Conditions: Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 457
Healthy volunteers: no

Brief summary:
This Phase 3 study was a randomized, double-blind, placebo-controlled, multicenter trial designed to evaluate the efficacy of tislelizumab in combination with either cisplatin or carboplatin and etoposide (Arm A), compared to placebo combined with either cisplatin or carboplatin and etoposide (Arm B), as a first-line treatment for participants with previously untreated extensive-stage small cell lung cancer (ES-SCLC).

Detailed description:

Arms:
arm 1: Participants received tislelizumab in combination with either cisplatin or carboplatin (at the investigator's discretion) and etoposide during the induction phase, administered every 3 weeks for 4 cycles. Upon completion of the induction phase, participants transitioned to maintenance therapy with tislelizumab only, administered once every 3 weeks. arm 2: Participants received a placebo in combination with either cisplatin or carboplatin (at the investigator's discretion) and etoposide during the induction phase, given every 3 weeks for 4 cycles. Upon completion of the induction phase, participants transitioned to maintenance therapy with placebo only, administered once every 3 weeks.

Interventions: intervention 1: Tislelizumab intervention 2: Cisplatin intervention 3: Carboplatin intervention 4: Etoposide intervention 5: Placebo
Intervention descriptions: intervention 1: 200 mg administered intravenously on Day 1 of each 21-day cycle intervention 2: 75 mg/m² was administered intravenously on Day 1 of each 21-day cycle, infused over a duration of two hours. Treatment with cisplatin was discontinued starting in Cycle 5 and beyond. intervention 3: An area under the curve (AUC) of 5 mg/mL/min was administered intravenously on Day 1 of each 21-day cycle, infused over a duration of 15 to 60 minutes. Treatment with carboplatin was discontinued starting in Cycle 5 and beyond. intervention 4: 100 mg/m² was administered intravenously from Day 1 to Day 3 of each 21-day cycle, infused over a duration of 60 minutes. Treatment with etoposide was discontinued starting in Cycle 5 and beyond. intervention 5: 200 mg was administered intravenously on Day 1 of each 21-day cycle to match tislelizumab.

Protocol document:
Prot_000.pdf: 




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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Platinum 
Plus Etoposide With or Without Tislelizumab (BGB-A317) in Patients With Untreated 
Extensive-Stage Small Cell Lung Cancer 
Protocol Identifier: BGB-A317-312 
This protocol is a confidential communication of BeiGene (Shanghai) Co., Ltd., and its 
subsidiaries. I confirm that I have read this protocol, I understand it, and I will work according to 
this protocol and the terms of the clinical study agreement governing the study. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki and 
that are consistent with good clinical practices and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from BeiGene 
(Shanghai) Co., Ltd., or one of its subsidiaries. 
Instructions for Investigator: Please SIGN and DATE this signature page. PRINT your name, 
title, and the name and address of the center in which the study will be conducted.  Return the 
signed copy to BeiGene or its designee. 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator: 
_______________________________   Date:  _____________ 
Printed Name:  
 
_______________________________ 
Investigator Title:  
_______________________________ 
Name/Address of Center: 
_______________________________ 
_______________________________ 
_______________________________ 
_______________________________ 
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TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................11 
SYNOPSIS ....................................................................................................................................12 
LIST OF ABBREVIATIONS AND TERMS ................................................................................22 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Background Information on Small Cell Lung Cancer ................................................24 
1.1.1. 
Standard Therapy for Extensive-Stage Small Cell Lung Cancer ...............................24 
1.1.2. 
PD-1 Pathway-Targeting Studies in Patients With Extensive-Stage Small 
Cell Lung Cancer ........................................................................................................26 
1.2. 
Background Information on Tislelizumab ..................................................................28 
1.2.1. 
Pharmacology .............................................................................................................28 
1.2.2. 
Toxicology ..................................................................................................................29 
1.2.3. 
Clinical Pharmacology ................................................................................................29 
1.2.4. 
Prior Clinical Experience of Tislelizumab .................................................................30 
1.2.4.1. 
BGB-A317_Study_001 (Data Cutoff 28 August 2017) .............................................30 
1.2.4.2. 
Study BGB-A317-102 (Data Cutoff 28 August 2017) ...............................................31 
1.2.4.3. 
Immune-Mediated Reactions ......................................................................................31 
1.2.4.4. 
Study BGB-A317-206 (Data Cutoff 05 June 2018) ...................................................32 
1.3. 
Study Rationales .........................................................................................................32 
1.3.1. 
Rationale for Testing Tislelizumab in Combination with Chemotherapy in 
the Treatment of Extensive-Stage Small Cell Lung Cancer .......................................32 
1.3.2. 
Rationale for Selection of Tislelizumab Dose in Combination With 
Chemotherapy .............................................................................................................34 
1.3.3. 
Rationale for Placebo Plus Cisplatin or Carboplatin and Etoposide as the 
Comparator .................................................................................................................34 
1.3.4. 
Rationale for Overall Survival as Primary Endpoint ..................................................35 
1.3.5. 
Rationale for Allowing Selected Patients to Continue Treatment Beyond 
Radiographic Disease Progression per RECIST v1.1 .................................................35 
1.3.6. 
Rationale for Patient-Reported Outcome Assessments ..............................................35 
1.4. 
Benefit-Risk Assessment ............................................................................................36 
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2.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................37 
2.1. 
Study Objectives .........................................................................................................37 
2.1.1. 
Primary Objective .......................................................................................................37 
2.1.2. 
Secondary Objectives .................................................................................................37 
2.1.3. 
Exploratory Objectives ...............................................................................................37 
2.2. 
Study Endpoints ..........................................................................................................37 
2.2.1. 
Primary Endpoint ........................................................................................................37 
2.2.2. 
Secondary Endpoints ..................................................................................................38 
2.2.3. 
Exploratory Endpoints ................................................................................................38 
3.
STUDY DESIGN .......................................................................................................40 
3.1. 
Summary of Study Design ..........................................................................................40 
3.2. 
Screening Period .........................................................................................................42 
3.3. 
Treatment Period ........................................................................................................42 
3.4. 
Safety Follow-up ........................................................................................................43 
3.5. 
Survival Follow-up .....................................................................................................44 
3.6. 
Discontinuation From the Study Treatment or From the Study .................................44 
3.6.1. 
Patient Discontinuation From Study Treatment .........................................................44 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........45 
3.7. 
End of Study ...............................................................................................................45 
4.
STUDY POPULATION .............................................................................................46 
4.1. 
Inclusion Criteria ........................................................................................................46 
4.2. 
Exclusion Criteria .......................................................................................................47 
5.
STUDY TREATMENT ..............................................................................................51 
5.1. 
Formulation, Packaging, and Handling ......................................................................51 
5.1.1. 
Tislelizumab and Placebo ...........................................................................................51 
5.1.1.1. 
Tislelizumab ...............................................................................................................51 
5.1.1.2. 
Placebo ........................................................................................................................51 
5.1.2. 
Chemotherapy .............................................................................................................51 
5.2. 
Dosage, Administration, and Compliance ..................................................................51 
5.2.1. 
Tislelizumab or Placebo .............................................................................................53 
5.2.2. 
Chemotherapy .............................................................................................................54 
5.2.3. 
Supportive Care ..........................................................................................................55 
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5.3. 
Overdose .....................................................................................................................55 
5.4. 
Investigational Medicinal Product Accountability .....................................................55 
5.5. 
Dose Delay or Modification .......................................................................................55 
5.5.1. 
General Guidance Regarding Dose Modifications .....................................................55 
5.5.2. 
Dose Delay or Modification for Tislelizumab or Placebo ..........................................56 
5.5.3. 
Dose Delay, Interruption or Modifications for Chemotherapy ..................................57 
5.6. 
Blinding ......................................................................................................................58 
5.7. 
Criteria for Discontinuing Chemotherapy Regimens .................................................59 
6.
PRIOR AND CONCOMITANT THERAPY .............................................................61 
6.1. 
Prior Therapy ..............................................................................................................61 
6.2. 
Concomitant Therapy .................................................................................................61 
6.2.1. 
Permitted Concomitant Medications/Procedures .......................................................61 
6.2.2. 
Prohibited or Restricted Concomitant Medications/Procedures .................................62 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................63 
7.
STUDY ASSESSMENTS AND PROCEDURES ......................................................64 
7.1. 
Screening ....................................................................................................................64 
7.1.1. 
Demographic Data and Medical History ....................................................................64 
7.1.2. 
Females of Childbearing Potential and Contraception ...............................................65 
7.1.3. 
Informed Consent and Screening Log ........................................................................65 
7.1.4. 
Patient Numbering ......................................................................................................65 
7.1.5. 
Pulmonary Function Tests ..........................................................................................65 
7.2. 
Enrollment ..................................................................................................................65 
7.2.1. 
Confirmation of Eligibility .........................................................................................65 
7.2.2. 
Enrollment/Randomization .........................................................................................66 
7.3. 
Tislelizumab, Placebo and Chemotherapy Dispensation ............................................66 
7.4. 
Crossover ....................................................................................................................66 
7.5. 
Safety Assessments .....................................................................................................66 
7.5.1. 
Vital Signs ..................................................................................................................66 
7.5.2. 
Physical Examinations ................................................................................................66 
7.5.3. 
Eastern Cooperative Oncology Group Performance Status ........................................67 
7.5.4. 
Laboratory Safety Tests ..............................................................................................67 
7.5.5. 
Electrocardiograms .....................................................................................................68 
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7.5.6. 
Adverse Events ...........................................................................................................68 
7.5.7. 
Hepatitis B and C Testing ...........................................................................................68 
7.6. 
Tumor and Response Evaluations ..............................................................................68 
7.7. 
Pharmacokinetic and Antidrug Antibody Testing ......................................................70 
7.8. 
Biomarkers ..................................................................................................................70 
7.9. 
Health-Related Quality of Life ...................................................................................71 
7.10. 
Visit Windows ............................................................................................................71 
7.11. 
Unscheduled Visits .....................................................................................................71 
8. 
SAFETY MONITORING AND REPORTING .........................................................72 
8.1. 
Risks Associated With Study Drug ............................................................................72 
8.1.1. 
Risks Associated With Tislelizumab ..........................................................................72 
8.1.2. 
Risks Associated With Chemotherapy .......................................................................72 
8.2. 
General Plan to Manage Safety Concerns ..................................................................72 
8.2.1. 
Eligibility Criteria .......................................................................................................72 
8.2.2. 
Safety Monitoring Plan ...............................................................................................72 
8.3. 
Adverse Events ...........................................................................................................73 
8.3.1. 
Definitions and Reporting ...........................................................................................73 
8.3.2. 
Assessment of Severity ...............................................................................................74 
8.3.3. 
Assessment of Causality .............................................................................................74 
8.3.4. 
Following Adverse Events ..........................................................................................75 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................76 
8.4. 
Definition of a Serious Adverse Event .......................................................................76 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................77 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................77 
8.6.1. 
Adverse Event Reporting Period ................................................................................77 
8.6.2. 
Reporting Serious Adverse Events .............................................................................77 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................77 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................78 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................78 
8.6.3. 
Eliciting Adverse Events ............................................................................................78 
8.6.4. 
Disease Progression ....................................................................................................78 
8.6.5. 
Deaths .........................................................................................................................79 
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8.6.6. 
Pregnancies .................................................................................................................79 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................79 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................79 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................80 
8.7. 
Management of Adverse Events of Special Interest ...................................................80 
8.7.1. 
Infusion-Related Reactions .........................................................................................80 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................82 
8.7.3. 
Immune-Mediated Adverse Events ............................................................................82 
8.7.4. 
Renal Function Abnormalities ....................................................................................83 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................84 
9.1. 
Statistical Analysis ......................................................................................................84 
9.1.1. 
Randomization Methods .............................................................................................84 
9.1.2. 
Analysis Sets ...............................................................................................................84 
9.1.3. 
Patient Disposition ......................................................................................................84 
9.1.4. 
Demographic and Other Baseline Characteristics ......................................................85 
9.1.5. 
Prior and Concomitant Medications ...........................................................................85 
9.2. 
Efficacy Analyses .......................................................................................................85 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................85 
9.2.2. 
Secondary Efficacy Analysis ......................................................................................86 
9.2.3. 
Exploratory Efficacy Analysis ....................................................................................87 
9.3. 
Safety Analyses ..........................................................................................................88 
9.3.1. 
Extent of Exposure .....................................................................................................88 
9.3.2. 
Adverse Events ...........................................................................................................88 
9.3.3. 
Laboratory Analyses ...................................................................................................88 
9.3.4. 
Vital Signs ..................................................................................................................89 
9.4. 
Pharmacokinetic Analysis ..........................................................................................89 
9.5. 
Immunogenicity Analyses ..........................................................................................89 
9.6. 
Sample Size Consideration .........................................................................................89 
9.7. 
Interim Analyses .........................................................................................................90 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................90 
10.1. 
Independent Data Monitoring Committee ..................................................................90 
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................91 
11.1. 
Access to Information for Monitoring ........................................................................91 
11.2. 
Access to Information for Auditing or Inspections ....................................................91 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................91 
12.1. 
Regulatory Authority Approval ..................................................................................91 
12.2. 
Quality Assurance .......................................................................................................92 
12.3. 
Study Site Inspections .................................................................................................92 
12.4. 
Drug Accountability ...................................................................................................92 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................93 
13.1. 
Ethical Standard ..........................................................................................................93 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................93 
13.2.1. 
Protocol Amendments ................................................................................................93 
13.3. 
Informed Consent .......................................................................................................94 
13.4. 
Patient and Data Confidentiality .................................................................................94 
13.5. 
Financial Disclosure ...................................................................................................95 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................96 
14.1. 
Data Collection and Management Responsibilities ....................................................96 
14.1.1. 
Data Entry in the Electronic Case Report Form .........................................................96 
14.1.2. 
Data Collection ...........................................................................................................96 
14.1.3. 
Data Management/Coding ..........................................................................................96 
14.2. 
Data Integrity and In-house Blinding .........................................................................97 
14.3. 
Study Records Retention ............................................................................................97 
14.4. 
Protocol Deviations ....................................................................................................98 
14.5. 
Publication and Data Sharing Policy ..........................................................................98 
14.6. 
Study and Study Center Closure .................................................................................99 
14.7. 
Information Disclosure and Inventions ......................................................................99 
15. 
REFERENCES .........................................................................................................101 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................107 
APPENDIX 2. ECOG PERFORMANCE STATUS ................................................................112 
APPENDIX 3. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................113 
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APPENDIX 4. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................122 
APPENDIX 5. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................123 
APPENDIX 6. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................124 
APPENDIX 7. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................134 
APPENDIX 8. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................135 
APPENDIX 9. DOSE MODIFICATION OF CHEMOTHERAPY .........................................137 
APPENDIX 10. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30 .................................................................................139 
APPENDIX 11. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE QUESTIONNAIRE 
LUNG CANCER MODULE QLQ-LC13 ................................................................141 
APPENDIX 12. EUROQOL 5-DIMENSION, 5-LEVEL ........................................................142 
 
LIST OF TABLES 
Table 1. Results From Randomized Studies Using Platinum-Based Chemotherapy for 
Extensive-Stage Small Cell Lung Cancer ...................................................................25 
Table 2. Ongoing First-Line PD-1 Pathway-Targeting Immunotherapy Studies in ES-
SCLC ..........................................................................................................................28 
Table 3. Selection and Timing of Dose Administration of Tislelizumab or Placebo in 
Combination With Cisplatin and Etoposide ...............................................................52 
Table 4. Selection and Timing of Dose Administration of Tislelizumab or Placebo in 
Combination With Carboplatin and Etoposide ...........................................................53 
Table 5. Timeframes and Documentation Methods for Reporting Serious Adverse Events 
to the Sponsor or Designee .........................................................................................77 
Table 6. Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) ..............................................................................................................81 
Table 7. Immune-Mediated Adverse Events .................................................................................83 
Table 8. Analysis Timing and Stopping Boundaries for OS in the ITT Analysis Set ...................90 
 
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LIST OF FIGURES 
Figure 1. 
Study Schema .............................................................................................................41 
 
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SYNOPSIS 
Name of Sponsor/Company: BeiGene (Shanghai) Co., Ltd. 
Investigational Product: Tislelizumab (BGB-A317) 
Title of Study: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Platinum Plus 
Etoposide With or Without Tislelizumab (BGB-A317) in Patients With Untreated Extensive-Stage 
Small Cell Lung Cancer 
Protocol Identifier: BGB-A317-312 
Phase of Development: 3 
Number of Patients: Approximately 455 
Study Centers: Approximately 50 centers in China 
Study Objectives: 
Primary:   
• 
To evaluate the efficacy of tislelizumab + cisplatin or carboplatin + etoposide compared with 
placebo + cisplatin or carboplatin + etoposide in the Intent-to-Treat (ITT) Analysis Set as 
measured by overall survival (OS) 
Secondary: 
• 
To evaluate the efficacy of tislelizumab + cisplatin or carboplatin + etoposide compared with 
placebo + cisplatin or carboplatin + etoposide in the ITT Analysis Set as measured by 
investigator-assessed progression-free survival (PFS) according to Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST v1.1) 
• 
To evaluate the efficacy of tislelizumab + cisplatin or carboplatin + etoposide compared with 
placebo + cisplatin or carboplatin + etoposide in the ITT Analysis Set as measured by 
investigator-assessed overall response rate (ORR), duration of response (DOR), and disease 
control rate (DCR) according to RECIST v1.1 
• 
To evaluate the effect of tislelizumab + cisplatin or carboplatin + etoposide compared with 
placebo + cisplatin or carboplatin + etoposide on patients’ health-related quality of life 
(HRQoL) according to the European Organisation for the Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30) and the supplemental lung 
cancer module (QLQ-LC13).  
• 
To evaluate the safety and tolerability of tislelizumab in combination with cisplatin or 
carboplatin and etoposide compared with cisplatin or carboplatin and etoposide 
Exploratory: 
• 
To assess PFS after next line of treatment (PFS2) 
• 
To explore potential predictive biomarkers in archival and/or fresh tumor tissue and/or blood 
(or blood derivatives), including but not limited to programmed cell death protein ligand-1 
(PD-L1) expression by immunohistochemistry (IHC), multiplex IHC (mIHC), gene expression 
profiling (GEP), tumor mutation burden (TMB), microsatellite instability (MSI), and blood 
TMB (bTMB), to evaluate the association between these biomarkers and response to study 
treatment or mechanism of resistance 
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• 
To characterize pharmacokinetics (PK) of tislelizumab in patients with small cell lung cancer 
(SCLC) 
• 
To evaluate host immunogenicity to tislelizumab by assessing antidrug antibodies (ADAs) 
against tislelizumab in patients with SCLC 
• 
To examine the patients’ quality of life (QoL) as measured by EuroQoL 5-Dimension, 5-Level 
(EQ5D-5L) 
Study Endpoints: 
Primary: 
• 
OS, defined as the time from randomization to death from any cause 
Secondary: 
• 
PFS, defined as the time from randomization to the first occurrence of disease progression as 
determined by investigator using RECIST v1.1 or death from any cause, whichever occurs first 
• 
ORR, defined as the proportion of patients with partial response (PR) or complete response 
(CR) as determined by the investigator using RECIST v1.1 
• 
DOR, defined as the time from the first occurrence of a documented objective response to the 
time of relapse, as determined by the investigator per RECIST v1.1, or death from any cause, 
whichever comes first 
• 
DCR, defined as the proportion of patients whose best overall response (BOR) is CR, PR or 
stable disease per RECIST v1.1 
• 
Incidence and severity of treatment-emergent adverse events (TEAEs) graded according to 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
v5.0 
• 
Percentage of patients with clinically meaningful changes post baseline, defined as a 10-point 
improvement or worsening (to be defined in the Statistical Analysis Plan [SAP] if otherwise) 
in: 
o Global health status (GHS) and physical function (PF) per the QLQ-C30  
o Dyspnoea, coughing, haemoptysis, dysphagia, chest pain, pain in arms and shoulders, 
and peripheral neuropathy symptoms of QLQ-LC13 
• 
Time to deterioration, defined as the time from randomization to the first occurrence of 
worsening scores (10-point change; to be defined in the SAP if otherwise) confirmed at the 
following visit or death from any cause, in: 
o GHS and PF per the QLQ-C30  
o Dyspnoea, coughing, haemoptysis, dysphagia, chest pain, pain in arms and shoulders, 
and peripheral neuropathy symptoms of QLQ-LC13 
Exploratory: 
• 
PFS2, defined as the time from randomization to the objective disease progression after next 
line of treatment or death from any cause, whichever occurs first 
• 
Status of predictive and prognostic biomarkers including but not limited to programmed cell 
death protein ligand-1 (PD-L1) expression, mIHC, GEP, TMB, and MSI in archival and/or 
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fresh tumor tissue and bTMB in blood before study treatment and/or at disease progression, 
and the association between the biomarkers and disease status or response to study treatment 
• 
Summary of serum concentrations of tislelizumab 
• 
Assessments of immunogenicity of tislelizumab by determining the incidence of ADAs 
• 
QoL is defined as changes in patients’ general well-being measured by the scores of the EQ5D-
5L descriptive 5-dimension scores and the visual analog scale (VAS).  
Study Design: 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to compare the 
efficacy of tislelizumab + cisplatin or carboplatin + etoposide (Arm A) and placebo + cisplatin or 
carboplatin + etoposide (Arm B) as first-line treatment in approximately 455 patients who have 
previously untreated extensive-stage small cell lung cancer (ES-SCLC).  
The study consists of a Screening phase, a Treatment phase that includes an Induction treatment period 
and a Maintenance treatment period, a Safety Follow-up phase, and a Survival Follow-up phase.  
Eligible patients will be stratified by Eastern Cooperative Oncology Group (ECOG) Performance 
Status (0 versus 1), investigator-chosen chemotherapy (carboplatin versus cisplatin), and brain 
metastasis (yes versus no), and randomized in a 1:1 ratio to receive 1 of the following treatment 
regimens: 
• 
Induction period (administered on a 3-week cycle for 4 cycles): 
o Arm A: tislelizumab + cisplatin or carboplatin + etoposide 
o Arm B: placebo + cisplatin or carboplatin + etoposide 
• 
Maintenance period (administered once every 3 weeks): 
o Arm A: tislelizumab 
o Arm B: placebo 
Induction treatment will be administered on 21-day cycle for 4 cycles. The selection of platinum 
(cisplatin or carboplatin) will be at the investigator’s discretion and documented prior to randomization. 
Cycles in which no chemotherapy is given do not count toward the total number of Induction 
chemotherapy cycles. 
Following Induction treatment, patients will enter a Maintenance treatment period to receive either 
tislelizumab or placebo alone in accordance to the treatment arm to which they are randomized. During 
the Maintenance treatment period prophylactic cranial irradiation (PCI) is permitted as per local 
standard of care. 
Treatment may continue until the completion of the scheduled 4 cycles (only for Induction treatment 
period), disease progression as assessed by the investigator per RECIST v1.1, loss of clinical benefit, 
unacceptable toxicity, or withdrawal of informed consent, whichever occurs first. 
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune cell 
infiltration and other mechanisms leading to apparent increase of existing tumor masses or appearance 
of new tumor lesions. Thus, if radiographic progressive disease is suspected by the investigator to 
reflect pseudoprogression, patients may continue treatment until progressive disease is confirmed by 
repeated imaging ≥ 4 weeks later (but not exceeding 6 to 8 weeks from the date of initial 
documentation of progressive disease). If at the investigator’s discretion a patient could continue to 
benefit from study treatment after progressive disease per RECIST v1.1 criteria, the patient may 
continue study treatment. Patients who have suspected pseudoprogression or who may continue to 
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benefit from study treatment after progressive disease must meet the following criteria in order to be 
treated:  
• 
Absence of clinical symptoms and signs of disease progression (including clinically significant 
worsening of laboratory values)  
• 
Stable ECOG performance status ≤ 1 
• 
Absence of rapid progression of disease or of progressive tumor at critical anatomical sites (eg, 
cord compression) that requires urgent alternative medical intervention 
• 
Investigators must obtain written informed consent for treatment beyond radiologic disease 
progression and inform patients that this practice is not considered standard in the treatment of 
cancer. 
Patients who could derive benefit from study drug after progressive disease as assessed by the 
investigator per RECIST v1.1 criteria may continue treatment until loss of clinical benefit as assessed 
by the investigator, withdrawal of consent, unacceptable toxicity, study completion by the sponsor, 
start of a new anticancer therapy, or death, whichever occurs first. 
The decision to continue study drug beyond initial investigator-assessed progression must be agreed to 
by the medical monitor and documented in the study records. 
There is no crossover between the 2 arms in this study. 
Regular safety monitoring (at least every 6 months) and efficacy monitoring (eg, interim analysis for 
OS) will be performed by an Independent Data Monitoring Committee (IDMC). The first IDMC safety 
review will occur after ≥ 20 patients have been randomized to study treatment (ie, approximately 
10 patients per treatment arm) and have been on study treatment for ≥ 1 month in order to confirm if 
the proposed dosing schedule of tislelizumab or placebo is safe and tolerable. The IDMC may 
recommend study modifications including termination of the study due to safety and/or efficacy 
concerns, or in the event of compelling efficacy at a pre-planned interim analysis. One interim efficacy 
analysis of OS is planned for when approximately 282 OS events are observed. The early stopping rule 
for the interim analysis will be set for superiority. 
The function and membership of the IDMC are described in the IDMC charter (Section 10.1). In 
addition to the planned IDMC review(s), ad hoc reviews may be performed based on new information. 
Study Assessments: 
Patients will undergo tumor assessments at baseline and every 6 weeks (± 7 days) for the first 48 weeks 
following Cycle 1 Day 1, and every 9 weeks (± 7 days) thereafter, regardless of treatment dose delay. 
Tumor assessment at baseline must be performed within 28 days prior to randomization. Tumor 
assessment will be performed by the investigator and continue until radiographic disease progression 
per RECIST v1.1. 
Patients who discontinue study treatment early for reasons other than disease progression (eg, toxicity) 
will continue to undergo tumor assessments following the original plan until the patient begins a 
subsequent anticancer treatment, experiences disease progression, withdraws consent, is lost to 
follow-up, death, or until the study terminates, whichever occurs first. 
Patients who continue treatment beyond disease progression will continue to undergo tumor 
assessments following the original plan or as clinically indicated until treatment end. 
Patient-reported outcomes will be collected using the EORTC QLQ-LC13, EORTC QLQ-C30, and 
EQ5D-5L at baseline (predose at Day 1 of Cycle 1), at every cycle through Cycle 4, then every other 
cycle thereafter until the End-of-Treatment Visit, and at the Safety Follow-up Visit. 
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To determine the pharmacokinetic (PK) properties of tislelizumab and host immunogenic response to 
tislelizumab, blood samples will be collected at various timepoints as outlined in Appendix 1. 
Patients will be evaluated for adverse events (AEs) and immune-mediated adverse events (imAEs) (all 
grades according to NCI-CTCAE v5.0). Serious AEs (SAEs) and any AE will be followed and 
documented until the event resolves, the investigators assess the event as stable, or the patient is lost to 
follow-up, whichever occurs first.  
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until either 30 days after the last dose of study treatment (including chemotherapy) or 
initiation of new anticancer therapy, whichever occurs first. All imAEs (serious or nonserious) should 
be reported for 90 days after the last dose of tislelizumab or placebo, regardless of whether the patient 
starts a new anticancer therapy. The investigator should report any SAEs that are believed to be related 
to study treatment at any time after treatment discontinuation. 
Duration of Patient Participation: 
The duration of the study from the first enrolled patient to the final analysis for OS is estimated to be 
approximately 51 months. 
Study Population:  
Approximately 455 patients with previously untreated ES-SCLC will be enrolled and randomized in a 
1:1 ratio to receive 1 of the study treatment regimens.  
Key Eligibility Criteria: 
Key inclusion criteria: 
Each patient eligible to participate in this study must meet all of the following criteria: 
• 
Age ≥ 18 years on the day of signing the informed consent form (or the legal age of consent in 
the jurisdiction in which the study is taking place) 
• 
ECOG Performance Status of 0 or 1 
• 
Histologically or cytologically confirmed ES-SCLC (defined by the American Joint Committee 
on Cancer, Seventh Edition, as Stage IV [T any, N any, M 1a/b] or T3-4 due to multiple lung 
nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed 
in a tolerable radiation plan.) 
• 
No prior systemic treatment for ES-SCLC 
o Patients who have received prior chemoradiotherapy for limited-stage SCLC must 
have been treated with curative intent and experienced a treatment-free interval of 
≥ 6 months between the completion of chemotherapy, radiotherapy, or 
chemoradiotherapy and diagnosis of ES-SCLC. 
• 
Adequate hematologic and end organ function 
Key exclusion criteria: 
Patients who meet any of the following criteria are not eligible to enroll: 
• 
Active leptomeningeal disease or uncontrolled, untreated brain metastasis: 
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o Patients with a history of treated and, at the time of screening, asymptomatic central 
nervous system (CNS) metastases are eligible if they meet all the following: 
- 
Brain imaging at screening shows no evidence of interim progression between 
the completion of CNS-directed therapy and randomization 
- 
Only supratentorial metastases allowed 
- 
No ongoing requirement for corticosteroids as therapy for CNS disease; 
anticonvulsants at a stable dose allowed 
- 
No stereotactic radiation or whole-brain radiation within 14 days prior to 
randomization 
o Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases.  
- 
Following treatment, these patients may then be eligible, provided all other 
criteria, including those for patients with a history of brain metastases, are met. 
• 
Prior therapy with an antibody or drug against immune checkpoint pathways, including but not 
limited to, anti-programmed cell death protein-1 (anti-PD-1), anti-PD-L1, or anti-cytotoxic 
T-lymphocyte-associated antigen 4 (anti-CTLA-4) antibody 
• 
Was administered a live vaccine ≤ 4 weeks before randomization 
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines, and are not allowed 
• 
Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of 
prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
randomization 
• 
Active autoimmune diseases or history of autoimmune diseases that may relapse 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening:  
o Controlled type 1 diabetes 
o Hypothyroidism (provided it is managed with hormone replacement therapy only) 
o Controlled celiac disease 
o Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
o Any other disease that is not expected to recur in the absence of external triggering 
factors 
• 
With a history of interstitial lung disease, non-infectious pneumonitis, or uncontrolled systemic 
diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung diseases, etc 
• 
Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral 
therapy within 2 weeks prior to randomization, including but not limited to tuberculosis 
infection 
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o Received therapeutic oral or intravenous antibiotics within 2 weeks prior to 
randomization 
Investigational Product, Dose, and Mode of Administration:   
Tislelizumab and placebo should be administered at a dose of 200 mg intravenously once every 
3 weeks. 
Non-Investigational Therapy, Dose, and Mode of Administration:   
Cisplatin 75 mg/m2 should be administered as an intravenous infusion over 2 hours once every 3 weeks 
on Day 1 of each cycle for 4 cycles, or 
Carboplatin area under the plasma or serum concentration-time curve 5 (AUC 5) should be 
administrated as an intravenous infusion over 15 to 60 minutes once every 3 weeks on Day 1 of each 
cycle for 4 cycles 
Etoposide (100 mg/m2) should be administered as an intravenous infusion over 60 minutes on Days 1, 
2, and 3 of each 3-week cycle for 4 cycles 
Statistical Methods: 
Analysis Sets: 
The ITT Analysis Set includes all randomized patients. Patients will be analyzed according to their 
randomized treatment arms. This will be the primary Analysis Set for all efficacy analyses.  
The Safety Analysis Set includes all randomized patients who received ≥ 1 dose of any component of 
study treatment; it will be the Analysis Set for the safety analyses. Patients will be analyzed according 
to the actual treatment regimen received.  
The PK Analysis Set includes all patients who receive ≥ 1 dose of tislelizumab per the protocol, for 
whom any postdose PK data are available. 
The ADA Analysis Set includes all patients who are randomized to the tislelizumab arm and have a 
baseline and ≥ 1 postbaseline ADA result. 
Primary Efficacy Endpoint Analysis: 
Overall survival 
OS is defined as the time from randomization to death from any cause. OS will be analyzed in the ITT 
Analysis Set. Data for patients who are not reported as having died at the time of analysis will be 
censored at the date last known to be alive. Data for patients who do not have postbaseline information 
will be censored at the date of randomization. 
OS will be compared between tislelizumab + cisplatin or carboplatin + etoposide (Arm A) and placebo 
+ cisplatin or carboplatin + etoposide (Arm B) in a stratified log-rank test using a one-sided 
significance level of 0.025: 
The null hypothesis to be tested is: 
H0: OS in Arm A ≤ OS in Arm B 
against the alternative hypothesis: 
Ha: OS in Arm A > OS in Arm B 
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The p-value from a stratified log-rank test will be presented using stratification factors with actual 
values as recorded in the electronic data capture (EDC) system at randomization. The OS hazard ratio 
(HR) between the two arms and its 95% confidence interval (CI) will be estimated using a stratified 
Cox regression model with treatment arm as a factor and the model will be stratified by the actual value 
of the stratification factors. The median OS and the cumulative probability of OS at 1 year and 2 years, 
if estimable, will be calculated for each treatment arm and presented with two-sided 95% CIs using 
Kaplan-Meier methodology. A Kaplan-Meier curve will be constructed to provide a visual description 
of the difference between arms. 
Secondary Efficacy Endpoint Analyses: 
Progression-free survival (PFS)  
PFS is defined as the time from randomization to the first documented disease progression by RECIST 
v1.1 as assessed by the investigator, or death from any cause, whichever occurs first. PFS will be 
analyzed in the ITT Analysis Set. PFS will be calculated based on actual tumor assessment visit dates. 
Data for patients without disease progression or death at the time of analysis will be censored at the 
time of the last valid tumor assessment. Data for patients without postbaseline tumor assessment will 
be censored at the time of randomization. Data for patients who start to receive new anticancer therapy 
or are lost to follow-up will be censored at the last valid tumor assessment date prior to the introduction 
of new therapy or loss to follow-up. Patients who have a clinical determination of progression should 
undergo a radiographic imaging as required by RECIST v1.1, if possible, to correlate radiographic 
findings with the clinical findings. If a clinical determination of progression for a patient is confirmed, 
the date of the radiographic imaging will be considered as the progression date for that patient. 
The HR for PFS will be estimated using a stratified Cox regression model with treatment arm as a 
factor and stratified by the actual value of the stratification factors. The 95% CI for the HR will be 
provided. Kaplan-Meier methodology will be used to estimate median PFS, cumulative probabilities of 
PFS at 6 month and 1-year, and a Kaplan-Meier curve will be constructed to provide a visual 
description of the difference among arms. 
Overall response rate (ORR) 
ORR (confirmation not required according to RECIST v1.1) is the proportion of patients who had CR 
or PR per RECIST v1.1 in all randomized patients with measurable disease at baseline. Patients 
without any postbaseline assessment will be considered non-responders. The difference in ORR 
between arms in the ITT Analysis Set will be evaluated using the Cochran-Mantel-Haenszel (CMH) 
chi-square test with the actual stratification factors as strata for descriptive purpose only. The two-sided 
95% CIs for the odds ratio and the difference in ORR will be calculated, as well as Clopper-Pearson 
95% CIs for the ORR within each arm.  
Duration of response (DOR) 
DOR is defined for patients with an objective response as the time from the first documented objective 
response to documented disease progression as determined using the RECIST v1.1, or death from any 
cause, whichever occurs first. Data for patients who are alive and who have not experienced disease 
progression at the time of analysis will be censored at the date of the last tumor assessment. If no tumor 
assessments were performed after the date of the first occurrence of the objective response (CR or PR), 
DOR will be censored at the date of the first occurrence of the objective response. DOR will be 
estimated using Kaplan-Meier methodology. Comparisons between treatment arms will be made using 
the stratified log-rank test for descriptive purposes only.  
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Disease control rate (DCR) 
DCR is defined as the proportion of patients with objective response (CR or PR) or stable disease 
maintained for ≥ 6 weeks using the RECIST v1.1. The analysis methods for DCR will be the same as 
those for ORR.  
Health Related Quality of Life (HRQoL)  
HRQoL is assessed via the EORTC QLQ-C30 GHS/QoL, functional and symptom scales scores, and 
the single-item scores. Observed values and changes from baseline will be summarized using 
descriptive statistics. Clinically meaningful changes post baseline (percentage of patients with a 
10-point improvement or worsening; to be defined in the SAP if otherwise) for GHS and PF per the 
QLQ-C30 and dyspnoea, coughing, haemoptysis, dysphagia, chest pain, pain in arms and shoulders, 
and peripheral neuropathy symptoms of QLQ-LC13 will be calculated by timepoint and compared 
between the treatment arms.  
Time to deterioration of the aforementioned scales will be analyzed as well. It is defined as time from 
randomization to the first occurrence of a worsening score (10-point change; to be defined in the SAP 
if otherwise) confirmed at the following visit or death from any cause. Time to deterioration between 
treatment arms will be compared using log-rank test and its Kaplan-Meier probabilities for each arm 
will be plotted over time.  
Exploratory Efficacy Analyses: 
PFS after next line of treatment (PFS2) 
To calculate PFS2, data from patients without disease progression after next line of treatment or death 
at the time of analysis will be censored at the last time known to be alive. Kaplan-Meier method as 
described in the PFS and OS analyses will be used in the analysis of PFS2. 
PD-L1 expression as a predictive biomarker for efficacy 
Distribution of PD-L1 expression will be examined in the ITT Analysis Set. Any potential association 
between PD-L1 expression and tislelizumab treatment effect over control (PFS, OS, ORR, DOR, and 
DCR) may be explored. Other potential predictive markers, including but not limited to GEP, TMB and 
MSI in archival and/or fresh tumor tissue and bTMB may be assessed before study treatment and/or at 
disease progression, and the association with disease status and/or response to tislelizumab in 
combination with chemotherapy may be also assessed. 
Quality of Life (QoL) 
Summary statistics (mean, standard deviation, median, and range) of the postbaseline scores of the 
EQ5D-5L descriptive dimension and VAS will be reported. Summaries will be performed for the ITT 
Analysis Set only. 
Pharmacokinetic Analyses 
Pharmacokinetic samples will be collected in this study as outlined in Appendix 1. Tislelizumab 
lowest concentration before the next dose (Ctrough) data will be tabulated and summarized for each cycle 
at which PK is to be measured in the PK Analysis Set. Descriptive statistics will include means, 
medians, ranges, and standard deviations, as appropriate. 
Additional PK analyses may be conducted as appropriate. 
Immunogenicity Analyses 
Immunogenicity samples will be collected in this study as outlined in Appendix 1.  
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The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable antidrug antibodies (ADA). The incidence of positive 
ADA and neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on 
PK, efficacy and safety may be evaluated if data allow. 
Safety Analyses: 
Safety will be assessed throughout the study by monitoring and recording all AEs graded by NCI-
CTCAE v5.0. Laboratory values (eg, hematology, clinical chemistry, and urinalysis), vital signs, 
physical examinations, ECOG Performance Status change, electrocardiograms (ECGs), and other 
examinations will also be used in determining safety. Descriptive statistics will be used to analyze all 
safety data in the Safety Analysis Set. 
Sample Size Considerations: 
The sample size calculation is based on the number of events required to demonstrate the OS 
superiority of Arm A to Arm B in the ITT Analysis Set. The estimates of the number of events required 
to demonstrate efficacy with regard to OS is based on the following assumptions: 
Overall survival: 
• 
Median OS of 12 months in Arm B  
• 
At a one-sided α of 0.025, 80% power to detect an OS HR of 0.74 in the ITT Analysis Set. 
• 
One OS interim analysis is planned in the ITT Analysis Set when approximately 80% of total 
OS events occurred, with Lan-DeMets’ approximation to O’Brien-Fleming boundary. 
• 
Exponential survival distribution is assumed for both Arm A and Arm B. 
In addition, we assumed a randomization ratio of 1:1. Approximately 455 patients are to be enrolled 
over a 22-month period at a steady-state enrollment rate of 26 patients per month with enrollment 
ramp-up duration of 9 months, and assuming a dropout rate of 5% per year for OS endpoint, a total of 
353 OS events are required for the ITT Analysis Set for the final OS analysis.  
Interim Analyses: 
There will be 1 interim efficacy analysis of OS performed in the ITT Analysis Set. The interim efficacy 
analysis of OS will be performed with at least 282 OS events observed in the ITT Analysis Set. The 
analysis timing is projected at approximately 36 months after the first patient randomization. The final 
OS analysis will be conducted with 353 OS events at approximately 51 months after the first patient 
randomization.  
The interim boundary for OS is based on the Lan-DeMets approximation to O’Brien-Fleming 
boundary. The interim and final analysis timing, and stopping boundaries are summarized in Table a. 
Table a. Analysis Timing and Stopping Boundaries for OS in the ITT Analysis Set  
Type of Analysis 
Time 
(Months) 
# Events 
One-Sided Testing Boundary 
p-Value Boundary 
Approx. HR 
Threshold 
Interim Analysis 
36 
282 
0.0122 
0.765 
Final Analysis 
51 
353 
0.0214 
0.806 
Abbreviations: HR, hazard ratio; ITT, Intent-to-Treat; OS, overall survival 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma or serum concentration-time curve 
BGB-A317 
tislelizumab 
BOR 
best overall response 
bTMB 
blood tumor mutation burden  
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
Ctrough 
lowest concentration before the next dose 
DCR 
disease control rate 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture (system) 
EORTC 
European Organisation for the Research and Treatment of Cancer 
EOT 
End-of-Treatment (Visit) 
ES-SCLC 
extensive-stage small cell lung cancer 
Fc 
fragment crystallizable region (typically, of immunoglobulin G) 
FDG 
fluorodeoxyglucose 
GEP 
gene expression profiling 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IMP 
investigational medicinal products 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
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Abbreviation 
Definition 
ITT 
Intent-to-Treat (Analysis Set) 
NCCN 
National Comprehensive Cancer Network 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
ORR 
overall response rate 
OS 
overall survival 
PCI 
prophylactic cranial irradiation 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein ligand-1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFS2 
PFS after next line of treatment 
PK 
pharmacokinetic(s) 
PR 
partial response 
QLQ-C30 
Quality of Life Questionnaire – Core 30 
QLQ-LC13 
Quality of Life Questionnaire supplement lung cancer module 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCLC 
small cell lung cancer 
t1/2 
half-life  
TEAE 
treatment-emergent adverse event 
TMB 
tumor mutation burden 
ULN 
upper limit of normal 
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1. 
INTRODUCTION 
1.1. 
Background Information on Small Cell Lung Cancer 
Lung cancer is the most common cancer worldwide with approximately 1.8 million new 
diagnoses and 1.59 million deaths worldwide in 2012, which corresponds to the highest 
incidence among cancers and most common cancer-related mortality (Ferlay et al 2015). 
Globally, across all cancer types, lung cancer is more common in men (16.8%) as compared to 
women (8.8%). In China, there were estimated 733,300 new cases of lung cancer in 2015. Lung 
cancer is the leading cause of cancer-related death in both men and women with an estimated 
610,200 deaths in China in 2015 (Chen et al 2016).  
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer 
(Molina et al 2008; Howlader et al 2014). Small cell lung cancer (SCLC) accounts for 
approximately 13% of all cases, and it is distinguished from NSCLC by its rapid growth time 
and early development of metastatic disease (Govindan et al 2006). Nearly all cases of SCLC are 
attributable to cigarette smoking (Pesch et al 2012). Poor prognostic factors for survival in 
patients with SCLC include extensive-stage disease, poor Eastern Cooperative Oncology Group 
(ECOG) Performance Status, weight loss, and markers associated with excessive bulk of disease 
(eg, lactate dehydrogenase) (Yip et al 2000; Foster et al 2009). 
Patients with limited-stage SCLC (LS-SCLC) can be treated with chemotherapy and radiation 
with the potential for long-term survival (Stinchcombe et al 2010). Unfortunately, the treatment 
achieves to cure only approximately 20% of patients with LS-SCLC, and those patients still 
suffer relapse within months of completing initial therapy (Simon et al 2007). The majority 
(approximately 70%) of patients with SCLC are diagnosed with extensive-stage disease 
(ES-SCLC), which has poor survival prospects (median overall survival [OS] approximately 
10 months) (Socinski et al 2009). Chest pain, dyspnea, and cough are among the most frequent 
disease-related symptoms experienced by patients with lung cancer. Chemotherapy alone can 
palliate symptoms and prolong survival for patients with ES-SCLC; however, long-term survival 
is rare (Johnson et al 2004; Demedts et al 2010). 
1.1.1. 
Standard Therapy for Extensive-Stage Small Cell Lung Cancer 
In the United States, the current standard first-line treatment for patients with ES-SCLC is 
platinum-based chemotherapy (cisplatin or carboplatin) with etoposide, a topoisomerase II 
inhibitor, for 4 cycles, while in Japan irinotecan is often combined with a platinum agent (NCCN 
2019 v1, Fruh et al 2013). In the mid-1980s, clinical studies with the combination of cisplatin 
and etoposide as first-line treatment in patients with ES-SCLC showed complete response (CR) 
rates > 40% and median survival time of approximately 9 months (Evans et al 1985). 
Subsequently, small randomized studies have suggested similar efficacy of cisplatin and 
carboplatin in patients with SCLC (Skarlos et al 1994; Okamoto et al 2007). A meta-analysis of 
4 randomized studies compared cisplatin-based versus carboplatin-based regimens in patients 
with SCLC (Rossi et al 2012). Of the 663 patients included in this meta-analysis, 68% had 
extensive-stage disease. In patients receiving cisplatin- versus carboplatin-containing regimens, 
there was no significant difference observed in response rate (67% vs. 66%), progression-free 
survival (PFS) (5.5 vs. 5.3 months; hazard ratio [HR]: 1.10; 95% CI: 0.94, 1.29) or OS (9.6 vs. 
9.4 months; HR: 1.08; 95% CI: 0.92, 1.27), suggesting equivalent efficacy in patients with 
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SCLC. Several studies using cisplatin or carboplatin with etoposide (at various doses) have 
shown consistent outcomes (see Table 1). 
Table 1. Results From Randomized Studies Using Platinum-Based Chemotherapy for 
Extensive-Stage Small Cell Lung Cancer 
 
Platinum 
Dose* 
Etoposide 
Dose* 
ORR 
(%) 
Median 
PFS 
(months) 
Median 
OS 
(months) 
Roth et al 
1992 
Cisplatin 
20 mg/m2 
Days 1-5 
80 mg/m2 
Days 1-5 
61% 
4.3 
8.6 
Pujol et al 
2001 
Cisplatin 
100 mg/m2 
Day 2  
100 mg/m2 
Days 1-3  
61%  
6.3  
9.3 
Noda et al 
2002 
Cisplatin 
80 mg/m2 Day 1  
100 mg/m2 
Days 1-3  
68%  
4.8  
9.4 
Eckardt et al 
2006 
Cisplatin 
80 mg/m2 Day 1  
100 mg/m2 
Days 1-3  
69%  
6.3  
10.1 
Hanna et al 
2006 
Cisplatin 
60 mg/m2 Day 1  
120 mg/m2 
Days 1-3  
44%  
4.6  
10.2 
Okamoto et al 
2007 
Cisplatin 
25 mg/m2 
Days 1-3  
80 mg/m2 
Days 1-3  
73%  
4.7  
9.9 
Okamoto et al 
2007 
Carboplatin 
AUC 5 Day 1  
80 mg/m2 
Days 1-3  
73%  
5.2  
10.6 
Rudin et al 
2008 
Carboplatin 
AUC 5 Day 1  
100 mg/m2 
Days 1-3  
52%  
5.4  
10.6 
Socinski et al 
2009 
Carboplatin 
AUC 5 Day 1  
80 mg/m2 
Days 1-3  
60%  
7.6  
10.6 
Nagel et al 
2011 
Carboplatin 
AUC 6 Day 1  
120 mg/m2 
Days 1-3  
67%  
7.0  
11.0 
Schmittel et 
al 2011 
Carboplatin 
AUC 5 Day 1  
140 mg/m2 
Days 1-3  
52%  
6.0  
9.0 
Abbreviations: AUC, area under the concentration-time curve; ORR, overall response rate; OS, overall survival; 
PFS, progression-free survival 
*Both platinum and etoposide are administered on a 3-week cycle basis 
In the second-line setting, single-agent topotecan approved by the US Food and Drug 
Administration (US FDA) serves as subsequent therapy for patients with SCLC who initially 
respond to chemotherapy but then progress after 2-3 months. This treatment is based on a 
Phase 3 study in which intravenous topotecan was compared with the combination regimen CAV 
(cyclophosphamide, doxorubicin, and vincristine). Both arms had similar response rates and 
survival; however, the proportion of patients who experienced symptom improvement was 
greater in the topotecan group than in the CAV group for 4 of 8 symptoms evaluated, including 
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dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (Von Pawel 
et al 1999). Subsequently, a Phase 3 study also showed the superiority of oral topotecan versus 
best supportive care for patients who had relapsed SCLC and were not considered candidates for 
standard intravenous therapy (O’Brien et al 2006).  
In the third- and further-line setting, anlotinib, a novel multitarget small molecule tyrosine kinase 
inhibitor (TKI), has been approved by the National Medical Products Administration(NMPA) in 
China and serves as subsequent therapy for SCLC patients who had previously received at least 
2 chemotherapy regimens. The approval of this treatment is based on a Phase 2 randomized 
study which was initiated to confirm the efficacy and safety of anlotinib versus placebo in 
third-line and further-line treatment of SCLC. Median OS in the anlotinib arm was significantly 
improved compared with that in the placebo arm (7.3 months versus 4.9 months; HR, 0.53; 
95% CI, 0.30 to 0.92). The safety profile was consistent with what has been observed in patients 
with other solid tumors receiving anlotinib as single agent and no newly adverse events were 
identified (Cheng et al 2018). 
Despite the impressive initial response rates observed with first-line chemotherapy regimens and 
improved survival with further-line chemotherapy or novel small molecule, most patients with 
ES-SCLC develop chemotherapy resistant disease and their prognosis is still poor. PFS is mostly 
< 6 months and median survival remains <1 year. There is a significant need for novel treatment 
options for patients who have ES-SCLC. Immunotherapeutic agents, including antibodies that 
modulate immune cell activity, offer an alternative treatment approach that could potentially 
improve the prognosis of patients with this disease.  
1.1.2. 
PD-1 Pathway-Targeting Studies in Patients With Extensive-Stage Small Cell 
Lung Cancer 
Strategies targeting programmed cell death protein-1 (PD-1) pathway alone or in combination 
with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) agents have shown 
encouraging efficacy signals in patients with previously treated ES-SCLC. The Phase I/II 
CheckMate 032 study explored the efficacy of nivolumab, a human immunoglobulin G4 (IgG4) 
anti-PD-1 receptor antibody as monotherapy (3 mg/kg), or in combination with ipilimumab, an 
anti-cytotoxic-T lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody (1 mg/kg 
plus 1 mg/kg; 1 mg/kg plus 3 mg/kg or 3 mg/kg plus 1 mg/kg) followed by nivolumab 
maintenance therapy in patients who had progressed following at least one prior line of a 
platinum-containing systemic chemotherapy (Antonia et al 2016). Based on the overall response 
rate (ORR) and duration of response (DOR) in the monotherapy arm among 109 patients with 
SCLC data which showed an ORR of 12% (95% confidential interval [CI]: 6.5, 19.5) and a DOR 
of 13 months per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (RECIST 
v1.1) (range: 3.0, 42.1) both assessed by blinded independent central review (BICR), nivolumab 
has been granted accelerated approval for treating patients with metastatic SCLC whose cancer 
have progressed after platinum-based chemotherapy and ≥ 1 other line of therapy by US FDA in 
August 2018 (OPDIVO [nivolumab] package insert). Confirming the initial efficacy signal, more 
robust data from approximately 400 patients enrolled on the study displayed a doubling of the 
response rate in patients treated with the combination versus nivolumab alone (22% vs. 9%) 
(Hellmann et al 2017). Based on these data, in August 2018, nivolumab was approved by the US 
FDA to treat patients with metastatic SCLC whose disease has progressed after platinum-based 
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chemotherapy and ≥ 1 other line of therapy. The safety profile of nivolumab observed in patients 
with metastatic SCLC was generally similar to that observed in patients with other solid tumors 
who received it as a single agent (OPDIVO [nivolumab] package insert). 
Pembrolizumab, another monoclonal antibody against PD-1 was tested in the KEYNOTE-028 
study. KEYNOTE-028 is a nonrandomized, multicohort Phase 1b study in patients with 
programmed cell death protein ligand-1 (PD-L1)-positive advanced solid tumors. Patients 
received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed 
progression or intolerable toxicity, death, withdrawal of consent, or physician decision. This 
PD-1 antibody similarly demonstrated a promising response rate of 33% (8/24 patients) with 
median duration of response of 19.4 months and 1-year survival of 37.7% in previously treated 
PD-L1 positive (≥ 1% staining) ES-SCLC patients (Ott et al 2017). 
PD-1 pathway-targeting antibodies are under active investigation in the first-line treatment 
setting for ES-SCLC studies, as demonstrated by the list of currently ongoing studies (Table 2).  
IMpower133 is a Phase 3 study comparing the efficacy of atezolizumab, an anti-PD-L1 antibody, 
versus placebo when administered in combination with carboplatin and etoposide in patients with 
ES-SCLC and is the first frontline pivotal study to read out. Between 06 June 2016 and 
31 May 2017, a total of 403 patients were enrolled, with 201 patients randomly assigned to the 
atezolizumab group and 202 patients to the placebo group (Horn et al 2018). At a median 
follow-up of 13.9 months, the median OS was 12.3 months in the atezolizumab group and 
10.3 months in the placebo group (HR for death, 0.70; 95% confidence interval [CI], 0.54 to 
0.91; P = 0.007). The median PFS was 5.2 months and 4.3 months, respectively (HR for disease 
progression or death, 0.77; 95% CI, 0.62 to 0.96; P = 0.02) (Horn et al 2018). In the subgroup 
analysis of Japanese patients, the median OS in the atezolizumab group (n = 20, 14.6 months; 
95% CI, 11.8 to 17.8 months) was longer than that in the placebo group (n = 22, 11.9 months; 
95% CI, 8.4 to 15.8 months); HR is 0.72 (95% CI, 0.31 to 1.67) (Nishio et al 2019a). The safety 
profile of atezolizumab plus carboplatin and etoposide was consistent with the previously 
reported safety profile of the individual agents, with no new findings observed (Horn et al 2018). 
Based on those data, atezolizumab in combination with carboplatin and etoposide is now 
recommended as one of the treatment regimens for ES-SCLC by National Comprehensive 
Cancer Network (NCCN) guideline (NCCN 2019 v1). 
CASPIAN is a Phase 3 study comparing the efficacy of durvalumab, an anti-PD-L1 antibody, 
with or without tremelimumab, in combination with platinum (carboplatin or cisplatin)-etoposide 
in patients with ES-SCLC. Between 27 March 2017 and 29 May 2018, a total of 537 patients 
were enrolled; 268 patients were allocated to the durvalumab plus platinum-etoposide group and 
269 patients were to the platinum-etoposide group. At a median follow-up of 14.2 months, the 
median OS was 13.0 months in the durvalumab plus platinum-etoposide group and 10.3 months 
in the platinum-etoposide group (HR, 0.73; 95% CI, 0.59 to 0.91; P = 0.0047) (Paz-Ares et al 
2019). In the prespecified exploratory endpoints, OS analysis in the Asian subpopulation was 
consistent with that in the global population. The median OS was 14.8 months with durvalumab 
plus platinum-etoposide versus 11.9 months with platinum-etoposide (HR, 0.87; 95% CI, 0.45 to 
1.64) (Nishio et al 2019b). The safety profile of durvalumab plus platinum-etoposide was 
consistent with the known safety profiles of all drugs received (Paz-Ares et al 2019). Based on 
these data, durvalumab in combination with platinum-etoposide is also recommended as one of 
the treatment regimens for ES-SCLC by NCCN guideline (NCCN 2020 v2).  
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Keynote604 is another Phase 3 study comparing the efficacy of immunotherapy versus placebo 
when administered in combination with carboplatin or cisplatin and etoposide in patients with 
ES-SCLC. At a median follow-up of 21.6 months, the median OS was 10.8 months (95% CI, 9.2 
to 12.9 months) in the pembrolizumab plus platinum-etoposide arm and 9.7 months (95% CI, 8.6 
to 10.7 months) in the placebo plus platinum-etoposide arm. The significance boundary was not 
reached in the ITT population (HR, 0.80; 95% CI, 0.64 to 0.98; P = 0.0164). But in a post hoc 
analysis of OS in the as treated population: nominal P = 0.0124 (HR, 0.78; 95% CI, 0.63 to 0.97) 
(Rudin et al 2020).  
The findings in IMpower133 and CASPIAN, together with efficacy signals from Keynote604 
and other studies of monotherapy in later lines of therapy, support the benefit of checkpoint 
inhibitors as first line treatment in ES-SCLC.  
Table 2. Ongoing First-Line PD-1 Pathway-Targeting Immunotherapy Studies in ES-
SCLC 
Name 
Study arms 
Phase 
REACTION 
Platinum/etoposide +/– pembrolizumab 
2 
KEYNOTE 604 
Platinum/etoposide +/– pembrolizumab 
3 
IMpower133 
Carboplatin/etoposide +/– atezolizumab 
3 
Caspian 
Platinum/etoposide+ durvalumab +/– 
tremelimumab vs. chemotherapy alone 
3 
MCC-18914 
Platinum/etoposide followed by 
thoracic radiation +/– nivolumab 
+ipilimumab 
1/2 
NCT02402920 
Platinum/etoposide followed by 
thoracic radiation +/– pembrolizumab 
1 
Abbreviations: ES-SCLC, extensive-stage small cell lung cancer; PD-1, programmed cell death protein-1; vs, versus 
1.2. 
Background Information on Tislelizumab 
1.2.1. 
Pharmacology 
Tislelizumab (also known as BGB-A317) is a humanized, IgG4-variant monoclonal antibody 
against PD-1 under clinical development for the treatment of several human malignancies.  
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as 
well as high affinity (dissociation constant [KD]=0.15 nM). It competitively blocks binding 
efforts by both programmed cell death protein ligand-1 (PD-L1) and programmed cell death 
protein ligand-2 (PD-L2), thus inhibiting PD-1-mediated negative signaling in T cells. In in vitro 
cell-based assays, tislelizumab was observed to consistently and dose-dependently enhance the 
functional activity of human T cells and pre-activated, primary peripheral blood mononuclear 
cells. In addition, tislelizumab has demonstrated antitumor activity in several allogeneic 
xenograft models, in which peripheral blood mononuclear cells were co-injected with human 
cancer cells (A431 [epidermoid carcinoma]) or tumor fragments (BCCO-028 [colon cancer]) into 
immunocompromised mice.  
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In addition, tislelizumab is an IgG4-variant antibody to gamma fragment crystallizable region 
(Fc) receptors (FcγR) such as FcγRI and FcγRIIIA. It has very low binding affinity to 
Complement 1q (C1q), a subunit of complement 1. In vitro assays with tislelizumab suggest 
either low or no antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular 
phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC) effects in humans (Labrijn 
et al 2009; Zhang et al 2018). 
Please refer to the tislelizumab Investigator’s Brochure for additional details regarding 
nonclinical studies of tislelizumab. 
1.2.2. 
Toxicology 
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology 
studies in mice and monkeys and in a 13-week, repeat-dose toxicology study in cynomolgus 
monkeys. Tissue cross-reactivity was evaluated in the normal frozen tissues from both humans 
and monkeys. The cytokine release assays were also evaluated using fresh human whole blood 
cells. The pivotal toxicology studies were conducted following Good Laboratory Practice (GLP) 
regulations. The single-dosing regimens spanned from the intended human doses to 10-fold 
higher than the maximum of the intended human doses, and the repeat-dosing regimens spanned 
to 3-fold higher than the maximum of the intended human doses. Cynomolgus monkey was the 
only relevant species based on the target sequence homology and binding activity.  
Overall, no apparent toxicity was noted in mice or monkey toxicity studies. No tissue 
cross-reactivity was found in either human or monkey tissues, nor was any effect on cytokine 
release observed in human whole-blood assay. The toxicokinetics profile was well characterized, 
with dose proportional increases in systemic exposure without apparent accumulation or sex 
difference. Immunogenicity was observed without apparent immunotoxicity or effect on the 
systemic exposure. The No Observed Adverse Effect Level (NOAEL) of tislelizumab in the 
13-week monkey toxicity study was considered to be 30 mg/kg. The safety profile of 
tislelizumab is considered adequate to support the current Phase 3 study BGB-A317-312. 
Please refer to the tislelizumab Investigator’s Brochure for more detailed information on the 
toxicology of tislelizumab. 
1.2.3. 
Clinical Pharmacology 
In the Phase 1 BGB-A317_Study_001 and Study BGB-A317-102, interim pharmacokinetics 
(PK) analysis (data cutoff date 28 August 2017) was conducted using noncompartmental 
methods, using serum concentrations from patients who received doses of 0.5, 2.0, 5.0, and 10 
mg/kg once every 2 weeks, and 2.0 mg/kg, 5.0 mg/kg, and 200 mg once every 3 weeks (Phase 1a 
Parts 1, 2, and 3, and Phase 1b in BGB-A317_Study_001), and patients who received doses of 
200 mg once every 3 weeks in Phase 1 of Study BGB-A317-102 (n=19). The maximum 
observed plasma concentration (Cmax) and the area under the plasma or serum concentration-time 
curve (AUC) increased in a nearly dose-proportional manner from 0.5 mg/kg to 10 mg/kg, both 
after single-dose administration at steady state. Preliminary PK data from 27 patients who were 
administered 1 dose of 200 mg once every 3 weeks (Phase 1a, Part 3 and Study BGB-A317-102) 
showed tislelizumab concentrations between the range of concentrations observed for patients 
who were administered 2 mg/kg and 5 mg/kg doses. 
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Preliminary population PK analysis using a 2-compartment model with first-order elimination 
shows a systemic plasma clearance (CL) of tislelizumab of 0.173 L/day, volume of distribution 
(Vd) in the central and peripheral compartments of 2.89 L and 1.76 L, respectively, and half-life 
(t1/2) of approximately 19 days. Race, gender, and body weight were not significant covariates on 
the CL of tislelizumab, which supports fixed-dosing across different ethnic groups. 
1.2.4. 
Prior Clinical Experience of Tislelizumab 
As of 28 February 2018, there are 13 ongoing studies with tislelizumab, including monotherapy 
and combination studies in solid tumors and hematological malignancies. Of the ongoing 
monotherapy studies in solid tumors, available data from BGB-A317_Study_001 and 
BGB-A317-102 are summarized below (with a data cutoff date of 28 August 2017). Data from 
one ongoing study, BGB-A317-206, on tislelizumab combined with chemotherapy as first-line 
treatment in patients with lung cancer including 1 cohort with 17 SCLC patients are also 
summarized below (Section 1.2.4.4). 
Please refer to the tislelizumab Investigator’s Brochure for more detailed information on efficacy 
and safety of tislelizumab. 
1.2.4.1. 
BGB-A317_Study_001 (Data Cutoff 28 August 2017)   
Study BGB-A317_Study_001 is a 2-stage study consisting of a Phase 1a dose-escalation and 
dose-finding component with 3 parts to establish the maximum tolerated dose (MTD), if any, a 
recommended Phase 2 dose (RP2D) for the Phase 1b, and a flat dose (fixed dose) followed by a 
Phase 1b component to investigate efficacy in select tumor types in indication expansion arms 
and to further evaluate safety and tolerability of tislelizumab.  
As of 28 August 2017, in Phase 1a, 116 patients had received tislelizumab at dose regimens 
including 0.5 mg/kg, 2 mg/kg, 5 mg/kg, or 10 mg/kg once every 2 weeks; 2 mg/kg or 5 mg/kg 
once every 3 weeks; and 200 mg once every 3 weeks. In Phase 1b, 323 patients had received 
tislelizumab in Phase 1b across 9 indication-expansion cohorts.  
Overall, for the 439 patients in the study, the median age was 60.0 years, 53.8% of the 
population was male, and 65.6% of patients were white. The median number of prior anticancer 
therapy regimens was 2 (range: 0 to 12). The median treatment exposure duration was 
2.50 months (range: 0 to 23.0), and the median study follow-up duration was 5.56 months 
(range: 0.0 to 26.9). As of 28 August 2017, there were 210 patients (47.8%) remaining on study 
in Study BGB-A317_Study_001.   
Preliminary Safety 
Of the 439 total patients in the Safety Population for BGB-A317_Study_001, 240 (54.7%) 
experienced at least 1 treatment-emergent adverse event (TEAE) assessed as related to 
tislelizumab by the investigator and 34 (7.7%) experienced at least 1 ≥ Grade 3 related TEAE. 
The most commonly occurring related TEAEs for patients treated with the tislelizumab 
monotherapy in BGB-A317_Study_001 were fatigue (12.8%), rash (7.7%), nausea (6.8%), 
diarrhoea (6.6%), and hypothyroidism (4.8%). The ≥ Grade 3 related TEAEs occurring in ≥ 2 
patients were pneumonitis (6 patients, 1.4%); colitis and alanine aminotransferase (ALT) 
increased (4 patients each, 0.9%); fatigue, type 1 diabetes mellitus, and aspartate 
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aminotransferase (AST) increased (3 patients each, 0.7%); and diarrhoea, 
gamma-glutamyltransferase (GGT) increased, and diabetic ketoacidosis (2 patients each, 0.5%). 
All other events occurred in single patients. Lastly, 18 patients (4.1%) experienced an infusion-
related reaction; all were mild/moderate in severity.  
Preliminary Efficacy 
• For patients in Phase 1a (n=116, evaluable), there were 20 patients with a confirmed 
response and 42 patients with a best overall response (BOR) of stable disease.  
• For patients in Phase 1b (n=286 evaluable), a total of 26 patients had a confirmed 
response. Additionally, there were 101 patients with a BOR of stable disease.  
1.2.4.2. 
Study BGB-A317-102 (Data Cutoff 28 August 2017)  
This Phase 1/2 study is a dose verification of tislelizumab and an indication-expansion study of 
tislelizumab conducted in Chinese patients with advanced solid tumors.   
Overall, for the 123 patients in Study BGB-A317-102, the median age was 54.0 years, 66.7% of 
the population was male, and 100% of patients were Asian (Chinese). The median number of 
prior anticancer therapy regimens was 2 (range: 0 to 9). The median treatment exposure duration 
was 1.78 months (range: 0 to 8.0), and the median study follow-up duration was also 
1.78 months (range: 0.0 to 8.0). As of 28 August 2017, there were 113 patients (91.9%) 
remaining on study in Study BGB-A317-102. 
Preliminary Safety 
Of the 123 total patients in the Safety Population for Study BGB-A317-102, 69 (56.1%) 
experienced at least 1 TEAE assessed as related to tislelizumab by the investigator and 10 (8.1%) 
were ≥ Grade 3 in severity. The most commonly occurring related TEAEs were AST increased 
(20 patients, 16.3%), ALT increased (17 patients, 13.8%), and blood bilirubin increased and 
anaemia (13 patients each, 10.6%). The ≥ Grade 3 related TEAEs occurring in ≥ 2 patients were 
AST increased (3 patients, 2.4%) and ALT increased (2 patients, 1.6%). All other events 
occurred in single patients, including a case of retinal detachment (Grade 4). 
Preliminary efficacy data are not yet available. 
1.2.4.3. 
Immune-Mediated Reactions  
In patients treated with tislelizumab monotherapy, the following immune-mediated adverse 
events (imAEs) were observed: 
• Acute hepatitis and abnormal liver function have been reported, including 1 patient with 
fatal hepatitis. Additionally, 3.2% of patients experienced treatment-related abnormal 
liver function tests, and 1.4% of patients experienced immune-mediated hepatitis or 
hyperbilirubinaemia. 
• Pneumonitis has been reported in 2.1% of patients, including 1 patient with fatal 
pneumonitis.  
• Colitis has been reported in approximately 2% of patients treated. Diarrhoea has been 
reported in 6.6% of patients.  
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• Endocrinopathies have been reported including diabetes mellitus (hyperglycemia and 
ketoacidosis). In addition, thyroiditis, including thyrotoxicosis and hypothyroidism has 
been reported. Furthermore, hypophysitis has been reported in < 1% of patients treated.  
• Other immune-mediated events (< 1% of patients with tislelizumab monotherapy except 
where noted): skin reactions (20.5%, including rash and pruritus); arthralgia (2.5%); 
haemolytic anaemia, nephritis, proteinuria (1.8%); encephalitis, neuropathy, arthritis, 
pancreatitis, stomatitis, uveitis, and dry eye (1.4%).   
Beyond patients treated with tislelizumab monotherapy, a case of fatal myocarditis and 
polymyositis was reported in 1 patient who received a single dose of tislelizumab, in 
combination with paclitaxel and cisplatin. The patient’s initial symptoms were dyspnea and 
tea-colored urine 2 weeks after starting treatment. Elevated urine and serum cardiac and skeletal 
muscle enzymes were reported. The patient died of multi-organ failure 6 days later.  
1.2.4.4. 
Study BGB-A317-206 (Data Cutoff 05 June 2018)  
BGB-A317-206 is a multi-arm Phase 2 study, consisting of safety run-in and dose-extension 
phases, to assess tislelizumab in combination with varying platinum-based chemotherapy (by 
tumor histology) in 4 cohorts as a potential first-line treatment for Chinese patients with lung 
cancer. All patients received tislelizumab at 200 mg once every 3 weeks in combination with 4–6 
cycles of platinum-doublet until disease progression. One cohort enrolled patients with small-cell 
lung cancer (SCLC) who received tislelizumab in combination with etoposide + platinum on a 3 
week cycle basis. Tumor response per RECIST v1.1 and safety/tolerability were evaluated. 
As of 05 June 2018, 54 patients received tislelizumab treatment, 17 of those were patients with 
SCLC. In the SCLC cohort, the median durations of tislelizumab and chemotherapy are 18.0 and 
16.0 weeks respectively, 10 patients are still on treatment, among the 7 patients who had 
discontinued treatment, 6 of them discontinued treatment due to disease progression. In the 
efficacy analysis, confirmed and unconfirmed partial response (PR) were observed in 8 and 6 
patients, respectively, and the median time to initial response is 7.0 weeks, the median duration 
of response is still not reached as of the data cutoff date. In the safety analysis, there are 13 
patients (76.5%) with at least one ≥ Grade 3 TEAE, 5 patients (29.4%) with ≥ 1 serious adverse 
event (SAE), which are all treatment related, 12 patients (70.6%) with TEAE leading to 
discontinuation of tislelizumab treatment. The most frequent adverse events (AEs) were 
chemotherapy-related hematologic toxicities. The most commonly reported ≥ Grade 3 TEAE 
was neutrophil count decreased (47.1%); there are 4 patients with ≥ 1 immune-mediated TEAE. 
The most commonly reported TEAE related to tislelizumab was decreased appetite (17.6%). 
1.3. 
Study Rationales  
1.3.1. 
Rationale for Testing Tislelizumab in Combination with Chemotherapy in the 
Treatment of Extensive-Stage Small Cell Lung Cancer 
Currently, the standard-of-care first-line treatment for patients with ES-SCLC is platinum-based 
chemotherapy (cisplatin or carboplatin) plus etoposide for 4 cycles (NCCN 2019 v1; Fruh et al 
2013). Despite the initial response rates observed with the first-line chemotherapy regimens, the 
prognosis of patients with ES-SCLC remains dismal, with a median OS of approximately 
9-11 months. Multiple targeted agents that have been investigated in the past 2 decades including 
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those targeting tyrosine kinases (TKIs) such as epidermal growth factor receptor (EGFR) TKIs 
and BCR-ABL TKIs, mammalian target of rapamycin (mTOR) signaling pathway, and vascular 
endothelial growth factor (VEGF) signaling pathway have been unsuccessful in showing a 
survival advantage in this disease (Mamdani et al 2015). There is a significant unmet clinical 
need for new agents with novel mechanisms of action and non-overlapping toxicity, which can 
be combined with established treatments. 
Drugs targeting PD-1 and its ligand, PD-L1, have shown a manageable safety profile and 
promising efficacy including increased response rate, prolongation of median duration of 
response and OS as first- and second-line treatment in SCLC patients whose disease progressed 
on platinum-based chemotherapy (Section 1.1.2). 
Increasing evidence suggests that the antitumor activity of chemotherapy is mediated not only 
through cytotoxic effects, but also through immunological effects, including reducing T 
regulatory cell activity and enhancing cross-presentation of tumor antigens. Chemotherapy has 
also been shown to induce PD-L1 expression on tumor cells (Jin and Yoon 2016; Ono 
Pharmaceutical 2017; Patel and Kurzrock 2015; Van Der Kraak et al 2016; McDaniel et al 2016; 
Gong et al 2011). 
Whole exome sequencing studies have shown that SCLC exhibits a high mutation rate 
(7.4 mut/Mb) compared with other types of tumors. Therefore, SCLC may be a highly 
immunogenic tumor with higher potential to benefit from treatment with immune-checkpoint 
inhibitors (Rudin et al 2012). In addition, nearly all cases of SCLC are attributable to cigarette 
smoking, which has been shown to be associated with benefit from anti-PD-L1/anti-PD-1 
antibodies (Borghaei et al 2015; Garon et al 2015). 
Multiple studies in SCLC showed that combining immunotherapy with chemotherapy has the 
potential to improve its anticancer activity. The manageable safety profile and promising 
antitumor activities observed with PD-1 or PD-L1 antibodies under investigation in combination 
with chemotherapy as first-line therapy in patients with SCLC provide justification for this study 
design (Section 1.1.2). 
High levels of FcγR-expressing myeloid derived cells (eg, M2 macrophage, MDSC) in tumor 
tissues predict a poor survival of tumor-bearing animals after anti-PD-1 monoclonal antibody 
treatment; this is possibly due to Fc-FcγR-mediated ADCC or antibody-dependent cellular 
phagocytosis (ADCP) depletion of effector T cells (Gül et al 2015; Prieto et al 2015; Makarova-
Rusher et al 2015; Beers et al 2016; Dahan et al 2015). As a no- to low-FcγR-binding agent (thus 
causing minimal ADCC/ADCP effect), tislelizumab may show superior efficacy and lower 
toxicity in clinical application. Based on preliminary data with tislelizumab monotherapy in a 
Phase 1 study (BGB-A317_Study_001), tislelizumab appears comparable to other anti-PD-1 
checkpoint inhibitors (CPI) in terms of safety and preliminary activity in patients with advanced 
solid tumors. In addition, the ongoing Phase 2 study (BGB-A317-206) which evaluates the 
combination of tislelizumab and various standard-of-care chemotherapies in first-line lung 
cancer did not show new safety signals compared to other checkpoint inhibitor plus 
chemotherapy. And the combination of tislelizumab with chemotherapy has demonstrated 
promising efficacy in ES-SCLC first line treatment (Section 1.2.4.4; Zhao et al 2018).  
According to data collected from the Phase 1 BGB-A317_Study_001 and the Phase 2 
BGB-A317-206, irrespectively of monotherapy or in combination with platinum-based 
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chemotherapy, tislelizumab has established a manageable safety profile, with the most common 
side effects consistent with known class effects of other anti-PD-1 antibodies (Section 1.4). 
1.3.2. 
Rationale for Selection of Tislelizumab Dose in Combination With 
Chemotherapy 
The PK, safety, and efficacy data obtained from the first-in-human study BGB-
A317_Study_001, as well as other clinical study data, were analyzed in aggregate to determine 
the recommended dose for pivotal studies of tislelizumab. The flat dose of 200 mg intravenously 
once every 3 weeks was selected for further evaluation. 
Rates of treatment-related AEs and SAEs observed in patients receiving 2 mg/kg and 5 mg/kg 
once every 2 weeks and once every 3 weeks were comparable, suggesting no clear dose-
dependence across these regimens. Similarly, confirmed overall response rates (ORRs) in 
patients treated with tislelizumab 2 mg/kg and 5 mg/kg once every 2 weeks ranged between 10% 
and 15%, compared to a range of 15% to 38% for patients treated at 2 mg/kg and 5 mg/kg once 
every 3 weeks. 
According to PK data from BGB-A317_Study_001, Phase 1a, the CL of tislelizumab was found 
to be independent of body weight, ethnicity, and gender, and the observed serum exposure of a 
200-mg dose fell between serum exposure observed after 2 mg/kg and 5 mg/kg doses (dose 
range with comparable safety and efficacy rates).  
Additionally, no unexpected treatment-related AEs occurred in the 200-mg fixed dose cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared to body-weight-based cohorts. Of the 
evaluable patients treated (n=13), 3 patients (23%) had a BOR of PR, 4 patients (31%) had a 
BOR of stable disease, and 6 patients (46%) had a BOR of progressive disease (PD). Therefore, 
clinical activity with a manageable and tolerable safety profile is expected to be maintained in 
patients receiving tislelizumab 200 mg once every 3 weeks. 
Further, preliminary data from the ongoing Phase II BGB-A317-206 study which evaluates the 
combination of tislelizumab at the fixed dose of 200 mg Q3W with etoposide and platinum 
chemotherapy at the dose of standard of care as treatment for first-line SCLC (see 
Section 1.2.4.4) supports the dose and schedule.  
The doses of all chemotherapy drugs are based on product labelling, literature, and local 
guidelines. Several Phase 1 and Phase 2 studies showed that the safety profile of anti-PD-1 
antibodies in combination with platinum-based chemotherapy was consistent with that expected 
in individual agents. There were no known overlapping, significant toxicities or drug-drug 
interactions between anti-PD-1 antibodies and platinum or etoposide observed in these studies.  
In conclusion, tislelizumab 200 mg once every 3 weeks is the recommended dose for pivotal 
studies.  
1.3.3. 
Rationale for Placebo Plus Cisplatin or Carboplatin and Etoposide as the 
Comparator 
The current standard-of-care first-line treatment for ES-SCLC is platinum-based chemotherapy 
plus etoposide. In this study, patients in the control arm (Arm B) will receive 4 cycles of 
placebo + platinum (cisplatin or carboplatin) + etoposide in the Induction treatment period, 
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followed by placebo alone in the Maintenance treatment period until radiographic disease 
progression per RECIST v1.1. Treatment for Arm B (control arm) has been widely applied as a 
standard of care for the first-line treatment of ES-SCLC (see Section 1.1.1). 
1.3.4. 
Rationale for Overall Survival as Primary Endpoint 
OS is the primary endpoint for this study. 
Improvement in OS is generally accepted as the best measure of clinical benefit for patients with 
advanced/unresectable or metastatic lung cancer. 
In addition, immunotherapies are emerging as highly effective regimens that are providing 
improvements in patient outcomes beyond what has been previously achieved (Ellis et al 2014), 
and has been demonstrated to be correlated or associated with durable responses, and eventually 
lead to a prolongation of OS. 
1.3.5. 
Rationale for Allowing Selected Patients to Continue Treatment Beyond 
Radiographic Disease Progression per RECIST v1.1 
First-line therapy with a platinum agent and etoposide has consistently demonstrated high 
response rates and significant clinical benefit in patients with ES-SCLC. However, after disease 
progression, treatment options are limited and such options have shown limited efficacy and 
significant toxicity (see Section 1.1.1). In light of the fact that the second-line therapies have an 
unfavorable benefit-risk profile manifested by poor efficacy and high toxicity, and the potential 
for pseudoprogression/tumor-immune infiltration as a result of immunotherapy which may not 
be reflected without bias in the initial radiographic evaluation, patients may be considered for 
treatment beyond radiographic disease progression per RECIST v1.1 at the discretion of the 
investigator and after discussion with the medical monitor. In addition, the treatment will be 
started only after appropriate discussion with the patient and informed consent being obtained, 
and only if the patient meets all of the criteria described in Section 3.3. 
Patients who continue treatment beyond radiographic disease progression per RECIST v1.1 
should be closely monitored clinically and tumor assessment should continue as scheduled until 
loss of clinical benefit (see Section 3.3). 
1.3.6. 
Rationale for Patient-Reported Outcome Assessments 
Patient-reported outcomes assessments have been shown to provide the most robust descriptions 
of the treatment experience, with the incorporation of multiple modes of endpoint measurements 
in clinical studies, and they would supplement the data derived from clinical reported CTCAE 
(Dajczman et al 2008). With growing recognition of the importance of patient-centered care, 
PROs have also been reported to have positive effects on the well-being of patients who have 
cancer (Basch et al 2016). 
In the treatment of lung cancer, it is important to increase survival and palliate symptoms 
because disease symptoms have negative impacts on health-related quality of life (HRQoL) 
(Hyde and Hyde 1974; Hopwood and Stephens 1995; Sarna et al 2004). This is especially true 
for studies that have PFS as a primary endpoint, where it is important to better understand in 
what regard the delay in disease progression is meaningful to patients. Evidence of benefits 
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assessed by PROs in the chemotherapeutic setting, specifically in patients with lung cancer, 
would further characterize clinical benefit beyond radiographic measures.  
The PRO instruments to be used in this study are the European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30) that 
measures cancer patients’ health status and general functionality and symptoms, EORTC 
supplemental lung cancer module (QLQ-LC13) that measures lung cancer specific symptoms, 
and the EuroQoL 5-Dimension, 5-Level (EQ5D-5L) that measures general health and well-
being. 
1.4. 
Benefit-Risk Assessment 
Available data from clinical trials of other anti-PD-1 antibodies, such as nivolumab and 
pembrolizumab, have demonstrated favorable benefit-risk profiles. Other immunotherapy 
targeting PD-1 and/or PD-L1, such as atezolizumab and avelumab, showed manageable safety 
profiles and antitumor activity in patients with advanced lung cancer. 
More than 400 patients have been treated with tislelizumab monotherapy at clinically relevant 
doses (≥ 2 mg/kg) and in combination therapies. The safety profile is largely consistent with that 
of other antibodies in its class targeting PD-1 and includes mostly mild or moderate AEs. Very 
few Grade 3/4 imAEs have been observed, and they have been generally reversible and 
manageable with study drug interruption and/or steroid treatment. In addition, antitumor activity 
with tislelizumab monotherapy has been observed in a range of tumor types. (For further 
information on the safety profile of tislelizumab, please refer to tislelizumab Investigator’s 
Brochure.) Therefore, the clinical development of tislelizumab, an anti-PD-1 antibody, in 
combination with chemotherapy, may improve the clinical outcomes for Chinese patients who 
have advanced solid tumors including SCLC. 
The present study is a randomized study designed to compare the efficacy of tislelizumab in 
combination with chemotherapy compared with placebo in combination with chemotherapy as 
first-line treatment in patients with ES-SCLC. Tislelizumab monotherapy and combination with 
chemotherapy have shown meaningful anti-tumor activity and manageable safety profiles in 
various types of tumors including ES-SCLC (Section 1.2.4). In addition, immunotherapy studies 
evaluating other PD-1 pathway-targeting antibodies in combination with chemotherapy also 
showed clinical benefit and favorable safety profile in the first-line or later line ES-SCLC 
settings (Section 1.1.2). Given the limited treatment options and unmet medical need in the 
treatment of ES-SCLC, and based on available tislelizumab Phase 1 and Phase 2 data, as well as 
the publication from other immunotherapy studies in ES-SCLC, the benefit-risk assessment is 
considered favorable; the study design which randomizes patients to tislelizumab combined with 
chemotherapy versus placebo combined with chemotherapy in a ratio of 1:1 to receive 4 cycles 
of Induction treatment that is in accordance with standard of care, followed by maintenance 
treatment is considered justified from clinical practice and benefit-risk prospective.  
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective  
• To evaluate the efficacy of tislelizumab + cisplatin or carboplatin + etoposide compared 
with placebo + cisplatin or carboplatin + etoposide in the Intent-to-Treat (ITT) Analysis 
Set as measured by overall survival (OS) 
2.1.2. 
Secondary Objectives  
• To evaluate the efficacy of tislelizumab + cisplatin or carboplatin + etoposide compared 
with placebo + cisplatin or carboplatin + etoposide in the ITT Analysis Set as measured 
by investigator-assessed progression-free survival (PFS) according to RECIST v1.1 
• To evaluate the efficacy of tislelizumab + cisplatin or carboplatin + etoposide compared 
with placebo + cisplatin or carboplatin + etoposide in the ITT Analysis Set as measured 
by investigator assessed overall response rate (ORR), duration of response (DOR), and 
disease control rate (DCR) according to RECIST v1.1 
• To evaluate the effect of tislelizumab + cisplatin or carboplatin + etoposide compared 
with placebo + cisplatin or carboplatin + etoposide on patients’ health-related quality of 
life (HRQoL) according to the EORTC Quality of Life Questionnaire – Core 30 
(QLQ-C30) and the supplemental lung cancer module (QLQ-LC13) 
• To evaluate the safety and tolerability of tislelizumab in combination with cisplatin or 
carboplatin and etoposide compared with cisplatin or carboplatin and etoposide 
2.1.3. 
Exploratory Objectives  
• To assess PFS after next line of treatment (PFS2) 
• To explore potential predictive biomarkers in archival and/or fresh tumor tissue and/or 
blood (or blood derivatives), including but not limited to PD-L1 expression by 
immunohistochemistry (IHC), multiplex IHC (mIHC), gene expression profiling (GEP), 
tumor mutation burden (TMB), microsatellite instability (MSI), and blood tumor 
mutation burden (bTMB), to evaluate the association between these biomarkers and 
response to study treatment or mechanism of resistance 
• To characterize PK of tislelizumab in patients with small cell lung cancer (SCLC) 
• To evaluate host immunogenicity to tislelizumab by assessing antidrug antibodies 
(ADAs) against tislelizumab in patients with SCLC 
• To examine the patients’ quality of life (QoL) as measured by EQ5D-5L 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint 
• OS, defined as the time from randomization to death from any cause 
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2.2.2. 
Secondary Endpoints  
• PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by investigator using RECIST v1.1 or death from any cause, 
whichever occurs first 
• ORR, defined as the proportion of patients with PR or CR as determined by the 
investigator using RECIST v1.1 
• DOR, defined as the time from the first occurrence of a documented objective response to 
the time of relapse, as determined by the investigator per RECIST v1.1, or death from 
any cause, whichever comes first 
• DCR, defined as the proportion of patients whose best overall response (BOR) is CR, PR 
or stable disease per RECIST v1.1 
• Incidence and severity of treatment-emergent adverse events (TEAEs) graded according 
to National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v5.0 
• Percentage of patients with clinically meaningful changes post baseline, defined as a 
10-point improvement or worsening (to be defined in the Statistical Analysis Plan [SAP] 
if otherwise) in: 
− Global health status (GHS) and physical function (PF) per the QLQ-C30  
− Dyspnoea, coughing, haemoptysis, dysphagia, chest pain, pain in arms and 
shoulders, and peripheral neuropathy symptoms of QLQ-LC13 
• Time to deterioration, defined as the time from randomization to the first occurrence of 
worsening scores (10-point change; to be defined in the SAP if otherwise) confirmed at 
the following visit or death from any cause, in: 
− GHS and PF per the QLQ-C30  
− Dyspnoea, coughing, haemoptysis, dysphagia, chest pain, pain in arms and 
shoulders, and peripheral neuropathy symptoms of QLQ-LC13 
2.2.3. 
Exploratory Endpoints 
• PFS2, defined as the time from randomization to the objective disease progression after 
next line of treatment or death from any cause, whichever occurs first 
• Status of predictive and prognostic biomarkers including but not limited to PD-L1 
expression, multiplex immunohistochemistry (mIHC), GEP, TMB, and MSI in archival 
and/or fresh tumor tissue and bTMB in blood before study treatment and/or at disease 
progression, and the association between the biomarkers and disease status or response to 
study treatment 
• Summary of serum concentrations of tislelizumab 
• Assessments of immunogenicity of tislelizumab by determining the incidence of ADAs 
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• QoL is defined as changes in patients’ general well-being measured by the scores of the 
EQ5D-5L descriptive 5-dimension scores and the visual analog scale (VAS).  
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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to compare 
the efficacy of tislelizumab + cisplatin or carboplatin + etoposide (Arm A) and 
placebo + cisplatin or carboplatin + etoposide (Arm B) as first-line treatment in approximately 
455 patients who have previously untreated ES-SCLC. The choice of platinum (cisplatin or 
carboplatin) will be at the investigator’s discretion. 
The primary endpoint of the study is measured by OS in the ITT Analysis Set. 
The study consists of a Screening phase, a Treatment phase that includes an Induction treatment 
period and a Maintenance treatment period, a Safety Follow-up phase, and a Survival Follow-up 
phase.  
Eligible patients will be stratified by ECOG Performance Status (0 versus 1) (Appendix 2), 
investigator-chosen chemotherapy (carboplatin versus cisplatin), and brain metastasis (yes versus 
no), and randomized in a 1:1 ratio to receive 1 of the following treatment regimens:  
• Induction period (administered on a 3-week cycle for 4 cycles): 
o Arm A: tislelizumab + cisplatin or carboplatin + etoposide 
o Arm B: placebo + cisplatin or carboplatin + etoposide 
• Maintenance period (administered once every 3 weeks): 
o Arm A: tislelizumab 
o Arm B: placebo 
The study design schematic is presented in Figure 1. 
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Figure 1. 
Study Schema 
 
Abbreviations: AUC, area under the plasma or serum concentration-time curve; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, 
intravenously; PD, progressive disease; RECIST v1.1, Response Evaluation Criteria in Solid Tumors Version 1.1; vs, versus 
a. 
Treatment may continue until the completion of the scheduled 4 cycles (only for Induction treatment period), disease progression as assessed by the 
investigator per RECIST v1.1, loss of clinical benefit, unacceptable toxicity, or withdrawal of informed consent, whichever occurs first. Note: For 
Induction treatment, cycles in which no chemotherapy is given do not count toward the total number of chemotherapy cycles. 
b. Patients with radiographic progressive disease suspected by the investigator to reflect pseudoprogression may continue treatment until progressive 
disease is confirmed by repeated imaging ≥ 4 weeks later (but not exceeding 6 to 8 weeks from the date of initial documentation of progressive disease); 
patients who at the discretion of investigator could derive benefit from study drug after investigator-assessed PD per RECIST v1.1 criteria, may 
continue treatment until any of the conditions as specified above occurs. 
For all study procedures, see Section 7 and Appendix 1.
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3.2. 
Screening Period 
Screening evaluations will be performed within 28 days prior to randomization. Patients who 
agree to participate in this study will sign the informed consent form (ICF) prior to undergoing 
any screening procedure. Screening evaluations may be repeated as needed within the screening 
period; the investigator is to assess preliminary patient eligibility according to the latest 
screening assessment results. 
Archival tumor tissue is required to be collected for the purpose of biomarker analysis. If no 
archival samples are available, a fresh tumor biopsy at screening (within 28 days before 
randomization) is required, if feasible. See Section 4.1 and Section 7.8 for details. 
3.3. 
Treatment Period 
After completing all screening activities, eligible patients will be randomized. The selection of 
platinum (cisplatin or carboplatin) will be at the investigator’s discretion and documented prior 
to randomization. Induction treatment will be administered on a 21-day cycle basis for 4 cycles.  
Following Induction treatment, patients will enter a Maintenance treatment period to receive 
either tislelizumab or placebo alone in accordance to the treatment arm to which they are 
randomized. During the Maintenance treatment period, prophylactic cranial irradiation (PCI) is 
permitted as per local standard of care. 
Treatment may continue until the completion of the scheduled 4 cycles (only for Induction 
treatment period), disease progression as assessed by the investigator per RECIST v1.1, loss of 
clinical benefit, unacceptable toxicity, or withdrawal of informed consent, whichever occurs 
first. 
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune cell 
infiltration and other mechanisms leading to apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, if radiographic progressive disease is suspected by the 
investigator to reflect pseudoprogression, patients may continue treatment until progressive 
disease is confirmed by repeated imaging ≥ 4 weeks later (but not exceeding 6 to 8 weeks from 
the date of initial documentation of progressive disease). If at the investigator’s discretion a 
patient could continue to benefit from study treatment after progressive disease per RECIST v1.1 
criteria, the patient may continue study treatment. Patients who have suspected 
pseudoprogression or who may continue to benefit from study treatment after progressive disease 
must meet the following criteria in order to be treated:  
• Absence of clinical symptoms and signs of disease progression (including clinically 
significantly worsening of laboratory values)  
• Stable ECOG Performance Status ≤ 1 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention 
• Investigators must obtain written informed consent for treatment after radiologic disease 
progression and inform patients that this practice is not considered standard in the 
treatment of cancer. 
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Patients who could derive benefit from study drug after progressive disease as assessed by the 
investigator per RECIST v1.1 criteria, may continue treatment until loss of clinical benefit as 
assessed by the investigator, withdrawal of consent, unacceptable toxicity, study completion by 
the sponsor, start of a new anticancer therapy, or death, whichever occurs first. 
The decision to continue study drug beyond initial investigator-assessed progression must be 
agreed to by the medical monitor and documented in the study records. 
There is no crossover between the 2 arms in this study. 
Patients will undergo tumor assessment by the investigator at baseline and every 6 weeks (± 7 
days) for the first 48 weeks following Cycle 1 Day 1, and every 9 weeks (± 7 days) thereafter, 
regardless of treatment dose delay. Tumor assessment at baseline must be performed within 
28 days before randomization. Tumor assessment will continue until radiographic disease 
progression per RECIST v1.1. Details are provided in Section 7.6 and the Schedule of 
Assessments (Appendix 1). 
Patient-reported outcomes will be collected using the EORTC QLQ-LC13, EORTC QLQ-C30, 
and EQ5D-5L at baseline (predose at Day 1 of Cycle 1), at every cycle through Cycle 4, every 
other cycle thereafter until the End-of-Treatment Visit (EOT), and at the Safety Follow-up Visit. 
To determine the PK properties of tislelizumab and host immunogenic response to tislelizumab, 
blood samples will be collected at various timepoints as outlined in Appendix 1. 
Safety will be assessed throughout the study by monitoring and recording all AEs graded per 
NCI-CTCAE v5.0. Laboratory values (eg, hematology, clinical chemistry, and urinalysis), vital 
signs, physical examinations, ECOG Performance Status change, electrocardiogram (ECG) 
results, and other examinations will also be used for safety assessment. Safety assessments are 
further detailed in Section 7.5 and the Schedule of Assessments (Appendix 1). 
The EOT is conducted when the investigator determines that none of the study treatment 
(tislelizumab, placebo, or chemotherapy) will be used any longer. If routine laboratory tests (eg, 
hematology, serum chemistry) are completed within 7 days before the EOT, these tests need not 
be repeated. Tumor assessment is not required at the EOT provided that if < 6 weeks have passed 
since the last assessment. 
3.4. 
Safety Follow-up 
Patients who discontinue treatment for any reason will be asked to return to the clinic for the 
Safety Follow-up Visit within 30 days (± 7 days) after the last dose of study drug (including 
chemotherapy-only), or before the initiation of a new anticancer treatment, whichever occurs 
first. In addition, telephone contacts with patients should be conducted to assess imAEs and 
concomitant medications if appropriate (ie, associated with an imAE or is a new anticancer 
therapy) at 60 days (± 14 days), and 90 days (± 14 days) after the last dose of tislelizumab or 
placebo, regardless of whether or not the patient starts a new anticancer therapy. If patients 
report a suspected imAE at a telephone follow-up contact, the investigator should arrange an 
unscheduled visit if further assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 8.6.   
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At the EOT Visit, if a response assessment showed progressive disease that resulted in patient 
discontinuation, the EOT Visit may be used as the Safety Follow-up Visit, if it occurred 30 days 
(± 7 days) after the last study treatment. Patients who discontinue study treatment prior to disease 
progression will have their tumors assessed as outlined in Section 7.6. 
See Appendix 1 for assessments to be performed at the Safety Follow-up Visit. 
3.5. 
Survival Follow-up 
After discontinuation of study treatment, patients will be followed for survival status and further 
anticancer therapy information via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 month (± 14 days) after the Safety Follow-up Visit or as directed by the 
sponsor until death, loss to follow-up, withdrawal of consent, or study completion by the 
sponsor. 
3.6. 
Discontinuation From the Study Treatment or From the Study 
3.6.1. 
Patient Discontinuation From Study Treatment 
Patients have the right to discontinue study treatment at any time for any reason. In addition, the 
investigator has the right to discontinue a patient from the study treatment at any time. Patients 
who discontinue study treatment for reasons other than disease progression, should be followed 
for assessments of antitumor activity (Section 7.6), safety (Section 7.5), and survival 
(Section 3.5), if possible. 
The primary reason for discontinuation from study treatment should be documented on the 
appropriate electronic case report form (eCRF). Patients may discontinue study treatment for 
reasons that include but are not limited to the following:  
• Disease progression 
• Adverse event 
• Patient decision 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines might jeopardize the 
patient’s safety, if he or she were to continue the study treatment 
• Use of any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese or other country 
herbal medicine or patent medicines] for the treatment of cancer) (Section 6.2.2) 
• Patient noncompliance 
Investigative site staff should first counsel patients who are significantly 
noncompliant (eg, missing 2 treatment cycles) on the importance of study drug 
compliance and drug accountability. The investigator may, in consultation with the 
medical monitor, discontinue patients from treatment who are consistently 
noncompliant. 
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3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) 
Patients may discontinue the study for reasons that include but are not limited to the following:  
• Patient withdrawal of consent 
• Death 
• Loss to follow-up 
• Patients have completed all study assessments 
3.7. 
End of Study 
The end of study is defined as the timepoint when final data point is collected from the last 
patient in the study. This is when the last patient dies, withdraws consent, completes all study 
assessments, or is lost to follow-up. The final analysis of OS will be conducted at the time when 
the predefined OS events have been observed (see Section 9.2), for efficacy evaluation. The 
study will continue until the last patient has disease progression or confirmed loss of clinical 
benefit (only for patients who receive treatment beyond disease progression), is lost to follow-up, 
or withdraws from the study, or until study completion by the sponsor. 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
early include but are not limited to the following:  
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients  
• Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients should be seen as soon as possible for an EOT 
Visit and Safety Follow-up Visit. 
The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing Institutional Review Board (IRBs)/Independent Ethics Committees 
(IECs) of the early termination of the study. 
The sponsor has the right to close a site at any time. The decision will be communicated to the 
site in advance. Reasons for closing a site include but are not limited to the following:  
• Excessively slow recruitment  
• Poor protocol adherence  
• Inaccurate or incomplete data recording  
• Noncompliance with Good Clinical Practice (GCP), applicable laws and regulations  
• Study activity is completed (ie, all patients have completed and all obligations have been 
fulfilled)]  
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4. 
STUDY POPULATION 
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all of the following criteria: 
1. Ability to provide written informed consent and to understand and agree to comply with 
the requirements of the study and the schedule of assessments 
2. Age ≥ 18 years on the day of signing the ICF (or the legal age of consent in the 
jurisdiction in which the study is taking place) 
3. Histologically or cytologically confirmed ES-SCLC (defined by the American Joint 
Committee on Cancer, Seventh Edition, as Stage IV [T any, N any, M 1a/b] or T3-4 due 
to multiple lung nodules that are too extensive or have tumor/nodal volume that is too 
large to be encompassed in a tolerable radiation plan.) 
4. No prior systemic treatment for ES-SCLC 
• Patients who have received prior chemoradiotherapy for limited-stage SCLC 
(LS-SCLC) must have been treated with curative intent and experienced a 
treatment-free interval of ≥ 6 months between the completion of chemotherapy, 
radiotherapy, or chemoradiotherapy and diagnosis of ES-SCLC.   
5. ECOG Performance Status ≤ 1 
6. Adequate organ function as indicated by the following laboratory values obtained 
≤ 7 days before randomization 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin 
≥ 90 g/L. Note: Patients must not have undergone a blood transfusion or growth 
factor support ≤ 14 days before sample collection at screening 
• International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x upper limit of 
normal (ULN) 
• Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN 
• Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients 
with Gilberts syndrome) 
• AST and ALT ≤ 2.5 x ULN or AST and ALT ≤ 5 x ULN for patients with liver 
metastases  
7. Females of childbearing potential must be willing to use a highly effective method of 
birth control (Appendix 8) through the duration of the study, for ≥ 120 days after the last 
dose of study treatment with either chemotherapy or tislelizumab (or placebo), whichever 
is given later, and have a negative urine or serum pregnancy test ≤ 7 days before 
randomization. 
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8. Nonsterile males must be willing to use a highly effective method of birth control 
(Appendix 8) for the duration of the study and for ≥ 120 days after the last dose of study 
treatment with either chemotherapy or tislelizumab (or placebo), whichever is given later. 
• A sterile male is defined as one for whom azoospermia has been previously 
demonstrated in a semen sample examination as definitive evidence of infertility.  
• Males with known “low sperm counts” (consistent with “subfertility”) are not to be 
considered sterile for purpose of this study 
9. Life expectancy ≥ 12 weeks. 
4.2. 
Exclusion Criteria 
Patients who meet any of the following criteria are not eligible to enroll: 
1. Received prior therapy with an antibody or drug against immune checkpoint pathways 
including but not limited to anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody 
2. Treatment with systemic immune-stimulating agents (including but not limited to 
interferons, interleukin-2, and tumor necrosis factor) within 4 weeks or 5 half-lives of the 
drug, whichever is shorter, prior to randomization (prior treatment with cancer vaccines is 
allowed) 
3. Has received any herbal medicine used to control cancer within 14 days of the first study 
drug administration 
4. Any condition that requires systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
randomization 
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded: 
• Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)  
• Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption 
• Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for 
contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, 
delayed-type hypersensitivity reaction caused by contact allergen) 
5. Was administered a live vaccine ≤ 4 weeks before randomization 
Note: Seasonal influenza vaccines are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines and are not allowed 
6. Any major surgical procedure requiring general anesthesia ≤ 28 days before 
randomization.  
Note: Diagnostic surgical procedures are not considered major surgical procedures, 
including but not limited to, tumor biopsy or endoscopic examinations regardless of the 
method of anesthesia 
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7. Prior allogeneic stem cell transplantation or organ transplantation 
8. Clinically significant pericardial effusion 
9. Clinically uncontrolled pleural effusion or ascites that requires pleurocentesis or 
abdominal tapping for drainage within 2 weeks before randomization 
10. Active leptomeningeal disease or uncontrolled, untreated brain metastasis: 
Note: Patients with a history of treated and, at the time of screening, asymptomatic 
central nervous system (CNS) metastases are eligible if they meet all the following: 
o Brain imaging at screening shows no evidence of interim progression, between the 
completion of CNS-directed therapy and randomization 
o Only supratentorial metastases allowed 
o No ongoing corticosteroids are required as therapy for CNS disease; 
anticonvulsants at a stable dose are allowed 
o Patient did not have stereotactic radiation or whole-brain radiation within 14 days 
before randomization 
Note: Patients with new asymptomatic CNS metastases detected at the screening scan 
must receive radiation therapy and/or surgery for CNS metastases  
o Following treatment, these patients may then be eligible if all other criteria, 
including those for patients with a history of brain metastases, are met. 
11. Active autoimmune diseases or history of autoimmune diseases that may relapse 
(Appendix 4). 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening:  
• Controlled type 1 diabetes 
• Hypothyroidism (if it is managed with hormone replacement therapy only) 
• Controlled celiac disease 
• Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
• Any other disease that is not expected to recur in the absence of external 
triggering factors 
12. With a history of interstitial lung disease, non-infectious pneumonitis, or uncontrolled 
systemic diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung 
diseases, etc. 
13. Severe chronic or active infections requiring systemic antibacterial, antifungal, or 
antiviral therapy within 2 weeks before randomization, including but not limited to 
tuberculosis infection:  
a. Received therapeutic oral or intravenous antibiotics within 2 weeks before 
randomization 
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14. Any active malignancy ≤ 2 years before randomization except for the specific cancer 
under investigation in this study and any locally recurring cancer that has been treated 
curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, 
carcinoma in situ of the cervix or breast)  
15. Patients with untreated chronic hepatitis B virus (HBV), or chronic HBV carriers with 
HBV DNA ≥ 500 IU/mL (or > 2500 copies/mL) at screening, or patients with active 
hepatitis C virus (HCV): 
• Patients with inactive hepatitis B surface antigen (HBsAg) or treated and stable 
hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. The 
HBV DNA test will be performed for patients who have a positive antibody to 
hepatitis B core antigen test. 
• Patients with a negative HCV antibody test at screening or positive HCV antibody 
followed by a negative HCV RNA test at screening are eligible. The HCV RNA 
test will be performed only for patients who test positive for HCV antibody test. 
Note: Patients with detectable HBsAg or detectable HBV DNA should be managed per 
treatment guidelines. Patients receiving antivirals at Screening should have been treated 
for > 2 weeks prior to enrollment and should continue treatment for 6 months after study 
drug treatment discontinues. 
16. A known history of HIV infection 
17. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain (defined as moderate pain that limits instrumental activities of 
daily living) ≤ 28 days before randomization  
b. Symptomatic pulmonary embolism ≤ 28 days before randomization  
c. Any history of acute myocardial infarction ≤ 6 months before randomization  
d. Any history of heart failure meeting New York Heart Association (NYHA) 
Classification III or IV (Appendix 5) ≤ 6 months before randomization  
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
randomization  
f. Any history of cerebrovascular accident ≤ 6 months before randomization  
g. Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure 
≥ 100 mmHg despite anti-hypertension medications ≤ 28 days before randomization  
h. Any episode of syncope or seizure ≤ 28 days before randomization 
18. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered 
to baseline or stabilized at the time of randomization, except for AEs not considered a 
likely safety risk (eg, alopecia, neuropathy and specific laboratory abnormalities) 
19. A history of severe hypersensitivity reactions to other monoclonal antibodies 
20. A history of allergic reactions to cisplatin, carboplatin, or etoposide 
21. ≥ Grade 2 peripheral neuropathy, as defined by NCI-CTCAE v5.0 criteria (cisplatin) 
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22. Creatinine clearance < 60 mL/min for cisplatin or < 45 mL/min for carboplatin 
23. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that would be unfavorable for the administration of study drug or 
affect the explanation of drug toxicity or AEs or result in insufficient or might impair 
compliance with study conduct. 
24. Concurrent participation in another therapeutic clinical study. 
Note: Concurrent participation in observational or noninterventional studies is allowed.  
25. Women who are pregnant or are breastfeeding. 
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5. 
STUDY TREATMENT 
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Tislelizumab and Placebo 
5.1.1.1. 
Tislelizumab 
Tislelizumab is a monoclonal antibody formulated for intravenous injection in a single-use vial 
(20R glass, United States Pharmacopeia [USP] type I), containing a total of 100 mg of antibody 
in 10 mL of isotonic solution. Tislelizumab is aseptically filled in single-use vials with a 
Flurotec-coated butyl rubber stopper and an aluminum cap. Each vial is packaged into a 
single-carton box.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label.   
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal. Please also see the Investigator’s Brochure for other details regarding tislelizumab. 
5.1.1.2. 
Placebo 
Placebo is a sterile, preservative-free solution for infusion formulated in the same buffer as 
tislelizumab. All excipients used for the manufacture of placebo are of pharmacopeial grade. No 
animal-derived components are used in the manufacture of placebo. Each vial is packaged into a 
single-carton box. 
As with tislelizumab, the contents of the label on placebo will be in accordance with all 
applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label.  
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal. 
5.1.2. 
Chemotherapy 
Handling, storage, administration, and disposal of cisplatin, carboplatin, and etoposide will be in 
accordance with relevant local guidelines, package insert/summary of product characteristics 
(SmPC). 
For further details, see the manufacturer’s prescribing information for the respective 
chemotherapies. 
5.2. 
Dosage, Administration, and Compliance 
Dosing schedules for tislelizumab or placebo and chemotherapy are provided in Table 3 and 
Table 4. All patients will be monitored continuously for AEs. Treatment modifications (eg, dose 
delay, reduction, interruption or discontinuation) will be based on specific laboratory and AE 
criteria, as described in Section 5.5. 
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Table 3. Selection and Timing of Dose Administration of Tislelizumab or Placebo in 
Combination With Cisplatin and Etoposide 
Abbreviations: IV, intravenous(ly); SmPCs, summaries of product characteristics 
a. These products should be prepared/stored/administered in accordance with the package inserts or SmPCs. 
b. Reduction of tislelizumab or placebo infusion time from 60 minutes to 30 minutes is based on the 60-minute 
infusion time being well tolerated.  
 
 
Order of 
Administration 
on Day 1 
Study Drug a 
Dose (Route) 
Induction Period 
Initial 4 Cycles b 
Maintenance Period 
Cycle 5 and Beyond 
First 
Tislelizumab or 
placebo 
200 mg (IV) 
Day 1 of each 21-day cycle: 
• Cycle 1: Infuse over 
60 minutes (wait ≥ 60 minutes 
before chemotherapy) 
• Cycles 2 to 4: Infuse over 
30 minutes (wait ≥ 60 minutes 
before chemotherapy at Cycle 
2 and thereafter wait 
≥ 30 minutes before 
chemotherapy) 
Day 1 of each 21-day 
cycle; Infuse over 
30 minutes  
Second 
Cisplatin 
75 mg/m2 (IV) 
Day 1 of each 21-day cycle: 
• Infuse over 2 hours 
Discontinue treatment 
Third 
Etoposide 
100 mg/m
2 (IV) 
Day 1 to Day 3 of each 21-day 
cycle: 
• Infuse over 60 minutes 
Discontinue treatment 
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Table 4. Selection and Timing of Dose Administration of Tislelizumab or Placebo in 
Combination With Carboplatin and Etoposide 
Abbreviations: AUC, area under the concentration-time curve; IV, intravenous(ly); SmPCs, summaries of product 
characteristics 
a. These products should be prepared/stored/administered in accordance with the package inserts or SmPCs. 
b. Reduction of tislelizumab or placebo infusion time from 60 minutes to 30 minutes is based on the 60-minute 
infusion time being well tolerated in previous cycles. 
c. Calvert formula: Total dose (mg) = (target AUC) × (glomerular filtration rate [GFR] + 25).  
GFR estimated by calculated creatinine clearance using Cockcroft-Gault Equation:  
Men: [(140 - age (y)) x weight (kg)] / [72 x serum creatinine (mg/dL)] 
Women: [(140 - age (y)) x weight (kg)] x 0.85 / [72 x serum creatinine (mg/dL)]. 
5.2.1. 
Tislelizumab or Placebo 
Tislelizumab 200 mg or placebo should be administered on Day 1 of each 21-day cycle (once 
every 3 weeks).  
Tislelizumab or placebo will be administered by intravenous infusion through an intravenous line 
containing a sterile, nonpyrogenic, low-protein-binding 0.2- or 0.22-micron in-line or add-on 
filter. Specific instructions for product preparation and administration are provided in the 
Pharmacy Manual. 
As a routine precaution, after infusion of tislelizumab or placebo on Day 1 of Cycle 1 and Cycle 
2, patients must be monitored for ≥ 60 minutes afterward in an area with resuscitation equipment 
and emergency agents before chemotherapy. From Cycle 3 onward, a ≥ 30-minute monitoring 
period is required in an area with resuscitation equipment and emergency agents. 
The initial infusion (Cycle 1 Day 1) will be delivered over 60 minutes; if this is well tolerated, 
then the subsequent infusions may be administered over 30 minutes, which is the shortest time 
Order of 
Administration 
on Day 1 
Study Drug a 
Dose (Route) 
Induction Period 
Initial 4 Cycles b 
Maintenance Period 
Cycle 5 and Beyond 
First 
Tislelizumab or 
placebo 
200 mg (IV) 
Day 1 of each 21-day cycle: 
• Cycle 1: Infuse over 
60 minutes (wait ≥ 60 minutes 
before chemotherapy) 
• Cycles 2 to 4: Infuse over 
30 minutes (wait ≥ 60 minutes 
before chemotherapy at Cycle 
2 and thereafter wait 
≥ 30 minutes before 
chemotherapy) 
Day 1 of each 21-day 
cycle; Infuse over 
30 minutes  
Second 
Carboplatin C 
AUC 5 (IV) 
Day 1 of each 21-day cycle: 
• Infuse over 15-60 minutes to 
achieve an AUC of 
5 mg/mL/min (Calvert 
formula dosing) 
Discontinue treatment 
Third 
Etoposide 
100 mg/m
2 
(IV) 
Day 1 to Day 3 of each 21-day 
cycle 
• Infuse over 60 minutes  
Discontinue treatment 
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period permissible for infusion. Tislelizumab or placebo must not be concurrently administered 
with any other drug (see Section 6). 
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of imAEs and infusion-related reactions are provided in detail in Section 5.5.2, 
Section 8.7 and Appendix 6. 
Details of tislelizumab or placebo and chemotherapy dose administration are summarized in 
Table 3 and Table 4. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.  
5.2.2. 
Chemotherapy  
All patients should receive antiemetics and intravenous hydration for cisplatin or carboplatin and 
etoposide according to the local standard of care and manufacturer’s instruction. In addition, all 
patients should receive the appropriate corticosteroid premedications as per the local approved 
label (Section 6.2.1). Additional pre-medications should be administered as per standard 
practice. All medications must be recorded on the appropriate Concomitant Medications eCRF. 
When the cisplatin and etoposide regimen is used as chemotherapy, patients will be treated with 
tislelizumab 200 mg or placebo intravenously, followed by cisplatin 75 mg/m² intravenously, 
and then etoposide 100 mg/m² intravenously on Day 1 of each 21-day cycle from Cycle 1 
through Cycle 4, as Induction treatment. Etoposide 100 mg/m² intravenously will also be 
administered on Days 2 and 3 in each of the 4 cycles. 
Similarly, when the carboplatin and etoposide regimen is used as chemotherapy, patients will be 
treated with tislelizumab 200 mg or placebo intravenously, followed by carboplatin AUC 5, and 
then etoposide 100 mg/m² intravenously on Day 1 of each 21-day cycle from Cycle 1 through 
Cycle 4, as Induction treatment. Etoposide 100 mg/m² intravenously will also be administered on 
Days 2 and 3 in each of the 4 cycles. 
Cycles in which no chemotherapy is given do not count toward the total number of Induction 
treatment chemotherapy cycles. 
Treatment may continue until the completion of the scheduled 4 cycles (only for Induction 
treatment period), disease progression as assessed by the investigator per RECIST v1.1, loss of 
clinical benefit, unacceptable toxicity, or withdrawal of informed consent, whichever occurs 
first. 
Drugs in each regimen should be administered sequentially on Day 1 of the first 4 cycles. Details 
of tislelizumab or placebo and chemotherapy dose administration, including order of dosing and 
time interval between doses, are summarized in Table 3 and Table 4. 
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any AEs. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of each therapy. 
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5.2.3. 
Supportive Care 
Patients should receive full supportive care, including epoetin and other hematopoietic growth 
factors (eg, colony-stimulating factors [CSFs]), transfusions of blood and blood products, 
antibiotics, anti-emetics, other applicable medications, as needed according to local 
standard-of-care guidelines or practice.  
5.3. 
Overdose 
Any overdose (defined as ≥ 600 mg of tislelizumab in a 24-hour period) or incorrect 
administration of study drug should be noted in the patient’s chart and on the appropriate eCRF. 
AEs associated with an overdose or incorrect administration of study drug will be recorded on 
the AE eCRF. Any SAEs associated with an overdose or incorrect administration are required to 
be reported within 24 hours of awareness via SAE reporting process as described in Section 8.7. 
Supportive care measures should be administered as appropriate. 
5.4. 
Investigational Medicinal Product Accountability 
The investigational medicinal products (IMPs) required for completion of this study 
(tislelizumab and placebo) will be provided by the sponsor, as required by local or country-
specific guidance. The investigational site will acknowledge receipt of tislelizumab and placebo. 
Any damaged shipments will be replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the sponsor. The 
site must obtain written authorization from the sponsor before any IMP is destroyed, and IMP 
destruction must be documented on the appropriate form. 
Accurate records of all IMPs received, dispensed, returned, and disposed should be recorded on 
the site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of IMP management. 
5.5. 
Dose Delay or Modification 
Every effort should be made to administer the study drug(s) according to the planned dose and 
schedule. In the event of significant toxicities, dosing may be delayed and/or reduced based on 
the guidelines provided below. Reasons for dose modifications or delays, the supportive 
measures taken, and the outcome will be documented in the patient's chart and recorded in the 
eCRF. 
The dose modification guidelines in this section are not intended to be a substitute for clinical 
judgment. Investigators may delay or modify doses in response to other reasons (eg, AEs, 
declining weight, laboratory findings) as appropriate. 
5.5.1. 
General Guidance Regarding Dose Modifications 
The severity of AEs will be graded according to the NCI-CTCAE v5.0 grading system. 
• Dose modifications for chemotherapy will be performed per local practice and per 
prescribing information according to the treating physician’s clinical judgment (see 
Section 5.5.3).  
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• Tislelizumab or placebo might be delayed as defined in Section 5.5.2. 
• For any events already apparent at baseline, the dose modifications will apply according 
to the corresponding shift in toxicity grade, if the investigator considers it is appropriate. 
For example, if a patient has Grade 1 asthenia at baseline that turns to Grade 2 during 
treatment, this will be considered a shift of 1 grade and treated as Grade 1 toxicity for 
dose modification purposes. 
• When several toxicities with different grades of severity occur at the same time, the dose 
modifications should be made according to the highest grade observed. 
• If, in the opinion of the investigator, a toxicity is considered to be solely due to 1 
component of the study treatment and the dose of that component is delayed or modified 
in accordance with the guidelines below, other components may be administered if there 
is no contraindication. 
o If 1 component of chemotherapy is discontinued permanently during the first 
4 cycles of treatment for reasons other than progressive disease (PD), the other 
component of chemotherapy may be continued per the guidelines in the study 
protocol and as per local practice. Tislelizumab or placebo may continue as 
indicated. 
o If both components of the chemotherapy are withheld because of toxicity for 
> 2 cycles, chemotherapy should be discontinued; tislelizumab or placebo may be 
continued if the toxicity resulting in chemotherapy discontinuation is not considered 
by the investigator to be related to tislelizumab or placebo. Exceptions based on 
clinical benefit require the prior approval of the medical monitor. 
o If tislelizumab or placebo is discontinued permanently during the first 4 cycles of 
chemotherapy treatment, the patient may continue the chemotherapy. 
• Administration of chemotherapy should ideally remain synchronized with predefined 
cycles and tislelizumab or placebo infusions (Section 5.2.1 and Section 5.2.2).  
o If chemotherapy-related toxicities warrant dose delays, chemotherapy 
administration should, ideally, be restarted to coincide with the next treatment cycle 
or may be given during an unscheduled visit and resynchronized at a later cycle, if 
possible.  
• Following either completion of or discontinuation from chemotherapy, tislelizumab or 
placebo should be continued as scheduled, if clinically appropriate (Section 3.3). 
Dose modification guidelines for chemotherapy, as described below (Section 5.5.3), will depend 
on the severity of toxicity and an assessment of the risk versus benefit for the patient, with the 
goal of maximizing the patient’s compliance and access to supportive care. 
5.5.2. 
Dose Delay or Modification for Tislelizumab or Placebo 
There will be no dose reduction for tislelizumab or placebo in this study.  
Patients may temporarily suspend study treatment if they experience toxicity that is considered 
related to tislelizumab or placebo and requires a dose to be withheld. If a dose of tislelizumab or 
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placebo is delayed for ≤ 10 days for a planned dosing cycle (eg, Cycle 3, Day 1), tislelizumab or 
placebo should be administered. If the delay is > 10 days, patients should skip the tislelizumab or 
placebo dose at this cycle and be dosed on the next planned cycle (see Section 5.5.1). 
Patients should resume tislelizumab or placebo treatment as soon as possible after the AEs 
recover to baseline level or Grade 1 (whichever is more severe) within 12 weeks after last dose 
of tislelizumab or placebo. If the patient is unable to resume tislelizumab or placebo within 
12 weeks after the last dose of tislelizumab or placebo, then the patient should be discontinued 
from treatment. 
If a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with the medical 
monitor. 
If a scheduled dose coincides with a holiday that precludes dosing, dosing should commence on 
the nearest following date and subsequent dosing can continue on a new 21-day schedule based 
on the infusion date.  
If tislelizumab or placebo is discontinued because of tolerability concerns during the first 4 
cycles of treatment, the patient may continue on the chemotherapy regimen (cisplatin + etoposide 
or carboplatin + etoposide) or 1 component of these regimens if agreed upon by the investigator 
and patient. 
Dose modification related to imAEs and infusion-related reactions are described in Appendix 6 
and Section 8.7.1, respectively.  
5.5.3. 
Dose Delay, Interruption or Modifications for Chemotherapy 
Dose modifications for chemotherapy should be performed per prescribing information and per 
local practice according to the investigator’s clinical judgment.  
Study drug-related toxicities must be resolved to baseline level or Grade 0 or 1 before the next 
dose is administered. This does not include alopecia, Grade 2 fatigue, or any other AE that, based 
on the investigator’s discretion, is not unfavorable to study drug administration nor affect the 
safety evaluation of the study drug(s). A maximum of 2 dose reductions for each 
chemotherapeutic agent except for carboplatin are permitted. Only 1 dose reduction is permitted 
for carboplatin. Once the dose has been decreased, it should remain reduced for all subsequent 
administrations or further reduced if necessary. There will be no dose escalations in this study. If 
additional reductions are required, that chemotherapeutic agent must be discontinued.  
Baseline body weight is used to calculate the required chemotherapy doses. Dose modifications 
are required if the patient’s body weight changes by ≥ 10% from baseline (or the new reference 
body weight).  
In case of chemotherapy-related toxicity, if the AE resolves within 10 days after a planned 
dosing date, chemotherapy will be administered. The administration of chemotherapy and 
tislelizumab or placebo will be resynchronized at the subsequent cycle, which will be scheduled 
according to the chemotherapy dose administration date. If the AE does not resolve within 
10 days, chemotherapy will be omitted. If the AE resolves within 21 days after a planned dosing 
date, chemotherapy and tislelizumab or placebo will be administered on Day 1 of the next 
treatment cycle according to the original schedule. 
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Chemotherapy treatment may be delayed up to 21 days, if the reason for the delay is toxicity/AE. 
All subsequent chemotherapy doses must be rescheduled according to the last chemotherapy 
dose administration date. 
SELECTED PRECAUTIONS: 
• Neutropenia: Fever or other evidence of infection must be assessed promptly and treated 
aggressively following the local clinical practice and/or the guidelines. 
• Renal Toxicity:  
o Nephrotoxicity is common with cisplatin. Encourage oral hydration. Avoid 
nephrotoxic drugs such as aminoglycoside antibiotics. 
o Patients should not be given cisplatin or carboplatin if their creatinine clearance is 
< 60 mL/min or < 45 mL/min, respectively.  
• Ototoxicity and sensory neural damage should be assessed prior to each cycle. Cisplatin 
is contraindicated in patients with a pre-existing hearing deficit.  
For toxicities not listed above, dose modifications are permitted per local standards.  
Guidance regarding dose modifications for certain toxicities is presented in detail in Appendix 9. 
5.6. 
Blinding 
This is a randomized, double-blind, Phase 3 study. Patients will be randomized to receive 
tislelizumab or placebo in a double-blind fashion such that neither the investigator, nor the 
patient, medical or ancillary medical staff, or the blinded sponsor staff or its designees, will 
know which drug is being administered in addition to chemotherapy. 
• Emergency unblinding  
Emergency unblinding for AEs may be performed through an Interactive Web Response 
System (IWRS). 
All AEs should be evaluated, and it should be determined whether they are related to 
tislelizumab plus chemotherapy or chemotherapy alone; treatment should be provided 
accordingly. Therefore, emergency unblinding should not be needed to manage the 
patient’s care. If knowledge of the investigational product is critical to the patient's 
management and the investigator decides that unblinding is required to manage an 
adverse reaction (eg, ≥ Grade 3 imAE or the event of a medical emergency or 
pregnancy), the investigator should make every effort to contact the medical monitor 
prior to unblinding a patient’s treatment assignment unless this could delay emergency 
treatment of the patient. If a patient’s treatment assignment is unblinded due to an 
emergency treatment, the sponsor must be notified immediately. 
• Inadvertent unblinding  
Every effort will be made to blind both the patient and the investigator to the identity of 
tislelizumab or placebo, but the inadvertent unblinding of a patient may occur. If an 
investigator, site personnel performing assessments, or patient is unblinded, the 
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unblinding will not be sufficient cause (in and of itself) for that patient to be discontinued 
from study therapy or excluded from any safety or efficacy analyses. 
• Unblinding for serious adverse reaction reporting 
The sponsor will unblind patients who experience an unexpected serious adverse 
reaction, for the purpose of reporting to the regulatory authorities. In such a case, the 
medical monitors will not be informed of the treatment allocation, according to the 
sponsor’s standard procedures. 
Bioanalytical laboratory may remain unblinded as long as there is no means for the investigators 
or blinded sponsor team to know which samples will be analyzed or not. 
Additionally, there may be ethical reasons to have the patient remain on the study treatment. For 
patients to continue on study treatment in the event of unblinding, the investigator must obtain 
specific approval from the medical monitor for the patient to continue in the study. 
5.7. 
Criteria for Discontinuing Chemotherapy Regimens 
Except where specified above, chemotherapy drugs should be discontinued for any of the 
following: 
• Any Grade 4 peripheral neuropathy requires discontinuation of platinum chemotherapy 
drugs (cisplatin or carboplatin). 
• Persistent Grade 3 paraesthesia requires discontinuation of platinum chemotherapy drugs 
(cisplatin or carboplatin). 
• Grade 3 or 4 drug-related thrombocytopenia associated with clinically significant 
bleeding. 
• Grade 3 or 4 total bilirubin elevation and Grade 4 ALT or AST elevation requires 
discontinuation of etoposide. 
• Any drug-related liver function test abnormality value that meets any of the following 
criteria requires discontinuation: 
o AST or ALT > 5-10 x ULN for > 2 weeks 
o AST or ALT > 10 x ULN 
o Total bilirubin > 5 x ULN 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• Any cisplatin-related decrease in creatinine clearance to < 60 mL/min (using the 
Cockcroft Gault formula) requires discontinuation of cisplatin or change to carboplatin. 
• Decrease in creatinine clearance to < 15 mL/min requires discontinuation of etoposide. 
• Any drug-related AE that recurs after 2 prior dose reductions (or 1 prior reduction for 
carboplatin) for the same drug-related AE requires discontinuation of the drug(s). 
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• Any Grade 3 or 4 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) thought to be causing the reaction. The drug not considered 
to be related to the hypersensitivity reaction or infusion reaction may be continued. 
• Any Grade 4 AE that the investigator considers related to study drug and inappropriate to 
be managed by dose reduction(s) requires discontinuation of drug(s). The drug not 
considered to be related to the event may be continued. 
• If any toxicity does not resolve within 21 days, that component will be discontinued. 
For toxicities not listed above, the investigator’s medical judgment would determine whether 
chemotherapy regimen should be discontinued, in accordance with patient’s well-being and local 
standards. 
Refer to Section 3.4 regarding safety follow-up procedures. 
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6. 
PRIOR AND CONCOMITANT THERAPY 
6.1. 
Prior Therapy 
The inclusion criteria specify that patients must not have received prior systemic treatment for 
ES-SCLC (Section 4.1). All prior cancer treatments and treatments for underlying active medical 
conditions must be recorded on the appropriate eCRF. All prior therapy and medications (eg, 
prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 30 days before randomization must be recorded on the 
appropriate CRF. 
6.2. 
Concomitant Therapy 
6.2.1. 
Permitted Concomitant Medications/Procedures  
Most concomitant medications and therapies that are in accordance with local standards of 
medical care and that are deemed necessary by the investigator for supportive care (eg, 
anti-emetics, antidiarrheals) and in a patient’s interest are allowed.   
Systemic corticosteroids given for the control of imAEs must be tapered gradually (see 
Appendix 6) and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) 
before the next IMP administration. Short-term use of steroids as prophylactic treatments (eg, 
patients with contrast allergies to diagnostic imaging contrast dyes) is permitted.  
Patients with active hepatitis B, defined as HBV DNA ≥ 500 IU/mL at screening, must initiate 
treatment 2 weeks before randomization and continue until 6 months after the last dose of study 
drug(s). Patients should continue effective antiviral treatment during the study to decrease 
potential viral re-activation risk. Tenofovir and entecavir are recommended in the American 
Association for the Study of Liver Disease (AASLD) guideline because they lack resistance with 
long-term use (Terrault et al 2016; AASLD/IDSA HCV Guidance Panel, 2015). The investigator 
might use other antiviral agents, if appropriate, following local guidelines. Management of 
antiviral therapy is at the discretion of the investigator; however, reason(s) must be provided in 
the eCRF if a patient with active HBV is not treated with antiviral prophylaxis.  
BeiGene does not require that patients with active HCV receive treatment with antiviral therapy. 
Patients with detectable HCV RNA and who are receiving treatment at screening should remain 
on continuous, effective antiviral therapy during the study. Investigators can consider treatment 
with sofosbuvir alone or in combination with other antivirals following the AASLD guideline or 
the local guidelines as appropriate. However, interferon-based therapy for either HBV or HCV is 
not permitted on study. Patients who are given antiviral therapy must initiate treatment at least 
2 weeks prior to randomization.  
Hematopoietic growth factors (ie, G-CSF or GM-CSF) may be used according to institutional or 
other specific guidelines (eg, country or regional guidelines or guidelines of oncology 
organizations, such as the American Society of Clinical Oncology [ASCO]) to treat febrile 
neutropenia but should not be used as primary prophylaxis. The use of any growth factor support 
must be documented in the patient’s record and eCRF. Growth factors must be discontinued at 
least 48 hours prior to initiation of the next cycle of chemotherapy.  
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Patients may continue to receive hormone replacement therapy or supportive care if initiated 
prior to enrollment. Bisphosphonates are allowed for bone metastases if initiated prior to 
enrollment and at a stable dose. Patients receiving bisphosphonates during the trial for a 
non-malignant indication are permitted for this study. 
Whole-brain radiation therapy and stereotactic radiosurgery are permitted for patients with 
disease progression limited to the CNS. During the Maintenance treatment period, PCI is 
permitted as per local standard of care. 
Patients in either arm who achieve CR or PR after Cycle 4 may be offered PCI at the discretion 
of the treating investigator. Imaging of the brain must occur prior to PCI. Patients selected to 
receive PCI may receive up to 25 Gy in 10 fractions (or the biologic equivalent), as tolerated by 
the patient. If given, PCI must begin within 6 weeks (preferably within 2 to 4 weeks) after the 
last dose of study medication in Cycle 4. Study medication may continue during PCI; however, if 
it is necessary to suspend study treatment, dosing must be restarted no later than 2 weeks after 
completion of PCI. Steroids can be administered, as required, during and after PCI. 
Palliative (limited-field) radiation therapy is permitted, but only for pain control or prophylaxis 
of bone fracture to sites of bone disease present at baseline if the following criteria are met:  
• Repeat imaging demonstrates no new sites of bone metastases  
• The lesion being considered for palliative radiation is not a target lesion for RECIST v1.1  
• The case is discussed with the medical monitor, and the medical monitor agrees that the 
conditions required to receive palliative radiation are met 
Opiates and other medication required for palliative management of patients are allowed. 
Patients must notify the investigator of all concurrent medications used during the study. 
Additionally, if clinically indicated, palliative radiation or other focally ablative therapy for other 
nontarget sites of the disease is permitted per investigators’ discretion. The medical monitor 
should be informed of the on-study radiotherapy. These patients should have a tumor assessment 
of the lesion(s) before receiving the radiotherapy in order to rule out progression of disease. It is 
not required to withhold treatment during palliative radiotherapy. 
6.2.2. 
Prohibited or Restricted Concomitant Medications/Procedures 
The following medications are prohibited or restricted at the time of screening and during the 
administration of tislelizumab or placebo: 
• Immunosuppressive agents (except to treat a drug-related AE). 
• Systemic corticosteroids > 10 mg daily (prednisone or equivalent), except to treat or 
control a drug-related AE (per protocol), or as pretreatment for chemotherapy, or for 
short-term use as prophylactic treatment. 
• Live vaccines within 28 days before randomization and 60 days following the last dose of 
tislelizumab or placebo. 
• Herbal remedies or other agents with immune-stimulating properties (eg, mistletoe 
extract) or that are known to potentially interfere with liver or other major organ 
functions (eg, hypericin). Patients must notify the investigator of all herbal remedies used 
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during the study. The concomitant use of herbal therapies is not recommended because 
their pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown. However, their use for patients in the study is allowed at the discretion of the 
investigator, provided that there are no known interactions with any study treatment. As 
noted above, herbal therapies intended for the treatment of cancer are prohibited. 
• RANK-L inhibitors (eg, denosumab) 
− Patients who are receiving denosumab prior to enrollment must be willing and 
eligible to receive a bisphosphonate instead 
The following medications are prohibited or restricted at the time of screening and during the 
administration of any component of study treatment: 
• Any concurrent antineoplastic therapy (ie, chemotherapy except for the defined 
chemotherapy in the study, hormonal therapy, immunotherapy, or standard or 
investigational agents [including Chinese herbal medicine and Chinese patent medicines] 
for treatment of cancer). 
• Extensive radiation therapy (except for local, palliative radiotherapy provided that it does 
not compromise tumor assessments of target lesions; or special circumstances such as 
described in Section 6.2.1). 
During the first 4 cycles of study treatment (ie, the Induction treatment period), patients will 
receive study-defined chemotherapies. The chemotherapeutic reagent might interfere with the 
PK of a concomitantly used medication or be impacted by a concomitant medication due to drug-
drug interactions, eg, warfarin in combination with etoposide, anticonvulsant agents in 
combination with cisplatin, or aminoglycosides in combination with carboplatin. Those 
medications should be avoided or be replaced. Refer to the manufacturer’s prescribing 
information for complete information regarding drug-drug interactions. 
The following guideline should also be followed during the study: 
• With the exception of diagnostic biopsy of tumor tissue or placement of a venous access 
device, the investigator should discuss with the medical monitor any individual patient 
requiring surgery during the study. 
• Patients should not abuse alcohol or other addictive drugs during the study. 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications 
The potential for drug-drug interaction between the study drugs (tislelizumab) and small-
molecule drug products is very low, given tislelizumab is therapeutic monoclonal antibody. 
Because tislelizumab is expected to be degraded into amino acids and recycled into other 
proteins, it is unlikely to have an effect on drug metabolizing enzymes or transporters. 
Co-administration of etoposide with warfarin may result in elevated international normalized 
ratio (INR). If the co-administration occurs, measure INR frequently (Etoposide prescribing 
information).  
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7. 
STUDY ASSESSMENTS AND PROCEDURES 
A table of scheduled study assessments is provided in Appendix 1. Patients will be closely 
monitored for safety and tolerability throughout the study. All assessments must be performed 
and documented in the medical record for each patient. 
Dosing will occur only if the clinical assessment and local laboratory test values (that must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines.  
7.1. 
Screening 
Screening evaluations will be performed within 28 days prior to randomization. Patients who 
agree to participate will sign the ICF prior to undergoing any screening procedure. The screening 
period begins on the first day that a screening procedure is conducted. Pulmonary function 
testing including spirometry and assessment of oxygenation is to be performed for all patients at 
baseline (Appendix 1). Screening evaluations may be repeated as needed within the screening 
period; the investigator is to assess patient eligibility according to the latest screening assessment 
results.  
Results of standard-of-care tests or examinations performed prior to obtaining informed consent 
and ≤ 28 days prior to randomization may be used for the purposes of screening rather than 
repeating the standard-of-care tests unless otherwise indicated. 
Procedures conducted only during the Screening Visit are described in this section. For the 
description of other assessments that are conducted during screening, as well as throughout the 
study, refer to Safety Assessments (Section 7.5), Tumor and Response Evaluations (Section 7.6), 
PK and Antidrug Antibody Testing (Section 7.7), and Biomarkers (Section 7.8). 
Rescreening under limited conditions may be allowed after consultation with BeiGene (eg, when 
a patient narrowly misses a laboratory criterion and it is correctable and not due to rapidly 
deteriorating condition or disease progression). Rescreening is allowed only once. 
7.1.1. 
Demographic Data and Medical History  
Demographic data will include the patient’s year of birth, age, gender, and self-reported 
race/ethnicity.  
Medical history includes any history of clinically significant disease, surgery, or cancer history; 
reproductive status (ie, of childbearing potential or no childbearing potential); history of alcohol 
consumption and tobacco (ie, former or current or never).  
Cancer history will include an assessment of prior surgery, prior radiotherapy, and prior drug 
therapy, including start and stop dates, best response and reason for discontinuation. 
Radiographic studies performed prior to study entry may be collected for review by the 
investigator. 
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7.1.2. 
Females of Childbearing Potential and Contraception 
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer 
to Appendix 8 for contraception guidelines and definitions of “women of childbearing potential” 
and “no childbearing potential.”  
7.1.3. 
Informed Consent and Screening Log 
Voluntary, written informed consent for participation in the study must be obtained before any 
study-specific procedures are performed. ICFs for enrolled patients and for patients who are 
screened but not enrolled will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization. The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable. 
7.1.4. 
Patient Numbering 
After obtaining informed consent, study site personnel will access the Interactive Response 
Technology (IRT) system to assign a unique patient number to a potential study participant. 
7.1.5. 
Pulmonary Function Tests 
Pulmonary function testing including spirometry and assessment of oxygenation, at a minimum 
pulse oximetry at rest and with exercise, or alternatively, assessment of diffusion capacity, are to 
be performed for all patients during screening to help the determine the patient’s suitability for 
the study. Respective test results need to be submitted to the sponsor. 
For test results indicative of significantly impaired pulmonary function, eg, resting pulse 
oximetry < 90% on room air and further de-saturation upon exercise, forced expiratory volume 
(FEV1) < 60% or diffusing capacity for carbon monoxide (DLCO) (if performed) < 60% of age 
and sex adjusted predicted performance levels (Pellegrino et al 2005), the medical monitor needs 
to be consulted to confirm eligibility. 
Tests may be repeated as clinically indicated during the study (refer to Appendix 1 for details). 
7.2. 
Enrollment 
7.2.1. 
Confirmation of Eligibility 
The investigator will assess and confirm the eligibility of each patient. All screening procedure 
results and relevant medical history must be available before eligibility can be determined. All 
inclusion criteria must be met and none of the exclusion criteria may apply. No eligibility 
waivers will be granted.   
After a patient is screened and the investigator determines that the patient is eligible for 
randomization, study site personnel will complete an Eligibility Authorization Packet and send it 
to the medical monitor or designee to confirm the patient’s eligibility before enrollment. Study 
site personnel should ensure that a medical monitor’s confirmation has been received before 
randomization. 
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7.2.2. 
Enrollment/Randomization 
Site personnel will access the IRT system to randomize patients to treatment assignment and to 
assign study drug. Study treatment must commence within 2 business days after 
randomization/treatment assignment. 
7.3. 
Tislelizumab, Placebo and Chemotherapy Dispensation 
Tislelizumab, placebo, and chemotherapy will be dispensed and administered as described in 
Section 5.2. 
7.4. 
Crossover 
There is no crossover between the 2 arms in this study. 
7.5. 
Safety Assessments 
7.5.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate and blood pressure 
(systolic and diastolic) while the patient is in a seated position after resting for 10 minutes. 
Height (at baseline only) and weight should be measured and recorded in the eCRF. 
For the first 2 infusions of tislelizumab or placebo, the patient’s vital signs should be measured 
within 60 minutes before the infusion, during and 30 minutes after the infusion. For subsequent 
infusions, vital signs will be collected within 60 minutes before infusion and, if clinically 
indicated, during and 30 minutes after the infusion. Patients will be informed about the 
possibility of delayed post-infusion symptoms and instructed to contact their study physician if 
they develop such symptoms. Refer to Section 5.2.1 regarding precautionary monitoring of 
patients after infusion of tislelizumab or placebo. 
7.5.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted including 
evaluations of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 4) 
musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) neurological systems. Any 
abnormality identified during screening will be graded according to NCI-CTCAE v5.0 and 
recorded on the eCRF with appropriate disease/condition terms.  
In addition, investigators should solicit patients regarding changes in vision, visual disturbance, 
or ocular inflammation at each scheduled study visit during study treatment. For any change in 
vision, referral to an appropriate specialist will be made for further management guidance 
(Appendix 6). 
At subsequent visits (and as clinically indicated), limited, symptom-directed physical 
examinations will be performed. New or worsened clinically significant abnormalities are to be 
recorded as AEs on eCRF. Refer to Section 8.3 regarding AE definitions and reporting and 
follow-up requirements. 
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7.5.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (Appendix 2) will be assessed at screening, Day 1 of each cycle 
through the study, EOT, and at Safety Follow-Up Visit (Appendix 1).  
7.5.4. 
Laboratory Safety Tests 
Local and/or central laboratory assessments of serum chemistry, hematology, coagulation, and 
urinalysis will be conducted, of which certain elements will be collected as specified below. 
If laboratory tests at screening are not performed within 7 days prior to the administration of 
study drug(s) on Cycle 1 Day 1, these tests should be repeated and reviewed before study drugs 
administration. Hematology, serum chemistry, serum creatine kinase (CK) and CK myocardial 
band (CK-MB) assessment, and coagulation tests as specified below should be performed at the 
beginning of each cycle, and at the EOT and Safety Follow-up Visits.  
Local laboratory assessments will include the following: 
• Hematology (complete blood count [CBC], including red blood cell [RBC] count, 
hemoglobin, hematocrit, WBC count with differential [neutrophils], and platelet count) 
• Serum chemistry (glucose, blood urea nitrogen [BUN] or urea, creatinine, sodium, 
potassium, magnesium, chloride, calcium, phosphorus, direct bilirubin, total bilirubin, 
ALT, AST, alkaline phosphatase, lactate dehydrogenase [LDH], total protein, and 
albumin) 
• Coagulation test (international normalized ratio, prothrombin time, and activated partial 
thromboplastin time) 
• Urine or serum pregnancy test (for women of childbearing potential, including 
premenopausal women who have had a tubal ligation) within 7 days prior to 
randomization. Urine pregnancy tests will be performed at each visit prior to dosing. A 
serum pregnancy test must be performed if the urine pregnancy test is positive or 
equivocal 
• Urinalysis (complete [including, but not limited to specific gravity, pH, glucose, protein, 
ketones] and/or microscopic at screening and if clinically indicated) 
• Thyroid function testing (thyroid stimulating hormone [TSH], free T3, free T4). Thyroid 
function tests will be performed at screening and every 3 cycles (ie, Cycles 4, 7, 10, etc), 
and at the Safety Follow-up Visit. 
• Total CK and CK-MB assessment (ECG, serum troponins, and other examinations as 
clinically indicated and as appropriate, if significant abnormalities are detected). In the 
event that CK-MB fractionation is not available, troponin I and/or troponin T should be 
assessed instead. 
Details about sample collection and shipment will be provided in a separate instruction manual. 
Investigators may use results from local laboratories for assessing eligibility, safety monitoring 
and dosing decision. 
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7.5.5. 
Electrocardiograms 
ECG recordings will be obtained at screening, at the Safety Follow-up Visit, and as clinically 
indicated. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient's permanent study 
file at the site. 
When coinciding with blood draws at the same timepoint, ECG assessment should be performed 
prior to blood draws. Patients should rest in semi-recumbent supine position for at least 
10 minutes prior to ECG assessment.  
7.5.6. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0 
(NCI-CTCAE, Nov 2017). Characterization of toxicities will include severity, duration, and time 
to onset.  
All AEs, including SAEs, will be collected as described in Section 8.6.   
7.5.7. 
Hepatitis B and C Testing 
Testing will be performed by the local laboratory or central laboratory at screening and will 
include HBV/HCV serology (HBsAg, hepatitis B surface antibody [HBsAb], hepatitis B core 
antibody [HBcAb], and HCV antibody) and viral load assessment (HBV DNA and HCV RNA).  
7.6. 
Tumor and Response Evaluations 
Tumor imaging will be performed within 28 days prior to randomization. During the study, 
tumor imaging will be performed approximately every 6 weeks (± 7 days) for the first 48 weeks 
following Cycle 1 Day 1, and every 9 weeks (± 7 days) thereafter, regardless of treatment dose 
delay. The investigator may perform additional scans or more frequent assessments if clinically 
indicated. Tumor assessment will continue until radiographic disease progression per RECIST 
v1.1. 
Patients who discontinue study treatment early for reasons other than disease progression (eg, 
toxicity) will continue to undergo tumor assessments following the original plan until the patient 
begins a subsequent anticancer treatment, experiences disease progression, withdraws consent, is 
lost to follow-up, death, or until the study terminates, whichever occurs first. 
Screening assessments and each subsequent assessment must include computed tomography 
(CT) scans (with oral/ intravenously contrast, unless contraindicated) or magnetic resonance 
imaging (MRI) of the chest, abdomen, pelvis and brain. Other known or suspected sites of 
disease must be included in the imaging assessments (neck, extremities, etc). 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit 
and reassessed at each subsequent tumor evaluation. The same radiographic procedure used to 
assess disease sites at Screening are required to be used throughout the study (eg, the same 
contrast protocol for CT scans). 
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• Imaging of the brain (preferably MRI, or CT) at baseline (≤ 28 days prior to 
randomization) is required for all screened patients.  
• For patients with known and previously treated brain metastases, the scan should be 
within 14 days of planned Cycle 1 Day 1. 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a non-contrast CT of the chest plus a contrast-enhanced 
MRI (if possible) of abdomen and pelvis should be performed. 
• If a CT scan for tumor assessment is performed on a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards of a 
diagnostic CT scan. 
• Bone scans (Technetium-99m [TC-99m]) or PET should be performed at screening only 
if clinically indicated. If bone metastases are present at screening and cannot be seen on 
CT or MRI scans, TC-99m or PET bone scans should be repeated when a CR is 
suspected in target lesion or when progression in bone is suspected. 
• CT scans of the neck or extremities should be performed at screening only if clinically 
indicated and followed throughout the study, if there is evidence of metastatic disease in 
these regions at screening. At the investigator’s discretion, other methods of assessment 
of target lesion and nontarget lesions per RECIST v1.1 may be used. 
Response will be assessed by the investigator using RECIST v1.1 (see Appendix 3). The same 
evaluator should perform assessments, if possible, to ensure internal consistency across visits. 
After first documentation of response (CR or PR), confirmation of tumor response should occur 
at 4 weeks or later after the first response or at the next scheduled assessment time point.   
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune cell 
infiltration and other mechanisms leading to apparent increase of existing tumor masses or 
appearance of new tumor lesions. Thus, if radiographic progressive disease is suspected by the 
investigator to reflect pseudoprogression, patients may continue treatment until progressive 
disease is confirmed by repeated imaging ≥ 4 weeks later (but not exceeding 6 to 8 weeks from 
the date of initial documentation of progressive disease). If at the investigator’s discretion a 
patient could continue to benefit from study treatment after progressive disease per RECIST v1.1 
criteria, the patient may continue study treatment. Patients who have suspected 
pseudoprogression or who may continue to benefit from study treatment after progressive disease 
must meet the following criteria in order to be treated:  
• Absence of clinical symptoms and signs of disease progression (including clinically 
significantly worsening of laboratory values)  
• Stable ECOG Performance Status ≤ 1 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention 
• Investigators must obtain written informed consent for treatment beyond radiologic 
disease progression and inform patients that this practice is not considered standard in the 
treatment of cancer. 
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Patients who continue treatment beyond disease progression will continue to undergo tumor 
assessments following the original plan or as clinically indicated until treatment end. 
The decision to continue study drug(s) beyond initial investigator-assessed progression must be 
agreed to by the medical monitor and documented in the study records. 
Tumor assessments are required to be performed on schedule regardless of whether study 
treatment has been administered or held. That is, they should not be adjusted for delays in cycles. 
7.7. 
Pharmacokinetic and Antidrug Antibody Testing  
Tislelizumab may elicit an immune response. Patients with signs of any potential immune 
response to tislelizumab or placebo will be closely monitored. Validated screening and 
confirmatory assays will be employed to detect ADAs at multiple time points throughout the 
study (see Appendix 1). The immunogenicity evaluation will utilize a risk-based immunogenicity 
strategy (Koren et al 2008; Worobec and Rosenberg 2004a; Worobec and Rosenberg 2004b) to 
characterize ADA responses to tislelizumab in support of the clinical development program. This 
tiered strategy will include an assessment of whether ADA responses correlate with relevant 
clinical endpoints. Implementation of ADA characterization assays will depend on the safety 
profile and clinical immunogenicity data.  
The following assessments will be performed at a designated bioanalytical laboratory:  
• ADA assays: serum samples will be tested for the presence of ADAs to tislelizumab 
using a validated immunoassay 
• PK assays: serum samples will be assayed for tislelizumab concentration with use of a 
validated immunoassay 
PK and ADA samples collected from patients randomized to receive placebo will not be 
analyzed. 
Shipping, storage, and handling of samples for the assessment of tislelizumab PK and ADA 
assays will be managed through a central laboratory. Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
7.8. 
Biomarkers 
Shipping, storage, and handling of blood, archival tumor, fresh tumor, and leftover tumor tissue 
for the assessment of biomarkers will be managed through a central laboratory. Refer to the 
laboratory manual for details of sample handling.  
Archival tumor tissues (formalin-fixed paraffin-embedded [FFPE] block or approximately 
15 [≥ 6] unstained slides) are required to be sent to central laboratory for central 
immunohistochemistry assay (IHC) of PD-L1 status. In addition to PD-L1 expression, other 
exploratory predictive biomarkers, such as TMB and immune-mediated GEP, biomarkers 
expression by multiplex IHC, and other immune-mediated markers that are related to response or 
clinical benefit of tislelizumab may also be evaluated. If no archival samples are available, a 
fresh tumor biopsy at screening is strongly recommended, if feasible. For fresh biopsy 
specimens, acceptable samples include core needle biopsies for deep tumor tissue or excisional, 
incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. 
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Optional biopsies will also be taken for the patients who have confirmed disease progression 
and/or at the time of first tumor response (CR/PR) during the study from accessible tumor sites 
to obtain samples to explore resistance mechanism. If feasible, any follow-up biopsy should be 
ideally taken from the same tumor lesion as the baseline biopsy. Written patient consent is 
required for fresh tumor biopsies.  
Tumor tissue should be of good quality based on total and viable tumor content. Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable.  
Blood samples will be taken at baseline (predose at Day 1 of Cycle 1) and optionally at the time 
of disease progression and/or at the time of first tumor response (CR/PR) (10 mL each timepoint) 
for all randomized patients to explore the association of blood-based biomarkers with response, 
resistance, and prognosis to tislelizumab in combination with chemotherapy or chemotherapy 
alone. Written patient consent is required for blood sample collections. The sampling at baseline 
will be mandatory after regulatory approval.  
If a patient undergoes a medically indicated procedure any time during the course of the study 
that has the likelihood of yielding tumor tissue, any remaining samples or a portion of the sample 
not necessary for medical diagnosis (leftover tumor tissue) may be obtained for exploratory 
analysis. 
7.9. 
Health-Related Quality of Life 
Patients will be asked to complete the EORTC-QLQ-C30 (Appendix 10), EORTC-QLQ-LC13 
(Appendix 11), and EQ5D-5L (Appendix 12) questionnaires before any clinical activities are 
performed during on-study clinic visits according to the schedule in Appendix 1. The 
questionnaires will be provided in the patient’s preferred language. 
7.10. 
Visit Windows 
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see 
Appendix 1). All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed prior to study treatment infusion/dose 
unless otherwise noted. Laboratory results are required to be reviewed prior to dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
events, the visit should be scheduled on the nearest feasible date (the visit window is provided in 
Appendix 1), with subsequent visits conducted according to the planned schedule every 3 weeks 
from Cycle 1 of Day 1. 
7.11. 
Unscheduled Visits 
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include vital signs/focused physical examination; ECOG Performance Status; AE 
review; concomitant medications and procedures review; radiographic assessments; physical 
examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms; and 
hematology and chemistry laboratory assessments. The date and reason for the unscheduled visit 
must be recorded in the source documentation.   
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If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, then 
diagnostic tests may be performed based on the investigator assessment as appropriate, and the 
results of these tests should be entered on the unscheduled visit eCRF. 
8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria of an AE or SAE as defined in this protocol.  
8.1. 
Risks Associated With Study Drug 
8.1.1. 
Risks Associated With Tislelizumab 
Tislelizumab is an investigational agent that is currently in clinical development. Limited safety 
data are available in patients and the full safety profile has not been characterized. The following 
recommendation is based on results from nonclinical and clinical studies with tislelizumab and 
published data on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions. AEs observed with anti-PD-1 therapy are presented in Section 8.7.3. 
Although most imAEs known to occur with immunomodulatory agents have been mild and 
self-limiting, such events should be recognized early and treated promptly to avoid potential 
major complications. Suggested workup procedures for suspected imAEs are provided in 
Appendix 6. 
8.1.2. 
Risks Associated With Chemotherapy 
Refer to the most recent, locally approved package insert for information on the risk associated 
with particular platinum-based (cisplatin or carboplatin) or etoposide-based chemotherapy. 
8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this study. Results from the 
nonclinical toxicology studies and clinical data with tislelizumab, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were considered. Specifically, 
patients who are at risk for study-emergent active autoimmune diseases or who have a history of 
autoimmune diseases that may relapse, patients who have undergone allogeneic stem cell or 
organ transplantation and patients who have received a live viral vaccine ≤ 28 days before 
randomization are excluded from the study. Patients with contraindications for comparator drug 
treatment are also excluded from the study (see Section 4.2 for the full list of exclusion criteria).  
8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v5.0. Patients will be assessed for safety (including laboratory values) 
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according to the schedule in Appendix 1. Clinical laboratory results must be reviewed prior to 
the start of each cycle.  
In this study, all enrolled patients will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study. Safety evaluations will 
consist of medical interviews, recording of AEs, physical examinations, laboratory 
measurements (hematology, chemistry, etc) and other assessments. In addition, patients will be 
closely monitored for the development of any signs or symptoms of autoimmune conditions and 
infection.  
Samples will be drawn from all randomized patients but will be analyzed only in patients who 
are treated with tislelizumab. Administration of tislelizumab or placebo will be performed in a 
setting where emergency medical equipment and staff who are trained to respond to medical 
emergencies are available (see Section 5.2.1).   
All AEs will be recorded during the study (AE from the time of the first dose and SAEs from the 
time of signing of informed consent) and for up to 30 days after the last dose of study drug(s) 
(including chemotherapy drugs) or until the initiation of another anticancer therapy, whichever 
occurs first. At the end of treatment, ongoing AEs considered related to study treatment will be 
followed until the event has resolved to baseline level or ≤ Grade 1, the event is assessed by the 
investigator as stable, the patient is lost to follow-up, the patient withdraws consent, or it has 
been determined that study treatment or participation is not the cause of the AE. 
imAEs will be recorded up to 90 days after the last dose of tislelizumab or placebo, regardless of 
whether the patient starts a new anticancer therapy. All drug-related SAEs will be recorded by 
the investigator after treatment discontinuation until patient death, withdrawal of consent, or loss 
to follow-up, whichever occurs first. 
Investigators are instructed to report all AEs (including pregnancy-related AEs). 
The potential safety issues anticipated in this study, as well as measures intended to avoid or 
minimize such toxicities, are outlined in the following sections.  
8.3. 
Adverse Events 
8.3.1. 
Definitions and Reporting 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not. 
Examples of AEs include:  
• Worsening of a chronic or intermittent preexisting condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome  
• Detection or diagnosis of a new condition after study drug administration, even though 
the condition may have been present before the start of the study  
• Signs, symptoms, or the clinical sequelae of a suspected interaction  
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• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or 
a concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results and diagnostics reports) relative to 
the AE or SAE. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor. In this instance, all patient identifiers will be blinded on the 
copies of the medical records prior to submission to the sponsor.  
8.3.2. 
Assessment of Severity 
The investigator will assess the severity for each AE and SAE reported during the study. AEs 
and SAEs should be assessed and graded based upon the NCI-CTCAE v5.0. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL  
• Grade 4: Life-threatening consequences; urgent intervention indicated  
• Grade 5: Death related to AE  
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions. Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.6.2 . 
8.3.3. 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE, using best clinical judgment. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the AE or SAE to the study drug should be considered and investigated. The investigator should 
consult the tislelizumab Investigator’s Brochure in the determination of his/her assessment.  
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always assess causality for every SAE prior to transmission of the SAE report to the 
sponsor, because causality assessment is one of the criteria used when determining regulatory 
reporting requirements. The investigator may subsequently change his/her opinion of causality 
considering follow-up information and may amend the SAE report accordingly.  
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The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related” based on the information available at the time of reporting. An AE is considered 
related if there is “a reasonable possibility” that the AE may have been caused by the study drug 
(ie, there are facts, evidence, or arguments to suggest possible causation). A number of factors 
should be considered in making this assessment, including:  
• Temporal relationship of the AE to the administration of study treatment/study procedure  
• Whether an alternative etiology has been identified  
• Mechanism of action of the study drug  
• Biological plausibility  
• An AE should be considered "related" to study drug if any of the following criteria are 
met, otherwise the event should be assessed as “not related” 
− There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out  
− There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely  
− There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of the study drug). However, the 
influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs).  
8.3.4. 
Following Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up or the patient 
withdraws consent. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
post-mortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the timeframes outlined in Section 8.6.2 . 
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8.3.5. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, complete blood count [CBC], coagulation, 
or urinalysis) or other abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen during the study. The definition of clinically significant is left 
to the judgment of the investigator. In general, these are the laboratory test abnormalities or other 
abnormal assessments that:  
• are associated with clinical signs or symptoms, or  
• require active medical intervention, or  
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or  
• further diagnostic investigation.  
8.4. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose:  
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE, 
which hypothetically might have caused death, if it were more severe.  
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
• Results in disability/incapacity 
• Note: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), which may interfere or prevent 
everyday life functions, but do not constitute a substantial disruption.  
• Is a congenital anomaly/birth defect 
• Is considered a significant medical AE by the investigator based on medical judgement 
(eg, may jeopardize the patient or may require medical/surgical intervention to prevent 
one of the outcomes listed above) 
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The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets 
the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is 
not consistent with those noted in the Investigator’s Brochure. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events 
8.6.1. 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until either 30 days after last dose of study drugs including chemotherapy drugs or 
initiation of new anticancer therapy, whichever occurs first. ImAEs (serious or nonserious) 
should be reported until 90 days after the last dose of tislelizumab or placebo, regardless of 
whether or not the patient starts a new anticancer therapy. All SAEs considered related to the 
study drug(s) that are brought to the attention of the investigator should be reported regardless of 
time since the last dose of treatment.  
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 5. 
Table 5. Timeframes and Documentation Methods for Reporting Serious Adverse Events to 
the Sponsor or Designee 
 
Timeframe for 
Making Initial 
Report 
Documentation 
Method 
Timeframe for 
Making Follow-up 
Report 
Documentation 
Method 
Reporting 
Method 
All 
SAEs 
Within 24 h of 
first knowledge of 
the SAE 
SAE Report 
As expeditiously as 
possible 
SAE Report 
Email or fax SAE 
form or 
Pregnancy form 
Abbreviations: AE, adverse event; h, hours; SAE, serious adverse event. 
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8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 8.6.2.1. The SAE Report 
will always be completed as thoroughly as possible with all available details of the event and 
forwarded to the sponsor or designee within the designated timeframes.  
If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 8.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both 
the local regulatory authority and other regulatory agencies about the safety of a product under 
clinical investigation.  
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
All SUSARs (as defined in Section 8.5), will be submitted to all applicable regulatory authorities 
and investigators for tislelizumab studies. 
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC. The investigator should place copies of 
Safety Reports from the sponsor in the Investigator Site File. 
8.6.3. 
Eliciting Adverse Events 
The investigator or designee will ask about AEs by asking the following standard questions:  
• How are you feeling?  
• Have you had any medical problems since your last visit?  
• Have you taken any new medicines since your last visit?  
8.6.4. 
Disease Progression  
Disease progression (including fatal disease progression), which is expected in this study 
population and measured as an efficacy endpoint, should not be reported as an AE term. Instead, 
the symptoms, signs or clinical sequelae that result from disease progression should be reported 
as the AE term(s).   
For instance, a patient presents with pleural effusion resulting from disease progression of 
metastasis to lungs. The event term should be reported as “pleural effusion” instead of disease 
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progression. If a patient experienced a fatal multi-organ failure due to disease progression, the 
term “multi-organ failure” should be reported as the SAE with death as outcome instead of 
reporting “fatal disease progression” or “death due to disease progression.”  
8.6.5. 
Deaths 
Death is an outcome and not usually considered an event. If the only information available is 
death and the cause of death is unknown, then the death is reported as an AE, eg, “death,” “death 
of unknown cause,” or “death unexplained.” 
8.6.6. 
Pregnancies 
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy or within 120 days after the last dose of tislelizumab or placebo, or 
chemotherapy drugs, whichever is given later, a pregnancy report form is required to be 
completed and expeditiously submitted to the sponsor to facilitate outcome follow-up. 
Information on the status of the mother and child will be forwarded to the sponsor. Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE.  
An abortion, whether accidental, therapeutic, or spontaneous should be always reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as an SAE. 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees 
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation.  
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information (RSI) documents: 
• tislelizumab Investigator’s Brochure 
• The prescribing information of chemotherapy 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events 
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-mediated (see Section 8.7.3) should be reported as imAEs and ticked 
as such in the eCRF AE page until Day 90, after treatment discontinuation.  
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 6. 
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An extensive list of potential imAEs appears in Section 8.7.3, Table 7. All conditions similar to 
those listed should be carefully evaluated to determine whether they are imAEs, based on a 
similar diagnostic process to those reactions that are presented in more detail in Appendix 6. 
8.6.9. 
Recording Infusion-Related Reactions 
The symptoms of infusion-related reactions may include, but are not limited to, fever, 
chills/rigor, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness, or hypertension. Severe reactions may include acute respiratory 
distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock.  
AEs should be recorded as “infusion-related reaction” instead of the individual signs and 
symptoms.  
8.7. 
Management of Adverse Events of Special Interest 
As a routine precaution, after infusion of tislelizumab or placebo on Day 1 of Cycle 1 and Cycle 
2, patients must be monitored for ≥ 60 minutes afterward in an area with resuscitation equipment 
and emergency agents before chemotherapy. From Cycle 3 onward, a minimum of a 30-minute 
monitoring period is required in an area with resuscitation equipment and emergency agents.  
The management of infusion-related reactions, severe hypersensitivity reactions, and imAEs 
according to the NCI-CTCAE criteria are outlined below. 
8.7.1. 
Infusion-Related Reactions 
The symptoms of infusion-related reactions include fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, 
or hypertension. Severe reactions may include acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, and cardiogenic shock. Patients should be closely monitored 
for such reactions. Immediate access to an Intensive Care Unit (ICU) or equivalent environment 
and appropriate medical therapy (including epinephrine, corticosteroids, intravenous 
antihistamines, bronchodilators, and oxygen) must be available to treat infusion-related 
reactions. 
Treatment modification for symptoms of infusion-related reactions due to study drug(s) is 
provided in Table 6.  
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Table 6. Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) 
NCI-CTCAE Grade 
Treatment Modification for Tislelizumab or 
Placebo 
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%.  Any worsening is 
closely monitored.  Medical management as needed.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate.  
Grade 2 - moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for ≤ 24 h 
Stop infusion.  Infusion may be resumed at 50% of 
previous rate once infusion-related reactions has 
resolved or decreased to Grade 1 in severity.  Any 
worsening is closely monitored.  Proper medical 
management should be instituted as described below.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Grade 4 – life threatening 
Life-threatening consequences; urgent intervention 
indicated. 
Immediately stop the infusion.  Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Hospitalization is recommended. 
Abbreviations: h, hours; IV, intravenous; NCI-CTCAE, National Cancer Institute-Common Terminology 
Criteria for Adverse Event; NSAIDs, nonsteroidal anti-inflammatory drugs. 
Once the tislelizumab or placebo infusion rate has been decreased by 50% or suspended due to 
an infusion-related reaction, it must remain decreased for all subsequent infusions with 
premedication. If the patient has a second infusion-related reaction (≥ Grade 2) on the slower 
infusion rate, infusion should be discontinued and the patient should be withdrawn from 
tislelizumab or placebo treatment. 
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be 
instituted, as indicated per the type of reaction. This includes but is not limited to an 
antihistamine (eg, diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), 
and if considered indicated oral or intravenous glucocorticoids, epinephrine, bronchodilators, and 
oxygen. In the next cycle, patients should receive oral premedication with an antihistamine (eg, 
diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or equivalent), and they 
should be closely monitored for clinical signs and symptoms of an infusion reaction.  
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction.  This includes but is not limited 
to oral or intravenous antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, 
and oxygen. 
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8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms 
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (UK) (Soar et al 2008). 
Patients should be instructed to report any delayed reactions to the investigator immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction (typically manifested within 
minutes following administration of the drug/antigen, and characterized by: respiratory distress; 
laryngeal edema; and/or intense bronchospasm; and often followed by vascular collapse or shock 
without antecedent respiratory difficulty; cutaneous manifestations such as pruritus and urticaria 
with/without edema; and gastrointestinal manifestations such as nausea, vomiting, crampy 
abdominal pain, and diarrhea), the infusion must be immediately stopped and the patient 
discontinued from the study. 
The patients will be administered epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed and then the patient should be placed on monitor 
immediately, and ICU should be alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drugs(s) infusion. 
Alternative treatments for fever (ie, paracetamol) may be given to patients at the discretion of the 
investigator. 
8.7.3. 
Immune-Mediated Adverse Events  
Immune-mediated AEs are of special interest in this study. If the events listed below or similar 
events occur, the investigator should exclude alternative explanations (eg, combination drugs, 
infectious disease, metabolic, toxin, disease progression, or other neoplastic causes) with 
appropriate diagnostic tests, which may include, but are not limited to, serologic, immunologic, 
and histologic (biopsy) data. If alternative causes have been ruled out; the AE required the use of 
systemic steroids, other immunosuppressants, or endocrine therapy, and is consistent with an 
immune-mediated mechanism of action, the imAE indicator in the eCRF AE page should be 
checked. 
A list of potential imAEs is shown below in Table 7. All conditions similar to those listed should 
be evaluated in patients receiving tislelizumab or placebo to determine whether they are 
immune-mediated.  
Recommendation for diagnostic evaluation and management of imAEs is based on European 
Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) 
guidelines (Haanen et al 2017, Brahmer et al 2018) and common immune-mediated toxicities are 
detailed in Appendix 6. For any AEs not included in Appendix 6, please refer to the ASCO 
Clinical Practice Guideline (Brahmer et al 2018) for further guidance on diagnostic evaluation 
and management of immune-mediated toxicities.    
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Table 7. Immune-Mediated Adverse Events 
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet’s 
syndrome 
Skin (severe-rare) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or endoscopic/radiographic 
evidence of inflammation); pancreatitis; hepatitis; aminotransferase (ALT/AST) 
elevation; bowel perforation 
Endocrine 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with features of 
hypopituitarism, eg, fatigue, weakness, weight gain; insulin-dependent diabetes 
mellitus; diabetic ketoacidosis; adrenal insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Neuromuscular 
arthritis; arthralgia; myalgia; neuropathy; Guillain-Barre syndrome; aseptic 
meningitis; myasthenic syndrome/myasthenia gravis, meningoencephalitis; 
myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Recommendations for managing imAEs are detailed in Appendix 6. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the sponsor.  Patients who experience a recurrence of any event at the 
same or higher severity grade with rechallenge should permanently discontinue treatment. 
8.7.4. 
Renal Function Abnormalities 
Patients with moderate renal dysfunction (estimated glomerular filtration rate > 30 
mL/min/1.73 m2 and < 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology 
Collaboration equation) may be enrolled into the study. For patients with baseline renal 
insufficiency, the following algorithm is proposed for the use of steroid treatment in the 
management of imAEs: 
• If the serum creatinine is normal at baseline, please see Section 8.7.3 and refer to 
Appendix 6 for diagnosis and management of patients with abnormal renal laboratory 
values.  
• If the serum creatinine is Grade 1 at baseline and increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 2 after starting treatment with tislelizumab 
or placebo, refer to Appendix 6 for diagnosis and management of patients with abnormal 
renal laboratory values. Check the estimated glomerular filtration rate (eGFR) using 
Appendix 7 and the eGFR calculator link. In the setting of a Grade 2 serum creatinine 
increase only, study treatment can continue unless the serum creatinine increases by 
≥ 50% from the baseline value OR the eGFR falls below 20 mL/min/1.73 m2.  
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• If the serum creatinine is Grade 2 at baseline and increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 3 after starting treatment with tislelizumab 
or placebo, refer to Appendix 6 for diagnosis and management of patients with abnormal 
renal laboratory values. In the setting of a Grade 3 serum creatinine increase only, study 
treatment will be held until serum creatinine improves to baseline and treatment may 
resume only after discussion with the medical monitor.  
9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
The statistical analyses will be performed by the sponsor or designee after data collection is 
completed and the database is locked and released. Data will be listed and summarized per 
sponsor agreed reporting standards, where applicable. Details of the statistical analyses will be 
included in a separate SAP.  
9.1. 
Statistical Analysis 
9.1.1. 
Randomization Methods 
As discussed in Section 7.2.2, patients will be randomized using the IRT system for this study by 
permuted block stratified randomization with stratification factors of ECOG Performance Status 
(0 versus 1), investigator-chosen chemotherapy (carboplatin versus cisplatin), and brain 
metastasis (yes versus no). 
The stratified randomization will be produced, reviewed, and approved by an independent 
statistician. 
9.1.2. 
Analysis Sets 
The ITT Analysis Set includes all randomized patients. Patients will be analyzed according to 
their randomized treatment arms. This will be the primary Analysis Set for all efficacy analysis.  
The Safety Analysis Set includes all patients who received ≥ 1 dose of any component of study 
drug; it will be the Analysis Set for the safety analyses. Patients will be analyzed according to the 
actual treatment regimen received. 
The PK Analysis Set includes all patients who receive ≥ 1 dose of tislelizumab per the protocol, 
for whom any postdose PK data are available. 
The ADA Analysis Set includes all patients who are randomized to the tislelizumab arm and 
have a baseline and ≥ 1 postbaseline ADA result. 
9.1.3. 
Patient Disposition 
The number of patients randomized, treated, and discontinued from study drug and/or the study, 
and those with major protocol deviations will be counted. The primary reason for study drug 
and/or study discontinuation will be summarized according to the categories in the eCRF. The 
end-of-study status (alive, dead, withdrew consent, or lost to follow-up) at the data cutoff date 
will be summarized using the data from the eCRF.  
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Major protocol deviations will be summarized and listed by each category. 
9.1.4. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics of the ITT Analysis Set will be summarized 
using descriptive statistics. Continuous variables include age, weight, vital signs, time since 
initial cancer diagnosis, and time since diagnosis of extensive-stage disease; categorical variables 
include histology, prior systemic therapy, prior radiation, stage of disease, PD-L1 expression in 
tumor cells, gender, ECOG Performance Status, race, smoking status, and metastatic site. 
9.1.5. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary drug codes. Prior and concomitant medications will be further coded to the 
appropriate Anatomical Therapeutic Chemical (ATC) code indicating therapeutic classification. 
Prior and concomitant medications will be summarized and listed by drug and drug class in the 
clinical study report (CSR) for this protocol. Prior medications will be defined as medications 
that were stopped before the day of first dose of study drug. Concomitant medications will be 
defined as medications that 1) started before the first dose of study drug and were continuing at 
the time of the first dose of study drug, or 2) started on or after the day of the first dose of study 
drug up to 30 days after the patient’s last dose (as of Safety Follow-up Visit). In addition, 
telephone contacts with patients should be conducted to assess imAEs and concomitant 
medications (if appropriate, ie, associated with an imAE or is a new anticancer therapy) at 
60 days (± 14 days) and 90 days (± 14 days) after the last dose of tislelizumab or placebo, 
regardless of whether or not the patient starts a new anticancer therapy. 
A listing of prior and concomitant medications will be included in the CSR for this protocol. 
9.2. 
Efficacy Analyses 
9.2.1. 
Primary Efficacy Analysis 
Overall Survival  
OS is defined as the time from randomization until death from any cause. OS will be analyzed in 
the ITT Analysis Set. Data for patients who are not reported as having died at the time of 
analysis will be censored at the date last known to be alive. Data for patients who do not have 
postbaseline information will be censored at the date of randomization. 
OS will be compared between tislelizumab + cisplatin or carboplatin + etoposide (Arm A) and 
placebo + cisplatin or carboplatin + etoposide (Arm B) in a stratified log-rank test using a one-
sided significance level of 0.025: 
The null hypothesis to be tested is: 
H0: OS in Arm A ≤ OS in Arm B 
against the alternative hypothesis: 
Ha: OS in Arm A > OS in Arm B 
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The p-value from a stratified log-rank tests will be presented using stratification factors with 
actual values as recorded in the electronic data capture (EDC) system at randomization. The HR 
for OS between the 2 arms and its 95% CI will be estimated using a stratified Cox regression 
model with treatment arm as a factor and stratified by the actual value of the stratification 
factors. The median OS and the cumulative probability of OS at 1 year and 2 years, if estimable, 
will be calculated for each treatment arm and presented with two-sided 95% CI using Kaplan-
Meier methodology. A Kaplan-Meier curve will be constructed to provide a visual description of 
the difference among arms. 
9.2.2. 
Secondary Efficacy Analysis 
Progression-Free Survival  
PFS is defined as the time from randomization until the first documented disease progression as 
assessed by the investigator with the use of RECIST v1.1, or death from any cause, whichever 
occurs first. PFS will be analyzed in the ITT Analysis Set. The actual tumor assessment visit date 
will be used to calculate PFS. Data for patients without disease progression or death at the time 
of analysis will be censored at the time of the last valid tumor assessment. Data for patients 
without postbaseline tumor assessment will be censored at the time of randomization. Data for 
patients who start to receive new anticancer therapy or are lost to follow-up will be censored at 
the last valid tumor assessment date prior to the introduction of new therapy or loss to follow-up. 
Patients who have a clinical determination of progression should undergo radiographic imaging 
as required by RECIST v1.1, if possible, to correlate radiographic findings with the clinical 
findings. If a clinical determination of progression for a patient is confirmed, the date of the 
radiographic imaging scan will be considered as the progression date for that patient. 
The HR for PFS will be estimated using a stratified Cox regression model with treatment arm as 
a factor and stratified by the actual value of the stratification factors. The 95% CI for the HR will 
be provided. Kaplan-Meier methodology will be used to estimate the median PFS and 
cumulative probabilities of PFS at 6 months and 1 year, and a Kaplan-Meier curve will be 
constructed to provide a visual description of the difference among arms. 
Overall Response Rate 
ORR (confirmation not required according to RECIST v1.1) is the proportion of patients who 
had CR or PR per RECIST v1.1 in all randomized patients with measurable disease at baseline. 
Patients without any postbaseline assessment will be considered as non-responders. The 
difference in ORR between arms in the ITT Analysis Set will be evaluated using the Cochran-
Mantel-Haenszel (CMH) chi-square test with the actual stratification factors as strata for 
descriptive purpose only. The two-sided 95% CIs for the odds ratio and the difference in ORR 
will be calculated, as well as Clopper-Pearson 95% CIs for the ORR within each arm.  
Duration of Response 
DOR is defined for patients with an objective response as the time from the first documented 
objective response to documented disease progression as determined using the RECIST v1.1, or 
death from any cause, whichever occurs first. Data for patients who are alive and who have not 
experienced disease progression at the time of analysis will be censored at the date of the last 
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tumor assessment. If no tumor assessments were performed after the date of the first occurrence 
of the objective response (CR or PR), DOR will be censored at the date of the first occurrence of 
the objective response. DOR will be estimated using Kaplan-Meier methodology. Comparisons 
between treatment arms will be made using the stratified log-rank test for descriptive purposes 
only.  
Disease Control Rate 
DCR is defined as the proportion of patients with objective response (CR or PR) or stable disease 
maintained for ≥ 6 weeks using the RECIST v1.1. The analysis methods for DCR will be the 
same as those for ORR. 
Health-Related Quality of Life Domain 
HRQoL is assessed via the EORTC QLQ-C30 GHS/QoL, functional and symptom scales scores, 
and the single item scores. Observed values and changes from baseline will be summarized using 
descriptive statistics. Clinically meaningful changes post baseline (percentage of patients with a 
10-point improvement or worsening; to be defined in the SAP if otherwise) for GHS and PF per 
the QLQ-C30 and dyspnoea, coughing, haemoptysis, dysphagia, chest pain, pain in arms and 
shoulders, and peripheral neuropathy symptoms of QLQ-LC13 will be calculated by time point 
and compared between the treatment arms.  
Time to deterioration of the aforementioned scales will be analyzed as well. It is defined as time 
from randomization to the first occurrence of a worsening score (10-point change; to be defined 
in the SAP if otherwise) confirmed at the following visit or death from any cause. Time to 
deterioration between treatment arms will be compared using log-rank test and its Kaplan-Meier 
probabilities for each arm will be plotted over time.  
9.2.3. 
Exploratory Efficacy Analysis 
PFS after next line of treatment (PFS2) 
To calculate PFS2, data from patients without disease progression after next line of treatment or 
death at the time of analysis will be censored at the last time known to be alive. The Kaplan-
Meier method as described in the PFS and OS analyses will be used in the analysis of PFS2. 
PD-L1 expression as a predictive biomarker for efficacy 
Distribution of PD-L1 expression will be examined in the ITT Analysis Set. Any potential 
association between PD-L1 expression and tislelizumab treatment effect over control (PFS, OS, 
ORR, DOR, and DCR) may be explored. Other potential predictive markers, including but not 
limited to GEP, TMB and MSI in archival and/or fresh tumor tissue and bTMB may be assessed 
before study treatment and/or at disease progression. The association with disease status and/or 
response to tislelizumab in combination with chemotherapy may be also assessed. 
Quality of Life (QoL)  
Summary statistics (mean, standard deviation, median, and range) of the postbaseline scores of 
the EQ5D-5L descriptive dimension and VAS will be reported. Summaries will be performed for 
the ITT Analysis Set only. 
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9.3. 
Safety Analyses 
Safety will be assessed by monitoring and recording all AEs graded by NCI-CTCAE. Laboratory 
values (eg, hematology, clinical chemistry, and urinalysis), vital signs, physical examinations, 
ECOG Performance Status change, ECGs, and other examinations will also be used in 
determining safety. Descriptive statistics will be used to analyze all safety data in the Safety 
Analysis Set. 
9.3.1. 
Extent of Exposure 
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose reduction, interruption, dose delay, and drug 
discontinuation due to AEs will be summarized for each study drug. Frequency of the above dose 
adjustments and discontinuation will be summarized by category.  
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.3.2. 
Adverse Events 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be coded to MedDRA 
(Version 20.0 or higher) by lower-level term, preferred term and primary system organ class 
(SOC). 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug and up to 30 days following study drug 
discontinuation or initiation of new anticancer therapy, whichever occurs first. For the 
tislelizumab arm, the TEAE classification also applies to imAEs that are recorded up to 90 days 
after discontinuation from tislelizumab, regardless of whether the patient started a new 
anticancer therapy. Only those AEs that were treatment-emergent will be included in summary 
tables. All AEs, treatment-emergent or otherwise, will be presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and preferred term. A patient will be counted only once by the highest severity grade per 
NCI-CTCAE v5.0 within an SOC and preferred term, even if the patient experienced > 1 TEAE 
within a specific SOC and preferred term. The number (percentage) of patients with TEAEs will 
also be summarized by relationship to the study drug. Treatment-related AEs include those 
events considered by the investigator to be related to study treatment or with missing assessment 
of the causal relationship. SAEs, deaths, TEAE with ≥ Grade 3 severity, imAE, treatment-related 
TEAEs and TEAEs that led to treatment discontinuation, dose interruption, dose reduction, or 
dose delay will be summarized. 
9.3.3. 
Laboratory Analyses 
Clinical laboratory (eg, hematology, serum chemistry) values will be evaluated for each 
laboratory parameter as appropriate. Abnormal laboratory values will be flagged and identified 
as those outside (above or below) the normal range. Reference (normal) ranges for laboratory 
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parameters will be included in the CSR for this protocol. Descriptive summary statistics (eg, n, 
mean, standard deviation, median, minimum, maximum for continuous variables; n [%] for 
categorical variables) for laboratory parameters and their changes from baseline will be 
calculated. Laboratory values will be summarized by visit and by worst postbaseline visit. 
Laboratory parameters that are graded in NCI-CTCAE v5.0 will be summarized by NCI-CTCAE 
grade. In the summary of laboratory parameters by NCI-CTCAE grade, parameters with 
NCI-CTCAE grading in both high and low directions (eg, glucose, potassium, sodium) will be 
summarized separately. 
9.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse rate, 
body temperature, weight) and changes from baseline will be presented by visit for all visits. 
Vital signs will be listed by patient and visit. 
9.4. 
Pharmacokinetic Analysis 
Pharmacokinetics samples will be collected in this study as outlined in Appendix 1.  
Tislelizumab lowest concentration before the next dose (Ctrough) data will be tabulated and 
summarized for each cycle at which PK is to be measured in the PK Analysis Set. Descriptive 
statistics will include means, medians, ranges, and standard deviations, as appropriate. 
Additional PK analyses may be conducted as appropriate. 
The PK Analysis Set includes all patients who receive ≥ 1 dose of tislelizumab per the protocol 
and for whom any postdose PK data are available.  
9.5. 
Immunogenicity Analyses 
Immunogenicity samples will be collected in this study as outlined in Appendix 1.  
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable antidrug antibodies (ADA). The incidence of 
positive ADA and neutralizing ADA will be reported for evaluable patients. The effect of 
immunogenicity on PK, efficacy, and safety may be evaluated if data allow. 
9.6. 
Sample Size Consideration 
The sample size calculation is based on the number of events required to demonstrate the OS 
superiority of Arm A to Arm B in the ITT Analysis Set. Driven by external data from studies 
described in Section 1.1.2 , statistical assumptions were updated in protocol amendment version 
1.0 and the number of events required to demonstrate efficacy with regard to OS is estimated 
based on the following assumptions: 
Overall survival: 
• Median OS of 12 months in Arm B. 
• At a one-sided α of 0.025, 80% power to detect an OS HR of 0.74 in the ITT Analysis 
Set. 
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• One OS interim analysis is planned in the ITT Analysis Set when approximately 80% of 
total OS events occurred, with Lan-DeMets approximation to O’Brien-Fleming 
boundary. 
• Exponential survival distribution is assumed for both Arm A and Arm B. 
In addition, we assumed a randomization ratio of 1:1. Assuming approximate 455 patients are to 
be enrolled over a 22-month period at a steady-state enrollment rate of 26 patients per month 
with enrollment ramp-up duration of 9 months, and assuming a dropout rate of 5% per year for 
OS endpoints, a total of 353 OS events are required for the ITT Analysis Set for the final OS 
analysis.  
9.7. 
Interim Analyses  
There will be 1 interim efficacy analysis of OS performed in the ITT Analysis Set. The interim 
efficacy analysis of OS will be performed with at least 282 OS events observed in the ITT 
Analysis Set. The analysis timing is projected at approximately 36 months after the first patient 
randomization. The final OS analysis will be conducted with 353 OS events at approximately 
51 months after the first patient randomization.  
The interim boundary for OS is based on the Lan-DeMets approximation to O’Brien-Fleming 
boundary. The interim and final analysis timing, and stopping boundaries are summarized 
in Table 8. As the exact timing of the analysis depends on when at least 282 OS events have 
occurred, the stopping boundaries in Table 8 may be updated based on the actual OS events 
observed in the ITT Analysis Set at the time of interim analysis. 
Table 8. Analysis Timing and Stopping Boundaries for OS in the ITT Analysis Set  
Type of Analysis 
Time 
(Months) 
# Events 
One-Sided Testing Boundary 
p-Value Boundary 
Approx. HR 
Threshold 
Interim Analysis 
36 
282 
0.0122 
0.765 
Final analysis 
51 
353 
0.0214 
0.806 
Abbreviations: HR, hazard ratio; ITT, Intent-to-Treat; OS, overall survival 
10. 
STUDY COMMITTEES AND COMMUNICATION 
10.1. 
Independent Data Monitoring Committee 
Regular safety monitoring (at least every 6 months), and efficacy monitoring (eg, interim 
analysis for OS) will be performed by an Independent Data Monitoring Committee (IDMC). The 
first IDMC safety review will occur after ≥ 20 patients have been randomized to study treatment 
(ie, approximately 10 patients per treatment arm) and have been on treatment for ≥ 1 month in 
order to determine if the proposed dosing schedule of tislelizumab or placebo is safe and 
tolerable. The IDMC may recommend study modifications including termination of the study 
due to safety and/or efficacy concerns, or in the event of compelling efficacy at a preplanned 
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interim analysis. The function and membership of the IDMC will be described in the IDMC 
charter. 
In addition to the planned IDMC review(s), ad hoc reviews may be performed based on new 
information.  
Following IDMC review and discussion, the sponsor will make all final decisions regarding any 
changes in study conduct. Please see the details in the IDMC charter. 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study may be fully documented. Such records include but are not limited to the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals. In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data.  
11.1. 
Access to Information for Monitoring 
In accordance with International Council for Harmonisation (ICH) GCP guidelines, the study 
monitor must have direct access to the investigator’s source documentation in order to verify the 
data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately. The investigator agrees to provide to representatives of a regulatory agency or 
BeiGene access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study with the investigational drug from the 
China regulatory agency in accordance with applicable regulatory requirements in China before 
the study is initiated at a study center. 
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12.2. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Site Inspections 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study.  
12.4. 
Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug.  This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records, and returned or 
destroyed study product. Dispensation records will document quantities received from BeiGene’s 
designated depot or its designee and quantities dispensed to patients, including batch/lot number, 
date dispensed, patient identifier number, and the initials of the person dispensing the 
medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene’ requirements specified in the 
Pharmacy Manual. At appropriate times during the conduct of the study or at the end of the 
study, the study site will dispose of and/or destroy all unused study drug supplies following drug 
inventory reconciliation by the monitor. These include empty containers, according to these 
procedures. If the site cannot meet BeiGene’s requirements specified in the Pharmacy Manual 
for disposal, arrangements will be made between the site and BeiGene or its representative for 
destruction or return of unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
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13. 
ETHICS/PROTECTION OF HUMAN PATIENTS 
13.1. 
Ethical Standard 
This study will be conducted by the principal investigator and the study center in full 
conformance with the ICH E6 guideline for GCP and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual. The study will comply with the requirements of 
the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). 
13.2. 
Institutional Review Board/Independent Ethics Committee 
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted, reviewed, and approved by the IRB/IEC before the study is 
initiated. In addition, any patient recruitment materials must be approved by the IRB/IEC. Copies 
of the IRB/IEC correspondence and approval of the amended ICF/other information and the 
approved amended ICF/other information must be forwarded to the sponsor promptly.  
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments. In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority (eg, if local health authority has no requirement for reporting 
SAEs, investigators are not mandated to report SAEs to health authority) and IRB/IEC. 
Investigators may receive written investigational new drug (IND) safety reports or other safety-
related communications from the sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with health authority requirements and the 
policies and procedures established by their IRB/IEC and archived in the site’s study file.  
13.2.1. 
Protocol Amendments 
Any protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements. Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming their willingness to remain in the study. 
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13.3. 
Informed Consent 
The sponsor’s sample ICF will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. The final IRB/IEC-approved ICFs must be provided to 
the sponsor for health authority submission purposes according to local requirements.  
The ICFs must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study.  
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate. The 
final revised IRB-/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes.  
Patients must be reconsented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study. For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study.  
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time.  
13.4. 
Patient and Data Confidentiality 
The principle investigator and sponsor will maintain confidentiality and privacy standards by 
following applicable data privacy laws covering the collection, storage, transmission, and 
processing of patients’ personal and medical information.  
The principle investigator shall code the medical information obtained during the study with a 
unique patient identification number assigned to each patient enrolled in the study. This approach 
ensures that patients’ names are not included in any data set transmitted to any sponsor location.  
Patient medical information obtained during this study is confidential and may be disclosed only 
to third parties as permitted by the signed ICF (or a separate authorization for the use and 
disclosure of personal health information that has been signed by the patient), unless permitted or 
required by law.  
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
principle investigator and sponsor, as appropriate, shall fulfill all medication steps and reporting 
obligations under applicable data privacy laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes.  
Data generated during this study must be available for inspection upon request by representatives 
of the NMPA and all other national and local health authorities; by sponsor monitors, 
representatives, and collaborators; and by the IRBs/IECs for each study site, as appropriate.  
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The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. The investigator agrees that all information 
received from the sponsor, including but not limited to the Investigator's Brochure, this protocol, 
eCRFs, the IND, and any other study information, remain the sole and exclusive property of the 
sponsor during the conduct of the study and thereafter. This information is not to be disclosed to 
any third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from the sponsor. The investigator further agrees 
to take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain. 
If a written contract for the conduct of the study is executed, and that contract includes 
confidentiality provisions inconsistent with this section, that contract’s provision shall apply to 
the extent they are inconsistent with this section. 
13.5. 
Financial Disclosure 
Investigators are required to provide the sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interest of the clinical investigators and/or disclose those 
financial interests, as required to the appropriate health authorities. This is intended to ensure 
financial interests and arrangements of the clinical investigators with BeiGene that could affect 
reliability of data submitted to health authorities are identified and disclosed by the sponsor.  
Investigators are responsible for providing information about their financial interests before 
participation in the study, and to update this information if any relevant changes occur during the 
study and for 1 year after completion of the study (ie, last patient, last visit). 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Data Collection and Management Responsibilities 
14.1.1. 
Data Entry in the Electronic Case Report Form 
All study-related data collected or received by the investigator or study team shall be promptly 
entered into the eCRFs. In no event should the entry of the study data into the eCRF be later than 
what is stipulated in the site contract after the data is collected or received by the investigator or 
study team without prior communication with and approval by the sponsor. 
14.1.2. 
Data Collection 
Data required by the protocol will be entered into an EDC system.  
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The investigator must provide e-signature in the EDC system 
to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available 
in any form to third parties without written permission from BeiGene, except for authorized 
representatives of BeiGene or appropriate regulatory authorities.  
14.1.3. 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol, will be stored by BeiGene at the end of the study.  
Standard procedures (including following data review guidelines, computerized validation to 
produce queries and maintenance of an audit file that includes all database modifications) will be 
followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records, and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. Checking the 
eCRFs for completeness, clarity, and cross-checking with source documents is required to 
monitor the progress of the study. Direct access to source data is also required for inspections 
and audits and will be carried out with due consideration given to data protection and medical 
confidentiality. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
the MedDRA Version 20.0 or higher. AEs will be coded to MedDRA by lower level term, 
preferred term, and primary system organ class (SOC). Concomitant medications will be coded 
using the WHO Drug Dictionary. Concomitant diseases/medical history will be coded using the 
MedDRA Version 20.0 or higher. 
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14.2. 
Data Integrity and In-house Blinding 
In this double-blinded, placebo-controlled study, all patients and personnel involved in the 
conduct and interpretation of the study, including the investigators, BeiGene study team, and site 
personnel, will be blinded to the treatment assignment. Randomization data will be kept strictly 
confidential; filed securely by the appropriate groups for BeiGene, the IRT and the IDMC; and 
will be accessible only to authorized persons per SOPs until the time of unblinding. 
14.3. 
Study Records Retention 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least 1 of the following 2 categories: 1) investigator’s study file, and/or 2) 
patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, ICFs, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include documents such as 
(although not be limited to) the following: patient hospital/clinic records, physician’s and nurse’s 
notes, appointment book, original laboratory reports, ECG, electroencephalogram, x-ray, 
pathology and special assessment reports, consultant letters, screening and enrollment log, etc.  
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location. The records must be maintained to allow easy and timely retrieval, when needed 
(eg, audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel. Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must assure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating a hard copy, if required. Furthermore, the investigator must 
ensure there is an acceptable backup of these reproductions and that an acceptable quality control 
process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements, local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including 
but not limited to the following: archival at an off-site facility, or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all the 
documents, special arrangements must be made between the investigator and BeiGene to store 
these in sealed containers outside of the site so that they can be returned sealed to the 
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investigator in case of a regulatory audit. When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
Biological samples at the conclusion of this study may be retained as outlined in the agreement 
with the CRO managing the biological samples, for the shorter of: a period of up to 5 years or as 
allowed by your IRB/IEC. 
14.4. 
Protocol Deviations 
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert they will apply due 
diligence to avoid protocol deviations and shall report all protocol deviations to sponsor. 
The investigator is to document and explain any deviations from the approved protocol. The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures.  
14.5. 
Publication and Data Sharing Policy 
A clinical study report will be prepared and provided to the regulatory agency(ies). BeiGene will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance and the need to protect the intellectual property of BeiGene (the sponsor), 
regardless of the outcome of the study. The data generated in this clinical study are the exclusive 
property of the sponsor and are confidential. As this is a multicenter study, the first publication 
or disclosure of study results shall be a complete, joint multicenter publication or disclosure 
coordinated by the sponsor. Thereafter, any secondary publications will reference the original 
publication(s). Authorship will be determined by mutual agreement and all authors must meet the 
criteria for authorship established by the International Committee of Medical Journal Editors 
Uniform Requirements for Manuscripts or stricter local criteria (International Committee of 
Medical Journal Editors 2016). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsors to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this trial will be presented in the investigator’s clinical study agreement. Each investigator 
agrees that, in accordance with the terms of clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 
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14.6. 
Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Collection of all study documents for the trial master file filing according to GCP and 
local regulation 
• Shipment of samples (including, but not limited to, those for PK, ADA, and biomarkers) 
to assay lab for central lab analysis according to protocol and lab manual requirements 
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for reason. Potential 
reasons for suspension or discontinuation include, but not limited to safety or ethical issues or 
noncompliance with this protocol, GCP, the sponsor’s written instructions, the clinical study 
agreement, or applicable laws and regulations. If the sponsor determines such action is needed, 
the sponsor will discuss this with the investigator (including the reasons for taking such action) 
at that time. When feasible, the sponsor will provide advance notification to the investigator of 
the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons. The sponsor will also inform the 
regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action. If required by applicable regulations, the investigator must inform the IEC/IRB promptly 
and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data obtained must still be provided to the 
sponsor. In addition, arrangements will be made for the return of all unused study drug(s) in 
accordance with the applicable sponsor procedures for the study.  
Financial compensation to the investigators and/or institutions will be in accordance with the 
clinical study agreement established between the investigator and/or institutions and the sponsor. 
14.7. 
Information Disclosure and Inventions 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights which are conceived or reduced to practice by the study center personnel during 
the course of or as a result of the study are the sole property of the sponsor and are hereby 
assigned to the sponsor. 
If a written contract for the conduct of the study, which includes ownership provisions 
inconsistent with this statement, is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
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All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel. 
This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor.   
These restrictions do not apply to: 
• Information that becomes publicly available through no fault of the investigator or study 
center personnel 
• Information that is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information that is necessary to disclose to provide appropriate medical care to a patient 
• Study results that may be published as described in Section 14.5  
If a written contract for the conduct of the study which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
 
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RECIST, Response Evaluation Criteria in Solid Tumors; RNA, ribonucleic acid; SAE, serious adverse event; TEAE, treatment-emergent adverse event; TSH, 
thyroid stimulating hormone; v, version. 
1. Written informed consent is required prior to performing any study-specific tests or procedures. Results of standard-of-care tests or examinations performed 
prior to obtaining informed consent and within 28 days prior to randomization may be used for Screening assessments rather than repeating such tests. 
2. The End-of-Treatment Visit is conducted when the investigator determines that study treatment will no longer be used. If routine laboratory tests (eg, 
hematology, serum chemistry) are completed within 7 days before the End-of-Treatment Visit, tests need not be repeated. Tumor assessment is not required 
at the End-of-Treatment Visit provided that fewer than 6 weeks have passed since the last assessment. 
3. The Safety Follow-up Visit is required to be conducted 30 days (± 7 days) after the last dose of study treatment, or before the initiation of a new anticancer 
treatment, whichever occurs first. 
4. Survival Follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months after the 
Safety Follow-up Visit until death, loss to follow-up, withdrawal of consent, or study termination by sponsor. All patients will be followed for survival and 
subsequent anticancer therapy information unless a patient requests to be withdrawn from follow-up. 
5. Patients will be randomized into either Arm A or Arm B via IRT. All patients are required to receive study treatment within 2 business days of 
randomization. 
6. Demographics includes age, year of birth, gender, and self-reported race/ethnicity; Refer to Section 7.1.1 for medical history and cancer history: history of 
treatment for the primary diagnosis, including prior medication, loco-regional treatment(s), and surgical treatment(s). Information on radiographic studies 
performed prior to study entry may be collected for review by the investigator. 
7. Vital signs collected on study include temperature, pulse rate, and blood pressure (systolic and diastolic) while the patient is in a seated position after resting 
for 10 minutes. The patient’s vital signs are required to be recorded within 60 minutes before; during; and 30 minutes after the first infusion of tislelizumab 
or placebo. For subsequent infusions, vital signs will be collected within 60 minutes before infusion and if clinically indicated, during and 30 minutes after 
the infusion. Height should be measured and recorded only during screening. 
8. During Screening Visit, a complete physical examination will be conducted. At subsequent visits (and as clinically indicated), limited, symptom-directed 
physical examinations will be performed. 
9. The ECG recordings will be obtained during screening, the Safety Follow-up Visit, and as clinically indicated at other time points. When coinciding with 
blood draws at the same timepoint, ECG assessment should be performed prior to blood draws. Patients should be resting in a semi-recumbent supine 
position for at least 10 minutes prior to each ECG collection. 
10. The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0. All AEs will also be evaluated for seriousness. After the informed consent form 
has been signed, but prior to the administration of study drug, only SAEs should be reported. After initiation of study drug, all AEs and SAEs, regardless of 
relationship to study drug, will be reported until either 30 days after last dose of study drug(s) (including chemotherapy) or the initiation of new anticancer 
therapy, whichever occurs first. In addition, telephone contacts with patients should be conducted to assess immune-mediated AEs and concomitant 
medications (if appropriate, ie, associated with an immune-mediated AE or is a new anticancer therapy) at 60 (± 14 days) days, and 90 days (± 14 days) after 
the last dose of tislelizumab or placebo, regardless of whether the patient starts a new anticancer therapy. Immune-mediated AEs (serious or nonserious) 
should be reported until 90 days after the last dose of tislelizumab or placebo, regardless of whether the patient starts a new anticancer therapy. 
11. Local and/or central laboratory assessments on serum chemistry, hematology, coagulation, and urinalysis will be conducted, of which certain elements will 
be collected as specified in Section 7.5.4. If laboratory tests at screening are not performed within 7 days of administration of study drug(s) on Cycle 1 Day 
1, these tests should be repeated and reviewed before study drug(s) administration. Hematology, serum chemistry, CK and CK-MB assessment, and 
coagulation tests should be performed at the beginning of each cycle, and at the End-of-Treatment and Safety Follow-up Visits (Section 7.5.4). In the event 
that CK-MB fractionation is not available, troponin I and/or troponin T should be assessed instead. Urinalysis is to be conducted during the treatment period 
only if clinically warranted. Coagulation parameters include international normalized ratio, prothrombin time, and activated partial thromboplastin time. 
Refer to Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities.  
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12. Urine or serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as 
negative within 7 days prior to randomization. Urine pregnancy tests will be performed at each visit prior to dosing. A serum pregnancy test must be 
performed if the urine pregnancy test is positive or equivocal. 
13. Analysis of FT3, FT4, and TSH will be performed by a central laboratory or the local study site laboratory. Thyroid function tests will be performed at 
screening and every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc), and at the Safety Follow-up Visit. 
14. Testing will be performed by a central laboratory and/or the local laboratory at screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, 
and HCV antibody) and viral load assessment (HBV DNA and HCV RNA).  
15. Pulmonary function testing including spirometry and assessment of oxygenation, at a minimum pulse oximetry at rest and with exercise, or alternatively, 
assessment of diffusion capacity, are to be performed for all patients during the Screening Period to assist the determination of suitability on the study. 
Respective test results need to be submitted to the sponsor. Refer to Section 7.1.5 for further details. Tests may be repeated as clinically indicated while on 
study. 
16. Procedures for collection of PK samples are described in the Laboratory Manual. Predose (within 60 minutes before starting infusion) samples are required 
to be collected at Day 1 of Cycles 1, 2, 5, 9 and 17; A postdose (within 30 minutes after completing tislelizumab or placebo infusion) sample is required to 
be collected at Day 1 of Cycles 1 and 5. An additional PK sample is required to be collected at the Safety Follow-up. Should a patient present with any 
≥ Grade 3 imAE, an additional blood PK sample may be taken to determine the serum concentration of tislelizumab. These tests are required when it is 
allowed by local regulations/IRBs/ECs.  
17. Blood used to test for anti-tislelizumab antibodies should be collected within 60 minutes before beginning the Day 1 infusion of Cycles 1, 2, 5, 9, and 17 and 
at the mandatory Safety Follow-up Visit. All samples should be drawn at the same time as blood collection for predose PK analysis. These tests are required 
when it is allowed by local regulations/IRBs/ECs. 
18. Radiological images captured as standard of care prior to obtaining written informed consent and within 28 days before randomization may be used rather 
than repeating tests. All measurable and evaluable lesions are required to be assessed and documented at the Screening Visit. An MRI (or CT scan if MRI is 
contraindicated or not readily available) of the head may be required at screening based on clinical judgement; bone scan or PET is required if clinically 
indicated. The same radiographic procedure must be used throughout the study for each patient.  
The investigator must review radiograph results before dosing at the next cycle. During the study, tumor imaging will be performed approximately every 
6 weeks (± 7 days) for the first 48 weeks following Cycle 1 Day 1 based on RECIST v1.1, and every 9 weeks (± 7 days) thereafter, regardless of treatment 
dose delay. The investigator may perform additional scans or more frequent assessments if clinically indicated. See Section 7.6 for more information. 
Patients who discontinue study treatment early for reasons other than disease progression (eg, toxicity) will continue to undergo tumor assessments 
following the original plan until the patient begins a subsequent anticancer treatment, experiences disease progression, withdraws consent, is lost to 
follow-up, death, or until the study terminates, whichever occurs first. Patients who continue study treatment beyond radiographic disease progression 
(Section 3.3) will be monitored with a follow-up scan as defined in Section 7.6 before discontinuation of study treatment. 
19. Patients are required to provide archival tumor tissues (FFPE blocks or approximately 15 [≥ 6] unstained slides) for biomarker analysis. 
20. Fresh biopsy: In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at baseline (within 28 days before randomization) is strongly 
recommended, if feasible. Optional biopsies will also be taken for the patients who have confirmed disease progression and/or at the time of first tumor 
response (CR/PR) for the assessment of mechanism of resistance (written informed consent is required prior to fresh tumor biopsies). See Section 7.8 for 
more information.  
21. Blood samples will be taken at baseline (predose on Cycle 1 Day 1) and optionally at the time of disease progression and/or at the time of first tumor 
response (CR/PR) (10 mL each timepoint) for all randomized patients to explore the association with response, resistance, and prognosis to tislelizumab in 
combination with chemotherapy or chemotherapy alone. If disease progression is confirmed at the EOT Visit, the blood sample should be collected at the 
EOT Visit. If the patient continues study treatment after confirmed disease progression, the blood sample should be collected at the visit when the patient is 
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confirmed to have disease progression. Written patient consent is required for blood sample collection. The sampling at baseline will be mandatory after 
regulatory approval. 
22. If at any time during the study a patient undergoes a medically indicated procedure that has the likelihood of yielding tumor tissue, any remaining sample or 
a portion of the sample not necessary for medical diagnosis (leftover tumor tissue) may be obtained for exploratory analysis.  
23. Tislelizumab or placebo should be given intravenously once every 3 weeks. The initial infusion (Cycle 1 Day 1) will be delivered over 60 minutes, and then 
can be administered over 30 minutes for subsequent infusions if well tolerated. Patients must be monitored for 1 hour after infusion of tislelizumab or 
placebo on Day 1 of Cycle 1 and Cycle 2; from Cycle 3 onward, at least a 30-minute monitoring period is required. The first dose will be given on Cycle 1 
Day 1 and subsequent dosing will continue on the scheduled 21-day intervals. The chemotherapy regimens will be chosen at investigator’s discretion and be 
given intravenously on 21-day cycle for the first 4 cycles. On Day 1 of Cycles 1 to 4, chemotherapy drugs will be administered separately after the infusion 
of tislelizumab or placebo, in a sequential manner. Platinum (cisplatin or carboplatin) will be administered on Day 1 of each cycle; etoposide will be 
administered on Days 1, 2 and 3 of each cycle. Refer to Section 5.2, Table 3 and Table 4 for more details.  
24. To be completed prior to any clinical activities during on-study site visits. EORTC QLQ-C30, EORTC QLQ-LC13, and EQ5D-5L will be completed at 
baseline (predose at Day 1 of Cycle 1), at every cycle through Cycle 4, then every other cycle thereafter until End-of-Treatment Visit, and at Safety 
Follow-up Visit. 
25. Review of AEs and concomitant medications and procedures may be conducted by telephone on Days 8 and 15. 
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APPENDIX 2. ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 
As published by (Oken et al 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
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APPENDIX 3. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1 
The text below was obtained from the following reference:  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
DEFINITIONS 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (v1.1).  Changes in 
only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria.  
Note: Lesions are either measurable or non-measurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT and MRI (no less than double the slice thickness and a minimum of 
10 mm) 
• 10 mm caliper measurement by clinical exam (when superficial) 
• 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
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 (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter ≥ 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered nonmeasurable 
disease.  Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable. 
Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• 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 
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considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above 
• Blastic bone lesions are nonmeasurable 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 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.  Trial protocols should detail the conditions under 
which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which 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 2 dimensions in the plane in which 
the image is obtained (for CT scan, 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 which is reported as being 20 mm × 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 nontarget lesions.  Nodes that have a short axis < 10 mm are 
considered nonpathological and should not be recorded or followed. 
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.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
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Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as “present”, “absent”, or in rare cases “unequivocal 
progression” (more details to follow).  In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph node” or “multiple liver metastases”). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are accessible by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10 mm diameter as assessed using calipers (eg, skin nodules).  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the trial. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
• CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on 
CT scan based on the assumption that 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 twice the slice thickness.  MRI is also acceptable in certain situations (eg, for body 
scans). 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from 
1 assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, they can be useful to confirm complete pathological 
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response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor response.  
If markers are initially above the upper normal limit, however, they must normalize for a 
patient to be considered in CR.  Because tumor markers are disease specific, instructions 
for their measurement should be incorporated into protocols on a disease specific basis.  
Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and prostate-
specific antigen response (in recurrent prostate cancer), have been published.  In addition, 
the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are 
to be integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer. 
• Cytology, histology: These techniques 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 (eg, 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. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or nontarget) must have 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 (this includes the baseline sum if 
that is the smallest 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 on study 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the “sum” of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
< 10 mm.  Case report recorded in a separate section where, 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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• Target lesions that become “too small to measure”.  While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded at 
each subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes 
lesions or lymph nodes which are recorded as target lesions at baseline become so faint 
on CT scan that the radiologist may not feel comfortable assigning an exact measure and 
may report them as being “too small to measure”.  
When this occurs, it is important that a value be recorded on the eCRF.  If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement should 
be recorded as 0 mm.  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 (Note: It is less likely that 
this rule will be used for lymph nodes since they usually have a definable size when 
normal and are frequently surrounded by fat such as in the retroperitoneum; however, if a 
lymph node is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned in this circumstance as well).  This default 
value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness).  The measurement of these lesions is potentially 
non-reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error.  To reiterate, however, if the radiologist is 
able to provide an actual measure, that should be recorded, even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment”, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion”. 
Evaluation of Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker level.  All 
lymph nodes must be nonpathological in size (<10 mm short axis). 
• PD: Unequivocal progression (as detailed below) of existing nontarget lesions.  (Note: 
the appearance of one or more new lesions is also considered progression.) 
• Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance of 
tumor marker level above the normal limits 
• When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the nontarget disease, there must be an overall level of 
substantial worsening in nontarget disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of one or more nontarget 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
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designation of overall progression solely on the basis of change in nontarget disease in 
the face of SD or PR of target disease will therefore be extremely rare. 
• When the patient has only non-measurable disease: This circumstance arises in some 
phase 3 trials when it is not a criterion of trial entry to have measurable disease.  The 
same general concept applies here as noted above, however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in nontarget disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if 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: 
ie, an increase in tumor burden representing an additional 73% increase in “volume” 
(which is equivalent to a 20% increase diameter in a measurable lesion).  
• Examples include an increase in a pleural effusion from “trace” to “large”, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as 
“sufficient to require a change in therapy”.  If “unequivocal progression” is seen, the 
patient should be considered to have had overall PD at that point.  While it would be ideal 
to have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so, therefore the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the patient’s baseline lesions show partial or CR.  For example, necrosis of a 
liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression.  An example of this is the 
patient who has visceral disease at baseline and while on trial has a CT or MRI brain ordered 
which reveals metastases.  The patient’s brain metastases are considered to be evidence of PD 
even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if 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. 
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible “new” disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of PD based on 
a new lesion. 
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• 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. 
Evaluation of Best Overall Response 
The BOR is the best response recorded from the start of the study drug treatment until the end of 
treatment taking into account any requirement for confirmation.  On occasion a response may not 
be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of BOR.  Protocols must specify how any new 
therapy introduced before progression will affect best response designation.  The patient’s BOR 
assignment will depend on the findings of both target and nontarget disease and will also take 
into consideration the appearance of new lesions.  Furthermore, depending on the nature of the 
trial and the protocol requirements, it may also require confirmatory measurement.  Specifically, 
in non-randomized trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the “best overall response”. 
The BOR is determined once all the data for the patient is known.  Best response determination 
in trials where confirmation of complete or partial response IS NOT required: Best response in 
these trials is defined as the best response across all time points (for example, a patient who has 
SD at first assessment, PR at second assessment, and PD on last assessment has a BOR of PR).  
When SD is believed to be best response, it must also meet the protocol specified minimum time 
from baseline.  If the minimum time is not met when SD is otherwise the best time point 
response, the patient’s best response depends on the subsequent assessments.  For example, a 
patient who has SD at first assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD.  The same patient lost to follow-up after the first SD 
assessment would be considered inevaluable. 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
CR 
PR 
 
SD 
 
Not all evaluated 
PD 
Any 
Any 
CR 
Non-CR/non-PD 
Not evaluated 
Non-PD or not all 
evaluated 
Non-PD or not all 
evaluated 
Non-PD 
Any 
PD 
Any 
No 
No 
No 
No 
 
No 
 
No 
Yes or No 
Yes or No 
Yes 
CR 
PR 
PR 
PR 
 
SD 
 
NE 
PD 
PD 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease. 
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When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of “zero.” 
In trials where confirmation of response is required, repeated "NE" time point assessments may 
complicate best response determination.  The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression.  For 
example, in most trials it is reasonable to consider a patient with time point responses of 
PR-NE-PR as a confirmed response. 
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”.  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/) before assigning a status of CR.  FDG-PET may be 
used to upgrade a response to a CR in a manner similar to a  in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring.  The use of FDG-PET in 
this circumstance should be prospectively described in the protocol and supported by disease 
specific medical literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and resolution/ 
sensitivity. 
For equivocal findings of progression (eg, 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. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error.  This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials.  However, in all other circumstances, ie, in 
randomized trials (phase 2 or 3) or trials where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results.  However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in trials which 
are not blinded. 
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In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks). 
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 measurements 
recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases.  If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between 2 measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation.  It is not in the scope of this 
guideline to define a standard follow-up frequency.  The frequency should take into account 
many parameters including disease types and stages, treatment periodicity, and standard practice.  
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made. 
 
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APPENDIX 4. PRE-EXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES 
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease.  
Please contact the medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions.  
Acute disseminated encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture’s syndrome  
Granulomatosis with polyangiitis  
Graves’ disease  
Guillain-Barré syndrome 
Hashimoto’s disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki’s disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren’s ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord’s thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodusa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter’s syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren’s syndrome  
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
 
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APPENDIX 5. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION 
 
Class 
Symptoms 
I 
No limitation of physical activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity results 
in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort.  Symptoms of heart failure at rest.  
If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria 
Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, MA: 
Lippincott Williams and Wilkins; March 1, 1994. 
Original source: Criteria Committee, New York Heart Association, Inc.  Diseases of the Heart and Blood 
Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 
 
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APPENDIX 6. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT 
The recommendations below for the diagnosis and management of any immune-mediated AE 
(imAE) are intended as a guidance.  This document should be used in conjunction with expert 
clinical judgement (by specialist physicians experienced in the treatment of cancer using 
immunological agents), and individual institutional guidelines or policies. 
Criteria used to diagnose imAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, 
and adverse effects of concomitant drugs.  In addition to the results of these tests, the following 
factors should be considered when making an imAE diagnosis:  
• What was the temporal relationship between initiation of tislelizumab and the adverse 
event? 
• How did the patient respond to withdrawal tislelizumab? 
• Did the event recur when tislelizumab was reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the imAE field 
associated with the AE in the eCRF should be checked.  
Recommended Diagnostic Tests in the Management of  
Possible Immune-Mediated Adverse Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4). 
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile.  Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such 
as an upper respiratory infection, new cough, shortness of breath or hypoxia should 
be assessed by high-resolution CT.  Consider pulmonary function test including 
DLCO.  
Radiographic appearance is often nonspecific.  Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung  may be 
considered.  Consult with a respiratory medicine physician for cases of uncertain 
cause.  
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Recommended Diagnostic Tests in the Management of  
Possible Immune-Mediated Adverse Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications.  Conduct a diabetic 
screen, and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology.  Consider the need for brain/spine MRI/MRA and nerve conduction study 
for peripheral neuropathy.  Consult with a neurologist if there are abnormal 
findings. 
Colitis 
Review dietary intake and exclude steatorrhea.  Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, cryptosporidia (drug-resistant 
organism).  
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan.  If a patient 
experiences bleeding, pain or distension, consider colonoscopy with  and surgical 
intervention, as appropriate.  
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye inflammation, 
blurred vision, or other visual disturbances, refer the patient urgently to an 
ophthalmologist for evaluation and management.   
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend on 
severity of the AE (eg, daily if Grade 3-4; every 2-3 days if Grade 2, until 
recovering).  Review medications (eg, statins, antibiotics) and alcohol history.  
Perform liver screen including Hepatitis A/B/C serology, Hepatitis E PCR and 
assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies.  Consider imaging, eg, 
ultrasound scan for metastases or thromboembolism.  Consult with a hepatologist 
and consider liver .  
Renal toxicity 
Review hydration status and medication history.  Test and culture urine.  Consider 
renal ultrasound scan, protein assessment (dipstick/24-hour urine collection), or 
phase-contrast microscopy.  Refer to nephrology for further management 
assistance.  
Dermatology 
Consider other causes by conducting a physical examination, consider dermatology 
referral for skin . 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination.  Consider joint X-ray and other imaging as required to exclude 
metastatic disease.  Perform autoimmune serology and refer to rheumatology for 
further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin and consider a muscle . 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and refer to a 
cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatinine kinase; CK-MB, creatinine kinase cardiac isoenzyme; CNS, central nervous 
system; CRP, C-reactive protein; CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; ECG, 
electrocardiogram; ESR, erythrocyte sedimentation rate; FBC, full blood count; HIV, human immunodeficiency 
virus; INR, international normalized ratio; LCI, liver cytosolic antigen; LFT, liver function test; LKM, liver kidney 
microsomal antibody; LP, liver pancreas (antigen); MRA, magnetic resonance angiogram; MRI, magnetic resonance 
imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, 
thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC,  urea electrolytes and creatinine. 
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Treatment of Immune-Mediated Adverse Events 
• Immune-mediated AEs can escalate quickly; study treatment interruption, close 
monitoring, timely diagnostic work-up and treatment intervention, as appropriate, with 
patients is required 
• Immune-mediated AEs should improve promptly after introduction of 
immunosuppressive therapy.  If this does not occur, review the diagnosis, seek further 
specialist advice and contact the study medical monitor 
• For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after consultation 
with the study medical monitor 
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone.  
Equivalent dosages of other corticosteroids can be substituted.  For steroid-refractory 
imAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
• Consider prophylactic antibiotics for opportunistic infections if the patient is receiving 
long-term immunosuppressive therapy 
 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Patient to 
Clinical Judgement) 
Study Drug 
Management 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to normal 
range. 
Thyrotoxic patients should be 
referred to an endocrinologist.  In 
cases with systemic symptoms: 
withhold study treatment, treat with a 
beta blocker and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain.  Taper corticosteroids 
over 2-4 weeks.  Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist.   
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for the 
elderly or those with co-morbidities, 
the suggested starting dose is 0.5 
µg/kg/day).  Add oral prednisolone 
0.5 mg/kg/day for thyroid pain.  
Thyrotoxic patients require treatment 
with a beta blocker and may require 
carbimazole until thyroiditis 
resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Patient to 
Clinical Judgement) 
Study Drug 
Management 
Hypophysitis 
1-2 
Mild-moderate 
symptoms 
Refer patient to an endocrinologist 
for hormone replacement.  Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation.  
Taper corticosteroids over at least 
1 month.  If there is no improvement 
in 48 hours, treat as Grade 3-4.  
Taper corticosteroids over at least 
1 month. 
Continue study 
treatment. 
3-4 
Severe or life-
threatening symptoms 
Refer patient to an endocrinologist 
for assessment and treatment.  
Initiate pulse IV methylprednisolone 
1 mg/kg for patients with 
headache/visual disturbance due to 
pituitary inflammation.  Convert to 
oral prednisolone and taper over at 
least 1 month.  Maintain hormone 
replacement according to 
endocrinology advice.  Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less.  
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days.  
If appearance worsens, treat as Grade 
2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected.  Add oral prednisolone 
1 mg/kg/day if symptoms/appearance 
persist for 48 hours or worsen.  
Consider Pneumocystis infection 
prophylaxis.  Taper corticosteroids 
over at least 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment.  
Retreatment is 
acceptable if symptoms 
resolve completely or 
are controlled on 
prednisolone 
≤ 10 mg/day.  
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Patient to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with IV 
methylprednisolone 2-4 mg/kg/day.  
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement).  Convert to oral 
prednisolone and taper over at least 2 
months.  Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-1 
mg/kg/day.  Taper over at least 4 
weeks.  Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms.  Taper 
corticosteroids over at least 4 weeks.  
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: 
< 3 liquid stools per day 
over baseline and feeling 
well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-6 
liquid stools per day 
over baseline, or 
abdominal pain, or blood 
in stool, or nausea, or 
nocturnal episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment.  Taper steroids 
over 2-4 weeks, consider endoscopy 
if symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe 
symptoms: > 6 liquid 
stools per day over 
baseline, or if episodic 
within 1 hour of eating 
 
Initiate IV methylprednisolone 1-2 
mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks.  Consider 
prophylaxis for adverse steroid 
effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the 
study medical monitor. 
 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Patient to 
Clinical Judgement) 
Study Drug 
Management 
4 
Life-threatening 
symptoms 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg if no perforation, 
sepsis, TB, hepatitis, NYHA Grade 
III/IV CHF or other 
immunosuppressive treatment: MMF 
or tacrolimus. 
Consult gastroenterologist to conduct 
colonoscopy/ sigmoidoscopy. 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or 
without symptoms, 
< 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
 
Continue study 
treatment. 
2 
Rash covers 10%-30% 
of BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate strength 
cream once a day or potent cream 
twice a day) ± oral or topical 
antihistamines for itch.  Consider a 
short course of oral steroids. 
Continue study 
treatment. 
3 
Rash covers > 30% BSA 
or Grade 2 with 
substantial symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows based on 
clinical judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day for 3 
days then taper over 2-4 weeks. 
For severe symptoms: IV 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and 
taper over at least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment)  
Initiate IV methylprednisolone 1-2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 4 
weeks. 
Admit to a hospital and seek urgent 
dermatology consultation. 
Discontinue study 
treatment. 
 
Hepatitis 
1 
ALT or AST > ULN to 
3X ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Patient to 
Clinical Judgement) 
Study Drug 
Management 
2 
ALT or AST 3-5X ULN 
Recheck LFTs every 48-72 hours:   
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-1 
mg/kg/day for 3 days then taper over 
2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement.  
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline Grade and 
prednisolone tapered to 
≤ 10 mg. 
3 
ALT or AST 5-20X 
ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
IV (methyl)prednisolone 
2 mg/kg/day.  When LFTs improve 
to Grade 2 or lower, convert to oral 
prednisolone and taper over at least 4 
weeks.  
Hold study treatment 
until improved to 
baseline Grade; 
reintroduce only after 
discussion with the 
study medical monitor. 
 
4 
ALT or AST > 20X 
ULN 
Initiate IV methylprednisolone 2 
mg/kg/day.  Convert to oral 
prednisolone and taper over at least 6 
weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
• 
If on oral prednisolone, change to pulsed IV methylprednisolone 
• 
If on IV, add MMF 500-1000 mg twice a day 
• 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
 
2 
Creatinine > 1.5X-3X 
baseline or > 1.5X-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection.  Discuss with 
nephrologist the need for kidney. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-72 
hours. 
Hold study treatment. 
If not attributed to drug 
toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered to 
< 10 mg prednisolone. 
3 
Creatinine > 3X baseline 
or > 3X-6X ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
every 24 hours; refer to a 
Hold study treatment 
until the cause is 
investigated.  
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Patient to 
Clinical Judgement) 
Study Drug 
Management 
nephrologist and discuss need for .  If 
worsening, initiate IV 
(methyl)prednisolone 1-2 mg/kg. 
Taper corticosteroids over at least 4 
weeks. 
If study drug suspected: 
Discontinue study 
treatment. 
4 
Creatinine > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; 
ULN to 8.9 mmol/L 
Monitor closely and treat according 
to local guideline.  Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and islet 
cells are recommended 
Continue study 
treatment. 
2 
Fasting glucose value 
160-250 mg/dL; 8.9-      
13.9 mmol/L 
Obtain a repeat blood glucose level 
at least every week.  Manage 
according to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening.  Resume 
treatment when blood 
glucose is stabilized at 
baseline or Grade 0-1. 
3 
Fasting glucose value 
250-500 mg/dL; 13.9- 
27.8 mmol/L 
Admit patient to hospital and refer to 
a diabetologist for hyperglycemia 
management.  Corticosteroids may 
exacerbate hyperglycemia and should 
be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline or 
Grade 0-1. 
4 
Fasting glucose 
value > 500 
mg/dL; > 27.8 mmol/L 
Admit patient to hospital and 
institute local emergency diabetes 
management.  Refer the patient to a 
diabetologist for insulin maintenance 
and monitoring. 
Ocular Toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment.  Consider a 
course of oral steroids. 
Continue study 
treatment or hold 
treatment if symptoms 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior uveitis/ 
panuveitis or significant 
symptoms 
Refer patient urgently to an 
ophthalmologist.  Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1; reintroduce only 
after discussion with 
the study medical 
monitor. 
4 
Blindness (at least 
Initiate IV (methyl)prednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at least 
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Patient to 
Clinical Judgement) 
Study Drug 
Management 
20/200) in the affected 
eyes 
4 weeks. 
Pancreatitis 
2 
Asymptomatic, blood 
test abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, nausea 
and vomiting 
Admit to hospital for urgent 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks. 
Hold study treatment; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.  
Continue study 
treatment. 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental 
(fine motor) activities 
Management as per local guideline.  
Consider referring patient to a 
rheumatologist.  If symptoms worsen 
on treatment manage as a Grade 3 
event. 
Continue treatment or, 
if symptoms continue 
worsens, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with 
inflammation or 
permanent joint damage, 
daily living activity 
limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management.  Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments and 
oral hygiene care.  Ensure adequate 
hydration.  If symptoms worsen or 
there is sepsis or bleeding, manage as 
a Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited 
food and fluid intake, 
daily living activity 
limited 
Admit to hospital for appropriate 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
symptoms improved to Grade 2 and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1. 
4 
Life-threatening 
complications or 
Admit to hospital for emergency 
care.  Consider IV corticosteroids if 
not contraindicated by infection. 
Discontinue study 
treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Patient to 
Clinical Judgement) 
Study Drug 
Management 
dehydration 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2  
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3X ULN or worse, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks 
Hold study treatment 
until improved to Grade 
0-1 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg.  Consider 
bolus IV (methyl)prednisolone and 
1-2 mg/kg/day maintenance for 
severe activity restriction or 
dysphagia.  If symptoms do not 
improve add immunosuppressant 
therapy.  Taper oral steroids over at 
least 4 weeks 
Hold study treatment 
until improved to Grade 
0-1. Discontinue if any 
evidence of myocardial 
involvement 
Myocarditis 
< 2 
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant 
intraventricular 
conduction delay 
Initiate cardiac evaluation under 
close monitoring with repeat serum 
testing; consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2 
 
Hold study treatment. 
 
If a diagnosis of 
myocarditis is 
confirmed, permanently 
discontinue study 
treatment in patients 
with moderate or severe 
symptoms.  Patients 
with no symptoms or 
mild symptoms may 
not restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline and 
after discussion with 
the study medical 
monitor. 
2 
Symptoms on mild-
moderate exertion 
Admit to hospital and initiate oral 
prednisolone or IV 
(methyl)prednisolone at 
1-2 mg/kg/day.  Consult with a 
cardiologist and manage symptoms 
of cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of (methyl)prednisolone 
1g/day and add MMF, infliximab or 
anti-thymocyte globulin 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatinine kinase; CK-MB, creatinine kinase cardiac isoenzyme; 
INR, international normalized ratio; IV, intravenous; LFT, liver function test; MMF, mycophenolate mofetil; 
NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; TSH, 
thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 
 
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APPENDIX 7. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation1 and the Modification of Diet in Renal Disease (MDRD) Study equation.  The National 
Kidney Disease Education Program (NKDEP) calculators rely on creatinine determinations 
which are isotope dilution mass spectrometry (IDMS) traceable.  All laboratories should be using 
creatinine methods calibrated to be IDMS traceable.   
This CKD-EPI equation calculator should be used when Scr reported in mg/dL.  This equation is 
recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
 
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-
calculators 
 
1. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 
2009;150(9):604-12. 
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APPENDIX 8. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL” 
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control.  
These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized male partner, provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of exposure associated with the study treatment). 
− NOTE: Total sexual abstinence should only be used as a contraceptive method if 
it is in line with the patient’s usual and preferred lifestyle.  Periodic abstinence 
(eg, calendar, ovulation, symptothermal, postovulation methods), declaration of 
abstinence for the duration of exposure to study drug, and withdrawal are not 
acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
combined with a highly effective form of birth control, listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant.  
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
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− < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, 
etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
 
Adapted from Clinical Trials Facilitation Group (CTFG).  Recommendations related to contraception and pregnancy 
testing in clinical trials. September 15, 2014. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
 
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APPENDIX 9. DOSE MODIFICATION OF CHEMOTHERAPY  
Dose modifications for chemotherapy agents are permitted according to the respective local prescribing 
information and local standard-of-care. The following are suggested recommendations for dose 
modification of chemotherapy for hematologic and non-hematologic toxicities. 
Recommended Dose Modifications for Hematologic Toxicity 
Dose adjustments are based on nadir blood counts since the preceding chemotherapy 
administration. Dose level adjustments are relative to that of the preceding administration. 
Recommended dose modifications for hematologic toxicity are provided in Table 1.  
Table 1. Chemotherapy Dose Modification* for Hematological Toxicity 
Adverse Event 
Treatment  
Febrile neutropenia; documented 
infection 
1) The first episode of febrile neutropenia or documented infection will 
result in antibiotic treatment and reduction by 25% of both drugs doses. 
2) If there is a second episode despite dose reduction, the patient must 
receive prophylactic antibiotics during the subsequent cycles. 
3) If there is a third episode, the chemotherapy will be discontinued. 
Neutropenia  
Grade 3 
(0.5-0.99 x 
109/L) 
Chemotherapy delay until ≤Grade 1 (≥ 1.5 x 109/L); restart with the full 
dose 
Grade 4 
(< 0.5 x 
109/L) 
Chemotherapy delay until recovered to ≤Grade 1; dose reduction of all 
further doses by 25% 
Thrombocytopenia 
Grade 1 
Chemotherapy delay until recovered to normal; restart with the full dose 
≥ Grade 2 
Chemotherapy delay until recovered to normal; dose reduction of all further 
doses by 25% 
* If considered in the best interest of the patient and consistent with local practice, the investigators may decide to 
use supportive measures/treatment and/or secondary prophylaxis instead of dose reductions for the next cycle. The 
provided triggers for dose modifications are recommendations only. Carboplatin is only permitted to reduce to -
20% doses once (from AUC 5 to AUC 4). 
Recommended Dose Modifications for Non-Hematologic Toxicities 
The dose adjustments of chemotherapy for non-hematologic toxicity are described in Table 2. 
All dose modifications should be made based on the worst grade toxicity. 
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Table 2. Chemotherapy Dose Modifications for Non-Hematological Toxicity 
Toxicity 
Grade 
Treatment  
Renal toxicity 
≥ Grade 1 
Delay chemotherapy until recovered to Grade 0 or baseline, change cisplatin to 
carboplatin, if possible; dose reduction by 25% for other drug; if recur, stop 
chemotherapy 
Ototoxicity  
Grade 2 
Dose reduction of all further doses of cisplatin by 25% 
Grade 3-4 
Delay chemotherapy until recovered to ≤ Grade 2, change cisplatin to carboplatin 
Sensory 
neuropathy 
Grade 2 
Dose reduction for all further doses of cisplatin by 25% 
Grade 3 
Stop cisplatin, change cisplatin to carboplatin 
Grade 4 
Stop cisplatin/carboplatin 
Total 
bilirubin 
Grade 2 
Two dose reduction level for all further doses of etoposide (each dose level 
requires a deduction by 25%) 
Grade 3-4 
Stop etoposide 
AST or ALT 
Elevation 
Grade 3 
Dose reduction for all further doses of by 25% 
Grade 4 
Stop chemotherapy 
Other organ 
toxicity 
Grade 2 
Delay chemotherapy until ≤ Grade 1 or baseline* 
Grade 3-4 
Delay chemotherapy until recovered to ≤ Grade 1 or baseline*, dose reduction of 
all further dose by 25% 
Note: If considered in the best interest of the patient and consistent with local practice, the investigators may decide 
to use supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle. 
The provided triggers for dose modifications are recommendations only.  
*Skin reactions, paronychia, alopecia, fatigue, nausea/vomiting which may have resolved to Grade 2 or baseline. 
 
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APPENDIX 10. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30 
 
 
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APPENDIX 11. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE 
QUESTIONNAIRE LUNG CANCER MODULE QLQ-LC13 
 
 
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APPENDIX 12. EUROQOL 5-DIMENSION, 5-LEVEL 
 
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BGB-A317-312 
PROTOCOL AMENDMENT NO. 1.0  
SUMMARY OF CHANGES 
 
Study Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Platinum Plus Etoposide With or Without 
Tislelizumab (BGB-A317) in Patients With Untreated Extensive-Stage Small Cell Lung Cancer (Original Protocol Version 0.0 
to Protocol Amendment 1.0) 
BeiGene, Ltd., updated the BGB-A317-312 clinical study original protocol version 0.0 (28 January 2019) to protocol amendment 1.0 
(02 September 2020). The main purpose of this update is to:  
• Remove PFS as assessed by the investigator from the primary objectives/endpoints 
• Update the overall survival statistical assumptions and sample size 
In addition, editorial and formatting changes have been made throughout to enhance clarity and readability. 
The key changes from original protocol version 0.0 to protocol amendment version 1.0 are summarized by section in the following 
table. 
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Section 
Key Changes 
Rationale for the 
Change 
Substantial 
Change 
(Y/N) 
Potential Impact on 
the Safety of 
Patients, Study 
Conduct, or 
Expectedness of 
Suspected Serious 
Adverse Effects 
Synopsis 
• The number of study centers 
was increased to about 50. 
To be consistent with 
the protocol  
N 
NA 
• The synopsis was updated - 
to reflect changes made 
throughout the protocol. 
NA 
NA 
NA 
Throughout the protocol 
• Changed “subject(s)” to 
“patient(s)” 
For consistency 
N 
NA 
• “Immune-related” was 
revised to “Immune-
mediated” 
For consistency among 
all BeiGene studies 
N 
NA 
• “To evaluate and compare 
the efficacy of 
tislelizumab…” was revised 
to “to evaluate the efficacy 
of tislelizumab…” 
To clarify the syntax. 
N 
NA 
Section 1.1.1 Standard 
Therapy for Extensive-
Stage Small Cell Lung 
Cancer 
• Third- and further- line 
therapies were updated.  
To update the 
information of standard 
therapy for ES-SCLC in 
China 
N 
NA 
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Section 1.1.2 PD-1 
Pathway-Targeting 
Studies in Patients With 
Extensive-Stage Small 
Cell Lung Cancer 
• New data from Impower133, 
CASPIAN, and Keynote604 
were updated. 
To further support the 
rationale of combining 
immune checkpoint 
inhibitors to 
chemotherapy as 
treatment option for 
SCLC 
N 
NA 
Section 1.3.4 Rationale 
for Overall Survival as 
Primary Endpoint, 
Section 2.1.1 Primary 
Objective, Section 2.2.1 
Primary Endpoint, 
Section 9.2.1 Primary 
Efficacy Analysis 
• PFS and rationale of using 
PFS was removed from the 
primary analyses 
After having the 
consultation with local 
health authority and 
taking competitor’s data 
as reference, PFS was 
not proved to be a 
convincing surrogate 
endpoint for OS in 
SCLC and was therefore 
removed from the 
primary analysis. 
Y 
NA 
Section 2.1.2 Secondary 
Objectives, Section 2.2.2 
Secondary Endpoints, 
Section 9.2.2 Secondary 
Efficacy Analyses 
• PFS was added to secondary 
analyses 
PFS is not a convincing 
surrogate endpoint for 
OS, but it is still 
important for efficacy 
analysis 
N 
NA 
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• The secondary analysis of 
HRQoL was clarified as to 
evaluate the effect of study 
drugs by comparing with the 
control arm using 10-point 
change of the score from 
baseline and time to 
deterioration per the 
QLQ-C30 and QLQ-LC13. 
Global health status and 
physical function were 
updated to the scope of 
QLQ-C30 assessment. 
Dyspnoea, coughing, 
haemoptysis, dysphagia, 
chest pain, pain in arms and 
shoulders, and peripheral 
neuropathy symptoms were 
updated to the scope of 
QLQ-LC13 assessment. 
To clarify the concept of 
HRQoL and the analysis 
plan  
N 
NA 
Section 1.3.6 Rationale 
for Patient-Reported 
Outcome Assessments, 
Section 2.1.3 
Exploratory Objectives, 
Section 2.2.3 
Exploratory Endpoints,  
Section 9.2.3 
Exploratory Efficacy 
Analysis 
• Patients’ Quality of Life was 
added to exploratory 
analyses 
• Patients’ Quality of Life 
measured by EuroQoL 
questionnaire was added 
This PRO is essential in 
all pivotal clinical trials 
and is suggested to be 
added to the exploratory 
analysis in this pivotal 
clinical trial amendment. 
Y 
NA 
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Section 3.1 Summary of 
Study Design  
• Sample size in both the text 
and Figure 1 was updated; 
•  PFS as primary analysis was 
removed. 
To be consistent with 
the updates in primary 
analysis. 
Y 
NA 
Section 3.2 Screening 
Period 
• Original: Archival tumor 
tissue must be collected for 
the purpose of biomarker 
analysis 
Revised: Archival tumor 
tissue is required to be 
collected for the purpose of 
biomarker analysis. 
For clarification  
N 
NA 
Section 3.3 Treatment 
Period 
• Examples of laboratory 
values were added to safety 
assessment;  
For clarification 
N 
NA 
• Collection of EQ5D-5L 
questionnaire was added 
To be consistent with 
the update in 
exploratory analysis 
Y 
NA 
Section 3.6.1 Patient 
Discontinuation From 
Study Treatment 
• The criteria for patient 
discontinuation from study 
treatment were revised per 
BeiGene A317 Phase 3 IO 
protocol template Version 
3.0. 
For clarification 
N 
NA 
Section 3.7 End of Study 
• The definition of end of 
study was updated per 
BeiGene A317 Phase 3 IO 
protocol template Version 
3.0; 
• PFS requirement for final 
analysis was removed. 
For clarification, and to 
be consistent with the 
updates in primary 
analysis. 
N 
NA 
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Section 4.1 Inclusion 
Criteria 
• Item 4: no prior treatment for 
ES-SCLC was updated to no 
prior systemic treatment for 
ES-SCLC. 
The study allows 
patients to receive local 
palliative therapy for 
metastasis lesion before 
randomization.  
N 
NA 
• Item 8: definition of sterile 
male and clarification of 
males with known low sperm 
counts were added per 
BeiGene A317 Phase 3 IO 
protocol template Version 
3.0. 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 4.2 Exclusion 
Criteria 
• Original: Patients who meet 
any of the following criteria 
will be excluded from study 
entry 
Revised: Patients who meet 
any of the following criteria 
are not eligible to enroll. 
For clarification  
N 
NA 
• Item 2: longer duration 
between systemic immune-
stimulating treatment and 
randomization of 4 weeks or 
5 half-lives was updated to 
shorter range 
For clarification and to 
be consistent with 
protocol template 
Y 
NA 
• Item 6: a clarification of 
major surgical procedures 
was added to Item 6. 
For clarification  
N 
NA 
• Item 10, the requirement of 
measurable disease outside 
of the CNS was removed 
To clarify that the study 
does not require patients 
to have measurable 
disease for assessment. 
N 
NA 
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• Item 13: a clarification of the 
use of antibiotics was added 
to Item 13 
To be consistent with 
synopsis 
N 
NA 
• Item 15: the criterion of 
patients with HBV and HCV 
was revised per BeiGene 
A317 Phase 3 IO protocol 
template Version 3.0 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
• Item 24: a note was added to 
the concurrent participation 
in another therapeutic 
clinical study 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
• Item 25: the exclusion 
criterion of “Women who are 
pregnant or are 
breastfeeding” was added 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 5.1.1.2 Placebo 
• Components of placebo were 
removed 
To be consistent with 
supply chain internal 
reviewing documents 
N 
NA 
Section 5.2 Dosage, 
Administration, and 
Compliance 
• Table 4: the Calvert formula 
and GFR estimation using 
Cockcroft-Gault equation 
were added 
To provide the formula 
for clarification  
N 
NA 
Section 5.5.3 Dose Delay, 
Interruption or 
Modifications for 
Chemotherapy 
• Clarification was added to 
determination of AE 
resolution 
For clarification 
N 
NA 
• The timing of chemotherapy-
related AE resolution was 
specified as after a planned 
dosing date.  
To clarify the timing 
definition 
N 
NA 
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Section 5.7 Criteria for 
Discontinuing 
Chemotherapy 
Regimens 
• The speed of any cisplatin-
related decrease in creatinine 
clearance was updated to be 
< 60 mL/min 
To be consistent with 
Section 5.5.3 
N 
NA 
Section 6.1 Prior 
Therapy 
• Patients with prior treatment 
for ES-SCLC was updated to 
patients with prior systemic 
treatment for ES-SCLC 
To be consistent with 
the revision in the 
inclusion criteria 
N 
NA 
Section 6.2.1 Permitted 
Concomitant 
Medications/Procedures 
• Permitted concomitant 
therapy in patients with 
active HBV was updated per 
BeiGene A317 Phase 3 IO 
protocol template Version 
3.0 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
• It was clarified that the 
medical monitor should be 
informed of the on-study 
radiotherapy 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 6.2.2 Prohibited 
or Restricted 
Concomitant 
Medications/Procedures 
• Other agents with immune-
stimulating properties were 
added 
For clarification 
N 
NA 
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Protocol Amendment 1.0 
 02 September 2020 
 
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Section 7.2.1 
Confirmation of 
Eligibility 
• The confirmation of 
eligibility was clarified as:  
the sponsor will assess and 
confirm the eligibility of 
each patient, and after a 
patient is screened and the 
investigator determines the 
patient’s eligibility, the 
medical monitor or designee 
will then confirm the 
patient’s eligibility before 
enrollment. 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 7.5.4 Laboratory 
Safety Tests 
• Coagulation test was added 
to the running text. 
To be consistent with 
the bullets. 
N 
NA 
• 48-hour sample review 
requirement was removed 
The visit window is 
±3days prior to D1, 
48hours is not consistent 
with protocol 
requirement. 
N 
NA 
Section 7.5.7 Hepatitis B 
and C Testing 
• Central laboratory was added 
to perform the tests 
To be consistent with 
Appendix 1 
N 
NA 
Section 7.6 Tumor and 
Response Evaluations  
• “The investigator may 
perform additional scans or 
more frequent assessments if 
clinically indicated” was 
added. 
To be consistent with 
Appendix 1 
N 
NA 
• The statement of “Tumor 
assessment should not be 
adjusted for delays in cycles” 
was added 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 7.8 Biomarkers 
• Optional biopsy was added at 
CR/PR 
To add 1 more optional 
biopsy collection. 
N 
NA 
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 02 September 2020 
 
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• Optional blood collection 
was added at CR/PR 
To add 1 more optional 
blood collection 
N 
NA 
• To add the statement for the 
leftover samples to be used 
for exploratory analysis  
to add 1 more optional 
tissue collection 
timepoint 
N 
NA 
Section 7.9 Health-
Related Quality of Life 
• Heading was revised  
For clarification  
N 
NA 
• EQ5D-5L was added  
To be consistent with 
the update in the 
exploratory analyses 
Y 
NA 
Section 8.2.2 Safety 
Monitoring Plan 
• Deleted the statement 
“Serum samples will be 
drawn for determination of 
ADAs to tislelizumab in 
patients randomized to the 
tislelizumab arm, if treatment 
assignment is known. 
Otherwise,” 
This statement does not 
apply to this study and is 
redundant. 
N 
NA 
Section 8.3.1 Definitions 
and Reporting 
• Examples of AEs were 
rephrased per BeiGene A317 
Phase 3 IO protocol template 
Version 3.0. 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 8.3.3 Assessment 
of Causality 
• The phrase of “based on the 
information available at the 
time of reporting” was added 
per BeiGene A317 Phase 3 
IO protocol template Version 
3.0 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 8.6.1 Adverse 
Event Reporting Period 
• SAE reporting was further 
clarified. 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
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 02 September 2020 
 
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Section 8.6.8 Assessing 
and Recording Immune-
Mediated Adverse 
Events 
• imAE reporting and 
assessment was further 
clarified 
For clarification  
N 
NA 
Section 8.6.9 Recording 
Infusion-Related 
Reactions 
• A new section of recording 
infusion-related reactions 
was added 
To be consistent with 
protocol template 
N 
NA 
Section 8.7.4 Renal 
Function Abnormalities 
• The statement of steroid 
treatment for patients with 
imAE was specified to 
patients with baseline renal 
insufficiency. 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 9 Statistical 
Methods and Sample 
Size Determination  
• “After the study is 
completed” was updated to 
“after the data collection is 
completed.” 
For clarification 
N 
NA 
9.6 Sample Size 
Consideration 
• HR assumption was adjusted 
to 0.74 with one-sided α 
being 0.025; the number of 
OS events for interim and 
final analysis were 282 and 
353 respectively; the sample 
size was adjusted to 455 
• Median OS of Arm B was 
updated to 12 months 
• Enrollment period was 
updated to 22 months with 
steady enrollment rate being 
26 patients per month, and 
the enrollment ramp-up 
period is updated to 9 
months 
The analyses of external 
data drove the updates 
in HR and median OS. 
Considering the delayed 
treatment effect and 
updated HR assumption, 
the OS events number at 
both interim and final 
analysis were updated. 
Y 
NA 
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 02 September 2020 
 
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Section 9.7 Interim 
Analyses 
• The interim analysis 
(including Table 8) was 
updated based on the updated 
overall survival analysis  
Interim analysis was 
updated based on the 
revised assumptions. 
Y 
NA 
Section 13.2 Institutional 
Review 
Board/Independent 
Ethics Committee 
• Requirement of sending 
amended ICF to the sponsor 
was added. 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
 
• Annotation for the 
investigator note being 
required to report SAEs to 
local authority per new 
China GCP was added 
For clarification  
N 
NA 
Section 13.4 Patient and 
Data Confidentiality  
• The policy and conduction of 
patient and data 
confidentiality was updated 
and clarified per BeiGene 
A317 Phase 3 IO protocol 
template Version 3.0 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 14.1.1 Data 
Entry in the Electronic 
Case Report Form  
• Instruction of data entry in 
the electronic case report 
form was added. 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 14.1.3 Data 
Management/Coding 
• Data management/coding of 
AE was updated with 
clarification per BeiGene 
A317 Phase 3 IO protocol 
template Version 3.0 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 14.3 Study 
Records Retention 
• Instructions for handling 
biological samples after 
study closure were revised 
per protocol template. 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
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 02 September 2020 
 
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Section 14.4 Protocol 
Deviations 
• Clarification of reporting all 
protocol deviations to the 
sponsor was added 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 14.5 Publication 
and Data Sharing Policy 
• The requirement for the 
processes of producing and 
reviewing reports, 
manuscripts, and 
presentations was added. 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
Section 14.6 Study and 
Study Center Closure 
• Requirement of collection of 
all study documents after 
study closure was added. 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
• Text regarding shipment of 
ADA and biomarkers 
samples was added 
For clarification and to 
be consistent with 
protocol template 
N 
NA 
• The statement of potential 
reasons for suspension or 
discontinuation was clarified.  
For clarification and to 
be consistent with 
protocol template 
N 
NA 
References 
• Six references were added 
To support the update in 
the introduction 
N 
NA 
Appendix 1 Schedule of 
Assessment 
• The mandatory EORTC 
QLQ-C30 and EORTC 
QLQ-LC13 at Screening was 
removed.  
To be consistent with 
main text 
N 
NA 
• The statements in footnote 
11, 20, and 21 were revised 
based on main text in the 
protocol 
To be consistent with 
main text 
N 
NA 
• EQ5D-5L was added to the 
assessment 
To be consistent with 
main text 
Y 
NA 
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Protocol Amendment 1.0 
 02 September 2020 
 
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• Foot 22 was added  
To add 1 more tissue 
collection and to be 
consistent with main 
text. 
N 
NA 
Appendix 12 EuroQoL 
5-Dimension, 5-Level 
• EQ-5D-5L questionnaire 
sample was added 
To support the update in 
the exploratory analyses 
Y 
NA 
 
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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
Study Protocol Number:
BGB-A317-312
Study Protocol Title:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
of Platinum Plus Etoposide With or Without Tislelizumab 
(BGB-A317) in Patients With Untreated Extensive-Stage Small 
Cell Lung Cancer
Date:
24 Apr 2022
Version:
1.0




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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................. 5 
1. ................. INTRODUCTION ....................................................................................................... 7 
2. ................. STUDY OVERVIEW.................................................................................................. 7 
2.1. .............. Study Design................................................................................................................ 7 
2.2. .............. Study Assessment ........................................................................................................ 7 
3. ................. STUDY OBJECTIVES................................................................................................ 8 
3.1. .............. Primary Objective ........................................................................................................ 8 
3.2. .............. Secondary Objective .................................................................................................... 8 
3.3. .............. Exploratory Objective.................................................................................................. 9 
4. ................. DEFINITION OF ESTIMANDS................................................................................. 9 
5. ................. STUDY ENDPOINTS............................................................................................... 10 
5.1. .............. Primary Endpoint(s)................................................................................................... 10 
5.2. .............. Secondary Endpoints ................................................................................................. 10 
5.3. .............. Exploratory Endpoints ............................................................................................... 10 
6. ................. SAMPLE SIZE CONSIDERATIONS....................................................................... 11 
7. ................. STATISTICAL METHODS...................................................................................... 11 
7.1. .............. Analysis Sets.............................................................................................................. 11 
7.2. .............. Multiplicity Adjustment............................................................................................. 12 
7.3. .............. Data Analysis General Considerations ...................................................................... 12 
7.3.1. .......... Definitions and Computations ................................................................................... 12 
7.3.2. .......... Conventions ............................................................................................................... 12 
7.3.3. .......... Handling of Missing Data.......................................................................................... 13 
7.3.4 ............ Adjustments for Covariates/Stratification.................................................................. 13 
7.3.5 ............ Data Integrity ............................................................................................................. 13 
7.4 ............... Patient Characteristics................................................................................................ 13 
7.4.1 ............ Patient Disposition..................................................................................................... 13 
7.4.2 ............ Protocol Deviations.................................................................................................... 13 
7.4.3 ............ Demographic and Other Baseline Characteristics ..................................................... 14 
7.4.4 ............ Disease History.......................................................................................................... 14 
7.4.5 ............ Prior Anticancer Drug Therapies and Surgeries ........................................................ 15 
7.4.6 ............ Prior and Concomitant Medications .......................................................................... 15 
7.4.7 ............ Medical History ......................................................................................................... 15 
7.5 ............... Efficacy Analysis....................................................................................................... 15 
7.5.1 ............ Primary Efficacy Endpoint(s) .................................................................................... 15 


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7.5.2 ............ Secondary Efficacy Endpoints................................................................................... 17 
Progression Free Survival (PFS) by investigators ........................................................................ 17 
Objective Response Rate (ORR) by investigators ........................................................................ 17 
Duration of Response (DOR)........................................................................................................ 17 
Disease control rate (DCR)........................................................................................................... 18 
Health-Related Quality of Life (HRQoL)..................................................................................... 18 
7.5.3 ............ Subgroup Analyses .................................................................................................... 19 
7.5.4 ............ Exploratory Efficacy Endpoints................................................................................. 19 
7.5.5 ............ Post-treatment Anti-Cancer Therapy......................................................................... 19 
7.6 ............... Safety Analyses.......................................................................................................... 20 
7.6.1 ............ Extent of Exposure..................................................................................................... 20 
7.6.2 ............ Adverse Events .......................................................................................................... 21 
Treatment-emergent AE................................................................................................................ 22 
Immune-mediated AE................................................................................................................... 22 
Infusion-related reaction ............................................................................................................... 23 
Death .........23 
7.6.3 ............ Laboratory Values...................................................................................................... 23 
7.6.4 ............ Vital Signs.................................................................................................................. 24 
7.6.5 ............ Electrocardiograms (ECG)......................................................................................... 24 
7.6.6 ............ Eastern Cooperative Oncology Group (ECOG) Performance Status ........................ 24 
7.7 ............... Pharmacokinetic Analyses......................................................................................... 24 
7.8 ............... Immunogenicity Analyses ......................................................................................... 24 
8 .................. INTERIM ANALYSES............................................................................................. 25 
9 .................. CHANGES IN THE PLANNED ANALYSIS .......................................................... 25 
10 ................ REFERENCES .......................................................................................................... 26 
APPENDIX 1. IMPUTATION OF MISSING OR PARTIALLY MISSING DATES ................ 27 
APPENDIX 2 HEALTH RELATED QUALITY OF LIFE ......................................................... 30 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
<<Include a table of abbreviations if they are used in this document. Abbreviations should be sorted 
alphabetically.>>
Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma or serum concentration-time curve
BGB-A317
tislelizumab
BOR
best overall response
CR
complete response
Ctrough
lowest concentration before the next dose
DCR
disease control rate
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture (system)
EORTC
European Organisation for the Research and Treatment of Cancer
EOT
End-of-Treatment (Visit)
ES-SCLC
extensive-stage small cell lung cancer
HR
hazard ratio
ICF
informed consent form
ICH
International Council for Harmonisation 
IDMC
Independent Data Monitoring Committee
ITT
Intent-to-Treat (Analysis Set)
MedDRA
Medical Dictionary for Regulatory Activities
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PD-1
programmed cell death protein-1
PD-L1
programmed cell death protein ligand-1
PFS
progression-free survival
PFS2
PFS after next line of treatment
PK
pharmacokinetic(s)
PR
partial response


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QLQ-C30
Quality of Life Questionnaire – Core 30
QLQ-LC13
Quality of Life Questionnaire supplement lung cancer module
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCLC
small cell lung cancer
TEAE
treatment-emergent adverse event


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1.
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical methods 
that will be used to analyze and report results for BGB-A317-312: A Phase 3, Randomized, Double-
Blind, Placebo-Controlled Study of Platinum Plus Etoposide With or Without Tislelizumab (BGB-A317) 
in Patients With Untreated Extensive-Stage Small Cell Lung Cancer (ES-SCLC). This SAP is based on 
BGB-A317-312 Protocol Amendment 1.0 dated Sep 02, 2020. The focus of this SAP is for the planned 
interim analysis and the final analysis specified in the study protocol. The analysis details for 
Pharmacogenomics and Biomarker analyses are not described in this SAP. 
2.
STUDY OVERVIEW
2.1.
Study Design
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to compare the 
efficacy of tislelizumab  cisplatin or carboplatin + etoposide (Arm A) and placebo  cisplatin or 
carboplatin  etoposide (Arm B) as first-line treatment in patients who have previously untreated ES-
SCLC. The choice of platinum (cisplatin or carboplatin) will be at the investigator’s discretion.
The study consists of a Screening phase (up to 28 days before randomization), a Treatment phase (until
disease progression as assessed by the investigator per RECIST v1.1, loss of clinical benefit, unacceptable 
toxicity, or withdrawal of informed consent, whichever occurs first) that includes an Induction treatment 
period and a Maintenance treatment period, a Safety Follow-up phase (30 days (± 7 days) after the last 
dose of study drug (including chemotherapy-only), or before the initiation of a new anticancer treatment, 
whichever occurs first), and a Survival Follow-up phase (every 3 month (± 14 days) after the Safety 
Follow-up Visit or as directed by the sponsor until death, loss to follow-up, withdrawal of consent, or 
study completion by the sponsor).
At randomization, eligible patients will be stratified by the following 3 factors: 
x
ECOG Performance Status (0 versus 1)
x
Investigator-chosen chemotherapy (carboplatin versus cisplatin)
x
Brain metastasis (yes versus no)
Randomized patients will be in a 1:1 ratio to receive 1 of the following treatment regimens: 
x
Induction period (administered on a 3-week cycle for 4 cycles):
o
Arm A: tislelizumab  cisplatin or carboplatin  etoposide
o
Arm B: placebo + cisplatin or carboplatin  etoposide
x
Maintenance period (administered once every 3 weeks):
o
Arm A: tislelizumab
o
Arm B: placebo
Crossover between treatment arms is not allowed in this study. 
2.2.
Study Assessment
Tumor imaging will be performed within 28 days prior to randomization. During the study, tumor 
imaging will be performed approximately every 6 weeks (± 7 days) for the first 48 weeks following Cycle 
1 Day 1, and every 9 weeks (± 7 days) thereafter, regardless of treatment dose delay. The investigator 


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may perform additional scans or more frequent assessments if clinically indicated. Tumor assessment will 
continue until radiographic disease progression per RECIST v1.1.
Patients who discontinue study treatment early for reasons other than disease progression (eg, toxicity) 
will continue to undergo tumor assessments following the original plan until the patient begins a 
subsequent anticancer treatment, experiences disease progression, withdraws consent, is lost to follow-up,
death, or until the study terminates, whichever occurs first.
After informed consent has been signed but prior to the administration of the study drug, only SAEs 
should be reported.
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be reported 
until either 30 days after last dose of study drugs including chemotherapy drugs or initiation of new 
anticancer therapy, whichever occurs first. ImAEs (serious or nonserious) should be reported until 90 days 
after the last dose of tislelizumab or placebo, regardless of whether or not the patient starts a new 
anticancer therapy. All SAEs considered related to the study drug(s) that are brought to the attention of 
the investigator should be reported regardless of time since the last dose of treatment.
In this double-blind, placebo-controlled study, all patients and personnel involved in the conduct and 
interpretation of the study, including the investigators, BeiGene study team, and site personnel, will be 
blinded to the treatment assignment. Randomization data will be kept strictly confidential; filed securely 
by the appropriate groups for BeiGene, the Interactive Response Technology (IRT) and the Independent 
Data Monitoring Committee (IDMC); and will be accessible only to authorized persons per SOPs until the 
time of unblinding. 
Unblind safety and efficacy monitoring will be performed by an IDMC. The IDMC may recommend 
modifications to the study, including termination due to safety and/or efficacy concerns. The functions and 
membership of the IDMC will be described in the IDMC Charter.
3.
STUDY OBJECTIVES
3.1.
Primary Objective
x
To evaluate the efficacy of tislelizumab + cisplatin or carboplatin + etoposide compared with 
placebo + cisplatin or carboplatin + etoposide in the Intent-to-Treat (ITT) Analysis Set as 
measured by overall survival (OS)
3.2.
Secondary Objective
x
To evaluate the efficacy of tislelizumab + cisplatin or carboplatin + etoposide compared with 
placebo + cisplatin or carboplatin + etoposide in the ITT Analysis Set as measured by 
investigator-assessed progression-free survival (PFS) according to RECIST v1.1
x
To evaluate the efficacy of tislelizumab + cisplatin or carboplatin + etoposide compared with 
placebo + cisplatin or carboplatin + etoposide in the ITT Analysis Set as measured by investigator
assessed overall response rate (ORR), duration of response (DOR), and disease control rate (DCR) 
according to RECIST v1.1
x
To evaluate the effect of tislelizumab + cisplatin or carboplatin + etoposide compared with 
placebo + cisplatin or carboplatin + etoposide on patients’ healthrelated quality of life (HRQoL) 
according to the EORTC Quality of Life Questionnaire – Core 30 (QLQC30) and the 
supplemental lung cancer module (QLQLC13)


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x
To evaluate the safety and tolerability of tislelizumab in combination with cisplatin or carboplatin 
and etoposide compared with cisplatin or carboplatin and etoposide
3.3.
Exploratory Objective
x
To assess PFS after next line of treatment (PFS2)
x
To explore potential predictive biomarkers in archival and/or fresh tumor tissue and/or blood (or 
blood derivatives), including but not limited to PDL1 expression by immunohistochemistry (IHC), 
multiplex IHC (mIHC), gene expression profiling (GEP), tumor mutation burden (TMB), 
microsatellite instability (MSI), and blood tumor mutation burden (bTMB), to evaluate the 
association between these biomarkers and response to study treatment or mechanism of resistance
x
To characterize PK of tislelizumab in patients with small cell lung cancer (SCLC)
x
To evaluate host immunogenicity to tislelizumab by assessing antidrug antibodies (ADAs) against 
tislelizumab in patients with SCLC
x
To examine the patients’ quality of life (QoL) as measured by EQ5D-5L
4.
DEFINITION OF ESTIMANDS
Primary scientific question of interest is: will the addition of tislelizumab to chemotherapy doublet 
(platinum and etoposide) prolong survival in first-line patients who have untreated ES-SCLC, regardless
of any anticancer therapy received subsequently.
The primary estimand is described by the following attributes: 
1. Treatment of interest: 
Experimental treatment constitutes tislelizumab plus chemotherapy (either cisplatin or carboplatin 
+ etoposide). Control treatment constitutes placebo plus chemotherapy (either cisplatin or 
carboplatin + etoposide).
2. Population: 
Patients with ES-SCLC who had not received first-line treatment.
3. Primary variable: 
Overall survival (see Section 5.1)
4. Handling of intercurrent events: 
x
Anticancer therapy subsequent to assigned therapy that is started prior to death: Any incidence 
will be ignored, i.e., any death or patients’ data collected after the new anticancer therapy will 
be considered for analysis. (treatment policy strategy) 
x
Insufficient study treatment or discontinuation of any study drug: Early discontinuation or 
interruption or any study drug due to any cause (including COVID-19) will be ignored, i.e., 
any death or patients’ data collected after the interruption or discontinuation of treatment will 
be considered for analysis. (treatment policy strategy)
x
Any other unforeseen intercurrent events: OS analysis will take into account all deaths
regardless of any unforeseen intercurrent events  
5. Population-level summary:
Hazard ratio (HR) of OS comparing tislelizumab plus platinum and etoposide versus placebo plus 
platinum and etoposide, estimated using Cox proportional hazard model stratified by prespecified 
stratification factors (see Section 7.3.4)


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5.
STUDY ENDPOINTS
5.1.
Primary Endpoint(s)
x
OS, defined as the time from randomization to death from any cause
5.2.
Secondary Endpoints
x
PFS, defined as the time from randomization to the first occurrence of disease progression as 
determined by investigator using RECIST v1.1 or death from any cause, whichever occurs first
x
ORR, defined as the proportion of patients with PR or CR as determined by the investigator using 
RECIST v1.1
x
DOR, defined as the time from the first occurrence of a documented objective response to the time 
of relapse, as determined by the investigator per RECIST v1.1, or death from any cause, 
whichever comes first
x
DCR, defined as the proportion of patients whose best overall response (BOR) is CR, PR or stable 
disease per RECIST v1.1
x
CBR, defined as the proportion of patients whose best overall response (BOR) is CR, PR or 
durable stable disease per RECIST v1.1
x
Incidence and severity of treatment-emergent adverse events (TEAEs) graded according to 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0
x
Percentage of patients with clinically meaningful changes post baseline, defined as a 10-point 
improvement or worsening (detailed in Section 7.5.2) in:

Global health status (GHS) and physical function (PF) per the QLQ-C30 

Dyspnoea, coughing, haemoptysis, dysphagia, chest pain, pain in arms and shoulders, and 
peripheral neuropathy symptoms of QLQ-LC13
x
Time to deterioration, defined as the time from randomization to the first occurrence of worsening 
scores (10-point change; detailed in Section 7.5.2) confirmed at the following visit or death from 
any cause, in:

GHS and PF per the QLQ-C30 

Dyspnoea, coughing, haemoptysis, dysphagia, chest pain, pain in arms and shoulders, and 
peripheral neuropathy symptoms of QLQ-LC13
5.3.
Exploratory Endpoints
x
PFS2, defined as the time from randomization to the objective disease progression after next line 
of treatment or death from any cause, whichever occurs first
x
Status of predictive and prognostic biomarkers including but not limited to PD-L1 expression,
multiplex immunohistochemistry (mIHC), GEP, TMB, and MSI in archival and/or fresh tumor 
tissue and bTMB in blood before study treatment and/or at disease progression, and the 
association between the biomarkers and disease status or response to study treatment
x
Summary of serum concentrations of tislelizumab
x
Assessments of immunogenicity of tislelizumab by determining the incidence of ADAs


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x
QoL is defined as changes in patients’ general well-being measured by the scores of the EQ5D-5L 
descriptive 5-dimension scores and the visual analog scale (VAS).
6.
SAMPLE SIZE CONSIDERATIONS
The sample size calculation is based on the number of events required to demonstrate the OS superiority 
of Arm A to Arm B in the ITT Analysis Set. Driven by external data from studies described in Protocol 
Section Error! Reference source not found. , statistical assumptions were updated in protocol 
amendment version 1.0 and the number of events required to demonstrate efficacy with regard to OS is 
estimated based on the following assumptions:
x
Median OS of 12 months in Arm B.
x
A one-sided α of 0.025 and 80% power for the target OS HR of 0.74 in the ITT Analysis Set.
x
One OS interim analysis planned in the ITT Analysis Set when approximately 80% of total 
required OS events occurred, with Lan-DeMets approximation to O’Brien-Fleming boundary.
x
Exponential survival distribution is assumed for both Arm A and Arm B.
Assuming approximate 455 patients are to be enrolled and randomized at 1:1 ratio over a 22-month period 
at a steady-state enrollment rate of 26 patients per month with enrollment ramp-up duration of 9 months, 
and assuming a dropout rate of 5% per year for OS endpoints, a total of 353 OS events are required for the 
ITT Analysis Set for the final OS analysis. 
7.
STATISTICAL METHODS
7.1.
Analysis Sets
The Intent-to-Treat (ITT) analysis set consists of all randomized patients. The ITT analysis set is the 
primary analysis set and will be used for demography and efficacy analyses.
The safety analysis set includes all patients randomized and received any dose of any study drug, and 
patients will be grouped by actual treatment received. Patients randomized to arm A but never took any 
dose of Tislelizumab will be included in arm B. Patients randomized to arm B but took any dose of 
Tislelizumab will be included in arm A. The safety analysis set is used for all safety analyses.
The per-protocol analysis set consists of all the patients in the ITT analysis set, excluding those with 
critical protocol deviations. Critical protocol deviations are a subset of important protocol deviations. 
Criteria for exclusion from the PP will be determined and documented before the database lock for the 
primary analysis. This will be the secondary analysis set for efficacy analysis when there are over 10% 
ITT patients with critical protocol deviations. 
The HRQoL analysis set includes all randomized patients who received any dose of study drug and 
completed at least one HRQoL assessment. This will be the analysis set for HRQoL analysis. 
PK Analysis Set includes all patients who received ≥ 1 dose of tislelizumab per the protocol for whom 
any post dose PK data were available.
Antidrug antibody (ADA) Analysis Set includes all patients who received ≥ 1 dose of tislelizumab for 
whom both baseline ADA and ≥ 1 postbaseline ADA results were available.


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7.2.
Multiplicity Adjustment
Hypothesis testing of the secondary endpoint PFS in ITT analysis set will be performed at the same time 
as the OS analysis, either at interim or final analysis. Only when the superiority of OS is demonstrated, 
full alpha of 1-sided 0.025 will be passed to hypothesis testing of PFS. 
Multiplicity adjustment of interim analysis is described in Section 8. 
7.3.
Data Analysis General Considerations
7.3.1.
Definitions and Computations
Study drugs include tislelizumab, cisplatin, carboplatin and etoposide.
Study day will be calculated in reference to the date of the first dose of study drug for safety analyses. For 
derivation of the duration of any efficacy endpoint, the reference date will be date of randomization. For 
assessments conducted on or after the date of first dose date, study day will be calculated as (assessment 
date –first dose date + 1). For assessments conducted before first dose date, study day is calculated as 
(assessment date – first dose date). If no dose is given, then the date of first randomization will be used. 
There is no study day 0.
Unless otherwise specified, a baseline value is defined as the last non-missing value collected before or on 
randomization for ITT analysis set. If not available, last non-missing value collected before or on first 
dose date will be used. For safety analysis set, a baseline value is defined as the last non-missing value 
collected before or on first dose date.
Unscheduled measurements will not be included in by-visit table summaries and graphs but will 
contribute to best/worst case value where required (e.g. shift table). Listings will include scheduled, 
unscheduled and retest data.
Study follow-up duration is defined as the duration from the randomization date to the study 
discontinuation date (e.g. death, consent withdrawal, lost to follow-up) or to cutoff date if a patient is still 
ongoing.
All calculations and analyses will be conducted using SAS® Version 9.4 or higher.
7.3.2.
Conventions
Unless otherwise specified, the following conventions will be applied to all analyses:
x
1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
significant digit.
x
1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up to 1 
significant digit.
x
Age will be calculated as the integer part of (date of informed consent – date of birth 
+ 1)/365.25.
x
P-values will be rounded to 4 decimal places. P-values that is less than 0.0001 will be 
presented as '< 0.0001' and p-values that is larger than 0.9999 will be presented as '> 0.9999'. 
x
Time-to-event or duration of image-based event endpoints will be based on the actual date the
event occurs (i.e., radiograph was obtained) rather than the associated visit date.
x
For laboratory results collected in numerical range with the symbol ‘<’ or ‘>=’, use the rule: if
results >= x then set as x; if <x then set as x/2.


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x
For by-visit observed data analyses, percentages will be calculated based on the number of 
patients with non-missing data as the denominator, unless otherwise specified.
x
For continuous endpoints, summary statistics will include n, mean, standard deviation, median, 
Q1, Q3 and range (minimum and maximum).
x
For discrete endpoints, summary statistics will include frequencies and percentages.
7.3.3.
Handling of Missing Data
Handling of missing data related to primary estimand is elaborated in Section 7.5.1. Missing dates or 
partially missing dates will be imputed conservatively for adverse events and prior/concomitant 
medications/procedures. Specific rules for the handling of missing or partially missing dates for adverse 
events and prior/concomitant medications/procedures are provided in 0. Other missing data will not be 
imputed unless otherwise specified elsewhere in this SAP.
By-visit endpoints will be analyzed using observed data unless otherwise specified. For observed data 
analyses, missing data will not be imputed, and only the observed records will be included.
7.3.4
Adjustments for Covariates/Stratification
The value of the stratification factors used at randomization (recorded in electronic data capture (EDC) 
system), including ECOG performance status (0 vs 1), and investigator-chosen platinum (cisplatin vs 
carboplatin) will be used in stratified log-rank test for primary endpoint OS, and stratified Cox 
proportional hazard model for OS and secondary endpoint PFS. In order to avoid over-stratification, brain 
metastasis (yes vs no) will not be included as number of patients enrolled with brain metastasis is small.
The actual value of the stratification factors (collected in IRT) and other baseline covariates may be used 
in statistical models as covariates as sensitivity or supplementary analyses for endpoints. 
7.3.5
Data Integrity
The data set for analysis should be an accurate and complete representation of the patients' relevant 
outcomes from the clinical database. All data should be complete and reviewed up to a pre-specified 
cutoff date as specified in the Data Extract and Snapshot Plan. Consistency checks and appropriate source 
data verification should be completed as specified in the Site Monitoring Plan.
7.4 Patient Characteristics
7.4.1
Patient Disposition
The number (percentage) of patients randomized, treated, discontinued from the study, reasons for 
discontinued from the study, and the duration of study follow-up will be summarized in the ITT analysis 
set. Study follow-up summary will be descriptively. The patients who discontinued treatment and the 
primary reason for the end of treatment will be summarized among patients who were treated. The 
reasons for treatment/study discontinuation will be summarized according to the categories in CRF, and 
those related to COVID-19 will also be summarized, if applicable.
7.4.2
Protocol Deviations
Protocol deviation criteria will be established together with its category/term of important and not 
important. Patients with important protocol deviations will be identified and documented before the 
database lock. Important protocol deviations will be summarized for all patients in the ITT analysis set. 


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Critical protocol deviation that significantly impacts efficacy or safety evaluation will be reviewed prior 
to data base lock. 
Protocol deviations that are related to COVID-19 will be summarized and all patients affected by 
COVID-19-related protocol deviations will be listed along with site information and specific deviation
description.
7.4.3
Demographic and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized using descriptive statistics in the ITT
analysis set, including the following variables:
x
Age (continuously and by categories [<65 or >=65 years])
x
Sex
x
Ethnicity
x
Race
x
Region
x
Baseline weight (kg)
x
Height (m)
x
BMI
x
Smoking status
x
baseline LDH (categorized as <=ULN or >ULN)
Meanwhile, stratification factors per IRT and per EDC will be summarized in ITT analysis set:
x
ECOG Performance (0 versus 1)
x
Investigator-chosen chemotherapy (carboplatin versus cisplatin)
x
Brain metastasis (yes versus no)
7.4.4
Disease History
The number (percentage) of patients reporting a history of disease and characteristics, as recorded on the 
eCRF, will be summarized in the ITT analysis set. 
Disease characteristics include:
x
Time from initial diagnosis to study entry 
x
Time from extensive-stage diagnosis to study entry 
x
Stage at initial diagnosis
x
AJCC staging at study entry
x
Metastatic site(s) at study entry
x
Number of metastatic sites
x
Target lesion sum of diameter


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7.4.5
Prior Anticancer Drug Therapies and Surgeries
Prior anti-cancer drug therapies, prior anti-cancer radiotherapy, and prior anti-cancer surgeries including 
number (%) of patients with any use and treatment intent will be summarized in the ITT analysis set. In 
addition, number of prior lines and best overall response to last drug therapy will be included in the prior 
anti-cancer drug therapies summary.
The therapies and surgeries with the same sequence/regimen number are counted as one prior 
therapy/surgery.
7.4.6
Prior and Concomitant Medications
Prior medications are defined as medications that stopped before the first dose of study drug. Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug and were 
continuing at the time of the first dose of study drug, or (2) started on or after the date of the first dose of 
study drug up to 30 days after the patient's last dose or the initiation of a new anti-cancer therapy.
Prior and concomitant medications will be coded using the version of World Health Organization Drug 
Dictionary (WHO DD) drug codes effective for the study at the time of database lock. They will be 
further classified to the appropriate Anatomical Therapeutic Chemical (ATC) code. 
The number (percentage) of patients reporting prior and concomitant medications will be summarized by 
ATC medication class and WHO DD preferred name in the safety analysis set. A listing of prior and 
concomitant medications will be provided.
7.4.7
Medical History
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) effective 
for the study at the time of database lock. The number (percentage) of patients reporting a history of any 
medical condition, as recorded on the CRF, will be summarized by system organ class and preferred term 
in the ITT analysis set. A listing of medical history will be provided.
7.5 Efficacy Analysis
7.5.1
Primary Efficacy Endpoint(s)
Primary estimand is defined in Section 4. Details of the statistical methods used in OS derivation and 
analysis are provided in this section including pre-defined sensitive analyses of the primary estimand and 
supplementary analyses of OS.     
Overall survival is defined as time from randomization date to the documented death date for patients who
died prior to or on the clinical cutoff date. For patients who are alive by the clinical cutoff date, OS will 
be censored at the last known alive date (LKADT). The last known alive date will be defined as either the 
clinical data cutoff date for patients who are still on treatment, or last available date showing patients alive
or cut-off date whichever comes first.
Every effort should be made to ensure complete death dates. In the rare case, if day of death date is 
missing, death date is imputed as the max (last available date showing patients alive + 1, first day of 
year/month of death date). The patient with imputed death date will be considered as an event for OS 
analysis. Death with missing month and/or year will not be imputed for OS analysis and will not be 
considered as OS event and will be censored at LKADT.
The null and alternative hypotheses to be evaluated for OS are:
H0 : OSA ≤ OSB,


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Ha : OSA > OSB,
where OSA and OSB represent the OS of arm A (the experimental treatment) and arm B (the control
group), respectively. The primary efficacy analyses of OS will be tested using stratified log-rank test with
ECOG performance status and investigator-chosen platinum as recorded in EDC as strata. In order to 
avoid over-stratification, brain metastasis (yes vs no) will not be included as number of patients enrolled 
with brain metastasis is small.
The survival distribution of OS will be estimated using Kaplan-Meier method. The results will be plotted 
graphically (Kaplan-Meier curves) by treatment. The plots will display the number of patients at risk at 
equidistant time point. The median OS for each treatment group will be provided along with the 
approximate 95% confidence intervals using the method of Brookmeyer and Crowley (Brookmeyer & 
Crowley, 1982). Additionally, 25% and 75% percentiles will also be provided. The cumulative probability 
of OS at every 3 months if estimable, will be calculated for each treatment arm and presented with 2-sided
95% CIs. The CIs will be estimated using Greenwood's formula (Greenwood, 1926).
The HR and its 2-sided 95% CI will be estimated from a stratified Cox regression model with Efron’s 
method of tie handling, and with the same stratification factors above. Unstratified analysis will also be 
presented.
Handling of intercurrent events is described in Section 5.1.
Sensitivity analyses
Sensitivity analysis 1: OS will be analyzed using an unstratified Cox model, and the treatment effect will 
be summarized by the hazard ratio with its 95% confidence interval. 
Sensitivity analysis 2: OS will be analyzed with stratification factors as recorded from IRT
Supplementary analyses
Supplementary analysis 1 “OS analysis based on Restricted Mean Survival Time method”:  This analysis 
targets an estimand which has the same attributes as the primary estimand except the population level 
summary will be different in restricted mean survival time (RMST) between two treatment groups. In
order to account for the possible non-proportional hazard effect, the restricted mean survival time 
(RMST) (RMST, Uno H, Claggett B, Tian L, Inoue E, et al. 2014) will be computed for OS separately 
using the area under the curve from baseline to the minimum of the largest observed time on each of the 
two treatment groups. RMST will be computed for each treatment arm and the difference with its 95% CI 
will be displayed. 
Supplementary analysis 2 “OS analysis adjusted for baseline covariates”: OS will be also analyzed by 
adjusting multivariate covariates at baseline.  The analysis addresses a different scientific question. i.e., will 
the addition of tislelizumab to chemotherapy doublet prolong survival, adjusting for covariates liver metastasis, 
LDH, and smoking status. Covariate adjusted multivariate Cox regression provides a conditional treatment 
effect and a stratified Cox regression model will be performed adjusted for the above mentioned key
baseline prognostic factors. 
Supplementary analyses exploring the impact on OS from other confounding factors, including but not 
limited to between-arms imbalance of clinically meaningful baseline characteristics, post-treatment anti-
cancer therapy, or COVID-19, might be performed as appropriate.


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7.5.2
Secondary Efficacy Endpoints
Progression Free Survival (PFS) by investigators
The methods used to analyze OS will be applied to the analysis for PFS. Table 1 shows the derivation rule 
for PFS. 
Table 1: Censoring Rules for Progression-free Survival Per RECIST Version 1.1
Derivation rules
Outcome 
No progression at the time of data cut-
off or withdrawal from study or lost to 
follow up 
Date of last adequate radiologic assessment prior to 
or on date of data cut-off or withdrawal from study or 
lost to follow up
Censored 
New anticancer therapy started prior to 
disease progression or death
Last adequate radiological assessment before the new 
anticancer therapy (hypothetical strategy)
Censored 
No baseline or post-baseline tumor 
assessments without death within 13 
weeks after randomization
Date of randomization 
Censored 
No baseline or post-baseline tumor 
assessments with death within 13 
weeks after randomization
Date of death
Event 
Death or progression after more than 
one consecutive missed visit
Date of last adequate radiologic assessment before 
missed tumor assessments
Censored 
PFS will be analyzed in similar methodology as OS.
Additional analyses exploring the impact on PFS from other confounding factors, including but not 
limited to COVID-19, might be performed per needs.
Objective Response Rate (ORR) by investigators
Best overall response (BOR), defined as the best response recorded from randomization until data cut or 
the start of new anticancer treatment. Patients with no post-baseline response assessment (due to any reason) 
will be considered non-responders for BOR. ORR is defined as the number of patients whose BOR is CR 
or PR divided by the number of randomized patients in each arm. Patients with no baseline response 
assessment (for any reason) will be considered as non-responders. Confirmation on response is required as
primary analysis, and analysis based on unconfirmed response might be presented as well. The 2-sided 95% 
CIs for the odds ratio in ORR will be calculated, as well as Clopper-Pearson 95% CIs for ORR and its 
corresponding Clopper-Pearson 95% CI for each of the response categories (CR, PR, SD, and PD) will be 
presented by treatment arm.
Duration of Response (DOR)
Duration of Response (DOR) is defined as progression/death event free time counted from the first objective 
response date to the first documented radiological PD date/or death date, whichever occurs first. 
Confirmation on response is required as primary analysis, and analysis based on unconfirmed response 


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might be presented as well. All the censoring rules for PFS should be applied to DOR. DOR will be analyzed 
in the responders only and in similar methodology as PFS except that no hypothesis testing will be 
performed and no HR will be reported.
Disease control rate (DCR)
Disease control rate (DCR) defined as the proportion of patients whose best overall response (BOR) is
CR, PR, or SD including non-CR/non-PD ≥6 weeks. Confirmation on response is required as primary 
analysis, and analysis based on unconfirmed response might be presented as well. DCR by investigators 
will be analyzed similarly to ORR.
Clinical benefit rate (CBR)
Clinical benefit rate (CBR) defined as the proportion of patients who have CR, PR, or SD including non-
CR/non-PD of ≥24 weeks in duration. Confirmation on response is required as primary analysis, and 
analysis based on unconfirmed response might be presented as well. CBR assessed by investigators will 
be analyzed similarly to ORR.
Health-Related Quality of Life (HRQoL)  
All HRQoL analyses will be based on HRQoL analysis set, unless otherwise specified. 
Compliance
Compliance for EORTC QLQ-C30, QLQ-LC13 modules, defined as the proportion of questionnaires 
actual received out of the expected number, in the HRQoL analysis set will be summarized for each 
scheduled assessment and treatment arm.
Change from baseline by visit
Descriptive analysis will be performed for all the scales and single items of the PRO questionnaires in all 
cycles. Details of HRQoL scoring are specified in Appendix 2 according to the algorithm described in the 
EORTC QLQ-C30 and EORTC QLQ-LC13 scoring manual (Fayers 2001).
A mixed effect model analysis for measuring clinically meaningful changes will be performed on selected
PRO endpoints (GHS and PF in QLQ-C30, coughing, dysphagia, and chest pain in QLQ-LC13).
Differences in change from baseline between arms at the key clinical cycles of 4 and 6, if data allows, will 
be assessed in the mixed models which include baseline score, stratification factors, treatment arm, visit,
and treatment arm by visit interaction as fixed effects and visit as a repeated measure with an unstructured 
covariance structure.
Time to deterioration
Time to deterioration (TTD) is defined as the time from randomization to first occurrence of a worsening 
score confirmed at the subsequent visit or death from any cause. The minimum important clinically 
meaningful difference change (e.g. worsening) in symptoms of QLQ-C30 and QLQ-LC13 is defined as 
≥10 points increase from baseline (Osoba et al 1998; King, 1996; Maringwa et al 2011). The clinically 
meaningful deterioration in function and global health status/quality of life is defined as ≥10 points 
decrease from baseline. The median TTD of selected PRO endpoints (PF in QLQ-C30, coughing and 
chest pain in QLQ-LC13) will be calculated using Kaplan-Meier estimates, and presented with 2-sided
95% CIs.


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7.5.3
Subgroup Analyses
To determine if the treatment effect is consistent across various subgroups, the median OS in each 
subgroup along with unstratified OS hazard ratio and its 95% CI will be estimated and plotted within each 
category of the following variables:
x
age (≤ 65 vs > 65 years)
x
gender (Female vs Male)
x
ECOG PS (0 vs 1)
x
brain metastasis (yes vs no)
x
choice of platinum (cisplatin vs carboplatin)
x
liver metastasis (yes vs no)
x
baseline LDH (<=ULN vs >ULN)
x
Smoking status (never vs smoker) where smoker includes both current and former smoker
x
AJCC staging at study entry (III vs IV)
For patients with evaluable PD-L1 expression, subgroups with PD-L1 score <1% vs >=1% will be 
analyzed in a similar way but in a separate output and not included in forest plot, and other cutoffs and 
algorithms might be explored as well. PD-L1 expression is determined by PD-L1 score assessed by tumor 
area positive score (TAP), which is defined as the total percentage of the tumor area covered by tumor 
cells with any membrane staining above background and tumor-associated immune cells with any staining 
above background using Ventana PD-L1 (SP263) assay.
If a subgroup includes only few patients, then the subgroup variable might be ignored. 
7.5.4
Exploratory Efficacy Endpoints
Progression-free survival after next-line of treatment (PFS2) is defined as time from the randomization date 
to the first documented disease progression on next-line therapy or death from any cause, whichever occurs 
first. Next-line therapy is defined as the first subsequent treatment initiated after the discontinuation of the
study treatment . The first documented progression on next-line treatment will be recorded by investigator 
(i.e. captured on the post treatment discontinuation anti-cancer systemic therapy CRF page). Patients alive 
and for whom a disease progression on next-line therapy has not been observed will be censored at the last 
known alive date. If a second new anti-cancer therapy is introduced, then PFS2 will be censored at the end 
date of prior line of therapy. Any death prior to initiation of next-line therapy will be considered as an event 
for PFS2.
Kaplan-Meier (KM) method as described in the PFS and OS analyses will be used in the analysis of 
PFS2. The median PFS2 and the cumulative probability of PFS2 estimated at every 3 months will be 
calculated using Kaplan-Meier estimates for each treatment arm and presented with 2-sided 95% CIs 
computed by Brookmeyer and Crowley method. The HR of PFS2 from stratified Cox model will be 
estimated and presented with a 2-sided 95% CI.
7.5.5
Post-treatment Anti-Cancer Therapy
Post treatment anti-cancer therapy is defined as the anti-cancer therapy started after the last dose of study 
drug(s). A summary of number and percentage of patients who received subsequent systematic anticancer 
therapy, chemotherapy, I/O, target therapy(refer to coding), others will be provided by arm in ITT 
analysis set.


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Separate flags of start date of new anti-cancer therapy for efficacy and safety analyses are derived 
individually.
-
As for efficacy analysis, start date of new anti-cancer therapy could be the earliest of date of 
prohibited anti-cancer therapy taken during treatment, date of the post-treatment systemic anti-cancer 
therapy or include other anti-cancer therapy such as post-treatment surgery and radiotherapy as deem 
appropriate.
-
The start date of new anti-cancer therapy in defining TEAE for safety is always the first date 
of new systemic anti-cancer therapy taken after the last study treatment.
Since the Tumor response per RECIST or event driven endpoints have not been commonly used for the 
efficacy evaluation of Tradition Chinese Medicine, The ORR, PFS or OS benefit of Chinese herbal 
medicines and Chinese patent medicines has not yet been established. Therefore, they will not be 
considered as new anti-cancer therapy in the efficacy and safety analyses.
Patient data listings of post-treatment anti-cancer therapy, radiotherapy, and procedure or surgery will be 
provided.
7.6 Safety Analyses
All safety analyses will be performed by treatment arms based on the safety analysis set. Safety and 
tolerability will be assessed, where applicable, by incidence, severity, and change from baseline values for 
all relevant parameters including AEs, laboratory values, vital signs and ECG findings. Descriptive 
statistics (e.g., n, mean, standard deviation, median, Q1, Q3, minimum, maximum for continuous 
variables; n [%] for categorical variables) will be used to analyze all safety data.
7.6.1
Extent of Exposure
The following measures of the extent of exposure will be summarized with descriptive statistics for each 
study drug separately. One cycle is defined as 21 days of treatment.
x
Duration of exposure: defined as the duration from the first dose date of study drug to the last 
dose date of the study drug, and calculated as (last date of exposure – date of first dose +1)

If patients discontinued treatment (with non-missing EOT date), using min (cutoff date,
death date, last dose date + 20) as the “last date of exposure” for tislelizumab, cisplatin and 
carboplatin; min (cutoff date, death date, last dose date + 18) as the “last date of exposure” 
for etoposide

otherwise, if patient has treatment ongoing, using cutoff date as the “last date of exposure” 
x
Number of treatment cycles received: defined as the total number of treatment cycles in which 
at least one dose of the study drug is administered.
x
Total dose received per patient: defined as the cumulative dose received of the study drug 
during the treatment period of the study, and calculated as sum (all actual dose per 
administration at all visits prior to or on the cutoff date)
x
Actual dose intensity (ADI): defined as the total dose received by a patient divided by the 
duration of exposure, and calculated as

For tislelizumab, ADI (mg/cycle) = 21*total cumulative dose (mg) / (last dose date prior to 
cut off date+ 21 - first dose date)

For chemotherapy, derivations are shown in Table 2.


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x
Relative dose intensity (RDI): defined as the ratio of the actual dose intensity and the planned 
dose intensity. Planned dose intensity is defined as the planned dose on study day 1 by a 
patient divided by the duration of exposure. RDI is calculated as 

For tislelizumab, RDI (%) = ADI/200 *100%; Planned dose intensity (mg/cycle) = 
200mg/cycle

For chemotherapy, derivations are shown in Table 2.
Table 2. ADI, Planned dose and RDI for Chemotherapy
 
                                          ADI(mg/m2/cycle for Cisplatin and 
Etposide; AUC/cycle for Carboplatin) 
Planned dose 
per cycle  
RDI 
Cisplatin 
∑
ܽܿݐݑ݈ܽ ݀݋ݏ݁
ܤܵܣ
× 21
#௢௙ ௖௬௖௟௘௦
ଵ
݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 21 −݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁ 
 
75 mg/m2 
 
ܣܦܫ
75  
 
Carboplatin 
∑
ܽܿݐݑ݈ܽ ݀݋ݏ݁
(ܩܨܴ+ 25) × 21
#௢௙ ௖௬௖௟௘௦
ଵ
݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 21 −݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁ 
   
AUC 5 
 
ܣܦܫ
5  
Etoposide 
∑
ܽܿݐݑ݈ܽ ݀݋ݏ݁
ܤܵܣ
#௢௙ ௖௬௖௟௘௦
ଵ
max( ݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 19 −݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁
21
,
݊ݑܾ݉݁ݎ ݋݂ ܿݕ݈ܿ݁ݏ ݅݊ ݈ܽݏݐ ݀݋ݏ݅݊݃ ܥܴܨ ݌ܽ݃݁)
       
100 *3 mg/m2 
ܣܦܫ
300  
 
Patient data listings will be provided for all dosing records.
7.6.2
Adverse Events 
AEs will be graded by the investigators using CTCAE version 5.0. The AE verbatim descriptions 
(investigator reported terms from the eCRF) will be classified into standardized medical terminology 
using MedDRA. Adverse events will be coded to the MedDRA (version for the study at the time of 
database lock) lowest level term closest to the verbatim term, along with the linked MedDRA preferred 
term (PT) and primary system organ class (SOC).
A treatment-emergent adverse event (TEAE) is defined as an AE that had onset or increase in severity 
level date on or after the date of the first dose of study drug through 30 days following study drug 
discontinuation or initiation of new anticancer therapy, whichever is earlier. Summary tables will only 
include TEAEs. All AEs, treatment-emergent or otherwise, will be presented in patient data listings.
COVID-19 related adverse events will be summarized separately.  
Treatment-related AEs include those events considered by the investigator to be "related" to study drug or 
with a missing assessment of the causal relationship.
For AE grading, if the grade is missing for one of the treatment-emergent occurrences of an adverse 
event, the maximal grade on the remaining occurrences with the same preferred term of the same patient 
will be used. If the patient has no other TEAE with the same preferred term, then impute as the maximum 
grade on all TEAE with the same preferred term; If the grade is missing for all the occurrences, do not 
impute, a “missing” category will be added in the summary table.
For incidences, a patient will be counted only once by the highest severity grade within an SOC and PT, 
even if the patient experienced more than 1 TEAE within a specific SOC and PT.


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Incidences of TEAEs by induction and maintenance phase will also be provided, and definitions of the 
phases are as below:
x
Induction phase: defined as time from first dose date to 1 day before the first dose in maintenance 
phase
x
Maintenance phase: defined as time from the first monotherapy dose date (all chemotherapies are 
completed) to end of TEAE reporting period
Treatment-emergent AE
An AE overview table, including the number and percentage of patients with 
x
TEAEs
x
TEAEs with Grade 3 or above
x
treatment-emergent serious adverse events (SAEs) 
x
treatment-related TEAEs
x
TEAEs leading to treatment discontinuation
x
TEAEs leading to dose modification
x
infusion-related reactions
x
TEAEs leading to death
The incidence of following TEAEs will be reported as the number (percentage) of patients by SOC and 
PTs:
x
treatment-related TEAEs 
x
TEAEs with grade 3 or above 
x
serious TEAEs
x
TEAEs leading to treatment discontinuation 
x
TEAEs leading to treatment modification
x
TEAEs leading to death 
Immune-mediated AE
Immune-mediated AEs will be identified from all AEs that had an onset date or a worsening in severity 
from baseline (pretreatment) on or after the first dose of study drug (tislelizumab/placebo) and up to 90 
days from the last dose of study drug (tislelizumab/placebo), regardless of whether the patient starts a new 
anticancer therapy. The identification of immune-mediated adverse events is described in immune-
mediated adverse event charter. Immune-mediated adverse events are of special interest and summarized 
by category.
Summaries of the following incidence of immune-mediated adverse events will be provided:
x
Immune-mediated adverse events by category and maximum severity 
x
Immune-mediated adverse events with NCI-CTCAE grade ≥3 by category
x
Immune-mediated adverse events leading to treatment discontinuation by category
x
Immune-mediated adverse events leading to death by category


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x
Immune-mediated adverse events leading to dose modification by category
x
Immune-mediated adverse events treated with systematic corticosteroid by category
x
Time to onset of Immune-mediated adverse events by category
x
Time to resolution of Immune-mediated adverse events by category
x
Duration of resolved Immune-mediated adverse events by category
Infusion-related reaction
For infusion related reaction (IRR), a summary of incidence by SOC, PT and maximum severity will be 
provided,. Summaries of IRRs, IRRs with NCI-CTCAE grade ≥3 and IRRs leading to treatment 
discontinuation will also be provided.
Death
All deaths and causes of death will be summarized by treatment arms, including those occurred during the 
study treatment period and those reported during the survival follow-up period after treatment 
completion/discontinuation.
7.6.3
Laboratory Values
Laboratory safety tests will be evaluated for selected parameters described in Error! Reference source 
not found.3.
Descriptive summary statistics (n, mean, standard deviation, median, minimum, maximum for continuous 
variables; n [%] for categorical variables) for laboratory parameters and their changes from baseline will 
be summarized by visit. Laboratory values will be summarized by visit and by worst postbaseline visit.
The summary tables will report lab assessments up to 30 days after the last dose date.
Laboratory parameters (Table 3) that are graded in NCI CTCAE Version 5.0 will be summarized by shifts 
from baseline CTCAE grades to maximum post-baseline grades. In the summary of laboratory parameters 
by CTCAE grade, parameters with CTCAE grading in both high and low directions will be summarized 
separately.
Table 3:
Serum Chemistry and Hematology Laboratory Tests
Serum Chemistry
Hematology
Thyroid Function
Alanine aminotransferase (ALT)
Hemoglobin
Free Triiodothyronine (FT3)
Aspartate aminotransferase (AST)
Platelet counts
Free Thyroxine (FT4)
Creatinine
White blood cell (WBC) 
count
Thyroid Stimulating Hormone 
(TSH)
Potassium
Neutrophil (Absolute)
Sodium
Creatine kinase (CK)
Creatine kinase-cardiac muscle isoenzyme
(CK-MB)
Total Bilirubin
LDH


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Serum Chemistry
Hematology
Thyroid Function
Calcium
7.6.4
Vital Signs
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse rate,
temperature, weight) and changes from baseline will be presented by visit.
7.6.5
Electrocardiograms (ECG)
The number and percentage of patients satisfying the following QTcF conditions at any time post-baseline 
will be summarized:
x
>450, > 480, or > 500 msec 
x
≤30 msec increase from baseline, > 30 and ≤60 msec increase from baseline, or > 60 msec 
increase from baseline
7.6.6
Eastern Cooperative Oncology Group (ECOG) Performance Status
A shift table from baseline to worst post-baseline in ECOG performance status will be summarized. 
ECOG status will be summarized by visit and treatment arm.
7.7 Pharmacokinetic Analyses
Tislelizumab post-dose and Ctrough (pre-dose) will be tabulated and summarized for each cycle at which 
these concentrations are collected. Descriptive statistics will include means, medians, ranges, standard 
deviations, coefficient of variation (CV%), geometric mean and geometric CV%, as appropriate.
Additional PK analyses, including population PK analyses and exposure-response (efficacy, safety 
endpoints) analyses may be conducted as appropriate and the results from these analyses will be reported 
separately from the CSR.
7.8 Immunogenicity Analyses
Human anti-drug antibodies (ADA) to tislelizumab will be assessed during the study as defined in the 
protocol.
ADA attributes:
x
Treatment-boosted ADA is defined as ADA positive at baseline that was boosted to a 4-fold or 
higher level following drug administration. 
x
Treatment-induced ADA is defined as ADA negative at baseline and ADA positive post-baseline. 
x
Persistent ADA response is defined as Treatment-induced ADA detected at 2 or more time points 
during treatment or follow-up, where the first and last ADA positive samples are separated by 16 
weeks or longer; or detected in the last time point.
x
Transient ADA response is defined as Treatment-induced ADA detected only at 1 time point during 
treatment or follow-up, excluding last time point; or detected at 2 or more timepoints during 
treatment or follow-up, where the first and last positive samples (irrespective of any negative 
samples in between) are separated by less than 16 weeks and the last time point is negative. Transient 
ADA is a treatment-induced response that is not considered persistent.
x
Neutralizing ADA is defined as ADA that inhibits or reduces the pharmacological activity.


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ADA response endpoints:
x
ADA incidence is defined as sum of treatment-emergent ADA, which include both treatment-
induced and treatment-boosted ADA-positive patients, as a proportion of the ADA evaluable 
population.
x
ADA prevalence is defined as proportion of all patients that are ADA positive, including pre-
existing ADA, at any time point.
The immunogenicity results will be summarized using descriptive statistics by the number and percentage 
of patients who develop detectable ADA. The incidence of positive ADA and neutralizing ADA will be 
reported for evaluable patients.  The effect of immunogenicity on PK, efficacy, and safety may be evaluated 
if data allow, and reported separately from the CSR.
8
INTERIM ANALYSES
There will be one interim efficacy analysis of OS performed in the ITT Analysis Set. The interim efficacy 
analysis of OS will be performed with approximately 282 OS events observed in the ITT Analysis Set. 
The analysis timing is projected at approximately 36 months after the first patient randomization. The 
final OS analysis will be conducted with approximately 353 OS events projected to occur roughly 
51 months after the first patient randomization. 
The interim boundary for OS is based on the Lan-DeMets approximation to O’Brien-Fleming boundary. 
The interim and final analysis timing, and stopping boundaries are summarized in Table . The stopping 
boundaries in Table may be updated based on the actual OS events observed in the ITT Analysis Set at 
the time of interim analysis.
Table 4. Analysis Timing and Stopping Boundaries for OS in the ITT Analysis Set
Type of Analysis
Time 
(Months)
# Events
One-Sided Testing Boundary
p-Value Boundary
Approx. HR 
Threshold
Interim Analysis
36
282
0.0122
0.765
Final analysis
51
353
0.0214
0.806
Abbreviations: HR, hazard ratio; ITT, Intent-to-Treat; OS, overall survival
An interim analysis for OS will be performed by an independent statistician external to the Sponsor. The 
independent statistician will work with the blinded study statistician to provide statistical outputs to the IDMC 
as described in the IDMC charter and perform any ad-hoc analyses requested by the IDMC.
9
CHANGES IN THE PLANNED ANALYSIS
If the SAP needs to be revised, the sponsor will determine how the revision impacts the study and how the 
revision should be implemented.  The details of the revision will be documented and described in the 
clinical study report.


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10 REFERENCES
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 1982;38:29-
41.
Greenwood M. The Natural Duration of Cancer. Reports on Public health and medical subjects. 
1926;33:1-26.
ICH.Addendum on Estimands and Sensitivity Analyses in Clinical Trials to the Guideline on Statistical 
Principles for Clinical Trials: E9(R1). 2019.
Mantel N, Haenszel W. Statistical Aspects of Analysis of Data from Retrospective Studies of Disease. 
Journal of the National Cancer Institute. 1959;22:719–748.
Sato T. On the Variance Estimator of the Mantel-Haenszel Risk Difference. Biometrics. 1989; 45:1323–
1324.


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APPENDIX 1. IMPUTATION OF MISSING OR PARTIALLY MISSING DATES
In general, missing or partial dates will not be imputed at the data level. The following rules will apply for 
the specific analysis and summary purposes mentioned below only.
1. Prior/Concomitant Medications
When the start date or end date of a medication/therapy/procedure is partially missing, the date will be 
imputed to determine whether the medication/therapy/procedure is prior or concomitant. The following 
rules will be applied to impute partial dates for medications.  
If start date of a medication/therapy/procedure is partially missing, impute as follows:
x
If both month and day are missing, then set to January 01
x
If only day is missing, then set to the first of the month
x
If the imputed start date > death date, then set to death date
If end date of a medication/therapy/procedure is partially missing, impute as follows:
x
If both month and day are missing, then set to December 31
x
If only day is missing, then set to last day of the month
x
If the imputed end date > death date, then set to death date
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the start date 
or end date is completely missing, do not impute.
2. Adverse Events
If year of the start date is missing or start date is completely missing, do not impute. Impute AE end date 
first if both AE start date and end date are partially missing.
If end date of an adverse event is partially missing, impute as follows:
x
If both month and day are missing, then set to December 31
x
If only day is missing, then set to last day of the month
x
If the imputed end date > death date, then set to death date
If year of the end date is missing or end date is completely missing, only if subject is died and AE is 
ongoing, then impute end date to death date, otherwise do not impute. 
If start date of an adverse event is partially missing, impute as follows:
x
If both month and day are missing and year = year of treatment start date, then set to treatment 
start date
x
If both month and day are missing and year ≠ year of treatment start date, then set to January 
01
x
If day is missing and month and year = month and year of treatment start date, the set to 
treatment start date
x
If day is missing and month and year ≠ month and year of treatment start date, the set to first 
of the month
x
If the imputed AE start date is after AE end date (maybe imputed), then update AE start date 
with AE end date as final imputed AE start date. If the imputed end date > death date, then set 
to death date.


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3. Subsequent Anti-cancer Therapies/Surgery/Procedure
When the start date of subsequent anti-cancer therapy is partially missing, the following rules will be 
applied to impute partial dates.
If start date of is partially missing, impute as follows:
x
If both month and day are missing, then set to December 31
x
If only day is missing, then set to last day of the month
x
If the imputed start date > min (death date, study discontinuation date, data cutoff date, start 
date of the next subsequent therapy), then set to min (death date, study discontinuation date, 
data cutoff date, start date of the next subsequent therapy)
x
The imputed start date must be before or equal to the end date
If stop date of is partially missing, impute as follows:
x
If both month and day are missing, then set to December 31
x
If only day is missing, then set to last day of the month
x
If the imputed stop date > min (death date, study discontinuation date, data cutoff date, start 
date of the next subsequent therapy), then set to min (death date, study discontinuation date, 
data cutoff date, start date of the next subsequent therapy)
x
The imputed stop date must be after or equal to the end date
If year of the start date/stop date is missing, do not impute.
4. Prior anti-cancer therapy (drug, surgery/procedure, radiotherapy)
Impute end date first. If end date is partially missing, impute as follows:
x
If both month and day are missing, then set to December 31
x
If only day is missing, then set to the last day of the month
x
For start date of prior systemic therapy for cancer, if imputed end date > randomization date –
6 months, then set to randomization date – 6 months
x
For start date of prior radiotherapy/surgery, if imputed end date > randomization date, then set 
to randomization date - 1
If start date is partially missing, impute as follows:
x
If both month and day are missing, then set to January 01
x
If only day is missing, then set to the first of the month
x
If the imputed start date > end date, then set to the end date
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the start date 
or end date is completely missing, do not impute. 
5. Diagnosis
If a diagnosis date is partially missing, impute as follows:
x
If both month and day are missing, then set to January 01
x
If only day is missing, then set to the first of the month


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If a diagnosis date is completely missing, do not impute.


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APPENDIX 2 HEALTH RELATED QUALITY OF LIFE
EORTC QLQ-C30 measures HRQoL of general cancer and includes two items that measure Global health 
status and quality of life (Global health status/QoL). The instrument is also consisted of two Functional 
Scales and Symptom Scales/ Items. Functional scales are Physical (2 items), Role (2 items), Emotional (4 
items), Cognitive (2 items) and Social (2 items) functioning. Symptom scales are Fatigue (3 items), 
Nausea (2 items), Pain (2 items) symptoms. The single-items measuring symptoms include Dyspnoea, 
Insomnia, Appetite loss, Constipation, Diarrhoea and Financial Difficulties.
QLQ-LC13, which is the lung cancer module of the QLQ-C30, measure symptoms specific to lung cancer 
and its treatment. It is comprised of 13 items including Dyspnoea scale (2 items) and single items 
measuring Coughing, Haemoptysis, Sore month, Dysphagia, Perpherial neuropathy, Alopecia and Pain in 
chest, Pain arm/shoulder and Pain other parts. 
EQ5D-5L measures general HRQoL consists for 5 scales (descriptive dimension) and a Visual Analogue 
Scale (VAS). The descriptive Dimensions scale includes Mobility, Self-Care, Usual Activities, 
Pain/Discomfort and Anxiety/Depression.
QLQ-C30 and QLQ-LC13 scale scores as well as EQ-5D-5L will be calculated as described below.
Scoring Process
QLQ-C30 and QLQ-LC13: The principle for scoring applies to all scales/scores: Raw scores are 
calculated as the average of the items that contribute to the scale. 
A linear transformation to standardize the raw scores is utilized, so that the scores are ranged from 0 to 
100.  Increases in scores for functional domains (e.g., physical, role, social, emotional, etc.) are 
improvements while increases in scores for symptoms (e.g., fatigue, vomiting and nausea, diarrhea, pain, 
etc.) are deteriorations.
Missing Items
If at least half of the items for a scale are answered, then all the completed items are used to calculate 
the score.  Otherwise, the scale score is set to missing.
In practical terms, if items I1, I2, ... In are included in a scale, the procedure is as follows:
Raw Score
For all scores, the raw score (RS), is the mean of the component items
RS = (I1+I2+…+In)/n
Derived Scale
The derived scales are obtained from the raw scores as defined in the EORTC manual. The 
derived scales have a more intuitive interpretation: larger function scale or global health status / 
QoL are improvements while larger symptom scales (e.g., pain, nausea, etc.) are deteriorations. 
The derivation formulas are as follows.


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The Index scores
To calculate QlQ-C30 index-score, individual functioning scale are subtracted by 100 to convert 
them into having the same meaning as symptom/problem scales. These 6 subtracted scores are 
subsequently summed with the 9 symptom/problem scales, and then divided by 15 (the total 
number of QLQ-C30 scales).  A higher C30 index-score reflects a worse overall HRQOL. This is 
the mathematical formula:
QlQ- C30 index score =  ∑[(100 -  Physical functioning score), (100 -  Role functioning score ), 
(100 -  Emotional functioning score),  (100 -  Cognitive functioning score), (100 -
Social functioning score) , (100 -  global QOL score),  Fatigue score, 
Nausea/vomiting score , Pain score,  Dyspnoea score,  Insomnia score,  Appetite 
loss score,  Constipation score, Diarrhea score, Financial Difficulty score] ÷ 15
LC13 index-score is defined as the sum of all 10 QLQ-LC13 symptom/problem scales divided by 
10 (the total number of QLQ-LC13 scales). A higher LC13 index-score reflects a worse overall 
HRQOL. This is the mathematical formula:
LC13 index score = Σ (scores of Dyspnoea, Coughing, Haemoptysis, Sore mouth, Dysphagia, 
Peripheral neuropathy, Alopecia, Pain in chest, Pain in arm or shoulder, Pain in 
other parts) ÷ 10
Table 5 Scoring of QLQ-C30
Scale
Number 
of items
Item 
range
Item 
Numbers
Global health status/ QoL
Global health status/QOL
QL2
2
6
29,30
Functional Scales
Physical functioning 
PF2
5
3
1, 2, 3, 4, 5 
Role functioning 
RF2
2
3
6, 7 
Emotional functioning 
EF
4
3
21, 22, 23, 24 
Cognitive functioning 
CF
2
3
20, 25 
Social functioning 
SF
2
3
26, 27 


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Symptom Scales/ items
Fatigue
FA
3
3
10, 12, 18
Nausea and vomiting
NV
2
3
14, 15
Pain
PA
2
3
9, 19
Dyspnoea
DY
1
3
8
Insomnia
SL
1
3
11
Appetite loss
AP
1
3
13
Constipation
CO
1
3
16
Diarrhoea
DI
1
3
17
Financial Difficulties
FI
1
3
28
Table 6 Scoring of QLQ-LC13
Scale
Number 
of items
Item 
range
Item 
Numbers
Symptom scales/items
Dyspnoea
LCDY
3
3
3,4,5
Coughing 
LCCO
1
3
1
Haemoptysis
LCHA
1
3
2
Sore mouth
LCSM
1
3
6
Dysphagia
LCDS
1
3
7
Peripheral neuropathy
LCPN
1
3
8
Alopecia
LCHR
1
3
9
Pain in chest
LCPC
1
3
10
Pain in arm or shoulder
LCPA
1
3
11
Pain in other parts
LCPO
1
3
12


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