Clinical trial NCT03417895
Conditions: Small-cell Lung Cancer
Sponsor: Jiangsu HengRui Medicine Co., Ltd.
Start date: 2018-04-20; Completion date: 2021-08-04
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, open-label, phase II study of intravenous (IV) SHR-1210 at 200mg,q2w in combination with Apatinib at one dose (375mg). Comparison of 3 different dose schedules in subjects with extensive-stage disease small cell lung cancer. SHR-1210 is a humanized monoclonal antibody against Programmed death 1(PD-1). Apatinib is a new kind of selective Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) tyrosine kinase inhibitor (TKI).

The study is composed of two parts. Part 1 of the study will determine the safety and tolerability of SHR-1210 in combination with Apatinib in first 6 subjects of each arm. The second phase of treatment was carried out by selecting one group of administration mode and the tolerated dose of Apatinib. Part 2 of the study will determine the safety and efficacy of SHR-1210 in combination with Apatinib in 39 subjects.

Detailed description:

Arms: arm 1: SHR-1210 200mg, IV, Q2W and Apatinib 375mg, PO, QD arm 2: SHR-1210 200mg, IV, Q2W and Apatinib 375mg, PO, QD (5 Days on, 2 Days off) arm 3: SHR-1210 200mg, IV, Q2W and Apatinib 375mg, PO, QD (7 Days on, 7 Days off)
Interventions: intervention 1: SHR-1210 intervention 2: Apatinib
Intervention descriptions: intervention 1: A humanized anti-PD-1 monoclonal antibody intervention 2: A tyrosine kinase inhibitor selectively targeting VEGFR-2

Protocol documents:
Prot_000.pdf: 
Title: A phase II clinical study of SHR-1210 combined with apatinib mesylate for the 
treatment of extensive-stage small cell lung cancer failing first-line standard therapy 
(PASSION) 
NCT number: NCT03417895 
Date: 12 Jun., 2018 


Immune Checkpoint Inhibitor 
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Version 2.0, Version Date: 12 Jun., 2018 
 
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A PHASE II CLINICAL STUDY OF SHR-1210 COMBINED WITH 
APATINIB MESYLATE FOR THE TREATMENT OF EXTENSIVE-STAGE 
SMALL CELL LUNG CANCER FAILING FIRST-LINE STANDARD 
THERAPY 
(PASSION) 
 
Protocol No.:  
SHR-1210-II-206 
Study Phase:  
II 
Investigational Drug No.:  
SHR-1210 
Medical Director:  
 
Leading Center 1 of Clinical Study:  Cancer Hospital of Chinese Academy of Medical Science 
Principal Investigator 1:  
Prof. Jie Wang 
Leading Center 2 of Clinical Study:  Zhejiang Cancer Hospital  
Principal Investigator 2:  
Prof. Yun Fan 
Version No.:  
2.0 
Version Date:  
12 Jun. 2018 
 
 
Sponsor:  
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
No. 7 Kunlunshan Road, Lianyungang Economic and 
Technological Development Zone, Jiangsu 222047, China 
Confidentiality Statement 
The information contained in this protocol is confidential and is intended for use by clinical 
investigators only. Any disclosure is not permitted unless requested by current laws or regulations. 
The copyright is owned by Jiangsu Hengrui Pharmaceuticals Co., Ltd. or its subsidiaries. Any 
copy or distribution of information herein to any individuals not participating in this clinical study 
is not allowed, unless a confidentiality agreement has been signed with Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. or its subsidiaries. 
Translated from Original Document 


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VERSION HISTORY/REVISION HISTORY 
Document 
Version Date 
Amendment Rationale and Summary of Changes 
Version 1.0 
14 Nov., 2017 
Not applicable 
Version 2.0 
12 Jun., 2018 
 


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Sponsor's Signature Page 
I have read and confirmed this clinical study protocol (protocol number: SHR-1210-II-206, 
version number: 2.0, version date: 12 Jun., 2018). I agree to fulfill my duties in accordance with 
Chinese laws, the Declaration of Helsinki, the Chinese GCP, and this study protocol. 
 
 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
 
 
 
 
 
Study Director (print) 
Study Director (signature) 
Signature Date 
(DD/MM/YYYY) 


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Principal Investigator's Signature Page (Leading Center) 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. I have received the Investigator's 
Brochure for the study drugs; I have read the materials of preclinical studies of the study drugs and 
the protocol for this clinical study. I agree to fulfill my duties in accordance with Chinese laws, the 
Declaration of Helsinki, the Chinese GCP, and this study protocol. I agree that any modifications 
to the protocol must be reviewed and approved by the sponsor, and can only be implemented upon 
approval by the ethics committee, unless measures must be taken to protect the safety, rights, and 
interests of the subjects. It is my responsibility to make clinically relevant medical decisions to 
ensure appropriate and timely treatments in subjects experiencing adverse events during the study 
period, and to document and report such adverse events in accordance with relevant state 
regulations. I will document all data in a truthful, accurate, complete and timely manner. I agree to 
be monitored and audited by the clinical research associate or auditor assigned by the sponsor, and 
to be inspected by the drug regulatory authorities, to ensure the quality of the clinical study. I will 
keep the personal information of and matters related to the subjects confidential. I agree to disclose 
my full name and occupation to the sponsor, and the expenses related to the clinical study upon 
request. I agree not to engage in any commercial and economic activities related to this study. I 
agree for the study results to be used for drug registration and publication. I will provide a resume 
before the start of the study, submit it to the ethics committee, and to the drug regulatory authority 
for filing purposes. 
 
 
Study Center: _____________________________________________ 
 
 
 
 
 
 
Principal Investigator (print) 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 


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Principal Investigator's Signature Page (Participating Center) 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. I have received the Investigator's 
Brochure for the study drugs; I have read the materials of preclinical studies of the study drugs and 
the protocol for this clinical study. I agree to fulfill my duties in accordance with Chinese laws, the 
Declaration of Helsinki, the Chinese GCP, and this study protocol. I agree that any modifications 
to the protocol must be reviewed and approved by the sponsor, and can only be implemented upon 
approval by the ethics committee, unless measures must be taken to protect the safety, rights, and 
interests of the subjects. It is my responsibility to make clinically relevant medical decisions to 
ensure appropriate and timely treatments in subjects experiencing adverse events during the study 
period, and to document and report such adverse events in accordance with relevant state 
regulations. I will document all data in a truthful, accurate, complete and timely manner. I agree to 
be monitored and audited by the clinical research associate or auditor assigned by the sponsor, and 
to be inspected by the drug regulatory authorities, to ensure the quality of the clinical study. I will 
keep the personal information of and matters related to the subjects confidential. I agree to disclose 
my full name and occupation to the sponsor, and the expenses related to the clinical study upon 
request. I agree not to engage in any commercial and economic activities related to this study. I 
agree for the study results to be used for drug registration and publication. I will provide a resume 
before the start of the study, submit it to the ethics committee, and to the drug regulatory authority 
for filing purposes. 
 
Study Center: __________________________________________ 
 
 
 
  
 
 
Principal Investigator (print) 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................. 6 
LIST OF TABLES ...................................................................................................................... 11 
LIST OF FIGURES .................................................................................................................... 11 
PROTOCOL SYNOPSIS ........................................................................................................... 12 
SCHEDULE OF ACTIVITIES ................................................................................................. 19 
ABBREVIATIONS ..................................................................................................................... 25 
1 
KEY FUNCTIONAL ROLES ........................................................................................... 28 
2 
BACKGROUND AND SCIENTIFIC RATIONALE ...................................................... 28 
2.1 Disease Background ..................................................................................................... 28 
2.1.1 Non-small cell lung cancer ................................................................................ 29 
2.1.2 Small cell lung cancer ....................................................................................... 31 
2.2 Immune Checkpoint Therapy ....................................................................................... 32 
2.2.1 PD-1/PD-L1 and tumors ................................................................................... 32 
2.2.2 Anti-PD-1/PD-L1 agents ................................................................................... 33 
2.3 Scientific Rationale ...................................................................................................... 35 
2.3.1 Basis of SHR-1210 combined with apatinib in the second-line  
treatment of SCLC ............................................................................................ 35 
2.3.2 Basis for SHR-1210 administration at the fixed dose of 200 mg...................... 37 
2.3.3 Basis for continued medication beyond progression ........................................ 37 
2.3.4 Basis for selecting PD-L1 as the exploratory biomarker .................................. 37 
2.4 Preclinical Studies ........................................................................................................ 38 
2.5 Clinical Studies ............................................................................................................. 38 
2.6 Potential Risks and Benefits ......................................................................................... 38 
3 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 38 
3.1 Study Objectives ........................................................................................................... 38 
3.1.1 Primary objective .............................................................................................. 38 
3.1.2 Secondary objective .......................................................................................... 38 
3.1.3 Exploratory objective ........................................................................................ 38 
3.2 Study Endpoints ............................................................................................................ 39 
3.2.1 Primary endpoints ............................................................................................. 39 
3.2.2 Secondary endpoints ......................................................................................... 39 


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3.2.3 Exploratory endpoint ......................................................................................... 39 
4 
STUDY DESIGN ................................................................................................................. 39 
5 
STUDY POPULATION ..................................................................................................... 42 
5.1 Inclusion Criteria .......................................................................................................... 42 
5.2 Exclusion Criteria ......................................................................................................... 43 
5.3 Randomization Standard .............................................................................................. 46 
5.4 Withdrawal from Study or Treatment Discontinuation ................................................ 46 
5.4.1 Study withdrawal criteria .................................................................................. 46 
5.4.2 Criteria for treatment discontinuation ............................................................... 46 
5.4.3 Procedures for withdrawal or discontinuation .................................................. 47 
5.5 Termination or Suspension of Study ............................................................................ 47 
6 
STUDY DRUGS .................................................................................................................. 48 
6.1 Treatment Regimen ...................................................................................................... 48 
6.1.1 Administration regimen .................................................................................... 48 
6.1.2 Continued medication beyond progression ....................................................... 49 
6.1.3 Continued treatment after study completion ..................................................... 49 
6.2 Study Drugs .................................................................................................................. 50 
6.2.1 Description ........................................................................................................ 50 
6.2.2 Packaging and labeling of study drugs .............................................................. 50 
6.3 Study Drug Preparation ................................................................................................ 50 
6.3.1 SHR-1210 .......................................................................................................... 50 
6.4 Dose Modifications and Delay ..................................................................................... 50 
6.4.1 General rules for dose modification .................................................................. 50 
6.4.2 Apatinib ............................................................................................................. 51 
6.4.3 SHR-1210 .......................................................................................................... 54 
6.5 Concomitant Medications ............................................................................................. 57 
6.5.1 Permitted concomitant medications and/or treatment ....................................... 57 
6.5.2 Prohibited concomitant medications and/or treatment ...................................... 58 
6.5.3 Drugs that must be used with caution ............................................................... 59 
6.6 Medication During Pregnancy, Childbearing Age, and Lactation ............................... 60 
6.6.1 Pregnancy .......................................................................................................... 61 
6.6.2 Childbearing potential ....................................................................................... 61 


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6.6.3 Lactation ............................................................................................................ 62 
6.7 Subject Compliance ...................................................................................................... 62 
6.8 Return and Disposal of Drugs ...................................................................................... 62 
6.9 Handling of Complaints ............................................................................................... 63 
7 
STUDY PROCEDURES .................................................................................................... 63 
7.1 Procedures of Subject Enrollment and Randomization ................................................ 63 
7.1.1 Subject enrollment ............................................................................................ 63 
7.1.2 Handling procedures for mistakenly enrolled subjects ..................................... 64 
7.1.3 Randomization and blinding ............................................................................. 64 
7.2 Main Study Procedures ................................................................................................. 64 
7.2.1 Screening period (visit 1) .................................................................................. 64 
7.2.2 Treatment period (visits 2 to N) ........................................................................ 66 
7.2.3 End of treatment ................................................................................................ 68 
7.2.4 Safety follow-up ................................................................................................ 69 
7.2.5 Survival follow-up ............................................................................................ 70 
7.3 Procedures of Continued Medication After Progressive Disease ................................. 70 
8 
STUDY ASSESSMENT ..................................................................................................... 70 
8.1 Efficacy Evaluation ...................................................................................................... 70 
8.1.1 Sites of radiographic scans ................................................................................ 70 
8.1.2 Evaluation time points ....................................................................................... 71 
8.2 Safety Evaluation .......................................................................................................... 72 
8.2.1 Routine laboratory safety evaluation ................................................................ 72 
8.2.2 Physical examination ........................................................................................ 72 
8.2.3 12-Lead ECG .................................................................................................... 72 
8.2.4 Vital signs .......................................................................................................... 73 
8.2.5 Weight and height ............................................................................................. 73 
8.2.6 Pregnancy test ................................................................................................... 74 
8.2.7 Other safety examinations ................................................................................. 74 
8.3 Pharmacokinetics .......................................................................................................... 74 
8.4 Pharmacodynamics ....................................................................................................... 74 
8.5 Immunogenicity ............................................................................................................ 74 
8.6 Biomarker Analysis ...................................................................................................... 75 


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8.7 Storage and Destruction of Biological Samples ........................................................... 75 
9 
SAFETY EVALUATION ................................................................................................... 76 
9.1 AE ................................................................................................................................. 76 
9.1.1 Definition of AE ................................................................................................ 76 
9.1.2 AE severity grading criteria .............................................................................. 76 
9.1.3 Causality assessment of AEs ............................................................................. 76 
9.2 Serious Adverse Event (SAE) ...................................................................................... 77 
9.2.1 Definition of SAE ............................................................................................. 77 
9.2.2 Hospitalization .................................................................................................. 77 
9.2.3 Progressive disease ............................................................................................ 78 
9.2.4 Potential drug-induced liver injury ................................................................... 78 
9.2.5 Other anti-tumor treatments .............................................................................. 79 
9.2.6 SAE reporting .................................................................................................... 79 
9.2.7 Follow-up of AEs/SAEs .................................................................................... 80 
9.3 Pregnancy ..................................................................................................................... 80 
9.4 Adverse Events of Special Interest ............................................................................... 81 
10 
DATA ANALYSIS/STATISTICAL METHODS ............................................................ 81 
10.1 Sample Size .................................................................................................................. 81 
10.2 Statistical Analysis Plan ............................................................................................... 82 
10.3 Statistical Hypotheses ................................................................................................... 82 
10.4 Analysis Sets ................................................................................................................ 82 
10.5 Statistical Methods ....................................................................................................... 83 
10.5.1 Basic methods ................................................................................................... 83 
10.5.2 Primary efficacy endpoint analysis ................................................................... 83 
10.5.3 Secondary efficacy endpoint analysis ............................................................... 83 
10.5.4 Safety analysis ................................................................................................... 84 
10.5.5 Exploratory analysis .......................................................................................... 84 
10.5.6 Subgroup analysis ............................................................................................. 84 
10.5.7 Multiple comparison/Multiplicity ..................................................................... 85 
11 
DATA MANAGEMENT .................................................................................................... 85 
11.1 Data Recording ............................................................................................................. 85 
11.1.1 Study medical recording ................................................................................... 85 


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11.1.2 eCRF entry ........................................................................................................ 85 
11.1.3 eCRF review ...................................................................................................... 85 
11.2 Data Monitoring ........................................................................................................... 86 
11.3 Data Management ......................................................................................................... 86 
11.3.1 EDC database establishment ............................................................................. 86 
11.3.2 Data entry and verification ................................................................................ 86 
11.3.3 Data review and database locking ..................................................................... 86 
11.3.4 Data archiving ................................................................................................... 87 
12 
SOURCE DATA AND DOCUMENTS ............................................................................. 87 
13 
QUALITY ASSURANCE AND QUALITY CONTROL ................................................ 87 
14 
REGULATIONS, ETHICS, ICF, AND SUBJECT PROTECTION ............................. 88 
14.1 Regulatory Considerations ........................................................................................... 88 
14.2 Ethical Standards .......................................................................................................... 89 
14.3 Independent Ethics Committee ..................................................................................... 89 
14.4 ICF ................................................................................................................................ 89 
14.4.1 ICFs and other written information for subjects ............................................... 89 
14.4.2 Informed consent process and recording ........................................................... 90 
14.5 Confidentiality of Subject Information ........................................................................ 90 
14.6 Sample Storage and Use ............................................................................................... 90 
15 
PUBLICATION OF STUDY RESULTS .......................................................................... 91 
16 
CLINICAL TRIAL PROGRESS ...................................................................................... 91 
17 
REFERENCES .................................................................................................................... 92 
Appendix 1 ECOG PS Scoring Criteria........................................................................................ 95 
Appendix 2 Calculation of Creatinine Clearance ......................................................................... 96 
Appendix 3 Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) ............ 97 
Appendix 4 List of Autoimmune Diseases That May Exist Before Enrollment ......................... 111 
Appendix 5 Prohibited Traditional Chinese Medicines During the Study Period ....................... 112 
Appendix 6 Guidelines on Dose Modifications and Handling of Toxicities of SHR-1210 ........ 113 


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LIST OF TABLES 
Table 1. Schedule of activities ...................................................................................................... 19 
Table 2. Individualized treatment of NSCLC ............................................................................... 30 
Table 3. PD-L1 expression in multiple types of tumors ............................................................... 34 
Table 4. Marketed anti-PD-1/PD-L1 monoclonal antibodies ....................................................... 34 
Table 5. Treatment regimen .......................................................................................................... 48 
Table 6. Description of study drugs .............................................................................................. 50 
Table 7. Requirements of dose modification of apatinib .............................................................. 51 
Table 8. Principles for SHR-1210 dose modification ................................................................... 55 
Table 9. Treatment recommendations for infusion reactions of SHR-1210 ................................. 56 
Table 10. CYP2C9 and CYP2C19 substrates that should be used with caution ........................... 59 
Table 11. Procedures of visits during the screening period .......................................................... 64 
Table 12. Procedures of visits during the treatment period........................................................... 66 
Table 13. Procedures of the end-of-treatment visit ....................................................................... 68 
Table 14. Procedures of the safety follow-ups .............................................................................. 69 
Table 15. Routine laboratory safety evaluation ............................................................................ 72 
 
LIST OF FIGURES 
Figure 1. PD-1's role in T cell activation, aging, and response..................................................... 33 
Figure 2. Design of the phase II study of SHR-1210 combined with apatinib ............................. 40 
Figure 3. Process of the study of SHR-1210 combined with apatinib .......................................... 41 
 
 


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PROTOCOL SYNOPSIS 
Study Title 
A phase II clinical study of SHR-1210 combined with apatinib mesylate for the treatment of 
extensive-stage small cell lung cancer failing first-line standard therapy (PASSION) 
Protocol No. 
SHR-1210-II-206 
Version No. 
2.0 
Sponsor 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Principal 
Investigators 
Prof. Jie Wang, Cancer Hospital of Chinese Academy of Medical Science 
Prof. Yun Fan, Zhejiang Cancer Hospital 
Participating 
Study Centers 
Approximately 20 centers 
Study 
Objectives 
Primary objective: 
• 
To evaluate the safety and efficacy of SHR-1210 combined with apatinib in the treatment of 
extensive-stage small cell lung cancer failing first-line standard therapy 
Secondary objective: 
• 
To evaluate the immunogenicity of SHR-1210 
Exploratory objective: 
• 
To evaluate the correlation between biomarkers (including but not limited to programmed 
death ligand 1 [PD-L1] and tumor mutation burden [TMB]) and efficacy 
Study endpoints Primary endpoints: 
• 
Incidence of AE evaluated as per CTCAE 4.03 
• 
Overall response rate (ORR) evaluated as per RECIST v1.1 
Secondary endpoints: 
• 
Incidence of AEs and serious adverse events (SAEs) assessed as per CTCAE 4.03, laboratory 
test values, ECG, vital signs, and other safety endpoints 
• 
Overall survival (OS), 6-month OS rate and progression free survival (PFS) evaluated as per 
RECIST v1.1, time to response (TTR), duration of response (DoR), disease control rate 
(DCR) 
• 
Immunogenicity evaluation: positive rate of anti-drug antibody (ADA) and neutralizing 
antibody (NAb) 
Exploratory endpoint: 
• 
Tumor biomarkers (including but not limited to expression levels of PD-L1 and TMB in 
tumor samples) 
Study 
Population 
Subjects who have previously received first-line platinum-based treatment for small cell lung 
cancer and have shown objective radiographic progression. Including patients who meet any of the 
following conditions: 
• 
Sensitive recurrence: progression in ≥ 90 days from the last chemotherapy 
• 
Drug-resistant recurrence: progression during chemotherapy or within 90 days from the last 
chemotherapy  


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Study Design 
This is a randomized, open-label, multi-center phase II clinical study. Eligible subjects after 
screening will be randomized into the following three groups in a 1:1:1 ratio, with 4 weeks as 1 
treatment cycle:  
A: SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, PO, QD 
B: SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, PO, QD (5 days on, 2 days off) 
C: SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, PO, QD (7 days on, 7 days off) 
The study consists of two stages. In Stage I, subjects will be randomized into 3 different dose 
groups, with 6 subjects in each group. It is planned that after the last subject in Stage I completes 
Cycle 1 treatment (28 days), the leading center's principal investigator and the sponsor will jointly 
perform a safety assessment of subjects enrolled in Stage I, decide the treatment group of Stage II, 
and choose one group of method of administration and a tolerated dose of apatinib for Stage II 
treatment. 
A total of 39 subjects will be enrolled in Stage II. The primary analysis will be performed when the 
last subject has been treated for 180 days. 
For any treatment group entering Stage II, if the safety is acceptable and the efficacy meets the 
corresponding statistical criteria, it indicates potential needs of further development. 
Study Drugs 
and Method of 
Administration 
A: SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, PO, QD 
B: SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, PO, QD (5 days on, 2 days off) 
C: SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, PO, QD (7 days on, 7 days off) 
Note: PO: per os; QD: quaque die; IV: intravenous infusion; Q2W: once every 2 weeks; 5 Days on, 
2 Days off: administration for 5 days and interrupt for 2 days; 7 Days on, 7 Days off: administration 
for 7 days and interrupt for 7 days 
Inclusion 
Criteria 
Patients must meet all of the following inclusion criteria to be eligible for this study. 
1. 
All patients should sign the informed consent form (ICF) before starting study-related 
operations 
2. 
Aged ≥ 18 and ≤ 70 years 
3. 
With histologically or cytologically confirmed SCLC 
4. 
Staged as ED-SCLC according to Veterans Administration Lung Study Group (VALG) 
staging 
5. 
Have previously received first-line platinum-based treatment for ED-SCLC and have shown 
objective imaging progression. Including: 
• 
Sensitive recurrence: progression in ≥ 90 days from the last chemotherapy 
• 
Drug-resistant recurrence: progression during chemotherapy or within 90 days from the 
last chemotherapy 
6. 
Able to provide tumor tissue samples for diagnosis, either archived samples within 12 months 
prior to the first dose of study drug or freshly obtained. The specimens shall meet the 
requirements of formalin-fixed and paraffin-embedded (FFPE) tumor tissue blocks allowing 
the cutting of 5-10 slices with a thickness of 4-6 μm for staining and testing. Cell smears from 
fine needle aspiration or centrifuged pleural fluid, bone lesions without soft tissue 
components or decalcified bone tumor specimens, and drill biopsy tissues are not acceptable, 
as they are insufficient for biomarker detection 
7. 
ECOG PS of 0-1 
8. 
Expected survival of ≥ 8 weeks 


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9. 
With at least one target lesion without previous radiotherapy (RECIST v1.1) shown by CT or 
MRI scan ≤ 28 days prior to the first dose of study drug 
10. Males and females of reproductive potential must take contraceptive measures from the first 
dose of study drug to within 24 weeks after the last dose of study drug (see 6.6.2 of the 
protocol for recommended contraceptive methods) 
11. Had no transfusion of blood or blood products within the last 14 days prior to the first dose, 
not corrected with G-CSF or other hematopoietic colony-stimulating factors. Before the first 
dose of study drug, laboratory test values must meet the following conditions: 
(1) 
Hematology: white blood cell count (WBC) ≥ 3.0 × 109/L; absolute neutrophil count 
(ANC) ≥ 1.5 × 109/L; platelet (PLT) ≥ 100 × 109/L; hemoglobin content (HGB) ≥ 9.0 g/dL 
(2) 
Liver function: for patients without liver metastasis, aspartate transferase (AST) ≤ 2.5 × 
ULN, and alanine aminotransferase (ALT) ≤ 2.5 × ULN; for patients with liver metastasis, 
ALT and AST < 5 × ULN, serum total bilirubin (TBIL) ≤ 1.5 × ULN (except for Gilbert 
syndrome, total bilirubin < 3.0 mg/dL), and albumin (ULB) ≥ 3 g/dL 
(3) 
Kidney function: serum creatinine ≤ 1.5 × ULN or creatinine clearance rate (CrCl) ≥ 
40 mL/minute (Cockcroft/Gault formula, see Appendix 2); urine protein (UPRO) negative  
(4) 
Coagulation function: international normalized ratio (INR) ≤ 1.5, activated partial 
thromboplastin time (APTT) ≤ 1.5 × ULN 
(5) 
Other: lipase ≤ 1.5 × ULN. If lipase is > 1.5 × ULN and no clinical or imaging evidence 
confirms pancreatitis, the patient can be enrolled; amylase ≤ 1.5 × ULN. If amylase is > 
1.5 × ULN and no clinical or imaging evidence confirms pancreatitis, the patient can be 
enrolled. Alkaline phosphatase (ALP) ≤ 2.5 × ULN; for patients with bone metastasis, ALP 
≤ 5 × ULN. 
Exclusion 
Criteria 
Patients meeting any one of the followings are not eligible to participate in this study:  
1. 
With histologically or cytologically confirmed mixed SCLC and NSCLC. 
2. 
Patients who have previously received anti-tumor viral treatment. Patients who have 
previously received T cell costimulation or immune checkpoint therapy, including but not 
limited to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, PD-1 inhibitors, 
PD-L1/2 inhibitors or other drugs targeting T cells. 
3. 
Patients who have previously received anti-vascular endothelial growth factor (VEGF) or 
vascular endothelial growth factor receptor (VEGFR) therapy. 
4. 
Patients with clinically symptomatic brain metastasis or meningeal metastasis. Treated 
patients with brain metastasis should meet the following conditions to be enrolled: 
• 
No MRI-proven progression ≥ 4 weeks after the end of treatment 
• 
Completed treatment within ≥ 28 days prior to the first dose of study drug 
• 
No need to receive systemic corticosteroid treatment (> 10 mg/day prednisone or an 
equivalent dose) in ≤ 14 days prior to the first dose of study drug 
5. 
Radiotherapy of the chest and whole brain should be completed less than 4 weeks prior to the 
first dose of study drug (patients whose palliative radiotherapy for bone lesions was 
completed prior to the first dose of study drug are allowed to be enrolled) 
6. 
Clinically symptomatic effusion in the third space, such as pericardial effusion, pleural 
effusion, and ascites effusion that cannot be controlled by drainage or other treatments 


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7. 
Active, known or suspected autoimmune diseases (see Appendix 4). Patients with vitiligo, 
type I diabetes, or residual hypothyroidism caused by autoimmune thyroiditis that only 
requires hormone replacement therapy or is unlikely to recur in the absence of external 
stimulation can be enrolled 
8. 
Treated with systemic corticosteroids (> 10 mg prednisone or equivalent) or other 
immunosuppressants within ≤ 14 days prior to the first dose of study drug. In the absence of 
active autoimmune diseases, inhaled or topical use of steroids and adrenal replacement 
steroids is permitted 
9. 
Patients who have received or plan to receive live vaccines within 4 weeks prior to the first 
dose of study drug 
10. Interstitial pneumonia (ILD), drug-induced pneumonia, radiation pneumonia requiring 
steroid therapy, or active pneumonia with clinical symptoms or severe pulmonary 
dysfunction 
11. Patients with active tuberculosis (TB) or a history of active tuberculosis infection ≤ 48 weeks 
before screening, regardless of whether they have been treated 
12. Except for alopecia and fatigue, other toxicities caused by previous anti-tumor treatments 
should have recovered to CTCAE 4.03 Grade ≤ 1 prior to the first dose of study drug Patients 
with other toxicities caused by previous anti-tumor treatments that cannot be resolved within 
expectations and have long-lasting sequelae, such as neurotoxicity caused by platinum-based 
treatments, are allowed to be enrolled 
13. Imaging (CT scan or MRI) showed tumor invasion of large blood vessels, symptoms of 
hemoptysis of daily hemoptysis ≥ 2.5 mL within 3 months before screening 
14. Patients who have undergone minor surgery (including catheterization) within 48 hours 
before the first dose of study drug 
15. Currently or recently (within 10 days prior to the first dose of study drug) using aspirin 
(> 325 mg/day) or other non-steroidal anti-inflammatory drugs known to inhibit platelet 
function 
16. Currently or recently (within 10 days prior to the first dose of study drug) being treated with 
full-dose oral or parenteral anticoagulant or thrombolytic agents. But prophylactic use of 
anticoagulants is allowed 
17. Patients with hereditary bleeding tendency or coagulation dysfunction. Patients with 
clinically significant bleeding symptoms or a clear bleeding tendency within 12 weeks prior 
to screening, such as hemorrhage of digestive tract, stomach ulcer with hemorrhage, baseline 
fecal occult blood++ and above, or vasculitis  
18. Had arterial/venous thrombosis within 24 weeks prior to signing of ICF, such as 
cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, and 
brain infarction), deep vein thrombosis, and pulmonary embolism 
19. Uncontrolled hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood 
pressure ≥ 90 mmHg), a history of hypertensive crisis or hypertensive encephalopathy 
20. With a history of the following diseases within 24 weeks prior to the signing of ICF: peptic 
ulcer, gastrointestinal perforation, corrosive esophagitis or gastritis, inflammatory bowel 
disease or diverticulitis, abdominal fistula, tracheo-esophageal fistula, or intra-abdominal 
abscess 


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21. Patients with clinical symptoms or diseases of the heart that are not well controlled, such as: 
(1) > NYHA class 2 cardiac failure; (2) unstable angina; (3) myocardial infarction within 
24 weeks; (4) patients with clinically significant supraventricular or ventricular arrhythmia 
requiring treatment or intervention 
22. Known to be allergic to drugs or excipients, known to have severe allergic reactions to any 
kind of monoclonal antibody 
23. Patients complicated with other malignant tumors ≤ 5 years before the first dose, except for 
cervical carcinoma in situ, basal cell or squamous cell skin cancer that can be adequately 
treated, local prostate cancer after radical resection, and ductal carcinoma in situ after radical 
resection 
24. With evidence or history of psychiatric disorders, alcoholism, narcotics or drug abuse 
25. Patients who are HBsAg positive with HBV DNA test value exceeding the upper limit of 
normal (1000 copies/mL or 500 IU/mL), or HCV positive (HCV RNA or HCV Ab test 
indicates acute and chronic infection); with known HIV-positive medical history or known 
acquired immune deficiency syndrome (AIDS) 
26. Have received any other investigational drug or participated in other interventional clinical 
study within 4 weeks prior to signing the ICF 
27. The investigator determines that the patient may have other factors leading to the 
discontinuation of the study, such as protocol incompliance, other serious diseases (including 
mental illness) requiring concomitant treatment, serious laboratory test abnormalities, 
accompanied by family or social factors that may affect the safety of the subject or the 
collection of data and samples 
Study 
Withdrawal 
Criteria 
Reasons for withdrawal may include: 
1. 
The subject withdraws the ICF and refuses further follow-ups 
2. 
Any clinical adverse drug reactions, laboratory abnormalities, or complications that renders 
the subject not benefiting from further treatment, as determined by the investigator 
3. 
Other reasons investigator deems necessary for withdrawal, such as the inability to provide 
voluntary consent due to imprisonment or quarantine 
4. 
Lost to follow-up 
5. 
Death 
6. 
Study termination by the sponsor 
Study 
Treatment 
Discontinuation 
Criteria 
Criteria for treatment discontinuation are as follows: 
1. 
Treatment discontinuation requested by subjects 
2. 
Radiographic or clinical evidence of progressive disease, unless the subject meets the criteria 
for continuing treatment beyond progression (see 6.1.2 of the protocol) 
3. 
Occurrence of pregnancy during the study 
4. 
Any clinical AEs, laboratory abnormalities, or other medical conditions indicating that the 
subject can no longer benefit from study treatment  
5. 
General deterioration of health status suggesting that the subject cannot continue to involve 
the study 
6. 
The enrolled subject is found to have important protocol deviations such as ineligibility  
7. 
Lost to follow-up 


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8. 
Termination by sponsor 
9. 
Death 
10. Other reasons as determined by the investigator 
Determination 
of Sample Size 
Assume that in this study, the expected ORR in each treatment group of SHR-1210 + apatinib 
combination therapy is ≥ 30% (alternative hypothesis), and that there is no need to continue the 
study if the ORR is ≤ 15% (null hypothesis), at the significance level of 0.1 and a power of 80%, 
40 subjects should be enrolled. If ≥ 9 (22.5%) of the 40 subjects have response, it can be considered 
that the ORR in this treatment group is 15% and the investigational drug is worthy of continued 
development. 
With a dropout rate of 10% taken into account, each treatment group needs to enroll about 
45 subjects. A total of 57 subjects are required in Stages I and II. 
Data Analysis/ 
Statistical 
Methods 
General analysis: 
Unless otherwise stated, the following descriptive statistics will be summarized based on data 
types. 
 
Continuous variables will be summarized using the mean, standard deviation, median, 
maximum, and minimum. 
 
Categorical variables will be summarized using the frequency and percentage. 
 
For time-to-event data, the survival rate and median survival will be estimated using the 
Kaplan-Meier method. A corresponding 95% confidence interval will be provided for the 
aforementioned analyses, when necessary. 
Efficacy analysis: 
ORR is the primary efficacy endpoint of this study, which refers to the proportion of all enrolled 
subjects assessed to have complete response (CR) or partial response (PR) as per RECIST 1.1 
criteria. Response confirmation should be conducted for CR and PR. The point estimate of ORR 
and two-sided 95% confidence interval based on the Clopper-Pearson method will be calculated. 
The statistical analysis of ORR will be based on the full analysis set (FAS) and evaluable set (ES), 
with FAS as the primary analysis set. 
The secondary efficacy endpoints of the study include the 6-month OS rate, OS, as well as PFS, 
TTR, DoR, and DCR evaluated per RECIST v1.1. 
The statistical analysis of DoR, TTR, and PFS will be based on the FAS and ES, with FAS as the 
primary analysis set. The statistical analysis of OS will be based on the FAS. 
PFS, TTR, DoR, and OS will be estimated based on the Kaplan-Meier method, and the 
corresponding two-sided 95% confidence interval will be calculated. 
The point estimate of DCR and the 95% confidence interval based on the Clopper-Pearson method 
will be calculated. 
Safety analysis: 
The following safety analyses (including but not limited to) will be performed according to the 
existing report criteria of Hengrui by group: 
 
Analysis of treatment discontinuation, dose reduction, or treatment interruption due to AEs 
 
Incidence and severity of AEs 
 
Causality analysis between AEs and study drug 
 
Analysis of outcomes of AEs 
 
Analysis of SAEs 


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 
Descriptive statistical summary of laboratory test, vital signs, and ECG data 
 
Incidence of laboratory abnormalities 
 
Analysis of normal and abnormal changes in laboratory parameters, vital signs, and ECG data 
compared to baseline. 
Interim 
Analysis 
This study does not involve an interim analysis 
Study Period 
Anticipated enrollment of the first subject: Q1 of 2018 
Anticipated enrollment of the last subject: Q4 of 2018 
Anticipated time of last subject last visit: Q3 of 2019 
Anticipated study completion: Q1 of 2020 
 


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SCHEDULE OF ACTIVITIES 
Table 1. Schedule of activities 
Stage 
Screening Period 
Treatment Period (4 weeks/cycle) 
End of 
Treatment26 
Safety 
Follow-Up27 
Survival 
Follow-Up28 
Cycle 125 
Cycle 2 and thereafter 
Visit 
1 
2 
3 
N 
N + 1 
 
 
 
Day 
-28 to -1 -7 to 1 -3 to 1 
1 
15 
(± 3 days) 
1 
(± 3 days) 
15 
(± 3 days) 
± 3 days 
90 days  
(± 7 days) 
Every 8 weeks  
(± 7 days) 
Baseline 
 
 
 
 
 
 
 
 
 
 
Written Informed Consent Form1 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics/Medical History/ 
Medication History2 
X 
 
 
 
 
 
 
 
 
 
Vital Signs3 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Weight/Height4 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Physical Examinations5 
X 
 
 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status6 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG7 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Hematology/Clinical Chemistry/ 
Urinalysis/Routine Stool8 
 
X 
 
 
X 
X 
X 
X 
X 
 
Coagulation Function9 
 
X 
 
 
 
X 
 
X 
X 
 
Pregnancy Test10 
 
 
X 
 
 
 
 
X 
 
 
Thyroid Function11 
X 
 
 
 
 
X 
 
X 
X 
 
Myocardial Zymogram12 
 
X 
 
 
 
 
 
X 
 
 


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Stage 
Screening Period 
Treatment Period (4 weeks/cycle) 
End of 
Treatment26 
Safety 
Follow-Up27 
Survival 
Follow-Up28 
Cycle 125 
Cycle 2 and thereafter 
Visit 
1 
2 
3 
N 
N + 1 
 
 
 
Day 
-28 to -1 -7 to 1 -3 to 1 
1 
15 
(± 3 days) 
1 
(± 3 days) 
15 
(± 3 days) 
± 3 days 
90 days  
(± 7 days) 
Every 8 weeks  
(± 7 days) 
Pituitary Adrenal Axis Test[13] 
X 
 
 
 
 
X 
 
X 
 
 
HIV, HBV, and HCV14 
X 
 
 
 
 
 
 
 
 
 
Echocardiography15 
X 
 
 
 
 
 
 
X 
 
 
Pulmonary Function Test and 
Arterial Blood Gases16 
X 
 
 
 
 
 
 
 
 
 
Immunogenicity (ADA, Nab)17 
 
 
 
X 
 
X 
 
X 
X 
 
AE Assessment18 
X 
 
 
X 
 
X 
 
X 
X 
 
Concomitant Medications19 
X 
 
 
X 
 
X 
 
X 
X 
 
End of treatment visit 
 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
X 
X 
Subsequent Anti-Tumor 
Treatment 
 
 
 
 
 
 
 
 
X 
X 
Response Evaluation 
 
 
 
 
 
 
 
 
 
 
Imaging Evaluation20 
X 
 
 
X 
X 
X 
 
 
Infusion of Study Drugs 
 
 
 
 
 
 
 
 
 
 
SHR-121021 
 
 
 
200 mg, IV, Q2W 
 
 
 
Apatinib22 
 
 
 
375 mg, PO 
 
 
 
Exploration of Biomarkers 
 
 
 
 
 
 
 
 
 
 
Archived or Fresh Tumor Tissue 
Sample23 
X 
 
 
 
 
 
 
X 
 
 


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Stage 
Screening Period 
Treatment Period (4 weeks/cycle) 
End of 
Treatment26 
Safety 
Follow-Up27 
Survival 
Follow-Up28 
Cycle 125 
Cycle 2 and thereafter 
Visit 
1 
2 
3 
N 
N + 1 
 
 
 
Day 
-28 to -1 -7 to 1 -3 to 1 
1 
15 
(± 3 days) 
1 
(± 3 days) 
15 
(± 3 days) 
± 3 days 
90 days  
(± 7 days) 
Every 8 weeks  
(± 7 days) 
Peripheral Blood24 
X 
 
 
 
 
X 
 
X 
 
 
Note: 
1. Except for tumor imaging and tumor biopsy within the prescribed time limit before the first dose, the ICF should be signed before any operation specified in the 
protocol. 
2. The medications include treatment for initial diagnosis, including chemotherapy, radiotherapy, and surgical treatment. The time of the last anti-tumor treatment 
must be recorded. 
3. Vital signs include body temperature, pulse, respiratory rate, and blood pressure. Measurements will be conducted during the screening period, before each 
SHR-1210 administration, at the end of the treatment, and at safety follow-ups. Blood pressure monitoring: cigarettes and caffeine are prohibited within 30 min 
before each blood pressure measurement, and subjects shall rest for at least 10 min. The blood pressure will be measured at sitting position with elbow on the 
same level as heart. All measurements should be taken on the same side. During the screening period and before each scheduled SHR-1210 infusion, the 
investigator will measure the blood pressure of the subject. During the study, the subject will monitor the blood pressure and record on the diary card. Blood 
pressure shall be measured at least 3 times per week in the first 2 cycles. For subjects with abnormal blood pressure, the blood pressure shall be measured daily; 
if normal, the blood pressure shall be measured twice per week after Cycle 2. 
4. Height will be measured only during the screening period. Weight will be measured during the screening period, before each SHR-1210 administration, at the 
end of the treatment, and at safety follow-ups. 
5. Physical examinations will be conducted during the screening period, before each SHR-1210 administration, at the end of the treatment, and at safety 
follow-ups. 
6. ECOG PS scoring will be conducted during the screening period, before each SHR-1210 administration, at the end of the treatment, and at safety follow-ups. 
7. 12-lead ECG examination time: during the screening period, after each SHR-1210 infusion, at the end of treatment, and during safety follow-up. The 
examination results during screening may be used for the ECG examination at C1D1 visit. Refer to Section 8.2.3 of the protocol for details. 


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8. Hematology includes: red blood cell count (RBC), hemoglobin (HGB), hematocrit value (HCT), white blood cell count (WBC), platelet (PLT), and white blood 
cell differential [lymphocyte count (LYM), absolute neutrophil count (ANC), monocyte count (MONO), eosinophil count (EOS), and basophil count (BASO)]. 
Clinical chemistry includes: liver function [serum total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate transferase (AST), gamma- 
glutamyltransferase (γ-GT), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), and lactic dehydrogenase (LDH)]; renal function [blood urea 
nitrogen (BUN) and creatinine (Cr)]; blood electrolytes (Na, K, Cl, Mg, Ca, and P); lipase, amylase, and fasting blood glucose (FBG). Urinalysis includes: pH, 
urine albumin (UALB), urine protein (UPRO), urine red blood cell (URBC), and urine glucose (UGLU). The subject may be enrolled only if urinalysis shows 
negative urine protein at screening. Routine stool test: occult blood; re-examination is needed for fecal occult blood+; if fecal occult blood is confirmed, then a 
gastroenterological endoscopy will be performed. Hematology, clinical chemistry, urinalysis, and routine stool will be performed during the screening period 
(within 7 days before the first dose of the study drug), before each SHR-1210 administration, at the end of the treatment, and at safety follow-ups. Tests will be 
performed at each study center. 
9. Coagulation function tests include: thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized 
ratio (INR). Tests will be performed within 7 days prior to the first dose, before the administration of SHR-1210 on day 1 of each cycle, at the end of the 
treatment, and at safety follow-ups. Tests will be performed at each study center. 
10. Women of childbearing potential will undergo a serum pregnancy test within 3 days prior to the first dose and at the end of the treatment. Tests will be 
performed at each study center. 
11. Thyroid function tests include: thiiodothronine (T3), thyroxine (T4), free thiiodothronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH). 
Tests will be performed during the screening period, before the administration of SHR-1210 on day 1 of each cycle, at the end of the treatment, and at safety 
follow-ups; the results from the screening period may be used for the thyroid function tests at the C1D1 visit. Tests will be performed at each study center. 
12. Myocardial zymography: including LDH, AST, creatine kinase (CK), creatine kinase isoenzyme (CK-MB), and ALT. Tests will be performed once within 
7 days prior to the first dose and performed again only upon the onset of symptoms of precordial pain and palpitations, and abnormal ECG hereafter, as well as 
at the end of the treatment.  
13. Hypothalamic-pituitary-adrenal (HPA) axis tests: including corticotropin releasing hormone (CRH), adrenocorticotropic hormone (plasma ACTH), and 
adrenocortical hormones. Adrenocortical hormone tests include serum cortisol, urinary free cortisol (UFC), urinary 17-ketosteroids (17-KS), and urinary 
17-ketogenic steroids (17-KGS). For hospitals where conditions permit, the tests are recommended during the screening period, before the administration of 
SHR-1210 on day 1 of each cycle, and at the end of the treatment. 


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14. Include HBV, HCV, and HIV antibody tests; requirements for HBV testing: HbsAg shall be tested during the screening period to determine the presence of 
HBV infection; if positive, HbsAg (quantitative), HbsAb (qualitative), HbcAb (qualitative), HbeAg (qualitative), HbeAb (qualitative), and HBV-DNA 
(qualitative; quantitative test required if positive) shall be tested. Requirements for HCV testing: HCV-Ab is tested at screening to determine the presence of 
HCV infection. If positive, HCV-RNA will be tested (qualitative, and if positive, quantitatively). The investigator must arrange for appropriate anti-viral 
treatment for HBV carriers participating in this study. Tests will be performed at each study center. 
15. Echocardiography: Perform once within 28 days before the first dose and at the end of the treatment, and when clinically significant ECG abnormalities are 
found during the study. 
16. Pulmonary function test: Maximum vital capacity, the forced expiratory flow at 25-75% of forced vital capacity (FEF25-75), the peak expiratory flow rate 
(PEF), the maximum expiratory volume per second, diffusing capacity of the lungs for carbon monoxide (DLCO) and oxygen saturation, which will be 
performed during the screening period and based on clinical indicators as determined by the investigator thereafter. Arterial blood gas test: optional. This test 
includes partial arterial pressure of oxygen (PaO2), partial arterial pressure of carbon dioxide (PaCO2), arterial oxygen saturation (SaO2), and pH, and can be 
performed during the screening period. Pulmonary function test and arterial blood gas test indicators will be based on the actual conditions at each site. 
17. Immunogenicity blood samples will be collected once within 0.5 h before SHR-1210 infusion on D1 of cycle 1, cycle 2, and the third cycle of every three cycles 
thereafter (cycles 5, 8, 11, etc.), once at the end of the treatment, and once per month at safety follow-ups after withdrawal for 3 times (if applicable). In case of 
national holidays, the blood collection time may be adjusted as appropriate. If the subject develops SHR-1210 infusion-related reactions, blood samples should 
be collected as close as possible to the onset of the event, to the end of the event, and about 30 days after the end of the event, for immunogenicity comparison 
and analysis. Immunogenicity blood samples should be collected following the study protocol. However, if deemed necessary by the investigator, unscheduled 
immunogenicity blood samples may be collected. Tests will be performed at the central laboratory. Four (4) mL of blood will be collected each time for 
immunogenicity. 
18. The safety assessment for AEs and laboratory tests will be performed according to NCI CTCAE v4.03. All AEs/SAEs will be recorded in the CRF from the 
time of signing the ICF to the end of safety follow-up or the start of new anti-tumor therapy (whichever occurs first). The definition, recording, causality 
assessment, severity assessment, reporting time limit, handling, and follow-up of AE and SAE should refer to the description in Section 9 of the protocol. 
19. All drugs related to the treatment of AEs other than solvents within 28 days before the first dose of the study drug until 30 days after and 30-60 days after the end of 
the treatment should be documented in the CRF, including the name, dose, route of administration, frequency of administration, purpose, and start and end dates. 
20. The method used for tumor imaging evaluation during the baseline period must be consistent with the method used for each subsequent follow-up evaluation. 
Computerized tomography (CT) or magnetic resonance imaging (MRI) scans are recommended. Other involved parts are examined based on the symptoms and 
signs of each subject. Baseline imaging evaluations should include thoracic, abdominal, and pelvic scans (from apex of lungs to pubic symphysis), brain scan, 


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bone scan, and scan of all known or suspected lesions. Each subsequent clinical tumor imaging evaluation should include thoracic, abdominal, and pelvic scans; 
brain and/or bone scans may be performed when clinically indicated. The frequency of imaging monitoring can be increased by the investigator as needed. The 
baseline tumor evaluation will be performed within 28 days before the first dose. Imaging data obtained before the signing of informed consent form may be 
used for tumor evaluation during the screening period as long as it meets the requirements of the protocol. During the study, imaging assessment will be 
performed on C1D28 (± 3 days) and every 8 weeks (± 7 days) after C1D28 until radiographic progressive disease (PD) is documented. An additional imaging 
evaluation must be performed in 4 weeks (+ 7 days) for confirmation after the initial documentation of response (CR or PR) and imaging PD. If PD is not 
confirmed, the study medication and imaging evaluation are continued until relapse of PD. Refer to Section 6.1.2 of the protocol for the relapse of PD. Subjects 
with relapse of PD must discontinue treatment. If the treatment is discontinued for reasons other than radiologically confirmed PD, imaging evaluations shall be 
performed as much as possible per the scheduled imaging time points until any of the following events occurs: start of new anti-tumor therapy, PD, withdrawal 
of ICF and/or death. Refer to Section 8 of the protocol for details. 
21. 200 mg of SHR-1210, intravenous drip infusion, once every 2 weeks. Subjects who meet specific conditions may continue the medication after PD (refer to 
Section 6.1.2 of the protocol for continued medication beyond progression). 
22. Eligible subjects after screening will be randomized in a 1:1:1 ratio into the following three treatment groups: apatinib 375 mg, PO, QD; apatinib 375 mg, PO, 
QD (5 Days on, 2 Days off); or apatinib 375 mg, PO, QD (7 Days on, 7 Days off). Apatinib should be administered at a fixed time every day as much as 
possible. On the day of SHR-1210 infusion, apatinib shall be administered 30 min after the end of SHR-1210 infusion. 
23. Subjects are required to provide archived or fresh tumor tissue samples that meet the testing requirements during the screening period. After obtaining the 
subject's ICF, another biopsy may be performed at the end of treatment. Tumor tissue samples to be provided at screening (required) and the end of treatment 
shall be 5-10 unstained tissue slices with a thickness of 4-6 μm, among which at least 5 sections are used for PD-L1 testing. 
24. After the subject's ICF is obtained, about 16 mL of peripheral blood may be collected for tumor biomarker detection during the screening period, at each tumor 
evaluation, and the end of the treatment. 
25. Randomization must be completed within 24 h before the first dose of the study drug. 
26. End of treatment refers to confirmation of progressive disease or withdrawal from study, and shall be carried out within ± 3 days when the decision of treatment 
discontinuation and/or withdrawal from study is made. 
27. Safety follow-ups will be performed 90 ± 7 days after the last dose. 
28. Survival follow-ups: Performed once every 8 weeks (± 7 days) after the last dose, and telephone interviews are acceptable. 


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ABBREVIATIONS 
Abbreviations 
Full Name 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIDS 
Acquired Immune Deficiency Syndrome 
ALB 
Albumin 
ALP 
Alkaline phosphatase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate transferase 
BASO 
Basophil cell count 
CFDA 
China food and drug administration 
BUN 
Blood urea nitrogen 
CK 
Creatine kinase 
CK-MB 
Creatine kinase isoenzyme 
CR 
Complete response 
Cr 
Creatinine 
CRF 
Case report form 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen-4 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response 
EC 
Ethics Committee 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EOS 
Eosinophil count 
ED-SCLC 
Extensive-stage disease small cell lung cancer 
FGF 
Fibroblast growth factor 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 4 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 


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Abbreviations 
Full Name 
GMP 
Good Manufacturing Practices 
GLP 
Good Laboratory Practices 
HCT 
Hematocrit value 
HGB 
Hemoglobin 
HRT 
Hormone replacement therapy 
IB 
Investigator's brochure 
ICF 
Inform consent form 
INR 
International normalized ratio 
IU 
International unit 
irAE 
Immuno-related adverse event 
LDH 
Lactate dehydrogenase 
LD-SCLC 
Limited-stage disease small cell lung cancer  
LYM 
Lymphocyte count 
IVIgG 
Intravenous immunoglobulin G 
MedDRA 
Medical Dictionary for Regulatory Activities 
MONO 
Monocyte count 
MTD 
Maximum tolerated dose 
Na+ 
Plasma sodium 
Nab 
Neutralizing antibody 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PBMCs 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PD-1 
Programmed death-1 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-free survival 
PLT 
Platelet  
PR 
Partial response 
PT 
Prothrombin time 
RBC 
Red blood cell 
Q2W 
Every 2 weeks 
QD 
Once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Abbreviations 
Full Name 
RPLS 
Reversible posterior leukoencephalopathy syndrome 
SD 
Stable disease 
SDV 
Source data verification 
T3 
Triiodothyronine 
T4 
Thyroxine 
TCR 
T cell receptor 
TBIL 
Total bilirubin 
TP 
Total protein 
TSH 
Thyroid-stimulating hormone 
TT 
Thrombin time 
TTR 
Time to response 
UALB 
Urinary albumin 
UGLU 
Urine glucose 
UPRO 
Urine protein 
URBC 
Urine red blood cell 
VALG 
Veterans Administration Lung Study Group 
WBC 
White blood cell 
γ-GT 
γ-glutamyltransferase 
SAE 
Serious adverse event 
SCLC 
Small cell lung cancer 
SAP 
Statistical analysis plan 
TEAE 
Treatment emergent adverse event 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
CrCl 
Creatinine clearance rate 


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1 
KEY FUNCTIONAL ROLES 
Principal Investigator 
of Leading Center 
Prof. Jie Wang 
Contact:  
Cancer Hospital of Chinese Academy of Medical Science 
 
 
  
Principal Investigator 
of Cooperative 
Leading Center 
Prof. Yun Fan 
Contact: 
Zhejiang Cancer Hospital  
 
 
  
Sponsor's Medical 
Director 
, M.D., Clinical Medical Director 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
 
 
Statistician 
, Ph.D.,  
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
 
  
2 
BACKGROUND AND SCIENTIFIC RATIONALE 
2.1 
Disease Background 
Lung cancer is the most common malignant tumor in China. According to data released by the 
National Center for Cancer Registry in 2016, the incidence of lung cancer ranked first in males and 
second only to breast cancer in females [1]. The main types include non-small cell lung cancer 
(NSCLC) and small cell lung cancer (SCLC). 


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2.1.1 
Non-small cell lung cancer 
NSCLC accounts for approximately 85% of lung cancers[2,3]. NSCLC is classified by histology as 
adenocarcinoma, squamous carcinoma, large cell carcinoma, neuroendocrine tumor, sarcomatoid 
carcinoma, and poorly differentiated carcinoma. Among these subtypes, adenocarcinoma accounts 
for more than 50% and squamous cell carcinoma accounts for 25%[4]. The 5-year survival rate of 
NSCLC is 2-4%, depending on the lesion site[5]. Factors for poor prognosis include advanced stage 
at initial diagnosis, poor PS score, and history of surreptitious weight loss. Half of NSCLC patients 
have distant metastases when initially diagnosed. 
Adenocarcinoma and squamous cell carcinoma have different characteristics. First, squamous cell 
carcinoma is commonly the central type and mostly in the bronchial epithelium, whereas 
non-squamous carcinoma is commonly the peripheral type and mostly in the lung parenchyma. 
Evaluation of the histological type of NSCLC further shows the difference between squamous cell 
carcinoma (keratinization, intracellular bridges, and central necrosis) and adenocarcinoma 
(glandular structure). Immunohistochemical labeling further supports the diagnosis of NSCLC 
when the tumor specimens are limited in quantity or the degree of differentiation is low. TTF-1 is 
expressed highly in adenocarcinoma but rarely in squamous cell carcinoma. On the contrary, p63, 
CK5/6, and 34BE12 are highly expressed in squamous cell carcinoma but rarely in 
adenocarcinoma[6]. 
The driver genes of NSCLC include EGFR, ALK, and KRAS. These driver genes have different 
mutation rates in adenocarcinoma and squamous cell carcinoma. For example, 10-40% of 
adenocarcinoma patients are EGFRm+. Approximately 7% of adenocarcinoma patients are ALK 
fusion gene positive. And approximately 30% of adenocarcinoma patients are KRASm+. But 
these gene mutations are rare in patients with squamous cell carcinoma[4,6,7]. 
See Table 2 for the treatment of different types of NSCLC recommended by the FDA and EMA. 
No immunotherapy drug is available in China for the treatment of advanced NSCLC (Stage IV) 
with negative driver genes according to the guidelines of the Chinese Society of Clinical Oncology 
(CSCO) issued in 2017. For the second-line treatment of non-squamous cell carcinoma, 
mono-chemotherapy with docetaxel or pemetrexed is recommended for patients with a PS score of 
0-1. The best supportive treatment is recommended for patients with a PS score of 3-4, who are 
encouraged to participate in clinical studies. Mono-chemotherapy with docetaxel is recommended 
as second-line treatment of squamous cell carcinoma. Patients who are not suitable for cytotoxic 
chemotherapy may choose afatinib, vinorelbine, or gemcitabine. Few second-line treatment 
options are available for NSCLC, and new treatment methods are urgently needed. Most 
immunotherapy, anti-VEGFI therapy, immunotherapy-based combination therapy, or 
anti-VI(R)-based combination therapy are still under clinical studies. 


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Table 2. Individualized treatment of NSCLC 
Histology 
Molecular 
Pathology 
PD-L1 
Expression* First line 
Maintenance 
Second Line 
Squamous cell 
cancer 
NA 
< 50% 
Platinum-based 
chemotherapy ± 
necitumumab (EMA) 
Necitumumab 
Immunotherapy 
Chemotherapy 
Docetaxel + 
ramucirumab 
Afatinib 
NA 
≥ 50% 
Pembrolizumab 
Pembrolizumab 
Platinum-based 
chemotherapy 
Non-squamous 
cell cancer 
EGFRm+ NA 
Erlotinib + 
bevacizumab 
Erlotinib 
Afatinib 
Gefitinib 
Erlotinib + 
bevacizumab 
Erlotinib 
Afatinib 
Gefitinib 
Osimertinib 
Platinum-based 
chemotherapy 
ALK+ 
NA 
Crizotinib (also 
applicable to ROS1+) 
Ceritinib (FDA and 
EMA) 
Crizotinib (also 
applicable to ROS1+) 
Ceritinib (FDA and 
EMA) 
Ceritinib 
Alectinib 
(failure of first-line 
treatment with 
crizotinib) 
Platinum-based 
chemotherapy 
Wild-type < 50% 
Platinum-based 
chemotherapy 
(± bevacizumab) 
Pemetrexed 
(continued or 
transferred to 
maintenance 
treatment) 
Bevacizumab 
(continued 
maintenance 
treatment) 
Immunotherapy 
Chemotherapy 
Docetaxel + 
ramucirumab 
Docetaxel + nintedanib 
(adenocarcinoma, 
EMA) 
Erlotinib (EMA) 
 
Wild-type ≥ 50% 
Pembrolizumab 
Pembrolizumab 
Platinum-based 
Note: This table is from Reference 8.* Dako 22C3 kit is used for the detection of PD-L1. 


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2.1.2 
Small cell lung cancer 
SCLC accounts for 10-15% of new lung cancers. It is a highly aggressive neuroendocrine tumor. It 
is significantly different from NSCLC clinically and pathologically, characterized by rapid 
growth, proneness to drug resistance, and early metastasis. Almost all patients with SCLC have a 
history of heavy tobacco use[9,10]. Traditionally, SCLC is classified into limited-stage disease 
(LD-SCLC, where tumor tissue surrounds a radiotherapy field) and extensive-stage disease 
(ED-SCLC, where tumor tissue exceeds the boundary of a radiotherapy field)[11]. Most patients 
have ED-SCLC when first diagnosed. Platinum (cisplatin or carboplatin) combined with etoposide 
for 4-6 cycles is still the first-line standard treatment for LD-SCLC and ED-SCLC. The 
combination of platinum, etoposide, and thoracic radiotherapy can reach an ORR of 70-90% in 
LD-SCLC. The combination of platinum and etoposide can reach an ORR of 60-70% in 
ED-SCLC. The mOS is 14-20 months and 9-11 months, respectively. After proper treatment, the 
2-year survival rate is 40% and < 5%, respectively[12]. Concomitant thoracic radiotherapy can 
increase the local control rate by 25% in LD-SCLC [13,14]. The combination of radiotherapy and 
chemotherapy are recommended for LD-SCLC patients with negative cytological results or 
uncertain pleural effusion without pericardial effusion[15,16]. 
After the first-line treatment with the combination of platinum and etoposide, approximately 80% 
of LD-SCLC patients and almost all ED-SCLC patients develop progressive disease[17]. Subjects 
whose last dose of first-line chemotherapy is longer than 180 days ago may use platinum-based 
two-drug chemotherapy again. Other patients can only be treated with topotecan monotherapy, the 
only second-line medicine approved by the FDA. The approval of the second-line treatment of 
topotecan was based on a phase III study in subjects with recurrent SCLC to compare the efficacy 
and safety of topotecan monotherapy and the CAV regimen, i.e., cyclophosphamide, adriamycin, 
and vincristine. The results showed similar efficacy between the two groups in terms of the ORR 
(24.3% vs. 18.3%, p = 0.285), mPFS (13.3 wks vs. 12.3 wks, p = 0.552), and mOS (25 wks vs. 
24.7 wks, p = 0.795). In terms of safety, the incidence of non-hematologic toxicity in the topotecan 
group was lower than that in the CAV group, mostly Grade 1-2. In terms of hematologic toxicity, 
there were more Grade > 4 neutropenia cases in the CAV group than in the topotecan group, but 
the incidences of Grade > 4 thrombocytopenia and Grade 3-4 anemia were higher in the topotecan 
group [18]. Based on 21 meta-analyses published during 1984-2011, the mOS of second-line 
treatments of SCLC was 6.7 months[19]. In summary, SCLC has huge unmet clinical needs. 


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2.2 
Immune Checkpoint Therapy 
In the process of tumor occurrence and development, tumor cells undergo many hereditary and 
epigenetic changes compared with normal cells, and theoretically have enough antigens to be 
recognized by the human immune system, which can trigger an immune response to inhibit tumor 
growth. However, tumors can suppress the immune response through multiple pathways to evade 
the attack from immune system[20]. 
In the process of effective anti-tumor immunity, T cells as core executors are first recognized by 
antigen recognition signals mediated by T cell receptor (TCR), while numerous costimulatory 
signals and coinhibitory signals finely regulate the intensity and quality of T cell responses[21], of 
which the inhibitory signal is the checkmate inhibitor. Under physiological circumstances, these 
immune checkpoints are involved in maintaining immune tolerance to self-antigens on the one 
hand to avoid autoimmune diseases; on the other hand, they can avoid tissue damage caused by 
excessive activation of immune responses[22]. However, tumor cells can use these immune 
checkpoints to inhibit T cell activation, thereby evading immune killing. 
2.2.1 
PD-1/PD-L1 and tumors 
The induction of effective anti-tumor immune responses is a complex process involving multiple 
steps. The key step depends on the ability of the major executor, effector T-cells, to effectively 
recognize and kill tumor cells, while the activation of T-cells is the premise for their anti-tumor 
effects. 
Programmed death-1 (PD-1) is one of the many immune checkpoints that can inhibit T cell 
activation. It is one of the important inhibitory receptors on the surface of T cells and is 
homologous with CD28 and CTLA-4. It is named for its initial discovery in apoptotic T cell 
lymphoma and its ability to promote programmed cell death. PD-1 is expressed on activated T 
cells, depleted T cells, activated B cells, natural killer cells, dendritic cells, and activated 
monocytes, but not on the surface of resting lymphocytes[23,24]. Up-regulation of PD-1 expression 
on the surface of activated lymphocytes can lead to inhibition of acquired or innate immune 
responses, as PD-1-mediated immunosuppression can be triggered when the phosphorylase binds 
to the immunoreceptor tyrosine-based inhibitory motif and conversion motif of PD-1 in the 
cytoplasm[23]. PD-1 has two major ligands, programmed death factor ligand 1 (PD-L1 [B7-H1]) 
and programmed death factor ligand 2 (PD-L2 [B7-DC])[25,26]. 


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The PD-1/PD-L1 binding plays an important role in regulating T cell activation and maintaining 
peripheral immune tolerance (the role of PD-1 in the process of T cell activation, aging, and 
response is shown in Figure 1 below[8]). When T cells do not express PD-1, they interact with 
antigen-presenting cells to activate and proliferate T cells and secrete activated cytokines to act on 
tumor cells, mainly manifested as killing of tumor cells (Figure 1A); activated T cells begin to 
express PD-1, and when they bind to ligand PD-L1 on antigen-presenting cells or tumor cells, the 
inhibitory signals transmitted by PD-1 will inhibit the proliferation of T cells and the secretion of 
active cytokines, so that the function of T cells is reduced, and most tumor cells evade immune cell 
attack through this mechanism (Figure 1B); if the interaction between PD-1 and PD-L1 is blocked 
by drugs, the activity of T cells and the ability to kill cancer cells can be restored (Figure 1C)[27]. 
 
Figure 1. PD-1's role in T cell activation, aging, and response 
2.2.2 
Anti-PD-1/PD-L1 agents 
PD-L1 is widely expressed in solid tumors and hematological tumors (Table 3)[28]. A variety of 
tumor types rank among the top ten in incidence/mortality in China, such as lung cancer, colon 
cancer, gastric cancer, esophageal cancer, breast cancer, and liver cancer[29]. Anti-PD-1 agents 
play a therapeutic role by blocking the binding of PD-L1 on tumor cells and PD-1 of T cells, 
blocking its inhibition on T cells. Compared with traditional cytotoxic chemotherapy, PD-1 
targeted therapy has higher specificity, lower toxicity, and applicability to a variety of tumor types. 
Immune response of activated  
T cells 
Immune response of depleted T cells 
Immune response of effector T cells 
Cytokines 
(IFN-γ) 
Cell 
proliferation 
Cell 
proliferation 
Cytotoxicity 
Cytotoxicity 
Cytotoxicity 
Chronic 
inflammation 
Continuous 
antigen 
stimulation 
Cell 
proliferation 
Cytokines 
(IFN-γ) 
Cytokines 
(IFN-γ) 


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Table 3. PD-L1 expression in multiple types of tumors 
Types of Tumors 
Positive Rate of PD-L1 (%) 
Malignant glioma 
100 
Nasopharyngeal Carcinoma 
68-100 
Melanoma 
40-100 
Bladder cancer 
28-100 
Non-Small Cell Lung Cancer 
35-95 
Small Cell Lung Cancer 
28.6% 
Multiple Myeloma 
93 
Hepatic Cancer 
45-93 
Ovarian Cancer 
33-80 
Colon Cancer 
53 
Gastric Cancer 
42 
Esophageal Cancer 
42 
Pancreatic Cancer 
39 
Breast Cancer 
31-34 
Renal Cancer 
15-24 
Lymphoma 
17-94 
Leukaemia 
11-42 
Note: * The data comes from the 2016 World Conference on Lung Cancer. 
See Table 4 for anti-PD-1/PD-L1 monoclonal antibodies that have been marketed as of 27 Sep., 
2017. 
Table 4. Marketed anti-PD-1/PD-L1 monoclonal antibodies 
Generic Name (Trade 
Name) 
Company 
Target 
Category 
Time of 
Marketing 
Current Indication(s) 
Nivolumab 
(OPDIVO) 
BMS 
PD-1 
IgG-4 
2014 
Melanoma, non-small cell lung cancer, 
renal cell carcinoma, classic Hodgkin's 
lymphoma, head and neck squamous cell 
carcinoma, urothelial carcinoma, 
colorectal cancer (MSI-H or dMMR), 
and liver cancer 
Pembrolizumab 
(KEYTRUDA) 
Merck 
PD-1 
IgG-4 
2014 
Melanoma, non-small cell lung cancer, 
head and neck squamous cell carcinoma, 
classic Hodgkin's lymphoma, urothelial 
carcinoma, MSI-H tumor, and gastric 
cancer 
Atezolizumab 
(Tecentriq) 
Roche 
PD-L1 
IgG-1 
2016 
Urothelial cancer, non-small cell lung 
cancer 


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Generic Name (Trade 
Name) 
Company 
Target 
Category 
Time of 
Marketing 
Current Indication(s) 
Durvalumab 
(Imfinzi) 
AZ 
PD-L1 
IgG-1 
2017 
Urothelial carcinoma 
Avelumab (Bavencio) 
Merck & 
Pfizer 
PD-L1 
IgG-1 
2017 
Merkel cell carcinoma 
As of 27 Sep., 2017 
2.3 
Scientific Rationale 
2.3.1 
Basis of SHR-1210 combined with apatinib in the second-line treatment of SCLC 
Peripheral blood mononuclear cells (PBMCs) in SCLC patients show that there are more effector 
T cells in LD-SCLC patients than in ED-SCLC patients. SCLC patients with a long survival have a 
high ratio of effector T cells to regulatory T cells[30]. In the phase I study of nivolumab 1, 3, and 
10 mg/kg dose groups for the treatment of SCLC, the ORRs were 6%, 27%, and 17%, respectively, 
and the 24-week PFS rates were 25%, 44%, and 31%, respectively[31,32]. The CheckMate 032 study 
is a phase I/II open-label study comparing the ORRs of nivolumab 1 mg/kg, nivolumab 1 mg/kg 
combined with anti-CTLA-4 monoclonal antibody ipilimumab 3 mg/kg, and nivolumab 3 mg/kg 
combined with ipilimumab 1 mg/kg in SCLC patients who have previously undergone first-line or 
second-line standard treatment. The results showed that, regardless of PD-L1 expression, ORRs 
were 10%, 23%, and 19%, respectively; mPFSs were 1.4, 2.8, and 1.4 months, respectively; mOSs 
were 5.7, 7.7, and 7.2 months, respectively; and the 1-year OS rates were 33%, 43%, and 35%, 
respectively. Common adverse events included asthenia, diarrhea, vomiting, skin rash, and serum 
lipase increased. The incidence of Grade ≥ 3 adverse events in the combination group was greater 
than that in the monotherapy group[33]. The KEYNOTE 028 study is a phase Ib study evaluating 
pembrolizumab 10 mg/kg Q2W monotherapy as second-line treatment of advanced solid tumors. 
In SCLC patients with high PD-L1 expression, the ORR was 29.2% and the mPFS was 1.8 months. 
Common adverse events included joint pain, faintness, skin rash, diarrhea, and asthenia. The 
incidence of Grade ≥ 3 toxicity was 8.3%, with 1 case of enteritis resulted in death[34]. 
In vivo studies have shown that very early angiogenesis is caused by the imbalance of angiogenesis 
and anti-angiogenic mediators. Multiple factors, overlapping signal pathways and mechanisms are 
involved in angiogenesis. Hypoxia during tumor growth stimulates angiogenesis by inducing the 
production of VEGF. The binding of VEGF and VEGFR activates the VEGF signaling pathway. 
Fibroblast growth factor (FGF) and angiopoietin-2 continuously stimulate angiogenesis. 
Therefore, the angiogenesis signaling pathway plays a vital role in the process of SCLC 
metastasis[35]. 


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The phase I clinical study of ramucirumab combined with pembrolizumab in the first-line, 
second-line, and subsequent lines of treatments of gastric cancer (including gastroesophageal 
junction tumors) showed ORRs of 14% (4/28) and 7% (3/4), respectively, mPFSs of 5.6 (95% CI: 
2.4-NR) months and 2.6 (95% CI: 1.5-4.2) months, respectively, and 6-month PFS rates of 35% 
and 26.1%, respectively; in the second-line and subsequent lines of treatment, the mOS was 6.2 
(95% CI: 4.4-12.6) months. The safety and tolerability were similar to those of monotherapies. 
Grade ≥ 3 adverse events included asthenia, hypertension, and enteritis, without additional 
toxicity[36]. The phase II study in naive patients with metastatic renal carcinoma compared the 
efficacy and safety of atezolizumab combined with bevacizumab vs. atezulizumab monotherapy 
vs. sunitinib monotherapy, with the subjects in the atezulizumab monotherapy and sunitinib 
monotherapy groups crossing over to the atezolizumab combined with bevacizumab group for 
continued treatment after progressive disease assessment per RECIST v1.1. The results showed 
that the combination group was superior to the sunibinib group. Although atezulizumab 
monotherapy and sunitinib monotherapy had limited efficacy, the subjects still benefited after 
crossover to the combination group. The overall ORR of the crossover group was 26% (28% in the 
sunitinib group and 24% in the atezolizumab group), and the total mPFS was 8.8 months; the 
safety was consistent with the monotherapy and combination therapy groups. Grade ≥ 3 adverse 
events included asthenia, arthralgia, nausea, proteinuria, diarrhea, and vomiting[37]. Currently, 
studies evaluating the efficacy and safety of VEGF/VEGFR inhibitors combined with immune 
checkpoint inhibitors combined with or without chemotherapy have been carried out in multiple 
tumors such as NSCLC and SCLC. 
Apatinib mesylate (trade name: Aitan®) was developed by Jiangsu Hengrui Pharmaceuticals Co., 
Ltd. and was approved for marketing by the China Food and Drug Administration (CFDA; now 
National Medical Products Administration, or NMPA) in 2014. Apatinib is a small molecular 
targeted drug and exerts anti-angiogenic effect to treat cancer by inhibiting VEGFR. Recombinant 
humanized anti-PD-1 monoclonal antibody injection (SHR-1210), a new class 1 therapeutic 
biological product developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd., has not been 
marketed both in China and abroad. Jiangsu Hengrui Pharmaceuticals Co., Ltd. has initiated Phase 
I/II clinical studies of SHR-1210 in several types of tumors in both Australia and China, and 
preliminarily validated the safety, tolerability and efficacy of SHR-1210 monotherapy in the 
treatment of advanced solid tumors. 
Considering the role of immune-related therapies in SCLC, as well as the role of immune 
checkpoint inhibitors combined with VEGF and VEGFR-2 inhibitors in patients with gastric 
cancer and kidney cancer, the benefits of SHR-1210 combined with apatinib in the second-line 
treatment of SCLC are reasonable and worth looking forward to. 


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2.3.2 
Basis for SHR-1210 administration at the fixed dose of 200 mg 
PD-1 immune checkpoint inhibitors exert their effect on immunosuppression by blocking the 
binding of PD-1/PD-L1. Therefore, the receptor occupancy of these inhibitors is the basic 
pharmacological mechanism that reflects the ultimate anti-tumor effects. Phase I PK studies 
showed that, serum drug concentrations dropped below 1000 ng/mL on Day 15 after a single dose 
of SHR-1210 1 mg/kg and a fixed dose of 60 mg, and remained between 4000-9000 ng/mL after a 
single dose of 3 mg/kg and a fixed dose of 200 mg. Receptor occupancy assays suggest that to 
maintain the receptor saturation, a serum drug concentration of at least 2000 ng/mL is required. 
Clinical data also suggest that a fixed dose of 200 mg every 2 weeks can maintain a saturated 
receptor occupancy. In Phase I studies, the incidence of adverse events did not increase with dose, 
whether the drug was administered by weight or by a fixed dose. Based on results from the studies 
described above, and taking into account the convenience of clinical administration, a fixed dose 
of 200 mg Q2W was selected. 
2.3.3 
Basis for continued medication beyond progression 
Increasingly more clinical evidence shows that, after immunostimulant therapy in some patients, 
progressive disease (through traditional response evaluation, per RECIST v1.1) precedes objective 
clinical response and/or stable disease. This phenomenon was observed in approximately 10% of 
patients in the phase I study of nivolumab[38]. Two hypotheses attempt to explain this 
phenomenon. One is that the enhanced inflammatory response in the tumor leads to an increase in 
the size of the tumor. Over time, the seemingly worsening part and the inflammatory part 
disappear, and the therapeutic effect begins to appear. The other is that the growth rate of tumors 
exceeds the rate of immune anti-tumor. After a sufficiently long period of time, the anti-tumor 
activity finally dominates and the therapeutic effect begins to appear. Therefore, subjects who are 
clinically evaluated as beneficial and well tolerated are allowed to undergo immune checkpoint 
inhibitors again after the initial progressive disease as defined per RECIST v1.1. Such subjects 
shall discontinue the study treatment after relapse of progressive disease. 
2.3.4 
Basis for selecting PD-L1 as the exploratory biomarker 
As described in 2.2.2 of the protocol, PD-L1 is up-regulated in a variety of solid tumors. PD-L1 
expression is closely related to shortened survival and poor prognosis in various cancers, including 
lung cancer, liver cancer, gastric cancer, esophageal cancer, urothelial cancer, renal cancer, 
pancreatic cancer, and ovarian cancer[28]. In in vitro studies, tumor cells expressing PD-L1 
promote the apoptosis of activated tumor cell-specific T cells, while tumor cells avoid the killing 
effect of effector T cells. In a number of clinical studies of nivolumab and pembrolizumab, the 
expression level of PD-L1 in tumor tissues was positively correlated with the efficacy. Based on 
the above evidence, the expression level of PD-L1 in tumor tissues may be related to the efficacy 
of SHR-1210, and preliminary biomarker exploration is necessary. 


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2.4 
Preclinical Studies 
Refer to Investigator's Brochure (IB) (version number: 2.0, version date: 24 Nov., 2016) for the 
pharmacology studies, toxicology studies, and pharmacokinetics studies of SHR-1210. Refer to IB 
(version number: 2.0, version date: 8 Dec., 2016) for the pharmacokinetics studies, toxicology 
studies, and pharmacokinetics studies of apatinib mesylate tablets. 
2.5 
Clinical Studies 
Refer to the IB of SHR-1210 (version number: 2.0, version date: 24 Nov., 2016) and the IB of 
apatinib mesylate tablets (version number: 2.0, version date: 8 Dec., 2016). 
2.6 
Potential Risks and Benefits 
Only topotecan (intravenously or orally administered) has been approved by the FDA for the 
treatment of ED-SCLC after failure of first-line standard therapies. No immunotherapy is 
commercially available currently. SHR-1210 is a humanized PD-1 antibody independently 
developed by Hengrui. Preclinical data suggested that it has similar pharmacodynamics and 
anti-tumor effects to nivolumab and pembrolizumab. The studies on the PD-1/PD-L1-based 
combination therapy that have been published and undergoing abroad suggest that patients may 
benefit and the safety is controllable. For more detailed safety information of SHR-1210, please 
refer to the IB (version number: 2.0, version date: 24 Nov., 2016) and the informed consent 
form (ICF). 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 
Primary objective 
• 
To evaluate the safety and efficacy of SHR-1210 combined with apatinib in the treatment of 
ED-SCLC failing first-line standard therapy 
3.1.2 
Secondary objective 
• 
To evaluate the immunogenicity 
3.1.3 
Exploratory objective 
• 
To evaluate the correlation between biomarkers (including but not limited to PD-L1 and 
TMB) and efficacy 


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3.2 
Study Endpoints 
3.2.1 
Primary endpoints 
• 
Incidence of AEs evaluated per CTCAE 4.03, especially the incidence of AEs meeting any of 
the following criteria: 
o 
Hematologic toxicity 
- 
Grade 4, or 
- 
Grade ≥ 3 thrombocytopenia with hemorrhage, or 
- 
Grade ≥ 4 neutropenia with pyrexia and infection 
o 
Grade ≥ 3 non-hematologic toxicity (except for laboratory abnormalities), hypertension, 
rash, diarrhea, nausea and vomiting that cannot be controlled after symptomatic treatment 
o 
Grade ≥ 3 laboratory abnormalities that lead to medical interventions or hospitalization, 
or last for ≥ 7 days 
o 
Any Grade 5 AEs 
• 
ORR evaluated as per RECIST v1.1 
3.2.2 
Secondary endpoints 
• 
Incidence of AE and SAE assessed as per CTCAE 4.03, laboratory measurements, ECG, vital 
signs, and other safety endpoints 
• 
OS, 6-month OS rate, and PFS, TTR, DoR, and DCR evaluated as per RECIST v1.1 
• 
Immunogenicity evaluation: positive rates of ADA and NAb 
3.2.3 
Exploratory endpoint 
• 
Tumor biomarkers (including but not limited to expression levels of PD-L1 and TMB in tumor 
samples) 
4 
STUDY DESIGN 
This is a randomized, open-label, multi-center phase II clinical study. Eligible subjects after 
screening will be randomized into the following 3 groups in a 1:1:1 ratio, with 4 weeks as a 
treatment cycle. Refer to Figure 2 for the study design. Refer to Figure 3 for the study process.  
The study consists of two stages. In Stage I, subjects will be randomized into 3 different dose groups, 
with 6 subjects in each group. It is planned that after the last subject in Stage I completes Cycle 1 
treatment (28 days), the leading center's principal investigator and the sponsor will jointly perform a 
safety assessment of subjects enrolled in Stage I, decide the treatment group of Stage II, and choose 
one group of method of administration and a tolerated dose of apatinib for Stage II treatment. 


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A total of 39 subjects will be enrolled in Stage II. The primary analysis will be performed when the 
last subject has been treated for 180 days. 
For any treatment group entering Stage II, if the safety is acceptable and the efficacy meets the 
corresponding statistical criteria, it indicates potential needs of further development. 
 
Note: Subjects with PD for the first time must be confirmed; for medication after the initial PD, refer to Section 6.1.2 
of the protocol; for imaging confirmation and subsequent evaluation of the initial PD, refer to Section 8.1.2 of the 
protocol 
Figure 2. Design of the phase II study of SHR-1210 combined with apatinib 
• Previously 
received first-line 
platinum-based 
treatment for small 
cell lung cancer 
and have shown 
objective 
radiographic 
progression 
• ECOG PS of 0-1 
• Life expectancy of 
≥ 8 weeks 
Stage I 
Safety (N = 6) 
Stage II 
Safety and efficacy (N = 39) 
SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, 
PO, QD 
(n=45) 
SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, 
PO, QD (5 days on, 2 days off) 
(n=45) 
SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, 
PO, QD (7 days on, 7 days off) 
(n=45) 
Unblinded 
Randomiza- 
tion 
Until the occurrence of 
any of the following: start 
of new anti-tumor 
treatment, progressive 
disease, withdrawal of ICF 
by subjects, or death 


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Figure 3. Process of the study of SHR-1210 combined with apatinib 
 
Screening 
period 
Treatment period 
End of 
treatment/ 
withdrawal3 
Survival 
follow- 
up[5] 
Safety 
follow- 
up visit[4] 
SHR-1210 (Stage I/II) 
× 200 mg, IV, Q2W after C1D1 
Apatinib (Stage I/II) 
× 375 mg, PO, QD (continuous administration, or 5 days on, 2 days off, or 7 days on, 7 days off) after C1D1 
RECIST 1.1 
Assessment1 


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5 STUDY POPULATION 
5.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for this study. 
1. All patients must sign an ICF prior to starting any study-related procedures 
2. Aged ≥ 18 and ≤ 70 years 
3. Histologically or cytologically confirmed small cell lung cancer 
4. Staged ED-SCLC according to VALG staging 
5. Have previously received first-line platinum-based treatment for ED-SCLC and have 
shown objective imaging progression. Including: 
• 
Sensitive recurrence: progression in ≥ 90 days from the last chemotherapy 
• 
Drug-resistant recurrence: progression during chemotherapy or within 90 days from 
the last chemotherapy 
6. Able to provide tumor tissue samples for diagnosis, either archived samples within 
12 months prior to the first dose of study drug or freshly obtained. The specimens shall 
meet the requirements of formalin-fixed and paraffin-embedded (FFPE) tumor tissue 
blocks allowing the cutting of at least 5-10 slices with a thickness of 4-6 μm for staining 
and testing. Cell smears from fine needle aspiration or centrifuged pleural fluid, bone 
lesions without soft tissue components or decalcified bone tumor specimens, and drill 
biopsy tissues are not acceptable, as they are insufficient for biomarker detection 
7. ECOG PS of 0-1 
8. Life expectancy of ≥ 8 weeks 
9. With at least one target lesion without previous radiotherapy (RECIST v1.1) shown by 
CT or MRI scan ≤ 28 days prior to the first dose of study drug 
10. Males and females of reproductive potential must take contraceptive measures from the 
first dose of study drug to within 24 weeks after the last dose of study drug (see 6.6.2 of 
the protocol for recommended contraceptive methods) 
11. Had no transfusion of blood or blood products within 14 days prior to the first dose, not 
corrected with G-CSF or other hematopoietic colony-stimulating factors. Before the first 
dose of study drug, laboratory test values must meet the following conditions: 
(1) Hematology: WBC ≥ 3.0 × 109/L; ANC ≥ 1.5 × 109/L; PLT ≥ 100 × 109/L; HGB ≥ 
9.0 g/dL 


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(2) Liver function: AST ≤ 2.5 × ULN, ALT ≤ 2.5 × ULN for patients without liver 
metastasis; ALT and AST < 5 × ULN for patients with liver metastasis; TBIL ≤ 1.5 × 
ULN (TBIL < 3.0 mg/dL in patients with Gilbert syndrome); and ALB ≥ 3 g/dL 
(3) Renal function: Cr ≤ 1.5 × ULN or CrCl ≥ 40 mL/min (using Cockcroft/Gault 
formula, see Appendix 2); negative UPRO  
(4) Coagulation function: INR ≤ 1.5, APTT ≤ 1.5 × ULN  
(5) Others: Lipase ≤ 1.5 × ULN. Patients with lipase > 1.5 × ULN without clinical or 
radiographic evidence of pancreatitis may be enrolled; Amylase ≤ 1.5 × ULN. 
Patients with amylase > 1.5 × ULN without clinical or radiographic evidence of 
pancreatitis may be enrolled. ALP ≤ 2.5 × ULN; for patients with bone metastases, 
ALP ≤ 5 × ULN 
5.2 
Exclusion Criteria 
Patients meeting any one of the followings are not eligible to participate in this study:  
1. With histologically or cytologically confirmed mixed SCLC and NSCLC. 
2. Patients who have previously received anti-tumor viral treatment. Patients who have 
previously received any T cell costimulation or immune checkpoint therapy, including but not 
limited to CTLA-4 inhibitors, PD-1 inhibitors, PD-L1/2 inhibitors, or other drugs targeting T 
cells. 
3. Patients who have previously received anti-VEGF/VEGFR therapy. 
4. Patients with clinically symptomatic brain metastasis or meningeal metastasis. Treated 
patients with brain metastasis should meet the following conditions to be enrolled: 
• 
No MRI-proven progression ≥ 4 weeks after the end of treatment 
• 
Completed treatment within ≥ 28 days prior to the first dose of study drug 
• 
No need to receive systemic corticosteroid treatment (> 10 mg/day prednisone or an 
equivalent dose) in ≤ 14 days prior to the first dose of study drug 
5. Radiotherapy of the chest and whole brain should be completed less than 4 weeks prior to the 
first dose of study drug (patients whose palliative radiotherapy for bone lesions was 
completed prior to the first dose of study drug are allowed to be enrolled) 
6. Clinically symptomatic effusion in the third space, such as pericardial effusion, pleural 
effusion, and ascites effusion that cannot be controlled by drainage or other treatments 


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7. Active, known or suspected autoimmune diseases (see Appendix 4). Patients with vitiligo, 
type I diabetes, or residual hypothyroidism caused by autoimmune thyroiditis that only 
requires hormone replacement therapy or is unlikely to recur in the absence of external 
stimulation can be enrolled 
8. Have used corticosteroids (> 10 mg/day prednisone or equivalent dose) or other 
immunosuppressive agents within ≤ 14 days prior to the first dose of study drug. In the 
absence of active autoimmune diseases, inhaled or topical use of steroids and adrenal 
replacement steroids is permitted 
9. Patients who have received or plan to receive live vaccines within 4 weeks prior to the first 
dose of study drug 
10. With interstitial lung disease (ILD), drug-induced pneumonitis, radiation pneumonitis 
requiring steroid treatment, active pneumonitis with clinical symptoms, or severe pulmonary 
dysfunction 
11. Patients with TB or history of active TB infection within ≤ 48 weeks before screening, 
regardless of treatment status 
12. Except for alopecia and fatigue, other toxicities caused by previous anti-tumor treatments 
should have recovered to CTCAE 4.03 Grade ≤ 1 prior to the first dose of study drug Patients 
with other toxicities caused by previous anti-tumor treatments that cannot be resolved within 
expectations and have long-lasting sequelae, such as neurotoxicity caused by platinum-based 
treatments, are allowed to be enrolled 
13. Imaging (CT scan or MRI) showed tumor invasion of large blood vessels, symptoms of 
hemoptysis of daily hemoptysis ≥ 2.5 mL within 3 months before screening  
14. Patients who have undergone minor surgery (including catheterization) within 48 hours 
before the first dose of study drug 
15. Currently or recently (within 10 days prior to the first dose of study drug) using aspirin (> 325 
mg/day) or other non-steroidal anti-inflammatory drugs known to inhibit platelet function 
16. Currently or recently (within 10 days prior to the first dose of study drug) being treated with 
full-dose oral or parenteral anticoagulant or thrombolytic agents. But prophylactic use of 
anticoagulants is allowed 
17. Patients with hereditary bleeding tendency or coagulation dysfunction. Patients with 
clinically significant bleeding symptoms or a clear bleeding tendency within 12 weeks prior 
to screening, such as hemorrhage of digestive tract, stomach ulcer with hemorrhage, baseline 
fecal occult blood++ and above, or vasculitis  


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18. Had arterial/venous thrombosis within 24 weeks prior to signing of ICF, such as 
cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, and 
brain infarction), deep vein thrombosis, and pulmonary embolism 
19. Uncontrolled hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood 
pressure ≥ 90 mmHg), a history of hypertensive crisis or hypertensive encephalopathy 
20. With a history of the following diseases within 24 weeks prior to the signing of ICF: peptic 
ulcer, gastrointestinal perforation, corrosive esophagitis or gastritis, inflammatory bowel 
disease or diverticulitis, abdominal fistula, tracheo-esophageal fistula, or intra-abdominal 
abscess 
21. With clinical symptoms or diseases of the heart that are not well controlled, such as: (1) 
NYHA Class II or above heart failure (2) unstable angina (3) myocardial infarction within 24 
weeks (4) patients with clinically significant supraventricular or ventricular arrhythmia 
requiring treatment or intervention 
22. Known to be allergic to drugs or excipients, known to have severe allergic reactions to any 
kind of monoclonal antibody 
23. Patients complicated with other malignant tumors ≤ 5 years before the first dose, except for 
cervical carcinoma in situ, basal cell or squamous cell skin cancer that can be adequately 
treated, local prostate cancer after radical resection, and ductal carcinoma in situ after radical 
resection 
24. With evidence or history of psychiatric disorders, alcoholism, narcotics or drug abuse 
25. Patients with positive HBsAg and HBV DNA exceeding the upper limit of normal (1000 
copies/mL or 500 IU/mL) or positive HCV (HCV RNA or HCV Ab test shows acute/chronic 
infection); known history of positive HIV or known to have AIDS 
26. Have received any other investigational drug or participated in other interventional clinical 
study within 4 weeks prior to signing the ICF 
27. The investigator determines that the patient may have other factors leading to the 
discontinuation of the study, such as protocol incompliance, other serious diseases (including 
mental illness) requiring concomitant treatment, serious laboratory test abnormalities, 
accompanied by family or social factors that may affect the safety of the subject or the 
collection of data and samples 


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5.3 
Randomization Standard 
Subjects who do not meet the eligibility criteria shall not be enrolled in this study with no 
exceptions. In the event that an ineligible subject is randomized, or the treatment erroneously 
starts, or an enrolled subject no longer meets the eligibility criteria before starting the study 
treatment, the sponsor's medical representative and the investigator must jointly discuss whether 
the subject should continue or withdraw from the study. The sponsor should ensure that 
appropriate documentation is retained with regards to such decisions. 
Subjects who have failed previous screening may be screened again in this study. The informed 
consent form should be re-signed and a new subject number should be given for re-screening. The 
treatment will start within 24 hours after randomization. 
5.4 
Withdrawal from Study or Treatment Discontinuation 
5.4.1 
Study withdrawal criteria 
Reasons for withdrawal may include: 
1. 
The subject withdraws the ICF and refuses further follow-ups 
2. 
Any clinical adverse drug reactions, laboratory abnormalities, or complications that renders 
the subject not benefiting from further treatment, as determined by the investigator 
3. 
Other reasons investigator deems necessary for withdrawal, such as the inability to provide 
voluntary consent due to imprisonment or quarantine 
4. 
Lost to follow-up 
5. 
Death 
6. 
Study termination by the sponsor 
5.4.2 
Criteria for treatment discontinuation 
The study treatment must be discontinued when any of the following occurs: 
1.  Subject requests to discontinue the study treatment 
2.  Radiographic or clinical evidence of progressive disease, unless the subject meets the criteria 
for continuing treatment beyond progression (see 6.1.2 of the protocol) 
3.  Occurrence of pregnancy during the study 
4.  Any clinical AEs, laboratory abnormalities, or other medical conditions indicating that the 
subject can no longer benefit from the treatment 


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5. 
General deterioration of health status suggesting that the subject cannot continue to involve 
the study 
6.  The enrolled subject is found to have important protocol deviations such as ineligibility 
7.  Lost to follow-up 
8.  Study termination by the sponsor 
9.  Death 
10.  Other reasons as determined by the investigator 
5.4.3 
Procedures for withdrawal or discontinuation 
The end-of-treatment efficacy and safety examinations, safety follow-up, and survival follow-up 
as specified in the protocol must be completed as much as possible, and the AEs and their 
outcomes should be fully documented. The investigator can recommend or provide new or 
alternative treatments to a subject based on the condition of the subject. For subjects who 
discontinue the treatment for reasons other than radiologically confirmed PD, imaging evaluations 
shall be performed as much as possible per the scheduled time points until any of the following 
events occurs: start of new anti-tumor therapy, PD, withdrawal of ICF, or death. 
Subject's survival status should still be followed up even when the subject refuses to visit the study 
center, unless the subject withdraws consent to provide further information or consent to be further 
contacted. In such case, no study assessment is performed, nor any data are collected. The sponsor 
can retain and continue to use all data collected prior to withdrawal of ICF, unless the subject 
requests a retraction of collected data. 
5.5 
Termination or Suspension of Study 
This study can be terminated early or suspended if there are sufficient reasons. This may result 
from the decision of the regulatory authorities, changes in comments by the Ethics Committee, 
efficacy or safety issues of the study medications, or the judgment of the sponsor. In addition, 
Hengrui reserves the right to terminate the research and development of the investigational drug at 
any time. The party who decides to suspend/terminate the study should notify the investigator, 
sponsor, and regulatory authorities in writing, documenting the reasons for 
suspension/termination. The investigator must immediately notify the ethics committee and 
sponsor, and provide relevant reasons. 


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The reasons for termination or suspension of the study may include: 
1. 
Confirmed unexpected, major, or unacceptable risk to the subjects 
2. 
Existing efficacy data supporting study termination 
3. 
Poor protocol compliance 
4. 
Incomplete or undetectable data 
5. 
Valueless study results 
6 STUDY DRUGS 
6.1 
Treatment Regimen 
6.1.1 
Administration regimen 
Study drugs refer to SHR-1210 and apatinib, and other drugs during the study are non-study drugs. 
Refer to Table 5 for the treatment regimen. For the ease of liquid preparation, the protocol allows a 
deviation of ± 5% between the actual dosage and the theoretical dosage each time.  
The study drugs will be administered until PD (refer to Section 6.1.2 for continued medication 
beyond progression), intolerable toxicity, withdrawal of ICF, other reasons that require treatment 
discontinuation (whichever occurs first) 
Table 5. Treatment regimen 
Phase 
Drug 
Dose 
Route of 
Administration 
Administration Cycle 
II 
SHR-1210 
200 mg 
IV 
Q2W 
Apatinib, combined 
375 mg 
PO 
QD 
SHR-1210 
200 mg 
IV 
Q2W 
Apatinib, combined 
375 mg 
PO 
QD (5 days on, 2 days off)  
SHR-1210 
200 mg 
IV 
Q2W 
Apatinib, combined 
375 mg 
PO 
QD (7 days on, 7 days off) 
Note: 
1. 
On the day of SHR-1210 infusion, apatinib shall be administered 30 min after the end of SHR-1210 infusion. 
2. 
SHR-1210 is administered through intravenous drip infusion at 200 mg once every 2 weeks with 4 weeks as 1 
treatment cycle. 
3. 
Apatinib is administered orally once daily after meal with 4 weeks as 1 treatment cycle. Subjects are 
randomized into the three groups in a 1:1:1 ratio. Drugs should be administered at a fixed time every day as 
much as possible. 
4. 
PO: per os; QD: quaque die; IV: intravenous infusion; Q2W: once every 2 weeks; 5 Days on, 2 Days off: 
administration for 5 days and interrupt for 2 days; 7 Days on, 7 Days off: administration for 7 days and 
interrupt for 7 days 


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6.1.2 
Continued medication beyond progression 
Subjects are allowed to continue the original regimen of study treatment after the initial PD 
confirmed as per RECIST v1.1, provided that the following conditions are met: 
1. 
Investigator-assessed clinical benefit, and 
2. 
Tolerability in the subject 
Investigator-assessed clinical benefit and tolerability in the subject are based on the following 
considerations: 
1. 
No significant clinical symptoms and changes in laboratory parameters 
2. 
No change (deterioration) in the score of performance status 
3. 
No rapid tumor progression and no tumor progression involving vital organs/sites (such as 
metastases to central nervous system, respiratory failure due to tumor compression, and 
spinal cord compression) 
For subjects who continue the original regimen of study treatment after progression, the 
investigator must reassess the benefits and risks of the subject. The ICF must be re-signed. The 
longest duration of SHR-1210 administration is 2 years. 
An additional imaging evaluation must be performed in 4 weeks (+ 7 days) for confirmation after 
the initial documentation of imaging PD. If PD is not radiographically confirmed, the original 
study medication and imaging evaluation can be continued until relapse of PD (refer to Section 
8.1.2 of the protocol). Subjects with relapse of PD must discontinue treatment. 
6.1.3 
Continued treatment after study completion 
Study completion is defined as 180 days after the first dose of the last subject. 
Upon completion of the study, subjects who still benefit clinically may continue the study 
treatment provided by Hengrui until the criteria for discontinuation are met, and will be 
continuously followed for OS events. The study drug is provided through extension studies, 
rollover studies approved by the health regulatory authorities and ethics committee, or other ways 
determined by Hengrui. 
Hengrui reserves the right to stop providing the study drugs in any of the following cases: a) 
rejection of marketing application by health regulatory authorities; b) termination of the study due 
to safety issues; c) subjects able to obtain the study drugs from a public or privately-sponsored 
medical plan; or d) available replacement therapies in the local market. 


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6.2 
Study Drugs 
6.2.1 
Description 
The following study drugs will be supplied by the sponsor in a centralized manner. Refer to Table 6 
for the description of study drugs. 
Table 6. Description of study drugs 
Name 
SHR-1210 for injection 
Apatinib mesylate tablets 
Manufacturer 
Suzhou Suncadia Biopharmaceuticals Co., Ltd. Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Appearance 
White or off-white lyophilized powder  
Film-coated tablet, white or off-white after 
peeling off coating 
Route of 
Administration 
Intravenous injection 
Oral 
Strength 
200 mg/20 mL vial 
250 mg/tablet; 375 mg/tablet 
Storage and 
Stability 
Placed in a 2-8 °C medical refrigerator during 
storage and the shelf life is tentatively set to 2 
years. Do not freeze 
Sealed and stored below 25 °C and kept away 
from light. Valid for 2 years 
6.2.2 
Packaging and labeling of study drugs 
The sponsor will package and label the study drug in accordance with local regulatory requirements. 
6.3 
Study Drug Preparation 
The study drugs should be prepared by qualified or experienced study staff (such as physicians, 
pharmacists, or medical assistants) according to the drug brochures or package inserts (approved 
by national authorities or study center operating guidelines). 
6.3.1 
SHR-1210  
SHR-1210 is a lyophilized powder for injection that needs to be prepared before its administration 
via intravenous drip infusion. Refer to Drug Manual for the preparation of SHR-1210. 
6.4 
Dose Modifications and Delay 
6.4.1 
General rules for dose modification 
 
Reasons for dose modification or dose delay, actions taken, and results should be 
recorded in the medical record and eCRF of the subject. 
 
For the accompanying symptoms that existed at baseline, the investigator shall determine 
whether to adjust the dose according to the grade of adverse drug reactions. For example, 
at baseline, a subject's Grade 1 "asthenia" at baseline that becomes Grade 2 "asthenia" 
during the study treatment period is one level increase of "asthenia". The dose should be 
adjusted as a Grade 1 toxicity 


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 
If several adverse drug reactions of different grades or severity occur at the same time, 
the dose will be adjusted based on the highest level observed. 
 
If the dose is adjusted only due to abnormal hematological values, the dose will be 
adjusted based on the hematological values before the start of the treatment cycle. 
 
When the investigator judges that the adverse drug reaction is unlikely to further develop 
into a serious or life-threatening event, the current dose will be continued without dose 
modification or treatment interruption. In addition, no dose modification or treatment 
interruption is administered for anemia (non-hemolytic) because its symptoms can be 
relieved through blood transfusion. 
 
If, per the investigator's judgment, the toxic reaction is caused by a therapeutic drug, 
there is no need to adjust the dose of other drugs. 
 
Before PD, permanent discontinuation of a medication will not affect the continued 
administration of other treatments. 
 
If any treatment but not all drugs is interrupted due to adverse drug reactions of a drug, 
the treatment is still counted as a treatment cycle. 
6.4.2 
Apatinib 
Dose interruption of apatinib is allowed for up to 4 weeks (from the actual time of last dose); 
otherwise the treatment of apatinib shall be discontinued. A maximum of one dose modification is 
allowed; otherwise the subject will be considered intolerable and the treatment of apatinib shall be 
discontinued. Refer to Table 7 for the requirements of dose modification of apatinib. 
Table 7. Requirements of dose modification of apatinib 
Adverse Drug 
Reaction 
Grade 
Whether to 
Interrupt 
Treatment 
Rules for Dose Modification 
Hematologic 
Grade 1-2 
No 
— 
Grade 3 
Yes 
• 
For the first occurrence, interrupt the treatment until 
the adverse drug reactions recover to Grade ≤ 2, and 
resume the treatment at the original dose 
• 
For the second occurrence, interrupt the treatment 
until the adverse drug reactions recover to Grade ≤ 2, 
and resume the treatment at a reduced dose of 250 mg/d 
• 
For recurrence after dose reduction, the investigator 
should evaluate the risks/benefits of the continued 
apatinib treatment and determine whether the drug 
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Adverse Drug 
Reaction 
Grade 
Whether to 
Interrupt 
Treatment 
Rules for Dose Modification 
Grade 4 
Yes 
• 
Resume the treatment at a reduced dose of 250 mg/d 
after the adverse drug reactions recover to Grade ≤ 2 
• 
For the recurrence of Grade 4 toxicity after dose 
reduction, the treatment shall be permanently 
discontinued 
Non-Hematological 
Grade 1 
No 
— 
Grade 2 (lasting 
for ≥ 7 d) 
Yes 
• 
Resume the treatment at the original dose after the 
adverse drug reactions recover to Grade ≤ 1 
Grade 3 
Yes 
• 
For the first occurrence, interrupt the treatment until 
the adverse drug reactions recover to Grade ≤ 1, and 
resume the treatment at the original dose 
• 
For the second occurrence, interrupt the treatment 
until the adverse drug reactions recover to Grade ≤ 1, 
and resume the treatment at a reduced dose of 250 mg/d 
• 
For recurrence after dose reduction, the investigator 
should evaluate the risks/benefits of the continued 
apatinib treatment and determine whether the drug 
should be permanently discontinued 
Grade 4 
Yes 
• 
Resume the treatment at a reduced dose of 250 mg/d 
after the adverse drug reactions recover to Grade ≤ 1 
• 
For the recurrence of Grade 4 toxicity after dose 
reduction, the treatment shall be permanently 
discontinued 
In the case of the following circumstances, the measures to be taken for apatinib (the following 
grades are per CTCAE v4.03) are described as follows; if necessary, relevant departments should 
be consulted: 
Hemorrhage 
• 
Grade 3 or 4 bleeding should be treated accordingly and apatinib treatment should be 
permanently discontinued 
Thrombosis/embolism 
• 
For arterial thrombosis of any grade, apatinib treatment should be permanently 
discontinued 
• 
For Grade 4 venous thrombosis, apatinib treatment should be permanently discontinued 
• 
For Grade 3 venous thrombosis, apatinib treatment should be interrupted. For 
anticoagulant therapy at the planned therapeutic dose for ≤ 2 weeks, apatinib treatment 
should be interrupted until the end of anticoagulant therapy. For anticoagulant therapy at 


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the planned therapeutic dose for > 2 weeks, apatinib treatment should be interrupted for 
2 weeks until the following criteria are met, and the study treatment may be resumed 
during the anticoagulant treatment: 
− 
Before the resumption of study medication, the INR should be within the target 
range (usually 2-3) 
− 
Subjects should not have Grade 3 or 4 bleeding events since study enrollment 
− 
No finding of tumor invasion or adjacency to large blood vessels in previous tumor 
evaluations 
Note: Therapeutic dose of anticoagulant therapy is defined as the gradual escalation of the dose of 
warfarin or other anticoagulants to a dose level that maintains an INR not less than 1.5 (usually 
2-3). The dose of warfarin should be recorded in the eCRF, and the INR should be monitored 
throughout the treatment period for subjects receiving anticoagulant therapy. 
Hypertension 
The blood pressure should be regularly measured in order to monitor the occurrence and 
deterioration of the subject's hypertension. 
• 
Grade 1: Prehypertension (systolic blood pressure of 120-139 mmHg, diastolic blood 
pressure of 80-89 mmHg), no intervention is needed. 
• 
Grade 2: First-stage hypertension (systolic blood pressure of 140-159 mmHg, diastolic 
blood pressure of 90-99 mmHg), medical intervention is required; repeated or persistent 
(≥ 24 h), an increase in symptomatic systolic blood pressure by > 20 mmHg, or an 
increase in blood pressure within the normal range to > 140/90mmHg. Apatinib 
treatment should be interrupted. An antihypertensive drug may be used for treatment. 
Once the blood pressure is controlled to < 140/90 mmHg, the subject may continue the 
apatinib treatment. 
• 
Grade 3: Second-stage hypertension (systolic blood pressure of ≥ 160 mmHg, diastolic 
blood pressure of ≥ 100 mmHg), more than one antihypertensive drug or a higher 
intensity treatment are required. For persistent or symptomatic hypertension, apatinib 
treatment should be interrupted; if hypertension is still uncontrollable after 4 weeks of 
treatment, apatinib treatment should be permanently discontinued. 
• 
Grade 4: Life-threatening (malignant hypertension or persistent nerve damage, 
hypertensive crisis) emergency intervention, life-threatening (such as hypertensive 
crisis). For Grade 4 hypertension, apatinib treatment should be permanently 
discontinued. The dose of antihypertensive drugs used should be recorded at each visit. 


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The dose of antihypertensive drugs used should be recorded at each subject visit of the subjects. If 
hypertension still persists when the treatment is discontinued, blood pressure and the use of 
antihypertensive drugs should be monitored every 3 months until the blood pressure returns to 
normal or the study completion. 
Reversible posterior leukoencephalopathy syndrome (RPLS)  
Symptoms and signs consistent with RPLS are rarely reported in subjects receiving the drug 
treatment. This is a rare neurological disease. The symptoms and signs are: epilepsy, headache, 
mental status changes, visual disturbance, or cortical blindness, with or without hypertension. 
Once a subject develops RPLS, apatinib treatment should be permanently discontinued. 
Proteinuria 
Follow the schedule of study procedures for urinalysis, if: 
• 
< 2+, continue the administration of apatinib as planned, no additional tests are required 
• 
≥ 2+, immediately monitor the 24-hour urine protein. 24-hour urine protein:  
− 
< 1 g, continue apatinib treatment as planned 
− 
1-3.4 g, interrupt the apatinib medication until the 24-hour urine protein is < 1 g, and 
then resume the apatinib treatment. For the second occurrence, interrupt apatinib 
treatment until the 24-hour urine protein is < 1 g, and reduce the dose to 250 mg/d. 
For recurrence after dose reduction, the investigator should evaluate the 
risks/benefits of the continued apatinib treatment and determine whether the drug 
should be permanently discontinued 
− 
≥ 3.5 g or occurrence of nephrotic syndrome, apatinib treatment is permanently 
discontinued 
6.4.3 
SHR-1210  
Dose increase or reduction for SHR-1210 is prohibited. Only interruption or permanent 
discontinuation is allowed. Dose interruption of SHR-1210 is allowed for up to 8 weeks (from the 
actual time of last dose); otherwise the treatment of SHR-1210 shall be discontinued. For 
SHR-1210 interruption that exceeds 8 weeks, the investigator should discuss with the sponsor's 
medical department if he/she judges that the subjects can benefit from continued treatment. 
Refer to Table 8 for the requirements on dose modification of SHR-1210. Refer to Appendix 6 for 
the guidelines on dose modifications and handling of toxicities of SHR-1210. Refer to Table 9 for 
the treatment of SHR-1210 related infusion reactions. 


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In addition, treatment should be discontinued permanently if PD is determined by the investigator 
as per the RECIST v1.1 criteria (unless subjects meet the criteria for continued treatment after PD 
as described in Section 6.1.2 of the protocol). For treatment interruption due to medical events, 
surgeries, or unexpected (holidays) events unrelated to the study treatment, the subject should 
resume study treatment within 2 weeks after interruption (i.e., originally scheduled administration 
time), unless otherwise jointly determined by the investigator and the sponsor. The reasons for 
treatment interruption should be documented in the eCRF. 
Table 8. Principles for SHR-1210 dose modification 
Adverse Drug 
Reaction 
Severity 
Dose 
Modification 
Pneumonia 
Grade 2 pneumonia 
Treatment 
interruptiona 
Grade 3 or 4 pneumonia 
Permanent 
discontinuation 
Diarrhea/Entercolitis 
Grade 2 or 3 diarrhea or entercolitis 
Treatment 
interruptiona 
Grade 4 diarrhea or entercolitis 
Permanent 
discontinuation 
Dermatitis 
Grade 3 dermatitis 
Treatment 
interruptiona 
Grade 4 dermatitis 
Permanent 
discontinuation 
Hepatitis 
For subjects with normal baseline ALT, AST, or TBIL, Grade 2 AST, ALT, or 
TBIL increased, or 
For subjects with baseline AST, ALT, or TBIL > ULN, AST, ALT, or TBIL 
increased by ≥ 50% persisting for < 7 days 
Treatment 
interruptiona 
For subjects with normal baseline ALT, AST, or TBIL, Grade 3 or 4 AST, 
ALT, or TBIL increased, or 
For subjects with baseline AST, ALT, or TBIL > ULN, AST, ALT, or TBIL 
increased by ≥ 50% persisting for ≥ 7 days 
Permanent 
discontinuation 
Hypophysitis 
Grade 2 hypophysitis 
Treatment 
interruptionb 
Grade 3 or 4 hypophysitis 
Permanent 
discontinuation 
Adrenal cortical 
insufficiency 
Grade 2 adrenal cortical insufficiency 
Treatment 
interruptionb 
Grade 3 or 4 adrenal cortical insufficiency 
Permanent 
discontinuation 
Hyperthyroidism 
Grade 3 or 4 hyperthyroidism 
Permanent 
discontinuation 


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Adverse Drug 
Reaction 
Severity 
Dose 
Modification 
Type 1 diabetes 
Grade 3 hyperglycemia 
Treatment 
interruptionb 
Grade 4 hyperglycemia 
Permanent 
discontinuation 
Kidney dysfunction 
Grade 2 or 3 creatinine increased 
Treatment 
interruptiona 
Grade 4 creatinine increased 
Permanent 
discontinuation 
Neurotoxicity 
Grade 2 neurotoxicity 
Treatment 
interruptiona 
Grade 3 or 4 neurotoxicity 
Permanent 
discontinuation 
Infusion reactions 
Grade 3 or 4 infusion reaction 
Permanent 
discontinuation 
Other AEs 
First occurrence of other Grade 3 AE 
Treatment 
interruptiona 
Second occurrence of the same Grade 3 AE 
Permanent 
discontinuation 
Grade 3 AEs that cannot recover to Grade 0-2/baseline level within 7 days or 
recover to Grade 0-1/baseline level within 14 days 
Permanent 
discontinuation 
Grade 4 AE 
Permanent 
discontinuationc 
Note: 
a:  Resume the medication after the symptoms improve to Grade 0-1 or the baseline level.  
b:  For hypophysitis, adrenal insufficiency, and type 1 diabetes, medication may be resumed if the AEs are fully 
controlled and only require physiological hormone replacement therapy.  
c:  For Grade 4 abnormal laboratory findings, the decision of treatment discontinuation should be based on the 
accompanying clinical symptoms/signs and the clinical judgment of the investigator. 
Table 9. Treatment recommendations for infusion reactions of SHR-1210 
CTCAE 
Grade 
Dose Modification 
Treatment of Toxicity 
Any 
Grade 
 
- Treat according to local clinical practice 
- Monitor the subject's infusion-related reactions (e.g., pyrexia or 
shivers, flushing and/or pruritus, changes in heart rate and blood 
pressure, dyspnea, chest discomfort, and rash) and allergic 
reactions (e.g., generalized urticaria, angioedema, asthma, 
hypotension, and tachycardia) 


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CTCAE 
Grade 
Dose Modification 
Treatment of Toxicity 
Grade 1 
The infusion rate may be 
reduced by 50% or the infusion 
can be temporarily interrupted 
until the infusion reaction is 
relieved 
For Grade 1 or 2: 
- Give acetaminophen and/or antihistamines at the discretion of the 
investigator based on local clinical practice 
- Consider prophylactic medication before subsequent courses of 
treatment according to local clinical practice 
Grade 2 
The infusion rate may be 
reduced by 50% or the infusion 
can be temporarily interrupted 
until the infusion reaction is 
relieved. The subsequent 
infusion rate can be adjusted to 
50% of the initial rate 
Grade 3/4 
Permanent discontinuation 
For Grade 3 or 4: 
- Deal with severe infusion-related reactions according to local 
clinical practice (e.g., administration of epinephrine, 
diphenhydramine, ranitidine, and glucocorticoids) 
6.5 
Concomitant Medications 
The use of drugs or vaccines explicitly prohibited in the exclusion criteria is prohibited during the 
entire study. If any explicitly prohibited drug or vaccine is clinically indicated during the study, the 
interruption of study treatment may be required. The investigator shall discuss with the sponsor's 
medical department. The decision whether the subject continues to participate in the study 
treatment or vaccination arrangements needs to be jointly decided by the investigator, the sponsor, 
and the subject. The investigator and/or the subject's attending physician shall make the final 
decision on supportive therapy or vaccination. 
All drugs related to the treatment of AEs other than solvents within 28 days before the first dose of 
the study drug until 30 days after and 30-60 days after the end of the treatment should be 
documented in the CRF, including the name, dose, route of administration, frequency of 
administration, purpose, and start and end dates. 
6.5.1 
Permitted concomitant medications and/or treatment 
During the treatment period, the investigator, per his/her judgment, may give the subject the best 
supportive treatment for the health of the subject. The clinical comorbidities and various AEs 
should be actively treated, especially immune-related adverse events (irAEs). 
Subjects are allowed to receive bisphosphonate for the treatment of bone metastases. If systemic or 
local analgesia is not effective in controlling painful lesions of bone metastases, a small area of 
palliative radiotherapy irradiation (the area of the radiotherapy must be < 5% of the bone marrow 
region) is allowed. 


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Palliative treatment for lesions outside the lungs is allowed during the study (when the treatment of 
the subjects is needed to improve symptoms upon the onset of PD), including the treatments for 
pleural effusion, ascites, pericardial effusion, and radiotherapy for brain lesions. During such 
treatment, the study drugs should be interrupted until the end of the recovery period of palliative 
treatment. 
6.5.2 
Prohibited concomitant medications and/or treatment 
Subjects are prohibited from the following therapies during the treatment period of this study:  
 
Systemic chemotherapy and biological therapy (anti-tumor drugs with 
immunomodulatory effects, including but not limited to interferon, interleukin-2, 
thymosin, and immune cell therapy) 
 
Immunotherapy not specified in this protocol;  
 
The use of other drugs not specified in the protocol, including Chinese patent medicines 
with clear anti-tumor indications (refer to Appendix 5) 
 
Radiotherapy (Note: As long as it is not a lung or target lesion, the sponsor may approve 
and allow radiotherapy to symptomatic isolated lesions or to the brain) 
 
Inoculation of live vaccines within 28 days before the first dose of the study medication 
and during the course of the study. Live vaccines include but are not limited to the 
following: rubeola, epidemic parotitis, rubella, chickenpox, yellow fever, rabies, BCG, 
and typhoid (oral) vaccines. Seasonal inactivated flu vaccines for injection are permitted 
but intranasal live attenuated flu vaccines (e.g., FluMist®) are not permitted 
 
Corticosteroids. Inhaled steroids are permitted as part of a fixed treatment for asthma or 
chronic obstructive pulmonary disease (COPD). Corticosteroids to treat potential irAE 
are permitted. After consultation with the sponsor, physiological doses of corticosteroids 
are permitted. Corticosteroids may be used prophylactically to prevent allergic reactions 
(such as intravenous contrast agent) 
Based on the investigator's assessment, subjects who need to use any of the above therapies for 
clinical treatment should be excluded from the study. Subjects can receive other medications as 
deemed medically necessary by the investigator 
It is important for the investigator to review each drug (prescription and over-the-counter) the 
subject receives before the start of the study and at each study visit.  
 
At each visit, the subject must be asked about any new medication received since the last 
visit  


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 
In order to reduce the risk of drug interactions, all measures must be taken to limit the 
number of concomitant medications that are indeed necessary.  
 
During the administration period, drugs with hepatotoxicity should be avoided (i.e., 
drugs with hepatotoxicity warning in the package insert). The investigators are 
encouraged to review the potential hepatotoxicity of each drug at www.livertox.nih.gov.  
6.5.3 
Drugs that must be used with caution 
1. Drugs that may have drug-drug interactions with apatinib 
In vitro studies have shown that apatinib is primarily metabolized by the liver P450 enzyme 
CYP3A4. Apatinib has a strong inhibitory effect on CYP3A4 and CYP2C9, and has a moderate 
inhibitory effect on CYP2C19. CYP3A4 inducers (dexamethasone, carbamazepine, rifampicin 
and phenobarbital) and inhibitors (ketoconazole, itraconazole, erythromycin and clarithromycin), 
CYP3A4 substrates (simvastatin, cyclosporine and pimozide), and other drugs metabolized via 
CYP3A4 (such as benzodiazepines, dihydropyridine, calcium ion antagonist and HMG-COA 
reductase inhibitors) should be used with caution during the treatment. Omeprazole should be used 
with caution during the treatment (except when omeprazole must be used to treat serious adverse 
drug reactions). 
The substrates of CYP2C9 and CYP2C19 should be used with caution, as shown in Table 10. 
Table 10. CYP2C9 and CYP2C19 substrates that should be used with caution 
P450 Enzyme 
Substrate 
CYP2C9 
Diclofenac, phenytoin, piroxicam, S-warfarin, and tolbutamide 
CYP2C19 
Diazepam, imipramine, lansoprazole, and S-mephenytoin 
2. Drugs that prolong the QT interval of the heart 
As tinib drugs may cause toxicities of prolonged QT interval in clinical applications, drugs that 
may prolong the QT interval should be used with caution during the study. These mainly include, 
but are not limited to, the following categories of drugs: 
 
Antibiotics: fluoroquinolones: sparfloxacin, gatifloxacin, levofloxacin, moxifloxacin, 
ofloxacin, ciprofloxacin; macrolides: erythromycin, clarithromycin, telithromycin, 
azithromycin, roxithromycin, and metronidazole 
 
Antiarrhythmics: quinidine, procainamide, disopyramide, flecainide, propafenone, 
amiodarone, dronedarone, sotalol, dofetilide, and ibutilide 
 
Drugs used to relieve angina pectoris: ranolazine, ivabradine 


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 
Antipsychotics: risperidone, fluphenazine, droperidol, haloperidol, thioridazine, 
pimozide, olanzapine, and clozapine 
 
Antifungal drugs: voriconazole, posaconazole 
 
Antimalarial drugs: mefloquine, chloroquine 
 
Antihistamines: terfenadine, astemizole, hydroxyzine 
 
Gastrointestinal drugs: antiemetics: ondansetron, granisetron, dolasetron, droperidol 
(0.625 to 1.25 mg may be a safe dose), hydroxyzine; prokinetics: cisapride, domperidone, 
metoclopramide 
 
Antidepressants: amitriptyline, imipramine, clomipramine, dosulepin, and doxepin 
3. CYP3A4 substrates prohibited during the study (drugs with narrow safety windows and 
may cause serious adverse drug reactions when their metabolism is affected) include but 
are not limited to: 
 
Hypoglycemic agents: tolbutamide, chlorpropamide 
 
Ergot derivatives: dihydroergotamine, ergometrine, ergotamine, methyl ergometrine 
(potential risk of ergot poisoning, including severe vasospasm leading to peripheral and 
cerebral ischemia) 
 
Antipsychotic: pimozide (can potentially increase the risk of prolonged QT interval) 
 
Antiarrhythmics: amiodarone (prohibited within 6 months prior to randomization), 
bepridil, flecainide, lidocaine, mexiletine, quinidine, and propafenone 
 
Immunomodulators: cyclosporine, tacrolimus, sirolimus (may potentially increase the 
risk of nephrotoxicity and neurotoxicity) 
 
Miscellaneous: quetiapine, risperidone, clozapine, tomoxetine hydrochloride 
4. If warfarin is used for anticoagulation during the study, the dose should be reduced and 
closely monitored, and the study drug should be discontinued if necessary. 
5. During the treatment period, anti-tumor drugs and adjuvant drugs related to anti-tumor 
treatments, such as anti-tumor traditional Chinese medicine (refer to Appendix 6) and 
immunological agents, shall be discontinued. 
6.6 
Medication During Pregnancy, Childbearing Age, and Lactation 
The following lists the special restrictions on concomitant medications during the study period. 
Medication during pregnancy, childbearing age, and lactation 


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6.6.1 
Pregnancy 
SHR-1210 is an IgG4 that can cross the placental barrier. It has been suspected/confirmed to have 
teratogenicity/fetal toxicity. Pregnant women must not be enrolled in the study. 
6.6.2 
Childbearing potential 
Women of childbearing potential must have a negative serum pregnancy test within 3 days prior to 
the first dose of the study drug. 
Female subjects of childbearing age and male subjects with partners of childbearing age should be 
sterilized or agree to take highly effective contraceptive measures during the study period and 
24 days after the last study dose. 
After consulting with the subject, the investigator or designated personnel will select appropriate 
contraceptive methods for the subject and his/her partner from the following contraceptive 
methods, and confirm the subject's awareness of correct and consistent use the contraceptive 
method. At time points shown in the Schedule of Activities, the investigator shall notify the subject 
of the persistent and correct use of contraception. The subject should be aware that the investigator 
must be notified immediately once the selected method of contraception is stopped, or when the 
subject or the partner is suspected or confirmed of pregnancy. 
An effective contraception method refers to a method with an annual failure rate of < 1% when 
correctly used independently or with other methods, including: 
1. Commonly used hormonal contraceptive methods associated with the suppression of 
ovulation (e.g., oral, inserted, injectable, implants, subcutaneous) should meet the 
requirement that the female subject or partner of male subject has been using this method 
for a period of time with proven effectiveness, and plans to continue using it correctly 
throughout the study. 
2. Correctly inserted intrauterine devices. 
3. Male/female condom combined with topical spermicides (i.e., foams, gels, films, creams, 
or suppositories). 
4. Male sterilization by vasectomy. 
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusion (the occlusion 
should be proven effective by relevant instruments). 
Menopause refers to 12 months of amenorrhea in women ≥ 45 years old without biological or 
physiological reasons: 


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1. Women ≤ 55 years old must have a serum follicle-stimulating hormone (FSH) test, i.e., 
FSH > 40 mIU/mL to prove menopause 
2. Women who use hormone replacement therapy (HRT) may artificially suppress FSH 
levels and require a certain washout period to obtain a normal physiological level of 
FSH. The investigator is recommended to determine the washout period based on the 
level of FSH. Any serum FSH > 40 mIU/mL during the washout period is considered 
menopause. Recommended duration of the washout period: 
• 
≥ 1 week for vaginal hormone products (rings, ointments, and gels) 
• 
≥ 4 weeks for transdermal products 
• 
≥ 8 weeks for oral products 
6.6.3 
Lactation 
Whether SHR-1210 is secreted in breast milk is unknown. Considering that many drugs are 
present in breast milk, SHR-1210 may be potentially toxic to infants. Thus, lactating women who 
are breast feeding must not be enrolled in this study. 
6.7 
Subject Compliance 
The medication compliance of the subject undergoing study treatment at the study center will be 
monitored through the following visits:  
• 
Tablets: Subjects will be required to return all unused study drugs from the previous 
cycle before the commencement of the next cycle. The number of tablets returned by the 
subjects will be counted, recorded, and archived. 
• 
Drugs for intravenous infusion: The study center shall prepare the drugs and complete 
the documentation as per the product brochure or package insert of the study drugs. The 
documentation system of the study center should include all relevant or required 
information with regards to preparation and administration. 
6.8 
Return and Disposal of Drugs 
In this study, the containers, vials, infusion bags, and syringes of study drugs that are used and 
partially used may be destroyed on-site according to the guidelines and operating procedures 
established by the study center and local institutions. 
All unused study drugs shall be returned to the sponsor for destruction after the study is 
completed/terminated or after the expiry date. The return of the study drugs will be arranged by the 
clinical research associate designated by the sponsor. 


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6.9 
Handling of Complaints 
To ensure the safety of subjects and the quality of monitoring, and to assist in the improvement of 
processes and drugs, the sponsor will collect product complaints related to the study drugs used in 
the clinical study. 
Complaints related to concomitant medications will be reported directly to the manufacturer 
according to the product information. 
The investigator or designated person thereof is responsible for completing the following product 
complaint procedures in accordance with the relevant requirements of this study: 
• 
Use a study-specific complaint form to record the reported product complaints and 
relevant complete descriptions. 
• 
Fax the completed product complaint form to the sponsor or designated person thereof 
within 24 hours. 
If the investigator is required to return the product for investigation, the investigator should return 
a copy of the product complaint form together with the product. 
7 STUDY PROCEDURES 
7.1 
Procedures of Subject Enrollment and Randomization 
7.1.1 
Subject enrollment 
The investigator will enroll the subjects following the steps below: 
1. Obtain an ICF with the subject's signature before proceeding with any study-related 
procedures. 
2. The principal investigator or designated person thereof with appropriate training will 
formally determine the eligibility of the subject after reviewing the inclusion/exclusion 
criteria. 
The sponsor will monitor the enrollment of each cohort such that the sample size of each cohort 
meets the study requirements. 
Subjects who do not meet the relevant criteria of this study (screening failure) may be rescreened. 
If re-screening of subjects is considered, the investigator must contact the sponsor's medical 
department. Each subject may be re-screened once. For rescreening, the subject must re-sign the 
ICF and will be assigned another subject ID. 


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In the first stage, if the subject develops PD, withdraws the ICF, develops intolerability without 
completing the 28-day observation before withdrawal, or does not meet the inclusion/exclusion 
criteria, the principal investigator of the leading center and the sponsor may decide whether to 
enroll additional subjects as appropriate. 
7.1.2 
Handling procedures for mistakenly enrolled subjects 
The inclusion/exclusion criteria must be strictly followed. In the case where subjects who do not 
meet the inclusion/exclusion criteria are enrolled, the sponsor's medical department and the 
investigator shall discuss and determine whether to allow the subjects to continue to participate in 
the study, i.e., whether or not to administer the study drugs. If the investigator believes that it is 
medically appropriate for the subject to continue participating in the study, and the sponsor's 
medical department agrees with the investigator's decision, the subject may continue participating 
in the study and undergo the study treatment. If the investigator believes that it is medically 
appropriate for the subject to continue participating in the study, but the sponsor's medical 
department does not agree with the investigator's decision, the subject shall not continue 
participating in the study (whether or not to undergo the study treatment). Only after the 
investigator receives written approval from the sponsor can the subjects who are unqualified for 
the inclusion/exclusion criteria be enrolled for continued participation in the study. 
7.1.3 
Randomization and blinding 
This study is open-label and does not involve blinding. Eligible subjects after screening will be 
randomized into the following three treatment groups in a 1:1:1 ratio: SHR-1210 200 mg, IV, 
Q2W + apatinib 375 mg, PO, QD; SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, PO, QD 
(5 Days on, 2 Days off); or SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, PO, QD (7 Days on, 
7 Days off). 
7.2 
Main Study Procedures 
7.2.1 
Screening period (visit 1) 
Refer to Table 11 for procedures of visits during the screening period. 
Table 11. Procedures of visits during the screening period 
Period 
Screening Period 
Note 
Day 
-28 to -1 -7 to -1 -3 to -1 
Baseline 
 
 
 
 
ICF 
X 
 
 
Subjects who do not meet the relevant 
criteria of this study (screening failure) 
may be rescreened. See Section 7.1.1 of the 
protocol for rescreening procedures 


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Period 
Screening Period 
Note 
Day 
-28 to -1 -7 to -1 -3 to -1 
Inclusion/Exclusion Criteria 
X 
 
 
 
Demographics/Medical 
History/Medication History 
X 
 
 
The medications include treatment for 
initial diagnosis, including chemotherapy, 
radiotherapy, and surgical treatment. The 
time of the last anti-tumor treatment must 
be recorded. 
Vital Signs  
X 
 
 
Vital signs include body temperature, 
pulse, respiratory rate, and blood pressure. 
See Section 8.2.4 of the protocol for 
detailed requirements 
Weight/Height 
X 
 
 
 
Physical Examination 
X 
 
 
See Section 8.2.2 of the protocol 
ECOG PS 
X 
 
 
 
Laboratory tests 
 
 
 
 
12-Lead ECG 
X 
 
 
Refer to Section 8.2.3 of the protocol for 
details 
Hematology/Clinical Chemistry/ 
Urinalysis/Routine Stool 
 
X 
 
See Section 8.2.1 of the protocol 
Coagulation Function 
 
X 
 
 
Pregnancy Test 
 
 
X 
Serum pregnancy test 
Thyroid Function 
X 
 
 
See Section 8.2.7 of the protocol 
Myocardial Zymogram 
 
X 
 
See Section 8.2.7 of the protocol 
Pituitary Adrenal Axis Test 
X 
 
 
Applicable to hospitals where conditions 
permit 
HIV, HBV, and HCV 
X 
 
 
See Section 8.2.7 of the protocol 
Echocardiography 
X 
 
 
See Section 8.2.7 of the protocol 
Pulmonary function test and arterial blood 
gases 
X 
 
 
See Section 8.2.7 of the protocol 
AE Assessment 
X 
 
 
All AEs from the time of signing the ICF to 
the end of safety follow-up or the start of 
new anti-tumor therapy (whichever occurs 
first) and all SAEs from signing of ICF to 
the end of safety follow-up will be 
recorded in the CRF 
Concomitant Medications 
X 
 
 
Drugs related to the treatment of AEs other 
than solvents within 28 days before the first 
dose of the study drug until 30 days after 
and 30 to 60 days after the end of the 
treatment should be documented 
Response Evaluation 
 
 
 
 


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Period 
Screening Period 
Note 
Day 
-28 to -1 -7 to -1 -3 to -1 
Imaging Assessment 
X 
 
 
See Section 8.1 of the protocol 
Exploration of Biomarkers 
 
 
 
 
Archived or Fresh Tumor Tissue Sample 
X 
 
 
5-10 unstained tissue slices with thickness 
of 4-6 μm 
Peripheral Blood 
X 
 
 
Collect 16 mL of peripheral blood for 
tumor biomarker detection 
7.2.2 
Treatment period (visits 2 to N) 
Refer to Table 12 for procedures of visits during the treatment period. 
Table 12. Procedures of visits during the treatment period 
Period 
Treatment Period 
Note 
Cycle 1 
Cycle 2 and thereafter 
Day 
1 
15 
(± 3 days) 
1  
(± 3 days) 
15 
(± 3 days) 
Vital Signs  
X 
X 
X 
X 
Vital signs include body temperature, 
pulse, respiratory rate, and blood 
pressure. Before each SHR-1210 
administration. See Section 8.2.4 of 
the protocol for detailed requirements 
Body Weight 
X 
X 
X 
X 
Before each SHR-1210 
administration 
Physical Examination 
 
X 
X 
X 
Before each SHR-1210 
administration. See Section 8.2.2 of 
the protocol 
ECOG PS 
X 
X 
X 
X 
Before each SHR-1210 
administration 
Laboratory Tests 
 
 
 
 
 
12-Lead ECG 
X 
X 
X 
X 
After each SHR-1210 infusion. See 
Section 8.2.3 of the protocol for 
detailed requirements 
Hematology/Clinical 
Chemistry/Urinalysis/Routine 
Stool 
 
X 
X 
X 
Before each SHR-1210 
administration. See Section 8.2.1 of 
the protocol 
Coagulation Function 
 
 
X 
 
Before each SHR-1210 
administration 
Thyroid Function 
X 
 
X 
 
Before each SHR-1210 
administration 
Myocardial Zymogram 
 
 
 
 
Performed when clinically indicated 
per the investigator's judgment 


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Period 
Treatment Period 
Note 
Cycle 1 
Cycle 2 and thereafter 
Day 
1 
15 
(± 3 days) 
1  
(± 3 days) 
15 
(± 3 days) 
Pituitary Adrenal Axis Test 
 
 
X 
 
Applicable to hospitals where 
conditions permit; before each 
SHR-1210 administration 
Echocardiography 
 
 
 
 
Performed when clinically indicated 
per the investigator's judgment 
Pulmonary function test and 
arterial blood gases 
 
 
 
 
Performed when clinically indicated 
per the investigator's judgment 
Immunogenicity (ADA, Nab) 
X 
 
X 
 
Sampling will performed once within 
0.5 h prior to SHR-1210 infusion on 
D1 of Cycle 1, Cycle 2, and every 3 
cycles thereafter (Cycles 5, 8, 11, and 
so forth). If the subject develops 
SHR-1210-related infusion reactions, 
blood samples should be collected as 
close as possible to the onset of the 
event, to the end of the event, and 
about 30 days after the end of the 
event, for immunogenicity 
comparison and analysis. Tests will 
be performed at the central laboratory 
AE Assessment 
X 
 
X 
 
All AEs from the signing of the ICF 
to the end of safety follow-up or the 
start of a new anti-tumor treatment 
(whichever comes first) and all SAEs 
from the signing of the ICF to the end 
of safety follow-up should be 
recorded in the CRF 
Concomitant Medications 
X 
 
X 
 
Drugs related to the treatment of AEs 
other than solvents within 28 days 
before the first dose of the study drug 
until 30 days after and 30 to 60 days 
after the end of the treatment should 
be documented 
Response Evaluation 
 
 
 
 
 
Imaging Assessment 
X 
X 
See Section 8.1 of the protocol 
Infusion of Study Drugs 
 
 
 
SHR-1210 
IV, Q2W 
See Section 6.1.1 of the protocol for 
the administration regimen. Subjects 
who meet specific conditions may 
continue the medication after PD 
(refer to Section 6.1.2 of the protocol 
for continued medication beyond 
progression). 


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Period 
Treatment Period 
Note 
Cycle 1 
Cycle 2 and thereafter 
Day 
1 
15 
(± 3 days) 
1  
(± 3 days) 
15 
(± 3 days) 
Apatinib 
PO 
See Section 6.1.1 of the protocol for 
the administration regimen. 
Exploration of Biomarkers 
 
 
Peripheral Blood 
X 
Collect approximately 16 mL of 
peripheral blood for tumor biomarker 
detection during each tumor 
evaluation period 
7.2.3 
End of treatment 
End of treatment refers to confirmation of progressive disease or withdrawal from the study. The 
end-of-treatment visit should be performed within ± 3 days of the decision of treatment 
discontinuation and/or withdrawal from the study (refer to Table 13). 
Table 13. Procedures of the end-of-treatment visit 
Period 
End of 
treatment 
Note 
28 Days (± 7 Days) 
Day 
± 3 days 
Vital Signs  
X 
Vital signs include body temperature, pulse, respiratory 
rate, and blood pressure. See Section 8.2.4 of the protocol 
for detailed requirements 
Body Weight 
X 
 
Physical Examination 
X 
See Section 8.2.2 of the protocol 
ECOG PS 
X 
 
Laboratory tests 
 
 
12-Lead ECG 
X 
Refer to Section 8.2.3 of the protocol for details 
Hematology/Clinical 
Chemistry/Urinalysis/Routine Stool 
X 
See Section 8.2.1 of the protocol 
Coagulation Function 
X 
 
Pregnancy Test 
 
Serum pregnancy test 
Thyroid Function 
X 
 
Myocardial Zymogram 
X 
 
Pituitary Adrenal Axis Test 
X 
Applicable to hospitals where conditions permit 
Echocardiography 
X 
 
Pulmonary function test and arterial blood 
gases 
 
Performed when clinically indicated per the investigator's 
judgment 
Immunogenicity (ADA, Nab) 
X 
 


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Period 
End of 
treatment 
Note 
28 Days (± 7 Days) 
Day 
± 3 days 
AE Assessment 
X 
All AEs from the time of signing the ICF to the end of 
safety follow-up or the start of new anti-tumor therapy 
(whichever occurs first) and all SAEs from signing of ICF 
to the end of safety follow-up will be recorded in the CRF 
Concomitant Medications 
X 
Drugs related to the treatment of AEs other than solvents 
within 28 days before the first dose of the study drug until 
30 days after and 30 to 60 days after the end of the 
treatment should be documented 
Response Evaluation 
 
 
Imaging Assessment 
X 
See Section 8.1 of the protocol 
Exploration of Biomarkers 
 
 
Archived or Fresh Tumor Tissue Sample 
X 
5-10 unstained tissue slices with the thickness of 4-6 μm, 
among which at least 5 slices will be used for PDL1 
testing 
Peripheral Blood 
X 
16 mL of peripheral blood will be collected for tumor 
biomarker detection 
7.2.4 
Safety follow-up 
Safety follow-ups will be performed 90 ± 7 days after the last dose (refer to Table 14). 
Table 14. Procedures of the safety follow-ups 
Period 
Safety 
Follow-Up 
Note 
Day 
28 Days  
(± 7 Days) 
Vital Signs  
X 
Vital signs include body temperature, pulse, respiratory 
rate, and blood pressure. See Section 8.2.4 of the protocol 
for detailed requirements 
Body Weight 
X 
 
Physical Examination 
X 
See Section 8.2.2 of the protocol 
ECOG PS 
X 
 
Laboratory tests 
 
 
12-Lead ECG 
X 
Refer to Section 8.2.3 of the protocol for details 
Hematology/Clinical 
Chemistry/Urinalysis/Routine Stool 
X 
See Section 8.2.1 of the protocol 
Coagulation Function 
X 
 
Thyroid Function 
X 
 
Immunogenicity (ADA, Nab) 
X 
 


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Period 
Safety 
Follow-Up 
Note 
Day 
28 Days  
(± 7 Days) 
AE Assessment 
X 
All AEs from the time of signing the ICF to the end of 
safety follow-up or the start of new anti-tumor therapy 
(whichever occurs first) and all SAEs from signing of ICF 
to the end of safety follow-up will be recorded in the CRF 
Concomitant Medications 
X 
Drugs related to the treatment of AEs other than solvents 
within 28 days before the first dose of the study drug until 
30 days after and 30 to 60 days after the end of the 
treatment should be documented 
End of treatment visit 
 
 
Survival Status 
X 
 
Subsequent Anti-Tumor Treatment 
X 
 
Response Evaluation 
 
 
Imaging Assessment 
X 
If the treatment is discontinued for reasons other than 
radiologically confirmed PD, imaging evaluations shall 
be performed as much as possible per the scheduled time 
points until any of the following events occurs: start of 
new anti-tumor therapy, PD, withdrawal of ICF, or death. 
7.2.5 
Survival follow-up 
Survival follow-ups will be performed once every 8 weeks (± 7 days) after the last dose and 
telephone interviews are acceptable. 
7.3 
Procedures of Continued Medication After Progressive Disease 
See Section 6.1.2 of the protocol for the procedures of continued medication after PD. Refer to 
Table 1 Schedule of Study Procedures for details. 
8 STUDY ASSESSMENT 
8.1 
Efficacy Evaluation 
This study does not involve central imaging review. The primary analysis of this study will be 
based on the tumor assessment conducted by the study centers per RECIST v1.1 (refer to 
Appendix 3). The ORR, PFS, TTR, DoR, DCR, 6-month OS rate, and OS after medication are 
evaluated. 
8.1.1 
Sites of radiographic scans 
The method used for tumor imaging evaluation during the baseline period must be consistent with 
the method used for each subsequent follow-up evaluation. Computerized tomography (CT) or 
magnetic resonance imaging (MRI) scans is recommended. Other involved parts are examined 


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based on the symptoms and signs of each subject. Baseline imaging evaluations should include 
thoracic, abdominal, and pelvic scans (from apex of lung to pubic symphysis), brain scan, bone 
scan, and scan of all known or suspected lesions. Each subsequent clinical tumor imaging 
evaluation should include thoracic, abdominal, and pelvic scans; brain and/or bone scans may be 
performed when clinically indicated. The frequency of imaging monitoring can be increased by the 
investigator as needed. 
8.1.2 
Evaluation time points 
The baseline tumor evaluation will be performed within 28 days before the first dose. Imaging data 
obtained before the signing of informed consent form may be used for tumor evaluation during the 
screening period as long as it meets the requirements of the protocol. 
During the study, imaging assessment will be performed on C1D28 and every 8 weeks (± 7 days) 
after C1D28 until radiographic PD is documented. An additional imaging evaluation must be 
performed in 4 weeks (+ 7 days) for confirmation after the initial documentation of response (CR 
or PR) and imaging PD. 
Criteria for relapse of PD:  
1. At 2 consecutive visits, the sum of the diameters of the target lesions increased by ≥ 20% 
from the lowest value (the smallest sum of diameters may occur at baseline or subsequent 
visits) and the absolute value increased by ≥ 5 mm, and/or 
2. At the time point of confirming PD, non-target lesions or new lesions have significantly 
progressed (exacerbated) relative to the first time point when progression of non-target 
lesions are discovered or new lesions are discovered (such that if the target lesions 
appeared CR, PR, or SD, the total tumor burden has increased sufficiently to discontinue 
treatment), and/or 
3. Compared to the first time point when new lesions are discovered, new lesions appeared at 
the time point of confirming PD. 
If PD is not confirmed, the study medication and imaging evaluation are continued until relapse of 
PD. Refer to Section 6.1.2 of the protocol for the relapse of PD. Subjects with relapse of PD must 
discontinue treatment. If the treatment is discontinued for reasons other than radiologically 
confirmed PD, imaging evaluations shall be performed as much as possible per the scheduled time 
points until any of the following events occurs: start of new anti-tumor therapy, PD, withdrawal of 
ICF, or death. Refer to Section 7 of the protocol for details. 


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If the investigator is unable to determine whether the disease is progressing, especially if the 
determination of non-target lesions and new lesions is uncertain, the subject may continue the 
treatment, and when clinically indicated or at the next scheduled assessment, the subject will be 
reassessed for the disease status. If PD is confirmed by scan reexamination, the date of progression 
should be the date of initial discovery. 
The interruption of one or more study drug(s) does not affect the evaluation frequency per RECIST 
v1.1. 
8.2 
Safety Evaluation 
8.2.1 
Routine laboratory safety evaluation 
Table 15. Routine laboratory safety evaluation 
Hematology 
RBC, HGB, HCT, WBC, PLT, LYM, ANC, MONO, EOS, and BASO 
Coagulation 
Function 
TT, PT, APTT, and INR 
Clinical 
Chemistry 
TBILa, ALT, AST, γ-GT, ALP, ALB, TP, LDH, BUN, Cr, Na, K, Cl, Mg, Ca, P, lipase, amylase, 
and FBG 
Urinalysis 
PH, UALB, UPROb, URBCc, and UGLU 
Routine Stool 
Test 
Occult blood 
a.  If TBIL ≥ 2 × ULN (without evidence of Gilbert syndrome), then direct bilirubin and indirect bilirubin shall be 
tested separately. 
b.  The white blood cells should be examined microscopically (if appropriate), and the red blood cells should be 
examined with a high-power field of view. 
8.2.2 
Physical examination 
A complete physical examination includes: general conditions, respiratory tract, cardiovascular 
system, abdomen, skin, head and neck (including ears, eyes, nose, and throat), lymph nodes, 
thyroid, musculoskeletal (including spine and limbs), genitals/anus, and nervous system 
evaluation. 
Refer to the schedule of visits in Table 1 for the time points of examinations. Refer to Appendix 1 
for ECOG PS scoring criteria. 
8.2.3 
12-Lead ECG 
The resting 12-lead ECG will be analyzed in the local laboratory according to the visit schedule.  
The 12-lead ECG examination will be performed after the subject rests for at least 5 min in the 
lying position. All 12-lead ECGs should be recorded while the subject is lying and resting. When 
clinically needed, for example when a cardiac AE is noted, further ECG examinations will be 


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performed. On the day of the examination, the investigator completes the ECG assessment and 
records the assessment results on the electrocardiogram. The same assessment method should be 
used throughout the study period. 
The ECG will be recorded at a speed of 25 mm/s. The investigator should evaluate all ECGs based 
on clinically significant abnormalities/clinically non-significant abnormalities. The investigator 
should record clinically significant abnormal findings as AEs in the eCRF. 
8.2.4 
Vital signs 
Vital signs will be measured as described in the study visit schedule. Vital signs include body 
temperature, pulse rate, respiratory rate, and blood pressure. 
The investigator may perform additional vital sign assessment and monitoring according to 
standard clinical practice or based on clinical needs. 
In the event of an AE/SAE, additional vital sign records may be collected on the eCRF (if 
applicable). The date and time of collection and measurement will be recorded in the appropriate 
section of the eCRF. 
8.2.4.1 
Pulse and blood pressure 
Pulse and blood pressure are measured during the screening period and before the scheduled 
SHR-1210 infusion. 
Blood pressure monitoring: cigarettes and caffeine are prohibited within 30 min before each blood 
pressure measurement, and subjects shall rest for at least 10 min. The blood pressure will be 
measured at sitting position with elbow on the same level as heart. All measurements should be 
taken on the same side. 
During the screening period and before each scheduled SHR-1210 infusion, the investigator will 
measure the blood pressure of the subject. During the study, the subject will monitor the blood 
pressure and record on the diary card. Blood pressure shall be measured at least 3 times per week 
in the first 2 cycles. For subjects with abnormal blood pressure, the blood pressure shall be 
measured daily; if normal, the blood pressure shall be measured twice per week after Cycle 2. 
8.2.4.2 
Body temperature and respiration 
Body temperature and respiration are measured during the screening period and before the 
scheduled SHR-1210 infusion. 
8.2.5 
Weight and height 
Height will be measured only during the screening period. Weight will be measured during the 
screening period, before SHR-1210 administration at each visit, at the end of the treatment, and at 
safety follow-ups. 


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8.2.6 
Pregnancy test 
Women of childbearing potential undergo a serum human chorionic gonadotropin (hCG) 
pregnancy test within 3 days before the first dose of the study drug. Subjects with a positive result 
are not eligible or must discontinue participation in the study. Retests will be performed when 
pregnancy is suspected during the study period. 
8.2.7 
Other safety examinations 
• 
Hepatitis B tests: HBsAg, HBsAb, HBcAb, HBeAg, and HBeAb. 
• 
HIV antibodies and HCV antibodies 
• 
Thyroid function: T3, T4, TSH, FT3, and FT4 
• 
Myocardial zymography: LDH, AST, CK, CK-MB, and ALT  
• 
Pituitary adrenal axis test: Including tests of CRH, plasma ACTH, and adrenocortical 
hormone. Adrenocortical hormone tests include serum cortisol, UFC, 17-KS, and 17-KGS 
• 
Echocardiography 
• 
Pulmonary function test: maximum vital capacity, the forced expiratory flow at 25-75% 
of forced vital capacity (FEF25-75), the peak expiratory flow rate (PEF), the maximum 
expiratory volume per second, diffusing capacity of the lungs for carbon monoxide 
(DLCO) and oxygen saturation, which will be performed during the screening period and 
based on clinical indicators as determined by the investigator thereafter. Subject to the 
actual conditions of each site. 
• 
Arterial blood gas test: optional. This test includes partial arterial pressure of oxygen 
(PaO2), partial arterial pressure of carbon dioxide (PaCO2), arterial oxygen saturation 
(SaO2), and pH, and can be performed during the screening period. Subject to the actual 
conditions of each site. 
8.3 
Pharmacokinetics 
Not applicable. 
8.4 
Pharmacodynamics 
Not applicable. 
8.5 
Immunogenicity 
Immunogenicity blood samples will be collected once within 0.5 h before SHR-1210 infusion on 
D1 of cycle 1, cycle 2, and the third cycle of every three cycles thereafter (cycles 5, 8, 11, etc.), 
once at the end of the treatment, and once per month at safety follow-ups after withdrawal for 


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3 times (if applicable). In case of national holidays, the blood collection time may be adjusted as 
appropriate. If the subject develops SHR-1210-related infusion reactions, blood samples should be 
collected as close as possible to the onset of the event, to the end of the event, and about 30 days 
after the end of the event, for immunogenicity comparison and analysis. Immunogenicity blood 
samples should be collected following the study protocol. However, if deemed necessary by the 
investigator, unscheduled immunogenicity blood samples may be collected. 
Each subject shall be tested for anti-drug antibody (ADA) titer. ADA-positive serum samples will 
be further tested for neutralizing antibodies (NAb). Four (4) mL of blood will be collected each 
time for immunogenicity. Please refer to the Laboratory Manual provided by the sponsor-designated 
central laboratory for sampling methods, sample storage, transportation, and analysis. 
8.6 
Biomarker Analysis 
Subject to the permission of the ethics committee, all subjects who meet the inclusion criteria shall 
provide diagnostic tumor tissues at baseline. Acceptable tumor tissues include 5-10 unstained 
4-6 μm slices prepared with archived tumor tissues or freshly obtained during the screening period. 
After the subject's ICF is obtained and after the study medication, another biopsy is preformed 
before PD or treatment discontinuation to provide tumor tissue to the central laboratory for testing 
and analysis of the relationship between the change in PD-L1 expression before and after the 
administration and the efficacy. These samples may also be used for exploratory biomarker 
analysis, including but not limited to PD-L1 expression. 
After the subject's ICF is obtained, about 16 mL of peripheral blood may be collected for tumor 
biomarker detection during the screening period, at each tumor evaluation, and the end of the 
treatment. 
Refer to the Laboratory Manual for sample processing, handling, and transportation. 
8.7 
Storage and Destruction of Biological Samples 
The samples will be disposed of or destroyed, and pooled and anonymized. Additional analysis 
may be performed on the anonymized and pooled samples to further evaluate and validate the 
analysis method. Any results obtained from these analyses may be reported separately from CSR. 
The sample reproducibility analysis (if performed) will be performed simultaneously with the 
biological sample analysis. These evaluation results will not be reported in the clinical study 
report, but will be separately given in a biological sample analysis report. 


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9 
SAFETY EVALUATION 
9.1 
AE 
9.1.1 
Definition of AE 
AE refers to any untoward medical condition in a clinical study subject who receives a 
pharmaceutical product, and the condition does not necessarily have a causality with the treatment. 
All AEs from signing of the informed consent form to the end of the safety follow-up period (90 
days after the last dose) or the start of other anti-tumor treatments will be collected in this study. 
AEs can include any unfavorable and unintended symptoms, signs, abnormal laboratory findings, 
or diseases, including the following: 
1)  Worsening of pre-existing (prior to entering the clinical trial) medical conditions/diseases 
(including worsening symptoms, signs, or laboratory abnormalities); 
2)  Any new AE: Any new adverse medical conditions (including symptoms, signs, and newly 
diagnosed diseases); 
3)  Clinically significant abnormal laboratory findings. 
All AEs should be documented in detail by the study personnel, including: the name of the AE and 
description of all relevant symptoms, onset time, severity, causality assessment, duration, 
measures taken, as well as final results and outcomes. 
9.1.2 
AE severity grading criteria 
Please refer to NCI CTCAE 4.03 for grading standards. Refer to the following criteria for AEs not 
listed in NCI-CTCAE 4.03: 
Grade 
Clinical Description of Severity 
1 
Mild; asymptomatic or mild clinical symptoms; clinical or laboratory test abnormality only; intervention 
not indicated. 
2 
Moderate; minimal, local, or non-invasive interventions required; limited age-appropriate instrumental 
activities of daily living (ADL), e.g., cooking, shopping, using the telephone, counting money. 
3 
Severe or medically significant symptoms but not immediately life-threatening; hospitalization or 
prolonged hospitalization indicated; disabling; limiting self-care ADL. Self-care ADL: refer to bathing, 
dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Resulting in death 
9.1.3 
Causality assessment of AEs 
AEs include all unexpected clinical manifestations. All such events occurring after the signing of 
the ICF must be reported as AEs regardless of whether they are related to the study drugs or even 
whether the subject has received the drugs. All subject complaints and abnormal changes in 
laboratory tests during the treatment period will be documented truthfully. The severity, duration, 


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measures taken, and outcome of the AE will be noted. The investigator shall assess the causality 
between the AE and the study drug, such as whether there is a plausible temporal relationship with 
the study drug, the characteristics of the study drug, the toxicological and pharmacological effects 
of the study drug, whether there are concomitant medications, the subject's underlying diseases, 
medical history, family history, as well as dechallenge and rechallenge. The potential relationship 
between the AE and the study drug will be assessed with 5 grades of causality: "definitely related", 
"possibly related", "unlikely related", "not related", and "indeterminable". Events deemed 
"definitely related", "possibly related", "unlikely related", and "indeterminable" will be listed as 
adverse drug reactions. When calculating the incidence of AEs, the total of these four categories 
shall be used as the numerator and the total number of subjects for safety assessments shall be used 
as the denominator. 
9.2 
Serious Adverse Event (SAE) 
9.2.1 
Definition of SAE 
An SAE is any untoward medical occurrence at any dose. The following medical events are 
included: 
 
Events resulting in death; 
• 
Life-threatening events (defined as when the subject is at immediate risk of death at the 
time of the event); 
• 
Events resulting in hospitalization or prolonged hospitalization; 
• 
Events resulting in permanent or serious disability/incapacity/impairment of work 
ability; 
• 
Congenital anomalies or birth defects; 
• 
Other important medical events (defined as events that may jeopardize the subject or 
require interventions to prevent any of the above). 
9.2.2 
Hospitalization 
AEs that result in hospitalization (even if for less than 24 h) or prolonged hospitalization during the 
clinical study should be considered as SAEs. 
Hospitalization does not include the following: 
 
Hospitalization at a rehabilitation institution 
 
Hospitalization at a sanatorium 
 
General emergency admission 


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 
Day surgery (e.g., outpatient/same-day/ambulatory surgery) 
 
Social reasons (medical insurance reimbursement, etc.) 
Hospitalization or prolonged hospitalization unrelated to the worsening of an AE is not an SAE. 
For example: 
 
Hospitalization due to pre-existing disease without the occurrence of new AEs or 
worsening of the pre-existing diseases (e.g., in order to examine the persistent laboratory 
abnormalities that started before the study); 
 
Hospitalization for management reasons (e.g., annual physical examination); 
 
Hospitalizations during the study as specified in the protocol (e.g. hospitalization 
performed in accordance with study protocol); 
 
Elective hospitalization unrelated to worsening of AEs (e.g., elective surgery); 
 
Scheduled treatment or surgical procedures, which should be documented in the 
individual subject's baseline information; 
 
Hospitalization merely for use of blood products. 
Diagnostic or therapeutic invasive (e.g., surgery) and non-invasive procedures should not be 
reported as AEs. However, when a condition resulting in such procedures meets the definition of 
AE, it should be reported as such. For example, acute appendicitis during the AE reporting period 
should be reported as an AE, and the resulting appendicectomy shall be recorded as the treatment 
of the AE. 
9.2.3 
Progressive disease 
Progressive disease is defined as the worsening of the subject's conditions caused by the 
indications of the study, including radiological progressions and progressions in clinical symptoms 
and signs. New metastases relative to the primary tumor or progressions of the previous metastases 
are recognized as PD. Life-threatening events, hospitalization or prolonged hospitalization, or 
events resulting in permanent or severe disability/incapacity/impairment of work ability, 
congenital anomalies or birth defects arising from the symptoms and signs of PD are not reported 
as SAEs. Death caused by the symptoms and signs of PD will be reported as an SAE. 
9.2.4 
Potential drug-induced liver injury 
Drug-induced liver injury will be considered if AST and/or ALT levels are abnormal accompanied 
with abnormal elevation of total bilirubin, the following criteria are met, and when there are no 
other causes of liver injury. These cases should always be considered as important medical events. 


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Potential drug-induced liver injury is defined as follows: 
Baseline Period 
Normal (AST/ALT and TBIL) 
Abnormal (AST/ALT and TBIL) 
Treatment Period 
• 
ALT or AST > 3 × ULN  
• 
with TBIL ≥ 2 × ULN 
• 
and ALP ≤ 2 × ULN 
• 
and no hemolysis 
• 
AST or ALT ≥ 2 × baseline level, and values 
≥ 3 × ULN; or AST or ALT ≥ 8 × ULN 
• 
with TBIL increase ≥ 1 × ULN or TBIL ≥ 3 × 
ULN 
After being notified of the abnormal results, the subjects should return to the study center for an 
assessment as soon as possible (preferably within 48 h). Assessments include the laboratory tests, 
detailed medical history, and physical assessment, and the possibility of hepatic tumor (primary or 
secondary) should be considered. 
Except for the reexaminations of AST and ALT, albumin, creatine kinase, TBIL, direct and 
indirect bilirubin, γ-GT, prothrombin time (PT)/international normalized ratio (INR), and ALP 
should also be examined. Detailed medical history should include history of alcohol use, 
acetaminophen, soft drugs, various supplements, family diseases, occupational exposure, sexual 
behavior, travel, contact with jaundice patients, surgery, blood transfusion, hepatic diseases, and 
allergies. Further tests may include the testing for acute hepatitis A, B, C and E, and hepatic 
imaging (such as biliary tract). If the above laboratory criteria are confirmed upon re-examination, 
the possibility of potential drug-induced liver injury should be considered in the absence of any 
other causes of abnormal liver function, without waiting for all liver function test results. Potential 
drug-induced liver injury should be reported as an SAE. 
9.2.5 
Other anti-tumor treatments 
For subjects starting other anti-tumor treatments, unless suspected to be related to the study drugs, 
adverse events except death will be reported until the start of the new anti-tumor treatment. Deaths 
that occur within the SAE reporting period after study treatment is completed should be reported 
regardless of whether the subject has received other treatments. 
9.2.6 
SAE reporting 
SAEs should be collected from signing the ICF to the end of safety follow-up period. In the event 
of an SAE, whether it is the first report or a follow-up report, the investigator must complete the 
"Serious Adverse Event Report Form" immediately, with a signature and date, and notify the 
sponsor within 24 h of knowing of the event. Relevant authorities must be informed of such SAE 
in a timely manner according to regulatory requirements. 
Email the SAE reports to: hengrui_drug_safety@hrglobe.cn 


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SAEs that occur after the safety follow-up period will generally not be reported unless suspected to 
be treatment-related. Symptoms, severity, causality with the study drugs, time of occurrence, 
duration of treatment, measures taken, follow-up time and methods, and outcomes of SAEs shall 
be documented. If an SAE is potentially related to the study conditions (e.g., discontinuation of 
previous therapy, or comorbidities during the study procedure) rather than the study treatment as 
deemed by the investigator, this relationship shall be detailed in the narrative section of the SAE 
report form. If the severity of an ongoing SAE or its relationship to the study drug changes, a 
follow-up report should be submitted immediately. If an error is found in a previously reported 
SAE, such SAE may be revised, revoked, or downgraded in follow-up reports and reported in 
accordance with the SAE reporting procedure. 
9.2.7 
Follow-up of AEs/SAEs 
All the AEs/SAEs should be followed up until they resolve, recover to baseline levels or Grade ≤ 1, 
steady state, or reasonably are explained (e.g., lost to follow-up, death). 
During each visit, the investigator should ask about the situation of AEs/SAEs that occur after the 
last visit and provide follow-up information in a timely manner based on the sponsor's query 
request. Principles of collection and follow-up of AEs/SAEs after the last dose at the end of 
treatment are shown in the table below. 
Principles of AE/SAE collection and follow-up 
Classification 
Collection/Documentation 
Requirements 
Follow-Up Requirements 
Unrelated AEs 
Until the end of safety follow-up 
period or start of a new anti-tumor 
treatment (whichever comes first) 
Until the end of safety follow-up period 
Treatment-related AEs 
Until the end of safety follow-up 
period 
Until resolved, remission, or recovered to baseline 
levels or Grade ≤ 1, steady state, or reasonably 
explained (e.g., lost to follow-up, death). 
Unrelated SAEs 
(including SIEs) 
Until the end of safety follow-up 
period or start of a new anti-tumor 
treatment (whichever comes first) 
Until the end of safety follow-up period 
Treatment-related SAEs 
(including SIEs) 
No time limit 
Until resolved, remission, or recovered to baseline 
levels or Grade ≤ 1, steady state, or reasonably 
explained (e.g., lost to follow-up, death). 
9.3 
Pregnancy 
During the study, if a female subject becomes pregnant, she must immediately discontinue the 
study drug treatment. The investigator must report the event to the sponsor within 24 h of being 
notified and fill out the "Pregnancy Report/Follow-Up Form for Hengrui Clinical Studies". 


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During the study, if the partner of a male subject becomes pregnant, the subject can continue in the 
study. The investigator must report the event to the sponsor within 24 h of being notified and fill 
out the "Pregnancy Report/Follow-up Form for Hengrui Clinical Studies". 
The investigator should follow up the outcome of the pregnancy until 1 month after delivery, and 
report the outcome to the sponsor. 
Pregnancy outcomes such as stillbirth, spontaneous abortion, and fetal malformation are 
considered SAEs and need to be reported according to the time requirements for SAEs. 
If the subject also experiences an SAE during the pregnancy, the "NMPA Serious Adverse Event 
Report Form" should also be filled out and reported according to the SAE reporting procedure. 
9.4 
Adverse Events of Special Interest 
For adverse event of special interest (AESIs) specified in the study protocol, the investigator must 
complete the "Report of Adverse Event of Special Interest for Hengrui Clinical Studies" and report 
to the sponsor within 24 h of knowing of the event. If the AE of special interest is also an SAE, the 
"NMPA Serious Adverse Event Report Form" should also be completed and submitted to the 
relevant authorities according to SAE reporting procedure. 
• 
Grade ≥ 3 infusion reaction 
• 
Grade ≥ 3 other immune-related AEs 
10 DATA ANALYSIS/STATISTICAL METHODS 
10.1 Sample Size 
In this study, based on historical study data and study results of drugs of the same class and 
combined with clinical needs, a single-stage assessment method will be adopted to explore the 
efficacy of SHR-1210 combined with apatinib on ORR in ED-SCLC after failure of the first-line 
standard therapy. 
Assume that in this study, the expected ORR in each treatment group of SHR-1210 + apatinib 
combination therapy is ≥ 30% (alternative hypothesis), and that there is no need to continue the 
study if the ORR is ≤ 15% (null hypothesis), at the significance level of 0.1 and a power of 80%, 40 
subjects should be enrolled. If ≥ 9 (22.5%) of the 40 subjects have response, it can be considered 
that the ORR in this treatment group is 15% and the study drug is worthy of continued 
development. 
With a dropout rate of 10% taken into account, each treatment group needs to enroll about 45 
subjects. A total of 57 subjects are required in Stages I and II. 


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10.2 Statistical Analysis Plan 
Detailed summaries and methods of statistical analyses for the data collected from the study will 
be included in the statistical analysis plan (SAP), which will be finalized and filed by the sponsor. 
The SAP should be revised accordingly if there are any changes to the study protocol that may 
have an obvious impact on the SAP, as determined by the sponsors or principal investigators. The 
SAP must be finalized before database locking. 
10.3 Statistical Hypotheses 
This study does not involve any statistical hypotheses and inference. 
A single-stage assessment method will be adopted to explore the efficacy of SHR-1210 combined 
with apatinib on ORR in ED-SCLC after failure of the first-line standard therapy. The potential 
need for further development is indicated when the predefined number of responses (objective 
response) of a treatment group is reached (see Section 10.1 for details). 
10.4 Analysis Sets 
The analysis sets in this study include: 
Full analysis set (FAS): an analysis set determined based on the intent-to-treat principle. This 
analysis set includes all subjects who have been randomized and have received at least one dose of 
the study drug. In the FAS-based analysis, subjects will be analyzed by groups after randomization 
(regardless of the actual treatment they receive). 
Per-protocol set (PPS): a subset of the FAS. Subjects with protocol violations that are judged to 
have a significant effect on the efficacy will be excluded from this set. The list of subjects included 
into or excluded from the PPS should be reviewed and determined by the sponsor and the 
investigator before the database is locked. 
Evaluable set (ES): a subset of the FAS, defined as the all enrolled subjects receive at least one 
dose of the study drugs and receive post-baseline tumor assessment at least once. 
Safety set (SS): All subjects who have been randomized and have received at least one dose of the 
study drug. Analyses based on the safety set will be carried out according to the actual treatment 
received by the subjects. 
ADA set (ADAS): All enrolled subjects who have received at least one dose of the study drug and 
have baseline and at least one post-baseline ADA evaluation data. 
Tumor biomarkers set (TMKS): Subjects who have been randomized and received at least one 
dose of the study drugs, and have tumor biopsy samples make up the PD-L1 or TMB set. 


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10.5 Statistical Methods 
10.5.1 Basic methods 
Unless otherwise specified, standard descriptive statistics will be summarized by different type of 
variables: 
• 
Continuous data will be summarized using mean, standard deviation, median, maximum, 
and minimum; 
• 
Categorical data will be summarized using frequency and percentage; 
• 
For time-to-event data, Kaplan-Meier method will be used to estimate the survival 
function and median time to event onset, and a survival curve will be plotted. 
The baseline is generally defined as the last pre-administration observation before the first dose 
(including the very day). 
10.5.2 
Primary efficacy endpoint analysis 
ORR is the primary efficacy endpoint of the study. It refers to the proportion of all enrolled 
subjects with CR or PR evaluated by RECIST v1.1. Response confirmation should be conducted 
for CR and PR. The point estimate of ORR and two-sided 95% confidence interval based on the 
Clopper-Pearson method will be calculated. The statistical analysis of ORR will be based on the 
FAS and ES, with FAS as the primary analysis set. 
10.5.3 Secondary efficacy endpoint analysis 
The secondary efficacy endpoints of this study include OS, 6-month OS rate, PFS, TTR, DoR, and 
DCR evaluated as per RECIST v1.1 
The statistical analysis of DoR, TTR, and PFS will be based on the FAS and ES, with FAS as the 
primary analysis set. The statistical analysis of OS will be based on the FAS. 
PFS, TTR, DoR, and OS will be estimated based on the Kaplan-Meier method, and the 
corresponding two-sided 95% confidence interval will be calculated. 
The point estimate of DCR and the 95% confidence interval based on the Clopper-Pearson method 
will be calculated. 


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10.5.4 Safety analysis 
The safety analysis will be summarized primarily using descriptive statistics. The analysis set 
is SS. 
All AEs will be coded according to the latest version of MedDRA. AEs will be statistically 
summarized by AEs, SAEs, treatment-related AEs, AEs resulting in dose modification, and AEs 
resulting in study withdrawal. All AEs will also be graded by NCI CTCAE (v4.03). Grade ≥ 3 AEs 
will be statistically summarized. In addition, safety data such as laboratory tests and vital signs will 
also be statistically summarized. 
The safety data will be analyzed and summarized using Hengrui's current clinical study report 
standards. Such standards include but are not limited to the following: 
• 
Analysis of treatment discontinuation, dose reduction, or treatment interruption due 
to AEs 
• 
Incidence and severity of AEs 
• 
Causality analysis between AEs and study drug 
• 
Analysis of outcomes of AEs 
• 
Analysis of SAEs 
• 
Descriptive statistical summary of laboratory test, vital signs, and ECG data 
• 
Incidence of laboratory abnormalities 
• 
Analysis of normal and abnormal changes in laboratory parameters, vital signs, and ECG 
data compared to baseline 
10.5.5 Exploratory analysis 
The expression levels of PD-L1 and TMB will be analyzed using descriptive statistics. The 
analysis will be based on the TMKS. 
The immunogenicity will be analyzed using descriptive statistics. The analysis will be based on the 
ADAS. 
10.5.6 Subgroup analysis 
The analysis of the primary endpoint ORR will be carried out in the following subgroups: 
• 
Sensitive recurrence (progression in ≥ 90 days from the last chemotherapy) 
• 
Drug-resistant recurrence (progression during chemotherapy or within 90 days from the 
last chemotherapy) 


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Other subgroup analyses will be detailed in SAP. 
10.5.7 Multiple comparison/Multiplicity 
Not applicable. 
11 DATA MANAGEMENT 
11.1 Data Recording 
Study data will be collected and managed using the eCRF. 
11.1.1 Study medical recording 
As source documents of the study, medical records should be retained in their entirety. The 
investigator should be responsible for filling and keeping the study medical record. The subject 
information on the cover of the medical record should be checked each time before filling the 
record. The medical record should be written in a neat and legible way so that the sponsor's CRA 
could verify the data with eCRF during each monitoring visit. 
11.1.2 
eCRF entry 
Entry: The data in the eCRF are from and should be consistent with the source documents, such as 
the original medical records and laboratory test reports. Any observations or test results in the 
study should be entered in the eCRF in a timely, accurate, complete, clear, normative and true 
manner. Data should not be changed arbitrarily. All items in the CRF should be filled out, with no 
blank or omissions. 
Modifications: The system instructions must be followed when correcting the eCRF data as 
needed, and the reason for data correction must be recorded. The logic verification program in the 
system will verify the integrity and logic of the study data entered into the electronic data capture 
(EDC) system and generate an error message prompt for questionable data. The PI or data entry 
personnel (CRC) is permitted to modify or explain the problematic data. If necessary, multiple 
queries can be raised until the event of problematic data is resolved. 
11.1.3 eCRF review 
The investigator must complete, review, and submit the eCRF within 3 working days after the end 
of each subject's treatment course. The investigator or the data input staff (CRC) should promptly 
respond to queries raised by the monitor, data manager, and medical reviewer. After data cleaning 
is completed, the investigator will sign the completed eCRF for verification. 


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11.2 Data Monitoring 
Implemented by: CRA. 
Monitoring content: To confirm that the study protocol is adhered to; the records on eCRF are 
correct, and complete and consistent with the original medical records and laboratory test results, 
and whether there are errors or omissions in the data. According to the monitoring plan, the CRA 
will verify the completeness, consistency, and accuracy of study data in the database. The CRA 
will discuss any queries with study personnel and direct them to add or correct the data whenever 
necessary. Data in the eCRF will be ensured to be consistent with source data. This process is also 
known as source data verification (SDV). 
11.3 Data Management 
11.3.1 EDC database establishment 
The data manager will establish a study data collection system and database according to the study 
protocol, which will be available for online usage before the first subject is enrolled. Before use, all 
EDC users should receive adequate training and get the corresponding account to log into the 
system. (Access to EDC system will only be granted to the study center staff who have completed 
the training.) 
11.3.2 Data entry and verification 
The investigator or CRC should input data into the EDC system in accordance with the 
requirements of the visit procedures and the eCRF completion guide. After submitting the eCRF, 
the CRA, data manager, and medical personnel should review the data. Questions during the 
review will be submitted to the investigator or CRC in the form of queries. After data cleaning is 
completed, the investigator should sign the completed eCRF for verification. 
11.3.3 Data review and database locking 
After the study is completed, the study director, sponsor, statistician, and data manager will 
conduct a joint data review before statistical analysis mainly to determine the analysis data set 
(including FAS, PPS, and SS) for each case, the judgment of missing values, and the handling of 
outliers. All decisions made under data review must not be modified, and any decision must be 
documented. 
After the established database is considered correct by review, the database will locked. After the 
database is locked, the data must be properly stored for future reviews, and the database should be 
statistically analyzed by the statistician. 


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After SDV is completed by the CRA, the data manager and medical reviewer will conduct a final 
quality control of all data in the database, summarize all protocol deviations and violations during 
the study, and hold the data review meeting. The database will be locked after quality requirements 
are met. The data manager will export the data to the statistics department for data analysis. 
11.3.4 Data archiving 
After the study is completed, subject's eCRFs in PDF format must be generated from the EDC 
system and kept in CD-ROMs. These CD-ROMs will be archived by the sponsor and various 
institutions for auditing and/or inspection. 
All materials shall be preserved and managed in accordance with GCP requirements, and 
necessary documents of clinical studies shall be preserved until 2 years after the study drug is 
approved for marketing or 5 years after the termination of the clinical study. 
12 SOURCE DATA AND DOCUMENTS 
According to ICH E6, relevant regulations, and requirements for subject's personal information 
protection of the study centers, each study center must properly keep all the treatment and 
scientific records related to this study. As a part of the study that Jiangsu Hengrui Pharmaceuticals 
Co., Ltd. sponsors or participates in, each study center must allow the authorized representative of 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. and regulatory authorities to inspect the clinical 
records (which may be copied if permissible by law) for quality review, audit, and evaluations of 
safety, study progress, and data validity. 
Source data are information required to reconstruct and evaluate the clinical study, and are the 
original documentation of clinical findings, observations, and other activities. These source 
documents and data records include but are not limited to: hospital record, laboratory records, 
memos, subject diary cards, pharmacy dispensing records, recordings of advisory meetings, 
recorded data from automated devices, copies or transcripts that are verified to be accurate and 
intact, microfiche, photographic negatives, microfilms or magnetic disks, X-ray films, and 
subject's documents and records that are kept in the pharmacies, laboratories, and medical 
technology departments that are involved in this study. 
13 QUALITY ASSURANCE AND QUALITY CONTROL 
To ensure study quality, the sponsor and investigator will together discuss and formulate the 
clinical study plan before the official commencement of the study. GCP training will be conducted 
for relevant investigators participating in the study. 
All the study centers must comply with the SOPs for the management of the study drug, including 
receipt, storage, dispensing, return, and destruction (if applicable). 


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According to the GCP guidelines, necessary measures must be taken at the design and 
implementation phases of the study to ensure that all collected data are accurate, consistent, intact, 
and reliable. All observed results and abnormal findings in the study must be verified and recorded 
in a timely manner to ensure data reliability. All devices, equipment, reagents, and standards used 
in various tests in the study must have stringent specifications and be operated under normal 
conditions. 
The investigator will input data required by the protocol into the eCRF. The CRA will check 
whether the eCRF is completely and accurately filled and guide the study center personnel for 
necessary revision and addition. 
The drug regulatory authorities, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), sponsor's monitor and/or auditor may carry out systemic inspection of study-related 
activities or documents to assess whether the study is implemented based on the study protocol, 
SOPs, and relevant regulations (such as Good Laboratory Practices [GLP] and Good 
Manufacturing Practices [GMP]) and whether the study data is recorded in a prompt, truthful, 
accurate, and complete manner. The audit shall be conducted by persons not directly involved in 
the study. 
14 REGULATIONS, ETHICS, ICF, AND SUBJECT PROTECTION 
14.1 Regulatory Considerations 
According to the corresponding regulatory requirements in China, an application should be 
submitted to the NMPA before starting a new drug study and the clinical study can only be carried 
out after an approval is obtained. The clinical approval number for SHR-1210 is 2016L01455. 
The legal basis for the design of this protocol is as follows: 
1) 
Provisions for Drug Registration 
2) 
Good Clinical Practice 
3) 
Technical Guidelines for Clinical Pharmacokinetic Study of Chemical Drugs 
4) 
Consensus on ethical principles based on international ethics guidelines, including the 
Declaration of Helsinki and the Council for International Organizations of Medical 
Sciences (CIOMS) International Ethics Guidelines 
5) 
ICH Guidelines 
6) 
Other applicable laws and regulations 


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14.2 Ethical Standards 
The investigator will ensure that the trial in this study is fully implemented in accordance with the 
requirements for subject protection in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56 and/or 
ICH E6. 
This study protocol must first be reviewed and approved by the Ethics Committee of the Cancer 
Hospital before being implemented. The study protocol, protocol revisions, ICF, and other 
relevant documents such as recruitment advertisements should be submitted to the ethics 
committee. This clinical study must comply with the Declaration of Helsinki, Good Clinical 
Practice (GCP) enacted by the NMPA, and other relevant regulations. Before the study is initiated, 
approval must be obtained from the ethics committee of the hospital. 
The study protocol must not be unilaterally modified without approvals from both the sponsor and 
investigator. The investigator can modify or deviate from the study protocol before obtaining an 
approval from the IEC/IRB only when in purpose of eliminating direct and immediate harm to the 
subject. Besides, the deviation or change and the corresponding reason, and the recommended 
protocol modification should be submitted to the IEC/IRB for review. The investigator must 
provide explanations and document any protocol deviation. 
During the study, any changes to this study protocol must be submitted to the ethics committee. If 
necessary, corresponding changes should be simultaneously made to other study documents and 
submitted and/or be approved according to the pertinent requirements of the ethics committee. The 
investigator is responsible for submitting the interim reports regularly according to the pertinent 
requirements of the EC. After the end of the study, the completion should be informed to the EC. 
14.3 Independent Ethics Committee 
The protocol, ICF, recruitment material, and all subject materials must be reviewed and approved 
by the EC. Subjects may be enrolled only after the protocol and ICF have been approved. Any 
revisions to the protocol must be reviewed and approved by the EC prior to being implemented. 
All revisions to the ICF must be approved by the EC, who will decide whether the subjects who 
have signed the previous version of the ICF are required to sign the new one. 
14.4 ICF 
14.4.1 ICFs and other written information for subjects 
The ICF shall describe the study drugs and study process in detail and fully explain the risks of the 
study to the subjects. Written documentation of the ICF must be obtained before starting any 
study-related procedures. 


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14.4.2 Informed consent process and recording 
Informed consent will begin before an individual decides to participate in the clinical study and 
continues during the entire clinical study. The risks and potential benefits of participating in the 
study should be discussed fully and in detail with the subjects or their legal representatives. 
Subjects will be asked to read and review the ICF that has been approved by the EC. The 
investigator will explain the clinical study to the subjects and answer any questions posed by the 
subjects. Subjects can only participate in the study after they have signed the ICFs. During the 
clinical study, subjects can withdraw the informed consents at any time. One copy of the signed 
ICF will be kept by the subjects. Even if a patient refuses to participate in this study, his or her 
rights will be fully protected, and the nursing quality will not be affected. 
14.5 Confidentiality of Subject Information 
The confidentiality of subject information will be strictly enforced by the investigator, participated 
study personnel, and sponsor and its representative. In addition to the clinical information, 
confidentiality also simultaneously covers biological samples and genetic tests of the subjects. 
Therefore, the study protocol, documents, data, and other information generated from these 
materials will be kept strictly confidential. All relevant study or data information should not to be 
disclosed to any unauthorized third-party without prior written approval from the sponsor. 
Other authorized representatives of the sponsor, IRB or regulatory authorities, and the 
representatives of the pharmaceutical company that provide the study drugs can examine all the 
documents and records that are maintained by the investigator, including but are not limited to the 
medical records and subject's administration records. The study center should allow access to these 
records. 
The contact information of the subjects will be safely kept in each study center and only used 
internally during the study. When the study is ended, all the records will be kept in a secure place 
based on the time limit specified by local IRB and regulations. 
This should not include the contact information or identification information of subjects. Instead, 
individual subjects and their study data will be given a unique study identification number. The 
study data entry and study management system used by the study personnel at the study centers 
shall be confidential and password-protected. 
14.6 Sample Storage and Use 
Samples and data will be numbered for storage in this study. The data in the computer will also be 
password-protected. Only the study personnel can have access to these samples and data. The 
samples and data collected in accordance with the protocol will be used for biomarker detection 
and will not be used for any unrelated purposes. 


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15 PUBLICATION OF STUDY RESULTS 
The study results belong to Jiangsu Hengrui Pharmaceuticals Co., Ltd. If the investigator plans to 
publish any research-related data and information, Hengrui should be provided with the 
manuscript, abstract, or full text of all planned publications (poster, invited lectures, or guest 
lectures) at least 30 days prior to the submission of documents for publication or other forms of 
publication. 
16 CLINICAL TRIAL PROGRESS 
Anticipated enrollment of the first subject: Q1 of 2018 
Anticipated enrollment of the last subject: Q4 of 2018 
Anticipated time of last subject last visit: Q3 of 2019 
Anticipated study completion: Q1 of 2020 


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[7]  Herbst RS, et al. Lung cancer. N Engl J Med 2008;359:13670.  
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111:1710-1717, 1997  
[12]  NCCN Guidelines, Version 3.2017 Small Cell Lung Cancer v29, 2017 
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[14]  Waarde P, et al. Does thoracic irradiation improve survival and local control in limited-stage 
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[16]  Niho S, et al. Clinical outcome of small cell lung cancer with pericardial effusion but without 
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[30]  Koyama K, et al. Reciprocal CD4+ T-cell balance of effector CD62Llow CD4+ and 
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immune-related response criteria. Clin Cancer Res. 2009 Dec 1;15(23):7412-20 
 
 


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Appendix 1 ECOG PS Scoring Criteria 
 
Score 
ECOG Performance Status 
0 
Fully active, able to carry on normal activity without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work; confined to bed < 50% of 
waking hours 
3 
Capable of only limited self-care; confined to bed or chair of more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Death 
REFERENCES 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. 
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5:649-655. 
 


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Appendix 2 Calculation of Creatinine Clearance 
Creatinine Clearance Calculation Using the Cockcroft-Gault Formula 
Please choose the appropriate formula corresponding to the unit of serum creatinine test: 
If the unit of serum concentration of creatinine is mg/dL 
 
Creatinine Clearance in Males (mL/min) =
(140－Age)×(Weight)
72×Serum creatinine 
Creatinine Clearance in Females (mL/min) =
0.85×(140－Age)×(Weight)
72×Serum creatinine
 
If the unit of serum concentration of creatinine is μmol/L 
Creatinine Clearance in Males (mL/min) =
(140－Age)×(Weight)
0.81×Serum creatinine 
Creatinine Clearance in Females (mL/min) =
0.85×(140－Age)×(Weight)
0.81×Serum creatinine  
Note: The unit of age is years old, and the unit of body weight is kilogram (kg). 
 
 


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Appendix 3 Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) 
The following content is an excerpt from the RECIST v1.1 criteria. 
1  MEASURABILITY OF TUMOR AT BASELINE 
1.1  Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1.1.1  
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter is to be 
recorded) with a minimum size of: 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
• 
Malignant lymph nodes: pathologically enlarged and measurable, single 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 during follow-up, only the 
short axis will be measured and followed. 
1.1.2 
Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodule 
with ≥ 10 mm to < 15 mm short axis) as well as truly non-measurable lesions. Non-measurable 
lesions include: meningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
cancer, lymphangitis carcinomatosa of the skin or lung, abdominal masses unable to be diagnosed 
or followed by imaging techniques, and cystic lesions. 
1.1.3 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate to measure bone lesions. 
However, these techniques can be used to confirm the presence or disappearance of bone 
lesions; 


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• 
Lytic lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by tomography techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability 
described above; 
• 
Blastic lesions are non-measurable. 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) 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 
noncystic 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 
locoregional therapy, are usually considered non-measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
1.2 Specifications by Methods of Measurements 
1.2.1 
Measurement of lesions 
All measurements should be recorded in metric notation if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 21 
days (3 weeks) before the beginning of the treatment. 
1.2.2 
Method of assessment 
The same method and technique should be used to assess lesions 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 assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of cutaneous lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is suggested. 
When lesions can be evaluated by both imaging and clinical examination, imaging evaluation 
should be undertaken since it is more objective and may also be reviewed at the end of the study. 


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Chest X-ray: Chest CT is preferred over chest X-ray, especially when tumor progression is an 
important clinical endpoint, since CT is more sensitive, particularly in identifying new lesions. 
Chest X-ray is only applicable when the measured lesion boundary is clear and the lungs are well 
ventilated. 
CT and MRI: CT is currently the best available and reproducible method for response evaluation. 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is ≤ 5 mm. 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 (e.g. for whole body scans). 
Ultrasound: Ultrasound should not be used as a method to measure lesion size. Ultrasound 
examinations are operation-dependent, and cannot be reproduced at a later date. It cannot be 
guaranteed that the same technique and measurements will be taken from one 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. 
Endoscopy and laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm CR when biopsies are obtained, or to 
determine relapse in trials where recurrence following CR or surgical excision is an endpoint. 
Tumor biomarkers: Tumor biomarkers alone cannot be used to assess objective tumor response. 
However, if the marker levels exceed the upper normal limit at baseline, they must return to the 
normal levels for evaluation of complete response. Because tumor biomarkers 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 PSA 
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 studies 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 benign tumor tissue is commonly observed in 
lesions of germ cell neoplasm). When effusions are known to be a potential adverse effect of 
treatment (e.g., with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can 
be considered if the measurable tumor has met the criteria for response or stable disease in order to 
differentiate between response (or stable disease) and PD. 


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2  TUMOR RESPONSE EVALUATION 
2.1 Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable lesions at baseline should be included in protocols where objective response is the 
primary endpoint. Measurable lesion is defined by the presence of at least one measurable lesion. 
In study where the primary endpoint is tumor progression (either time to progression or proportion 
with progression at a fixed date), the protocol must specify if enrollment is restricted to those with 
measurable lesions or whether patients with non-measurable lesions are also eligible. 
2.2 Baseline Documentation of 'Target' and 'Non-Target' Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ), representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved, a maximum of two and four 
lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal tissues which may be visible by imaging 
even if not involved by tumor metastasis. Pathological nodes which are defined as measurable and 
may be identified as target lesions must meet the criterion of a short axis of ≥ 15mm by CT scan. 
Only the short axis of these nodes needs to be measured at baseline. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by tumor metastasis. 
Nodule size is normally reported as two 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 smallest 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. 
Nodes with short axis ≥ 10 mm but < 15 mm should be considered non-target lesions. Nodes that 
have a short axis < 10 mm are considered non-pathological and should not be recorded or 
followed. 


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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. 
All other lesions including pathological lymph nodes should be identified as non-target lesions, 
and while measurements are not required, they should be recorded at baseline. These lesions shall 
be recorded as "present", "absent", or in rare cases "unequivocal progression". It is possible to 
record multiple non-target lesions involving the same organ as a single item on the case record 
form (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). 
2.3  Response Criteria 
2.3.1  
Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodules 
(whether target or non-target) 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, compared 
with baseline. 
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, the sum must also demonstrate an absolute increase of at least 5 mm (the 
appearance of one or more new lesions is also considered PD). 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.3.2 
Special notes on the assessment of target lesions 
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 complete response criteria are met, since 
a normal lymph node is defined as having a short axis of < 10 mm. eCRFs or other data collection 
methods may therefore be designed to have target nodal lesions 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. 
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 (e.g., 2 mm). However, sometimes lesions or lymph nodes 


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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 can be assigned. (Note: It is less likely that this rule will be used 
for lymph nodules since they usually have a definable size when normal and are frequently 
surrounded by adipose tissues as in the retroperitoneum; however, if a lymph nodule is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm can 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 evaluation 
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: When non-nodal lesions fragmented, 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. 
2.3.3  
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target 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. 
Complete response (CR): Disappearance of all non-target lesions and normalization of tumor 
biomarker level. All lymph nodules must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
biomarker level above the normal limits. 
Progressive disease (PD): Unequivocal progression of existing non-target lesions. Note: the 
appearance of one or more new lesions is also considered PD. 


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2.3.4  
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: When 
the patient also has measurable disease, to achieve unequivocal progression on the basis of the 
non-target disease, there must be an overall level of substantial worsening in non-target disease 
such that the overall tumor load has increased sufficiently to the point where treatment must be 
discontinued. A modest increase in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. The designation of overall progression 
solely on the basis of change in non-target 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 Ⅲ 
trials when it is not a criterion of study inclusion to have measurable disease. The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment. Because worsening in non-target 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 load 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. For example, 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 treatment". 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. 
2.3.5  
New lesions 
The appearance of new malignant lesions denotes PD; therefore, some comments on detection of 
new lesions are important. There are no specific criteria for the identification of radiographically 
detected lesions; however, the finding of a new lesion should be unequivocal. For example, it 
should not be 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 
that may be simply healing, or re-occurrence of pre-existing lesions). This is particularly important 
when the patient's baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a new cystic lesion, which it is not. 


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A lesion identified on a follow-up study that is not scanned at baseline will be considered a new 
lesion and will indicate PD. An example of this is the patient who has visceral disease at baseline 
and while on study 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 treatment and 
follow-up evaluation are required to clarify if it represents a truly new disease. If repeated scans 
confirm there is definitely a new lesion, then progression should be declared using the date of the 
initial identification. 
While FDG-PET response evaluations generally 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 process: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
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, PD is 
confirmed. 
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 imaging examination, this is not PD. 
2.4  Evaluation of Best Overall Response 
The best overall response evaluation is the best response recorded from the start of the trial until 
the end of study, while all necessary requirements shall be taken into account at the same time for 
confirmation. On occasion a response may not be documented until after the end of treatment, so 
protocols should be clear if post-treatment assessments are to be considered in the evaluation of 
best overall response. Protocols must specify how any new treatment introduced before 
progression will affect best response evaluation. The subject's best overall response evaluation will 
depend on the findings of both target and non-target lesions and will also take into consideration 
the characteristics of new lesions. Furthermore, it also depends on the nature of the study, the 
protocol requirements, and the judgment criteria of results. Specifically, in non-randomized trials 
where response is the primary endpoint, confirmation of PR or CR is needed to determine which 
one is the best overall response. 


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2.4.1  
Time point response 
Efficacy evaluations are assumed at each time point specified in protocol. Table 1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. 
If the subject does not have measurable lesions (no target lesions), refer to Table 2. 
2.4.2  
Missing assessments and unevaluable designation 
When no imaging/measurement is done at all at a particular time point, the subject is not evaluable 
at that time point. If only a subset of lesion measurements is made at an evaluation, usually the case 
is also considered not evaluable at that time point, unless a convincing argument can be made that 
the contribution of the individual missing lesion(s) has/have no effect on the assigned time point 
response. This would be most likely to happen in the case of PD. For example, if a subject had a 
baseline sum of 50 mm with three measured lesions and at follow-up only two lesions are assessed, 
but those gave a sum of 80 mm, the subject will have achieved PD status, regardless of the 
contribution of the missing lesion. 
2.4.3  
Best overall response: all time points 
The BOR is determined once all the data for the subject are known. 
BOR determination in trials where confirmation of complete or partial response is not required: 
BOR in these studies is defined as the best response across all time points (for example, a subject 
who has SD in evaluation in cycle 1, PR in cycle 2, and PD in the last cycle has a BOR of PR). 
When SD is believed to be best response, it must also meet the protocol specified minimum time 
calculated from baseline. If the minimum time is not met when SD is otherwise the BOR, the 
subject’s best response depends on the subsequent assessments. For example, a subject who has 
SD at cycle 1, PD at cycle 2 and does not meet minimum duration for SD, will have a BOR of PD. 
The same subject lost to follow-up after the Day 1 SD assessment would be considered not 
evaluable. 
BOR determination in trials where confirmation of complete or partial response is required: 
Complete or partial responses may be claimed only if the criteria for each are met at a subsequent 
time point as specified in the protocol (generally 4 weeks later). In this circumstance, the BOR can 
be interpreted as in Table 3. 


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2.4.4 
Special notes on response evaluation 
When nodal disease is included in the sum of target lesions and the nodules decrease to a normal 
size of < 10 mm, they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodules are normal in order not to overstate progression should it be 
based on increase in size of the nodules. As noted earlier, this means that subjects with CR may not 
have a total sum of zero on the eCRF. 
In studies where confirmation of response is required, repeated "NE" time point evaluations may 
complicate the best response evaluation. The analysis plan for the trial must address how missing 
data/evaluations will be explained in determination of response. For example, in most trials it is 
reasonable to consider the PR-NE-PR responses of a subject as the confirmed response. 
Subjects with an overall deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as symptomatic deterioration. 
Efforts should be made to evaluate objective progression even after discontinuation of treatment. 
Symptomatic deterioration is not a description of an objective response: it is a reason for 
discontinuation of treatment. The objective response status of such subjects is to be determined by 
evaluation of target and non-target lesion as shown in Tables 1-3. 
Conditions that are defined as early progression, early death and not evaluable are study specific 
and shall be clearly described in each protocol (depending on treatment duration and treatment 
cycle). 
In some circumstances it may be difficult to distinguish residual lesions from normal tissues. 
When the evaluation of complete response depends upon this definition, it is recommended that 
the local lesion be investigated via biopsy before assigning a status of complete response. 
FDG-PET may be used to confirm a response to a CR in a manner similar to a biopsy 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 biopsy 
resolution/sensitivity. 
Table 1. Time point response: subjects with target (+/– non-target) disease 
Target Lesion 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
CR 
Non 
CR 
CR 
Non-CR/Non-PD 
Non 
PR 
CR 
Not evaluable 
Non 
PR 
PR 
Non-PD or not all 
Non 
PR 


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Target Lesion 
Non-Target Lesion 
New Lesion 
Overall Response 
evaluable 
SD 
Non-PD or not all 
evaluable 
Non 
SD 
Not all evaluable 
Non-PD 
Non 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = Complete 
response 
PR = Partial response 
SD = Stable disease 
PD = progressive disease NE = not 
evaluable 
Table 2.  Time point response: subjects with non-target lesion only 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
Non 
CR 
Non-CR/Non-PD 
Non 
Non-CR/Non-PD 
Not all evaluable 
Non 
Not evaluable 
Equivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Note: "Non-CR/non-PD" is preferred over SD for non-target lesion. Since SD is increasingly used as an endpoint for 
response evaluation, non-CR/non-PD response is developed to address the absence of lesion measurability.  
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled evaluation. If at 
the next scheduled evaluation, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
Table 3.  Best overall response when confirmation of CR and PR required 
Overall Response 
at First Time Point 
Overall Response 
at Subsequent 
Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
CR 
PD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
CR 
NE 
SD (provided minimum criteria for SD duration met, otherwise, NE) 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 


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Overall Response 
at First Time Point 
Overall Response 
at Subsequent 
Time Point 
Best Overall Response 
PR 
PD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
PR 
NE 
SD (provided minimum criteria for SD duration met, otherwise, NE) 
NE 
NE 
NE 
Note: CR is complete response, PR is partial response, SD is stable disease, PD is progressive disease, and NE is 
non-evaluable. a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even the 
disease meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared 
after CR). Best response will depend on whether minimum duration for SD is met. However, sometimes CR may be 
claimed when subsequent scans suggest small lesions are likely still present and in fact the subject has PR, not CR at 
the first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
2.5  Frequency of Tumor Re-Evaluation 
Frequency of tumor re-evaluation during treatment should be protocol-specific and consistent with 
the type and schedule of treatment. However, in the Phase II trials where the beneficial effect of 
treatment is not known, follow-ups for every 6-8 weeks (timed to coincide with the end of a cycle) 
is reasonable. Interval adjustments could be justified in specific regimens or circumstances. The 
protocol should specify which organ sites are to be evaluated at baseline (usually those most likely 
to be involved with metastatic disease for the tumor type under study) and how often evaluations 
are repeated. Normally, all target and non-target sites are evaluated at each assessment. In selected 
circumstances, certain non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when CR is identified in target disease or when progression in 
bone is suspected. 
After the treatment, the need for tumor re-evaluations depends on whether the trial has made the 
response rate or the time to an event (progression/death) an endpoint. If time to an event (e.g. 
TTP/DFS1/PFS) is the main endpoint of the study, then routine scheduled re-evaluation of protocol 
specified sites of disease is warranted. In randomized comparative studies in particular, the 
scheduled assessments should be performed as identified on a calendar schedule (for example: 
every 6-8 weeks on treatment or every 3-4 months after treatment) and should not be affected by 
delays in therapy, drug holidays or any other events that might lead to imbalance in a treatment 
group in the timing of disease assessment. 
2.6  Confirmatory Evaluation/Duration of Response 
2.6.1  
Confirmation 
In non-randomized 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 


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traditionally required confirmation in such trials. However, in all other circumstances, i.e., in 
randomized trials (phase II or III) or studies 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 studies which are not 
blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6-8 weeks) that is defined in the study protocol. 
2.6.2  
Duration of overall response 
The duration of overall response will be measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). The 
duration of overall complete response will be measured from the time criteria are first met for CR 
until the first date that recurrent or progressive disease is truly documented. 
2.6.3  
Duration of stable disease 
Stable disease will be measured from the start of the treatment (in randomized studies, 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 in a particular 
trial, the protocol shall specify the minimal time interval required between two measurements for 
determination of SD. 
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 accuracy of the measured endpoint shall be taken into account if 
comparisons between trials are to be made. 
2.7  PFS/TTP 
2.7.1  
Phase II clinical study 
This guideline is focused primarily on the use of objective response as study endpoints for phase II 
trials. In some circumstances, response rate may not be the optimal method to assess the potential 
anti-tumor activity of new agents/regimens. In such cases PFS/PPF at landmark time points, might 


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be considered appropriate alternatives to provide an initial signal of biologic effect of new agents. 
It is clear, however, that in an uncontrolled trial, these measures are subject to criticism since an 
apparently promising observation may be related to biological factors such as patient selection and 
not the impact of the intervention. Thus, phase II screening studies utilizing these endpoints are 
best designed with a randomized control. Exceptions may exist where the behavior patterns of 
certain cancers are so consistent (and usually consistently poor), that a non-randomized trial is 
justifiable. However, in these cases it will be essential to document with care the basis for 
estimating the expected PFS or PPF in the absence of a treatment effect. 
 
 


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Appendix 4 List of Autoimmune Diseases That May Exist Before Enrollment 
Carefully ask the subjects whether they have acquired or inherited immunodeficiency or 
autoimmune diseases. Such subjects must be excluded from this study, unless the possibility of the 
subject's history of allergies and childhood joint pain being suspected of an autoimmune disease is 
very low. In addition, subjects with transient autoimmune manifestations due to acute infectious 
diseases (such as Lyme arthritis) may be enrolled if they are cured with antibiotics. For 
indeterminate autoimmune diseases to be ruled out, contact the sponsor's medical department. 
Autoimmune diseases include but are not limited to: 
Acute sporadic encephalomyelitis 
IgA nephropathy 
Addison's disease 
Inflammatory bowel disease 
Alopecia universalis 
Interstitial cystitis 
Ankylosing spondylitis 
Myasthenia gravis syndrome 
Antiphospholipid antibody 
syndrome 
Lupus erythematosus 
Aplastic anemia 
Lyme disease (chronic) 
Asthma 
Meniere's syndrome 
Autoimmune hemolysis 
Anemia 
Corneal ulcer 
Autoimmune hepatitis 
Localized autoimmune 
hypophysitis 
Multiple sclerosis 
Autoimmune hypoparathyroidism 
Myasthenia gravis 
Autoimmune myocarditis 
Neuromyotonia 
Autoimmune oophoritis 
Myoclonus syndrome 
Autoimmune orchitis 
Optic neuritis 
Autoimmune thrombocytopenic 
purpura 
Ord's thyroiditis 
Behcet's disease 
Pemphigus 
Bullous pemphigoid 
Pernicious anemia 
Gluten sensitivity 
Polyarteritis 
Chronic fatigue syndrome 
Polyarthritis 
Chronic inflammatory demyelination 
Polyneuropathy 
Autoimmune syndrome 
Churg-Strauss syndrome 
Primary biliary cirrhosis 
Crohn's disease 
Psoriasis dermatomyositis 
Rett syndrome 
Type I diabetes mellitus 
Rheumatoid arthritis 
Autonomic dysfunction 
Sarcoidosis 
Eczema 
Scleroderma 
Sjogren syndrome 
Bullous skin lysis 
Stiff-man syndrome 
Pemphigoid gestationis 
Multi-takayasu arteritis 
Giant cell arteritis 
Ulcerative colitis 
Pulmonary hemorrhage-nephritic 
syndrome 
Vitiligo 
Graves' disease 
Vogt-Kovanagi-Harada disease 
Guillain-Barre syndrome 
Vulva sore 
Hashimoto's disease 
Wegener's granulomatosis 
Kawasaki disease 
 
 


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Appendix 5 Prohibited Traditional Chinese Medicines During the Study Period 
Traditional Chinese medicines prohibited during the study include but are not limited to the 
following: 
Huatan Huisheng tablet 
Brucea Javanica oil soft capsule 
Mandarin melon berry syrup 
Cantharidin 
Cinobufotalin 
Bufotoxin 
Kang'ai injection 
Kanglaite injection 
Zhongjiefeng injection 
Aidi injection 
Awei Huapi ointment 
Kangaiping pill 
Fukang capsule 
Xiaoaiping 
Pingxiao capsule 
Pingxiao tablet 
Shendan Sanjie capsule 
Ankangxin capsule 
Boshengaining 
Zedoary turmeric oil and glucose injection 
Kanglixin capsule 
Cidan capsule 
 
 


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Appendix 6 Guidelines on Dose Modifications and Handling of Toxicities of SHR-1210 
 
AE Grading/Dose Modification 
Treatment of Toxicity 
General Rules 
AEs are graded per the NCI CTCAE 
v4.03; if it is judged as an irAE, please 
refer to this guideline. 
The guidelines described in this table are recommended for the treatment of irAEs. 
- 
Subjects should be comprehensively evaluated to rule out any alternative causes 
(such as progressive disease, concomitant medication, infections, etc.) 
- 
When there is no clear alternative cause and glucocorticoid therapy is needed, it 
should be judged as an irAE. 
- 
For low-grade (Grade 1 or 2 unless otherwise specified) events, symptomatic and 
local treatment should be considered. 
- 
For persistent low-grade events (Grade 1 or 2) or severe (Grade ≥ 3) events, 
systemic glucocorticoid therapy should be considered. 
- 
If recurrence or deterioration occurs during the dose tapering of glucocorticoids, 
the dose of glucocorticoids should be increased until the symptoms are stable or 
improved, and then the dose of glucocorticoids should be tapered at a lower rate. 
- 
Once sustained clinical improvement is observed, subjects receiving intravenous 
glucocorticoids can switch to an equivalent dose of oral glucocorticoid therapy at 
the beginning of the dose tapering or earlier (the low bioavailability of oral 
glucocorticoids should be considered). 
- 
For events where systemic glucocorticoid therapy is ineffective, a stronger 
immunosuppressive agent, such as TNF antagonists (e.g., infliximab) or 
mycophenolate mofetil, should be considered after discussing with the study 
physician. 
- 
For local inflammatory reactions of Grade 3/4 lesions (such as local pain, 
irritation, and rashes) caused by potential tumor response, SHR-1210 may not be 
discontinued at the judgment of the investigator. 
Grade 1 Dose modification is not 
required. 
Grade 2 Treatment interruption 
• If aggravated, treat as 
Grade 3 or 4 
• If improved to Grade 
0-1 or baseline, 
continue the treatment 
on the next scheduled 
treatment date 
Grade 3 Treatment interruption or 
permanent discontinuation 
Grade 4 Permanent discontinuation 


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AE Grading/Dose Modification 
Treatment of Toxicity 
Pneumonia 
Any 
Grade 
 
- 
Monitor the subject for symptoms and signs of pneumonia or interstitial lung 
disease (such as new onset of shortness of breath, cough, chest pain, or 
deterioration of existing symptoms and signs), and use imaging, lung function, 
and other examinations to evaluate the subject. 
- 
The initial examination may include clinical evaluation, arterial oxygen 
saturation, laboratory tests, and high-resolution CT scan.  
Grade 1 Dose modification is not 
required. However, dose 
interruption may be 
considered based on 
clinical needs and during 
the diagnostic examination 
for other causes. 
For Grade 1: 
- 
Monitor symptoms and signs, arterial oxygen saturation for 2-4 days 
- 
Perform other laboratory tests as clinically indicated 
- 
Consider consultations of respiratory and infectious disease specialists 
Grade 2 Treatment interruption 
• If aggravated, treat as 
Grade 3 or 4 
• If improved to Grade 
0-1 or baseline, 
continue the treatment 
on the next scheduled 
treatment date 
For Grade 2 
- 
Monitor symptoms and signs daily and consider hospitalization 
- 
Discuss with the sponsor's medical department and consider giving systemic 
glucocorticoid therapy 
- 
Perform imaging examination again as clinically indicated 
- 
If no improvement is seen within 3-5 days, other examinations should be 
considered and the dose of glucocorticoid should be increased 
- 
If no improvement is seen within 3-5 days, a stronger immunosuppressant (such 
as infliximab) should be considered 
- 
Once improved, taper the dose of glucocorticoid within ≥ 4 weeks, and consider 
prophylactic antibiotics 
- 
Consider consultations of respiratory and infectious disease specialists 


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AE Grading/Dose Modification 
Treatment of Toxicity 
Grade 3 
or  
Grade 4 
Permanent discontinuation For Grade 3-4 
- 
Discuss with the sponsor's medical department 
- 
Consider consultations of respiratory and infectious disease specialists 
- 
Hospitalization 
- 
Supportive care (oxygen inhalation, etc.) 
- 
Systemic glucocorticoid therapy based on experience  
- 
If no improvement is seen within 3-5 days, other tests should be considered and 
other immunosuppressive agents (for example, infliximab) should be given 
- 
Once improved, taper the dose of glucocorticoid within ≥ 4 weeks, and consider 
prophylactic antibiotics 
Diarrhea or enterocolitis 
Any 
Grade 
 
- 
Monitor for symptoms and signs that may be related to diarrhea/entercolitis 
(abdominal pain, intestinal cramps, change of bowel habit, melena, mucous stools, 
bloody stools, muscle resistance, etc.) 
- 
Subjects should be comprehensively evaluated to rule out any alternative causes 
(such as progressive disease, infections, etc.) 
- 
If no alternative cause is determined, glucocorticoid therapy should also be 
considered for low-grade events to prevent the event from progressing to higher 
grades 
- 
Use painkillers with caution (as they can mask the symptoms of perforation and 
peritonitis) 
Grade 1 Dose modification is not 
required. 
For Grade 1 
- Monitor the deterioration of symptoms closely 
- Consider symptomatic treatment, including rehydration, electrolyte replacement, 
diet adjustment, and administration of loperamide 


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AE Grading/Dose Modification 
Treatment of Toxicity 
Grade 2 
or 
Grade 3 
Treatment interruption 
• If aggravated, treat as 
Grade 3 or 4 
• If improved to Grade 
0-1 or baseline, 
continue the treatment 
on the next scheduled 
treatment date 
For Grade 2-3 
- 
Consider symptomatic treatment, including rehydration, electrolyte replacement, 
diet adjustments, and loperamide and/or budesonide  
- 
If the event persists (> 3-5 days) or worsens, consider systemic glucocorticoid 
therapy 
- 
If the event does not resolve or worsens within 3-5 days, other tests should be 
considered and the dose of glucocorticoid should be increased 
- 
If the event does not resolve or worsens within 3-5 days, other tests should be 
considered and other immunosuppressive agents (e.g., infliximab) should be 
given  
- 
Once improved, taper the dose of glucocorticoid within ≥ 4 weeks, and consider 
prophylactic antibiotics 
Grade 4 Permanent discontinuation For Grade 4 
- 
Monitor the frequency and volume of bowel movements and maintain hydration 
- 
If applicable, conduct emergency gastrointestinal consultation and lower 
gastrointestinal endoscopy and imaging examinations to confirm whether there is 
intestinal perforation 
- 
Systemic glucocorticoid therapy based on experience 
- 
If no improvement is seen within 3-5 days, consider increasing the dose of 
systemic glucocorticoid 
- 
If no improvement is seen within 3-5 days, other immunosuppressive agents 
should be considered (such as infliximab, but infliximab must not be used in cases 
of perforation or septicemia) 
- 
Once improved, taper the dose of glucocorticoid within ≥ 4 weeks, and consider 
prophylactic antibiotics 


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AE Grading/Dose Modification 
Treatment of Toxicity 
Hepatitis (ALT, AST, or TBIL 
increased) 
Any 
Grade 
 
− 
Pay close attention to the symptoms and signs of hepatitis (such as jaundice, 
brown urine, nausea, vomiting, decreased appetite, pain in the liver area, 
bleeding tendency, etc.) 
− 
Monitor and evaluate hepatic function 
− 
Assess alternative causes (e.g., viral hepatitis, progressive disease, and 
combination medications) 
− 
The guidelines on dose modifications and handling of toxicities recommended in 
this table are applicable to subjects with normal baseline ALT, AST, and TBIL. 
For subjects with baseline ALT, AST, or TBIL > ULN, treatment should be 
interrupted when ALT, AST, or TBIL increases by ≥ 50% for < 7 days. For 
subjects with baseline ALT, AST, or TBIL > ULN, treatment should be 
permanently discontinued when ALT, AST, or TBIL increases by ≥ 50% for ≥ 7 
days. The investigator shall handle the toxicities based on the actual situation. 
Grade 1 
Dose modification is not 
required. 
For Grade 1 
- 
Continue hepatic function monitoring according to the protocol 
Grade 2 
Treatment interruption 
• If aggravated, treat as 
Grade 3 or 4 
• If improved to Grade 
0-1 or baseline, 
continue the treatment 
on the next scheduled 
treatment date 
For Grade 2 
- 
If the event does not recover to Grade ≤ 1 within 3-4 days, discuss with the 
sponsor's medical department 
- 
In the case of ALT, AST, or TBIL increased, retest the hepatic function within 3-4 
days and increase the monitoring frequency 
- 
If the event persists (> 3-5 days) or worsens, consider systemic glucocorticoid 
therapy 
- 
If no improvement is seen within 3-5 days, other examinations should be 
considered and the dose of glucocorticoid should be increased 
- 
If no improvement is seen within 3-5 days, a stronger immunosuppressant (e.g., 
mycophenolate mofetil) should be considered  
- 
Once improved, taper the dose of glucocorticoid within ≥ 4 weeks, and consider 
prophylactic antibiotics 


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AE Grading/Dose Modification 
Treatment of Toxicity 
Grade 3 
or 
Grade 4 
Permanent discontinuation For Grade 3-4 
- 
Discuss with the sponsor's medical department 
- 
Systemic glucocorticoid therapy based on experience 
- 
If no improvement is seen within 3-5 days, a stronger immunosuppressant (e.g., 
mycophenolate mofetil) should be considered 
- 
If no further improvement is seen within 3-5 days, consider other 
immunosuppressive therapies according to local guidelines 
- 
If applicable, perform gastroenterological consultations, abdominal examinations, 
and imaging examinations 
- 
Once improved, taper the dose of glucocorticoid within ≥ 4 weeks, and consider 
prophylactic antibiotics 
Dermatitis 
Any 
Grade 
 
- 
Monitor the signs and symptoms of dermatitis, such as rash, effusion, 
hypopigmentation, solar sensitiveness, and pruritus 
- 
If there is any bulla formed, contact the sponsor's medical department 
- 
Consider consultation with the Department of Dermatology 
- 
Perform skin biopsy if necessary 
Grade 1 Dose modification is not 
required 
For Grade 1 
- 
Consider symptomatic treatment including oral antipruritics (such as 
diphenhydramine or hydroxyzine) and local treatment (such as urea cream or 
topical glucocorticoid cream) 
Grade 2 Dose modification is not 
required. 
• 
For refractory Grade 
2 events (> 1-2 
weeks), treatment 
should be interrupted 
until the event 
For Grade 2: 
- 
Consider symptomatic treatment including oral antipruritics and topical treatment 
- 
Consider moderate-strength topical corticosteroids 
- 
If there is no improvement or deterioration within 3-5 days, discuss with the 
sponsor's medical department and consider systemic glucocorticoid therapy 


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AE Grading/Dose Modification 
Treatment of Toxicity 
recovers to Grade 0-1 
or baseline, and 
continue the treatment 
on the next scheduled 
treatment date 
- 
Consider consultation with the Department of Dermatology 
- 
If the event persists for > 1-2 weeks or recurs, consider skin biopsy 
- 
Once improved, taper the dose of glucocorticoid within ≥ 4 weeks, and consider 
prophylactic antibiotics 
Grade 3 Treatment interruption 
• 
If aggravated, treat it 
as Grade 4 
• 
If the Grade 3 rash 
does not recover to 
Grade 0-1 or baseline 
within 30 days, the 
treatment will be 
permanently 
discontinued 
For Grade 3-4: 
- 
Discuss with the sponsor's medical department 
- 
Consider hospitalization 
- 
Monitor the extent of the rash [Nine-Section method] 
- 
Consider consultation with the Department of Dermatology  
- 
If clinically feasible, consider skin biopsy (preferably more than once) 
- 
Systemic glucocorticoid therapy based on experience 
- 
If no improvement is seen within 3-5 days, other examinations should be 
considered and the dose of glucocorticoid should be increased 
- 
Once improved, taper the dose of glucocorticoid within ≥ 4 weeks, and consider 
prophylactic antibiotics 
Grade 4 Permanent discontinuation 
Hypopituitarism 
All 
grades 
 
- 
Monitor the subject's symptoms and signs of endocrine diseases, including faintness, 
fatigue, somnolence, nausea, vomiting, afraid of cold, abnormal defecation habits, 
behavior changes, mental status changes, hypotension, hypoglycemia, dizziness, 
headache, impaired vision, low libido in men, menstrual disorder, etc. 
- 
Subjects should be comprehensively evaluated to rule out any alternative causes 
(such as progressive disease, brain metastasis, infections, etc.) 
- 
Monitor and assess pituitary function tests: TSH, FT3, FT4, adrenocorticotropic 
hormone (ACTH), cortisol, luteinizing hormone, follicle stimulating hormone, 
growth hormone, prolactin, Na+, blood glucose, estradiol, testosterone, and other 
laboratory tests suspected to be related to endocrine disorders, as well as 
functional tests if necessary (including ACTH stimulation test and hypoglycemia 
stimulation test) 


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AE Grading/Dose Modification 
Treatment of Toxicity 
- 
Consider a pituitary MRI scan 
- 
Consider endocrinology consultation 
- 
Consider sending a blood sample for appropriate autoimmune antibody testing 
Grade 1 Dose modification is not 
required. 
For Grade 1: 
- 
Appropriately monitor the subject's pituitary function tests 
- 
Comprehensively evaluate the subject to rule out any alternative causes 
- 
Consider endocrinology consultation as clinically indicated 
Grade 2 Treatment interruption 
• 
If it aggravates to 
Grade 3-4, the 
treatment is 
permanently 
discontinued 
• 
If it recovers to 
Grade 0-1 or 
baseline, continue 
the treatment on the 
next scheduled 
treatment date 
For Grade 2-4: 
− 
Discuss with the sponsor's medical department 
− 
Consider endocrinology consultation 
− 
Consider hospitalization when necessary 
− 
Assess the endocrine function and consider a pituitary MRI scan as clinically 
indicated 
− 
Start hormone replacement therapy as needed (cortisone replacement therapy 
should start one week before levothyroxine treatment) 
− 
Start immunosuppressive therapy based on experience, and consider systemic 
glucocorticoid therapy 
− 
Once improved, taper the dose of glucocorticoid within ≥ 4 weeks (cortisone used 
for replacement therapy is adjusted according to the recovery of endocrine 
function, and subjects who cannot recover must receive long-term medication), 
and consider prophylactic antibiotics during the dose tapering to prevent 
opportunistic infections 
Grade 3 
or 
Grade 4 
Permanent discontinuation 


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AE Grading/Dose Modification 
Treatment of Toxicity 
Adrenal cortical hypofunction 
Any 
Grade 
 
- 
Monitor the subject's symptoms and signs of endocrine diseases, including 
fatigue, pigmentation, appetite absent, hypotension, and faintness 
- 
Comprehensively evaluate the subject to rule out any alternative causes 
- 
Monitor and evaluate adrenal cortex function: cortisol, ACTH, serum natrium, 
blood potassium, blood glucose, and other endocrine laboratory indicators 
suspected to be related to adrenocortical function, and perform ACTH stimulation 
test if necessary 
- 
Provide immunosuppressive therapy if necessary 
- 
Provide hormone replacement therapy (cortisone) if necessary 
- 
Consider endocrinology consultation 
- 
Consider sending a blood sample for appropriate autoimmune antibody testing 
Grade 1 Dose modification is not 
required. 
For Grade 1 
− 
Appropriately monitor the subject's adrenal gland function tests 
− 
Consider endocrinology consultation as clinically indicated 
Grade 2 Treatment interruption 
• 
If it worsens to Grade 
3 or 4, the treatment 
is permanently 
discontinued 
• 
If it recovers to 
Grade 0-1 or 
baseline, continue 
the treatment on the 
next scheduled 
treatment date 
For Grade 2 
− 
Discuss with the sponsor's medical department 
− 
Assess adrenal cortex function and start hormone replacement therapy as needed 


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AE Grading/Dose Modification 
Treatment of Toxicity 
Grade 3 
or 
Grade 4 
Permanent discontinuation For Grade 3-4: 
− 
Discuss with the sponsor's medical department 
− 
Consider endocrinology consultation 
− 
Consider systemic glucocorticoid therapy 
− 
For adrenal crisis, severe dehydration, hypotension, or shock, intravenous 
corticosteroids with mineralocorticoid activity should be started immediately 
− 
Once improved, taper the dose of glucocorticoid within ≥ 4 weeks (cortisone 
used for replacement therapy is adjusted according to the recovery of endocrine 
function, and subjects who cannot recover must receive long-term medication), 
and consider prophylactic antibiotics during the dose tapering to prevent 
opportunistic infections 
Hyperthyroidism/hypothyroidism Any 
Grade 
 
- 
Monitor the subject's symptoms and signs related to abnormal thyroid function, 
such as hyperthyroidism related (palpitations, sweating, increased food intake and 
bowel movements, weight loss, etc.) and hypothyroidism related (weakness 
generalized, fatigue, afraid of cold, decreased memory, constipation etc.) 
- 
Comprehensively evaluate the subject to rule out any alternative causes 
- 
Monitor and evaluate thyroid function 
- 
Consider endocrinology consultation 
- 
Consider sending a blood sample for thyroid autoantibody test (anti-thyroglobulin 
antibody, anti-thyroid peroxidase antibody, and thyroid stimulating hormone 
receptor antibody) 
Grade 1 
or  
Grade 2 
Dose modification is not 
required 
For Grade 1-2: 
- 
Regularly monitor thyroid function and thyroid autoantibodies 
- 
Provide levothyroxine replacement therapy or hyperthyroidism drug therapy if 
necessary 


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AE Grading/Dose Modification 
Treatment of Toxicity 
Grade 3 
or  
Grade 4 
Hyperthyroidism 
• 
Permanent 
discontinuation 
Hypothyroidism 
• 
Dose modification is 
not required. 
For Grade 3-4: 
- 
Discuss with the sponsor's medical department 
- 
Monitor thyroid function and thyroid autoantibodies 
- 
Consider endocrinology consultation 
Hyperthyroidism 
- 
Hyperthyroidism drug therapy 
- 
For tachycardia, consider beta blockers 
Hypothyroidism 
- 
Consider levothyroxine replacement therapy 
Type 1 diabetes 
Any 
Grade 
 
- 
Pay close attention to relevant symptoms and signs, such as polyuria, polydipsia, 
polyphagia, fatigue, faintness, weight loss, etc. 
- 
Comprehensively evaluate the subject to rule out any alternative causes 
- 
Monitor and evaluate pancreatic islet function: blood glucose, insulin, C-peptide, 
pancreatic β-cell autoantibodies, blood ketones, and other endocrine laboratory 
indicators suspected to be related to type 1 diabetes 
Grade 1 
or  
Grade 2 
Dose modification is not 
required 
For Grade 1-2 
− 
Monitor and evaluate pancreatic islet function 
− 
Provide insulin treatment if necessary 
Grade 3 Treatment interruption 
− Resume after blood 
glucose is controlled 
For Grade 3-4 
− 
Contact the sponsor's medical department 
− 
Monitor and evaluate pancreatic islet function 
− 
Consider endocrinology consultation 
− 
Prescribe insulin for blood glucose control, and adjust the dose of insulin based 
on the control of blood glucose 
Grade 4 
Permanent 
discontinuation 


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AE Grading/Dose Modification 
Treatment of Toxicity 
− 
Subjects who develop ketoacidosis must be admitted to the hospital for insulin, 
fluid replacement, and alkali supplement 
Renal insufficiency (blood 
creatinine increased) 
Any 
Grade 
 
− 
Pay close attention to relevant symptoms and signs (such as decreased urine 
output, darkened urine, anemia, fatigue and weakness, weight loss, etc.) 
− 
Comprehensively evaluate the subject to rule out any alternative causes 
− 
Monitor and evaluate renal function tests 
− 
Consider nephrology consultation 
− 
Consider a kidney biopsy to differentiate the cause of inflammation from 
non-inflammation when necessary 
Grade 1 Dose modification is not 
required 
For Grade 1 
- 
Monitor the creatinine level once a week 
- 
If it recovers to the baseline level, resume routine creatinine monitoring 
according to the study protocol 
Grade 2 
or  
Grade 3 
Treatment interruption 
• If it improves to Grade 
0-1, continue the 
treatment on the next 
scheduled treatment 
date 
• If it lasts > 7 days or 
aggravates, treat it as 
Grade 4 
For Grade 2-3 
- 
Discuss with the sponsor's medical department 
- 
Monitor the creatinine level every 2-3 days 
- 
Systemic glucocorticoid therapy based on experience 
- 
If it improves to Grade 1, taper the dose of glucocorticoid for ≥ 4 weeks, and 
consider prophylactic antibiotics to prevent opportunistic infections 
- 
Consider kidney biopsy 
- 
Conduct nephrology consultation 
Grade 4 Permanent discontinuation For Grade 4 
- 
Discuss with the sponsor's medical department 
- 
Monitor the creatinine level once a day 


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AE Grading/Dose Modification 
Treatment of Toxicity 
- 
Systemic glucocorticoid therapy based on experience 
- 
If it improves to Grade 1, taper the dose of glucocorticoid for ≥ 4 weeks, and 
consider prophylactic antibiotics to prevent opportunistic infections 
- 
Consult the nephrologists 
- 
Consider kidney biopsy 
Immune-related neurotoxicity 
(except for myasthenia gravis and 
Guillain-Barre syndrome) 
Any 
Grade 
 
- 
Monitor the subject's systemic symptoms (headache, nausea, dizziness, behavior 
changes, or faintness) 
- 
Subjects should be comprehensively evaluated to rule out any alternative causes 
(such as progressive disease, infections, metabolic syndrome, medications, etc.) 
- 
Consider appropriate diagnostic tests (e.g., electromyography and nerve 
conduction studies) 
- 
If applicable, conduct symptomatic treatment and neurology consultation 
Grade 1 Dose modification is not 
required. 
- 
Closely follow up the symptoms and signs 
Grade 2 Treatment interruption 
• 
If it improves to 
Grade 0-1, continue 
the treatment on the 
next scheduled 
treatment date 
• 
If it aggravates, treat 
it as Grade 3 
For Grade 2-4 
- 
Discuss with the sponsor's medical department 
- 
Consider neurology consultation 
- 
Consider hospitalization when necessary 
- 
Appropriate drugs (e.g., gabapentin, duloxetine, etc.) may be used to treat sensory 
neuropathy and neuropathic pain 
- 
Consider systemic glucocorticoid therapy 
- 
If no improvement is seen within 3-5 days, other tests should be considered and 
other immunosuppressive agents should be given (e.g., intravenous 
immunoglobulin G (IVIgG)) 
- 
Once stable, taper the dose of glucocorticoid within ≥ 4 weeks 
Grade 3 Permanent discontinuation 
Grade 4 


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AE Grading/Dose Modification 
Treatment of Toxicity 
Immune-related peripheral nerve 
syndromes, such as 
Guillain-Barre syndrome and 
myasthenia gravis 
Any 
Grade 
 
- 
Pay close attention to relevant symptoms and signs (myasthenia gravis: sore and 
discomfort of the eyes or limbs, blurred vision, fatigue, etc., characterized as 
milder in the morning and severer in the evening; Guillain-Barre syndrome: 
sudden severe radicular pain, flaccid paralysis of the limbs, abnormalities in limbs 
such as numbness, tingling, burning, etc.) 
- 
Subjects may experience unpredictable acute decompensation, leading to severe 
illness or death, and thus timely diagnosis of immune-related peripheral nerve 
syndrome is very important. Pay special attention to certain symptoms or signs 
that may indicate serious consequences, such as evident dysphagia, rapidly 
progressing faintness, respiratory insufficiency, or autonomic instability 
- 
Neural and electrophysiological examinations should be performed to rule out any 
alternative causes (such as progressive disease, infection, metabolic syndrome, and 
drug effects). It is worth noting that the disease itself and treatment of cancer subjects 
can affect neurological function. Diagnosis of immune-related peripheral nerve 
syndrome is difficult, and neurology consultation should be actively carried out. 
- 
For Guillain-Barre syndrome, plasma exchange or IVIgG therapy should be 
considered (glucocorticoid therapy is usually ineffective) 
Grade 1 Dose modification is not 
required. 
For Grade 1 
- 
Discuss with the study physician 
- 
Monitor the symptoms and signs 
- 
Consider neurology consultation 
Grade 2 Treatment interruption 
• 
If it improves to 
Grade 0-1, continue 
the treatment on the 
next scheduled 
treatment date 
• 
If it aggravates, treat 
it as Grade 3-4 
For Grade 2-4 
- 
Discuss with the sponsor's medical department 
- 
Monitor the symptoms and signs 
- 
Perform neurology consultation 
- 
Consider hospitalization when necessary 
 


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AE Grading/Dose Modification 
Treatment of Toxicity 
Grade 3 
or  
Grade 4 
Permanent discontinuation 
- 
Appropriate drugs (e.g., gabapentin, duloxetine, etc.) may be used to treat sensory 
neuropathy/neuropathic pain 
Myasthenia gravis 
- 
Glucocorticoids may be used to treat myasthenia gravis (glucocorticoid therapy 
(especially at high doses) may cause short-term deterioration of myasthenia and 
thus should be used under the supervision of a neurologist) 
- 
Subjects who cannot tolerate glucocorticoids may be treated with plasma 
exchange or IVIgG 
 
 
 
- 
In the case of myasthenia gravis-like neurotoxicity, consider giving 
acetylcholinesterase inhibitors in addition to glucocorticoids 
Guillain-Barre syndrome 
- 
For Guillain-Barre syndrome, plasma exchange or IVIgG therapy should be 
considered (glucocorticoid therapy is usually ineffective) 
 

SAP_001.pdf: 
Title: A phase II clinical study of SHR-1210 combined with apatinib mesylate for the 
treatment of extensive-stage small cell lung cancer failing first-line standard therapy 
(PASSION) 
NCT number: NCT03417895 
Date: 27 Jul., 2020 


Immune Checkpoint Inhibitor 
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A PHASE II CLINICAL STUDY OF SHR-1210 COMBINED WITH 
APATINIB MESYLATE FOR THE TREATMENT OF EXTENSIVE-
STAGE SMALL CELL LUNG CANCER FAILING FIRST-LINE 
STANDARD THERAPY 
(PASSION) 
(RANDOMIZED, OPEN-LABEL, MULTI-CENTER) 
 
 
STATISTICAL ANALYSIS PLAN 
(SAP) 
 
 
Translated from Original Document 


Immune Checkpoint Inhibitor 
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Drafted by:  
 
Company:  
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Version:  
1.0 
Date:  
27 Jul., 2020 
 
This SAP has been reviewed by the following personnel before being approved and effective. 
Functional Role 
Reviewer 
Signature 
Date 
Medical Science 
 
Refer to original for signature Refer to original for signature 
Statistics 
 
Refer to original for signature Refer to original for signature 
Programming 
 
Refer to original for signature Refer to original for signature 
 
 


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ABBREVIATIONS 
Abbreviations  
Full Name  
ADA 
Anti-drug antibody 
ADAS 
ADA set 
AE 
Adverse event 
BOR 
Best overall response 
CI 
Confidence interval 
CR 
Complete response 
DCR 
Disease control rate 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic case report form 
ED-SCLC 
Extensive-stage disease small cell lung cancer 
FAS 
Full analysis set 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 4 
irAE 
Immuno-related adverse event 
LD-SCLC 
Limited-stage disease small cell lung cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralizing antibody 
NE 
Not evaluable 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PBMCs 
Peripheral blood mononuclear cells 
PD 
Progressive disease 
PD-1 
Programmed death-1 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-free survival 
PPS 
Per-protocol set 
PR 
Partial response 
PT 
Preferred term 
Q2W 
Every 2 weeks 
QD 
Once daily 


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Abbreviations  
Full Name  
RECIST 
Response Evaluation Criteria in Solid 
Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SS 
Safety set 
T3 
Triiodothyronine 
T4 
Thyroxine 
TMB 
Tumor mutant burden 
TMKS 
Tumor biomarker set 
TSH 
Thyroid-stimulating hormone 
TTR 
Time to response 
VALG 
Veterans Administration Lung Study Group 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
 
 


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TABLE OF CONTENTS 
ABBREVIATIONS ....................................................................................................................... 3 
1 
REVISION ............................................................................................................................. 7 
2 
INTRODUCTION ................................................................................................................ 7 
2.1 Study Design .................................................................................................................. 7 
2.2 Study Objectives ........................................................................................................... 10 
2.2.1 Primary objectives ............................................................................................ 10 
2.2.2 Secondary objective ......................................................................................... 10 
2.2.3 Exploratory objective ....................................................................................... 10 
2.3 Sample Size .................................................................................................................. 10 
3 
STATISTICAL HYPOTHESIS ......................................................................................... 10 
4 
STUDY ENDPOINTS ......................................................................................................... 11 
4.1 Primary Endpoints ........................................................................................................ 11 
4.2 Secondary Endpoints .................................................................................................... 12 
4.3 Exploratory Endpoint ................................................................................................... 12 
5 
STATISTICAL ANALYSIS .............................................................................................. 13 
5.1 General Considerations ................................................................................................ 13 
5.1.1 Analysis sets ..................................................................................................... 13 
5.1.2 General analysis ............................................................................................... 14 
5.1.3 Derived variables .............................................................................................. 14 
5.1.4 Covariates and subgroups ................................................................................. 14 
5.1.5 Analysis window .............................................................................................. 15 
5.1.6 Missing data ..................................................................................................... 15 
5.2 Study Subjects .............................................................................................................. 18 
5.2.1 Disposition of subjects ..................................................................................... 18 
5.2.2 Demographics and baseline characteristics ...................................................... 19 
5.2.3 Prior illnesses ................................................................................................... 19 
5.2.4 Prior treatment and concomitant medication .................................................... 19 
5.2.5 New anti-tumor treatment ................................................................................ 20 
5.2.6 Protocol deviations ........................................................................................... 20 
5.3 Extent of Exposure and Treatment Compliance ........................................................... 21 
5.3.1 SHR-1210 ......................................................................................................... 21 


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5.3.2 Apatinib ............................................................................................................ 21 
5.4 Efficacy Analysis .......................................................................................................... 21 
5.4.1 Primary efficacy analysis ................................................................................. 21 
5.4.2 Secondary efficacy analysis ............................................................................. 22 
5.4.3 Exploratory analyses ........................................................................................ 25 
5.4.4 Subgroup analysis ............................................................................................. 25 
5.5 Safety Analysis ............................................................................................................. 25 
5.5.1 Adverse events ................................................................................................. 25 
5.5.2 Laboratory evaluations ..................................................................................... 27 
5.5.3 Vital signs ......................................................................................................... 27 
5.5.4 Electrocardiogram ............................................................................................ 27 
5.5.5 Physical examination ........................................................................................ 27 
5.5.6 ECOG PS .......................................................................................................... 27 
5.5.7 Other safety analyses ........................................................................................ 27 
6 
INTERIM ANALYSIS ....................................................................................................... 28 
7 
REFERENCES .................................................................................................................... 28 
8 
APPENDICES ..................................................................................................................... 28 
8.1 Appendix 1. Best Overall Response with CR and PR to Be Confirmed ...................... 28 
 
LIST OF FIGURES 
Figure 1. Design of the phase II study of SHR-1210 combined with apatinib ............................... 8 
Figure 2. Study procedures of SHR-1210 combined with apatinib ................................................ 9 
 
 


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1 REVISION 
Not applicable. 
2 INTRODUCTION 
Lung cancer is the most common malignancy in China. The main types include non-small cell 
lung cancer (NSCLC) and small cell lung cancer (SCLC). SCLC accounts for 10-15% of new 
lung cancers. As a highly aggressive neuroendocrine tumor, SCLC is significantly different from 
NSCLC clinically and pathologically, characterized by rapid growth, proneness to drug 
resistance, and early metastasis. Almost all patients with SCLC have a history of heavy tobacco 
use [9,10]. Traditionally, SCLC is classified into limited-stage disease (LD-SCLC, where tumor 
tissue surrounds a radiotherapy field) and extensive-stage disease (ED-SCLC, where tumor tissue 
exceeds the boundary of a radiotherapy field). Peripheral blood mononuclear cells (PBMCs) of 
patients with SCLC showed that those with a long survival have a high ratio of effector T cells to 
regulatory T cells [30]. Anti-PD-1 agents play a therapeutic role by blocking the binding of PD-
L1 on tumor cells and PD-1 of T cells, blocking its inhibition on T cells. Compared with 
traditional cytotoxic chemotherapy, PD-1-targeted therapy has higher specificity, lower toxicity, 
and applicability to a variety of tumor types. Apatinib is a small-molecular targeted drug and 
exerts anti-angiogenesis effect to treat malignant tumors by inhibiting VEGFR. Hengrui 
conducted phase I/II clinical studies of the recombinant humanized anti-PD-1 monoclonal 
antibody injection (SHR-1210) in several tumor types of tumors, and preliminarily validated the 
safety, tolerability, and efficacy of SHR-1210 monotherapy in the treatment of advanced solid 
tumors. Considering the role of immune-related therapies in SCLC, as well as the role of 
immune checkpoint inhibitors combined with VEGF and VEGFR-2 inhibitors in patients with 
gastric cancer and renal cancer, the benefits from SHR-1210 combined with apatinib in the 
second-line treatment of SCLC are reasonable and worth looking forward to. Only topotecan 
(intravenously or orally administered) has been approved for the treatment of ED-SCLC after 
failure of first-line standard therapy by the FDA. No immunotherapy is commercially available 
currently. Preclinical data suggested that it has similar pharmacodynamics and anti-tumor effects 
to those of nivolumab and pembrolizumab. The studies on the PD-1/PD-L1-based combination 
therapy that have been published and ongoing abroad suggested that patients may benefit and the 
safety is controllable. 
2.1 Study Design 
This is a randomized, open-label, multi-center phase II clinical study. Eligible subjects after 
screening will be randomized into the following 3 groups in a 1:1:1 ratio, with 4 weeks as 1 
treatment cycle. Refer to Figure 1 for the study design. Refer to Figure 2 for the study 
procedures. 


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The study consists of two stages. In Stage I, subjects will be randomized into 3 different dose 
groups, with 6 subjects in each group. It is planned that after the last subject in Stage I completes 
Cycle 1 treatment (28 days), the leading center's principal investigator and the sponsor will 
jointly perform a safety assessment of subjects enrolled in Stage I, decide the treatment group of 
Stage II, and choose one group of method of administration and a tolerated dose of apatinib for 
Stage II treatment. 
A total of 39 subjects will be enrolled in Stage II. The primary analysis will be performed when 
the last subject has been treated for 180 days. 
For any treatment group entering Stage II, if the safety is acceptable and the efficacy meets the 
corresponding statistical criteria, it indicates potential needs of further development. 
 
Note: Subjects with PD for the first time must be confirmed; for medication after the first PD, refer to Section 6.1.2 
of the protocol; for imaging confirmation and subsequent evaluations of the first PD, refer to Section 8.1.2 of the 
protocol 
Figure 1. Design of the phase II study of SHR-1210 combined with apatinib
• Patients who have 
previously received 
first-line platinum-
based treatment for 
small cell lung 
cancer and have 
shown objective 
radiographic 
progression. 
• ECOG PS of 0-1 
• Expected survival 
≥ 8 weeks 
Stage I 
Safety (N = 6) 
Stage I 
Safety (N = 6) 
A: 
SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, 
PO, QD 
(n = 45) 
B: 
SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, 
PO, QD (5 days on, 2 days off) 
(n = 45) 
C: 
SHR-1210 200 mg, IV, Q2W + apatinib 375 mg, 
PO, QD (7 days on, 7 days off) 
(n = 45) 
1:1:1 
Randomized, 
unblinded 
Until the occurrence of 
any of the following: 
start of new anti-tumor 
treatment, progressive 
disease, withdrawal of 
ICF by subjects, and death 


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Figure 2. Study procedures of SHR-1210 combined with apatinib
Screening 
Period 
Evaluation per 
RECIST 1.11 
Treatment Period 
End of 
Treatment/ 
Withdrawal3 
Safety 
Follow-
Up4 
Survival 
Follow-
Up5 
SHR-1210 (Stage I/II) 
× 200 mg, IV, Q2W after C1D1 
Apatinib (Stage I/II) 
× 375 mg, PO, QD (continuous administration, or 5 days on, 2 days off, or 7 days on, 7 days off) after C1D1 


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2.2 Study Objectives  
2.2.1 Primary objectives 
• 
To evaluate the safety and efficacy of SHR-1210 combined with apatinib in the treatment of 
ED-SCLC after failure of the first-line standard therapy 
2.2.2 Secondary objective 
• 
To evaluate the immunogenicity 
2.2.3 Exploratory objective 
• 
To evaluate the correlation between biomarkers (including but not limited to PD-L1 and 
TMB) and efficacy 
2.3 Sample Size 
In this study, based on historical study data and study results of drugs of the same class and 
combined with clinical needs, a single-stage assessment method will be adopted to explore the 
efficacy of SHR-1210 combined with apatinib on ORR in ED-SCLC after failure of the first-line 
standard therapy. 
Assume that in this study, it is expected that the ORR in each treatment group of SHR-1210 + 
apatinib combination therapy is ≥ 30% (alternative hypothesis), and assume that there is no need 
to continue the study if the ORR is ≤ 15% (null hypothesis), at the significance level of 0.1 and a 
power of 80%, 40 subjects should be enrolled. If ≥ 9 (22.5%) of the 40 subjects have response, it 
can be considered that the ORR in this treatment group is 15% and the investigational drug is 
worthy of continued development. 
With a dropout rate of 10% taken into account, each treatment group should enroll about 45 
subjects, for a total of 135 subjects. 
3 STATISTICAL HYPOTHESIS 
This study does not involve any statistical hypotheses and inference. 
A single-stage assessment method will be adopted to explore the efficacy of SHR-1210 
combined with apatinib on ORR in ED-SCLC after failure of the first-line standard therapy. The 
potential need for further development is indicated when the predefined number of responses 
(objective response) of a treatment group is reached (see Section 2.3 for details). 


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4 
STUDY ENDPOINTS 
4.1 Primary Endpoints 
1. 
Incidence rate of adverse events (AEs) evaluated per CTCAE 4.03, especially the incidence 
rate of AEs meeting any of the following: 
1) 
Hematologic toxicity: 
- 
Grade 4, or 
- 
Grade ≥ 3 thrombocytopenia with hemorrhage, or 
- 
Grade ≥ 4 neutropenia with pyrexia and infection 
2) 
Grade ≥ 3 non-hematologic toxicity (except for laboratory abnormalities), 
hypertension, rash, diarrhea, nausea, and vomiting that cannot be controlled after 
symptomatic treatment 
3) 
Grade ≥ 3 laboratory abnormalities that lead to medical interventions or hospitalization, 
or last for ≥ 7 days 
4) 
Any Grade 5 AEs 
2. 
Objective response rate (ORR): defined as the proportion of enrolled subjects with a best 
overall response (BOR) of CR or PR as per RECIST 1.1. Response confirmation should be 
conducted for CR and PR. 
Best overall response (BOR) is defined as the best response from the start of medication 
until progressive disease (PD) or the start of a new anti-tumor treatment. New anti-tumor 
therapy is defined as concomitant anti-tumor therapy that occurs after the start of 
medication. BOR in this study will be based on the confirmed efficacy, with reference to the 
RECIST 1.1 as the confirmation criteria (Appendix 1). 
• 
Confirmed PR: The response evaluated as CR should be reconfirmed as CR at a later 
time point (at least 4 weeks later). 
• 
Confirmed PR: 
- 
The response is evaluated as CR, but it is reconfirmed as PR (CR is not reached) at 
a later time point (at least 4 weeks later). 
- 
The response is evaluated as PR, but it is reconfirmed as CR/PR at a later time 
point (at least 4 weeks later). 


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• 
Confirmed SD: 
- 
The response is evaluated as CR/PR (at least 4 weeks from baseline evaluation), 
but it is reconfirmed as CR/PR not reached. 
- 
The response is evaluated as SD at least once within the shortest time interval (not 
less than 4 weeks) after the start of the study. 
4.2 Secondary Endpoints 
• 
Incidence of AEs and serious adverse events (SAEs) as per CTCAE V4.03, as well as 
laboratory measurements, ECG, vital signs, and other safety parameters 
• 
Overall survival (OS): defined as the time from the first dose to the death of the subject of 
any cause. 
• 
6- and 12-month OS rates 
• 
Progress-free survival (PFS): the time from the date of first dose to the first documented 
objective tumor progress as per RECIST 1.1 or death of any cause, whichever occurs first. 
• 
Time to response (TTR): defined as the period of time from the date of first dose to the first 
documented tumor response (CR or PR). CR and PR must be evaluated per the RECIST 1.1 
and confirmed for efficacy. 
• 
Duration of response (DoR): the date from the first documented tumor response (CR or PR) 
to the first documented objective tumor progress (PD) or the date of death of any cause. 
Response defined by CR and PR must be assessed per the RECIST 1.1 and confirmed for 
efficacy. The start date of response duration is the first observed response, instead of the 
confirmed response. 
• 
Disease control rate (DCR): defined as the proportion of enrolled subjects who are 
evaluated as CR, PR, or SD (for at least 4 weeks) per the RECIST 1.1. Response 
confirmation should be conducted for CR and PR. 
• 
Immunogenicity evaluation: Positive rates of ADA and NAb 
4.3 Exploratory Endpoint 
• 
Tumor biomarkers (including but not limited to expression levels of PD-L1 and TMB in 
tumor samples) 


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5 
STATISTICAL ANALYSIS 
5.1 General Considerations 
5.1.1 Analysis sets 
The analysis sets in this study included: 
Full analysis set (FAS): an analysis set determined based on the intent-to-treat principle. This 
analysis set includes all enrolled subjects who have received at least one dose of the study drug. 
Based on the FAS, the subjects will be analyzed according to their scheduled doses. 
Per-protocol set (PPS): a subset of the FAS. Subjects with major protocol violations that have a 
major effect on the study results will be excluded from this set. The list of subjects included into 
or excluded from the PPS should be reviewed and determined by the sponsor and the investigator 
before the database is locked. 
Safety set (SS): all subjects who have received at least one dose of the study drug and underwent 
post-administration safety evaluation. Analyses based on the safety set will be carried out 
according to the actual treatment received by the subjects. 
ADA set (ADAS): All enrolled subjects who have received at least one dose of the study drug 
and have baseline and at least one post-baseline ADA evaluation data. 
Tumor biomarkers set (TMKS): all enrolled subjects who have received at least one dose of the 
study drug and have tumor biopsy samples (including peripheral blood) make up the PD-L1 or 
TMB set. 
Table X. Analysis sets and corresponding endpoints 
Endpoint 
Analysis Sets 
 
FAS 
PPS 
SS 
ADAS 
TMKS 
Safety Endpoints 
 
 
X 
 
 
ORR 
X 
X 
 
 
 
OS and 6/12-month OS rates 
X 
 
 
 
 
PFS 
X 
 
 
 
 
TTR 
X 
 
 
 
 
DoR 
X 
 
 
 
 
DCR 
X 
 
 
 
 
Immunogenicity Evaluation 
 
 
 
X 
 
Tumor Biomarkers 
 
 
 
 
X 


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5.1.2 
General analysis 
Unless otherwise specified, standard descriptive statistics will be summarized by different type 
of variables: 
• 
Continuous variables will be summarized by mean, standard deviation, median, maximum, 
and minimum. The decimal places for the minimum and maximum should be consistent 
with those on the eCRF. There should be 1 additional decimal place for the mean and 
median compared to the raw data, and 2 additional decimal places for standard deviation, 
with up to 4 decimal places. 
• 
Categorical variables will be summarized by frequency and percentage, with 1 decimal 
place for percentages; 
• 
For time-to-event data, the Kaplan-Meier method will be used to estimate the survival 
function and median time to event onset, and the survival curves will be plotted. 
If not otherwise specified, the baseline is generally defined as the last pre-administration 
observation before the first dose (including the day of administration). The last non-missing 
measurement value will be decided by the date of measurement. If there are multiple 
measurements on the same day, then: 
• 
If both scheduled and unscheduled visits are present, the value obtained from the scheduled 
visit will be considered as the last non-missing measured value. 
• 
If there are multiple scheduled visits, the value obtained from the visit with the largest visit 
number will be considered as the last non-missing measured value. 
• 
If there is no scheduled visit but are multiple unscheduled visits, the value obtained from the 
visit with the largest number of unscheduled visit will be considered as the last non-missing 
measured value. 
The date of first dose in this study is defined as the date of first dose of apatinib or the date of 
first dose of SHR-1210, whichever is earlier. 
5.1.3 Derived variables 
Not applicable. 
5.1.4 Covariates and subgroups 
Subgroup analysis of the primary endpoint ORR will be based on the FAS: 
• 
Sensitive recurrence: progress in ≥ 90 days from the last chemotherapy 
• 
Drug-resistant recurrence: progress during chemotherapy or within 90 days from the last 
chemotherapy 


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The time between progress and the last chemotherapy is calculated as follows: date of the most 
recent progress/relapse − date of the last chemotherapy. Sensitive recurrence is determined if the 
time between progress and the last chemotherapy is ≥ 90 days; otherwise, drug-resistant 
recurrence is determined. 
5.1.5 Analysis window 
The study days is defined as the days from the first dose of study drugs to the safety/efficacy 
evaluation. The day of first dose of study drugs (SHR-1210 or apatinib, whichever is used first) 
is used as the start date of the study (Day 1). 
The study date is calculated as follows: 
Study days = evaluation date – start date of study + 1, in the case of evaluation after the first dose 
of study drugs 
Or 
Study date = evaluation date – start date of study, in the case of evaluation before the first dose 
of study drugs. 
Data obtained from post-baseline visits will be summarized by protocol visits of SHR-1210 
shown in eCRF. There is no need to consider whether the visit window specified by the protocol 
has been exceeded. 
5.1.6 Missing data 
5.1.6.1 
Medical history 
For disease-related records before the first dose of study drugs: 
● 
If the day is missing, the day will be imputed with the 1st of the month; 
● 
If the month and day are missing, the day will be imputed with 1 Jan.; 
● 
If the date is completely missing, the day will not be imputed. 
5.1.6.2 
Adverse Event 
● 
If the day of the onset date is missing, and the year and month are the same as those of the 
first dose, the day will be imputed with the date of first dose; otherwise, it is imputed with 
the 1st of the month; 
● 
If the month and day of the onset date are missing, and the year is the same as those of the 
first dose, the day will be imputed with the date of first dose; otherwise, it is imputed with 
1 Jan. of the year; 


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● 
If the onset date is completely missing, the day will be imputed with the date of first dose; 
● 
If the day of the end date is missing, the day will be imputed with the last day of the month 
or the date of death (if applicable), whichever is earlier; 
● 
If the year or month of the end date is missing, the day will not be imputed. 
5.1.6.3 
Concomitant medications 
The dates of concomitant medications are imputed in the same way as AEs. 
5.1.6.4 
Last survival date 
If the investigator is not informed of subject's death by the cutoff date of analysis, the latest 
complete date of the following data will be used as the last survival date: 
● 
The dates of the subject's all assessments 
● 
The start and end dates of new anti-tumor treatment after the discontinuation of study 
treatment 
● 
The start and end dates of AEs 
● 
The date of the last known survival status of the subject on the survival follow-up page 
● 
The start and end dates of study treatment 
● 
The date of withdrawal of informed consent form 
● 
The date on the study discontinuation page (if the reason for discontinuation is "lost to 
follow up", the date of lost to follow up will not be calculated) 
Only the date of actual examinations can be used to derive the last survival date. The dates of 
examinations and evaluations carried out after the cutoff date will not be used to derive the last 
survival date. 
5.1.6.5 
Death date 
● 
If the day of the death date is missing, the day will be imputed with the last day of the 
month or the last survival date + 1, whichever is later; 
● 
If the month and day of the death date are missing, the day will be imputed with 1 Jan. of 
the year or the last survival date + 1, whichever is later; 
● 
If the death date is completely missing, the day will be imputed with the last survival date 
+ 1. 


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5.1.6.6 
New anti-tumor treatment 
If the start date of a new anti-tumor treatment is not completely missing, it will be imputed 
according to the following rules and used to derive the end date of the study treatment. The date 
of PD mentioned below is date of the first documented PD. 
● 
If the end date of the new anti-tumor treatment is partially missing or not missing, the end 
date of the new anti-tumor treatment will be used to derive the start date of the new anti-
tumor treatment 
- 
If the month and day of the end date of the new anti-tumor treatment are missing but 
the year is not missing, 31 Dec. is used as the end date of the new anti-tumor treatment. 
- 
If only the day of the end date of the new anti-tumor treatment is missing, the last day 
of the month will be used as the end date of the new anti-tumor treatment. 
● 
If the month (MM) or day (DD) of the start date of new anti-tumor treatment are missing or 
the date of the start date of new anti-tumor treatment is completely missing, the rules for 
deriving and imputing the date are as follows: 
- 
If the start date of a new anti-tumor treatment is completely missing, the imputed start 
date = min [max (PD date + 1, date of the last dose + 1), end date of the new anti-tumor 
treatment] 
- 
Only the year (YYYY) of the start date of new anti-tumor treatment is not missing 
1)  If YYYY < min (year) [max (PD date + 1, date of last dose + 1), end date of new 
anti-tumor treatment], the date is imputed as 31 Dec., YYYY. 
2) 
If YYYY = min (year) [max (PD date + 1, date of the last dose + 1), end date of 
new anti-tumor treatment], the imputed date = min [max (PD date + 1, date of the 
last dose +1), end date of new anti-tumor treatment]. 
3) 
If YYYY > min (year) [max (PD date + 1, date of the last dose + 1), end date of 
new anti-tumor treatment], then the imputed date = 1 Jan. YYYY. 
● 
The year (YYYY) and month (MM) of the start date of new anti-tumor treatment are not 
missing 
- 
If YYYY = min (year) [max (PD date + 1, date of the last dose + 1), end date of new 
anti-tumor treatment], and if MM < min (month) [max (PD date + 1, date of the last 
dose + 1), end date of new anti-tumor treatment], the date will be imputed with the last 
day of MM. 


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- 
If YYYY = min (year) [max (PD date + 1, date of the last dose + 1), end date of new 
anti-tumor treatment], and MM = min (month) [max (PD date +1, date of the last dose 
+1), end date of new anti-tumor treatment], the date imputed = min [max (PD date + 1, 
date of the last dose + 1), end date of new anti-tumor treatment]. 
- 
If YYYY = min (year) [max (PD date + 1, date of the last dose + 1), end date of new 
anti-tumor treatment], and if at the same time MM > min (month) [max (PD date +1, 
date of the last dose +1), the end date of new anti-tumor treatment], then the imputed 
date = 1 MM, YYYY. 
- 
If YYYY < min (year) [max (PD date + 1, date of the last dose + 1), end date of new 
anti-tumor treatment], then the day of the imputed date is the last day of MM. 
- 
If YYYY > min (year) [max (PD date + 1, date of the last dose + 1), end date of new 
anti-tumor treatment], then the imputed date = 1 MM, YYYY. 
All imputed dates must be before the date of withdrawal of informed consent form, lost to 
follow-up, and death. 
Missing data of laboratory evaluations are not imputed. 
The rules for imputation of missing data for the remaining study endpoints will be detailed in the 
specific sections of analyses. 
5.2 Study Subjects 
5.2.1 Disposition of subjects 
All enrolled subjects will be divided by stage and dose group using frequency and percentage. In 
addition, in the disposition of subjects, the frequency and percentage of the following 
information will be summarized by dose group: 
• 
Number of screened subjects and reasons for screening failure; 
• 
Number of enrolled subjects; 
• 
Number of subjects with study termination/treatment discontinuation; 
• 
Reasons for study termination/treatment discontinuation; 
Reasons for screening failure, subject enrollment, treatment discontinuation and reasons, and 
study discontinuation and reasons will be listed. 
A listing will be provided on whether the enrolled subjects are included in the FAS, PPS, SS, 
ADAS, and TMKS. The listing will include rejected analysis sets and reasons for rejection at 
least. 


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5.2.2 
Demographics and baseline characteristics 
5.2.2.1 
Demographics 
The subjects' age, gender, ethnicity, height, weight, and body mass index will be summarized 
using descriptive statistics. Quantitative variables such as age, height, weight, and body mass 
index will be summarized using descriptive statistics such as number of evaluable subjects, mean 
and standard deviation, median, minimum and maximum. Categorical variables such as gender 
and ethnicity will be summarized using descriptive statistics, including number of evaluable 
subjects per category and corresponding percentage in total population. 
5.2.2.2 
Other baseline characteristics 
The subjects' allergy, smoking, and alcohol history will be summarized and listed using 
descriptive statistics. 
The diagnosis of small cell lung cancer in the subjects, including the VALG stage of the initial 
diagnosis, presence of metastases, course of disease, and time to the most recent 
progress/recurrence will be summarized using descriptive statistics. The course of disease 
(month) is defined as the time from the date of first pathological diagnosis to the date before the 
first dose, calculated as: (date of the first dose − date of the first pathological diagnosis) / 
30.4375. The time to the most recent progress/recurrence (month) is defined as the time from the 
most recent progress/recurrence to the date before the first dose, calculated as: (date of the first 
dose − date of the most recent progress/recurrence) / 30.4375. The date of the first diagnosis, 
location of the primary tumor, location of the metastasis, diagnostic method, the VALG stage of 
the first diagnosis, date of the most recent progress/recurrence, course of the disease, and time to 
the most recent recurrence/progress will be listed. 
5.2.3 Prior illnesses 
Medical history will be coded by system organ class (SOC) and preferred term (PT) in the 
Chinese version of the ICH Medical Dictionary for Regulatory Activities (MedDRA) 21.0. 
The prior illness of the subjects will be statistically summarized correspondingly by treatment 
group. 
All prior illness will be listed. 
5.2.4 Prior treatment and concomitant medication 
5.2.4.1 
History of anti-tumor treatment 
History of anti-tumor treatment mainly includes systemic anti-tumor treatment, radiotherapy, and 
surgery, which correspond to history of anti-tumor treatment, radiotherapy history, and surgical 
history, respectively. 


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Anti-tumor treatments are descriptively summarized by the following categories, and the 
numbers and percentages of subjects undergoing corresponding anti-tumor treatment are 
calculated: 
- 
Classification and indication of systemic treatment 
- 
Number of systemic regimens (using different chemotherapy drugs) received in the past 
- 
Indication of radiotherapy 
- 
Type of surgery and classification of tumor surgery 
The duration between the end date of the last anti-tumor treatment and the time (months) of the 
first dose will be summarized, calculated as: (date of the first dose − end date of the last anti-
tumor treatment) / 30.4375. 
All treatment histories (including anti-tumor treatment and non-anti-tumor treatment) are listed 
in detail. 
5.2.4.2 
Prior/concomitant medication 
A list of prior medications and concomitant medications will be provided. 
5.2.5 New anti-tumor treatment 
The number and percentage of subjects who have received new anti-tumor treatment after 
withdrawal will be summarized by dose group, and a detailed listing will be provided. 
5.2.6 Protocol deviations 
Before database locking, data of all subjects on the eCRF will be checked for important protocol 
deviations. All potential important protocol deviations will be reviewed and evaluated by the 
investigator and the sponsor. 
All important protocol deviations will be summarized and described by type and tabulated for 
analysis. 
Definitions of important protocol deviations: 
• 
Serious violation of the inclusion/exclusion criteria; 
• 
Incorrect treatment by study drugs (not treated using the drug or dose as per randomization); 
• 
Other protocol deviations jointly recognized by the investigator and the sponsor. 


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5.3 Extent of Exposure and Treatment Compliance 
Based on the SS, the use of study drugs will be summarized using descriptive statistics by drug 
and dose group. The use of all study drugs will be listed in detail. 
5.3.1 SHR-1210 
Compliance (%) = (actual number of doses / scheduled number of doses) × 100%  
Scheduled number of doses = scheduled duration of administration / 14 (days). 
The frequency and reasons of SHR-1210 treatment interruption and permanent discontinuation 
will be summarized. 
5.3.2 Apatinib 
Actual dose (tablets): The sum of the documented actual doses of a subject during the treatment 
period, calculated as the actual number of days of administration × 1 tablet/day. The actual 
number of days of administration is subject to the records of apatinib administration. The number 
of consecutive dosing days for each period is calculated as: end date − start date + 1. 
Scheduled dose (tablets): number of treatment cycles during the treatment period × scheduled 
number of days of administration × 1 tablet/day. O ne treatment cycle contains 28 days. 
Apatinib Treatment Cycle 
Scheduled Number of Days of Administration 
in Each Treatment Cycle 
QD 
28 
QD (5 days on, 2 days off) 
20 
QD (7 days on, 7 days off) 
14 
Subject compliance (%) = (actual dose / scheduled dose) × 100%. 
The frequency and reasons of apatinib dose reduction, treatment interruption, and permanent 
discontinuation will be summarized. 
5.4 Efficacy Analysis 
5.4.1 Primary efficacy analysis 
Based on the FAS, the number and percentage of subjects of BOR, ORR, and DCR are 
calculated by dose group, and 95% CIs are estimated using the Clopper-Pearson method. 
The above analyses will be repeatedly conducted based on the PPS. 
Handling of missing data: When calculating CR, missing data will be considered as cases not 
achieving CR, while the handling of PR, SD, and PD is the same as that of CR. 


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5.4.2 
Secondary efficacy analysis 
5.4.2.1 
OS 
The analysis of OS will be based mainly on the FAS. 
The Kaplan-Meier product-limit approach will be used to calculate the median survival, its 95% 
CI will be calculated using the Brookmeyer-Crowley method based on log-log transformation, 
and the survival curves will be plotted. Also, the 6- and 12-month OS rates will be calculated 
using the Kaplan-Meier product-limit approach and their 95% CIs will be calculated using the 
pointwise method based on log-log transformation. 
OS (months) is calculated as: (OS event or censoring date − date of the first dose + 1) / 30.4375. 
Missing data: This study will do everything possible to track subject survival until an OS event is 
observed. Inevitably, an OS event may not be observed for a subject before the end of the study, 
or a subject drops out before an OS event is observed, in this case, the time from the start date of 
randomization of this subject to the last observed survival date of the subject is taken as the 
subject's survival time, and this survival time is recorded as right censored data (the actual 
survival time is greater than the recorded time). If the date of death is incomplete, the day will be 
imputed with the earliest possible date. 
5.4.2.2 
PFS 
The analysis of PFS will be based mainly on the FAS using the same method as that of OS. 
PFS (months) is calculated as: (PFS event or censoring date − date of the first dose + 1) / 
30.4375. 
The baseline tumor evaluation is defined as the last tumor evaluation before the first dose. 
The date of visit corresponding to the PD as shown in tumor evaluation will be based on the 
earlier date of the following: 
• 
The date of imaging examination showing a new lesion (if PD is based on the occurrence of 
a new lesion), or 
• 
The date of the last imaging examination of observed lesions (if progressive disease is based 
on the increased total observed lesions). If there is no PD (including PR, CR, SD, and NE), 
the date of tumor evaluation will be based on the latest date recorded in the visit (target 
lesion or non-target lesion). 


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The censoring rules for PFS events are as follows: 
For subjects experiencing PD or death: 
• 
If a subject has begun a new anti-tumor treatment (excluding radiotherapy) before the PFS 
event, the date will be censored based on the date of the last tumor evaluation before the 
start of new anti-tumor treatment or the date of the first dose (whichever is later). 
• 
Progressive disease or death after two or more scheduled tumor evaluations that are missing 
will be censored based on the date of the last tumor response evaluation before PD or death 
or the date of first dose (whichever is later). The missing of two or more scheduled tumor 
evaluations is defined as a situation where the interval between the event and the most 
recent tumor evaluation (including baseline) is longer than 126 days. 
For subjects experiencing no PD or death: 
• 
If there is no baseline tumor evaluation or post-baseline tumor evaluation (missing tumor 
evaluation or tumor evaluation as NE/NA at the corresponding visit), censoring will be 
based on the date of the first dose. 
• 
If a subject has not experienced a PFS event on the end date of study/analysis or before 
dropout, the censoring will be carried out using the date of the last tumor response 
evaluation. 
If the date of death is incomplete, the day will be imputed with the earliest possible date. 
If the start date of the new anti-tumor treatment is incomplete, it will be imputed with the earliest 
possible date. 
5.4.2.3 
TTR 
The analysis of TTR will be based mainly on the FAS. Only subjects with confirmed tumor 
response (CR or PR) are descriptively summarized by treatment group. 
TTR (months) is calculated as: (date of the first documented CR or PR − date of the first 
dose +1) / 30.4375. 
5.4.2.4 
DoR 
DoR will only be analyzed for subjects with confirmed tumor response (CR or PR) after 
treatment. The censoring rules for DoR are the same as those for PFS, and the end date of 
response must be consistent with the date of progressive disease or death of the PFS. For DoR, 
the Kaplan-Meier product-limit approach will be used to calculate the median survival by treatment 
group, the corresponding 95% confidence interval (CI) will be calculated using the Brookmeyer-
Crowley method based on log-log transformation, and the survival curves will be plotted. 


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DoR (months) is calculated as: (date of PFS event − date of the first documented CR or PR + 1) / 
30.4375. 
5.4.2.5 
Immunogenicity evaluation 
Immunogenicity analysis will be based on the ADAS. 
The ADA will be statistically analyzed using descriptive statistics in the form of listing based on 
the confirmatory results of immunogenicity. 
The numbers and percentages of subjects who are non-treatment emergent ADA positive, 
treatment-enhanced ADA positive, treatment-induced ADA positive, ADA positive, and ADA 
negative will be summarized. 
In treatment-induced ADA positive subjects, the time when first tested positive, as well as the 
number and percentage of transiently positive, persistently positive, and other positive subjects 
after baseline will be summarized. 
Also, the number and percentage of neutralizing antibody (Nab) positive and negative subjects 
will be summarized. 
The classification of immunogenicity is as follows: 
(1) Non-treatment emergent ADA positive includes two situations: (a) positive at baseline and 
negative after baseline; (b) positive at baseline and positive after baseline, with a titer < 4 × 
that of the baseline ADA positive sample. 
(2) Treatment-enhanced ADA positive: positive at baseline and positive after baseline, with a 
titer ≥ 4 × that of the baseline ADA positive sample; treatment-induced ADA positive: 
negative at baseline and positive after baseline; ADA positive: including treatment-
enhanced ADA positive as well as treatment-induced ADA positive. Situations other than 
ADA positive are regarded as ADA negative. 
(3) Transiently positive refers to negative at baseline and with ADA positive for only once that 
is not persistent after baseline to the time before the last test. 
Persistently positive consists of two categories: (a) negative at baseline but with at least 2 post-
baseline samples, with the interval between the first and last positive samples more than 16 
weeks; (b) negative at baseline but with last post-baseline sample tested positive, or with the last 
post-baseline sample negative and the penultimate post-baseline sample tested positive. 
"Other" refers to negative at baseline, with at least two ADA-positive samples but not 
persistently positive and with negative last sample. 
(4) Nab positive: negative at baseline and positive after baseline; Nab negative: negative after 
baseline; all other circumstances are classified as indeterminable. 


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5.4.3 Exploratory analyses 
PD-L1 expression will be analyzed using descriptive statistics based on the TMKS. 
5.4.4 Subgroup analysis 
Based on the FAS, the following subgroup analyses will be performed on the primary efficacy 
endpoint ORR, as well as the secondary endpoints OS, PFS, and 6/12-month OS rates: 
• 
Sensitive recurrence: progress in ≥ 90 days from the last chemotherapy 
• 
Drug-resistant recurrence: progress during chemotherapy or within 90 days from the last 
chemotherapy 
5.5 Safety Analysis 
Unless otherwise specified, the safety statistical analysis will be summarized and tabulated by 
the treatment group. All safety analyses will be conducted based on the SS. Normal and 
abnormal parameters for safety evaluation will be summarized based on scheduled and 
unscheduled visits. Single unscheduled examinations will only be listed. 
5.5.1 Adverse events 
Adverse events (AEs) will be analyzed based on the treatment-emergent adverse events 
(TEAEs): 
1) 
All AEs that occur from the first study dose to 90 days after the last dose; 
2) 
An AE that starts before the first study dose but worsens after administration. 
Treatment-related AEs are defined as TEAEs with a causality of definitely related, possibly 
related, or indeterminable. If the relationship between an AE and the study drug is missing, the 
AE will be considered as a treatment-related AE. 
All AEs will be coded with MedDRA 21.0. and graded by NCI-CTCAE v4.03. For the same 
SOC and/or PT, multiple cases of the same events that occur in one subject will be counted only 
once. For the same AE reported in one subject multiple times but varying in CTCAE grade, the 
AE of the greatest grade will be enumerated. 
The incidence of AEs will be sorted from high to low based on their corresponding SOC in the 
SHR-1210 200 mg, IV, Q2W + apatinib 375 mg (or apatinib 250 mg), PO, QD group. The 
incidence of AEs in each SOC will be sorted from high to low based on their PT. If the 
incidences of ≥ 2 PTs are equal, the AEs will be sorted alphabetically. If there is no AE under a 
SOC or PT, then analysis is not conducted. 


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The number of TEAE cases as well as the number of subjects based on the SS will be 
summarized in a table by dose group. The summary table should at least include the number of 
subjects with at least one TEAE/SAE/, TEAEs leading to treatment discontinuation, TEAEs 
leading to dose interruption or dose reduction, SAEs, SAEs leading to death, TEAEs of special 
interest, immune-related TEAEs (irAEs), and CTCAE grading. For all categories included in the 
summary table, CTCAE Grade ≥ 3 TEAEs and treatment-related AEs with an incidence of ≥ 5% 
will be summarized by SOC and PT, respectively. Laboratory abnormalities with an incidence of 
≥ 10% will be summarized. TEAEs leading to treatment discontinuation, TEAEs leading to dose 
interruption or dose reduction, and all treatment-related AEs will be analyzed respectively for 
SHR-1210 and apatinib. An immune-related AE is determined in the case of an indeterminable 
immune-related AE. 
In particular, the incidences and outcomes of AEs assessed per the CTCAE 4.03 below are 
separately analyzed: 
○ 
Hematologic toxicity 
- 
Grade 4, or 
- 
Grade ≥ 3 thrombocytopenia with hemorrhage, or 
- 
Grade ≥ 4 neutropenia with pyrexia and infection 
○ 
Grade ≥ 3 non-hematologic toxicity (except for laboratory abnormalities), hypertension, 
rash, diarrhea, nausea and vomiting that cannot be controlled after symptomatic treatment 
○ 
Grade ≥ 3 laboratory abnormalities that lead to medical interventions or hospitalization, or 
last for ≥ 7 days 
○ 
Any Grade 5 TEAE 
The following protocol-specified AEs of special interest will be summarized by SOC and PT: 
○ 
Grade ≥ 3 infusion reaction 
○ 
Other Grade ≥ 3 immune-related adverse events (irAEs) 
For reactive capillary endothelial proliferation, the collected patient information will also be listed. 
Important TEAEs will be summarized by SOC and PT. Important TEAEs are defined as: 
○ 
Any TEAE leading to interruption or permanent discontinuation of SHR-1210 or apatinib 
○ 
Any TEAE leading to dose reduction of SHR-1210 
○ 
Any targeted treatment with concomitant medication, i.e., TEAE with corrective treatment 
All AEs (including non-TEAEs) are listed. 


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5.5.2 Laboratory evaluations 
A baseline laboratory evaluation is defined as the last evaluations prior to the first dose 
(screening period). 
The worst grade (abnormality grade sorted from high to low: abnormality with clinical 
significance > abnormality without clinical significance > normal) of results of such laboratory 
evaluations as hematology, clinical chemistry, myocardial zymography, coagulation function, 
routine stool, urinalysis, thyroid function tests (T3, T4, FT3, FT4, and TSH) at baseline and post-
baseline of each dose group will be summarized using a shift table. 
All laboratory evaluations will be listed by subject ID and indicated for clinical significance 
if any. 
5.5.3 Vital signs 
Vital sign measurements at each scheduled visit point (including baseline) will be summarized 
and listed using descriptive statistics. Changes in vital signs from baseline at each visit point 
after baseline will be summarized and listed using descriptive statistics. 
Baseline is defined as the last measurement before the first dose. 
5.5.4 Electrocardiogram 
Normal/abnormal ECG changes from baseline at each visit point after baseline will be 
summarized using a shift table. ECG results will be listed. 
5.5.5 
Physical examination 
Physical examinations are only listed for reporting. 
5.5.6 ECOG PS 
The ECOG PS of each dose group will be analyzed using descriptive statistics. The worst ECOG 
PS at baseline and post-baseline will be summarized using a shift table. 
All ECOG PS will be listed. 
5.5.7 Other safety analyses 
Pituitary-adrenal axis test, echocardiography, pulmonary function examination, arterial blood gas 
analysis, virology, blood pregnancy test, and tumor tissue sample collection are listed in detail. 


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6 INTERIM ANALYSIS 
It is planned that after the 18th subject in Stage I completes Cycle 1 treatment (28 days), a safety 
analysis will be conducted. The leading center's principal investigator and the sponsor will 
jointly perform a safety assessment of subjects enrolled in Stage I and decide the treatment 
groups of Stage II. 
This analysis only provides a listing of subjects' AEs and laboratory evaluations and does not 
involve the analysis of the efficacy endpoints. 
7 REFERENCES 
8 APPENDICES 
8.1 Appendix 1. Best Overall Response with CR and PR to Be Confirmed 
Overall Response at 
First Time Point 
Overall Response 
at Subsequent 
Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
CR 
PD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
CR 
NE 
SD (provided minimum criteria for SD duration met, otherwise, NE) 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
PR 
NE 
SD (provided minimum criteria for SD duration met, otherwise, NE) 
NE 
NE 
NE 
Note: CR is complete response, PR is partial response, SD is stable disease, PD is progressive disease, and NE is 
non-evaluable. a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even the 
disease meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best overall response will depend on whether minimum duration for SD is met. However, 
sometimes CR may be claimed when subsequent scans suggest small lesions are likely still present and in fact the 
subject has PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR 
and the best response is PR.