will be able to 
receive HLX10 or placebo therapy in the post-PD treatment. 
1. With no clinical signs and symptoms (including worsening of 
laboratory findings) indicating a significant disease progression. 
2. Subjects eligible for continued treatment in the post-PD 
treatment period, as judged by the investigator. 
2. A stable Eastern Cooperative Oncology Group (ECOG) performance 
status score. 
In combination with second-
line chemotherapy in the post-
PD treatment period, subjects 
are prevented from being 
exposed to placebo alone. 

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3. The subject should sign the supplementary informed consent 
form to receive investigational product with 2nd line chemotherapy. 
4.The subject is clinically stable, defined as: 
a) With no clinical signs and/or symptoms (including worsening of 
laboratory findings) that might indicate disease progression. 
b) A stable Eastern Cooperative Oncology Group (ECOG) 
performance status score. 
c) No rapid disease progression or tumor progression requiring 
urgent alternative medical intervention at critical anatomical sites 
(e.g., spinal cord compression). 
3. No rapid disease progression or tumor progression requiring urgent 
alternative medical intervention at critical anatomical sites (e.g., spinal 
cord compression). 
4. The major organ function meets the inclusion and exclusion criteria 
of this study. 
5. The subject should sign the supplementary informed consent form to 
continue treatment. 
 The primary objective of this study is to compare the PFSs of HLX10 
in combination with chemotherapy versus placebo in combination with 
chemotherapy, as assessed by an Independent Radiology Review 
Committee (IRRC) using RECIST v1.1. 
1.1 Synopsis 
Treatment Groups and 
Duration: 
8.2.2 Treatment Period 
This study is divided into three periods: Screening period (28 days), 
treatment period (initial treatment and post-PD treatment 
[Optional], until disease progression loss of clinical benefit, death, 
intolerable toxicity, withdrawal of informed consent, or occurrence of 
other reasons specified in the protocol, whichever occurs first), and 
Follow-up period (including safety follow-up and survival follow-up). 
Adjustment of treatment 
periods because of the 
addition of post-PD treatment. 

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1.1 Synopsis Other study 
drugs: combined 
chemotherapy 
4.1 Overall Design 
6.2 Dosing Regimen 
Preparation/Handling/Storag
e/Accountability 
6.6 Dose Modification 
Carboplatin: Area under the concentration-time curve (AUC) = 5, IV 
infusion, on Day 1 of each cycle up to a dose of 800750 mg. On Day 1, 
etoposide shall be administered following infusion of carboplatin. 
To adjust the maximum 
dosage of carboplatin 
according to the NCCN 
Chemotherapy Order 
Templates about Maximum 
Carboplatin Dose Calculation. 
To clarify the order of drug 
administration. 
1.2 Schema 
Screening period: The maximum screening period is 28 days. At least 
28 days. 
Treatment period: Including initial treatment and post-PD treatment 
(optional) 
After finishing the initial treatment period, patients in both arms 
who had 1st disease progression per RECIST 1.1 and might benefit 
from their assigned treatment in addition to 2nd line chemotherapy, 
may be eligible to continue to receive their assigned treatment in the 
post-PD treatment period (Optional) until the 2nd disease 
progression, intolerable toxicity, death, withdrawal of consent, or 
lost to follow-up. 
Safety follow-up period: 90 days after the last study drug 
administration dose. Safety visit is required at the site 30 days (±7 
days) after the last study drug administration dose, and telephone 
follow-up is required 90 days (±7 days) after the last study drug 
administration dose. 
Survival follow-up period: Every 12 weeks ± 7 days 
To keep the study periods 
consistent throughout the 
protocol. 
1.3 Schedule of Activities 
(SoA) 
Study Procedures Initial Treatment Period and Post-PD Treatment 
Period (Optional) 
To keep the study periods 
consistent throughout the 
protocol. 

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1.3 Schedule of Activities 
(SoA) Initial Treatment 
Period footnote #7 
Re-assessments Quality of life assessment could be performed either 
on Day -7 to Day -1 of the screening period or prior to dosing in 
Cycle 1 are not required for subjects who had a quality of life 
assessment on Day -7 to Day -1 of the screening period. 
To clarify the acceptable time 
window for performing 
quality of life assessment 
during the screening period. 
1.3 Schedule of Activities 
(SoA) Initial Treatment 
Period footnote #8 
Adding footnote #8: Re-assessments prior to dosing in Cycle 1 are 
not required for subjects who had 12-lead ECG and ECOG scores 
assessment on Day -7 to Day -1 of the screening period 
To clarify the acceptable time 
window for performing 12-
lead ECG and ECOG scores 
assessment during the 
screening period. 
1.3 Schedule of Activities 
(SoA) Initial Treatment 
Period footnote #9 
8.1 Tests and Evaluations 
during the Study 
If the change in the subject’s body weight from baseline during the 
study is ≤10%, dose adjustment of investigational product study drug 
will not be required, and if the weight change is >10%, the dose of 
study drug must be recalculated. If the subject’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the dose 
of investigational product, the dose of investigational product must 
be recalculated. All doses should be rounded to the nearest 
milligram. 
To substitute “study drug” 
with “investigational product” 
as investigational product 
stands for HLX 10/placebo 
only and does not include 
chemotherapy drugs. 
Language has been edited to 
make the dose modifications 
of investigational product 
clearer. 
1.3 Schedule of Activities 
(SoA) Initial Treatment 
Period footnote #12 
8.1 Tests and Evaluations 
during the Study 
Laboratory Tests 
12.serum biochemistry items include blood urea/urea nitrogen, 
creatinine, sodium, potassium, magnesium, chloride, carbon dioxide 
binding capacity or bicarbonate or total carbon dioxide, calcium, 
phosphorus, blood glucose, total bilirubin, direct bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase, lactate dehydrogenase, total cholesterol, total protein, 
albumin; coagulation test consist of prothrombin time (PT), 
activated partial thromboplastin time (APTT) and international 
normalized ratio (INR); myocardial enzymogram detection includes 
troponin-I, creatine kinase isoenzyme (CK-MB) and myoglobin; 
To delete “carbon dioxide 
binding capacity or 
bicarbonate or total carbon 
dioxide” from the serum 
biochemistry test as these 
items are not required but can 
be performed if considered 
standard of care in the region.  

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urinalysis items include specific gravity, urine leukocytes, pH, urine 
glucose, urine protein, ketone body and blood cellsurine occult blood, 
microscopic examination of white blood cells and red blood cells 
should be collected if urine leukocytes and urine occult blood are 
out of normal range. Can be performed within 3 days before dosing in 
each cycle; for aforementioned laboratory tests scheduled on the same 
day as study treatment, the study treatment can be arranged only after 
the test results are obtained. For laboratory tests from the screening 
period completed on Day -7 ~ Day -1, it is not necessary to repeat 
the test again before the first administration (C1D1). For combined 
chemotherapy, routine blood tests should be performed on Day 8 (± 3 
days) of each treatment cycle to closely monitor bone marrow 
suppression. 
To include myocardial 
enzymogram detection to 
address safety concern. 
Language has been added to 
clarify the urinalysis items. 
To clarify time window of 
local lab test at screening 
period. 
1.3 Schedule of Activities 
(SoA) Initial Treatment 
Period footnote #14 
8.1 Tests and Evaluations 
during the Study 
Laboratory Tests  
Patients with HBsAg (+) and/or HBcAb (+) HBsAg positive subjects 
should be further tested for hepatitis B virus (HBV) DNA titer; and 
HCV antibody positive subjects should be further tested for HCV RNA. 
Language has been edited to 
clarify the HBV testing 
requirements. 
1.1 Synopsis 
9.2 Sample Size 
Determination 
9.5 Interim Analyses 
Number of Participants: 
Approximately 489567 (326 378 for HLX10 and 163189 for placebo). 
Corresponding wording and recalculation were applied to section 9.2 
and 9.5 
Sample size was recalculated 
due to change of primary 
endpoint to OS. 
2.2.2 Clinical Study of 
HLX10 
Phase I clinical trial of HLX10: A prospective, open-label, dose-
escalation study of HLX10 in patients with metastatic or recurrent 
solid tumors who had failed standard therapy. Bayesian optimal 
interval design (BOIN) was used to determine the maximum 
tolerated dose (MTD) of HLX10. The objective of this study was to 
evaluate the safety, PK characteristics, biomarkers, PD markers, 
To make the description of 
phase I study clearer. 

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immunogenicity and preliminary efficacy of the study drug. Eligible 
subjects who meet the inclusion criteria in the screening period will 
receive infusion of HLX10 at a dose level specified in the protocol 
once every 2 weeks until disease progression, or up to one year, 
withdrawal from study, or death, whichever occurs first. Each 
treatment cycle consists of two doses of study drug, once every 2 
weeks. The trial is currently ongoing. The enrollment of patients 
into the 0.3, 1, and 3 mg/kg groups has been completed, and the 
safety evaluation is ongoing. 
for a dose escalation phase I clinical trial. There are four dose groups 
(0.3, 1, 3 and 10 mg/kg, once two weeks) in the trial, with a maximum 
enrollment of about 30 subjects. At present, three patients in the fourth 
dose group have completed the enrollment, and no dose-limiting 
toxicity was observed in all dose groups during the dose-limiting 
toxicity observation period. 
4.1 Overall Design 
The primary endpoint of this study is to compare the OS PFSs of 
HLX10 in combination with chemotherapy versus placebo in 
combination with chemotherapy, as assessed by an IRRC using RECIST 
v1.1 as evaluation criteria. 
Change OS to primary 
efficacy endpoint. 
4.1 Overall Design  
Figure 1: Schematic of 
study treatment 
1st Disease Progression  
The subject should re-consent and meet the following conditions: The 
subject (tending to receive 2nd line chemotherapy treatment 
subsequently) should re-consent and meet the following conditions: 
(1) Subjects who had received HLX10 or placebo in combination 
with chemotherapy, who may benefit from continuing 
HLX10/placebo treatment despite progression, will be able to 
receive HLX10 or placebo therapy in the post-PD treatment period 
With no clinical signs and symptoms (including worsening of laboratory 
findings) indicating a significant disease progression.  
To keep the study design 
consistent throughout the 
document. 

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(2) Subjects eligible for continued treatment in the post-PD 
treatment period, as judged by the investigator. A stable ECOG 
performance status score.  
(3) The subject should sign the supplementary informed consent 
form to receive investigational product with 2nd line chemotherapy. 
(4) The subject is clinically stable. No rapid disease progression or 
tumor progression requiring urgent alternative medical intervention at 
critical anatomical sites (e.g., spinal cord compression).  
(4) The major organ function meets the inclusion and exclusion criteria 
of this study.  
(5) The subject should sign an informed consent form again. 
Continue the treatment until persistent disease progression, worsening 
of symptoms due to disease progression, or intolerant toxicities 
Continue the treatment until the 2nd disease progression, intolerant 
toxicities, death, withdrawal of consent, or lost to follow-up. 
Continue the treatment until persistent disease progression, worsening 
of symptoms due to disease progression, or intolerant toxicities 
* Follow-Up Period includes safety follow-up and survival follow-
up. Patients who are not eligible for post-PD treatment will be 
followed up for safety and survival status. 
4.2 Scientific Rationale for 
Study Design 
Rationale for Post-PD 
Treatment 
Patients with ES-SCLC experience rapid tumor growth, fast clinical 
deterioration, and have an overall poor prognosis. First-line 
therapy with a platinum agent and etoposide has consistently 
demonstrated high response rates and significant clinical benefit. 
However, considering the limited availability and efficacy or greater 
toxicity of treatment options after withdrawal, and for better 
adaptation to standard clinical practice, subjects may be considered 
for subsequent treatment assignment blinded beyond radiographic 
disease progression per RECIST 1.1, at the discretion of the 
To clarity the rationale for 
post-PD treatment. 

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investigator, after appropriate discussion with the patient and 
obtaining informed consent. 
In addition, conventional response criteria may not adequately 
assess the activity of immunotherapeutic agents because disease 
progression (by initial radiographic evaluation) does not necessarily 
reflect therapeutic failure. Related research shows that shorter 
treatment increases the risk of relapse or progression, and there are 
potential benefits to patients receiving longer IO (Immunotherapy) 
treatment21. Because of the potential for pseudoprogression/tumor-
immune infiltration, this study will allow patients to remain on 
treatment after apparent radiographic disease progression per 
RECIST 1.1, provided all criteria meet post-PD treatment 
conditions. 
4.4 End of Study Definition 
“The end of the study, defined as the final analysis of PFS OS, will be 
performed when a target number of PFS OS events (approximately 
336342) are observed...” 
To redefine End of Study due 
to change of primary endpoint  
5.1 Inclusion Criteria #2 
Male or female aged ≥ 18 between 18 to 75 (inclusive) years at the time 
of signing the ICF. 
Remove upper age limit as 
patients older than 75 years 
represent a substantial 
proportion of patients with 
ES-SCLC. 
5.1 Inclusion Criteria #6 
Note: Measurable lesions are not from previously irradiated sites. If the 
lesion at the previously irradiated site is the only selectable target lesion, 
a radiological assessment showing significant progression of the 
irradiated lesion should be provided by the investigator. 
anteroposterior images showing significant progression of the lesion 
should be provided by the investigator. 
Wording re-edit. 

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5.1 Inclusion Criteria #12 
≤ 1.5×ULN; 
In case of > 1.5 × ULN, creatinine clearance ≥ 6050 mL/min 
Increase the value of 
creatinine clearance to take 
into account the renal toxicity 
of carboplatin. 
5.1 Inclusion Criteria #13 
Agree to use birth control methods with an annual failure rate of <1% or 
maintain abstinence (avoid heterosexual intercourse) (from the signing 
of informed consent form (ICF) to at least 6 months 120 days after the 
final dose of study drug or at least 150 days after the final dose of 
chemotherapy drug) (birth control methods with an annual failure rate 
of <1% include bilateral tubal ligation, male sterilization, proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine contraceptive devices and copper containing intrauterine 
contraceptive devices or condoms) 
Extending of time limits of 
using birth control methods or 
maintain abstinence after the 
final dose of study drug 
5.1 Inclusion Criteria #14 
Male patients must: agree to abstinence (avoid heterosexual intercourse) 
or take contraception measures as follows: male patients with a pregnant 
partner or a partner with of childbearing potential must remain abstinent 
or use a condom to prevent embryonic exposure during study 
treatment chemotherapy treatment (carboplatin or etoposide) and for at 
least 150 days6 months after the last dose of study drug chemotherapy. 
Periodic abstinence (e.g., contraceptive methods based on calendar day, 
ovulation, basal body temperature or post-ovulation) and external 
ejaculation are ineligible methods of contraception. 
Extending of time limits of 
abstinence or use a condom to 
prevent embryonic exposure 
after the last dose of study 
drug. 
 
 6.2 Dosing Regimen 
Preparation/Handling/Storag
e/Accountability 
Other study drugs: chemotherapy 
• Etoposide: 100 mg/m2, IV infusion, on Days 1, 2, and 3 of each 
cycle. On Day 1, etoposide shall be administered following infusion 
of carboplatin. 
To clarify the order of 
adminstration of study drugs 
6.5 Concomitant Therapy 
6.5.3 Subsequent Anti-Cancer Therapy Status 
Adding subsequent anti-
cancer therapy status, to 

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The investigator or his/her qualified designee will review all new 
anti-cancer therapy initiated after the discontinuation of trial 
treatment. If the subject continues the post-PD treatment, he/she 
must choose to receive 2nd line chemotherapy. The preferred 2nd line 
chemotherapy was determined by the investigators following the 
NCCN /or ESMO guidelines and communicated as such to the 
subjects who chose to continue the Post-PD treatment. Any other 
anti-PD1 and anti-PD-L1 therapy are not allowed.  
clarify the concomitant 
therapy in post-PD treatment 
6.6 Dose modification  
In the event of intolerance to etoposide/carboplatin, doses may be 
adjusted twice in accordance with the prescribing information of 
carboplatin and etoposide and local treatment standards. Once reduced, 
the dose cannot be increased back to 100%. 
Make adjustment in” Non-hematological toxicities” in both text and 
table for recommended carboplatin dose modification 
To make adjustment to 
recommended dose 
modification. 
7.1.2 Management of 
premature discontinuations 
All subjects who discontinue the trial prematurely (except patients who 
withdraw informed consent) shall undergo an EOT visit and be 
followed up for safety. 
To exclude subjects who 
withdraw their informed 
consent from the EOT visit 
and safety follow-up. 
8.2.4 Follow-Up period 
During the survival follow-up period, subjects without PD and not 
receiving any other anti-tumor therapy should return to the hospital 
according to the established schedule for radiologic assessment should 
be followed up until PD, initiation of a new anti-tumor therapy, ICF 
withdrawal, death, the patient is lost to follow-up, study termination 
by the sponsor, or study completion, whichever occurs first.; while 
subjects experiencing PD or undergoing any other anti-tumor therapy 
just need to be followed up for survival status by telephone call once 
every 12 weeks (±7 days). 
To update the condition of 
survival follow up  

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8.4 Safety Assessment 
The structure and wording were re-edited, changes are listed below： 
1. Any death confirmed to be PD-induced should be reported as an SAE 
and reported to the clinical research associate (CRA)/clinical site 
manager (CSM), the sponsor, or a representative of the sponsor 
within 24 hrs. to the sponsor at the next monitoring visit. It should be 
documented but not reported as an SAE. 
2. Insert a section “8.4.2. 1 Drug-induced liver injury, (DILI)” 
 
3. 8.4.3. Documentation of AEs. All AEs occurring in a period from 
signing ICF (either main or supplementary) through 90 days after the 
final administration of the study drug should be documented in 
corresponding AE pages in EDC. If a subject starts a new 
antineoplastic therapy during the AE collection period, only 
information on AEs related to study treatment are documented 
after the new antineoplastic therapy. The investigator shall provide all 
detailed information required to be completed, including date of onset, 
severity, action, outcome, and causality to the study drug. When 
collecting AE data, one has better recording diagnosis information (if 
possible), rather than recording a number of signs and symptoms. 
However, if a diagnosis is known but the patient still has other 
symptoms or signs not contributing to such diagnosis, then each 
symptom or sign should be documented separately. 
 
4. Add AESI as follows: AESIs are events of scientific and medical 
concern related to use of the investigate drug that may need to be 
closely monitored and communicated to sponsors by investigators. 
AESI can be a serious or non-serious event. The AESI expedited 
To rearrange this section 
according to the updated 
Pharmacovigilance rules. 
 

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report enables continuous monitoring of these events in order to 
describe and understand their association with the drug used in the 
study.  
In this study, AESI include infusion reaction (infusion-related 
adverse reactions, IRR) and immune-related adverse events (irAE). 
5. Each fertile subject shall take appropriate contraceptive measures in a 
period from signing ICF through at least120 days 6 months after the 
final dose of the study drug and in at least 150 days 6 months after the 
final dose of chemotherapy drug. 
6. The investigator will evaluate whether causality between the study 
drug and the AE is "definitely related", "possibly related", "unlikely 
related", "definitely unrelated", or "not evaluable unknown". AEs other 
than "unlikely related" and "not related" are recorded as adverse 
reactions. Any AE without given causality to the study drug will be 
deemed as "possibly related" to the study drug. 
7. All AEs and SAEs that occur in each subject throughout the 
study should be actively followed up. Even if such events persist 
after discontinuation or study termination, the investigator should 
follow them up until all events meet any of the following criteria: 
All AEs occurring in a period from signing ICF through 90 days after 
the final dose of the study drug should be followed up until any of the 
following circumstances occurs: 
9.4.1 Efficacy Analyses 
Analyses of the primary efficacy endpoint and the secondary efficacy 
endpoints will be performed for both the ITT and PPS, mainly on the 
ITT. analyses of the secondary and exploratory efficacy endpoints will 
be performed for the ITT only. 
To correct population for 
analyses due to changing of 
endpoints. 
9.4.1.1 Analysis of primary 
efficacy endpoint 
9.4.1.1 Analysis of primary efficacy endpoint 
Overall survival (OS): Defined as a period from randomization 
through death regardless of causality. Data of patients without a 
To keep consistency in the 
document text after changing 
of endpoints. 

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9.4.1.2 Analysis of 
secondary efficacy 
endpoints 
death record will be censored on the last known survival date. 
Progression free survival (assessed by the IRRC as per RECIST v1.1): 
PFS is defined as a period from randomization initiation to the first 
documentation of PD or death regardless of causality (whichever occurs 
first). Data of subjects with neither PD nor death will be censored on the 
day of the final valid tumor evaluation. Data of surviving subjects not 
undergoing any tumor assessment during the study will be censored on 
the day of randomization. Data of subjects who have no PD reported 
and initiate any antitumor therapy not specified in the protocol will be 
censored on the day of the last evaluable tumor assessment prior to the 
initiation of subsequent antitumor treatment. The between-group 
comparison of OS PFS is performed by a stratified log-rank test with 
the following stratification factors: PD-L1 expression level (negative: 
TPS <1%, positive: TPS ≥1%, or not evaluable/not available), brain 
metastasis (yes versus no), and age (≥ 65 years versus < 65 years); a 
stratified COX proportional risk model will be used to estimate HR and 
its 95% CI; the Kaplan-Meier method will be used to estimate the 
median, and the Kaplan–Meier curve will be plotted. 
9.4.1.2 Analysis of secondary efficacy endpoints 
Progression free survival (assessed by the IRRC as per RECIST 
1.1): PFS is defined as a period from randomization initiation to the 
first documentation of PD or death regardless of causality 
(whichever occurs first). Censor rules will be defined in SAP. 
Overall survival (OS): Defined as a period from randomization through 
death regardless of causality. Data of patients without death record will 
be censored on the last known survival date. Data of patients not 
providing any follow-up information will be censored on the 
randomization day. The PFSOS will be analyzed using the same method 
as that for primary efficacy endpoints. 
 
 

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Brief Rationale 
 
9.4.1.3 Subgroup analyses 
Add the new section as 9.4.1.3 “Subgroup analyses” 
To assess the consistency of 
the study PFS and OS, results 
in subgroups will be 
examined. 
9.5 Interim Analyses 
Add the stopping boundary for OS interim and final analyses 
To add description per ICH-
E9  
10.10 Appendix 8 
Replaced Appendix 8 with NCCN Guidelines®: Management of 
Immunotherapy-Related Toxicities (2019 V2) 
To update the guidelines  
Throughout the protocol 
Some editorial changes were made. 
To keep the consistency 
throughout protocol. 
 
Overall Rationale for the Amendment 1: 
The structure of protocol Version 2.0 was updated and rearranged based on Version 1.0 in accordance with ICH guidance. Additional 
changes made during development of Version 2.0 are clarified as follows. 
Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
Title page  
A Randomized, Double-Blind, Multicenter, Phase III Study to Evaluate 
Compare Clinical Efficacy and Safety of HLX10 (Recombinant 
Humanized Anti-PD-1 Monoclonal Antibody Injection) in Combination 
with Chemotherapy (Carboplatin-Etoposide) in Previously Untreated 
Patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC) 
A short title was added. 
To include the objective in 
the title for clarifying the 
purpose and objective of 
the study. 

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Brief Rationale 
Title Page, Regulatory 
Agency Identifying 
Number(s) 
NMPA Approval Document Number: 2018L02201, EudraCT 
Number: 2019-003063-21 
To add the NMPA approval 
document Number and 
EudraCT Number for this 
protocol. 
Investigator Agreement 
Page 
Updated the Agreement pages, one page for Principal Investigator, the 
other page for Global Coordinating Investigator. 
To provide agreement 
pages for Principal 
Investigator and the Global 
Coordinating Investigator. 
1. Protocol Summary 
Inserted a header of section 1: protocol summary 
To give an overview of the 
protocol. 
1.3 Schedule of Activities 
(SoA) footnote #11 
8.1 Tests and Evaluations 
during the Study 
Laboratory Tests 
total cholesterol, total protein, albumin; urinalysis items include specific 
gravity, urine leukocytes, pH, urine glucose, urine protein, ketone body 
and blood cells. 
To include urine leukocytes 
for urinalysis to monitor the 
subject’s immune response.  
1.1 Synopsis 
3 Secondary Efficacy 
Objective 
Progression-free survival (PFS) assessed by the investigator based on 
RECIST v1.1 and modified RECIST criteria a modified RECIST 1.1 
for immune-based therapeutics (termed iRECIST). 
To add consensus guideline 
(iRECIST) developed for 
the use in cancer 
immunotherapy trials for 
the evaluation of PFS. 
9.4.1.2 Analysis of 
Secondary Efficacy 
Endpoints 
PFS assessed by the investigator as per RECIST v1.1 and iRECIST: Its 
statistical method is the same as that for primary efficacy endpoints. 
10.4 Appendix 2-2 
“Modified Response Evaluation Criteria in Solid Tumors” was replaced 
with “iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics”. 
1.1 Synopsis 
3 Objectives and Endpoints 
Exploratory 
• Exploratory population pharmacokinetic (PopPK) analysis  
To delete the secondary 
objective of “Exploratory”. 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
1.1 Synopsis 
1.2 Shema 
4.1 Overall Design 
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding 
9.4.1.1 Analysis of primary 
efficacy endpoint 
Randomization are stratified by PD-L1 expression level (negative: 
tumor proportion scores [TPS] <1%, positive: TPS ≥1%, or not 
evaluable/not available), brain metastasis (yes versus no), and age (≥ 
65 years versus < 65 years) 
To define the limits for 
PD-L1 expression levels 
specifically. 
1.3 SoA footnote #8 
The height measurement is performed only at screening; vital signs 
include body temperature, pulse, respiratory rate, and blood pressure. 
Body weight is measured before each dose, and no dose adjustment of 
the study drug is required if the subject's body weight differs ≤ 10% 
from the reference value of the current dose during the study, otherwise 
the dose should be recalculated. This new body weight will serve as the 
baseline value for subsequent body weight measurements. Body weight 
will be measured prior to drug administration at each treatment 
cycle. If the change in the subject’s body weight from baseline 
during the study is ≤10%, dose adjustment of study drug will not be 
required, and if the weight change is >10%, the dose of study drug 
must be recalculated. 
To clarify the timing of 
bodyweight measurement 
to allow an adjustment of 
the administration dose. 
1.3 SoA footnote #16 
Patients must provide tumor tissues that meet the requirements for 
the determination of PD-L1 expression levels. It is recommended to 
provide formalin-fixed tumor tissue samples, paraffin-embedded 
tumor specimens (preferred), formalin-fixed paraffin embedded 
(FFPE), tumor specimens or newly prepared unstained serial tissue 
sections (preferably adhesive slides) within 6 months prior to the 
first dose of study medication. A relevant pathology report must 
also be provided for the above specimens. To the extent possible, 
formalin-fixed paraffin-embedded (FFPE) tumor samples (paraffin 
To clarify the tumor tissue 
assessment procedure and 
purpose. 

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(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
blocks or unstained sections) collected at or after the diagnosis of ES-
SCLC and within 6 months prior to the start of study medication or 
pathological reports of such specimens should be provided. In case of 
no archived tumor tissue samples available, it is recommended to 
conduct a fresh tumor lesion biopsy at screening to obtain the 
corresponding tumor sample (the number of specimens required is 
based on the biopsy result). Tumor tissue sections will be used for 
immunohistochemical analysis to evaluate the expression level of PD-
L1 in tumor cells and tumor-infiltrating immune cells and other 
purposes. Freshly collected specimens, radical resections, core needle 
biopsy, excisions, incisions, punch or clamp biopsies are acceptable 
(newly obtained tissues are preferred). Fine-needle aspirations (i.e., 
samples that lack a complete tissue structure and provide only cell 
suspension and/or cell smear), brush biopsies, and cell pellet samples 
from pleural or peritoneal effusions are unacceptable. For detailed 
requirements for tissue samples, see the laboratory manual. 
3 Objectives and Endpoints 
Primary endpoint Primary Efficacy Endpoint 
Secondary endpoint Secondary Efficacy Endpoint 
• Incidence rates of AEs and SAEs 
• Pharmacokinetics (PK): serum HLX10 concentration 
• Immunogenicity evaluation: positive anti-drug antibody (ADA) rate 
• Relationship between PD-L1 expression level, MSI, TMB in tumor 
tissues and efficacy 
• Quality of life assessment 
Safety Endpoints 
• 
Adverse events (AEs) (including serious adverse events 
[SAEs]), laboratory tests (routine blood test, blood chemistry, 
coagulation function, urinalysis, thyroid function), 12-lead 
Endpoints classification 
were re-organized for better 
readability and to ensure the 
clarification of the 
endpoints.  

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Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
electrocardiogram (12 lead ECG), vital signs, and physical 
examination, etc. 
 
PK Endpoint 
• 
Concentration of HLX10 in serum 
Immunogenicity Endpoint 
• 
HLX10 anti-drug antibody (ADA) positive rate 
 
Biomarker Endpoint 
• 
Relationship between PD-L1 expression, microsatellite 
instability (MSI), tumor mutation burden (TMB) in tumor 
tissue and efficacy. 
 
Quality of life assessment 
4.Study Design  
Inserted section 4.4 End of study definition, and description started 
from “The end of the study is defined as the final analysis of PFS 
will be performed when a target number of PFS events 
(approximately 336)…etc.” 
To clarify the definition of 
the end of the study. 
5.1 Inclusion Criteria # 2  
2. Male or female between 18 to 75 (inclusive) years at the time of 
signing the ICF. 
To clarify the gender 
requirement of the subjects. 
5.1 Inclusion Criteria # 7 
Patients must provide tumor tissues that meet the requirements for the 
determination of PD-L1 expression levels. Subjects are assessed for an 
evaluable PD-L1 expression category (negative: TPS <1%, positive: 
TPS ≥1%, or not evaluable/not available) by the central laboratory for 
randomization. 
To define the limits for 
PD-L1 expression levels 
specifically. 
5. study population  
1. Inserted section 5.3 Lifestyle Consideration and description of “No 
restrictions are required.” 
1. To clarify the concerns to 
the subject’s lifestyle and to 

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Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
2. Inserted section 5.4 Screen failures and description started from 
“Screen failures are defined as participants who consent to 
participate in the clinical study but are not subsequently entered in 
the study. A minimal set of screen failure…etc.” 
follow the common 
protocol template structure. 
2. To clarify the definition 
of screen failures and the 
information required. 
6. Study Intervention  
Inserted the new header of Section 6 Study Intervention and 
description started from “Study drug is defined as any investigational 
interventions, marketed products…etc.” 
To clarify the definition of 
the study drug and to 
follow the common 
protocol template structure. 
6.1 Study Interventions 
Administered 
Name : Recombinant anti-PD-1 humanized monoclonal antibody 
injection (HLX10) 
Formulations: Liquid 
Specifications: 100 mg (10 mL)/vial 
To clarify the formulation 
of the study drug. 
6.2 Dosing Regimen 
Preparation/Handling/Stora
ge/Accountability 
Investigational/reference product: 
• HLX10: 4.5 mg/kg, IV infusion for 30 to 90 minutes, administered 
on Day 1 of each cycle, once every 3 weeks (21 days). 
• Placebo: IV infusion, administered on Day 1 of each cycle, once 
every 3 weeks (21 days). 
The infusion of study drug is completed between 30 mins and 90 
mins if there is not any infusion reaction. 
To define the completion of 
study drug infusion 
duration.  
6.3 Measure to Minimize 
Bias: Randomization and 
Blinding 
1.Inserted the new header of Section 6.3 Measure to Minimize Bias: 
Randomization and Blinding and description started from “All 
subjects will be centrally randomized the IWRS/IVRS. Each subject 
will be assigned a unique number (randomization number)…etc.’ 
 
2. Inserted subtitle of Blinding and the description started from. “ 
The blinding will be performed by the Data Management and 
Statistical Unit during study treatment…etc.” 
To clarify the randomizing 
and blinding procedure to 
minimize bias. 

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Section # and Name 
Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
6.7 Intervention After the 
End of the Study 
Inserted the new header of Section 6.7: Intervention After the End of 
the Study and description started from “Subjects will receive 
standard of care…etc.” 
To clarify the treatment 
subject will receive after 
the completion of the study 
and to follow the common 
protocol template structure.  
7. Discontinuation of Study 
Intervention and Participant 
Discontinuation 
Inserted the section 7.2 and 7.3. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
7.3 
Loss of Participants to Follow-Up 
To clarify the 
discontinuation/ 
withdrawal, and lost to 
follow- up from the Study. 
8.1 Tests and Evaluations 
during the Study 
Table 5 and footnotes 
Routine blood test 
 
Basophils (BAS&BAS%) 
 
Eosinophils (EOS&EOS%) 
 
Lymphocytes (LYM&LYM%) 
 
Monocytes (MON&MONO%) 
 
Neutrophils (NEU&NEUT%) 
Biochemistry 
 
Fasting blood glucose (GLU) 
Urinalysis 
 
Urine Specific gravity (SG) 
 
Urine leukocytes 
 
Urine pH value 
 
Urine protein (U PRO) 
 
Urinary glucose (U GLU) 
 
Ketones (KET) 
 
Urine occult blood (BLO) 
 
Microscopic examination of white blood cells (U-WBC) 
 
Microscopic examination of red blood cells (U-RBC) 
Coagulation function 
 
Prothrombin time (PT) or international normalized ratio (INR) 
To update Table 5 and 
footnotes to clarify the 
variables to be collected 
during laboratory 
examination.  

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Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
 
Activated Partial thromboplastin time (APTT) 
 
Footnote  
c. Thyroid function tests will be performed during screening and 
within 3 days prior to drug administration every 2 treatment cycles 
during the treatment period 
 
**Routine blood test, blood chemistry, coagulation function and 
urinalysis must be performed at screening and within 3 days prior 
to drug administration every treatment cycle. When the 
aforementioned laboratory tests and study drug administration are 
scheduled on the same day, the study drug administration must be 
scheduled only after the test results are obtained. Routine blood 
tests will be performed on Day 8 (±3 days) of each treatment cycle 
during treatment with carboplatin, and close attention should be 
paid to bone marrow suppression. 
8.1 Tests and Evaluations 
during the Study  
Tumor imaging 
Imaging studies in this trial include computed tomography or magnetic 
resonance imaging (CT/MRI). Images will be assessed by the IRRC 
according to RECIST v1.1 (see Appendix 2-1 Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1)) and modified RECIST 
iRECIST criteria (see Appendix 2-2: iRECIST: guidelines for 
response criteria for use in trials testing immunotherapeutics). 
To keep consistent with the 
study endpoint assessment 
criteria, changed from 
“RECIST V1.1 and 
modified RECIST” to 
“RECIST V1.1 and 
iRECIST”. 
8.1 Tests and Evaluations 
during the Study 
Biomarker sample 
collection 
At screening, blood samples and tumor tissue samples must be 
collected for biomarkers detecting.  
Inserted the description started from: “Patients must provide tumor 
tissues that meet the requirements for the determination of PD-L1 
expression levels...etc.” 
To update the requirement 
of tissue collection 
according to inclusion 
criteria #7. 

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Description of Change(s) 
(new text is in bold and underlined, deleted text is struck-through) 
Brief Rationale 
Deleted the description started from: “As far as possible, FFPE tumor 
samples…etc.” 
9.3 Populations for 
Analyses 
The definition of the enrolled population was added. 
Definition wordings of other populations including ITT set, PPS, SS and 
PKS were re-organized. 
To clarify and define the 
populations to be analyzed 
in the study.  
9.5 Interim Analysis 
Wordings were re-organized. 
To clarify the definition of 
the interim analysis.  
9.5.1 Independent Data 
Monitoring Committee 
(IDMC) 
10.1.3 Financial Disclosure 
10.1.11 Source Documents 
10.1.14 Protocol Approval 
and Amendment 
Several sections were added. 
To adhere to the ICH 
guidance. 
10.2 Appendix 1 
The version of Common Terminology Criteria for Adverse Events 
(CTCAE) is updated from v4.03 to v5. 
To update the version of 
CTCAE. 
10.5 Appendix 3 
Quality of Life Scale EORTC QLQ-C30, EQ-5D-5L and EORTC QLQ-
LC13 are updated. 
To update the Quality of 
Life Scale. 
Throughout the protocol 
Some editorial changes were made. 
To keep the consistency 
throughout protocol. 

Shanghai Henlius Biotech, Inc.                                                                                             
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                             Page 1 of 63 
 
 
  
Shanghai Henlius Biotech, Inc. 
 
HLX10-005-SCLC301 
 
A Randomized, Double-Blind, Multicenter, Phase III Study to Compare 
Clinical Efficacy and Safety of HLX10 (Recombinant Humanized Anti-PD-1 
Monoclonal Antibody Injection) in Combination with Chemotherapy 
(Carboplatin-Etoposide) in Previously Untreated Patients with Extensive 
Stage Small Cell Lung Cancer (ES-SCLC) 
Statistical Analysis Plan 
Version: 1.0_30Nov2021 
 
 

Shanghai Henlius Biotech, Inc.                                                                                             
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                                                                              CONFIDENTIAL                        Project Document Version No. 1.0 
                                                                                      
                             Page 2 of 63 
SPONSOR SIGNATURE PAGE 
 
Author: 
 
_________________________ 
 
_______________ 
            Dan Lu 
 
 
 
            Date 
 
Biostatistics Manager 
 
 
Shanghai Henlius Biotech, Inc. 
 
 
 
 
Approved by:  
_________________________ 
 
_______________ 
            Boyao Shan        
 
 
 
Date 
 
Biostatistics Senior Manager 
 
 
Shanghai Henlius Biotech, Inc. 
 
 
 
 
Approved by:  
_________________________ 
 
_______________ 
            Sherry Xu       
 
 
            Date 
 
Medical Associate Director 
 
 
Shanghai Henlius Biotech, Inc. 
 
 
 
 
Approved by:  
_________________________ 
 
_______________ 
            Xiaodong Dong   
 
 
            Date 
 
Clinical Pharmacologist Senior Manager 
 
 
Shanghai Henlius Biotech, Inc. 
 
 
 

Shanghai Henlius Biotech, Inc.                                                                                             
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                             Page 3 of 63 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................................ 3 
REVISION HISTORY ................................................................................................................................................ 5 
LIST OF ABBREVIATIONS ..................................................................................................................................... 6 
1 
INTRODUCTION .............................................................................................................................................. 8 
2 
STUDY OBJECTIVES ...................................................................................................................................... 9 
2.1 
PRIMARY OBJECTIVE ....................................................................................................................................... 9 
2.2 
SECONDARY OBJECTIVE(S) .............................................................................................................................. 9 
3 
INVESTIGATIONAL PLAN ............................................................................................................................ 9 
3.1 
OVERALL STUDY DESIGN AND PLAN ............................................................................................................... 9 
3.2 
ENDPOINTS..................................................................................................................................................... 14 
3.2.1 
Efficacy Endpoints ....................................................................................................................... 14 
3.2.2 
Safety Endpoints .......................................................................................................................... 16 
3.2.3 
Pharmacokinetics Endpoint .......................................................................................................... 17 
3.2.4 
Immunogenicity Endpoint ............................................................................................................ 17 
3.2.5 
Biomarker Endpoint ..................................................................................................................... 17 
3.2.6 
Quality of life (QoL) Endpoint .................................................................................................... 17 
4 
STATISTICAL METHODS ........................................................................................................................... 17 
4.1 
DATA QUALITY ASSURANCE .......................................................................................................................... 17 
4.2 
GENERAL PRESENTATION CONSIDERATIONS .................................................................................................. 18 
4.2.1 
Baseline ........................................................................................................................................ 18 
4.2.2 
Reference Start Date and Study Day ............................................................................................ 18 
4.2.3 
Dosing Window ........................................................................................................................... 18 
4.2.4 
End of Treatment/End of Study ................................................................................................... 18 
4.2.5 
Unscheduled Visits ...................................................................................................................... 19 
4.2.6 
Continuous Data ........................................................................................................................... 19 
4.2.7 
Categorical Data ........................................................................................................................... 19 
4.2.8 
Survival Analyses ........................................................................................................................ 19 
4.2.9 
P-values and 95% Confidence Intervals ....................................................................................... 19 
4.2.10 
Missing Data Handling ............................................................................................................ 20 
4.2.11 
Software ................................................................................................................................... 20 
4.3 
ANALYSIS SETS .............................................................................................................................................. 20 
4.3.1 
Enrolled Population ...................................................................................................................... 20 
4.3.2 
Intent-to-Treat Population (ITT) .................................................................................................. 20 
4.3.3 
Per Protocol Set (PPS) ................................................................................................................. 20 
4.3.4 
Safety Set (SS) ............................................................................................................................. 20 
4.3.5 
Pharmacokinetics Set (PKS) ........................................................................................................ 21 
4.4 
STUDY SUBJECTS ........................................................................................................................................... 21 
4.4.1 
Disposition of Subjects ................................................................................................................ 21 
4.4.2 
Protocol Deviations ...................................................................................................................... 21 
4.5 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ........................................................................................ 22 
4.6 
MEDICAL HISTORY ........................................................................................................................................ 22 
4.7 
PRIOR AND CONCOMITANT MEDICATION AND PROCEDURE ........................................................................... 22 
4.8 
ANTI-CANCER HISTORY ................................................................................................................................. 23 
4.9 
TUMOR ASSESSMENT ..................................................................................................................................... 24 
4.9.1 
Response Assessment (RECIST 1.1) ........................................................................................... 24 
4.9.2 
Response Assessment (iRECIST) ................................................................................................ 24 

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4.9.3 
Imaging Data Status ..................................................................................................................... 25 
4.9.4 
Target Lesion Assessment ............................................................................................................ 25 
4.9.5 
Non-Target Lesion Assessment ................................................................................................... 25 
4.9.6 
New Lesion Assessment .............................................................................................................. 25 
4.10 
TREATMENT EXPOSURE AND COMPLIANCE ............................................................................................... 25 
4.10.1 
Treatment Exposure ................................................................................................................. 25 
4.10.2 
Treatment Compliance ............................................................................................................ 26 
4.11 
EFFICACY EVALUATION ............................................................................................................................ 27 
4.11.1 
Analysis and Data Conventions ............................................................................................... 27 
4.11.2 
Primary Efficacy Variable ....................................................................................................... 29 
4.11.3 
Secondary Efficacy Variables ................................................................................................. 30 
4.12 
SAFETY EVALUATION ................................................................................................................................ 32 
4.12.1 
Adverse Events ........................................................................................................................ 32 
4.12.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events ................................ 33 
4.12.3 
Clinical Laboratory Evaluation ............................................................................................... 34 
4.12.4 
Vital Signs, Physical Findings and Other Observations Related to Safety .............................. 35 
4.13 
OTHER ANALYSES ..................................................................................................................................... 36 
4.13.1 
Pharmacokinetics ..................................................................................................................... 36 
4.13.2 
Immunogenicity ....................................................................................................................... 37 
4.13.3 
Biomarker Analysis ................................................................................................................. 37 
4.13.4 
Quality of Life Assessment ..................................................................................................... 38 
4.14 
SAFETY MONITORING (INDEPENDENT DATA MONITORING COMMITTEE [IDMC]) .................................... 40 
4.15 
DETERMINATION OF SAMPLE SIZE ............................................................................................................ 41 
4.16 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS ......................................................... 41 
4.17 
ANALYSES OF DATA FROM ASIAN AND NON-ASIAN ................................................................................. 41 
5 
INCONSISTENCY FROM PROTOCOL...................................................................................................... 41 
6 
REFERENCES ................................................................................................................................................. 42 
7 
APPEXDIX ....................................................................................................................................................... 43 
7.1 
APPENDIX 7. 1 SCHEDULE OF ACTIVITIES ...................................................................................................... 43 
7.2 
APPENDIX 7. 2 LIST OF LABORATORY TESTS ................................................................................................. 56 
7.3 
APPENDIX 7. 3 ECOG PERFORMANCE STATUS SCORE ................................................................................... 58 
7.4 
APPENDIX 7. 4 SCORING THE QLQ-C30 VERSION 3.0..................................................................................... 59 
7.5 
APPENDIX 7. 5 SCORING THE QLQ-LC13 ...................................................................................................... 62 
7.6 
APPENDIX 7. 6 TEAE PARTIAL DATE CONVENTIONS ..................................................................................... 63 
  

Shanghai Henlius Biotech, Inc.                                                                                             
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HLX10-005-SCLC301 
                                                                              CONFIDENTIAL                        Project Document Version No. 1.0 
 
                           Page 5 of 63 
REVISION HISTORY 
 
Version No. 
Effective Date 
Summary of Change(s) 
1.0 
30Nov2021 
Final version 
 
 
 

Shanghai Henlius Biotech, Inc.                                                                                             
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HLX10-005-SCLC301 
                                                                              CONFIDENTIAL                        Project Document Version No. 1.0 
 
                           Page 6 of 63 
LIST OF ABBREVIATIONS 
Abbreviation / 
Acronym 
Definition / Expansion 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
AUC 
Area under the curve 
CI 
Confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
CR 
Complete Response 
CRF 
Case Report Form 
CV 
Coefficient of variation 
DOR 
Duration of Response 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
EOCG 
Eastern Cooperative Oncology Group 
ES-SCLC 
Extensive stage small cell lung cancer 
EQ-5D-5L 
5-level EQ-5D version 
EORTC QLQ-C30 
 
European Organization for Research and Treatment of Cancer 
Quality of Life Scale 
EoS 
End of Study 
EoT 
End of Treatment 
ICF 
Informed Consent Form 
iCPD 
Immune Confirmed Progressive Disease 
iUPD 
Immune Unconfirmed Progressive Disease 
IP 
Investigational Product 
iRECIST 
Modified RECIST 1.1 for immune-based therapeutics 
IRRC 
Independent Radiology Review Committee 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSI 
Microsatellite instability 
NA 
Not available 
NE 
Not evaluable 
ORR 
Objective Response Rate 
OS 
Overall Survival 
QoL 
Quality of Life 
PD 
Progressive Disease 
PD-1 
Programmed Death-1 
PD-L1 
Programmed Death-Ligand 1 
PFS 
Progression-free Survival 
PR 
Partial Response 

Shanghai Henlius Biotech, Inc.                                                                                             
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HLX10-005-SCLC301 
                                                                              CONFIDENTIAL                        Project Document Version No. 1.0 
 
                           Page 7 of 63 
Abbreviation / 
Acronym 
Definition / Expansion 
PT 
Preferred Term 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumor guideline, version 1.1 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCLC 
Small Cell Lung Cancer 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TLF 
Tables, Listings and Figures 
 

Shanghai Henlius Biotech, Inc.                                                                                             
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HLX10-005-SCLC301 
                                                                              CONFIDENTIAL                        Project Document Version No. 1.0 
                                                                             
                           Page 8 of 63 
1 
INTRODUCTION 
Small cell lung cancer (SCLC) is derived from epithelial cells with neuroendocrine differentiation, 
accounting for 15%-20% of the total number of lung cancers. The SCLC is staged using the United 
States (US) Veterans Administration staging system and is divided into a limited stage and an 
extensive stage. Most patients present with tumor metastases as the first symptom, and only 30% 
to 40% of patients are in the limited stage at the time of initial diagnosis. Patients with extensive 
disease have shorter survival due to extensive tumor metastasis and poor physical status only with 
supportive care. The median survival time of untreated extensive small-cell lung cancer (ES-SCLC) 
is reported to be 2-4 months. With a combination of surgery, radiotherapy and chemotherapy, the 
median survival of ES-SCLC patients can reach 8 to 13 months, with a 2-year survival rate of 5%. 
Based on the considerable benefits of PD-1(Programmed cell death 1)/PD-L1(Programmed cell 
death-ligand 1) inhibitors in patients with tumors, Shanghai Henlius Biotech, Inc. has developed 
an innovative monoclonal antibody HLX10 targeting PD-1. Based on preclinical animal studies of 
HLX10, it has the potential to treat a variety of different tumor types, either as monotherapy or in 
combination with chemotherapy. The present study is planned in previously untreated patients 
with ES-SCLC worldwide to compare clinical efficacy and safety of HLX10 (recombinant anti-
PD-1 humanized monoclonal antibody injection) in combination with chemotherapy 
(Carboplatin-Etoposide). 
This Statistical Analysis Plan (SAP) describes the detailed statistical methodology to be used in 
analyzing study data and outlines the statistical programming specifications for Tables, Listings 
and Figures (TLF). It includes the variables and analysis dataset, and manipulations as well as 
other types of analyses that was not mentioned in the protocol.  
The analyses described in this SAP are based upon the following study documents: 
• 
Study Protocol, Version 4.0 (05Feb2021) 
• 
Case Report Form (CRF), Version 6.0 (27Jul2021) 
• 
Medical Dictionary for Regulatory Activities (MedDRA), Version 24.0 
• 
World Health Organization’s Drug Dictionary, WHODrug Global Mar2021 
 
 
 

Shanghai Henlius Biotech, Inc.                                                                                             
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                                                                              CONFIDENTIAL                        Project Document Version No. 1.0 
                                                                             
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• 
To compare the clinical efficacy of HLX10 in combination with chemotherapy versus 
placebo in combination with chemotherapy in previously untreated patients with ES-
SCLC. 
2.2 
Secondary Objective(s) 
• 
To compare the safety and tolerability of HLX10 in combination with chemotherapy 
versus placebo in combination with chemotherapy in previously untreated patients with 
ES-SCLC. 
• 
To measure the exposure following HLX10 administration. 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, multicenter, clinical phase III study to 
compare the clinical efficacy, safety and tolerability of recombinant humanized anti-PD-1 
monoclonal antibody injection (HLX10) or placebo in combination with chemotherapy in patients 
with previously untreated ES-SCLC, to collect PK parameters and to investigate the biomarker 
related to efficacy. See Figure 1, Figure 2 for study schema and Appendix 7. 1 for Schedule of 
Activities. 
Approximately 567 (378 for HLX10 and 189 for placebo) subjects will be randomized to arm A 
or B at 2:1 ratio in this study as follows: 
• 
Arm A (HLX10): HLX10 + Chemotherapy (Carboplatin-Etoposide) 
• 
Arm B (Control): Placebo + Chemotherapy (Carboplatin-Etoposide) 
Subjects will be randomized and stratified by:  
• 
PD-L1 expression level (negative: tumor proportion scores [TPS] <1%, positive: TPS ≥
1%, or not evaluable/not available ) 
• 
Brain metastasis (yes vs. no) 
• 
Age (≥ 65 years vs. < 65 years) 
After screening, subjects meeting the inclusion criteria and not meeting the exclusion criteria will 
be enrolled. Included subjects will be treated with HLX10 or placebo in combination with 
chemotherapy once every 3 weeks, until disease progression, death, intolerable toxicity, 
withdrawal of informed consent, or occurrence of other reasons specified in the protocol 
(whichever occurs first). 
Initial treatment should be discontinued when they have evidence of disease progression as 
assessed per RECIST 1.1. However, considering the limited availability and efficacy or greater 
toxicity of treatment options after withdrawal, and for better adaptation to standard clinical practice, 

Shanghai Henlius Biotech, Inc.                                                                                             
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the subjects who meet the following conditions may continue the treatment after appropriate 
discussion with the subject and obtaining the supplementary informed consent. 
1. Subjects who had received HLX10 or placebo in combination with chemotherapy, and who 
may benefit from continuing HLX10/placebo treatment despite progression, will be able 
to receive HLX10 or placebo therapy in the post-PD treatment. 
2. Subjects eligible for continued treatment in the post-PD treatment period, as judged by the 
investigator. 
3. The subject should sign the supplementary informed consent form to receive 
investigational product with 2nd line chemotherapy. 
4. The subject is clinically stable, defined as: 
a) With no clinical signs and/or symptoms (including worsening of laboratory findings) 
that might indicate disease progression. 
b) A stable Eastern Cooperative Oncology Group (ECOG) performance status score. 
c) No rapid disease progression or tumor progression requiring urgent alternative medical 
intervention at critical anatomical sites (e.g., spinal cord compression). 
Treatment Groups and Duration: 
This study is divided into three periods:  
• 
Screening period: maximum 28 days.  
• 
Treatment period: initial treatment and post-PD treatment [Optional], until disease 
progression, death, intolerable toxicity, withdrawal of informed consent, or occurrence of 
other reasons specified in the protocol, whichever occurs first. After finishing the initial 
treatment period, patients in both arms who had 1st disease progression per RECIST 1.1 
and might benefit from their assigned treatment in addition to 2nd line chemotherapy may 
be eligible to continue to receive their assigned treatment in the post-PD treatment period 
(Optional) until the 2nd disease progression, intolerable toxicity, death, withdrawal of 
consent, or lost to follow-up. 
• 
Follow-up period (including safety follow-up and survival follow-up): Safety visit is 
required at the site 30 days (±7 days) after the last study drug administration, and telephone 
follow-up is required 90 days (±7 days) after the last study drug administration. Survival 
follow-up period is every 12 weeks ± 7 days. 
The study drugs including HLX10/placebo and chemotherapy drugs are administered every 3-
week (21-day) cycle as follows: 
Investigational Product: HLX10 or placebo 
• 
HLX10: Intravenous (IV) infusion, 4.5 mg/kg, administered on Day 1 of each 3-week (21 
day) cycle. 

Shanghai Henlius Biotech, Inc.                                                                                             
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• 
Placebo: Injection is not externally recognizable and contains no HLX10 active ingredient, 
IV infusion, administered on Day 1 of each cycle, once every 3 weeks (21 days). 
The infusion of investigational product is completed between 30 mins and 90 mins if there is not 
any infusion reaction. 
Other Study Drugs: Combined Chemotherapy 
The following regimen will be given every 21-day (3-week) cycle for a maximum of 4 cycles. 
• 
Etoposide: 100 mg/m2, IV infusion, on Days 1, 2, and 3 of each cycle. 
• 
Carboplatin: Area under the concentration-time curve (AUC) = 5, IV infusion, on Day 1 
of each cycle up to a dose of 750 mg.  
Refer to Figure 1 "Schematic of study treatment" for the regimen of each treatment arm. On Day 1 
of dosing in each treatment cycle, subjects will be given HLX10 or placebo intravenously first, 
followed by intravenous Carboplatin + Etoposide. Vital signs will be closely monitored during the 
administration. HLX10 or placebo is administered via a blinded infusion, Carboplatin + Etoposide 
(up to 4 cycles) via an open-label infusion, and subjects will continue receiving Etoposide on Days 
2 and 3. Treatment with study drug will continue until disease progression, intolerable toxicity, 
discontinuation decided by subject or investigator, death, withdrawal of informed consent, 
pregnancy, noncompliance with protocol or procedure requirements, administrative reasons, or 
other reasons specified in the protocol, whichever occurs first.  
If chemotherapy is not used due to toxicity or other reasons in a certain cycle, it is not counted as 
the number of chemotherapy cycles. After completing 4 cycles of chemotherapy, even if the 
subject does not meet the above criteria, the chemotherapy will not be continued. 

Shanghai Henlius Biotech, Inc.                                                                                             
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Figure 1. Schematic of Study Treatment 
 

Shanghai Henlius Biotech, Inc.                                                                                             
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Figure 2. Overall Study Design 
  

Shanghai Henlius Biotech, Inc.                                                                                             
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3.2 
Endpoints 
3.2.1 Efficacy Endpoints 
Primary Efficacy Endpoint 
• 
Overall survival (OS)  
Secondary Efficacy Endpoints 
• 
Progression-free survival (PFS) (assessed by the independent radiology review 
committee [IRRC] based on Response Evaluation Criteria in Solid Tumors [RECIST] 
1.1) 
• 
PFS (assessed by the investigator based on RECIST 1.1 and iRECIST) 
• 
PFS2 (assessed by the investigator based on RECIST 1.1) 
• 
Objective response rate (ORR) (assessed by the IRRC and investigator based on 
RECIST 1.1) 
• 
Duration of response (DOR) (assessed by the IRRC and the investigator based on 
RECIST 1.1) 
3.2.1.1 Efficacy Variables 
Efficacy assessment variables include overall survival (OS), progression-free survival (PFS), 
progression-free survival 2 (PFS2), objective response rate (ORR) and duration of response (DOR). 
PFS will be evaluated based on tumor response assessed by IRRC using RECIST 1.1 and by the 
investigator using RECIST 1.1 and iRECIST; PFS2 will be evaluated based on tumor response 
assessed by the investigator using RECIST 1.1; ORR and DOR will be assessed by RECIST 1.1 
only. The final results of tumor assessment will be determined by IRRC, and the results of the 
investigator’s assessment shall be used as a reference. RECIST1.1 and iRECIST are summarized 
below: 
 RECIST 1.1 
RECIST 1.1 will be used to define the overall tumor response based on the response statuses in 
target lesion, non-target lesion and new lesion for each assessment time point. The overall tumor 
response can be classified as complete response (CR), partial response (PR), stable disease (SD), 
progressive disease (PD), and not evaluable (NE).  
 iRECIST 
iRECIST was developed by the RECIST working group for the use of modified RECIST 1.1 in 
cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing 
collection of trial data, and ultimate validation of the guideline. iRECIST is based on RECIST 1.1. 
Responses assigned using iRECIST have a prefix of “i” (i.e., immune), e.g., “immune” complete 
response (iCR) or partial response (iPR), and unconfirmed progressive disease (iUPD) or 
confirmed progressive disease (iCPD) to differentiate them from responses assigned using 
RECIST 1.1. Similar nomenclature is used for stable disease (iSD). New lesions are assessed and 

Shanghai Henlius Biotech, Inc.                                                                                             
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subcategorized into those that qualify as target lesions (new lesion, target) or non-target lesions 
(new lesion, non-target). 
 Overall Survival (OS)  
OS is defined as a period from randomization through death regardless of causality. Data of 
patients without a death record will be censored on the last known survival date.  
The between-group comparison of OS is performed by a stratified log-rank test with the following 
stratification factors: PD-L1 expression level (negative: TPS <1%, positive: TPS ≥1%, or not 
evaluable/not available), brain metastasis (yes versus no), and age (≥ 65 years versus < 65 years); 
a stratified COX proportional risk model will be used to estimate HR and its 95% CI; the Kaplan-
Meier method will be used to estimate the median, and the Kaplan–Meier curve will be plotted. 
 Progression Free Survival (PFS) 
PFS is defined as a period from randomization initiation to the first documentation of PD or death 
regardless of causality (whichever occurs first). Data of subjects with neither PD nor death will be 
censored on the day of the final valid tumor evaluation. Data of surviving subjects not undergoing 
any tumor assessment during the study will be censored on the day of randomization. Data of 
subjects who have no PD reported and initiate any antitumor therapy not specified in the protocol 
will be censored on the day of the last evaluable tumor assessment prior to the initiation of 
subsequent antitumor treatment. The PFS will be analyzed using the same method as that for 
primary endpoints. 
PFS assessed by the IRRC and investigator based on RECIST 1.1 
According to RECIST 1.1, the PFS is defined as the time from randomization to the time of the 
first recorded PD or death due to any cause (whichever occurs first). IRRC will be a third-party 
company designated by the Sponsor for central imaging assessment. The investigator’s assessment 
will be recorded in CRF. 
PFS assessed by the investigator based on iRECIST 
According to iRECIST, the PFS is defined as the time from randomization to the time of the first 
recorded iUPD (Immune unconfirmed progressive disease) that is subsequently confirmed (at 4-8 
weeks) or death due to any cause (whichever occurs first). If iUPD occurs, but is disregarded 
because of later iSD, iPR or iCR, that iUPD date should not be used as the progression event date. 
 Progression-Free Survival 2 (PFS2) 
Progression-free survival 2 (assessed by the investigator based on RECIST 1.1).  
PFS2 is defined as the time from randomization to objective tumor progression on next-line 
treatment or death from any cause. It will be analyzed using the same method as that for PFS. 
 Objective Response Rate (ORR) 
ORR assessed by the IRRC and investigator based on RECIST 1.1 

Shanghai Henlius Biotech, Inc.                                                                                             
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The ORR is defined as the proportion of subjects with a best overall response of CR or PR, 
according to RECIST 1.1. The best overall response will be defined as the best response across all 
time points in the order of CR, PR, SD, PD, and not NE. 
 Duration of response (DOR) 
DOR assessed by the IRRC and investigator based on RECIST 1.1 
DOR is defined as a period from the first documentation of response (CR or PR) through the first 
documentation of PD or death (whichever occurs first). The DOR will be analyzed only for patients 
whose best overall responses are evaluated as CR or PR. Data of patients not experiencing PD or 
death after achieving response will be censored on the day of the final tumor assessment; if no 
tumor assessment is performed after response achievement, then data of such patients will be 
censored on the day of tumor assessment when response is achieved. The Kaplan-Meier method 
is used to estimate the median and plot the Kaplan-Meier curve. 
3.2.2 Safety Endpoints 
Adverse events (AEs) (including serious adverse events [SAEs]), laboratory tests (routine blood 
test, blood chemistry, coagulation function, urinalysis, myocardial function and thyroid function), 
12-lead electrocardiogram (12 lead ECG), vital signs, and physical examination, etc. 
3.2.2.1 Safety Variables 
Safety assessments variables include AEs (including SAEs), laboratory tests (routine blood test, 
blood chemistry test, coagulation test, routine urine test, myocardial function and thyroid function 
test), 12 lead ECG, vital signs, and physical examination. The timing of all such assessments could 
be referred to Appendix 7. 1. 
 Adverse Event 
AE is defined as an untoward medical event that occurs after a subject receives a drug, regardless 
of whether or not it is related to the study drug. AE will be described by MedDRA terms and 
graded in accordance with CTCAE v5.0. Serious adverse event (SAE), immune-related adverse 
event (irAE) and death will be collected in the adverse event CRF page. The progression of the 
underlying disease, that is, the underlying tumor, is not reported as AE, but the occurrence of new 
tumors should be considered as an SAE.  
A treatment-emergent adverse event (TEAE) is defined as an AE that begins or increases in 
severity or frequency at or after the first study drug administration through end of study (EOS). 
Adverse event of special interest (AESI) is defined as an AE of scientific and medical concern 
related to the use of the study drug that may need to be closely monitored and communicated to 
sponsors by investigators. In this study, AESIs include infusion reactions (infusion-related adverse 
reactions, IRRs) and immune-related adverse events (irAEs). 
 Laboratory Tests 
Laboratory test variables will be collected through routine blood test, serum biochemistry, 
coagulation, myocardial function, urinalysis, thyroid function, virology, tuberculosis screening (as 
requested by the Bulgarian Drug Agency for Bulgarian subjects) and pregnancy test. The details 
can be referred to Appendix 7. 2.  

Shanghai Henlius Biotech, Inc.                                                                                             
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 Vital Signs 
Vital sign variables will include height, weight, systolic and diastolic blood pressure, pulse, body 
temperature and respiratory rate. 
 Physical Examinations 
Physical examination variables will include the results of following examination: head and neck 
(including thyroid), chest (including heart and lungs), abdomen (including liver, gallbladder, 
spleen and kidney), limbs, skin, lymph nodes, neurological system and general appearance. 
 12-Lead Electrocardiograms 
12-Lead ECG variables will include heart rate, RR interval, PR interval, QRS interval, QT interval, 
QTc interval with Fridericia’s formula and overall assessment. 
 Eastern Cooperative Oncology Group (ECOG) 
ECOG performance status is a grading scale ranging from 0 to 5. Each grade of ECOG 
performance status can be referred to Appendix 7. 3. 
3.2.3 Pharmacokinetics Endpoint 
The pharmacokinetics (PK) samples of HLX10 will be collected from all subjects and 
descriptive statistics will be presented for PK concentrations  
3.2.4 Immunogenicity Endpoint 
Anti-drug antibody (ADA) samples of HLX10 will be collected and the positive rate will be 
summarized.  
3.2.5 Biomarker Endpoint 
Relationship between PD-L1 expression, microsatellite instability (MSI), tumor mutation burden 
(TMB) in tumor tissue and efficacy will be presented in biomarker analysis. 
3.2.6 Quality of life (QoL) Endpoint 
The health status and self-perceived health of each patient will be documented in the form of EQ-
5D-5L scale, EORTC QLQ-C30 scale, and EORTC QLQ-LC13 scale. 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
The Sponsor or Sponsor’s designee will conduct a site visit to verify the qualifications of each 
Investigator, inspect the site facilities, and inform the Investigator of responsibilities and the 
procedures for ensuring adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the study for each study participant. All 
information recorded on eCRF for this study must be consistent with the patients’ source 
documentation (i.e., medical records).  

Shanghai Henlius Biotech, Inc.                                                                                             
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All tables, figures and data listings to be included in the report will be independently checked for 
consistency and integrity. 
4.2 
General Presentation Considerations 
4.2.1 Baseline 
The last non-missing measurement prior to the first investigational product (IP) administration will 
be used as the baseline measurement for all safety and efficacy analysis.  
4.2.2 Reference Start Date and Study Day 
Reference start date is defined as the day of the first administration of IP in Treatment Period, (Day 
1 is the day of the first dose of study treatment in Treatment Period), and study day relative to the 
reference start date will appear in every listing where an assessment date or event date appears.  
Study day will be calculated from the reference start date and will be used to show start/stop day 
of the assessments and events relative to the first administration of study treatment.  
• 
If the date of the event is on or after the reference date, then:  
Study day = (date of event – reference start date) + 1. 
• 
If the date of the event is prior to the reference date, then:  
Study day = (date of event – reference start date). 
For AE where the event date is partial or missing, AEs will be assumed to be treatment-emergent, 
unless there is clear evidence (through comparison of partial dates) to suggest that the adverse 
event started prior to the first dose of study treatment.   
4.2.3 Dosing Window  
Dosing window is defined as the scheduled dosing date (calculated based on the first dosing date) 
± 3 days. If the dosing window is exceeded, it should be deemed as ‘dose delay’, and subsequent 
doses shall be administered according to the actual date of last administration.  
If a delay of more than 2 weeks is expected due to the toxicity of chemotherapy, only HLX10 or 
placebo will be administered until the toxicity returns to the standard of chemotherapy 
administration. Chemotherapy may be continuously suspended for a maximum of 6 weeks, 
otherwise the chemotherapy should be discontinued. 
If a delay of more than 2 weeks is expected due to the toxicity of HLX10 or placebo, only 
chemotherapy will be administered until the toxicity recovers to the HLX10 or placebo dosing 
criteria. HLX10 or placebo therapy may be continuously suspended for a maximum of 12 weeks, 
otherwise the HLX10 or placebo will be discontinued. In case of a delay due to toxicity with 
equivocal association, all the study drugs shall be synchronously delayed if the event is expected 
to return to re-dosing standards within 2 weeks. 
4.2.4 End of Treatment/End of Study 
• 
End of Treatment (EoT): For any subject withdrawing from the treatment or terminating 
the treatment regardless of causality, an EOT visit should be performed in 7 days after the 
end of treatment is learned of or confirmed.  

Shanghai Henlius Biotech, Inc.                                                                                             
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• 
End of Study (EoS): The end of the study, defined as the final analysis of OS, will be 
performed when a target number of OS events (approximately 342) are observed, and for 
final analysis the α is 0.046 (two-sided) based on the O'Brien-Fleming alpha spending 
function. Or the end of the study is defined as the date when all subjects enrolled completed 
the safety follow-up 90 days after the end of treatment visit. Whichever occurs first. 
Additionally, the sponsor may decide to terminate the study at any time. 
4.2.5 Unscheduled Visits 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. 
Unscheduled measurements will not be included in by-visit summaries but will contribute to 
best/worst case value where required (e.g., shift table). 
In the case of a re-test (visit-specific unscheduled visit number assigned), the re-test data will be 
used for by-visit summaries.  
Listings will include the scheduled, unscheduled, re-test, and early discontinuation data.  
4.2.6 Continuous Data 
Continuous data will be summarized in terms of the mean, standard deviation, median, minimum, 
maximum and number of observations, unless otherwise stated.  
Continuous data that are expected to be skewed will be presented in terms of the maximum, 3rd 
quartile, median, 1st quartile, minimum and number of observations. The minimum and maximum 
will be reported to the same number of decimal places as the raw data recorded in the database.  
The mean, median, 1st quartile and 3rd quartile will be reported to one more decimal place than the 
raw data recorded in the database. The standard deviation will be reported to two more decimal 
places than the raw data recorded in the database.  In general, the maximum number of decimal 
places reported shall be four for any summary statistic. 
4.2.7 Categorical Data  
Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point, frequency counts and percentages. Any planned collapsing of categories will 
be detailed in the SAP text and the data displays.  
Percentages will be presented to one decimal place. Percentages will not be presented for zero 
counts.  Percentages will be calculated using N as the denominator. If sample sizes are small, the 
data displays will show the percentages, but any textual report will describe frequencies only.  
Changes from baseline in categorical data will be summarized using shift tables where appropriate. 
4.2.8 Survival Analyses 
In survival analyses (including PFS, OS and DOR analyses), time-to-event in days will be 
calculated as (Event Date – Start Date + 1). The duration in days may be converted to months as 
(12 * Number of Days / 365.25)) or weeks as (Number of Days / 7). 
4.2.9 P-values and 95% Confidence Intervals 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  P-
values less than 0.001 will be presented as “<0.001”. 

Shanghai Henlius Biotech, Inc.                                                                                             
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Confidence intervals will be presented to one more decimal place than the raw data. 
4.2.10 Missing Data Handling  
For other unspecified analyses, missing data will not be imputed. In the situation where the event 
date is partial or missing, the date will appear partial or missing in the listings. 
Any AE corresponding durations will be presented based on the imputations specified in 
Appendix 7. 6 TEAE Partial Date Conventions 
4.2.11 Software 
All report outputs will be produced using SAS® version 9.3 or a later version in a secure and 
validated environment and provided in Microsoft Word 2016 or a later version document, RTF or 
PDF format. 
4.3 
Analysis Sets 
The analysis sets of this study are defined as follows. 
4.3.1 Enrolled Population 
Enrolled Population is defined as all participants who signed the informed consent form (ICF) 
(including screening failures). 
4.3.2 Intent-to-Treat Population (ITT) 
The ITT Population comprises all participants to whom study intervention has been randomized. 
Statistical analyses will be based on study intervention groups as per randomization, irrespective 
of the study intervention actually received. The ITT Population will serve as the primary 
population of efficacy assessment in this study. ITT Population will be analyzed based on planned 
treatment arms. 
4.3.3 Per Protocol Set (PPS) 
The PPS comprises a subset of the ITT. The PPS consists of all randomized subjects without any 
major protocol deviation that impacts the primary efficacy significantly. The PPS will be used to 
demonstrate robustness of results for the primary efficacy endpoint.  
The protocol deviations that significantly affect evaluation for the primary efficacy will be 
determined based on a blinded data review prior to interim/final database lock. Analyses for the 
PPS will be based on actual treatment received. PPS analysis will supplement the ITT analysis as 
supporting analysis to demonstrate robustness of results for the efficacy endpoint. 
4.3.4 Safety Set (SS) 
Safety Set (SS) is defined as all subjects who received at least one dose of study intervention. 
Participants will be analyzed according to the study intervention they actually received. The safety 
set is the primary population for safety endpoint analysis.  

Shanghai Henlius Biotech, Inc.                                                                                             
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4.3.5 Pharmacokinetics Set (PKS) 
The Pharmacokinetics Set (PKS) consists of all participants who received at least one dose of 
HLX10 with at least one measurable post-dose concentration at scheduled PK time points without 
any major protocol violation that may impact the PK assessment significantly. The PK analysis set 
will be used for PK analysis 
4.4 
Study Subjects 
4.4.1 Disposition of Subjects 
A clear accounting of the disposition of all subjects who enter the study will be provided, from 
screening to study completion. The following summaries of subject disposition will be provided: 
• 
A summary of the numbers and percentages of subjects screened, who are screen failures, 
who are randomized, who discontinue study treatment, whose primary reason for treatment 
discontinuation, who sign the ICF for continuous treatment, who ever received treatment 
after progressive disease, who completed the study and whose primary reason for study 
discontinuation by study treatment and overall. (Analysis set: Enrolled Population). 
• 
A cross-table will be presented to show the planned and actual treatment for ITT Population. 
• 
A by-subject listing of disposition will be provided, including subject identifier details, 
informed consent details (including informed consent for continuous treatment), 
randomization details, the first/last dosing date, details of end of treatment and end of study 
(including reason for treatment/study discontinuation) (Analysis set: Enrolled Population).  
The following summary will be provided: 
• 
A summary of the number and percentage of subjects entering each analysis set by study 
treatment and overall (Enrolled Population). 
• 
A summary of the number and percentage of subjects randomized by study treatment, 
country and site (Analysis set: Intent-to-treat Set). 
• 
A by-subject listing of analysis set details will be provided (Analysis set: Intent-to-treat 
Set).  
The listing will be presented by planned arm and include: actual arm, country, site, subject 
identifier, inclusion/exclusion flag for each analysis set and reason for exclusion from each 
analysis set (Analysis set: Intent-to-treat Set). 
4.4.2 Protocol Deviations 
Protocol deviations including those deviations from the protocol that will be assessed as “Major”, 
“Major COVID-19”, “Minor” or “Minor COVID-19” in collaboration with Sponsor.  
Significant major deviations, which are defined as those major protocol deviations leading to 
exclusion from analysis sets, will be defined in a Data Review Meeting (DRM) shortly prior to the 
interim/final database lock. Results and population assignments will be summarized in a DRM 
report signed off by all relevant team leaders. 
The following summary will be provided: 

Shanghai Henlius Biotech, Inc.                                                                                             
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• 
A summary of the number and percentage of subjects with a major protocol deviation by 
type of deviation and study treatment (Analysis set: Intent-to-treat Set) 
• 
A by-subject listing of major/ major COVID-19/ minor/ minor COVID-19 protocol 
deviations will be provided (Listing analysis set: Intent-to-treat Set). 
4.5 
Demographic and Baseline Characteristics  
Subject demographic, baseline characteristics, and randomization stratification factors will be 
summarized descriptively by study treatment in ITT Set. The following demographics and baseline 
characteristics and stratification factors will be summarized: 
• 
Demographic variables: Age, Sex, Childbearing potential for female, Race, Ethnicity, 
Height, Weight, and Body mass index. 
Age (years): (date of given informed consent – date of birth + 1) / 365.25. The integer part 
of the calculated age will be used for reporting purpose. 
• 
Baseline characteristic variables: ECOG, biomarker assessment (MSI, TMB), anti-HIV 
assessment, anti-HCV assessment, History of smoking, Alcohol consumption, Drug 
dependence (yes/no) and Allergies (yes/no).  
• 
Stratification factors: PD-L1 expression level (negative, positive, not available), Brain 
metastasis (yes vs. no), and Age (≥ 65 vs. < 65 years). 
• 
Baseline SCLC characteristics: Time since initial diagnosis (years), VALG stage at initial 
diagnosis, Overall stage at study entry, VALG stage at study entry, Overall stage at study 
entry, Metastasis status and Sites of Metastasis. 
• 
Baseline Echocardiogram: LVEF (%), Assessment (Normal, Abnormal - Not Clinically 
Significant, Abnormal - Clinically Significant). 
By-subject listings of demographics as well as baseline characteristics and stratification factors 
and baseline SCLC characteristic will be provided (Listing analysis set: Intent-to-treat Set). 
4.6 
Medical History 
Patient’s medical history including previous and existing clinically significant abnormality, 
medical conditions, diagnostic results, (drug) sensitivities/allergies, major surgeries and relevant 
physical examination findings will be recorded in eCRF “Medical History” with CTCAE grade 
(grade 1 - grade 5).  
Medical history are conditions (other than the indication being studied) which started prior to ICF 
is signed or on the date of screening. Medical history still ongoing at enrolment or ended prior to 
enrolment will be listed together for the ITT Population. Number and percentage of subjects with 
any medical history will be summarized by System Organ Class (SOC) and Preferred Term (PT) 
of MedDRA coding system (version 24.0) in the order of frequency for the ITT Population with a 
corresponding listing (Listing analysis set: Intent-to-treat Set). 
4.7 
Prior and Concomitant Medication and Procedure 
Concomitant medication is any medication other than the IP that is taken from the time of first 
dose to the end of study. Upon entering the study, each subject will be instructed to report the use 

Shanghai Henlius Biotech, Inc.                                                                                             
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of any medication to the investigator. Prior medication will be recorded up to 30 days before 
signing the ICF on the eCRF (Form: Prior and Concomitant Medication). All prior and 
concomitant medications will be listed individually. The prior and concomitant medications will 
be summarized with the number and percentage of subjects by anatomical main group and 
pharmacological subgroup using WHODrug Global Mar2021 or higher in the order of frequency 
for the ITT Population with a corresponding listing.  
If medication start and/or stop dates are missing or partial, the dates will be compared as far as 
possible with the date of first dose of study medication.  Medications will be assumed to be 
Concomitant only, unless there is clear evidence (through comparison of partial dates) to suggest 
that the medication started prior to the first dose of study medication.  If there is clear evidence to 
suggest that the medication started prior to the first dose of study medication, the medication will 
be assumed to be both Prior and Concomitant, unless there is clear evidence to suggest that the 
medication stopped prior to the first dose of study medication.  If there is clear evidence to suggest 
that the medication stopped prior to the first dose of study medication, the medication will be 
assumed to be Prior only. 
• Medications collected in the CRF “Prior and Concomitant Medication” will be classified 
as Prior only if they start and stop prior to the date of first dose of study drug.   
• If medication start before the date of first dose of study drug and stop on or after the date 
of first dose of study drug, then they will be classified as both Prior and Concomitant.   
• Medications will be classified as Concomitant only if they have a start date on or after the 
date of first dose of study drug.  
• Medications starting after the EOT date will be listed but will not be classified or 
summarized. 
Based on the same classified rule of medication, the procedures collected in the eCRF (Prior and 
Concomitant Procedures) will also classified as “Prior only”, “both Prior and Concomitant” and 
“Concomitant only”. 
The following summary will be provided: 
• Summary of the classification of medications (Prior only, both Prior and Concomitant, and 
Concomitant only) by anatomical therapeutic chemical (ATC) and preferred term by Prior 
only, both Prior and Concomitant, and Concomitant only (Analysis set: Intent-to-treat Set) 
• Summary of the classifications of procedure (Prior only, both Prior and Concomitant, and 
Concomitant only) by SOC and preferred term (Analysis set: Intent-to-treat Set) 
• By-subject listings of medication and procedure will be provided respectively (Listing 
analysis set: Intent-to-treat Set). 
4.8 
Anti-Cancer History 
Anti-cancer procedures, therapy and radiotherapy will be collected for following information 
(eCRF: Prior Anti-Cancer Surgery or Procedures; Anti-Cancer Surgery or Procedures After Study 
Drug; Prior Systemic Anti-Cancer Therapy; Anti-Cancer Therapy After Study Drug; Prior 
Radiotherapy; Concomitant or Post-Treatment Radiotherapy; Anti-Cancer Treatment after First 
Disease Progression).  

Shanghai Henlius Biotech, Inc.                                                                                             
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• 
Prior Anti-Cancer Surgery or Procedures: Surgery or Procedure Description; Start Date; 
Stop Date; Category (Major vs. Minor). 
• 
Prior Systemic Anti-Cancer Therapy: Regimen number; Type; Line of therapy; Best 
response; Medication; Start date; End date; Dose; Unit; Frequency; Route. 
• 
Prior Radiotherapy: Type of radiotherapy; Anatomical location; Start date; End date; 
Indication; Total cumulative dose; Progression status of the lesion(s) since the last 
radiotherapy. 
• 
Concomitant or Post-Treatment Radiotherapy: Type of radiotherapy; Anatomical 
location; Start date; End date; Indication; Total cumulative dose. 
• 
Anti-Cancer Therapy After Study Drug: Regimen number; Type; Line of therapy; 
Medication; Start Date; End Date; Dose; Unit; Frequency; Route. 
• 
Anti-Cancer Surgery or Procedures After Study Drug: Surgery or procedure 
description; Reason for Surgery or Procedure; Date of surgery or procedure; Biopsy 
location; Biopsy result. 
• 
Anti-Cancer Treatment after First Disease Progression: Regimen number; Type; Line 
of therapy; Medication; Start Date; End Date; Dose; Unit; Frequency; Route. 
Overall summary tables will be summarized by SOC and PT separately for the above 7 anti-cancer 
histories in ITT Population with corresponding listings (Listing analysis set: Intent-to-treat Set).  
4.9 
Tumor Assessment  
4.9.1 Response Assessment (RECIST 1.1) 
Response assessment (RECIST 1.1) will be collected for following information (eCRF: Response 
Assessment (RECIST 1.1)): Date of Assessment; Response of target lesions (CR, PR, PD, SD, NA, 
NE); Response of non-target lesions (CR, Non-CR/Non-PD, PD, NA, NE); Any new lesion; 
Overall assessment (CR, PR, SD, PD, NE).  
4.9.2 Response Assessment (iRECIST) 
Response assessment (iRECIST) will be collected for following information (eCRF: Response 
Assessment (iRECIST)): Date of Assessment; Response of target lesions (iCR, iPR, iUPD, Non-
iUPD/PD, iCPD, iSD, NA, NE); Response of non-target lesions (iCR, Non-iCR/Non-iUPD, iUPD, 
iCPD, NA, NE); Overall status of new non-target lesions (Present, Improved, Absent/Normal, 
Unequivocal progression, Not evaluable); Overall assessment (iCR, iPR, iSD, iUPD, iCPD, NE, 
ND). 

Shanghai Henlius Biotech, Inc.                                                                                             
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4.9.3 Imaging Data Status 
Imaging data status will be collected for following information (eCRF: Imaging Data Status): Scan 
Date; Scan Method (Plain CT, Enhanced CT, MRI, Enhanced MRI, Chest X-ray, Bone Scan, 
Other); confirmation of scan used for lesion assessment. 
4.9.4 Target Lesion Assessment 
Target lesion assessments will be collected for following information (eCRF: Target Lesion 
Assessment): Sum of Diameters (mm) (For Lesions detected at Baseline); Sum of Diameters (mm)  
(For Lesions detected at Rebaseline); Lesion number; Location; Imaging performed date; and 
Imaging performed methods; Longest diameter (mm); Short axis (mm). 
4.9.5 Non-Target Lesion Assessment 
Non-target lesion assessments will be collected for following information (eCRF: Non-Target 
Lesion Assessment): Lesion number; Location; Imaging performed date; and Imaging performed 
methods; Status of lesion. 
4.9.6 New Lesion Assessment 
New lesion assessments will be collected for following information (eCRF: New Lesion 
Assessment): Lesion number; Location; Imaging performed date; and Imaging performed 
methods; Measure status of lesion; Target status of lesion; New lesion target longest diameter 
(mm); New lesion target short axis (mm); Status of new lesion non-target; Sum of diameters (mm); 
Overall status of new lesion non-target. 
The overall summary tables will be summarized between Arm A and Arm B separately for Target 
lesion, non-target lesion and new lesion assessments in ITT Population with corresponding listings.  
4.10 Treatment Exposure and Compliance 
4.10.1 Treatment Exposure  
Summary statistics will be provided for the actual duration of exposure, actual cumulative total 
dose received, dose intensity and relative dose intensity by visit and study drugs (HLX10/placebo, 
Carboplatin and Etoposide) in Safety Set. The exposure indices are defined as follows: 
• 
The planned duration of exposure is defined as the planned number of treatment and it can 
be calculated as 
(the last planned dosing date −the first dosing date + 1) 7
⁄  
• 
The actual duration of exposure is defined as the duration from the first dosing date to the 
last dosing date. Actual duration of exposure (in weeks) will be calculated as 
(the last dosing date −the first dosing date + 1) 7
⁄  
• 
The actual cumulative total dose received (mg) is defined as the summation of all actual 
dose administrated from the first dosing date to the last doing date.  
• 
The planned cumulative total dose received (mg) is defined as the summation of all planned 
dose administrated from the first dosing date to the last planned doing date.  
• 
Planned dose intensity (PDI) and Average dose intensity (ADI) will be calculated as 

Shanghai Henlius Biotech, Inc.                                                                                             
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PDI = Planned cumulative total dose received
Planned duration of exposure
 
ADI = Actual cumulative total dose received
Actual duration of exposure
 
• 
Relative dose intensity (RDI) will be defined as 
RDI = ADI
PDI × 100% 
• 
Planned dose 
The planned dose of HLX10 is 4.5 mg/kg, on Day 1 of each cycle, once every 3 weeks.  
The planned dose of Etoposide is 100 mg/m2, on Days 1, 2, and 3 of each cycle.  
Etoposide planned dose = 100 mg/m2*BSA(m2). 
The planned dose of Carboplatin is AUC = 5, up to a dose of 750 mg, on Day 1 of each 
cycle, calculated using the following Calvert formula: 
➢ 
Dose of Carboplatin (mg) = target AUC x [(CrCl (mL/min) + 25)] 
where AUC is the target area under the Carboplatin plasma concentration versus 
time curve and AUC = 5, and CrCl is the estimated creatinine clearance and its 
calculation is based on the following Cockcroft-Gault formula: 
Male: [(140 −age in years) ×  body weight (kg)] / [Serum creatinine × 𝑘]  
Female:[(140 −age in years) ×  body weight (kg)] / [Serum creatinine × 𝑘] ×  0.85  
where k = 72 if the unit of serum creatinine is mg/dL; k = 1/1.23 if the unit of serum 
creatinine is mol/L. Maximum dose of Carboplatin ≤ 750 mg if AUC = 5. 
If the change in the subject’s body weight from baseline during the study is less than or 
equal to 10%, dose adjustment of investigational product will not be required; if the weight 
change is greater than 10%, the dose of investigational product must be recalculated and 
specified in the planned dose data. 
4.10.2 Treatment Compliance 
Administration of study drugs (HLX10; Placebo; Carboplatin; Etoposide) will be collected for the 
following information (eCRF: Administration-HLX10/Placebo; Administration-Carboplatin; 
Administration-Etoposide): Actual dose (unit); Start date/time; End date/time; Action taken during 
the infusion; Infusion rate change; Reason for the action taken during the infusion.  
Medication compliance of the study drugs be summarized by study treatment using Safety Set. 
The following summary will be provided: 
• 
Summary of action taken and the reason for the action taken during the HLX10/Placebo 
infusion with cross tabulation by visit and study treatment. The summary will be presented 
repeatedly on Carboplatin and Etoposide (Analysis set: Safety Set). 

Shanghai Henlius Biotech, Inc.                                                                                             
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• 
Summary of infusion rate change HLX10/Placebo by visit and study treatment. The 
summary will be presented repeatedly on Carboplatin and Etoposide (Analysis set: Safety 
Set). 
• 
By-subject listings of administration of HLX10/Placebo, Carboplatin, and Etoposide will 
be provided respectively (Listing analysis set: Safety Set). 
4.11 Efficacy Evaluation 
Analyses of the primary efficacy endpoint and the secondary efficacy endpoints will be performed 
for both the ITT and PPS, mainly on the ITT.  
4.11.1 Analysis and Data Conventions 
This study is designed to test for superiority. For the time-to-event endpoint (e.g., PFS, OS), the 
null hypothesis (H0) and the alternative hypothesis (H1) can be expressed as follows: 
H0: 𝑆𝐴(𝑡) = 𝑆𝐵(𝑡) for all 𝑡
H1: 𝑆𝐴(𝑡) ≠𝑆𝐵(𝑡) for some 𝑡 
where 𝑆𝐴(𝑡) and 𝑆𝐵(𝑡) are the rates of time-to-event for Arm A (HLX10 + chemotherapy) and 
Arm B (Placebo + chemotherapy) at time 𝑡, 𝑡> 0. The comparison of the time-to-event between 
the two arms will be performed by a two-sided stratified log-rank test and the prespecified 
stratification factors. Time-to-event distributions will be estimated using the Kaplan-Meier (KM) 
product-limit method. If median event time is evaluated, the corresponding two-sided 95% 
confidence interval (CI) will be computed using the Brookmeyer-Crowley approach. The standard 
error of the survival rate at a fixed time point (e.g. PFS rate at 6 months) will be estimated using 
Greenwood’s formula. The hazard ratio and its 95% CI will be estimated by stratified Cox 
proportional hazards model. Efron’s method will be used to handle ties. All CIs will be presented 
to one more decimal place than the point estimate. 
For binomial proportions endpoints (e.g., ORR), considering the stratified randomization, the 
stratified Cochran-Mantel-Haenszel method is used to test the between-group variation in the ORR 
and to estimate the odds ratio and its 95% CI. For each single arm, the 95% CI for the proportion 
will be derived using Clopper-Pearson method.  
Considering the stratified randomization, the stratified Cochran-Mantel-Haenszel method is used 
to test the between-group variation in the ORR and to estimate the odds ratio and its 95% CI. The 
estimate for ORR and 95% Clopper-Pearson CI will also be provided. 
Any major protocol deviation potentially affecting the efficacy analysis would be discussed in 
DRM. If there is any doubt about the efficacy data involving major protocol deviation, the efficacy 
data will be available up to the last efficacy assessment prior to the major protocol deviation 
4.11.1.1 Adjustments for Covariates 
All analyses of efficacy endpoints will be stratified by PD-L1 expression level (negative: TPS <1%, 
positive: TPS ≥1%, or not evaluable/not available), brain metastasis (yes versus no), and age (≥ 65 
years versus < 65 years). If a subject is assigned in a wrong stratum, he/she will be analyzed per 
“randomized stratum”. A sensitivity analysis will be performed for PFS and OS using “actual 
stratum”. 

Shanghai Henlius Biotech, Inc.                                                                                             
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4.11.1.2 Multiple Comparisons/Multiplicity 
One primary variable has been defined for this study, one critical treatment contrast (Arm A vs. 
Arm B). The secondary variables defined are intended to provide supportive evidence relating to 
the primary objective and no labeling claims are intended. There is a planned interim analysis 
whose approach of controlling type I error will be described in the interim analysis section 4.11.1.3. 
Hence, except the interim analysis, no adjustments for multiplicity are required. 
4.11.1.3 Interim Analyses 
This study plans to carry out an interim analysis. An Independent Data Monitoring Committee 
(IDMC) will be established for the interim analysis. The O’Brien-Fleming type alpha-spending 
function (using the Lan-DeMets method to approximate) shall be used to control overall type I 
error rate. The stopping boundary for OS interim and final analyses are shown in Table 1. 
Table 1. Analysis Timing and Stopping Boundary of Overall Survival 
Analysis Timing 
Information Fraction  
(Number of Events) 
Estimated Time  
(month) 
Stopping Boundary 
(p-value) 
OS interim analysis 
66% (226) 
19 
<0.012 
OS final analysis 
100% (342) 
34 
<0.046 
 
• 
The first interim analysis is scheduled to be conducted when 66% (approximately226) of 
OS events are observed, and the interim analysis will assess the safety and efficacy of the 
trial group. The α for the first interim analysis will be 0.012 (two-tailed) based on the 
O’Brien Fleming type alpha-spending function. 
• 
The final analysis of OS will be performed when a target number of OS events 
(approximately342) are observed, and the α for the final analysis will be 0.046 (two tailed) 
based on the O’Brien-Fleming type alpha-spending function. 
4.11.1.4 Examination of Subgroups 
To assess the consistency of the study OS, PFS and PFS2, results in subgroups will be examined. 
The following subgroups will be considered: 
• 
Age (≥ 65 years vs.  < 65 years) 
• 
Sex (Male vs. Female) 
• 
Race (Asian vs. non-Asian) 
• 
Ethnicity (Hispanic of Latino vs. non-Hispanic of Latino) 
• 
Baseline ECOG performance status (0, 1) 
• 
Baseline smoking status 
• 
Baseline brain metastasis (yes vs. no) 
To explore the efficacy under different PD-L1 expression level, the following subgroups will be 
examined. 

Shanghai Henlius Biotech, Inc.                                                                                             
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• 
PD-L1 expression level based on tumor proportion scores (positive TPS ≥1% vs. negative 
TPS <1%) 
• 
PD-L1 expression level based on combined positive score (positive CPS ≥1% vs. negative 
CPS < 1%) 
Summaries of OS, PFS and PFS2, including unstratified HRs estimated from Cox proportional 
hazards models will be displayed in a forest plot. Kaplan-Meier estimates of median OS, PFS and 
PFS2 will be produced separately for each level of the categorical variables for the comparisons 
between treatment arms. 
The survival curve and median survival time will be estimated by Kaplan-Meier approach for 
subgroups (including: Age, Baseline brain metastasis, PD-L1 expression level based on TPS and 
CPS). The Brookmeyer-Crowley method will be used to construct the 95% CI for the median 
survival time.  
All the subgroup analyses will be summarized using the ITT Set and Per Protocol Set. 
4.11.2 Primary Efficacy Variable 
Overall Survival  
The primary efficacy endpoint is the OS. OS is defined as the time from randomization to death 
from any cause. Subjects with no death record will be censored at the last known date of survival. 
Subjects who did not provide any follow-up information within the study period will be censored 
on the date of randomization.  
If the death year and months is available but date is missing, the 1st day of the month or the latest 
known alive date will be used to impute the death date, whichever later. 
If both month and day are missing for death date or a death date is totally missing, do not impute 
and censor the subject at the last known alive date. 
The comparison of OS between the two arms will be performed by stratified log-rank test at α =
0.05 with the following stratification factors: PD-L1 expression level (negative: TPS <1%, 
positive: TPS ≥1%, or not evaluable/not available), Brain metastasis (yes versus no), Age (≥ 65 
years versus < 65 years). 
Median OS and OS curve will be estimated using Kaplan-Meier method. The Brookmeyer-
Crowley method will be used to construct the 95% CI for the median OS. The standard error of 
the Kaplan-Meier quartile estimates will be estimated using Greenwood’s formula. The hazard 
ratio and its 95% CI will be estimated by stratified Cox proportional hazards model. Efron’s 
method will be used to handle ties.  
The analysis of primary efficacy endpoint will be using ITT Population, and the analysis will be 
repeated on PPS as a supporting analysis. 
The following summary will be provided: 
• A summary of the median OS with corresponding two-sided 95% CI by study treatment 
(Analysis set: ITT set, PPS) 

Shanghai Henlius Biotech, Inc.                                                                                             
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• A summary of the OS rate at 3, 6 and 9 months with corresponding two-sided 95% CI by 
study treatment (Analysis set: ITT set, PPS) 
• A summary of the OS hazard ratio based on the stratified Cox proportional hazards model 
and the p-value for stratified long-rank test (Analysis set: ITT set, PPS) 
• A plot of Kaplan-Meier survival curve with two-sided 95% CI by study treatment (Analysis 
set: ITT set, PPS) 
A by-subject listing of the primary efficacy data will be provided (Listing analysis set: ITT 
Population). 
4.11.3 Secondary Efficacy Variables 
4.11.3.1 Progression Free Survival (PFS) 
All assessment date will be based on the date of scans. In the instance where there are different 
dates of scans within the same tumor assessment, the response assessment will use the last scan 
date where lesions are defined and an assessment of PD, iCPD or iUPD will be dated on the earliest 
scan date that demonstrates PD. 
PFS assessed by the IRRC and investigator based on RECIST 1.1 
PFS is defined as the time from randomization to the first recorded PD/death due to any cause 
(whichever occurs first).  
The PFS will be censored based on the following algorithms: 
• 
Subjects without PD/death at the end of study or the cut-off date will be censored at the 
date of last effective tumor evaluation.  
• 
Subjects who did not undergo any tumor assessment during the study and did not die at the 
end of study or the cut-off date will be censored on the day of randomization.  
• 
Subjects who had no PD and started anticancer treatment which is not stipulated in the 
protocol will be censored at the day of the last effective tumor assessment before anticancer 
treatment. 
• 
Subjects who had a major protocol deviation that is prior to the unblinding and affects the 
efficacy analysis will be censored at the day of the last effective tumor assessment prior to 
the day of major protocol deviation. The impact of major protocol deviation on efficacy 
analysis will be discussed in the DRM. 
• 
Subjects who had the 1st PD assessed by IRRC after the 2nd line anti-cancer therapy will be 
censored at the day of the last effective tumor assessment prior to the day of 2nd line 
chemotherapy. This rule only applies to subjects who assigned the 2nd line anti-cancer 
therapy after 1st PD assessed by investigator. 
If PD/death year and month (YYYYMM) are available but day (DD) is missing: 
• 
If YYYYMM for last date of effective tumor assessment where subjects are known to be 
alive > YYYYMM for PD/death date, then that is a data error and do not impute; otherwise 
• 
set PD/death date to the day after the last date of effective tumor assessment or to the first 
day of the PD/death month, whichever is later. 

Shanghai Henlius Biotech, Inc.                                                                                             
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If both month and day are missing for PD/death date or a PD/death date is totally missing, do not 
impute and censor the subject at the last date of effective tumor assessment. 
Statistical methods for PFS are the same as those for the primary efficacy endpoint (Analysis set: 
ITT Set, PPS). 
PFS assessed by the investigator based on iRECIST 
If iUPD is observed and the subsequent tumor assessment is not done at the following 4-8 weeks 
or out of the time window, the PFS should be calculated as below:  
• 
If iCPD is less than 4 weeks after iUPD, the iCPD will be disregarded. 
• 
If there are multiple iUPD before the iCPD, the latest iUPD date will be used to calculate 
PFS. 
• 
If there is iUPD followed by “Death” without any iCPD, the PFS will be treated as an event, 
and the latest iUPD date before death will be used to calculate PFS. 
• 
If there is no iCPD or “Death” after iUPD, the PFS will be censored to the day of last 
effective tumor assessment.  
Statistical methods are the same PFS based on RECIST 1.1 (Analysis set: ITT Population, PPS).  
4.11.3.2 Progression Free Survival 2 (PFS2) 
PFS2 is defined as the time from randomization to objective tumor progression on next-line 
treatment or death from any cause. If a patient dies without any progression events, the patient’s 
PFS and PFS2 event dates would be equivalent. If a patient dies after their primary PFS event, but 
prior to the initiation of subsequent anti-cancer therapy, their death date is still considered their 
PFS2 event. Patients alive and for whom a second disease progression has not been observed 
should be censored at the last tumor assessment date. 
PFS2 will be analyzed using the same method as the analysis of PFS (Analysis set: ITT Population, 
PPS). 
4.11.3.3 ORR assessed by the IRRC and investigator based on RECIST 1.1 
ORR will be defined as the proportion of subjects with a best overall response of CR or PR as 
defined by RECIST 1.1 during the study. Subjects without post-baseline tumor assessments will 
be counted as non-responders in calculating the ORR. Considering the stratified randomization, 
the stratified Cochran-Mantel-Haenszel method is used to test the between-group variation in the 
ORR and to estimate the odds ratio and its 95% CI. The estimate for ORR and 95% Clopper-
Pearson CI will also be provided. 
4.11.3.4 DOR assessed by the IRRC and investigator based on RECIST 1.1 
DOR will be defined as the time from the first recorded CR or PR to the first recorded PD or death 
(whichever occurs first). The tumor responses CR, PR, and PD will follow the definition in 
RECIST 1.1. DOR will be only analyzed for subjects who achieved CR or PR best overall response. 
Subjects who do not experience PD or death after the first CR or PR will be censored on the final 

Shanghai Henlius Biotech, Inc.                                                                                             
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tumor assessment day; Subjects who had no any tumor assessment after achieving the first CR or 
PR will be censored on the day of achieving the first CR or PR. The Kaplan-Meier method is used 
to estimate the median and plot the Kaplan-Meier curve (Analysis set: ITT Set, PPS).  
A by-subject listing of the secondary efficacy data will be provided (Listing analysis set: ITT 
Population). 
4.12 Safety Evaluation 
Safety evaluation is often based upon summaries of the data rather than formal statistical inference. 
All safety summaries and analyses will be based upon the Safety Set (SS). 
4.12.1 Adverse Events 
All AEs will be coded using the latest version of MedDRAcoding system.  
If an AE is reported for a given subject more than once for a period, the worst severity and the 
strongest relationship to study treatment will be used for that period. 
All the records belonging to the same AE set will be kept in the analysis datasets as separate records 
• 
If an AE started before treatment start and improved during treatment, it should not be 
counted as TEAE 
• 
If an AE worsened during the treatment period, it is counted as TEAE even if there was an 
observation with start date before treatment period. 
Adverse events with relationship “Related”, “Possibly Related” and “Unknown” will be classified 
as “Related” with the study drug. 
An overall summary table of the following AEs will describe the number of events, number of 
subjects with events and incidence rate and also be tabulated by SOC and PT. 
• 
Incidence = 
(Number of Subject with TEAE)
Number of subjects in the Safety Set   
• 
AEs 
• 
TEAEs 
• 
TEAEs by Severity (Grade1, 2, 3, 4 and 5) 
• 
Related TEAEs 
• 
Grade ≥ 3 TEAEs 
• 
Related Grade ≥ 3 TEAEs 
• 
TEAEs leading to discontinuation of study drugs (HLX10/Placebo) 
• 
Related TEAEs leading to discontinuation of study drugs (HLX10/Placebo) 
• 
TEAEs leading to discontinuation of Carboplatin 
• 
Related TEAEs leading to discontinuation of Carboplatin 
• 
TEAEs leading to discontinuation of Etoposide 

Shanghai Henlius Biotech, Inc.                                                                                             
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• 
Related TEAEs leading to discontinuation of Etoposide 
• 
TEAEs leading to interruption of study drugs (HLX10/Placebo) 
• 
Related TEAEs leading to interruption of study drugs (HLX10/Placebo) 
• 
TEAEs leading to interruption of Carboplatin 
• 
Related TEAEs leading to interruption of Carboplatin 
• 
TEAEs leading to interruption of Etoposide 
• 
Related TEAEs leading to interruption of Etoposide 
Adverse event summaries will be ordered in terms of decreasing frequency for SOC, and PT within 
SOC, in Arm A (HLX10 + chemotherapy), and then similarly by decreasing frequency in Arm B 
(Placebo + chemotherapy), and then alphabetically for SOC, and PT within SOC treatment 
(Analysis set: Safety Set). 
A by-subject listing of all AEs (including non-treatment-emergent events) will be provided 
(Listing analysis set: Safety Set). 
4.12.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
4.12.2.1 Death 
All deaths that occur during the study or the follow-up period after the final dose of study drug as 
specified in the protocol must be reported in accordance with the requirements in the protocol. The 
following summary will be provided: 
• 
A summary of the number and percentage of deaths during the study, by study treatment 
and overall (Analysis set: Safety Set). 
• 
A by-subject listing of all deaths (Listing analysis set: Safety Set). 
4.12.2.2 Serious Adverse Event and Immune-related Adverse Event 
All AEs that meet any one or more of the following situations during the clinical trial should be 
considered SAE: 
1. Leading to death 
2. Life-threatening 
3. Hospitalization (initial or prolonged) 
4. Permanent or severe disability/dysfunction 
5. Congenital anomaly or birth defect 
6. Other important Medical Events  
The treatment-emergent serious AE (TESAE) is an SAE which is also treatment-emergent. The 
present of SAE and immune-related adverse event (irAE) are collected in the CRF. Subject 
incidence of the following SAEs, TESAEs and irAEs will be tabulated by study treatment, SOC 
and PT treatment (Analysis set: Safety Set): 
• 
TESAEs 

Shanghai Henlius Biotech, Inc.                                                                                             
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• 
Related TESAEs 
• 
TESAEs leading to discontinuation of study drugs 
• 
TESAEs leading to discontinuation of any component of chemotherapy 
• 
irAEs 
The following listings will be provided (Listing analysis set: Safety Set): 
• 
A by-subject listing of all SAEs  
• 
A by-subject listing of all irAEs 
4.12.3 Clinical Laboratory Evaluation 
The clinical laboratory tests include the following tests: 
• 
Blood routine (eCRF: Hematology) 
• 
Blood biochemistry (eCRF: Clinical Chemistry) 
• 
Urinalysis (eCRF: Urinalysis and 24-hr Urinalysis)  
• 
Coagulation function (eCRF: Coagulation) 
• 
Myocardial Enzymogram (eCRF: Myocardial Enzymogram) 
• 
Thyroid function (eCRF: Endocrine function tests) 
• 
Virology testing (eCRF: Viral Serology) 
• 
Serum Pregnancy test (eCRF: Serum Pregnancy test) 
The details are shown in Appendix 7. 2. The baseline clinical laboratory assessments will be the 
last non-missing measurement prior to the administration date and time. If the baseline clinical 
laboratory data is missing, no imputation will be made, and therefore the change from baseline 
value will be missing. All clinical laboratory data will be summarized by descriptive statistics of 
each follow-up, including n, mean, SD, median, minimum, maximum and change from baseline 
for quantitative data, and count, percentage and shift at post-baseline for qualitative data. 
The following summaries will be provided: 
• 
Summary of each clinical laboratory test and its change from baseline by visit and study 
treatment (Analysis set: Safety Set). 
• 
A summary of the number and percentage of subjects who are low, normal or high at 
baseline and the shift at post-baseline for each clinical laboratory test by visit and study 
treatment (Analysis set: Safety Set). 
• 
By-subject listings of all laboratory tests (Listing analysis set: Safety Set). 
All values outside the clinical reference ranges will be flagged in the data listings. The abnormal 
values will be flagged with ‘L’ for values below the lower limit of the clinical reference range and 
‘H’ for values above the upper limit of the clinical reference range and included in the listings. 

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4.12.4 Vital Signs, Physical Findings and Other Observations Related to Safety 
4.12.4.1 Vital Signs 
The vital sign variables include height, weight, systolic blood pressure, diastolic blood pressure, 
pulse, temperature, and respiratory rate (eCRF: Vital Sign).  
The following summaries will be provided: 
• 
A summary of each vital sign by visit and study treatment (Analysis set: Safety Set). 
• 
A summary of change from baseline in each vital sign by visit and study treatment 
(Analysis set: Safety Set). 
• 
A by-subject listing of all vital signs will be provided (Listing analysis set: Safety Set). 
4.12.4.2 Physical Examinations 
Physical examination variables will include the results (clinical significance) of following 
examination: head and neck (including thyroid), chest (including heart and lungs), abdomen 
(including liver, gallbladder, spleen and kidney), limbs, skin, lymph nodes, neurological system 
and general appearance (eCRF: Physical Examination). The Full physical examination will be 
performed at screening period. Symptom-directed physical examination will be carried out during 
study treatment.   
The following summaries will be provided: 
• 
A summary of each physical examination by body system, visit and study treatment 
(Analysis set: Safety Set). 
• 
A summary of change from baseline using shift table in each physical examination by visit 
and study treatment (Analysis set: Safety Set). 
• 
A by-subject listing of all physical examination will be provided (Listing analysis set: 
Safety Set). 
4.12.4.3 12-Lead ECG 
ECG parameters (Heart Rate; PR interval; RR interval; QRS duration; QT interval; QTcF) will be 
summarized by observed time point using appropriate descriptive statistics by treatment group 
(eCRF: 12-lead ECG). 
The overall assessment of 12-lead ECG will be evaluated by the Investigator as ‘Normal’, 
‘Abnormal - Not Clinically Significant’ or ‘Abnormal - Clinically Significant’. The baseline 
assessments of ECG will be the last non-missing measurement prior to the administration date/time. 
If the baseline measurement of ECG is missing, the change from baseline value will also be 
missing since no imputation will be made. 
The following summaries will be provided: 
• 
Summary of each ECG parameter, including overall assessment, by visit and study 
treatment (Analysis set: Safety Set).  
• 
Summary of the change from baseline in each ECG parameter, including overall 
assessment, by visit and study treatment (Analysis set: Safety Set). 

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• 
Summary of the number and percentage of subjects with QTcF exceeding the predefined 
upper limit (>450ms, >480ms, >500ms) (Analysis set: Safety Set). 
• 
A by-subject listing of all ECG parameters will be provided (Listing analysis set: Safety 
Set). 
4.12.4.4 ECOG Performance Status 
ECOG performance status (ECOG PS) score (0,1,2,3,4,5) should be rated prior to the first dose of 
study drug as Appendix 7. 3. If it is evaluated on Day -7 to Day -1 during screening period, a 
repeat evaluation will not be required. 
The following summaries will be provided: 
• 
Summary of the ECOG PS score by visit and study treatment (Analysis set: Safety Set). 
• 
Summary of the change from baseline in the ECOG PS score by visit and study treatment 
(Analysis set: Safety Set). 
• 
A by-subject listing of ECOG PS score will be provided (Listing analysis set: Safety Set). 
4.13 Other Analyses 
At the initial treatment period, PK and ADA samples for HLX10 or placebo will be collected at 
the following time points: within 7 days pre-dose in Cycle 1, within 3 days pre-dose in Cycles 2, 
4, 6, 8 and every 4 cycles thereafter, within 2 hours after the end of dosing in Cycles 1 and 8 of 
treatment period (for PK only), at EOT visit and safety follow-up.  
At the post-PD treatment period, PK and ADA samples for HLX10 or placebo will be collected at 
the following time points: within 3 days pre-dose in cycle 1 and thereafter every 4 cycles, at EOT 
visit and safety follow-up. 
4.13.1 Pharmacokinetics 
A by-subject listing of PK concentration will be provided based on PKS. PK concentrations below 
the lower limit of quantification (LLOQ) will be presented as BLQ in the listings and set to zero 
for descriptive statistics. Subjects ADA/NAb (positive or negative) status will be included in 
listings. The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of concentration data:  
− Source data shall be used in all derived PK concentrations without prior rounding.  
− The mean, geometric mean and median will be tabulated to one more decimal digit 
compared to the source data, but with a maximum of four decimal digits, standard 
deviation (SD) will have one more decimal digit than arithmetic mean.  
− Minimum and maximum values will be tabulated to the same precision as the source 
data, but with a maximum of four decimal digits. Median values will have one more 
decimal digit than source data. 
− Geometric coefficient of variation (CVb%) and coefficient of variation (CV%) will be 
presented to one decimal place. 
A summary of PK concentrations by timepoint and study treatment will be provided using PKS.  
The following descriptive statistics will be presented for PK concentrations: n, arithmetic mean, 
SD, coefficient of variation (CV%), geometric mean, geometric CV% (CVb%, calculated as: 

Shanghai Henlius Biotech, Inc.                                                                                             
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%𝐶𝑉𝑏= 100 ∗√exp (𝑠2) −1; where 𝑠 is the standard deviation of the log-transformed values), 
median, minimum and maximum values. 
If 3 or more subjects who have received HLX10 treatment were ADA or NAb positive (if a subject 
has at least one positive ADA or NAb sample after receiving HLX10 treatment, he/she will be 
considered ADA or NAb positive subject), all PK concentrations will be stratified by ADA or NAb 
status for descriptive statistics.  
The arithmetic means and SD of initial treatment period and post-PD treatment period will be 
presented using linear and semi-log coordinate. If the ADA/NAb stratification criteria is met, the 
mean and SD for ADA/NAb positive and negative subjects will be displayed separately.  
The accumulation index (RCmax and RCtrough, ratio of HLX10 drug cumulation) following multiple 
HLX10 dosing will be calculated by the nominal sampling time, listed, and summarized by 
descriptive statistics including n, arithmetic mean, SD, CV%, geometric mean, geometric CV% 
(CVb%), median, minimum, and maximum. RCmax=concentration after Cycle 8 dosing / 
concentration after Cycle 1 dosing, RCtrough=concentration before Cycle 8 dosing / concentration 
before Cycle 2 dosing. RCmax and RCtrough will be presented to 2 decimal digits. If the ADA/NAb 
stratification criteria is met, the PK parameters (Cmax, Ctrough, RCmax and RCtrough) will be stratified 
by ADA or NAb status for descriptive statistics. 
4.13.2 Immunogenicity 
The following ADA/NAb summaries will be provided: 
• 
A summary of the number and percentage of positive ADA/NAb by visit and study 
treatment (Analysis set: Safety Set). 
• 
A by-subject listing of ADA will be provided (Listing analysis set: Safety Set). 
• 
The number and percentage of patients with at least one positive ADA/NAb at any 
timepoint after receiving HLX10 administration.  
4.13.3 Biomarker Analysis 
In this study, the biomarkers include PD-L1 expression status, MSI and TMB. The OS and PFS 
assessed by IRRC and Investigator based on RECIST 1.1 will be analyzed the relationship with 
biomarkers. 
The following summaries will be provided: 
• 
Summary of the OS including the median OS with corresponding two-sided 95% CI if it is 
evaluable, and the quartile OS with corresponding two-sided 95% CI by categorical 
biomarker (PD-L1 status, MSI) and study treatment (Analysis set: ITT Set, PPS). 
• 
Kaplan-Meier OS survival curve with two-sided 95% CI by categorical biomarker (PD-L1, 
MSI) and study treatment (Analysis set: ITT Set, PPS). 
• 
OS hazard ratios and its 95% CI for each continuous biomarker (PD-L1 expression, TMB) 
will be estimated by the Cox proportional hazards model with study treatment. Efron’s 
method will be used to handle ties (Analysis set: ITT Set, PPS). 

Shanghai Henlius Biotech, Inc.                                                                                             
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• 
Summary of the PFS including the median PFS with corresponding two-sided 95% CI if it 
is evaluable, and the quartile PFS with corresponding two-sided 95% CI by categorical 
biomarker (PD-L1 status, MSI) and study treatment (Analysis set: ITT Set, PPS). 
• 
Kaplan-Meier PFS survival curve with two-sided 95% CI by categorical biomarker (PD-
L1, MSI) and study treatment (Analysis set: ITT Set, PPS). 
• 
PFS hazard ratios and its 95% CI for each continuous biomarker (PD-L1 expression, TMB) 
will be estimated by the Cox proportional hazards model with study treatment. Efron’s 
method will be used to handle ties (Analysis set: ITT Set, PPS). 
4.13.4 Quality of Life Assessment  
The health status and self-perceived health of each patient will be documented in the form of EQ-
5D-5L scale, EORTC QLQ-C30 scale, and EORTC QLQ-LC13 scale. 
Descriptive statistics are based on the allocation for the scale scores, subscale scores, and 
individual scores at each visit and their changes from baseline., Patient-reported outcomes (PROs) 
analysis of all data will be performed based on the ITT Set. 
4.13.4.1 EQ-5D-5L 
The 5-level EQ-5D 3rd version (EQ-5D-5L) has five descriptive dimensions of health score as:  
• 
Mobility:  
- Level 1 (No problems) 
- Level 2 (Slight problems) 
- Level 3 (Moderate problems) 
- Level 4 (Severe problems) 
- Level 5 (Unable to) 
• 
Self-care: 
- Level 1 (No problems) 
- Level 2 (Slight problems) 
- Level 3 (Moderate problems) 
- Level 4 (Severe problems) 
- Level 5 (Unable to) 
• 
Usual activities: 
- Level 1 (No problems) 
- Level 2 (Slight problems) 
- Level 3 (Moderate problems) 
- Level 4 (Severe problems) 
- Level 5 (Unable to) 

Shanghai Henlius Biotech, Inc.                                                                                             
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• 
Pain or discomfort:  
- Level 1 (No pain) 
- Level 2 (Slight pain) 
- Level 3 (Moderate pain) 
- Level 4 (Severe pain) 
- Level 5 (Extremely pain) 
• 
Anxiety or depression:  
- Level 1 (No anxious) 
- Level 2 (Slight anxious) 
- Level 3 (Moderate anxious) 
- Level 4 (Severe anxious) 
- Level 5 (Extremely anxious) 
The respondent is asked to indicate his/her health state by checking the box next to the most 
appropriate response level for each of the five dimensions. Responses are coded as single-digit 
numbers expressing the severity level selected in each dimension.  
A visual analogue scale (EQ VAS) records the respondent’s overall current health on a vertical 
visual analogue scale, where the endpoints are labelled ‘The best health you can imagine’ and ‘The 
worst health you can imagine’. The EQ VAS (0-100) provides a quantitative measure of the 
patient’s perception of their overall health. 
EQ-5D scores during treatment period and changes from baseline will be summarized by visit and 
treatment arms. Five descriptive dimensions of health score will be analyzed as categorical 
variables and the self-estimated EQ VAS will be analyzed as continuous variable. A summary 
statistics table and listing will be provided for all 5 dimensions’ health scores and self-estimated 
health score by ITT Population with a corresponding listing (Listing analysis set: ITT Set). 
4.13.4.2 EORTC-QLQ-C30 
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30) is a cancer health-related quality-of-life questionnaire that has 
been widely used in clinical trials and investigations using PROs for individual patient 
management. 
The EORTC QLQ-C30 v3 questionnaire is an established measure of health-related quality of life 
(HRQoL) and is commonly used as an endpoint in oncology clinical trials. The questionnaire 
assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, 
cognitive, emotional, and social), 3 symptom scales (fatigue, pain, nausea and vomiting), and 1 
global health and QoL (quality of life) scale. The 6 individual symptom measures include: dyspnea, 
insomnia, loss of appetite, constipation, diarrhea, and financial difficulties. For the 15 domains 
described above, the total score is standardized to a range from 0 to 100, where higher scores 
indicate stronger functioning, higher HRQoL or higher symptom levels. 

Shanghai Henlius Biotech, Inc.                                                                                             
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For ease of presentation and interpretation, all scale and item scores are linearly transformed to a 
0 to 100 scale, with higher scores representing increasing symptom levels. The transformed score 
for a subject and missing data handling can be expressed as Appendix 7. 4 Scoring the QLQ-C30 
version 3.0. 
EORTC-QLQ-C30 scores during treatment period and changes from baseline will be summarized 
by visit and treatment arms for ITT Population. A summary statistics table will be provided for all 
5 function domains and self-estimated health score by ITT Set with a corresponding listing (Listing 
analysis set: ITT Set). 
4.13.4.3 EORTC-QLQ-LC13 
The EORTC-QLQ-LC13 is a 13-item self-administered questionnaire for lung cancer disease that 
will be used along with the EORTC QLQ-C30. The scale includes both multiple and single lung 
cancer-related symptom parameters (i.e., cough, hemoptysis, dyspnea and pain), as well as side 
effects of conventional chemotherapy and radiotherapy (i.e., alopecia, neurological disorders, oral 
pain and dysphagia). Similar to the EORTC QLQ-C30, all questions (except one) are on a 4-point 
scale: "not at all", "a little", "quite a bit", and "very much". Only 1 question (43rd question "Did 
you take any medicine for pain?") is with response options of "yes" or "no". The QLQ-LC13 are 
scored similarly to the EORTC-QLQ-C30. The scoring approach for  QLQ-LC13 can be expressed 
as Appendix 7. 5 Scoring the QLQ-LC13. 
For ease of presentation and interpretation, all scale and item scores are linearly transformed to a 
0 to 100 scale, with higher scores representing increasing symptom levels.  
Transformed QLQ-LC13 score = Sum of item scores −Number of items
3 × Number of items 
× 100 
The observed values and changes from baseline for overall score, sub-scores and individual scores 
for each visit will be statistically described (Analysis set: ITT Set). The overall score is defined as 
the sum of all item scores except pain medication. The sub-scores are  
• 
Lung cancer related symptoms including cough, hemoptysis and dyspnea; 
• 
Treatment related side-effects including sore mouth or tongue, dysphagia, hair loss, 
tingling hands and feet; 
• 
Pain.  
The summary statistics for the overall score, sub-scores and individual scores and the changes 
from baseline will be tabulated by study treatment and visit.  
Statistical analyses including baseline, post baseline, change from baseline are the same as the 
EORTC-QLQ-LC13 score. All QoL analysis will be performed based on the ITT Set. A by-subject 
listing of EORTC-QLQ-LC13 will be provided (Listing analysis set: ITT Set). 
4.14 Safety Monitoring (Independent Data Monitoring Committee [IDMC])  
The IDMC will be assembled to evaluate safety data for the study. The IDMC will also evaluate 
efficacy data, such as OS for the planned interim analysis. Following the data review, the IDMC 
will provide a recommendation as to whether the study may continue, whether amendments to the 
protocol should be implemented, or whether the study should be stopped. The final decision will 

Shanghai Henlius Biotech, Inc.                                                                                             
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rest with the sponsor. The details of procedures including roles and responsibility, composition, 
meetings, data package of meeting, decision making and confidentiality, can be referred to a 
separate IDMC charter. 
4.15 Determination of Sample Size 
The randomization ratio for this study is 2:1. The sample size is estimated based on the assumption 
that the median OS for treatment with placebo + chemotherapy (Carboplatin–Etoposide) is 10 
months and the hazard ratio (HR) of (HLX10 + chemotherapy) group versus the control group is 
0.7, and it is further assumed that when the enrollment period is 24 months and the whole study 
period is 34 months, to achieve a confidence level of 85% at an overall significance level α = 0.05 
(two-sided), at least 342 OS events have to be observed. Considering a dropout rate of 20%, a total 
of 567 subjects (378 in treatment arm and 189 in control arm) need to be enrolled in the 2 arms. 
It is planned in this study that, when the 378 subjects (about 2/3 of the number of subjects planned 
to be enrolled) was enrolled under supervision of the Independent Data Monitoring Committee 
(IDMC), the sponsor will consider performing a blinded sample size estimation, and if the blinded 
overall median OS is lower than the expected value, then the sponsor will communicate with 
principal investigator and regulatory authorities about the necessary increase in the sample size 
(number of OS events). 
4.16 Changes in the Conduct of the Study or Planned Analysis 
Not applicable. 
4.17 Analyses of Data from Asian and Non-Asian 
This study is a multi-regional clinical trial. Therefore, besides the global data analysis, statistical 
analysis will also be reported in Asian and Non-Asian population separately.  
All analyses detailed in 4.1 to 4.16 will be repeated for the subjects randomized in Asian and Non-
Asian. 
5 
Inconsistency from Protocol 
The definition of PKS in protocol was:  
The PKS consists of all participants who received at least one dose of study intervention with at 
least one post-dose concentration measurement at scheduled PK time points without any major 
protocol violation that may impact the PK assessment significantly. The PK analysis set will be 
used for PK analysis. 
The concept of “study intervention” contains both HLX10 and placebo, while HLX10 
concentration from placebo group are presumed to be LLOQ. To describe the population for PK 
analysis more precisely, the definition of PKS is changed as follows: 
The PKS consists of all participants who received at least one dose of HLX10 with at least one 
measurable post-dose concentration at scheduled PK time points without any major protocol 

Shanghai Henlius Biotech, Inc.                                                                                             
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violation that may impact the PK assessment significantly. The PK analysis set will be used for 
PK analysis. 
The definition of PPS in protocol was:  
The PPS comprises a subset of the ITT. The PPS consists of all randomized subjects undergoing 
at least one post-treatment tumor assessment without any major protocol deviation that impacts 
the primary efficacy significantly. The PPS will be used to demonstrate robustness of results for 
the primary efficacy endpoint.  
Whether the subject has at least one post-treatment tumor assessment that do not affect the primary 
efficacy OS. To describe PPS more precisely, the definition of PPS is changed as follows: 
The PPS comprises a subset of the ITT. The PPS consists of all randomized subjects without any 
major protocol deviation that impacts the primary efficacy significantly. The PPS will be used to 
demonstrate robustness of results for the primary efficacy endpoint. 
6 
REFERENCES 
Not applicable. 
 

Shanghai Henlius Biotech, Inc.                                                                                             
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7 
APPEXDIX 
7.1 
Appendix 7. 1 Schedule of Activities 
 
  

Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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Shanghai Henlius Biotech, Inc.                                                                                             
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7.2 
Appendix 7. 2 List of Laboratory Tests 
Routine blood test 
Biochemistry 
Urinalysisa 
Others 
Red blood cell count 
(RBC) 
Hemoglobin (HGB) 
Platelet (PLT) 
White blood cell count 
(WBC) 
White blood cell 
differential count and 
percentage 
 
Basophils 
(BAS&BAS%) 
 
Eosinophils 
(EOS&EOS%) 
 
Lymphocytes 
(LYM&LYM%) 
 
Monocytes 
(MON&MONO%) 
 
Neutrophils 
(NEU&NEUT%) 
 
Urea (UREA)/Blood 
urea nitrogen (BUN) 
Creatinine (CR) 
Fasting blood 
glucose (GLU) 
Total bilirubin (TB) 
Direct bilirubin (TB) 
Alanine 
aminotransferase 
(ALT) 
Aspartate 
aminotransferase 
(AST) 
Alkaline phosphatase 
(ALP) 
Lactate 
dehydrogenase 
(LDH) 
Total cholesterol 
(CHOL) 
Total protein (TP) 
Albumin (ALB) 
Sodium (Na) 
Potassium (K) 
Magnesium (Mg) 
Chloride (Cl) 
Calcium (Ca) 
Phosphorus (P) 
Specific gravity (SG) 
Urine leukocytes 
Urine pH value 
Urine protein (U-PRO) 
Urinary glucose 
(U-GLU) 
Ketones (KET) 
Urine occult blood 
(BLO) 
Microscopic 
examination of white 
blood cells (U-WBC) 
Microscopic 
examination of red 
blood cells (U-RBC) 
Coagulation function 
Prothrombin Time（PT） 
Activated Partial 
Thromboplastin Time 
(APTT) 
International Normalized 
Ratio (INR) 
Myocardial function 
Troponin-I (TnI)/troponin-T 
(TnT), creatine kinase 
isoenzyme (CK-
MB)/creatine kinase (CK), 
myoglobin Brain Natriuretic 
Peptide (BNP)/N-terminal 
pro-Brain Natriuretic Peptide 
(NT-pro BNP) 
Thyroid function testsb 
Triiodothyronine (T3 or FT3) 
Thyroxine (T4 or FT4) 
Thyroid-stimulating hormone 
(TSH) 
Virologyc 
Hepatitis B Surface Antigen 
(HBsAg) 
Anti-HBs (HBsAb) 
Anti-HBc (HBcAb) 
Anti-Hepatitis C (HCV) 
Antibody 

Shanghai Henlius Biotech, Inc.                                                                                             
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Routine blood test 
Biochemistry 
Urinalysisa 
Others 
HBV DNA (optional) 
HCV RNA (optional) 
Anti-HIV 
Pregnancy testd 
Tuberculosis teste 
a. If a subject has two consecutive 2++ urine protein or one ≥ 3+++, urine protein should be tested at 24 
hours; 
Microscopic examination of white blood cells (U-WBC) should be collected if urine leukocytes is out of 
normal range. Microscopic examination of red blood cells (U-RBC) should be collected if urine occult 
blood is out of normal range. 
b. Thyroid function tests will be performed during screening and within 3 days prior to drug 
administration every 2 treatment cycles during the treatment period; 
c. All subjects are tested for HBsAg or HCV antibody at screening; Patients with HBsAg (+) and/or 
HBcAb (+) should be further tested for HBV DNA titer; and HCV antibody positive subjects should be 
further tested for HCV RNA. In case of HBV DNA (-) and: 1) HBsAg (+), or 2) HBcAb (+) and 
HBsAg (-) at baseline, HBV antibody and HBV DNA should be tested every 2 cycles during the 
treatment period. In case of HCV antibody (+) and HCV RNA (-) at baseline, HCV antibody and HCV 
RNA should be tested every 2 cycles during the treatment period. 
d. Women of childbearing potential should have a blood pregnancy test within 7 days prior to 
randomization and must have a negative result for enrollment; this is also tested within 3 days pre-dose 
every 2 cycles. 
**Routine blood test, blood chemistry, coagulation function, myocardial function and urinalysis must be 
performed at screening and within 3 days prior to drug administration every treatment cycle. When the 
aforementioned laboratory tests and study drug administration are scheduled on the same day, the study drug 
administration must be scheduled only after the test results are obtained. Data from screening period should 
be completed on Day -7 ~ Day -1, and it is not necessary to perform the test again before the first 
administration (C1D1). Routine blood tests will be performed on Day 8 (±3 days) of each treatment cycle 
during treatment with carboplatin, and close attention should be paid to bone marrow suppression. 
e. Bulgarian subjects must undergo tuberculosis testing for active and latent tuberculosis using a testing 
method as per local standard practice (as requested by the Bulgarian Drug Agency for Bulgarian 
subjects). 
 
 

Shanghai Henlius Biotech, Inc.                                                                                             
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7.3 
Appendix 7. 3 ECOG Performance Status Score 
Score 
ECOG Status 
0 
Mobility is completely normal, and there is no difference before and after the onset of the 
disease. 
1 
Free to walk and engage in light physical activities, including general housework or office 
work, but not heavy physical activities. 
2 
Able to walk and independently take care of oneself but cannot do any work. Able to get up 
and move around for at least half of the time during the day. 
3 
Able to only finish some of self-care activities and spend more than half of the time during 
the day in bed or in a wheelchair. 
4 
Complete disability. Cannot take care of oneself at all. Totally confined to bed or in a 
wheelchair. 
5 
Death 
ECOG = Eastern Cooperative Oncology Group 
 
 

Shanghai Henlius Biotech, Inc.                                                                                             
Statistical Analysis Plan 
HLX10-005-SCLC301 
                                                                                       CONFIDENTIAL                           Project Document Version No. 1.0 
 
                                                                                                                           Page 59 of 63 
7.4 
Appendix 7. 4 Scoring the QLQ-C30 version 3.0 
 
 

Shanghai Henlius Biotech, Inc.                                                                                             
Statistical Analysis Plan 
HLX10-005-SCLC301 
                                                                                       CONFIDENTIAL                           Project Document Version No. 1.0 
 
                                                                                                                           Page 60 of 63 

Shanghai Henlius Biotech, Inc.                                                                                             
Statistical Analysis Plan 
HLX10-005-SCLC301 
                                                                                       CONFIDENTIAL                           Project Document Version No. 1.0 
 
                                                                                                                           Page 61 of 63 
 
 
 

Shanghai Henlius Biotech, Inc.                                                                                             
Statistical Analysis Plan 
HLX10-005-SCLC301 
                                                                                       CONFIDENTIAL                           Project Document Version No. 1.0 
 
                                                                                                                           Page 62 of 63 
7.5 
Appendix 7. 5 Scoring the QLQ-LC13 
 
 
 

Shanghai Henlius Biotech, Inc.                                                                                             
Statistical Analysis Plan 
HLX10-005-SCLC301 
                                                                                       CONFIDENTIAL                           Project Document Version No. 1.0 
 
                                                                                                                           Page 63 of 63 
7.6 Appendix 7. 6 TEAE Partial Date Conventions 
• Algorithm for Treatment Emergence of Adverse Events: 
Start Date  
Stop Date 
Action 
Known 
Known 
• If start date < study med start date, then not TEAE. 
• If start date ≥ study med start date, then TEAE. 
Partial 
• If start date < study med start date, then not TEAE. 
• If start date ≥ study med start date, then TEAE. 
Missing 
• If start date < study med start date, then not TEAE. 
• If start date ≥ study med start date, then TEAE. 
Partial, but known components 
show that it cannot be on or 
after study med start date 
Known 
Not TEAE 
Partial 
Not TEAE 
Missing 
Not TEAE 
Partial, could be on or  
after study med start date 
Known 
• If stop date < study med start date, then not TEAE. 
• If stop date ≥ study med start date, then TEAE. 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
• If stop date < study med start date, then not TEAE. 
• If stop date ≥ study med start date, then TEAE. 
Missing 
Assumed TEAE 
Missing 
Known 
• If stop date < study med start date, then not TEAE. 
• If stop date ≥ study med start date, then TEAE. 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
• If stop date < study med start date, then not TEAE. 
• If stop date ≥ study med start date, then TEAE. 
Missing 
Assumed TEAE.