Conditions: Esophageal Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 457
Healthy volunteers: no

Brief summary:
In this study, participants with advanced or metastatic squamous cell carcinoma of the esophagus that has progressed after first-line standard therapy will be randomized to receive either single agent SHR-1210 or the Investigator's choice of standard therapy with docetaxel or irinotecan. The primary study hypothesis is that treatment with SHR-1210 will prolong overall survival (OS) as compared to treatment with standard therapy.

Detailed description:

Arms:
arm 1: None arm 2: Docetaxel or Irinotecan

Interventions: intervention 1: camrelizumab intervention 2: Docetaxel intervention 3: Irinotecan
Intervention descriptions: intervention 1: Subjects receive camrelizumab intravenous infusion at the dose 200mg on Day 1 every 2 weeks intervention 2: Subjects receive Docetaxel intravenous infusion at the dose 75mg/m2 on Day 1 every 3 weeks intervention 3: Subjects receive Irinotecan intravenous infusion at the dose 180mg/m2 on Day 1 every 2 weeks

Protocol document:
Prot_000.pdf: 
Title: A Randomized, Open-Label, Active-Controlled, Multi-Center, Phase III Clinical 
Study of Anti-PD-1 Antibody SHR-1210 vs. Investigator's Choice of Chemotherapy in 
Subjects with Locally Advanced or Metastatic Esophageal Cancer 
NCT number: NCT03099382 
Date: 12 Apr., 2018 


 
A RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED, 
MULTI-CENTER, PHASE III CLINICAL STUDY OF ANTI-PD-1 
ANTIBODY SHR-1210 VS. INVESTIGATOR'S CHOICE OF 
CHEMOTHERAPY IN SUBJECTS WITH LOCALLY 
ADVANCED OR METASTATIC ESOPHAGEAL CANCER 
 
Protocol No.: SHR-1210-III-301-ESC 
Study Phase: III 
Compound Code: SHR-1210 
 
Medical Director:
 
 
Institution of Principal Investigator: 307 Hospital of the Chinese 
People's Liberation Army 
Principal Investigator: Prof. Jianming Xu 
 
Institution of Principal Investigator: Cancer Hospital Chinese Academy 
of Medical Sciences  
Principal Investigator: Prof. Jing Huang 
 
Version No.: 5.0 
Version Date: 12 Apr., 2018 
 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
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 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
1 
 
Sponsor's Signature Page 
 
I have read and confirmed this clinical study protocol (protocol number: SHR-1210-III-301-ESC, 
version number: 5.0, version date: 12 Apr., 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. 
 
 
 
 
 
 
 
 
 
Medical Director 
(print) 
 
Medical Director 
(signature) 
 Signature Date 
(DD/MM/YYYY) 
 
 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
2 
 
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 investigational drug; I have read the materials of preclinical studies of the 
investigational drug 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: The 307th Hospital of the Chinese People's Liberation Army 
 
 
 
Jianming Xu 
 
 
Principal Investigator 
(print) 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
3 
 
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 investigational drug; I have read the materials of preclinical studies of the 
investigational drug 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: Cancer Hospital, Chinese Academy of Medical Sciences 
 
 
 
Jing Huang 
 
 
Principal Investigator 
(print) 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
4 
 
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 investigational drug; I have read the materials of preclinical studies of the 
investigational drug 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 medical 
records 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) 
 
 


<SHR-1210> 
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<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................ 8 
SCHEDULE OF ACTIVITIES ............................................................................................ 14 
ABBREVIATIONS ................................................................................................................ 26 
1. 
KEY FUNCTIONAL ROLES ....................................................................................... 28 
2. 
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE ............... 28 
2.1. Background ............................................................................................................. 28 
2.2. Scientific Rationale ................................................................................................. 30 
2.3. Potential Risks and Benefits ................................................................................... 35 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................... 36 
3.1. Study Objectives ..................................................................................................... 36 
3.2. Study Endpoints ...................................................................................................... 36 
4. 
STUDY DESIGN ............................................................................................................ 37 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................... 39 
5.1. Inclusion Criteria ..................................................................................................... 39 
5.2. Exclusion Criteria.................................................................................................... 41 
5.3. Rescreening Criteria ................................................................................................ 42 
5.4. Randomization Criteria ........................................................................................... 43 
5.5. Withdrawal or Discontinuation ............................................................................... 43 
5.6. Termination or Suspension of Study ....................................................................... 44 
6. 
INVESTIGATIONAL DRUG ....................................................................................... 45 
6.1. Description of the Investigational Drug and Control Drugs ................................... 45 
6.2. Drug Management, Dispensation and Return ......................................................... 55 
7. 
STUDY PROCEDURES ................................................................................................ 55 
7.1. Study Procedures/Assessments ............................................................................... 55 
7.2. Concomitant Treatment ........................................................................................... 61 
8. 
IMMUNOGENICITY STUDY ..................................................................................... 66 
8.1. Immunogenicity and Drug Trough Concentration Blood Sampling  
and Processing ......................................................................................................... 66 
9. 
BIOMARKER BLOOD SAMPLING ........................................................................... 67 
10. SAFETY EVALUATION .............................................................................................. 67 
10.1. Safety Parameters .................................................................................................... 67 
10.2. Adverse Event Classification .................................................................................. 69 


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10.3. Duration and Frequency of Adverse Event Assessment and Follow-Up Visit ....... 70 
10.4. Reporting Procedures .............................................................................................. 71 
11. Data Analysis/Statistical Methods ................................................................................. 73 
11.1. Statistical Analysis Plan .......................................................................................... 73 
11.2. Statistical Hypotheses ............................................................................................. 73 
11.3. Analysis Set/Population .......................................................................................... 74 
11.4. Statistical Methods .................................................................................................. 75 
11.5. Sample Size ............................................................................................................. 77 
11.6. Methods to Reduce Bias.......................................................................................... 78 
12. QUALITY ASSURANCE AND QUALITY CONTROL ........................................... 78 
13. REGULATORY ETHICS, INFORMED CONSENT, AND SUBJECT  
PROTECTION ............................................................................................................... 79 
13.1. Regulatory Considerations ...................................................................................... 79 
13.2. Ethical Standards ..................................................................................................... 79 
13.3. Independent Ethics Committee ............................................................................... 80 
13.4. Informed Consent .................................................................................................... 80 
13.5. Confidentiality of Subject Information ................................................................... 81 
14. DATA MANAGEMENT ................................................................................................ 81 
14.1. Data Collection and Management ........................................................................... 81 
14.2. Data Monitoring ...................................................................................................... 82 
14.3. Data Management ................................................................................................... 82 
14.4. Protocol Deviations ................................................................................................. 83 
15. PUBLICATION OF STUDY RESULTS ...................................................................... 83 
16. STUDY CENTER AND TRIAL STAFF ...................................................................... 84 
16.1. Study Center ............................................................................................................ 84 
16.2. Sponsor .................................................................................................................... 84 
17. CLINICAL STUDY PROGRESS ................................................................................. 84 
18. REFERENCES ............................................................................................................... 85 
Appendix I. ECOG PS ........................................................................................................... 86 
Appendix II. Creatinine Clearance Calculation ................................................................. 87 
Appendix III. Prohibited Traditional Chinese Medicine ................................................... 88 
Appendix IV. TNM Staging of Esophageal Cancer ............................................................ 89 
Appendix V. Response Evaluation Criteria in Solid Tumors ............................................ 91 


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LIST OF TABLES 
Table 1. 
Efficacy of existing second-line chemotherapies for esophageal cancer .................... 29 
Table 2. 
Binding affinity of SHR-1210 to human, monkey, and murine PD-1 antigens .......... 31 
Table 3. 
Binding affinity of SHR-1210, nivolumab, and MK3475 to PD-1 antigen ................ 32 
Table 4. 
PK parameters after a single intravenous infusion of SHR-1210 at different  
doses in cynomolgus monkeys.................................................................................... 33 
Table 5. 
SHR-1210 dose modifications .................................................................................... 52 
Table 6. 
Docetaxel dose modifications ..................................................................................... 54 
Table 7. 
Criteria for docetaxel treatment/resumption ............................................................... 54 
Table 8. 
Irinotecan dose modifications ..................................................................................... 54 
Table 9. 
Criteria for irinotecan treatment/resumption .............................................................. 55 
Table 10. Criteria for causality between adverse events and study drugs. ................................. 70 
Table 11. SAE report contacts .................................................................................................... 72 
 
LIST OF FIGURES 
Figure 1. Inhibition of PD-1/PD-L1 binding by SHR-1210 and pembrolizumab ...................... 32 
Figure 2. Inhibition of PD-1/PD-L1 binding by SHR-1210 and nivolumab .............................. 32 
Figure 3. Study design schematic ............................................................................................... 39 
 


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PROTOCOL SYNOPSIS 
Study Title 
A Randomized, Open-Label, Active-Controlled, Multi-Center, Phase III Clinical Study of 
Anti-PD-1 Antibody SHR-1210 vs. Investigator's Choice of Chemotherapy in Subjects with 
Locally Advanced or Metastatic Esophageal Cancer 
Protocol No. 
SHR-1210-III-301-ESC 
Version No. 
5.0 
Sponsor 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Principal 
Investigators 
Prof. Jianming Xu 307 Hospital of the Chinese People's Liberation Army 
Prof. Jing Huang 
Cancer Hospital Chinese Academy of Medical Sciences 
Participating Study 
Centers 
Approximately 40 centers in China 
Study Objectives 
Primary objective: To evaluate the efficacy of SHR-1210 vs. investigator's choice of 
chemotherapy in subjects with locally advanced or metastatic esophageal cancer who are 
refractory to the first-line chemotherapy. 
Secondary objective: To evaluate the safety of SHR-1210 vs. investigator's choice of 
chemotherapy in subjects with locally advanced or metastatic esophageal cancer who are 
refractory to the first-line chemotherapy. 
Exploratory objectives: (1) To evaluate the relationship between biomarkers in tumor tissue 
and/or blood (such as PD-L1) and the efficacy of SHR-1210. 
(2) To evaluate the immunogenicity of SHR-1210 in subjects with locally advanced or 
metastatic esophageal cancer, and to investigate the correlation between immunogenicity 
and drug trough concentration, efficacy and safety. 
Study Population 
Patients with locally advanced or metastatic esophageal cancer who are refractory to the 
first-line chemotherapy 
Study Design 
This is a randomized, open-label, active-controlled, multi-center study. A total of 438 
eligible subjects with locally advanced or metastatic squamous cell carcinoma of the 
esophagus who are refractory to first-line chemotherapy will be randomized to 
investigational treatment group or control group in a 1:1 ratio and stratified by: 1. locally 
advanced lesion vs. distant metastasis; 2. ECOG PS (0 vs. 1). 
Subjects in the investigational treatment group will receive SHR-1210 (200 mg/dose, on 
Day 1 of each 2-week cycle) until confirmed disease progression, intolerable toxicity, 
voluntary withdrawal by the subject, or treatment discontinuation determined by the 
investigator. Temporary accelerated tumor growth, i.e., pseudoprogression, may occur soon 
after immunotherapy is started; therefore, when a subject who has PD in the first assessment 
is clinically stable, the treatment can be continued, and a tumor assessment should be 
performed again 4 weeks (± 7 days) later; when a non -PD result is confirmed using both 
iRECIST and RECIST v1.1 criteria, the treatment may be continued, and otherwise, the 
treatment should be discontinued. For subjects who are clinically unstable, treatment should 
be discontinued after the first PD, and a new imaging assessment is not required. 
Subjects in the control group will receive the investigator's choice of chemotherapy, either 
docetaxel (75 mg/m2, on Day 1 of each 3-week cycle) or irinotecan (180 mg/m2, on Day 1 
of each 2-week cycle). Chemotherapy will continue until the occurrence of disease 
progression, intolerable toxicity, voluntary withdrawal by the subject, or discontinuation 
determined by the investigator. 


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The study procedure is divided into three stages. The screening period is 28 days. After 
completing the screening examination and evaluation, the eligible subjects enter the 
treatment period and undergo visits by the dosing frequency. Relevant examinations and 
assessments must be completed before each dose. In particular, tumor imaging will be 
assessed once every 8 weeks (± 7 days) (including the chemotherapy control group). All 
subjects must complete safety examinations and tumor assessments before the end of 
treatment. These subjects then enter the follow-up period. The safety follow-up visits of all 
subjects should be carried out 90 days after the last dose. The follow-up visits scheduled for 
30 days after the last dose should be carried out at the study center, while those scheduled for 
60 days and 90 days after the last dose via telephone. Survival follow-up visits should begin 
from the last dose and be carried out once a month; subjects ending the treatment due to 
reasons other than progressive disease should continue to undergo imaging assessment 
once every 8 weeks (± 7 days) until progressive disease, initiation of new anti -cancer 
treatments or death. 
Study Drugs 
Investigational drug: SHR-1210 
Control drugs: docetaxel or irinotecan 
Method of 
Administration 
Investigational treatment group: SHR-1210, 200 mg/dose, intravenous infusion over 30 min 
(no less than 20 min and no more than 60 min) on Day 1 of each 2-week cycle. The 
treatment will continue until the occurrence of confirmed PD, intolerable toxicity, voluntary 
withdrawal by the subject, or treatment discontinuation determined by the investigator. 
Control group: Investigator's choice of chemotherapy (previously-adopted chemotherapy 
not available). Choose one of the active drugs below for treatment. 
Docetaxel: 75 mg/m2, intravenous infusion over approximately 1 h (drip rate may be 
adjusted accordingly) on Day 1 of each 3-week cycle. The treatment will continue until the 
occurrence of PD, intolerable toxicity, voluntary withdrawal by the subject, or 
discontinuation determined by the investigator. 
Irinotecan: 180 mg/m2, intravenous infusion over approximately 1 h (drip rate may be 
adjusted accordingly) on Day 1 of each 2-week cycle. The treatment will continue until the 
occurrence of PD, intolerable toxicity, voluntary withdrawal by the subject, or 
discontinuation determined by the investigator. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for this study: 
1. 
Aged 18-75 years, male or female; 
2. 
Patients with histologically or cytologically confirmed squamous cell carcinoma of the 
esophagus, unresectable locally advanced, locally recurrent or distant metastasis; 
3. 
Patients who have received first-line systemic chemotherapy (which may include 
chemotherapies based on platinum, paclitaxel or fluorouracil) and showed disease 
progression or intolerance (patients who have progression in maintenance treatment 
after first-line chemotherapy can also be included). Concurrent chemoradiotherapy for 
postoperative recurrence or metastasis is considered as first-line treatment; 
For radical concurrent chemoradiotherapy and neoadjuvant/adjuvant therapy 
(chemotherapy or chemoradiotherapy), it should be considered as first-line treatment 
failure when progressive disease occurs during the treatment or within 6 months after 
the treatment discontinued; 
4. 
Patients with at least one measurable lesion according to Response Evaluation Criteria 
in Solid Tumors (RECIST v1.1), and the measurable lesion(s) should not have been 
locally treated such as radiotherapy (lesions in previous radiotherapy sites may also be 
selected as target lesions when PD is confirmed and RECIST v1.1 are met); 


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5. 
Patients with available tissue samples for biomarker (such as PD-L1) analysis; fresh 
tissue is preferred; archival samples of 5-8 paraffin embedded sections that are 5 μm 
thick are also acceptable when a fresh biopsy is not accessible; 
6. 
ECOG PS: 0-1 (see Appendix I); 
7. 
Life expectancy ≥ 12 weeks; 
8. 
Major organ functions must meet the following rules (no blood components or cell 
growth factors are allowed to be used within 2 weeks before the start of study 
treatment): 
a. 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
b. 
Platelets ≥ 100 × 109/L; 
c. 
Hemoglobin ≥ 9 g/dL; 
d. 
Serum albumin ≥ 2.8 g/dL; 
e. 
Total bilirubin ≤ 1.5 × ULN, ALT and AST ≤ 2.5 × ULN; for liver metastasis, 
ALT and AST ≤ 5 × ULN; 
f. 
CrCl ≥ 50 mL/min (Cockcroft-Gault, see Appendix II); 
9. 
Female patients of childbearing potential must have a negative urine or serum 
pregnancy test result within 72 h before the first dose of study drugs and must be 
willing to use effective contraceptive measures during the study and within 3 months 
after the last dose of SHR-1210 (180 days after the last dose for the control group). 
Male patients with partners of childbearing potential must be willing to take effective 
contraceptive measures during the study and within 3 months after the last dose of SHR-
1210 (180 days after the last dose for the control group); 
10. Patients must participate voluntarily, sign the informed consent form, have good 
compliance, and cooperate with follow-up visits. 
Exclusion Criteria 
Patients meeting any of the following are ineligible to participate in this study 
1. 
Patients who are diagnosed with other malignant tumors (excluding curatively treated 
basal cell carcinoma of skin and squamous cell carcinoma of skin, and/or curatively 
resected cervical carcinoma in situ and/or breast cancer in situ) within 5 years from the 
first dose of study drugs; 
2. 
Patients with central nervous system (CNS) metastasis; 
3. 
Patients with active autoimmune disease or history of autoimmune diseases (such as 
interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, myocarditis, 
nephritis, hyperthyroidism, hypothyroidism (enrollment is not restricted when 
hormone replacement therapy is effective)); patients with vitiligo or who had 
completely resolved pediatric asthma requiring no intervention after adulthood may be 
enrolled, while those still requiring medical intervention with bronchodilators should 
not be enrolled; 
4. 
Patients with uncontrolled cardiac symptoms or disease, such as: (1) > NYHA Class II 
heart failure, (2) unstable angina, (3) myocardial infarction within the past year, and 
(4) clinically significant supraventricular or ventricular arrhythmias requiring clinical 
intervention; 
5. 
Patients with active infection or unexplained fever > 38.5 °C within 2 weeks before 
randomization (patients with tumor-induced fever, as determined by the investigator, 
may be enrolled); 
6. 
Patients with a known history or evidence of interstitial lung disease or pneumonitis 
that has been treated with corticosteroids; 
 
 


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7. 
Patients with congenital or acquired immune deficiency (such as HIV infection), active 
hepatitis B (HBV-DNA ≥ 104 copies/mL or 2000 IU/mL), or hepatitis C (positive anti-
HCV antibodies, and HCV RNA titer higher than the lower limit of detection of the 
analytical method); 
8. 
Patients with a BMI less than 18.5 kg/m2 or weight loss of ≥ 10% within 2 months 
before screening (at the same time, the effect of massive pleural effusions and ascites 
on body weight should be considered); 
9. 
Previous treatment with other anti-PD-1 antibodies or immunotherapy targeting  
PD-1/PD-L1; 
10. Patients with known allergies to macromolecular protein preparations or any 
components of SHR-1210, or allergic reaction, hypersensitivity reaction, or 
contraindications to any components of docetaxel or irinotecan, or their in-preparation 
components; 
11. Patients who require systemic treatment with corticosteroids (prednisone of > 10 mg/day 
or equivalent) or other immunosuppressive medications within 14 days before the 
administration of study drugs. In the absence of active autoimmune disease, inhaled or 
topical use of corticosteroids or an equivalent dose of > 10 mg/day of prednisone for 
adrenal hormone replacement is permitted; 
12. Patients who received anti-tumor treatment with monoclonal antibodies (mAbs), 
chemotherapy, targeted small molecule therapy, or radiotherapy within 4 weeks before 
the first dose of study drugs or with adverse events caused by previously-received 
medications but not recovered (Grade ≤ 1 or baseline reached). Note: Except for 
patients with Grade ≤ 2 neuropathy or Grade ≤ 2 alopecia. If the patient has undergone 
major surgery, toxicities and/or complications resulting from the surgical intervention 
must be fully recovered before the study treatment. 
13. Patients who currently participate in or participated in another clinical study within 4 weeks 
before the first dose of study drugs (for patients in the follow-up period, calculation 
will be carried out using the time of the last use of study drugs or devices); 
14. Patients who inoculated with live vaccine within 4 weeks before the first dose of study 
drugs; injections of inactivated influenza vaccine for seasonal influenza are permitted, 
but not live attenuated influenza vaccines for intranasal use; 
15. Pregnant or lactating women; 
16. Patients with other factors, as determined by the investigator, which may result in 
study termination; for example, other serious medical conditions (including mental 
illnesses) requiring concomitant treatment, serious laboratory abnormalities, family or 
social factors, and other conditions that may affect subjects' safety or collection of 
study data. 
Immunogenicity 
Study 
Collection time for immunogenicity and drug trough concentration blood samples: 
Within 30 min before the first, second, third, fifth, and seventh doses, within 30 min before 
every four doses thereafter, and at visits carried out on Day 30, Day 60 (optional), and Day 
90 (optional) after the last treatment. 
Study Endpoints 
(I) Efficacy 
Primary endpoint 
1 
Overall survival (OS); 
Secondary endpoints 
1. 
Progression-free survival (PFS); 
2. 
Objective response rate (ORR); 
3. 
Quality of life score (EORTC QLQ-C30, EORTC QLQ-OES18); 
 


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Exploratory endpoints 
1. 
To evaluate the relationship between the expression of PD-L1 and/or other biomarkers 
and the efficacy of SHR-1210. 
2. 
To evaluate the incidence of anti-SHR-1210 antibody (ADA), time to the first positive 
ADA result, duration of ADA, incidence of anti-SHR-1210 antibody with neutralizing 
activity, and the correlation between immunogenicity and drug trough concentration, 
efficacy and safety. 
(I) Safety 
Adverse events, laboratory measurements. 
Sample Size 
Determination 
This is parallel study with its primary endpoint being OS. Subjects will be randomized in a 
1:1 ratio. Assuming that the median OS of the control group is 7 months and the median OS 
of the investigational treatment group is 9.5 months (the investigational treatment group is 
extended by 2.5 months compared with that of the control group), the inter-group OS 
distribution will be compared using a stratified log-rank test at an overall significance level 
 = 0.025 (one-sided); when the duration of enrollment is assumed to be 18 months and the 
entire study lasts for 36 months, at least 365 OS events need to be collected to obtain a 
power of 80% according to the calculation by East v6.3. Furthermore, assuming a drop-out 
rate of 20%, a total of 438 subjects need to be enrolled in this study (219 in the 
investigational treatment group and 219 in the control group). 
Statistical Methods 
Analysis Set/Population 
• 
Informed consent set (ICS) 
All subjects who have signed the informed consent form will be included in this analysis set. 
• 
Full analysis set (FAS) 
Based on the intention-to-treat (ITT) principle, all randomized subjects who have received 
study drug at least once will be included in FAS. 
• 
Per-protocol set (PPS) 
PPS is a subset of FAS, defined as subjects who do not have major protocol deviations or do 
not have protocol deviations that may have major impacts on study results. 
• 
Immunogenicity analysis set 
Subjects who have received at least one dose of SHR-1210 and have baseline and at least one 
post-baseline immunogenicity evaluation data constitute the immunogenicity analysis set. 
• 
Safety set (SS) 
All subjects who have received study drug at least once (whether they have participated in 
randomized grouping or not) constitute the safety set. 
Statistical Methods 
Basic methods 
This is a parallel-controlled study. Unless otherwise stated, all data will be analyzed by 
treatment group (SHR-1210 group and investigator selected chemotherapy group) and 
appropriate statistics will be applied according to the data type: measurement data will be 
summarized by mean, standard deviation (STD), median, minimum, and maximum; count 
data will be summarized by frequency and proportion for descriptive statistics; for time-to-
event data, median time and the corresponding overall 95% confidence interval will be 
estimated by the Kaplan-Meier method. 
Primary efficacy endpoint analysis 
1. 
Primary analysis 
The primary analysis is to evaluate the efficacy difference between investigational treatment 
group and control group based on the FAS. In the primary analysis, the null hypothesis that 
the distributions of OS are identical between groups will be verified by the stratified log-
rank test with randomized stratification factors considered. 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
13 
 
2. 
Secondary analysis 
The hazard ratio (HR) of OS of investigational treatment group to control group will be 
estimated using a Cox proportional hazards model, and the corresponding 95% confidence 
interval will be calculated. In the fitting of the primary analysis based on this model, 
treatment group will be set as a fixed effect. In addition, to explore the effects of other 
factors on efficacy, stratification factors [1. locally advanced lesion vs. distant 
metastasis; 2. ECOG PS (0 vs. 1)], gender, and PD-L1 expression level can also be used to 
fit the model except for the treatment group. 
The above analysis for the primary efficacy endpoint will be repeated in FAS and PPS. 
Secondary efficacy endpoint analysis 
The analysis of secondary efficacy endpoints in this study will be based on FAS only and 
will be carried out for all efficacy endpoints except OS (progression-free survival (PFS), 
objective response rate (ORR), and quality of life score EORTC QLQ-C30 and EORTC 
QLQ-OES18). For PFS, the inter-group differences will be compared using the log-rank 
test, and meanwhile, HR of PFS will be estimated using a Cox proportional hazards model 
and the effects of factors other than treatment group on the differences in PFS will be 
investigated, with both test and model similar to those of OS-related analysis. For ORR, the 
difference in ORR between the two groups and the corresponding 95% confidence interval 
will be estimated. 
Analysis of exploratory endpoints 
Based on the immunogenicity analysis set, descriptive statistics for the time to the first 
positive ADA result and the duration of ADA will be summarized. The incidence of ADA, 
the incidence of anti-SHR-1210 antibody with neutralizing activity, and the correlation 
between immunogenicity and drug trough concentration, efficacy and safety will be 
calculated. 
Safety analysis 
The safety analysis is based on the safety set (by actual treatment received). According to 
Hengrui's Standard Reporting Procedures, safety will be summarized using descriptive 
statistics, including but not limited to the following: 
• 
Subject disposition and populations; 
• 
Subjects' basic characteristics (including demographics, medical history, and 
medication history); 
• 
Discontinuations; 
• 
Summary of adverse events (of all causes and treatment-related); 
• 
Incidence and severity of adverse events (of all causes and treatment-related); 
• 
Summary of serious adverse events; 
• 
Causality analysis of adverse events; 
• 
Laboratory measurements, vital signs, ECG, and their changes from baseline; 
• 
Number and rate of laboratory measurements, vital signs, and ECG data 
"changed from normal to abnormal" or "exacerbated abnormally" after the trial. 
In this study, adverse events will be evaluated by NCI-CTCAE v4.03. 
End of Study 
The study will end upon the completion of the final analysis. 
Study Date 
Anticipated enrollment of the first subject: Apr. 2017 
Anticipated enrollment of the last subject: Oct. 2018 
Anticipated study completion: Apr., 2019 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
14 
 
SCHEDULE OF ACTIVITIES 
Schedule of Activities for Investigational Treatment Group (SHR-1210) 
 
Screening Period 
 
 
End of 
Treatment/Withdrawal 
(+ 3 days) 
After End of Treatment 
C1 
C2+ 
Visit Window  
D-28 to D-1 
D-7 to D-1 
D1 
D1 ± 3  
90 days (± 7 days) after 
the last dose[24] 
Survival follow-up 
(± 7 days) [25] 
Signing of Informed 
Consent Form[1] 
√ 
 
 
 
 
 
 
Verification of Eligibility 
 
√ 
 
 
 
 
 
Demographics 
√ 
 
 
 
 
 
 
Medical History[2] 
√ 
 
 
 
 
 
 
ECOG PS[3] 
 
√ 
 
√ 
√  
  
 
Vital Signs[4] 
 
√ 
 
√ 
√ 
  
 
Physical Examination[5] 
 
√ 
 
√ 
√ 
  
 
Hematology[6] 
 
√ 
 
√ 
√ 
√ 
 
Urinalysis[7] 
 
√ 
 
√ 
√ 
  
 
Fecal Occult Blood[8] 
 
√ 
 
√ 
 
 
 
Clinical Chemistry[9] 
 
√ 
 
√ 
√ 
√ 
 
Thyroid Function[10] 
 
√ 
 
√ 
√ 
√ 
 
Coagulation Function[11] 
 
√ 
 
  
  
 
 
Virological Examination[12] 
√ 
 
 
 
 
 
 
ECG[13] 
 
√ 
 
√ 
√ 
  
 
Echocardiography[14] 
 
√ 
 
 
 
 
 
Pregnancy Test[15] 
 
√ 
 
 
√ 
 
 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
15 
 
 
Screening Period 
 
 
End of 
Treatment/Withdrawal 
(+ 3 days) 
After End of Treatment 
C1 
C2+ 
Visit Window  
D-28 to D-1 
D-7 to D-1 
D1 
D1 ± 3  
90 days (± 7 days) after 
the last dose[24] 
Survival follow-up 
(± 7 days) [25] 
Tumor Imaging 
Evaluation[16] 
√ 
 
√ 
 
 
Randomization  
 
√ 
 
 
 
 
 
Administration of SHR-
1210[17] 
 
 
√ 
√ 
 
 
 
Adverse Events[18] 
√ 
√ 
√ 
√ 
√ 
√ 
 
Concomitant Medication[19] 
√ 
√ 
√ 
√ 
√ 
√ 
 
Quality of Life Score[20] 
 
 
√ 
√ 
√ 
√ 
 
Blood Sampling for 
Immunogenicity and Drug 
Trough Concentration[21] 
 
 
√ 
√ 
 
√ 
 
Biomarker Blood 
Sampling[22] 
 
 
√  
√   
 
 
 
Tumor Tissue[23] 
√ 
 
 
 
 
 
 
Note: Other than the examinations and time points listed in the table, the investigator may add visits and other investigations at any time when needed. Results 
should be documented in the "Unscheduled Examinations" section of eCRF. 
[1] 
An informed consent form signed by the subject or legal representative must be first obtained before starting screening. 
[2] 
Medical history: including tumor history (diagnosis, surgery, radiotherapy, chemotherapy history) and history of other concurrent diseases. 
[3] 
ECOG PS: within 7 days prior to the first dose, before administration on Day 1 of each cycle (do not need to be tested for the first dose if completed 
within 7 days prior to the first dose at screening), and at the end of treatment/upon withdrawal. 
[4] 
Vital signs: blood pressure, heart rate, body temperature and respiratory rate; within 7 days prior to the first dose, before administration on Day 1 of each 
cycle (do not need to be tested for the first dose if completed within 7 days prior to the first dose at screening), and at the end of treatment/upon 
withdrawal. 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
16 
 
[5] 
Physical examination: within 7 days prior to the first dose and at the end of treatment/upon withdrawal, a comprehensive physical examination (including 
head and face, skin, lymph nodes, eyes, ears, nose and throat, mouth, respiratory system, cardiovascular system, abdomen, reproductive and urinary 
system, musculoskeletal system, nervous system and mental state) is performed; before administration on Day 1 of each cycle (do not need to be tested for 
the first dose if completed within 7 days prior to the first dose at screening), symptom-directed physical examination can be performed when clinically 
indicated. 
[6] 
Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, lymphocyte count; within 7 days prior to the first dose, before 
administration on Day 1 of each cycle (do not need to be tested for the first dose if completed within 7 days prior to the first dose at screening), at the end 
of treatment/upon withdrawal, and 30 days after the last dose. 
[7] 
Urinalysis: WBC, RBC, and urine protein. Within 7 days prior to the first dose, before administration on Day 1 of every 2 cycles, and at the end of 
treatment/upon withdrawal. In the case of urine protein ≥ 2+, a 24-h urine protein test (quantitative) must be added. 
[8] 
Fecal occult blood: within 7 days prior to the first dose, on Day 1 of every 2 cycles.  
[9] 
Clinical chemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, blood urea nitrogen (preferred) or urea, total protein, albumin, creatinine, 
blood glucose, lactate dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-. Within 7 days prior to the first dose, before administration on Day 1 of each cycle (do 
not need to be tested for the first dose if completed within 7 days prior to the first dose at screening), at the end of treatment/upon withdrawal, and 30 days 
after the last dose. 
[10] 
Thyroid function: TSH, FT3, FT4. Within 7 days prior to the first dose, before administration on Day 1 of every 2 cycles, at the end of treatment/upon 
withdrawal, and 30 days after the last dose. 
[11] 
Coagulation function: APTT, PT, FIB, INR. Within 7 days prior to the first dose. 
[12] 
Serology: HBsAg (if positive, HBV-DNA test required), HBsAb, HBeAg, HBeAb, HBcAb, HCV-Ab (if positive, HCV-RNA test required), and HIV-Ab. 
Within 14 days prior to the first dose. 
[13] 
ECG: within 7 days prior to the first dose, pre-administration on Day 1 of each cycle (do not need to be tested for the first dose if completed within 7 days 
prior to the first dose at screening), and at the end of treatment/upon withdrawal. 
[14] 
Echocardiography: within 7 days prior to the first dose; performed when clinically indicated. 
[15] 
Pregnancy test: for women of childbearing potential only. Within 72 h prior to the first dose, and at the end of treatment/upon withdrawal. 
[16] 
Tumor imaging evaluation: CT or MRI of the neck, chest and abdomen (including pelvic cavity). Brain MRI is required when brain metastasis is 
suspected and confirmed (if MRI is contraindicated, CT can be used instead). Bone scan is performed only when clinically indicated and must be 
performed within 42 days before the first dose. 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
17 
 
✓ 
At screening, tumor evaluations up to 4 weeks before randomization and before informed consent may be used as long as they meet the RECIST 1.1. 
✓ 
During the treatment period, lesions found at baseline should be examined every 8 weeks. Examinations should also be performed as appropriate 
when new lesions are suspected. Tumor evaluations should be performed when subjects withdraw due to any reason (± 4 weeks, bu t do not need to 
be repeated if the time from the last evaluation is no more than 4 weeks). Imaging conditions should be the same as those at baseline (including slice 
thickness and contrast agent). 
✓ 
The time window for imaging examination is ± 7 days. Unscheduled imaging examination may be perform ed if PD is suspected (for example, 
worsening of symptoms). Except for imaging confirmed PD, subjects who discontinue the study treatment for any other reasons must also undergo a 
tumor evaluation every 8 weeks until documentation of confirmed PD, start of a new anti-tumor treatment, lost to follow-up, or death. 
[17] 
SHR-1210 administration: on Day 1 of each 2-week cycle. 
[18] 
Adverse events: AEs collection begins from signing of informed consent form to 90 days after the last dose. Only treatment-related AEs, including AEs of 
special interest (AESI), will be collected 30 days after the last dose. 
[19] 
Concomitant medications: Concomitant medications from 30 days before the first dose to 90 days after the last dose should be collected; only concomitant 
medications for treatment-related AEs should be collected from 30 days after the end of treatment.  
[20] 
Quality of life score (EORTC QLQ-C30, EORTC QLQ-OES18): before the first dose, every 8 weeks, at the end of treatment, 30 days after the last 
dose, with a time window of ± 7 days. It is recommended to be performed prior to administration as well as AE and tumor evaluations. 
[21] 
Collection time for immunogenicity and drug trough concentration blood samples: within 30 min before the first, second, third, fifth, and seventh doses, 
within 30 min before every four doses thereafter, and at visits carried out on Day 30, Day 60 (optional), and Day 90 (optional) after the last treatment. 
[22] 
Biomarker blood sampling: before the first dose, at the occurrence of first tumor response, and at the presence of progressive disease. 
[23] 
Tumor tissue: Fresh biopsy is preferred, otherwise use archival tumor tissue specimens. 
[24] 
90 days after the last dose: Subjects must return to the study center for a follow-up on Day 30 after the last dose, and the safety information are obtained 
via telephone calls on Day 60 and Day 90 after the last dose (including AE outcomes, new SAEs, and AEs of special interest); the time window is ± 7 days.  
[25] 
Survival follow-up: once per month, with a time window of ± 7 days.  
 
 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
18 
 
Schedule of Activities for Control Group (Docetaxel) 
 
Screening Period 
Treatment Period 
End of 
Treatment/Withdrawal 
(+ 3) 
After End of Treatment 
C1 
C2+ 
Visit Window  
D-28 to D-1 
D-7 to D-1 
D1 
D1 ± 3  
90 days (± 7 days)  
after the last dose[22] 
Survival follow-up 
(± 7 days) [23] 
Signing of Informed 
Consent Form[1] 
√ 
 
 
 
 
 
 
Verification of 
Eligibility 
 
√ 
 
 
 
 
 
Demographics 
√ 
 
 
 
 
 
 
Medical History[2] 
√ 
 
 
 
 
 
 
ECOG PS[3] 
 
√ 
 
√ 
√  
  
 
Vital Signs[4] 
 
√ 
 
√ 
√ 
  
 
Physical 
Examination[5] 
 
√ 
 
√ 
√ 
  
 
Hematology[6] 
 
√ 
 
√ 
√ 
√ 
 
Urinalysis[7] 
 
√ 
 
√  
√ 
  
 
Fecal Occult Blood[8] 
 
√ 
 
√ 
 
 
 
Clinical Chemistry[9] 
 
√ 
 
√ 
√ 
√ 
 
Thyroid Function[10] 
 
√ 
 
√ 
√ 
√ 
 
Coagulation 
Function[11] 
 
√ 
 
 
  
 
 
Virological 
Examination[12] 
√ 
 
 
 
 
 
 
ECG[13] 
 
√ 
 
√ 
√ 
  
 
Echocardiography[14] 
 
√ 
 
 
 
 
 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
19 
 
 
Screening Period 
Treatment Period 
End of 
Treatment/Withdrawal 
(+ 3) 
After End of Treatment 
C1 
C2+ 
Visit Window  
D-28 to D-1 
D-7 to D-1 
D1 
D1 ± 3  
90 days (± 7 days)  
after the last dose[22] 
Survival follow-up 
(± 7 days) [23] 
Pregnancy Test[15] 
 
√ 
 
 
√ 
 
 
Tumor Imaging 
Evaluation[16] 
√ 
 
√ 
√ 
 
 
Randomization  
 
√ 
 
 
 
 
 
Docetaxel 
Administration[17] 
 
 
√ 
√ 
 
 
 
Adverse Events[18] 
√ 
√ 
√ 
√ 
√ 
√ 
 
Concomitant 
Medication[19] 
√ 
√ 
√ 
√ 
√ 
√ 
 
Quality of Life 
Score[20] 
 
 
√ 
√ 
√ 
√ 
 
Tumor Tissue[21] 
√ 
 
 
 
 
 
 
Note: Other than the examinations and time points listed in the table, the investigator may add visits and other investigations at any time when needed. Results 
are documented in the "Unscheduled Examinations" section of eCRF. 
[1] 
An informed consent form signed by the subject or legal representative must be first obtained before starting screening. 
[2] 
Medical history: including tumor history (diagnosis, surgery, radiotherapy, chemotherapy history) and history of other concurrent diseases. 
[3] 
ECOG PS: within 7 days prior to the first dose, before administration on Day 1 of each cycle (do not need to be tested for the first dose if completed 
within 7 days prior to the first dose at screening), and at the end of treatment/upon withdrawal. 
[4] 
Vital signs: blood pressure, heart rate, body temperature and respiratory rate; within 7 days prior to the first dose, before administration on Day 1 of each 
cycle (do not need to be tested for the first dose if completed within 7 days prior to the first dose at screening), and at the end of treatment/upon 
withdrawal. 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
20 
 
[5] 
Physical examination: within 7 days prior to the first dose and at the end of treatment/upon withdrawal, a comprehensive physical examination (including 
head and face, skin, lymph nodes, eyes, ears, nose and throat, mouth, respiratory system, cardiovascular system, abdomen, reproductive and urinary 
system, musculoskeletal system, nervous system and mental state) is performed; before administration on Day 1 of each cycle (do not need to be tested for 
the first dose if completed within 7 days prior to the first dose at screening), symptom-directed physical examination can be performed when clinically 
indicated. 
[6] 
Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, lymphocyte count; within 7 days prior to the first dose, before 
administration on Day 1 of each cycle (do not need to be tested for the first dose if completed within 7 days prior to the first dose at screening), at the end 
of treatment/upon withdrawal, and 30 days after the last dose. 
[7] 
Urinalysis: WBC, RBC, and urine protein. Within 7 days prior to the first dose, before administration on Day 1 of every 2 cycles, and at the end of 
treatment/upon withdrawal. In the case of urine protein ≥ 2+, a 24-h urine protein test (quantitative) must be added. 
[8] 
Fecal occult blood: within 7 days before the first administration and after enrollment when clinically indicated.  
[9] 
Clinical chemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, blood urea nitrogen (preferred) or urea, total protein, albumin, creatinine, 
blood glucose, lactate dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-. Within 7 days prior to the first dose, before administration on Day 1 of each cycle (do 
not need to be tested for the first dose if completed within 7 days prior to the first dose at screening), at the end of treatment/upon withdrawal, and 30 days 
after the last dose. 
[10] 
Thyroid function: TSH, FT3, FT4. Within 7 days prior to the first dose, before administration on Day 1 of every 2 cycles, at the end of treatment/upon 
withdrawal, and 30 days after the last dose. 
[11] 
Coagulation function: APTT, PT, FIB, INR. Within 7 days prior to the first dose. 
[12] 
Serology: HBsAg (if positive, HBV-DNA test required), HBsAb, HBeAg, HBeAb, HBcAb, HCV-Ab (if positive, HCV-RNA test required), and HIV-Ab. 
Within 14 days prior to the first dose. 
[13] 
ECG: within 7 days prior to the first dose, pre-administration on Day 1 of each cycle (do not need to be tested for the first dose if completed within 7 days 
prior to the first dose at screening), and at the end of treatment/upon withdrawal. 
[14] 
Echocardiography: within 7 days prior to the first dose; performed when clinically indicated. 
[15] 
Pregnancy test: for women of childbearing potential only. Within 72 h prior to the first dose, and at the end of treatment/upon withdrawal. 
[16] 
Tumor imaging evaluation: CT or MRI of the neck, chest and abdomen (including pelvic cavity). Brain MRI is required when brain metastasis is 
suspected and confirmed (if MRI is contraindicated, CT can be used instead). Bone scan is performed only when clinically indicated and must be 
performed within 42 days before the first dose. 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
21 
 
✓ 
At screening, tumor evaluations up to 4 weeks before randomization and before informed consent may be used as long as they meet the RECIST 1.1. 
✓ 
During the treatment period, lesions found at baseline should be examined every 8 weeks. Examinations should also be performed as appropriate 
when new lesions are suspected. Tumor evaluations should be performed when subjects withdraw due to any reason (± 4 weeks, bu t do not need to 
be repeated if the time from the last evaluation is no more than 4 weeks). Imaging conditions should be the same as those at baseline (including slice 
thickness and contrast agent). 
✓ 
The time window for imaging examination is ± 7 days. Unscheduled imaging examination may be performed if PD is suspected (for  example, 
worsening of symptoms). Except for imaging confirmed PD, subjects who discontinue the study treatment for any other reasons must also undergo a 
tumor evaluation every 8 weeks until documentation of confirmed PD, start of a new anti-tumor treatment, lost to follow-up, or death. 
[17] 
Docetaxel administration: on Day 1 of each 3-week cycle. 
[18] 
Adverse events: AE collection begins from signing of informed consent form to 90 days after the last dose. Only treatment-related AEs, including AEs of 
special interest (AESIs), will be collected 30 days after the last dose.  
[19] 
Concomitant medications: Concomitant medications from 30 days before the first dose to 90 days after the last dose should be collected; only concomitant 
medications for treatment-related AEs should be collected from 30 days after the end of treatment.  
[20] 
Quality of life score (EORTC QLQ-C30, EORTC QLQ-OES18): before the first dose, every 8 weeks, at the end of treatment, 30 days after the last 
dose, with a time window of ± 7 days. It is recommended to be performed prior to administration as well as AE and tumor evalu ations. 
[21] 
Tumor tissue: Fresh biopsy is preferred, otherwise use archival tumor tissue specimens. 
[22] 
90 days after the last dose: Subjects must return to the study center for a follow-up on Day 30 after the last dose, and the safety information are obtained 
via telephone calls on Day 60 and Day 90 after the last dose (including AE outcomes, new SAEs, and AEs of special interest); the time window is ± 7 days.  
[23] 
Survival follow-up: once per month, with a time window of ± 7 days.  
 
 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
22 
 
Schedule of Activities for Control Group (Irinotecan) 
 
Screening Period 
Treatment Period 
End of 
Treatment/Withdrawal 
(+ 3 days) 
After End of Treatment 
C1 
C2+ 
Visit Window  
D-28 to D-1 
D-7 to D-1 
D1 
D1 ± 3  
90 days (± 7 days)  
after the last dose[22] 
Survival follow-up 
(± 7 days) [23] 
Signing of Informed 
Consent Form[1] 
√ 
 
 
 
 
 
 
Verification of 
Eligibility 
 
√ 
 
 
 
 
 
Demographics 
√ 
 
 
 
 
 
 
Medical History[2] 
√ 
 
 
 
 
 
 
ECOG PS[3] 
 
√ 
 
√ 
√  
  
 
Vital Signs[4] 
 
√ 
 
√ 
√ 
  
 
Physical 
Examination[5] 
 
√ 
 
√ 
√ 
  
 
Hematology[6] 
 
√ 
 
√ 
√ 
√ 
 
Urinalysis[7] 
 
√ 
 
√  
√ 
  
 
Fecal Occult Blood[8] 
 
√ 
 
√ 
 
 
 
Clinical Chemistry[9] 
 
√ 
 
√ 
√ 
√ 
 
Thyroid Function[10] 
 
√ 
 
√ 
√ 
√ 
 
Coagulation 
Function[11] 
 
√ 
 
 
  
 
 
Virological 
Examination[12] 
√ 
 
 
 
 
 
 
ECG[13] 
 
√ 
 
√ 
√ 
  
 
Echocardiography[14] 
 
√ 
 
 
 
 
 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
23 
 
 
Screening Period 
Treatment Period 
End of 
Treatment/Withdrawal 
(+ 3 days) 
After End of Treatment 
C1 
C2+ 
Visit Window  
D-28 to D-1 
D-7 to D-1 
D1 
D1 ± 3  
90 days (± 7 days)  
after the last dose[22] 
Survival follow-up 
(± 7 days) [23] 
Pregnancy Test[15] 
 
√ 
 
 
√ 
 
 
Tumor Imaging 
Evaluation[16] 
√ 
 
√ 
√ 
 
 
Randomization  
 
√ 
 
 
 
 
 
Irinotecan 
Administration[17] 
 
 
√ 
√ 
 
 
 
Adverse Events[18] 
√ 
√ 
√ 
√ 
√ 
√ 
 
Concomitant 
Medication[19] 
√ 
√ 
√ 
√ 
√ 
√ 
 
Quality of Life 
Score[20] 
 
 
√ 
√ 
√ 
√ 
 
Tumor Tissue[21] 
√ 
 
 
 
 
 
 
Note: Other than the examinations and time points listed in the table, the investigator may add visits and other investigations at any time when needed. Results 
are documented in the "Unscheduled Examinations" section of eCRF. 
[1] 
An informed consent form signed by the subject or legal representative must be first obtained before starting screening. 
[2] 
Medical history: including tumor history (diagnosis, surgery, radiotherapy, chemotherapy history) and history of other concurrent diseases. 
[3] 
ECOG PS: within 7 days prior to the first dose, before administration on Day 1 of each cycle (do not need to be tested for the first dose if completed 
within 7 days prior to the first dose at screening), and at the end of treatment/upon withdrawal. 
[4] 
Vital signs: blood pressure, heart rate, body temperature and respiratory rate; within 7 days prior to the first dose, before administration on Day 1 of each 
cycle (do not need to be tested for the first dose if completed within 7 days prior to the first dose at screening), and at the end of treatment/upon 
withdrawal. 


<SHR-1210> 
<SHR-1210-III-301-ESC> 
<Version No.: 5.0>, <Version Date: 12 Apr., 2018>   
 
 
24 
 
[5] 
Physical examination: within 7 days prior to the first dose and at the end of treatment/upon withdrawal, a comprehensive physical examination (including 
head and face, skin, lymph nodes, eyes, ears, nose and throat, mouth, respiratory system, cardiovascular system, abdomen, reproductive and urinary 
system, musculoskeletal system, nervous system and mental state) is performed; before administration on Day 1 of each cycle (do not need to be tested for 
the first dose if completed within 7 days prior to the first dose at screening), symptom-directed physical examination can be performed when clinically 
indicated. 
[6] 
Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, lymphocyte count; within 7 days prior to the first dose, before 
administration on Day 1 of each cycle (do not need to be tested for the first dose if completed within 7 days prior to the first dose at screening), at the end 
of treatment/upon withdrawal, and 30 days after the last dose. 
[7] 
Urinalysis: WBC, RBC, and urine protein. Within 7 days prior to the first dose, before administration on Day 1 of every 2 cycles, and at the end of 
treatment/upon withdrawal. In the case of urine protein ≥ 2+, a 24-h urine protein test (quantitative) must be added. 
[8] 
Fecal occult blood: within 7 days before the first administration and after enrollment when clinically indicated.  
[9] 
Clinical chemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, blood urea nitrogen (preferred) or urea, total protein, albumin, creatinine, 
blood glucose, lactate dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-. Within 7 days prior to the first dose, before administration on Day 1 of each cycle (do 
not need to be tested for the first dose if completed within 7 days prior to the first dose at screening), at the end of treatment/upon withdrawal, and 30 days 
after the last dose. 
[10] 
Thyroid function: TSH, FT3, FT4. Within 7 days prior to the first dose, before administration on Day 1 of every 2 cycles, at the end of treatment/upon 
withdrawal, and 30 days after the last dose. 
[11] 
Coagulation function: APTT, PT, FIB, INR. Within 7 days prior to the first dose. 
[12] 
Serology: HBsAg (if positive, HBV-DNA test required), HBsAb, HBeAg, HBeAb, HBcAb, HCV-Ab (if positive, HCV-RNA test required), and HIV-Ab. 
Within 14 days prior to the first dose. 
[13] 
ECG: within 7 days prior to the first dose, pre-administration on Day 1 of each cycle (do not need to be tested for the first dose if completed within 7 days 
prior to the first dose at screening), and at the end of treatment/upon withdrawal. 
[14] 
Echocardiography: within 7 days prior to the first dose; performed when clinically indicated. 
[15] 
Pregnancy test: for women of childbearing potential only. Within 72 h prior to the first dose, and at the end of treatment/upon withdrawal. 
[16] 
Tumor imaging evaluation: CT or MRI of the neck, chest and abdomen (including pelvic cavity). Brain MRI is required when brain metastasis is 
suspected and confirmed (if MRI is contraindicated, CT can be used instead). Bone scan is performed only when clinically indicated and must be 
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✓ 
At screening, tumor evaluations up to 4 weeks before randomization and before informed consent may be used as long as they meet relevant criteria. 
✓ 
During the treatment period, lesions found at baseline should be examined every 8 weeks. Examinations should also be performed as appropriate 
when new lesions are suspected. Tumor evaluations should be performed when subjects withdraw due to any reason (± 4 weeks, but do not n eed to 
be repeated if the time from the last evaluation is no more than 4 weeks). Imaging conditions should be the same as those at baseline (including slice 
thickness and contrast agent). 
✓ 
The time window for imaging examination is ± 7 days. Unscheduled imaging examination may be performed if PD is suspected (for  example, 
worsening of symptoms). Except for imaging confirmed PD, subjects who discontinue the study treatment for any other reasons must also undergo a 
tumor evaluation every 8 weeks until documentation of confirmed PD, start of a new anti-tumor treatment, lost to follow-up, or death. 
[17] 
Irinotecan administration: on Day 1 of each 2-week cycle. 
[18] 
Adverse events: AE collection begins from signing of informed consent form to 90 days after the last dose. Only treatment-related AEs, including AEs of 
special interest (AESIs), will be collected 30 days after the last dose.  
[19] 
Concomitant medications: Concomitant medications from 30 days before the first dose to 90 days after the last dose should be collected; only concomitant 
medications for treatment-related AEs should be collected from 30 days after the end of treatment. 
[20] 
Quality of life score (EORTC QLQ-C30, EORTC QLQ-OES18): before the first dose, every 8 weeks, at the end of treatment, 30 days after the last 
dose, with a time window of ± 7 days. It is recommended to be performed prior to administration as well as AE and tumor evalu ations. 
[21] 
Tumor tissue: Fresh biopsy is preferred, otherwise use archival tumor tissue specimens. 
[22] 
90 days after the last dose: Subjects must return to the study center for a follow-up on Day 30 after the last dose, and the safety information are obtained 
via telephone calls on Day 60 and Day 90 after the last dose (including AE outcomes, new SAEs, and AEs of special interest); the time window is ± 7 days.  
[23] 
Survival follow-up: once per month, with a time window of ± 7 days.  


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ABBREVIATIONS 
Abbreviation 
Full Name 
AKP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CFDA 
China Food and Drug Administration 
CR 
Complete response 
Cr 
Creatinine 
CRF 
Case report form 
CRO 
Contract research organization 
D 
Day 
DLT 
Dose-limiting toxicity 
EC 
Ethics committee 
EDC 
Electronic data collection 
FAS 
Full analysis set 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transpeptidase 
h 
Hour 
Hb 
Hemoglobin 
IB 
Investigator's brochure 
IC50 
Half maximal inhibitory concentration 
ICS 
Informed consent set 
irAE 
Immune-related adverse event 
iRECIST 
Immune-related response evaluation criteria in solid tumors 
IU 
International unit 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 


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Abbreviation 
Full Name 
MRI 
Magnetic resonance imaging 
ORR 
Objective response rate 
OS  
Overall survival 
PR 
Partial response 
PD 
Progressive disease 
PFS 
Progression-free survival 
PPS 
Per-protocol set 
PLT 
Blood platelet 
RBC 
Red blood cell count 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SS 
Safety set 
T-BIL 
Total bilirubin 
TSH 
Thyroid-stimulating hormone 
UA 
Uric acid 
ULN  
Upper limit of normal 
WBC 
White blood cell count 
 
 


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1. KEY FUNCTIONAL ROLES 
Sponsor's Medical Director 
, M.D., Clinical Medical Director 
 
 
 
 
 
 
Statistician 
 
 
 
 
 
 
Project Manager 
 
 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
No. 7 Kunlunshan Road, Lianyungang Economic and Technological 
Development Zone, Jiangsu 
 
 
2. INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE 
2.1. 
Background 
Esophageal cancer, a type of malignant tumor, occurs in the esophageal mucosa, including the 
tumor that arises in the gastroesophageal junction or within 5 cm of the junction and has invaded 
the lower esophagus or esophagogastric junction[1]. Worldwide, esophageal cancer ranks 8th in 
cancer incidence and 6th in mortality. China accounts for more than 50% of global cases[2]. In 
2015, the number of new esophageal cancer patients in China was 477,900. From 2001 to 2011, 
the incidence ranked 5th and mortality 4th among all cancers in males. The incidence and 
mortality showed an annual decline in females[3]. About 90% of esophageal cancers are 
squamous cell carcinoma, and there are obvious regional differences. High-risk 
provinces/municipalities/autonomous regions include Hebei, Henan, Fujian, and Chongqing, 
followed by Xinjiang, Jiangsu, Shanxi, Gansu, and Anhui[1]. 
Endoscopic treatment is preferred for early esophageal cancer (involving mucosa or submucosa 
only). The 5-year survival rate is as high as 95%. However, as most patients are not treated early 
in the disease, the five-year survival rate for esophageal cancer is less than 20%[4]. The first-line 
treatment for advanced unresectable, relapsed, metastatic esophageal cancer is platinum-based 
combination chemotherapy, for example, cisplatin-5-fluorouracil and paclitaxel-cisplatin. The 
response rate is between 30-60% and median OS is 5-10 months[1, 5]. There is no standard 


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second-line treatment for patients who failed the first-line treatment. Even though paclitaxel, 
docetaxel, and irinotecan can be used as monotherapy or in combination with other treatments as 
the second-line treatment, the efficacy rates are low (see Table 1) and no large-scale studies 
confirm their efficacy. Therefore, there is a dire need to develop new drugs as the second-line 
treatment for esophageal cancer. 
Table 1. Efficacy of existing second-line chemotherapies for esophageal cancer 
Chemotherapy 
Number of Subjects and Cases 
ORR 
TTP/PFS 
(Months) 
OS (Months) 
Paclitaxel[6] 
53 patients with relapsed or advanced 
esophageal cancer; 51 cases of 
squamous cell carcinoma and 1 case of 
esophageal adenocarcinoma 
44.2% 
4.8 
10.4 
Docetaxel[7] 
49 patients with metastatic esophageal 
cancer; 46 cases of squamous cell 
carcinoma, 1 case of adenocarcinoma, 
and 2 cases of other carcinomas 
16% 
Unknown 
8.1 
Docetaxel[8] 
Docetaxel Plus 
Platinum 
85 patients with metastatic/relapsed 
squamous cell carcinoma of the 
esophagus; 41 cases in docetaxel 
group and 44 cases in docetaxel + 
platinum group 
19.5% 
29.5% 
3.2 
3.6 
5.2 
5.7 
Docetaxel + 
Cisplatin[9] 
35 patients with metastatic/relapsed 
squamous cell carcinoma of the 
esophagus 
34.2% 
4.5 
7.4 
Docetaxel + 
Nedaplatin[10] 
33 patients with relapsed or 
unresectable squamous cell carcinoma 
of the esophagus 
21.2% 
2.3 
6.9 
Gemcitabine + 
Vinorelbine[11] 
35 patients with advanced esophageal 
cancer, 34 cases of squamous cell 
carcinoma, 1 case of adenocarcinoma 
31.3% 
4.3 
7.3 
Irinotecan[12] 
14 patients with advanced esophageal 
cancer, 7 cases of squamous cell 
carcinoma, 7 cases of esophageal 
adenocarcinoma 
15% 
2 
5 
Irinotecan[13] 
13 patients with advanced esophageal 
cancer, 10 cases of esophageal 
squamous cell carcinoma (10), 3 cases 
of esophageal adenocarcinoma 
10% (squamous cell 
carcinoma) 
33% 
(adenocarcinoma) 
3.8 
6.1 
Irinotecan + 
Docetaxel[14] 
24 patients with locally advanced or 
metastatic esophageal cancer; 11 cases 
of squamous cell carcinoma and 13 
case of adenocarcinoma 
12.5% 
Unknown 
6.5 
Vinorelbine[15] 
46 patients with metastatic squamous 
cell carcinoma of the esophagus;  
30 treatment-naive and  
16 chemotherapy refractory 
6% in relapsed 
patients 
Unknown 
6 (treatment-
naive and 
relapsed) 


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2.2. 
Scientific Rationale 
2.2.1. 
Study rationale 
The programmed cell death protein-1 (PD-1) pathway is one of the most critical checkpoint 
pathways responsible for regulating tumor-induced immunosuppression. PD-1 is a protein 
receptor expressed on the surface of T cells discovered in 1992 and is involved in the process of 
cell apoptosis. PD-1 is a member of the CD28 family and has a 23% consistency in amino acid 
sequence with cytotoxic T lymphocyte antigen 4 (CTLA-4). However, its expression is different 
from CTLA. It is primarily expressed by activated T cells, B cells, and myeloid cells. PD-1 has 
two ligands, PD-L1 and PD-L2. PD-L1 is primarily expressed on T cells, B cells, macrophages, 
and dendritic cells (DCs), and is up-regulated on activated cells. According to the literature, 
about 41.4% of squamous cell carcinoma of the esophagus has PD-L1 expression (a meta-analysis 
of 1,350 Chinese and Japanese subjects), and the overexpression of PD-L1 may reduce OS[16]. 
Therefore, immune checkpoint inhibitors against PD-1/PD-L1 may be a new method of treating 
esophageal cancers. 
An open-label, single-arm, multi-center, phase II study was conducted in Japan for nivolumab, a 
PD-1 inhibitor developed by Bristol-Myers Squibb. Patients with advanced esophageal cancer 
refractory or intolerant to more than one line of chemotherapy were treated with 3 mg/kg 
nivolumab every 2 weeks. A total of 65 subjects were enrolled, with 64 being assessable. ORR 
was 17.2% (1 CR/10 PR), DCR 42.2% (1 CR/10 PR/16 SD), and median OS 10.8 months, 
regardless of PD-L1 status[17]. In a phase Ib study involving pembrolizumab (MK-3475), a PD-1 
inhibitor developed by Merck, 23 patients with advanced esophageal cancer (PD-L1+) refractory 
to standard treatment were enrolled and treated with 10 mg/kg drugs every 2 weeks. Among the 
22 assessable subjects, ORR was 30% (7 PR) and DCR 40.9% (7 PR/2 SD). ORRs were 29% 
(5 PR) among the 17 patients with squamous cell carcinoma and 40% (2 PR) among the 5 with 
adenocarcinoma[18]. Currently, phase III clinical studies are underway for both nivolumab and 
pembrolizumab as second-line treatments for advanced esophageal cancer. Preliminary efficacy 
of PD-1/PD-L1 immune checkpoint inhibitors in the treatment of esophageal cancer suggests that 
it may be a new effective drug for treating esophageal cancers. 
2.2.2. 
Rationale for drug development 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. used PD-1 as a target and recombinant PD-1 protein 
as an immunogen to obtain a series of PD-1 antibodies in mice. Through a large number of in 
vitro binding assays, in vitro ligand blocking assays, T cell proliferation assays, animal 
experiments, and antibody druggability assessments, an antibody prototype was selected. Then, a 
humanized design of the murine antibody prototype was carried out through computer 


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simulations, resulting in several humanized anti-PD-1 monoclonal antibodies. Finally, SHR-
1210, the one with the highest activity among those antibodies, was selected for further 
development. Phase I clinical studies have been conducted by Hengrui in Australia and China 
since 2015. Several clinical studies are currently underway. 
2.2.2.1. Preclinical study results of SHR-1210 
2.2.2.1.1. 
Product name and physicochemical properties 
[Generic Name]: SHR-1210 Injection 
[English Name]: SHR-1210 Injection 
[Molecular Weight]: approx. 146.3 kDa 
2.2.2.1.2. 
Pharmacology and mechanism of action 
The humanized anti-PD-1 monoclonal antibody can specifically bind to PD-1, blocking the 
interaction between PD-1 and its ligands and thereby restoring T-cell immune response to tumor 
cells. 
2.2.2.1.3. 
Pharmacodynamics 
(1) Affinity 
Results from affinity assays involving SHR-1210 and human, monkey, and murine PD-1 
antigens showed that the affinities of SHR-1210 for human and monkey PD-1 antigens were 6.9 
nM and 4.1 nM, respectively. No binding was detected with murine PD-1 antigens. See Table 2 
for details. 
Table 2. Binding affinity of SHR-1210 to human, monkey, and murine PD-1 antigens 
Stationary Phase 
Mobile Phase 
Affinity (nM) 
SHR-1210 
Human PD-1 antigen 
6.9 
SHR-1210 
Murine PD-1 antigen 
Extremely weak signals, no binding 
detected 
Monkey PD-1 antigen (-hFc) 
SHR-1210 
4.1 
Results from the binding affinity assay showed that the binding affinity of SHR-1210 to human 
PD-1 antigen was 3.0 nM, similar to nivolumab and MK3475. See Table 3 for details. 
 
 


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Table 3. Binding affinity of SHR-1210, nivolumab, and MK3475 to PD-1 antigen 
Antibody 
Antigen 
Affinity (nM) 
SHR-1210 
Human PD-1 antigen 
3.0 
Nivolumab 
Human PD-1 antigen 
4.0 
MK3475 
Human PD-1 antigen 
3.2 
(2) Inhibition of PD-1/PD-L1 binding by SHR-1210 
Results from inhibition of PD-1/PD-L1 binding by SHR-1210 showed that the in vitro binding 
inhibition of SHR-1210 was similar to those of nivolumab and pembrolizumab (see Figure 1 and 
Figure 2). IC50 values were 0.70 nM/0.79 nM and 0.79 nM/0.77 nM, respectively. 
PD1 antibody blocking
-2
-1
0
1
2
3
0.0
0.5
1.0
1.5
2.0
2.5
HR301210
lambrolizumab
IC50
HR301210
0.7007
lambrolizumab
0.7864
negative control
Log[Concentration]/ug/mL
OD 450 nm
 
Figure 1. 
Inhibition of PD-1/PD-L1 binding by SHR-1210 and pembrolizumab 
PD1 antibody blocking
-2
-1
0
1
2
3
0
1
2
3
4
HR301210
Nivolumab
IC50
HR301210
0.7913
Nivolumab
0.7745
Log[Concentration]/ug/mL
OD 450 nm
 
Figure 2. 
Inhibition of PD-1/PD-L1 binding by SHR-1210 and nivolumab 
 
 


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2.2.2.1.4. 
Toxicology studies 
In a pre-clinical single dose toxicity study in cynomolgus monkeys, 8 monkeys (half male and 
half female) were randomized to 2 groups. The animals in Group 2 were given an intravenous 
injection of SHR-1210 once every other day at doses of 200, 400, and 800 mg/kg, respectively, 
in a dose-escalation manner. No changes in clinical symptoms, body weight, food intake, and 
coagulation related to SHR-1210 were observed. Lymphocytes decreased for both sexes at doses 
≥ 200 mg/kg. Serum globulin increased and albumin decreased at doses ≥ 400 mg/kg. Since the 
magnitude of these changes was small, they were not considered harmful effects. The maximum 
tolerated dose (MTD) of SHR-1210 was ≥ 800 mg/kg. 
In a completed preclinical repeated dose toxicity study in cynomolgus monkeys, consecutively 
intravenous administration of SHR-1210 at 20, 50, and 100 mg/kg/dose for 4 weeks (5 doses in 
total) was well-tolerated in animals of both sexes. Clinical symptoms, including injection site 
irritation, or changes in body weight, food intake, body temperature, ECG, blood pressure, heart 
rate, and respiratory measurements related to SHR-1210 were not observed. No changes in B and 
T cell differentiation, cytokines, immunoglobulins, and complements were observed. No changes 
in organ weight, gross lesions, or histopathological changes associated with SHR-1210 were 
found. 
2.2.2.1.5. 
Pharmacokinetic study 
For SHR-1210 PK parameters after a single intravenous infusion in cynomolgus monkeys, see 
Table 4. 
Table 4. PK parameters after a single intravenous infusion of SHR-1210 at different doses 
in cynomolgus monkeys 
Dose 
(mg/kg) Gender 
T1/2 
Tmax 
Cmax 
AUClast 
Vz 
Cl 
MRTlast 
(hr) 
(hr) 
(µg/mL)  
(hr·µg/mL)  
(mL/kg) 
(mL/hr/kg) 
(hr) 
1 
Female 
76.06±32.93  
0.83±0.29  
31.16±11.25  
1716.12±453  
54.09±14.85  
0.57±0.17  
80.95±18.58  
Male 
91.72±25.26  
0.83±0.29  
35.96±13.09  
2359.7±684.07  
55.15±20.51  
0.37±0.06  
102.23±38.56  
Overall 83.89 ±27.62  0.83 ±0.26  33.56± 11.23  
2037.91± 627.32  
54.62± 16.02  0.47± 0.15  
91.59 ±29.47  
3 
Female 
92.95±22.60  
0.83±0.29  
81.09±12.66  
6896.79±1673.36  
40.75±12.66  
0.44±0.11  
120.92±49.96  
Male 
113.54±8.26  
1.67±0.58  
71.65±10.85  
6380.25±2062.85  
47.05±27.05  
0.47±0.12  
127.10±59.25  
Overall 103.25±18.94  1.25 ±0.61  76.37 ±11.74  6638.51 ±1703.60  43.91 ±19.21  0.46 ±0.11  125.01±49.13  
10 
Female 169.70±38.96  2.17±1.76  217.46±20.22  31357.28±9338.28  41.25±25.76  
0.33±0.1  
179.68±73.6  
Male 
128.94±35.93  0.67±0.29  
251.88±6.49  26779.98±7205.43  
30.9±30.2  
0.31±0.05  
113.25±44.39  
Overall 149.32±40.28  1.42±1.39  234.67±23.15  29068.63±7869.83  36.07±25.34  
0.32±0.07  
146.46±65.42  


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2.2.2.2. Clinical study results 
Four open-label, dose-escalation, phase I clinical studies are underway to evaluate the safety and 
tolerability of SHR-1210 in patients with advanced solid tumors refractory to existing standard 
treatment. 
In 2015, the first-in-human study (INCSHR-1210-101) was initiated in Australia. It was an open-
label, multi-center, non-randomized, dose-escalation, and tumor-expansion phase I study 
consisting of two stages. The first stage employed a 3+3 dose escalation design with 4 doses of 
1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg being set (the first four weeks were the DLT 
observation period, with only one dose administered; thereafter, the drug was administered every 
2 weeks); the phase 2a stage was a stage of monotherapy expansion and 600 mg (once every 4 weeks) 
was selected for the expansion. Approximately 52 patients with advanced endometrial cancer, 
thymic cancer, biliary tract cancer, and cancers of unknown origin refractory to standard 
treatment were enrolled. As of 15 Dec., 2016, a total of 32 subjects were enrolled. 
In 2016, three phase I clinical trials were initiated in China: SHR-1210-101, SHR-1210-102, and 
SHR-1210-103. SHR-1210-101 was an open-label, single-center, dose-escalation, phase I study 
consisting of 3 stages. The first stage employed a 3+3 dose-escalation design with 4 doses of 
1 mg/kg, 3 mg/kg, 200 mg/kg, and 10 mg/kg being set (the first four weeks were the DLT 
observation period, with only one dose administered; thereafter, the drug was administered every 
2 weeks); the second stage was a stage of expansion, and the number of subjects was expanded 
to 8-12 for the 4 groups; in the third stage, a fixed dose of 200 mg (once every 2 weeks) was 
selected to expand the study clinically in patients with nasopharyngeal cancer and non-small cell 
lung cancer. As of 15 Dec., 2016, a total of 39 subjects were enrolled. SHR-1210-102 was an 
open-label, single-center, dose-escalation, phase I study prominently enrolling patients with 
advanced malignant melanoma refractory to standard treatment. The study consisted of 2 stages. 
The first stage employed a 3+3 dose-escalation design with 3 fixed doses of 60 mg, 200 mg, and 
400 mg being set (the first eight weeks were the DLT observation period, with only one dose 
administered in the first four weeks and every 2 weeks thereafter); the second stage was a stage 
of expansion, and the number of subjects was expanded to 8-12 for the 3 groups. As of 15 Dec., 
2016, a total of 16 subjects were enrolled. SHR-1210-103 was an open-label, single-center, dose-
escalation, phase I study consisting of 3 stages. The first stage employed a 3+3 dose-escalation 
design with 3 doses of 60 mg, 200 mg and 400 mg being set (the first four weeks were the DLT 
observation period, with only one dose administered; the drug was administered every 2 weeks 
thereafter); the second stage was a stage of expansion and the number of subjects was expanded 
to 9-12 for the 3 groups; in the third stage, a fixed dose of 200 mg (every 2 weeks) was selected 
to expand the study clinically in patients with GI cancers (mainly esophageal cancer, liver cancer, 
and gastric cancer) and triple negative breast cancer. As of 15 Dec., 2016, a total of 61 subjects 
were enrolled. 


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As of 15 Dec., 2016, a total of 32 subjects were enrolled overseas and a total of 116 subjects 
were enrolled in China. DLT was not observed in all high-dose groups. Preliminary safety results 
suggested that SHR-1210 is safe and well-tolerated. The common hematologic AE was anemia 
and non-hematologic AEs were hemangioma of skin, pyrexia, ALT and AST increased, blood 
bilirubin increased, rash, and hypothyroidism (refer to the Investigator's Brochure for preliminary 
safety data). As of 28 Dec., 2016, a total of 36 patients with advanced esophageal cancer who 
were refractory to standard treatment were enrolled in Study 103. Among the 21 subjects who 
had at least one efficacy assessment, ORR was 23.8% (5 PR), and DCR 52.4% (5 PR and 6 SD). 
Preliminary results showed that SHR-1210 is effective in treating patients with advanced 
esophageal cancer to certain extents.  
2.2.3. 
Basis of dosing regimen 
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-cancer effects. Phase I PK studies 
showed that serum drug concentrations dropped below 1000 ng/mL on Day 15 after a single dose 
of 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 suggested that a serum 
drug concentration of at least 2000 ng/mL is required to maintain the receptor saturation. Clinical 
results also suggested that a fixed dose of 200 mg every 2 weeks can maintain a saturated 
receptor occupancy. In phase I studies, the incidence of AEs did not increase with the dose, 
whether the drug was administered by weight or by dose fixed. Based on results from the studies 
described above and the convenience of clinical administration, a fixed dose of 200 mg every 
2 weeks is selected as the treatment regimen for this study. 
There are no second-line standard treatments for patients with locally advanced or metastatic 
esophageal cancer after being treated with the first-line standard chemotherapy. The NCCN 
guideline recommends docetaxel and irinotecan as the second-line chemotherapy for esophageal 
cancer. To demonstrate the clinical efficacy of SHR-1210 in patients with locally advanced or 
metastatic esophageal cancer, these two drugs are selected as the controls for this study. 
2.3. 
Potential Risks and Benefits 
Drugs similar to SHR-1210 have demonstrated efficacy in patients with advanced esophageal 
cancer. The control group will receive an investigator's choice of routine second-line 
chemotherapy for advanced esophageal cancer. Therefore, subjects will benefit from the study 
regardless of group allocation. 
Refer to the Investigator's Brochure and the Informed Consent Form for detailed information on 
subject's benefits and risks. 


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3. OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
Primary objective: To evaluate the efficacy of SHR-1210 vs. investigator's choice of 
chemotherapy in subjects with locally advanced or metastatic esophageal cancer who are 
refractory to the first-line chemotherapy. 
Secondary objective: To evaluate the safety of SHR-1210 vs. investigator's choice of 
chemotherapy in subjects with locally advanced or metastatic esophageal cancer who are 
refractory to the first-line chemotherapy. 
Exploratory objectives: (1) To evaluate the relationship between biomarkers in tumor tissue 
and/or blood (such as PD-L1) and the efficacy of SHR-1210. 
(2) To evaluate the immunogenicity of SHR-1210 in subjects with locally advanced or metastatic 
esophageal cancer, and to investigate the correlation between immunogenicity and drug trough 
concentration, efficacy and safety. 
3.2. 
Study Endpoints 
3.2.1. 
Primary endpoint 
Overall survival (OS): defined as the time from the start of randomization to the death of the 
subject caused by any reason.  
3.2.2. 
Secondary endpoints 
Progression-free survival (PFS): defined as the time from the start of randomization to the first 
documented objective tumor progression or death caused by any reason, whichever occurs first. 
Objective response rate (ORR): the proportion of subjects who achieved CR and PR. 
Quality of life score: As a core scale for all cancer patients, the EORTC QLQ-C30 scale 
comprises 30 items, 5 functional scales (physical, role, cognitive, emotional and social), 3 symptom 
scales (fatigue, pain and nausea/vomiting), 1 global health status/quality of life scale and 6 single-
item scales (dyspnoea, insomnia, appetite loss, constipation, diarrhea and financial impact). The 
EORTC QLQ-OES18 scale is mainly used for patients with esophageal cancer and contains 
18 symptom items. The assessment should be completed at various time points based on the 
schedule of activities, starting from the first cycle until 30 days after the last dose. 


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3.2.3. 
Exploratory endpoints 
To evaluate the relationship between the expression of PD-L1 and/or other biomarkers with the 
efficacy of SHR-1210. 
To evaluate the incidence of ADA, time to the first positive ADA result, duration of ADA, 
incidence of anti-SHR-1210 antibody with neutralizing activity, and the correlation between 
immunogenicity and drug trough concentration, efficacy and safety. 
Tumor tissues and/or blood obtained during the study may also be used in the future to determine 
tumor mutation burden, proteomics, or other analytes. 
4. STUDY DESIGN 
This is a randomized, open-label, active-controlled, multi-center study. A total of 438 eligible 
subjects with locally advanced or metastatic squamous cell carcinoma of the esophagus who are 
refractory to first-line chemotherapy will be randomized to investigational treatment group or 
control group in a 1:1 ratio and stratified by: 1. locally advanced lesion vs. distant metastasis; 2. 
ECOG PS (0 vs. 1). 
Subjects in the investigational treatment group will receive SHR-1210 (200 mg/dose, on Day 1 
of each 2-week cycle) and those in the control group will receive the investigator's choice of 
chemotherapy, either docetaxel (75 mg/m2, on Day 1 of each 3-week cycle) or irinotecan (180 mg/m2, 
on Day 1 of each 2-week cycle). Both investigational treatment group and control group will 
continue treatment until the occurrence of progressive disease (PD), intolerable toxicity, 
voluntary withdrawal by the subject, or treatment discontinuation determined by the investigator. 
Based on SHR-1210 being an immune checkpoint inhibitor and the experience of similar drugs, 
some subjects may experience delayed or early tumor pseudoprogression after receiving the 
immunotherapy. Therefore, the use of RECIST v1.1 alone may underestimate the benefits of the 
immunotherapy. As a result, it is suggested in this study to carry out a comprehensive imaging 
assessment based on both RECIST v1.1 and iRECIST, i.e., for subjects experiencing progressive 
disease for the first time but whose clinical symptoms are stable, the investigator may decide to 
allow the subjects to continue using SHR-1210 and take the imaging assessment again after 4 weeks 
(± 7 days); when the subsequent imaging assessment confirms progressive disease, the subjects 
need to discontinue SHR-1210 unless the investigator believes that the subjects can continue to 
gain clinical benefits from SHR-1210 and makes the decision following the discussion with the 
sponsor. 
The study procedure is divided into three stages. The screening period is 28 days. After 
completing the screening examination and evaluation, the eligible subjects enter the treatment 


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period and undergo visits by the dosing frequency. Relevant examinations and assessments must 
be completed before each dose. In particular, tumor imaging will be assessed once every 8 weeks 
(± 7 days) (including the chemotherapy control group). All subjects must complete safety 
examinations and tumor assessments before the end of treatment. These subjects then enter the 
follow-up period. The safety follow-up visits of all subjects will be carried out until 90 days after 
the last dose. The follow-up visits scheduled for 30 days after the last dose will be carried out at 
the study center, while those scheduled for 60 days and 90 days after the last dose via telephone. 
Survival follow-up visits begin from the last dose and are carried out once a month; subjects 
ending the treatment due to reasons other than PD will continue to undergo imaging assessment 
once every 8 weeks (± 7 days) until PD, initiation of new anti -tumor treatment or death. Refer to 
Section 7 for specific study procedures. 
Refer to  
Figure 3 for study design. 
 
 


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Figure 3. 
Study design schematic 
5. SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible. 
1. Aged 18-75 years, male or female; 
2. Patients with histologically or cytologically confirmed squamous cell carcinoma of the 
esophagus, unresectable locally advanced, locally recurrent or distant metastasis; 
3. Patients who have received first-line systemic chemotherapy (which may include 
chemotherapies based on platinum, paclitaxel or fluorouracil) and showed disease 
progression or intolerance (patients who have progression in maintenance treatment 
after first-line chemotherapy can also be included). Concurrent chemoradiotherapy for 
postoperative recurrence or metastasis is considered as first-line treatment; for radical 
concurrent chemoradiotherapy and neoadjuvant/adjuvant therapy (chemotherapy or 
chemoradiotherapy), it should be considered as first-line treatment failure when disease 
progression occurs during the treatment or within 6 months after the treatment discontinued; 
Patients with 
locally advanced 
or metastatic 
esophageal cancer 
refractory to first-
line chemotherapy 
Investigational treatment 
group (n = 219) 
SHR-1210, 200 mg, 
administered on Day 1 of 
each 2-week cycle. Treated 
until withdrawal due to 
confirmed PD or 
intolerable toxicity. 
Control group (n = 219) 
Docetaxel: 75 mg/m2, 
administered on Day 1 of each 
3-week cycle. 
Or 
Irinotecan: 180 mg/m2, 
administered on Day 1 of each 
2-week cycle. 
Treated until withdrawal due 
to PD or intolerable toxicity. 
Observations 
OS, PFS, 
ORR, quality 
of life score, 
and safety 
1:1 randomization, stratified by: 
Locally advanced lesion vs. 
distant metastasis 
ECOG 0 VS 1 


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4. Patients with at least one measurable lesion according to Response Evaluation Criteria 
in Solid Tumors (RECIST v1.1), and the measurable lesion(s) should not have been 
locally treated such as radiotherapy (lesions in previous radiotherapy sites may also be 
selected as target lesions when PD is confirmed and RECIST v1.1 are met); 
5. Patients with available tissue samples for biomarker (such as PD-L1) analysis; fresh 
tissue is preferred; archival samples of 5-8 paraffin embedded sections that are 5 μm 
thick are also acceptable when a fresh biopsy is not accessible; 
6. ECOG PS: 0-1 (see Appendix I); 
7. Life expectancy ≥ 12 weeks; 
8. Major organ functions must meet the following rules (no blood components or cell 
growth factors are allowed to be used within 2 weeks before the start of study 
treatment): 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
b. Platelets ≥ 100 × 109/L; 
c. Hemoglobin ≥ 9 g/dL; 
d. Serum albumin ≥ 2.8 g/dL; 
e. Total bilirubin ≤ 1.5 × ULN, ALT and AST ≤ 2.5 × ULN; for liver metastasis, ALT and 
AST ≤ 5 × ULN; 
f. 
CrCl ≥ 50 mL/min (Cockcroft-Gault, see Appendix II); 
9. Female patients of childbearing potential must have a negative urine or serum 
pregnancy test result within 72 h before the first dose of study drugs and must be willing 
to use effective contraceptive measures during the study and within 3 months after the 
last dose of SHR-1210 (180 days after the last dose for the control group). Male patients 
with partners of childbearing potential must be willing to take effective contraceptive 
measures during the study and within 3 months after the last dose of SHR-1210 (180 days 
after the last dose for the control group); 
10. Patients must participate voluntarily, sign the informed consent form, have good 
compliance, and cooperate with follow-up visits. 


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5.2. 
Exclusion Criteria 
1. Patients who are diagnosed with other malignant tumors (excluding curatively treated 
basal cell carcinoma of skin and squamous cell carcinoma of skin, and/or curatively 
resected cervical carcinoma in situ and/or breast cancer in situ) within 5 years from the 
first dose of study drugs; 
2. Patients with central nervous system (CNS) metastasis; 
3. Patients with active autoimmune disease or history of autoimmune diseases (such as 
interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, myocarditis, 
nephritis, hyperthyroidism, hypothyroidism (enrollment is not restricted when hormone 
replacement therapy is effective)); patients with vitiligo or who had completely resolved 
pediatric asthma requiring no intervention after adulthood may be enrolled, while those 
still requiring medical intervention with bronchodilators should not be enrolled; 
4. Patients with uncontrolled cardiac symptoms or disease, such as: (1) > NYHA Class II 
heart failure, (2) unstable angina, (3) myocardial infarction within the past year, and (4) 
clinically significant supraventricular or ventricular arrhythmias requiring clinical 
intervention; 
5. Patients with active infection or unexplained fever > 38.5 °C within 2 weeks before 
randomization (patients with tumor-induced fever, as determined by the investigator, 
may be enrolled); 
6. Patients with a known history or evidence of interstitial lung disease or active non-
infectious pneumonitis that has been treated with corticosteroids; 
7. Patients with a BMI less than 18.5 kg/m2 or weight loss of ≥ 10% within 2 months 
before screening (at the same time, the effect of massive pleural effusions and ascites on 
body weight should be considered); 
8. Patients with congenital or acquired immune deficiency (such as HIV infection), active 
hepatitis B (HBV-DNA ≥ 104 copies/mL or 2000 IU/mL), or hepatitis C (positive anti-
HCV antibodies, and HCV RNA titer higher than the lower limit of detection of the 
analytical method); 
9. Previous treatment with other anti-PD-1 antibodies or immunotherapy targeting PD-1/PD-L1; 


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10. Patients with known allergies to macromolecular protein preparations or any 
components of SHR-1210, or allergic reaction, hypersensitivity reaction, or 
contraindications to any components of docetaxel or irinotecan, or their in-preparation 
components; 
11. Patients who require systemic treatment with corticosteroids (prednisone of > 10 mg/day 
or equivalent) or other immunosuppressive medications within 14 days before the 
administration of study drugs. In the absence of active autoimmune disease, inhaled or 
topical use of corticosteroids or an equivalent dose of > 10 mg/day of prednisone for 
adrenal hormone replacement is permitted; 
12. Patients who received anti-tumor treatment with monoclonal antibodies (mAbs), 
chemotherapy, targeted small molecule therapy, or radiotherapy within 4 weeks before 
the first dose of study drugs or with adverse events caused by previously-received 
medications but not recovered (Grade ≤ 1 or baseline reached). Note: Except for patients 
with Grade ≤ 2 neuropathy or Grade ≤ 2 alopecia. If the patient has undergone major 
surgery, toxicities and/or complications resulting from the surgical intervention must be 
fully recovered before the study treatment. 
13. Patients who currently participate in or participated in another clinical study within 4 weeks 
before the first dose of study drugs (for patients in the follow-up period, calculation will 
be carried out using the time of the last use of study drugs or devices); 
14. Patients who inoculated with live vaccine within 4 weeks before the first dose of study 
drugs; injections of inactivated influenza vaccine for seasonal influenza are permitted, 
but not live attenuated influenza vaccines for intranasal use; 
15. Pregnant or lactating women; 
16. Patients with other factors, as determined by the investigator, which may result in study 
termination; for example, other serious medical conditions (including mental illnesses) 
requiring concomitant treatment, serious laboratory abnormalities, family or social 
factors, and other conditions that may affect subjects' safety or collection of study data. 
5.3. 
Rescreening Criteria 
Rescreening is permitted for this study; specifically, subjects who failed the screening and were 
not randomized can be screened again. Test/examination results from the first screening that 
meet the inclusion/exclusion criteria may be reused in the rescreening, provided that they are 
within the window period. A new screening number should be assigned during rescreening. 


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5.4. 
Randomization Criteria  
Only eligible subjects (those who meet inclusion/exclusion criteria) may undergo randomization.  
5.5. 
Withdrawal or Discontinuation 
Subjects may withdraw informed consent at any time for any reason. The investigator may 
decide whether the study treatment should be discontinued for a subject based on the subject's 
clinical manifestations or adverse events. In addition, if the subject is not eligible for enrollment, 
has poor compliance, or is not suitable due to management and/or other safety reasons, the 
investigator or the sponsor may withdraw the subject from the study treatment. 
5.5.1. 
Reasons for withdrawal or discontinuation 
Reasons for treatment discontinuation may include: 
 
Refusal to receive further treatment and/or withdrawal of informed consent; 
 
Objective tumor progression as determined by the investigator using iRECIST and 
RECIST criteria; 
 
Comprehensive deterioration of health status and inability to continue study 
participation; 
 
Intolerable toxicity; 
 
Significant protocol deviations; 
 
Termination of the study by the sponsor; 
 
Pregnancy; 
 
Lost to follow-up; 
 
Death. 
Reasons for withdrawal from study follow-ups may include: 
 
Refusal to receive follow-ups and withdrawal of informed consent; 
 
Study termination by the sponsor; 
 
Lost to follow-up; 
 
Death. 
 


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Note: Withdrawal of informed consent refers to the subject withdrawing the consent to be further 
contacted, or no longer agreeing to provide information from a previously authorized person. 
Whenever possible, subjects should notify the investigator in writing that they no longer agree to 
be followed. The investigator should specify the withdrawal of informed consent in the medical 
records, whether it is to discontinue study treatment, or to discontinue a study procedure and/or 
follow-up after completing the treatment period. Subject's survival status may only be 
determined using publicly available information in accordance with local laws. It should be 
noted that, unlike subjects withdrawing their informed consent, subjects who request a 
discontinuation will be remain in the trial and must be followed according to the specific follow-
up procedures specified in the protocol. 
5.5.2. 
Procedures for withdrawal or discontinuation 
Subjects will undergo efficacy and safety assessments as specified in the protocol at the end-of-
treatment/withdrawal visit as well as the visit 90 days after the last dose. All adverse events 
(AEs) and outcomes will be documented. The investigator may, based on the subject's 
conditions, suggest or provide new or alternative treatments. Subjects ending the treatment due 
to reasons other than PD should be followed for tumor progression, until PD, death, or start of a 
new anti-tumor treatment. 
Survival status should still be followed even when the subject refuses to visit the study center, 
unless the subject withdraws the consent to provide further information or to be further 
contacted. In that case, no further study assessments should be conducted and no further data 
should be collected. The sponsor can retain and continue to use all data collected before 
withdrawal of informed consent, unless the subject requests a retraction of collected data. 
5.6. 
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 SHR-1210 at any time. 
The party who decides to suspend/terminate the study should notify the investigator, the sponsor, 
and regulatory authorities in writing, with the reasons for the suspension/termination 
documented. 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: 
• 
Unexpected, significant, or unacceptable risks being identified; 
• 
Existing efficacy data supporting study termination; 
• 
Poor compliance with study protocol and regulations; 
• 
Inaccurate or incomplete documentation of data; 
• 
Change in the sponsor's development strategy for the investigational drug; 
The study may continue once that issues related to drug safety, protocol compliance, and data 
quality have been resolved and approved by the sponsor, ethics committee, or CFDA. 
6. INVESTIGATIONAL DRUG 
6.1. 
Description of the Investigational Drug and Control Drugs 
6.1.1. 
Access to drugs 
SHR-1210 is manufactured by Suzhou Suncadia Biopharmaceuticals Co., Ltd. Docetaxel and 
irinotecan are provided by Jiangsu Hengrui Pharmaceuticals Co., Ltd.  
6.1.2. 
Dosage form, appearance, packaging, and label 
Investigational drug: SHR-1210 for injection 
Manufacturer: Suzhou Suncadia Biopharmaceuticals Co., Ltd. 
Dosage form: lyophilized powder 
Strength: 200 mg in 20 mL vials 
Batch number: see Certificate of Analysis 
Route of administration: intravenous injection 
Shelf life: 2 years (tentative) from the date of manufacture 
Storage conditions: sealed, away from light, stored at 2-8 °C in medical refrigerator. Do not 
freeze  
Label: For illustrative purposes only; refer to the actual product label 


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Study drug: Docetaxel 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: injection 
Strength: 0.5 mL: 20 mg; 1.5 mL: 60 mg   
Batch number: see package insert 
Method of administration: intravenous infusion 
Shelf life: 24 months (0.5 mL: 20 mg); 18 months (1.5 mL: 60 mg) 
Storage conditions: 2-8 °C, sealed, away from light  
Label: For illustrative purposes only; refer to the actual product label 
A Randomized, Open-Label, Active-Controlled, Multi-Center, Phase III Clinical Study of 
Anti-PD-1 Antibody SHR-1210 vs. Investigator's Choice of Chemotherapy in Subjects with 
Locally Advanced or Metastatic Esophageal Cancer 
For Clinical Study Use Only 
Clinical study approval No.: 2016L01455 
Indication: locally advanced or metastatic esophageal cancer 
Strength: lyophilized powder for injection, 200 mg/vial 
Method of administration: Prepare the solution according to study protocol, for intravenous 
injection only. 
Storage: sealed, away from light, stored at 2-8 °C 
Batch No.: 
Expiry date: DD/MM/20YY 
Manufacturer: Suzhou Suncadia Biopharmaceuticals Co., Ltd. 


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Study drug: Irinotecan 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: injection 
Strength: 40 mg; 100 mg  
Batch number: see package insert 
Method of administration: intravenous infusion 
Shelf life: 24 months 
Storage conditions: away from light, sealed  
Label: For illustrative purposes only; refer to the actual product label 
 
Docetaxel 
 
For Clinical Study Use Only 
 
A Randomized, Open-Label, Active-Controlled, Multi-Center, Phase III Clinical Study of 
Anti-PD-1 Antibody SHR-1210 vs. Investigator's Choice of Chemotherapy in Subjects with 
Locally Advanced or Metastatic Esophageal Cancer 
(Study number: SHR-1210-III-301-ESC) 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining products to the pharmacist 
Irinotecan 
 
For Clinical Study Use Only 
 
A Randomized, Open-Label, Active-Controlled, Multi-Center, Phase III Clinical Study of Anti-
PD-1 Antibody SHR-1210 vs. Investigator's Choice of Chemotherapy in Subjects with Locally 
Advanced or Metastatic Esophageal Cancer 
(Study number: SHR-1210-III-301-ESC) 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining products to the pharmacist 


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6.1.3. 
Storage and stability of drugs 
The investigator or authorized personnel (such as a pharmacist) is responsible for ensuring all 
study drugs are stored in a secure, access-controlled area that meets the storage conditions and 
complies with applicable regulatory requirements. 
Study drugs should be stored under the storage conditions listed in Section 6.1.2. Where the 
protocol differs from other information, SHR-1210 will be stored according to the storage 
conditions listed on the label, and chemotherapies chosen by investigators will be stored 
according to the storage conditions outlined in the corresponding package insert. 
Daily maximum and minimum temperatures of all storage areas (such as freezer, refrigerator, 
and room temperature) must be measured and recorded by the study center. Documentation 
should begin with the receipt of the drugs until the last subject of the study center completes the 
last study treatment. Even if a continuous monitoring system is employed, a written log must be 
kept to ensure a correct record of storage temperature. The temperature monitoring and storage 
devices (such as refrigerator) should be regularly inspected to ensure proper operation. 
Deviations will be reported immediately if the storage conditions are found to deviate from drug 
label or package insert. The study center should actively adopt measures to ensure that the 
corresponding drugs are restored as required and the temperature deviations and measures 
adopted should be reported to the sponsor. 
Study drugs affected by the temperature deviation should be isolated temporarily and may only 
be used after approval by the sponsor and if it is not a protocol deviation. The use of affected 
study drugs without the approval of the sponsor is considered a protocol deviation. The sponsor 
will provide a detailed procedure on reporting temperature deviations to the study center. 
6.1.4. 
Preparation of study drugs 
Drugs used in this study are all administered via intravenous infusions. Therefore, these drugs 
should be prepared by qualified or experienced study staff such as a study nurse. The 
investigational drug SHR-1210 does not contain preservatives, and must be prepared using 
aseptic technique. Refer to the brochure for drug preparation. 
The control drugs used in this study have been approved for marketing. They should be prepared 
according to the package insert. 
 
 


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6.1.5. 
Administration of study drugs 
(1) Investigational drug 
SHR-1210: 200 mg/dose, intravenous infusion over 30 min (no less than 20 min and no more 
than 60 min) on Day 1 of each 2-week cycle. The treatment will continue until the occurrence of 
confirmed PD, intolerable toxicity, voluntary withdrawal by the subject, or treatment 
discontinuation determined by the investigator. 
Day 1 of Cycle 1 can be within 3 days from randomization, as close to the date of randomization 
as possible. For subsequent cycles, the drug may be administered 3 days before or after the 
scheduled Day 1 of the cycle. Administration beyond 3 days after the scheduled dosing day will 
be considered as a dose delay. Subsequent administrations will be based on the actual date of the 
previous dose. All required examinations and evaluations must be completed prior to each dose. 
The interval between two doses must not be less than 12 days. 
Some subjects may have temporary accelerated tumor growth in the first few months after 
starting immunotherapy, followed by response. Therefore, subjects are allowed to continue the 
treatment after the first PD. 
Accelerated tumor growth may include any of the following: 
 
Worsening of existing target lesions; 
 
Worsening of existing non-target lesions; 
 
Appearance of new lesions. 
If a subject develops PD as determined by RECIST v1.1, the investigator may decide whether 
treatment should be continued based on subject's overall clinical status, including performance 
status, clinical symptoms, and laboratory test results. Treatment can be continued when the 
subject is clinically stable, and a tumor assessment should be performed again 4 weeks (± 7  days) 
later. If non-PD is confirmed by both iRECIST and RECIST v1.1, the treatment will be 
continued, and otherwise, the treatment will be discontinued, unless the investigator believes the 
subject may continue benefiting from the study; the sponsor must be consulted to allow a subject 
with confirmed PD to continue the treatment. For subjects who are clinically unstable, treatment 
should be discontinued after the first PD, and a new imaging assessment is not required. 
 
 


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Definition of clinically stable: 
✓ No significant deterioration in subject's performance status, and no significant 
worsening of cancer-related symptoms; 
✓ No rapid disease progression; 
✓ No progressive tumor requiring other urgent medical interventions at important 
anatomical sites (e.g., spinal cord compression); 
In repeated imaging assessment, PD can be confirmed by the criteria listed below. 
 
Conditions for Confirming PD 
(Any of the following conditions) 
Conditions Unable to Confirm PD 
(Meet all of the following conditions) 
Target 
Lesion 
The absolute value of tumor load increases 
by ≥ 5 mm compared to the first episode of 
progressive disease. 
The absolute value of tumor load increases by < 5 mm 
compared to the first episode of progressive disease. 
Non-Target 
Lesion 
Compared to the first episode of PD, 
Non-target lesions shows clear and 
continued progression (qualitative). 
Compared to the first episode of PD, there is no clear 
progression (qualitative). 
New 
Lesion 
(1) A new lesion occurs compared to the 
first episode of PD; 
(2) A new lesion that has appeared before 
increases in size or other new lesion 
occurs. 
(1) Compared to the first episode of PD, no other 
new lesion occurs; 
(2) A new lesion that has appeared before is stable 
or diseases in size. 
For subjects who receive the first PD evaluation, the date of the initial progression that is 
assessed by the investigator will be used in all progression-involved statistical analyses, 
regardless of post-progression treatment/discontinuation. 
(2) Control drugs 
Investigator's choice of chemotherapy (prior chemotherapy should not be chosen). Subjects who 
once received docetaxel or irinotecan at the beginning of treatment must not switch to the other 
chemotherapy. 
Docetaxel: 75 mg/m2, intravenous infusion over approximately 1 h (drip rate may be adjusted 
accordingly) on Day 1 of each 3-week cycle. The treatment will continue until PD, intolerable 
toxicity, voluntary withdrawal by the subject, or treatment discontinuation determined by the 
investigator. Premedications should be given according to the clinical practice of the study center 
before treatment. 
 


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Day 1 of Cycle 1 can be within 3 days from randomization, and the premedication should be as 
close to the date of randomization as possible. The time window is 3 days for subsequent cycles. 
Administration beyond 3 days after the scheduled dosing day will be considered as a dose delay. 
Subsequent administrations will be based on the actual date of the previous dose. All required 
examinations and evaluations must be completed prior to each dose. 
Irinotecan: 180 mg/m2, the starting dose may being adjusted based on the results of the 
UGT1A1*28 assay. Intravenous infusion over approximately 1 h (drip rate may be adjusted 
accordingly) on Day 1 of each 2-week cycle. The treatment will continue until PD, intolerable 
toxicity, voluntary withdrawal by the subject, or treatment discontinuation determined by the 
investigator. Premedications should be given according to the clinical practice of the study center 
before treatment. 
Day 1 of Cycle 1 can be within 3 days from randomization, and the premedication should be as 
close to the date of randomization as possible. The time window is 3 days for subsequent cycles. 
Administration beyond 3 days after the scheduled dosing day will be considered as a dose delay. 
Subsequent administrations will be based on the actual date of the previous dose. All required 
examinations and evaluations must be completed prior to each dose. 
6.1.6. 
Route of Administration 
SHR-1210 and the control drugs docetaxel and irinotecan are all administered via intravenous 
infusion. 
6.1.7. 
Dose modifications and delay 
6.1.7.1. Dose modification 
(I) Dose modifications for SHR-1210 
Adverse events related to SHR-1210 may be immune-related (irAEs), and may develop shortly 
after the first dose or months after the last dose. SHR-1210 should be suspended when events 
listed in Table 5 occur. During the study, the investigator must consult with the sponsor when, 
based on the benefit to risk ratio of subjects, SHR-1210 should not be interrupted or continued 
according to recommendations found in Table 5 or when the situation is not listed. 
 
 


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Table 5. SHR-1210 dose modifications 
Treatment-Related 
Immune-Related Adverse 
Events (irAEs) 
Severity Grades for 
Treatment Interruption 
Resumption 
Discontinuation 
Diarrhea/Colitis 
2-3 
Recovery to Grade 0-1 
and corticosteroids 
reduction to ≤ 10 mg of 
prednisone or equivalent. 
Do not resolve within 
12 weeks from the last 
dose, or the dose of 
corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent 
within 12 weeks. 
4 
Discontinuation 
Discontinuation 
AST, ALT, or bilirubin 
increased 
2 
Recovery to Grade 0-1 
and corticosteroids 
reduction to ≤ 10 mg of 
prednisone or equivalent. 
Do not resolve within  
12 weeks from the last 
dose. 
3-4 
Discontinuation 
Discontinuation 
Hyperthyroidism 
3 
Recovery to Grade 0-1 
and corticosteroids 
reduction to ≤ 10 mg of 
prednisone or equivalent. 
Do not resolve within 
12 weeks from the last 
dose, or the dose of 
corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent 
within 12 weeks. 
4 
Discontinuation 
Discontinuation 
Hypothyroidism 
 
Treatment can be 
continued after starting 
thyroxine replacement 
therapy 
Treatment can be 
continued after starting 
thyroxine replacement 
therapy 
Pneumonia 
2 
Recovery to Grade 0-1 
and corticosteroids 
reduction to ≤ 10 mg of 
prednisone or equivalent. 
Do not resolve within 
12 weeks from the last 
dose, or the dose of 
corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent 
within 12 weeks. 
3-4 
Discontinuation 
Discontinuation 
Immune-Related 
Hypophysitis 
2-3 
Recovered to Grade 0-1; 
SHR-1210 treatment can 
be resumed after starting 
hormone replacement 
therapy 
Do not resolve within 
12 weeks from the last 
dose, or the dose of 
corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent 
within 12 weeks. 
4 
Discontinuation 
Discontinuation 


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Treatment-Related 
Immune-Related Adverse 
Events (irAEs) 
Severity Grades for 
Treatment Interruption 
Resumption 
Discontinuation 
Type I Diabetes Mellitus 
(New Onset) or 
Hyperglycemia 
New-onset type I diabetes 
mellitus or Grade 3-4 
hyperglycemia 
accompanied with 
evidence of β-cell 
depletion 
After clinical and 
metabolic conditions are 
stabilized 
Continue SHR-1210 
treatment. 
Renal Failure or Nephritis 
2 
Recovery to Grade 0-1 
and corticosteroids 
reduction to ≤ 10 mg of 
prednisone or equivalent. 
Do not resolve within 
12 weeks from the last 
dose, or the dose of 
corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent 
within 12 weeks. 
3-4 
Discontinuation 
Discontinuation 
Infusion Reaction 
2 
Symptoms disappear 
Re-administer at 50% of 
the initial rate after 
symptoms resolve. If no 
reaction occurs within 
30 min, restore the 
original infusion rate 
(100%). Closely monitor. 
If the symptoms recur, the 
administration of the 
current SHR-1210 dose 
will be discontinued. 
3-4 
Discontinuation 
Discontinuation 
Other Treatment-Related 
Adverse Events 
3 
Recovery to Grade 0-1 
and corticosteroids 
reduction to ≤ 10 mg of 
prednisone or equivalent. 
Do not resolve within 
12 weeks from the last 
dose, or the dose of 
corticosteroids cannot be 
reduced to ≤ 10 mg of 
prednisone or equivalent 
within 12 weeks. 
4 
Discontinuation 
Discontinuation 
Note: Treatment should be discontinued if any Grade 3 treatment-related AE recurs or any life-threatening event 
occurs. 
For subjects with metastasis to liver and grade 2 AST or ALT increased at baseline, the treatment 
should be terminated when a ≥ 50% increase in AST or ALT from baseline persists for at least 
1 week. 
The investigator may consider interrupting SHR-1210 in subjects who develop intolerable or 
persistent grade 2 treatment-related AEs. 


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The treatment should be terminated when a persistent grade 2 adverse drug reaction does not 
resolve to grade 0-1 within 12 weeks after the last dose. 
(II) Dose modifications for docetaxel and irinotecan 
The investigator will determine the criteria for the dose modifications of docetaxel and irinotecan 
as well as their treatment/resumption according to clinical practices. This section is used for the 
reference of investigators. 
The starting dose for docetaxel is 75 mg/m2, which may be reduced to 60 mg/m2 based on 
toxicities (refer to Table 6). The dose cannot be increased after being reduced. Treatment should 
be terminated for subjects who cannot tolerate the reduced dose. The treatment should be 
terminated for subjects who develop ≥ grade 3 or greater peripheral neuropathy or severe 
hypersensitivity reactions. 
Table 6. Docetaxel dose modifications 
Adverse Event 
Resumption 
Febrile neutropenia 
Reduce dose after recovery 
Grade 4 neutropenia persisting more than 1 week 
Reduce dose after return to Grade ≤ 1 
Severe or accumulated skin reactions 
Reduce dose after return to Grade ≤ 1 
Grade 3-4 non-hematological toxicities 
Reduce dose after return to Grade ≤ 1 
Table 7. Criteria for docetaxel treatment/resumption 
Laboratory Tests 
Criteria for Treatment 
Absolute Neutrophil Count 
> 1500/mm3 (1.5 × 10 9/L) 
Blood Bilirubin 
Normal or return to the baseline level 
AST, ALT, and AKP 
ALT and/or AST ≤ 1.5 × ULN and AKP ≤ 2.5 × ULN 
The starting dose for irinotecan is 180 mg/m2, which may be reduced by 25% based on toxicities 
(refer to Table 8). The dose cannot be increased after being reduced. Treatment should be 
terminated for subjects who still cannot tolerate the drug after dose reductions twice. 
Table 8. Irinotecan dose modifications 
Adverse Event 
Resumption 
Febrile Neutropenia 
Reduce dose after recovery 
Grade 3/4 Neutropenia, Leukopenia, 
Thrombocytopenia, and Anemia 
Reduce dose after return to Grade ≤ 1 
Grade 3/4 Diarrhea 
Reduce dose after recovery 
Grade ≥ 2 Non-Hematological Toxicity 
Reduce dose after return to Grade ≤ 1 


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Table 9. Criteria for irinotecan treatment/resumption 
Laboratory Tests and Clinical Manifestations 
Criteria for Treatment 
Absolute Neutrophil Count 
≥ 1500/mm3 (1.5 × 10 9/L) 
Platelet Count 
≥ 100 × 109/L 
Diarrhea 
Complete recovery 
6.2. 
Drug Management, Dispensation and Return 
Designated personnel are responsible for the management, dispensation, and retrieval of study 
drugs. The investigator must ensure that all study drugs are used by enrolled subjects only and 
the dose and route of administration comply with Section 6.1.5. Remaining or expired drugs 
should be returned to the sponsor and may not be used for non-participants. 
When drugs transport to the study center, a drug receipt form should be signed by both parties, 
one copy for the study center and the other for the sponsor. When returning remaining drugs and 
empty packaging, both parties must sign the drug retrieval form. The dispensation and return of 
every drug should be immediately documented on designated forms. 
The CRA is responsible for monitoring the supply, use, and storage of study drugs, and disposal 
of remaining medications. 
6.2.1. 
Disposal of study drugs 
The sponsor or authorized personnel is responsible for disposing the study drugs. Drug disposal 
should be well documented. 
7. STUDY PROCEDURES 
7.1. 
Study Procedures/Assessments 
7.1.1. 
Screening 
The screening period is the time from the signing of the informed consent form until start of 
study treatment or screen failure. Subjects must sign the informed consent form before 
undergoing screening procedures for this study. Data from laboratory tests and imaging 
evaluation performed prior to informed consent for routine clinical practice may be used if they 
are within the specified window period. 
Unless otherwise stated, the following screening procedures should be completed within 28 days 
prior to the start of the study treatment. 


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 
Signing the informed consent form; 
 
Collecting demographics: gender, date of birth, ethnicity, height, and weight. 
 
Tumor diagnosis: site of primary tumor, the date of pathological diagnosis, pathological 
staging, and the location of the metastatic lesion. 
 
History of cancer treatment 
✓ History of tumor surgery: name of surgery, date of surgery, postoperative TNM 
staging, and date of postoperative recurrence; 
✓ History of radiotherapy: site, dose, and start and end dates. 
✓ History of neoadjuvant chemotherapy: chemotherapy regimen, cycles, and start and 
end dates; 
✓ History of adjuvant chemotherapy: chemotherapy regimen, cycles, and start and end 
dates; 
✓ Rescue therapy: regimen, cycles, start and end dates, best overall response, reasons 
for changes in treatment; 
✓ History of concurrent disease, past medications, and medication allergies; 
✓ Serology (completed within 14 days before the first dose): HBsAg (if positive, 
HBV-DNA test required), HBsAb, HBeAg, HBeAb, HBcAb, HCV-Ab (if positive, 
HCV-RNA test required), and HIV-Ab; 
✓ Fresh (preferred) or archival tumor tissue specimens; 
The following screening procedures should be completed within 7 days before the start of study 
treatment. A pregnancy test should be completed within 72 h before the start of study treatment. 
✓ ECOG PS; 
✓ Vital signs: heart rate, respiratory rate, body temperature, and blood pressure; 
✓ Comprehensive physical examination: general condition, head and face, skin, 
lymph nodes, eyes, ears, nose and throat, mouth, respiratory system, cardiovascular 
system, abdomen, reproductive and urinary system, musculoskeletal system, 
nervous system, mental state, and others; 
✓ Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, 
and lymphocyte count; 


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✓ Urinalysis: WBC, RBC, and urine protein In the case of urine protein ≥ 2+, a 24-h 
urine protein test (quantitative) must be added; 
✓ Fecal occult blood; 
✓ Clinical chemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, blood 
urea nitrogen (preferred) or urea, total protein, albumin, creatinine, blood glucose, 
lactate dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-; 
✓ Thyroid function: TSH, FT3, and FT4; 
✓ Coagulation function: APTT, PT, FIB, INR; 
✓ Echocardiography: including LVEF assessment. Perform when clinically indicated. 
✓ 12-Lead ECG: additional necessary investigations required when an abnormality is 
seen as determined by the investigator; 
✓ Pregnancy test (for women of childbearing potential); 
✓ Imaging assessment: CT or MRI of neck, chest, and abdomen (including pelvic cavity). 
Brain MRI is required when brain metastasis is suspected and confirmed (if MRI is 
contraindicated, CT can be used instead). Bone scan is performed only when 
clinically indicated and must be performed within 42 days before the first dose. 
At screening, tumor evaluations up to 4 weeks before randomization and before 
informed consent may be used as long as they meet relevant criteria. 
✓ Adverse events: Documented from the signing of ICF. 
✓ Concomitant medications: Concomitant medications within 30 days before the first 
dose will be collected; 
7.1.2. 
Treatment period/follow-up visits 
The treatment period starts from subject randomization. The first administration should be 
completed within 3 days after randomization. 
⚫ All examinations and assessments (except quality of life score and tumor imaging 
assessment) should be completed within 3 days before administration. The following 
items should be examined/assessed before the administration in each cycle; items are 
not required for examination/assessment in the first cycle when they have been 
examined/assessed at screening within 7 days before the first administration. 


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✓ ECOG PS; 
✓ Vital signs: heart rate, respiratory rate, body temperature, and blood pressure; 
✓ Targeted physical examination: required when clinically indicated; 
✓ Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, 
and lymphocyte count; 
✓ Clinical chemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, blood 
urea nitrogen (preferred) or urea, total protein, albumin, creatinine, blood glucose, 
lactate dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-; 
✓ ECG; 
✓ Adverse events: document AEs in detail; 
✓ Concomitant medications: concomitant medications will be documented; 
⚫ The following investigations should be completed every 2 cycles before administration: 
✓ Urinalysis: WBC, RBC, and urine protein In the case of urine protein ≥ 2+, a 24-h 
urine protein test (quantitative) must be added; 
✓ Fecal occult blood (SHR-1210 group: before or after administration; control group: 
when clinically indicated); 
✓ Thyroid function: TSH, FT3, and FT4; 
⚫ Quality of life score (EORTC QLQ-C30 and EORTC QLQ-OES18): It should be 
obtained once every 8 weeks, with a time window of ± 7 days, and it is recommended to 
be obtained before administration and AE and tumor assessments. 
⚫ Imaging assessment: Lesions found at baseline should be assessed every 8 weeks, or 
when new lesions are suspected. For lesions of bone metastases, bone scans are only 
required when the assessment result of other lesions is CR and it is necessary to confirm 
the presence of lesions of bone metastases or when clinically indicated. For subjects 
ending the treatment for any reason, a tumor imaging assessment should be performed at 
the time of withdrawal when an assessment has not been carried out within 4 weeks 
before ending treatment. Imaging conditions should be the same as those at baseline 
(including slice thickness and contrast agent). The time window for imaging examination 
is ± 7  days. Unscheduled imaging examination may be performed if PD is suspected (for 
example, worsening of symptoms). Time of imaging evaluation will not be adjusted due 
to dose delays. 


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Subjects in the SHR-1210 group who are clinically stable should have a confirmation 
scan 4 weeks (± 7 days) after the first occurrence of PD based on iRECIST and RECIST 
v1.1. The subsequent tumor assessment will be performed at the pre-specified time 
point. 
⚫ Blood sampling for immunogenicity and drug trough concentration (treatment group 
only): within 30 min before the first, second, third, fifth, and seventh doses and within 
30 min before every four doses thereafter. 
⚫ Biomarker blood sampling (investigational treatment group only): before the first dose, 
at the occurrence of first tumor response, and at the presence of progressive disease. 
7.1.3. 
End of Treatment/Withdrawal Visit 
If relevant assessments and examinations have not been performed within 7 days before the 
subject s withdraw from the study, the following procedures should be followed: 
✓ ECOG PS; 
✓ Vital signs: heart rate, respiratory rate, body temperature, and blood pressure; 
✓ Comprehensive physical examination: general condition, head and face, skin, 
lymph nodes, eyes, ears, nose and throat, mouth, respiratory system, cardiovascular 
system, abdomen, reproductive and urinary system, musculoskeletal system, 
nervous system, mental state, and others; 
✓ Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, 
and lymphocyte count; 
✓ Urinalysis: WBC, RBC, and urine protein (in case of urine protein ≥ 2+, an 
additional 24-h urine protein test (quantitative) is required); clinical chemistry: 
ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, BUN or urea (BUN 
preferred), total protein, albumin, creatinine, blood glucose, lactate dehydrogenase, 
K+, Na+, Ca2+, Mg2+, and Cl-; 
✓ Thyroid function: TSH, FT3, and FT4; 
✓ ECG; 
✓ Quality of life score; 


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✓ Imaging assessment: An imaging assessment should be performed at the end of 
treatment/upon withdrawal when it has not been done within 4 weeks before 
withdrawal. Subjects who discontinue treatment for reasons other than imaging-
confirmed PD must also undergo a tumor assessment every 8 weeks until 
documentation of confirmed PD, start of a new anti-cancer treatment, or death. 
✓ Adverse events: document AEs in detail; 
✓ Concomitant medications: concomitant medications will be documented; 
7.1.4. 
Follow-up visit 90 days after the last dose 
Subjects should return to the study center for a follow-up visit 30 days after the last treatment. 
Safety information will be obtained via telephone follow-up visits on 60 days and 90 days after 
the last treatment (including AE outcome, newly-occurred SAE, and AESI). In addition, patients 
from the treatment group will be asked to go back to the study center to collect their 
immunogenicity and drug trough concentration blood samples whenever possible. 
When a subject starts a new anti-cancer treatment within 30 days after the last treatment, the visit 
should be completed before the new treatment is started. 
✓ Hematology: RBC count, hemoglobin, platelet count, WBC count, neutrophil count, 
and lymphocyte count; 
✓ Clinical chemistry: ALT, AST, GGT, total bilirubin, direct bilirubin, AKP, blood 
urea nitrogen (preferred) or urea, total protein, albumin, creatinine, blood glucose, 
lactate dehydrogenase, K+, Na+, Ca2+, Mg2+, and Cl-; 
✓ Thyroid function: TSH, FT3, and FT4; 
✓ Blood sampling for immunogenicity and drug trough concentration (investigational 
treatment group only): at visits carried out on Day 30, Day 60 (optional), and Day 
90 (optional) after the last treatment. 
✓ Quality of life score; 
✓ Adverse events: document AEs in detail; 
✓ Concomitant medications: Concomitant medications within 90 days after the last 
treatment will be collected. Only concomitant medications for treatment-related 
AEs will be collected 30 days after the last treatment.  


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7.1.5. 
Unscheduled Visit 
The following items should be documented at unscheduled visits for subjects developing AEs 
during the trial: 
✓ Concomitant medications; 
✓ Adverse events; 
✓ All relevant examinations (including imaging evaluations, if any). 
7.1.6. 
Survival follow-up 
Survival follow-up visits will be conducted once a month after the last treatment via effective 
methods such as telephone. It is necessary to record whether the subjects have subsequently 
received new anti-cancer treatment. When there is any new anti-cancer treatment, record the 
treatment regimen and start/end time of the treatment while completing the survival follow-up 
visit records. 
For subjects ending the treatment due to "non-PD" (such as intolerable AEs) reasons, it is 
recommended to conduct tumor progression follow-up visit in the frequency identical to that for 
response evaluation (every 8 weeks ± 7 days) until PD, death, or start of a new anti-cancer 
treatment. Follow-up information should be documented in eCRF. 
7.2. 
Concomitant Treatment 
Prohibited medications and vaccines specifically found in the exclusion criteria are prohibited 
during the entire course of the study. If the subject develops a concurrent condition that requires 
the use of a prohibited drug, then study treatment may need to be stopped or the prohibited 
medication may need to be accepted. In this case, the investigator should consult with the 
sponsor. Whether the subject will continue the study treatment or accept a prohibited medication 
is ultimately decided together by the investigator, the sponsor, and the subject. 
7.2.1. 
Permitted concomitant medications 
Topical use of corticosteroids such as ophthalmic, nasal, intra-articular, and inhaled is permitted 
(only for the treatment group; pre-treatment with corticosteroids is permitted for the control group). 
Subjects should be given optimal supportive care during the treatment. The use of existing 
hormone replacement therapy and bisphosphonates for bone metastases are permitted. 


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Palliative treatment of local lesions that may cause significant symptoms is permitted. For 
example, local radiotherapy or surgery may be considered for bone lesions that cause pain. 
However, the following criteria must all be met. It is recommended to consult with the sponsor 
prior to starting palliative treatment. 
1. The investigator must assess whether there is PD in subjects who require local treatment 
due to symptom exacerbations during the study; 
2. Subjects with PD must meet the criteria for continuation of treatment beyond 
progression; 
3. The locally treated lesions cannot be the target lesions. 
All concomitant medications should be documented in the eCRF. Concomitant medications from 
30 days before the first dose to 90 days after the last dose will be documented; only concomitant 
medications for treatment-related AEs will be documented from 30 days after the end of treatment.  
7.2.2. 
Prohibited concomitant medications 
 
Anti-tumor systemic chemotherapy and biological therapy; 
 
Modern TCM preparations approved by CFDA (now NMPA) for anti-cancer treatment 
(refer to Appendix III); 
 
Immunotherapy not specified in the protocol; 
 
Chemotherapy not specified in the protocol; 
 
Immunomodulators with auxiliary anti-tumor effects, such as thymosin, lentinan, 
interleukin-12, etc. 
 
Inoculation of live vaccines within 4 weeks before the first dose and during the study. 
Live vaccines include, but not limited to, rubeola, epidemic parotitis, rubella, chicken 
pox, yellow fever, rabies, BCG, and typhoid. Injections of inactivated influenza vaccine 
for seasonal influenza are permitted, but not live attenuated influenza vaccines for 
intranasal use; 
 
Applicable to the investigational treatment group only: Physiological doses of systemic 
corticosteroids for purposes other than the relief of symptoms due to immunological 
causes may, after the consultation with the sponsor, be approved (inhaled steroids are 
permitted as a part of fixed treatment for asthma or chronic obstructive pulmonary 
disease). Corticosteroids may be used prophylactically to prevent allergic reactions 
(such as intravenous contrast agent); 


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 
Subjects receiving docetaxel should avoid strong CYP3A4 inhibitors. If it cannot be 
avoided, the dose of docetaxel should be reduced according to the package insert; 
 
Refer to the package insert for other prohibited medications in terms of investigator's 
choice of chemotherapy. 
7.2.3. 
Supportive care 
(I) Guidance for SHR-1210 supportive care 
Subjects should receive appropriate supportive treatment measures deemed necessary by the 
investigator. Supportive treatment measures for managing immune-related adverse events (irAE) 
are listed below, including oral or intravenous corticosteroids and other anti-inflammatory 
medications when symptoms are not relieved after the use of corticosteroids. Corticosteroids 
may need to be tapered over several cycles since symptoms may worsen during dose reduction. 
Other reasons requiring other supportive treatments, such as metastatic disease or bacterial or 
viral infections, should be ruled out where possible. When the investigator is sure that the AE is 
related to SHR-1210, the supportive treatments listed below may be followed. Otherwise, the 
supportive treatments listed below are not required. 
1. Hemangioma of skin 
Subjects with skin hemangioma should undergo biopsy and pathological examination whenever 
possible. Endoscopic and MRI examinations are recommended for subjects with relatively severe 
or long-lasting skin hemangioma to confirm the involvement of internal organs and/or mucosa. 
2. Diarrhea/Colitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, hematochezia or mucus stools, with or without pyrexia) and intestinal 
perforations (such as peritonitis and intestinal obstruction). 
 
Subjects with diarrhea/colitis should drink an adequate amount of fluids. Fluids and 
electrolytes should be administered intravenously if adequate oral intake is not possible. 
GI consultation and endoscopy should be considered to confirm or rule out colitis for 
subjects with grade 2 or greater diarrhea. 
 
Oral corticosteroids should be prescribed for grade 2 diarrhea/colitis. 
 
Subjects with grade 3 or 4 diarrhea/colitis should be treated with intravenous 
corticosteroids followed by oral high-dose corticosteroids. 
 
Corticosteroids should begin to taper after symptoms improve to grade 1 or lower. Taper 
will last for no less than 4 weeks. 


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3. AST, ALT, or bilirubin increased 
 
Subjects should receive intravenous or oral corticosteroids for grade 2 events. Liver 
function should be monitored with an increased frequency until it/they recover(s) to 
baseline (testing once per week considered). 
 
Corticosteroids via intravenous route for 24-48 h should be given for Grade 3-4 events. 
 
Corticosteroids should begin to taper after symptoms improve to grade 1 or lower. Taper 
will last for no less than 4 weeks. 
4. Hyperthyroidism/hypothyroidism 
Thyroid disorder may occur at any time during the course of the treatment period. Monitor 
changes in subjects' thyroid function (when starting treatment, regularly during the treatment 
period) as well as clinical signs and symptoms of thyroid disease. 
 
For subjects with Grade 2 hyperthyroidism, it is recommended to use non-selective 
beta-blockers (such as propranolol) as initial treatment. 
 
Subjects with Grade 3-4 hyperthyroidism should receive intravenous corticosteroids 
followed by oral corticosteroids. Corticosteroids should begin to taper after symptoms 
improve to grade 1 or lower. Taper will last for no less than 4 weeks. During the 
tapering process, appropriate hormone replacement therapy may be required. 
 
Thyroid hormone replacement therapy may be considered for Grade 2-4 hypothyroidism 
(such as levothyroxine). 
5. Pneumonia 
 
Subjects with Grade 2 pneumonia should receive systemic corticosteroids. 
Corticosteroids should begin to taper after symptoms improve to Grade 1 or lower. 
Taper will last for no less than 4 weeks. 
 
If chronic use of corticosteroids is acceptable, antibiotic prophylaxis should be used. 
6. Immune-related hypophysitis 
 
Persistent corticosteroid treatment should be used for Grade 2 hypophysitis. 
Corticosteroids should begin to taper after symptoms improve to Grade 1 or lower. 
Taper will last for no less than 4 weeks. During the tapering process, appropriate 
hormone replacement therapy may be required. 


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 
Subjects with Grade 3 or 4 hypophysitis should receive intravenous corticosteroids 
followed by oral corticosteroids. Corticosteroids should begin to taper after symptoms 
improve to Grade 1 or lower. Taper will last for no less than 4 weeks. During the 
tapering process, appropriate hormone replacement therapy may be required. 
7. Type I diabetes mellitus 
Insulin replacement therapy is recommended for T1DM and Grade 3-4 hyperglycemia 
accompanied by metabolic acidosis or ketonuria. Then, subjects' blood glucose, and full 
metabolic panel, urinary ketones, HbA1C, and C-peptide should be evaluated. 
8. Renal failure or nephritis 
 
Subjects with Grade 2 events should receive corticosteroids. 
 
Subjects with Grade 3-4 events should receive systemic corticosteroids. 
 
Corticosteroids should begin to taper after symptoms improve to Grade 1 or lower. 
Taper will last for no less than 4 weeks. 
9. Infusion reactions 
CTCAE Grade 
Clinical Symptoms 
Clinical Management 
SHR-1210 Treatment 
Grade 1 
Mild and transient 
reactions 
Bedside observation and close 
monitoring until recovery. 
Pre-administration prophylactics are 
recommended for subsequent 
infusions: 50 mg of diphenhydramine 
or equivalent and/or 325-1000 mg of 
acetaminophen at least 30 min before 
SHR-1210 being given. 
Continue  
Grade 2 
Moderate reactions 
requiring treatment or 
interruption; rapidly 
resolve after 
symptomatic treatment 
(such as antihistamines, 
non-steroidal 
antiphlogistics, 
anesthetics, 
bronchodilators, 
intravenous fluids, etc.) 
Intravenous infusion of normal saline, 
IV of 50 mg of diphenhydramine or 
equivalent and/or 325-1000 mg of 
acetaminophen; 
Bedside observation and close 
monitoring until recovery. 
Corticosteroids or bronchodilators can 
be considered based on clinical needs; 
The amount of study drug infused should 
be recorded in the original medical record; 
Pre-administration prophylactics are 
recommended for subsequent 
infusions: 50 mg of diphenhydramine 
or equivalent and/or 325-1000 mg of 
acetaminophen at least 30 min before 
SHR-1210 is given. Corticosteroids 
(equivalent to 25 mg of hydrocortisone) 
should be used when necessary. 
Interrupt. Re-administer at 
50% of the initial rate after 
symptoms resolve. If no 
reaction occurs within 30 min, 
restore the original infusion 
rate (100%). Closely 
monitor. If the symptoms 
recur, the administration of 
the current SHR-1210 dose 
will be discontinued. 


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CTCAE Grade 
Clinical Symptoms 
Clinical Management 
SHR-1210 Treatment 
Grade ≥ 3 
Grade 3: Severe 
reaction without rapid 
recovery with 
treatment and/or 
interruption; or 
symptoms recur after 
alleviation; or the 
subject develops 
sequelae that requires 
hospitalization. 
Grade 4: life-
threatening 
Immediately discontinue SHR-1210; 
Administer normal saline by 
intravenous infusion. 
• Bronchodilators are recommended: 
subcutaneous injection of 0.2-1 mg 
of 1:1000 adrenaline solution or 
slow intravenous infusion of  
0.1-0.25 mg of 1:10,000 adrenaline 
solution, and/or 50 mg of 
diphenhydramine + 100 mg of 
methylprednisolone or equivalent 
by intravenous injection when 
necessary; 
• Based on the guidelines for 
anaphylaxis of the study center; 
Bedside observation and close 
monitoring until recovery. 
Discontinuation 
8. IMMUNOGENICITY STUDY 
8.1. 
Immunogenicity and Drug Trough Concentration Blood Sampling and Processing 
8.1.1. 
Blood sampling timepoints 
Within 30 min before the first, second, third, fifth, and seventh doses, within 30 min before every 
four doses thereafter, and at visits carried out on Day 30 (when a new anti-cancer treatment is 
started, the blood samples will be collected before the new treatment), Day 60 (optional), and 
Day 90 (optional) after the last treatment. 
8.1.2. 
Processing and storage of blood samples 
At each of the above time points, 4-6 mL of venous blood samples will be collected into serum 
separation tubes to collect the serum, which will be then transferred to 4 cryotubes (aliquoted 
equally into 3 test tubes, 1 for ADA, 1 for drug trough concentration, and 1 for antibody 
neutralizing activity, and 1 backup tube). The cryotubes will be stored in a low temperature 
freezer at ≤ -60 °C until they are transported to the central laboratory for test. Please ref er to the 
Laboratory Manual for specific operation details. 
8.1.3. 
Shipping of clinical samples 
The samples in test tubes should be sent out first in dry ice storage state. The samples in the 
backup tubes will be sent out after the bioanalytical laboratory confirms the receipt of the test 
tube samples. Details of shipping frequency and other shipping information are described in the 
Laboratory Manual. 


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9. BIOMARKER BLOOD SAMPLING 
Before the first administration, at the occurrence of the first tumor response, and at the presence 
of progressive disease, one 4-mL tube of whole blood should be collected at each time point. 
Refer to the Biomarker Blood Sampling SOP for specific procedures.  
10. SAFETY EVALUATION 
10.1. 
Safety Parameters 
Safety parameters for this study include vital signs, physical examination, laboratory test 
(hematology, urinalysis, clinical chemistry, fecal occult blood, thyroid function, and coagulation 
function), 12-Lead ECG, pregnancy test, and clinical symptoms. 
10.1.1. Definition of adverse event 
An adverse event refers to any untoward medical condition in a subject who has received a 
pharmaceutical product in a clinical trial. An AE is not necessarily related to the treatment that 
the subject receives. AEs should be documented starting from signing of the informed consent 
form to 90 days after the last administration of study drugs. From 30 days after the end of 
treatment, only treatment-related AEs will be collected. An AE may be any untoward and 
unexpected symptom, vital sign, laboratory test abnormality, or disease. AEs include the 
following: 
1) Worsening of pre-existing (before enrollment) medical conditions/diseases (including 
symptoms, vital signs, and laboratory test abnormalities); 
2) Any new adverse medical conditions (including symptoms, vital signs, and newly diagnosed 
diseases); 
3) Clinically significant abnormal laboratory findings. 
Any AEs should be recorded in detail, including name of AE and description of all relevant 
symptoms, time of occurrence, severity, correlation with study drugs, duration, measures taken, 
and final results and outcomes. 
10.1.2. Definition of serious adverse event 
A serious adverse event (SAE) refers to a medical occurrence during the clinical study that 
results in hospitalization, prolonged hospitalization, disability, incapacity, life-threatening or 
death, or congenital malformation. The following unexpected medical events are included: 


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 
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). 
AEs that lead to hospitalization or prolonged hospitalization during 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 
 
Day surgery (e.g., outpatient/same-day/ambulatory surgery) 
 
Hospitalization or prolonged hospitalization unrelated to the worsening of an AE is not 
an SAE. For example: 
 
Hospitalization due to the pre-existing disease without new AEs and aggravation of the 
pre-existing disease (e.g., hospitalization to examine laboratory abnormalities that have 
persisted before the study until now); 
 
Hospitalization for management reasons (e.g., annual physical examination); 
 
Hospitalization during the study as specified in the study protocol (e.g., as required by 
the protocol); 
 
Elective hospitalization unrelated to worsening of AEs (e.g., elective surgery); 
 
Scheduled treatment or surgery that should be documented throughout the entire study 
protocol and/or in the subjects' individual baseline information; 
 
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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. 
10.1.3. Progressive disease 
Disease progression is defined as the worsening of clinical signs/symptoms of the target disease, 
appearance of a new metastatic lesion, or progression of existing lesions. Death, life-threatening 
event, hospitalization or prolonged hospitalization, permanent or severe 
disability/incapacity/impairment of working ability, congenital anomaly or birth defect resulting 
from vital signs and symptoms of progressive disease should not be reported as an SAE. 
10.1.4. Definition of unexpected safety events 
Unexpected safety events are events or outcomes that meet the following criteria: 
SHR-1210 Investigator's Brochure and package inserts of docetaxel/irinotecan are used as 
references for predictive assessments of AEs. An event is considered unexpected when the 
nature, specificity, severity, or result of the event is not consistent with the description found in 
the Brochure and (or) package inserts. 
10.2. 
Adverse Event Classification 
10.2.1. Criteria for the severity of adverse events 
The severity of AE is determined by NCI-CTCAE (v4.03). 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, etc. 
3 
Severe or medically significant symptoms but not immediately life-threatening; hospitalization or 
prolongation of 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 
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10.2.2. Criteria for the causality between AEs and investigational drug 
AEs include all unexpected clinical manifestations. All the AEs occurring after the signing of the 
ICF must be reported as an AE, regardless of whether the AEs are related to the study drugs, 
whether the subject is allocated to the investigational drug group, and whether the subject has 
been administered with the drug. Any discomforts complained by the subject or abnormal 
changes in laboratory tests during the treatment should be truthfully documented, noting event 
severity, duration, measures taken, and outcome. The clinical physician should comprehensively 
determine the relationship between event and study drugs and provide a causality assessment 
using the following five categories "definitely related, possibly related, unlikely related, not 
related, and indeterminable". "Definitely related, possibly related, and indeterminable" events are 
included as adverse drug reactions. The incidence of adverse drug reactions is calculated with 
events of these three categories as numerator and number of subjects used for safety evaluation 
as denominator. 
Table 10. Criteria for causality between adverse events and study drugs. 
Grade 
Criteria 
Definitely 
Related 
An AE occurs in a plausible time relationship to drug administration. The event is a 
recognized pharmacological phenomenon of the suspected drug, or the event resolves with 
drug discontinuation and recurs with drug readministration. 
Possibly Related 
The AE occurs in a plausible time relationship to drug administration. The event is not a 
recognized pharmacological phenomenon of the suspected drug. It can also be explained by 
patient's clinical status or other treatments. 
Unlikely Related 
The AE does not occur in a plausible time relationship to drug administration. The event is not 
a recognized pharmacological phenomenon of the suspected drug. It can also be explained by 
patient's clinical status or other treatments. 
Not Related 
The AE does not occur in a plausible time relationship to drug administration. The event is not 
a recognized pharmacological phenomenon of the suspected drug. It can also be explained by 
patient's clinical status or other treatments. The event resolves when patient's clinical status 
improves or other treatments are discontinued. The event recurs upon restarting other 
treatment. 
Indeterminable 
The time relationship between the AE and drug administration is unclear. The event is similar 
to a recognized pharmacological phenomenon of the product. It can also be explained by 
combined medications. 
10.3. 
Duration and Frequency of Adverse Event Assessment and Follow-Up Visit 
AE and SAE are collected by investigators during routine visits and inquiries. All AEs, including 
systemic or local reactions that do not meet the criteria for SAE, will be documented in eCRF. 
The following information should be included: event description, start date, severity, causality 
(determined by qualified personnel), resolution/stabilization time. Each AE should be 
documented accurately regardless of the relationship with drugs. Each AE should be followed 
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Conditions before the signing of informed consent form will be documented as baseline but not 
AEs. However, baseline medical conditions/diseases should be documented when they worsen or 
exacerbate during the trial.  
Changes in the severity of AE should be documented to evaluate the duration of each severity 
grade. The start time and duration should be documented for all intermittent AEs. 
All AEs reported after the informed consent form is signed should be documented. At each visit, 
the investigator should ask about AE/SAE that has/have occurred since the last visit. AEs should 
continue to be followed until being resolved or stabilized. 
10.4. 
Reporting Procedures 
10.4.1. Reporting of serious adverse events 
The reporting period for SAE begins with the signing of the informed consent form until 90 
calendar days (inclusive) after the last study drug treatment. Only treatment-related SAEs are 
reported from 30 days after the last dose. When an SAE occurs, regardless of being recorded in 
first report or follow-up report, the investigator must complete, sign, and date the "CFDA 
Serious Adverse Event Report Form" immediately. The event must be reported to the 
provincial/autonomous regional/municipal drug regulatory authorities, CFDA (via fax or EMS), 
health administration (via fax to bureau of medical administration), the sponsor (via email), and 
the ethics committee within 24 h after knowing the event. Refer to Table 11 below for contact 
details. 
Reporting of SAEs that occur from 90 days after the last dose is generally not required unless 
they are suspected to be drug-related. 
The symptoms, severity, causality with the study drug, time of onset, time of treatment, measures 
taken, time and method of follow-up, and outcome should be documented in detail in the SAE 
report. If the investigator believes that an SAE is not related to the study drug but potentially 
related to the study conditions (such as the termination of past treatment, or comorbidities during 
the study), then this relationship should be detailed in the description 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 
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Table 11. SAE report contacts 
Unit 
Contact 
Fax/Telephone/Address 
Jiangsu Hengrui Pharmaceuticals 
Co., Ltd. 
Drug Safety Group 
(SAE), Oncology 
Business Unit 
Tel.: 021-60453192 ext. 818 
Email: SHR1210safety@shhrp.com 
China Food and Drug 
Administration 
Division of Drug Research 
Supervision, Department of Drug 
and Cosmetics Registration 
 
Address: Building 2, No. 26, Xuanwumen West 
Street, Xicheng District, Beijing 
Postal Code: 100053 
Tel.: 010-68313344-1003 Fax: 010-88363228 
Medical Administration Bureau, 
Health Administration 
 
Address: No. 38, North Lishi Road, Xicheng 
District, Beijing (100810) 
Tel.: 010-68792201 
Fax: 010-68792734 (preferred) 
Food and Drug Administration of 
Provinces, Autonomous Regions and 
Municipalities 
Refer to the reporting requirements of the drug administration department 
of each province, autonomous region, or municipality 
10.4.2. Reports of adverse events of special interest 
The sponsor should be notified of any of the following AEs that occur in subjects from the 
treatment group during the study within 24 h, even though the events do not meet the definition 
of SAE. The Hengrui Clinical Trial Adverse Event of Special Interest Report should be filled out 
and the CFDA Serious Adverse Event Report Form should also be filled out when the events are 
classified as SAEs. AESI should be reported 90 days after the last dose. 
 
Grade ≥ 3 infusion reactions; 
 
Grade ≥ 2 diarrhea/colitis, uveitis, interstitial pneumonia; 
 
Other Grade ≥ 3 immune-related adverse events (irAEs); 
 
Any events that meet Hy's Law (ALT/AST > 3 × ULN accompanied with total 
bilirubin > 2 × ULN and without other causes);  
10.4.3. Pregnancy reporting 
During the study, if a female subject becomes pregnant, she must discontinue the study drugs 
immediately. The investigator must report to the sponsor within 24 hours and fill out the 
Pregnancy Report/Follow-up Form for Hengrui Clinical Studies. 
During the study, if the partner of a male subject becomes pregnant, the subject can continue in 
the study. The investigator must report to the sponsor within 24 hours and fill out the Pregnancy 
Report/Follow-up Form for Hengrui Clinical Studies. 


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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. 
11. Data Analysis/Statistical Methods 
Data analysis will be carried out without distinction of study centers (data from all participating 
study centers will be combined). 
Subjects who have failed the screening (those who do not receive any treatment despite signing 
informed consent) will not be included in any analysis. However, they will be reported in a 
separate listing. 
Reasons for withdrawal will be summarized and listed. The listing should include: date of first 
and last dose administration, duration of study drug exposure, and date of withdrawal. 
The statistical analysis in this study will be conducted when at least 365 OS events are collected. 
The analysis will be carried out after the database for the analysis is locked. 
11.1. 
Statistical Analysis Plan 
Statistical summaries and analytical methods of data collected from this study will be detailed in 
another individual statistical analysis plan (SAP). The finalized SAP will be kept by the sponsor. 
This SAP may contain revisions to the relevant contents in the protocol. However, when the 
revised content involves the main and/or key factors in the protocol, such as the definition of 
primary endpoints and the corresponding analysis, such a revision should be reflected in the 
protocol amendment version. 
11.2. 
Statistical Hypotheses 
The primary objective of this study is to compare the efficacy of SHR-1210 (treatment group) vs. 
investigator's choice of chemotherapy (control group) for the treatment of subjects with locally 
advanced or metastatic esophageal cancer who are refractory to the first-line chemotherapy. The 
primary efficacy endpoint is OS. In this study, the OS curve will be estimated by the Kaplan-
Meier method and a stratified log-rank test will be used as the primary statistical method to test 
the null hypothesis that the distributions of OS are identical between the two groups (one-sided 
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Superiority criteria: When the P value obtained in the final analysis by the log-rank test is ≤ 0.025 
and the median OS of the treatment group estimated by the Kaplan-Meier method is greater than 
that of the control group, the efficacy of the treatment group can be determined to be superior to 
that of the control group. 
11.3. 
Analysis Set/Population 
The following analysis sets will be involved in this study: 
• 
Informed consent set (ICS) 
All subjects who have signed the informed consent form will be included in this analysis set. 
• 
Full analysis set (FAS) 
Based on the intention-to-treat (ITT) principle, all randomized subjects who have received study 
drug at least once will be included in FAS. FAS is the main analysis set for this study. In the 
FAS-based analysis, subjects will be analyzed by group assigned by randomization (regardless of 
the actual treatment they receive). 
• 
Per-protocol set (PPS) 
PPS is a subset of FAS, defined as subjects who do not have major protocol deviations or do not 
have protocol deviations that may have major impacts on study results. Major protocol 
deviations or deviations that have major impacts on study results are defined as follows: 
• 
Violation of the inclusion and exclusion criteria; 
• 
Administration of drugs prohibited by the study; 
The screening and determination of subjects with major protocol deviations or deviations that 
have major impacts on study results will be carried out before database locking, and these 
subjects (if any) will be removed from PPS. The PPS-based analysis will serve as a 
secondary/supportive analysis. 
• 
Immunogenicity analysis set 
Subjects who have received at least one dose of SHR-1210 and have baseline and at least one 
post-baseline immunogenicity evaluation data constitute the immunogenicity analysis set. 
• 
Safety set (SS) 
All subjects who have received study drug at least once (whether they have participated in 
randomized grouping or not) constitute the safety set. The SS is the primary analysis population 
used for the safety analysis. The SS-based analyses will be carried out by the actual treatment 
that patients receive. 


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11.4. 
Statistical Methods 
11.4.1. Basic methods 
This is a parallel-controlled study. Unless otherwise stated, all data will be analyzed by treatment 
group (SHR-1210 group and investigator selected chemotherapy group) and appropriate statistics 
will be applied according to the data type: measurement data will be summarized by mean, 
standard deviation (STD), median, minimum, and maximum; count data will be summarized by 
frequency and proportion for descriptive statistics; for time-to-event data, median time and the 
corresponding 95% confidence interval will be estimated by the Kaplan-Meier method. 
11.4.2. Primary efficacy endpoint analysis 
The primary efficacy endpoint is OS. In addition to the descriptive statistical summary of time-
to-event data with basic methods listed in Section 10.4.1, the statistical analysis of OS will also 
include the following: 
1. Primary analysis 
The primary analysis is to evaluate the efficacy difference between investigational treatment 
group and control group based on the FAS. In the primary analysis, the null hypothesis that the 
distributions of OS are identical between the two groups will be tested using the stratified log-
rank test based on randomized stratification factors (1. locally advanced lesion vs. distant 
metastasis; and 2. ECOG PS 0 vs. 1). 
Missing data: This study will track subject survival until an OS event is observed where possible. 
Inevitably, when a subject drops out before an OS event is observed, the subject's survival time 
(from the start date of randomization of the subject) will be right-censored at the last known 
survival date (the actual survival time is greater than the recorded time). The survival time of 
drop-outs will be calculated using Hengrui's statistical criteria. 
2. Secondary analysis 
First, the above primary analysis will be repeated without the randomized stratification factors 
being considered. 
Secondly, the hazard ratio (HR) of OS of investigational treatment group to control group will be 
estimated using a Cox proportional hazards model, and the corresponding 95% confidence 
interval will be calculated. In the fitting of the primary analysis based on this model, treatment 
group will be set as a fixed effect. In addition, to explore the effects of other factors on efficacy, 
stratification factors [1. locally advanced lesion vs. distant metastasis; 2. ECOG PS (0 vs. 1)], 
gender, and PD-L1 expression level can also be used to fit the model except for the treatment group. 


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Moreover, the 6-month and 12-month OS rates and their 95% confidence intervals will be 
estimated. 
The above analysis for the primary efficacy endpoint will be repeated in FAS and PPS. The rule 
of missing data imputation is identical to that in the primary analysis. 
11.4.3. Secondary efficacy endpoint analysis 
The analysis of secondary efficacy endpoints in this study will be based on FAS only and will be 
carried out for all efficacy endpoints except OS (progression-free survival (PFS), objective 
response rate (ORR), and quality of life score EORTC QLQ-C30 and EORTC QLQ-OES18). 
Secondary efficacy endpoints will be summarized using descriptive statistics based on methods 
described in Section 10.4.1. Furthermore, for PFS, the inter-group differences will be compared 
using the log-rank test, and meanwhile, HR of PFS will be estimated using a Cox proportional 
hazards model and the effects of factors other than treatment groups on the differences in PFS 
will be investigated, with both test and model similar to those of OS-related analysis. For ORR, 
the difference in ORR between the two treatment groups and the corresponding 95% confidence 
interval will be estimated. 
Missing data: they will adopt the imputation method for PFS identical to that for OS; no 
imputation method will be used for ORR or QoL score. 
11.4.4. Analysis of exploratory endpoints 
Based on the immunogenicity analysis set, descriptive statistics for the time to the first positive 
ADA result and the duration of ADA will be summarized. The incidence of ADA, the incidence 
of anti-SHR-1210 antibody with neutralizing activity, and the correlation between 
immunogenicity and drug trough concentration, efficacy and safety will be calculated. Safety 
analysis 
The safety analysis is based on the safety set (by actual treatment received). According to 
Hengrui's Standard Reporting Procedures, safety will be summarized using descriptive statistics, 
including but not limited to the following: 
 
Subject disposition and populations; 
 
Subjects' basic characteristics (including demographics, life history, medical history, 
and medication history); 
 
Discontinuations; 
 
Summary of adverse events (of all causes and treatment-related); 


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 
Incidence and severity of adverse events (of all causes and treatment-related); 
 
Summary of serious adverse events; 
 
Causality analysis of adverse events; 
 
Laboratory measurements, vital signs, ECG, and their changes from baseline; 
 
Number and rate of laboratory measurements, vital signs, and ECG data "changed from 
normal to abnormal" or "exacerbated abnormally" after the trial. 
In this study, AEs will be evaluated and graded by NCI-CTCAE (v4.03). 
11.4.5. Baseline descriptive statistics 
Demographics (gender, age, body height, weight, etc.), medical history, and habituation of all 
randomized subjects will be summarized by treatment group after randomization using 
descriptive statistics based on FAS. 
11.4.6. Multiple comparison/multiplicity 
This study only involves one final analysis of the primary endpoint OS and multiplicity will not 
be involved. The secondary analysis in this study will be only used to provide supportive 
conclusions for the primary analysis and no  adjustments will be made for multiplicity. 
11.4.7. Individual data listings 
All data collected from this study will be presented in listings. 
11.5. 
Sample Size 
This is parallel study with its primary endpoint being OS. Subjects will be randomized in a 
1:1 ratio. Assuming that the median OS of the control group is 7 months and the median OS of 
the investigational treatment group is 9.5 months (the investigational treatment group is extended 
by 2.5 months compared with that of the control group), the inter-group OS distribution will be 
compared using a stratified log-rank test at an overall significance level  = 0.025 (one-sided); 
when the duration of enrollment is assumed to be 18 months and the entire study lasts for 36 months, 
at least 365 OS events need to be collected to obtain a power of 80% according to the calculation 
by East v6.3. Furthermore, assuming a drop-out rate of 20%, 438 subjects are required to be 
enrolled in this study (219 in the investigational treatment group and 219 in the control group). 


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11.6. 
Methods to Reduce Bias 
11.6.1. Randomization and blinding 
Randomization is the primary means of ensuring comparability between groups in this study. 
Personnel who participated in this study should ensure that the randomization procedure is 
strictly implemented where possible. The generation, review, quality assurance, testing, and 
validation of the randomized procedure will be in strict accordance with applicable Hengrui SOP 
(HRSOP STAT 01 Randomization and Blinding). 
This study will use a stratified randomization method. Subjects will be randomized in a 1:1 ratio 
to groups of SHR-1210 or investigator's choice of chemotherapy (docetaxel or irinotecan) within 
each stratum. Stratification factors for this study are: 1. locally advanced lesion vs. distant 
metastasis; 2. ECOG PS (0 vs. 1). Randomization will be performed in the HRTAU RTSM 
system. 
This is an open-label study. No blinding or subsequent procedures are involved. 
11.6.2. Blinding evaluation 
Not involved (see Section 10.6.1). 
11.6.3. Unblinding 
Not involved (see Section 10.6.1). 
Not applicable in this study. 
12. QUALITY ASSURANCE AND QUALITY CONTROL 
To ensure study quality, the sponsor and the investigator will jointly discuss and formulate a 
clinical study plan before the formal study initiation. All study personnel participating in the 
study will receive GCP training. 
All study centers must follow the SOPs for the management of study drugs, including drug 
receipt, storage, dispensing, retrieval, and disposal. 
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 clinical 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. 


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The investigator or designated personnel will input data required by the protocol into eCRF. 
CRA will check whether the eCRF is completely and accurately filled in and guide the study 
center personnel for necessary correction and supplement. 
The drug regulatory authorities, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), sponsor's CRA and/or auditor may carry out systemic inspection of clinical 
study-related activities or documents to assess whether the study is implemented based on the 
requirements of the study protocol, SOPs, and relevant regulations (such as Good Laboratory 
Practices (GLP) and Good Manufacturing Practices (GMP)), and whether the study data are 
recorded in a prompt, truthful, accurate, and complete manner. The audit should be performed by 
personnel not directly involved in this clinical study. 
13. REGULATORY ETHICS, INFORMED CONSENT, AND SUBJECT 
PROTECTION 
13.1. 
Regulatory Considerations 
According to the corresponding regulatory requirements in China, an application should be 
submitted to the CFDA before starting a new drug study and the study can only be carried out 
after approval is obtained. The clinical study approval number for SHR-1210 is 2016L01455. 
The legal basis for the design of this study protocol is as follows: 
1) Provisions for Drug Registration 
2) Good Clinical Practice 
3) 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 Ethical Guidelines 
4) Other applicable laws and regulations 
13.2. 
Ethical Standards 
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", CFDA's "Good 
Clinical Practice (GCP)", and relevant regulations. Before the study is initiated, approval must be 
obtained from the IEC/IRB of the hospital. 


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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 IRB/IEC 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 IRB/IEC 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 IEC/IRB. After the end of the study, the completion should 
be informed to the IEC/IRB. 
13.3. 
Independent Ethics Committee 
The protocol, ICF, recruitment material, and all subject materials must be reviewed and approved 
by the IEC/IRB. 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 IEC/IRB prior to being 
implemented. All revisions to the ICF must be approved by the IEC/IRB, who will decide 
whether the subjects who have signed the previous version of the ICF are required to sign the 
new one. 
13.4. 
Informed Consent 
The ICF describes the study drugs and study process in detail and fully explains the risks of the 
study to the subjects. Written ICFs must be obtained prior to screening. 
13.4.1. Informed consent process and records 
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 subjects and their dependents. Subjects will be 
asked to read and review the ICF that has been approved by the IEC/IRB. The investigator will 
explain the clinical study to the subjects and answer any questions posed by the subjects. An 
informed consent discussion will be conducted for all subjects, and based on their understanding, 
the purpose, process, and potential risks of the study and their rights as study participants will be 
explained. Subjects will have opportunities to carefully read the written informed consent form 
(ICF) and pose questions before signing. Subjects will also have opportunities to discuss with 
their representatives on this study and fully think through it before agreeing to participate in the 


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study. Subjects can only participate in the study after they have signed the ICFs. During the 
clinical study, subjects can withdraw the informed consent form at any time. One copy of the 
signed ICF will be kept by the subjects. Even if subjects refuse to participate in this study, their 
rights will be fully protected. It will also be emphasized to subjects that the medical care quality 
they obtain will not be affected. 
13.5. 
Confidentiality of Subject Information 
During the course of this study, every effort shall be made to protect the privacy of all subjects. 
Study-related documents, study reports, publications, other published data will not include the 
name or other private information of subjects involved, except as required by law. To ensure the 
confidentiality of subjects' data, subject information will be collected, transmitted, processed, 
and stored in accordance with applicable laws and regulations. 
14. DATA MANAGEMENT 
14.1. 
Data Collection and Management 
Data will be collected and managed using the electronic case report form (eCRF). 
14.1.1. Medical records 
As the source documents of the clinical trial, medical records should be retained in their entirety. 
The investigator is responsible for filling out and keeping medical records. Medical records should 
be neat and legible so that the sponsor's CRA could verify the data with eCRF at each inspection. 
14.1.2. eCRF entry 
Clinical study data will be collected using the HRTAU EDC system. 
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 eCRF should be filled out, with no 
blank or omission. 
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 clinical trial data entered into the EDC 
system and generate error message prompt for questionable data. The investigator or CRC is 
permitted to modify or explain the problematic data. If necessary, multiple inquiries can be 
raised until the event of problematic data is resolved. 


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14.1.3. eCRF review 
The investigator or designated personnel should fill out, review, and submit the eCRF in a timely 
manner. The PI or CRC should promptly respond to queries raised by the CRA, data manager, 
and medical reviewer. After data cleaning is completed, the investigator will sign the completed 
eCRF for verification. 
14.2. 
Data Monitoring 
Implemented by: CRA. 
To confirm the study protocol is adhered to, the information on eCRF is correct, complete, and 
consistent with the original medical records and laboratory test results, and the presence/absence 
of 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. 
Ensure that the data in the eCRF are consistent with source data. This process is also known as 
source data verification (SDV). 
14.3. 
Data Management 
14.3.1. 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. 
14.3.2. Data entry and verification 
The PI or dedicated data entry person (CRC) should input data into the EDC system in 
accordance with the requirements of visit procedures and eCRF completion guide. After eCRF is 
submitted, CRA, data manager, and medical reviewer should review the data. Questions during 
the review will be submitted to PI or CRC in the form of queries. After data cleaning is 
completed, the investigator should sign the completed eCRF for verification. 
14.3.3. Database lock 
After SDV is completed by CRA, data manager and medical reviewer will conduct the final 
quality control of all data in the database, summarize all protocol deviations during the trial, and 
hold a data verification 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. 


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14.3.4. Data archiving 
After the study is completed, subject's eCRFs in PDF format must be generated from the EDC 
system and kept in non-rewritable disks (DVD). These disks will be archived by the sponsor and 
various institutions for auditing and/or inspection. 
The preservation and management of the trial data must be in accordance with GCP 
requirements. The investigator must keep the clinical trial data at least 5 years after the 
termination of the clinical trial, and the sponsor must keep the clinical trial data at least 5 years 
after the approval of the drug for launching on the market. 
14.4. 
Protocol Deviations 
Protocol deviation refers to any practice that does not comply with trial protocol or GCP. This 
non-compliance may occur in the subject and may also occur in the investigator or other study 
personnel. The study center should prepare corresponding corrective measures and implement 
them immediately if a deviation occurs. 
Study centers have the responsibility to maintain constant vigilance, complete the identification 
of protocol deviations in a timely manner, and complete the actions required by the protocol, to 
identify and report protocol deviations in a timely manner. All deviations must be documented in 
the original documents. Protocol deviations must be submitted to local IRB in accordance with 
local ethical regulations. The principal investigator or study personnel of the study center is 
responsible for understanding and complying with local ethical standards. 
15. PUBLICATION OF STUDY RESULTS 
The study results belong to Jiangsu Hengrui Pharmaceuticals Co., Ltd. Hengrui does not restrict 
the publication of any collected or research information by investigators, regardless of whether 
the results are beneficial to the investigational drug or not. However, the investigator should let 
the sponsor have the opportunity to review any proposed publication or other forms of 
publication before document submission or publication to prevent unintentional leakage of 
confidential information or unprotected inventions. The investigator should provide Hengrui 
with the manuscript, abstract, or full text of all planned publications (poster, invited lectures, or 
guest lectures) at least 30 days prior to submission for publication or other forms of release. To 
protect the intellectual property rights that need to be patented, the investigator should agree to 
delay publications, and the delay period should not exceed 60 days. Before open publication, 
Hengrui can require the investigator to delete any previously unpublished confidential 
information (except for study results). If this study is part of a multicenter study, the investigator 
must agree that the first publication is an integrated result from all study centers. However, if a 


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manuscript of the integrated analysis is not submitted 12 months after the study is completed or 
terminated in all study centers, the investigator can independently publish results based on other 
requirements in this section. 
16. STUDY CENTER AND TRIAL STAFF 
16.1. 
Study Center 
16.1.1. Leading site 
Name: The 307th Hospital of the Chinese People's Liberation Army 
  
Principal Investigator: Jianming Xu 
Name: Cancer Hospital Chinese Academy of Medical Sciences 
 
Principal Investigator: Jing Huang 
16.2. 
Sponsor 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd.  
 
 
 
 
 
17. CLINICAL STUDY PROGRESS 
Anticipated enrollment of the first subject: Apr. 2017 
Anticipated enrollment of the last subject: Oct. 2018 
Anticipated study completion: Apr., 2019 


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18. REFERENCES 
1. Clinical Practice Guidelines for the Diagnosis and Treatment of Esophageal Cancer, 2011. 
2. Victoria E. Wang, Jennifer R. Grandis, et al. New Strategies in Esophageal Carcinoma: 
Translational Insights from Signaling Pathways and Immune Checkpoints. Clin Cancer Res. 
2016, 22(17):4283–90. 
3. Wanqing Chen, Rongshou Zheng, et al. Cancer Statistics in China, 2015. 
4. Yu X, Wang G. Endoscopic treatment of early esophageal cancer. Zhonghua Wei Chang 
Wai Ke Za Zhi. 2015, 18(9):860-3. 
5. Xi Wang, Xinwei Wang, et al. Irinotecan plus fluorouracil-based regimen as second or third-
line chemotherapy for recurrent or metastatic esophageal squamous cell carcinoma. Thoracic 
Cancer. 2016, 7:246–250. 
6. Ken Kato, Makoto Tahara, et al. A phase II study of paclitaxel by weekly 1-h infusion for 
advanced or recurrent esophageal cancer in patients who had previously received platinum-based 
chemotherapy. Cancer Chemotherapy and pharmacology. 2011, 67(6):1265-1272. 
7. K. Muro1, T. Hamaguchi, et al. A phase II study of single-agent docetaxel in patients with 
metastatic esophageal cancer. Annals of Oncology. 2004, 15:955-959. 
8. Zhengbo Song, Yiping Zhang. Second-line docetaxel-based chemotherapy after failure of 
fluorouracil-based first-line treatment for advanced esophageal squamous cell carcinoma. 
Onco Targets and Therapy. 2014, 7:1875-1881. 
9. Shim Hyun-Jeong, Cho Sang-Hee, etal. Phase II Study of Docetaxel and Cisplatin 
Chemotherapy in 5-Fluorouracil/Cisplatin Pretreated Esophageal Cancer. American Journal 
of Clinical Oncology. 2010, 33(6):624-628. 
10. Kanekiyo S, Takeda S, et al. Efficacy and Safety of Biweekly Docetaxel in Combination 
with Nedaplatin as Second-line Chemotherapy for Unresectable or Recurrent Esophageal 
Cancer. Anticancer Res. 2016, 36(4):1923-7. 
11. Yue-shen Wang, Jing Tian, et al. Gemcitabine Plus Vinorelbine as Second-Line Therapy in 
Patients With Metastatic Esophageal Cancer Previously Treated With Platinum-Based 
Chemotherapy. Oncology Research, 24: 129–135. 
12. CHRISTOF BURKART, CARSTEN BOKEMEYER, et al. A Phase II Trial of Weekly 
Irinotecan in Cisplatin-refractory Esophageal Cancer. ANTICANCER RESEARCH 27: 
2845-2848 (2007). 


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13. Mühr -Wilkenshoff F, Hinkelbein W, et al. A pilot study of irinotecan (CPT-11) as single-
agent therapy in patients with locally advanced or metastatic esophageal carcinoma. 
International Journal of Colorectal Disease. 2003, 18(4): 330–334. 
14. F Lordick, C von Schilling, et al. Phase II trial of irinotecan plus docetaxel in cisplatin-
pretreated relapsed or refractory oesophageal cancer. British Journal of Cancer (2003) 89, 
630-633. 
15. By Thierry Conroy, Pierre-Luc Etienne, et al. Phase II Trial of Vinorelbine in Metastatic 
Squamous Cell Esophageal Carcinoma. Journal of Clinical Oncology, 1996, 14(1): 164-170. 
16. Hai-Xia Qu, Li-Ping Zhao, et al. Clinicopathological and prognostic significance of 
programmed cell death ligand 1 (PD-L1) expression in patients with esophageal squamous 
cell carcinoma: a meta-analysis. Journal of Thoracic Disease, 2016,8(11):3197-3204. 
17. Toshihiro Kudo, Yasuo Hamamoto, et al. Nivolumab treatment for oesophageal squamous-
cell carcinoma: an open-label, multicentre, phase 2 trial.Lancet Oncol 2017. 
18. Toshihiko Doi, Sarina A Piha-Paul, et al. Updated Results for the Advanced Esophageal 
Carcinoma Cohort of the Phase 1b KEYNOTE-028 Study of Pembrolizumab (MK-3475). 
Presented at the 2016 Gastrointestinal Cancers Symposium (ASCO-GI) January 21-23, 
2016. 
Appendix I. ECOG PS 
Grade 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair 50% or more of waking hours. 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair. 
5 
Death. 
 
 


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Appendix II. Creatinine Clearance Calculation 
Creatinine Clearance Calculation Using the Cockcroft-Gault Formula 
 
Serum Creatinine (mg/dL): 
Creatinine Clearance in Males (mL/min) = 
(140 - Age) × (Weight) a 
72 × Serum Creatinine  
 
Creatinine Clearance in Females (mL/min) = 
0.85 × (140 - Age) × (Weight) a 
72 × Serum Creatinine  
 
Serum Creatinine Concentration (mol/L): 
Creatinine Clearance in Males (mL/min) = 
(140 - Age) × (Weight) a 
0.818 × Serum Creatinine  
 
Creatinine Clearance in Females (mL/min) = 
0.85 × (140 - Age) × (Weight) a 
0.818 × Serum Creatinine  
 
a 
Age in years, weight in kg. 
 
 


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Appendix III. Prohibited Traditional Chinese Medicine 
 
Prohibited Traditional Chinese Medicine 
Huatan Huisheng tablet 
Kangaiping pill 
Brucea Javanica oil soft capsule 
Fukang capsule 
Mandarin melon berry syrup 
Xiaoaiping 
Cantharidin 
Pingxiao capsule 
Cinobufotalin 
Pingxiao tablet 
Bufotoxin 
Shendan Sanjie capsule 
Kang'ai injection 
Ankangxin capsule 
Kanglaite injection 
Boshengaining 
Zhongjiefeng injection 
Zedoary turmeric oil and glucose 
injection 
Aidi injection 
Kanglixin capsule 
Awei Huapi ointment 
Cidan capsule 
 
 


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Appendix IV. TNM Staging of Esophageal Cancer 
(T)umor Classification 
Tx: Primary tumor that cannot be assessed 
T0: No evidence of primary tumor 
Tis: High-grade dysplasia 
T1: Invasion of lamina propria, muscularis mucosae, or submucosa 
T1a: Invasion of lamina propria or muscularis mucosae 
T1b: Invasion of submucosa 
T2: Invasion of muscularis propria 
T3: Invasion of adventitia 
T4: Invasion of adjacent structures 
T4a: Resectable (pleura, pericardium, or diaphragm) 
T4b: Unresectable (aorta, vertebral body, or trachea) 
(N)ode Classification 
Nx: Regional lymph nodes that cannot be assessed 
N0: Absent 
N1: 1-2 regional lymph nodes 
N2: 3-6 regional lymph nodes 
N3: ≥ 7 regional lymph nodes 
(M)etastasis Classification 
M0: Absent 
M1: Present 
Tumor Differentiation (G) 
GX: Differentiation that cannot be assessed, use G1 for classification 
G1: Well differentiated 


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G2: Moderately differentiated 
G3: Poorly differentiated 
G4: Undifferentiated, use G3 for classification 
Tumor Cell Type 
H1: Squamous cell carcinoma 
H2: Adenocarcinoma 
Stage 
T 
N 
M 
G 
Site* 
0 
is (HGD) 
0 
0 
1, X 
Any 
IA 
1 
0 
0 
1, X 
Any 
IB 
1 
0 
0 
2-3 
Any 
2-3 
0 
0 
1, X 
Lower segment, X 
IIA 
2-3 
0 
0 
1, X 
Middle and upper 
segments 
2-3 
0 
0 
2-3 
Lower segment, X 
IIB 
2-3 
0 
0 
2-3 
Middle and upper 
segments 
1-2 
1 
0 
Any 
Any 
IIIA 
1-2 
2 
0 
Any 
Any 
3 
1 
0 
Any 
Any 
4a 
0 
0 
Any 
Any 
IIIB 
3 
2 
0 
Any 
Any 
IIIC 
4a 
1-2 
0 
Any 
Any 
4b 
Any 
0 
Any 
Any 
Any 
3 
0 
Any 
Any 
IV 
Any 
Any 
1 
Any 
Any 
*The tumor site is defined by the position of the upper edge of the tumor in the esophagus, and X refers to the tumor 
site undocumented. 
 
 


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Appendix V. Response Evaluation Criteria in Solid Tumors 
Response Evaluation Criteria in Solid Tumors Version 1.1 (Excerpt) 
(New Response Evaluation Criteria in Solid Tumors: Revised RECIST Version 1.1) 
Note: This appendix is translated internally and is for reference only. Please refer to the English 
version during practice. 
1 BACKGROUND 
Omitted 
2 PURPOSE 
Omitted 
3 MEASURABILITY OF TUMOR AT BASELINE 
3.1 
Definition 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
3.1.1 Measurable lesions 
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 
by calipers should be recorded as non-measurable). 
 
20 mm by chest X-ray 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and during follow-up, only the short 
axis will be measured and followed. 
 
 


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3.1.2 Non-measurable lesions 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. 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. 
3.1.3 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; 
 
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. 
 
 


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3.2 
Specifications by Methods of Measurements 
3.2.1 Measurements 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 
28 days (4 weeks) before the beginning of the treatment. 
3.2.2 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., nodule skin). For 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. 
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 efficacy 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, celioscopy: 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. 


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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 trials in ovarian cancer. 
Cytology/histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where know residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met the criteria for 
response or stable disease in order to differentiate between response (or stable disease) and PD. 
4 TUMOR RESPONSE ASSESSMENT 
4.1 
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 trials 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. 
4.2 
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 subjects have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded). 
 
 


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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 ≥ 15 mm 
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, saggital or coronal). The smallest of these measures is the short axis. For example, 
an abdominal nodule which is reported as being 20 mm x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable nodule. 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. 
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 
should be recorded as "present", "absent", or in rare cases "unequivocal progression". It is 
possible to record multiple nontarget 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"). 
4.3 
Response Criteria 
4.3.1 Evaluation of target lesions 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(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, 
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Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable disease (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. 
4.3.2 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. Case report 
forms 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 nodule must achieve a 
short axis of < 10 mm. For PR, SD and PD, the actual short axis measurement of the nodules 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 
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 is recorded on the case report form. If it 
is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned. (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph nodule is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false 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. 


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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. 
4.3.3 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 
marker 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 
marker 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. 
4.3.4 Special notes on assessment of progression of non-target lesions 
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 quality 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 
studies 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 


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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 peritoneal effusion from 
trace to large, an increase in lymphangiopathy 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. 
4.3.5 New Lesion 
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. 
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 assessments 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: 
 


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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. 
4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the trial until the end of 
trial taking into account any necessary requirement 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 patient's best overall response evaluation will depend on the findings of both 
target and non-target diseases and will also take into consideration the characteristics of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in non-randomized studies where response 
is the primary endpoint, confirmation of PR or CR is needed to determine either one is the BOR. 
4.4.1 Time point response 
It is assumed that at each time point specified in protocol, an efficacy response occurs. Table 1 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
Table 1. Time point response: patients with target (+/– non-target) disease. 
Target Lesion 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 


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Target Lesion 
Non-Target Lesion 
New Lesion 
Overall Response 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable 
If patient does not have measurable lesions (no target lesions), refer to Table 2. 
Table 2. Time point response: patients with non-target disease only. 
Non-Target Lesion 
New Lesion 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PDa 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a: "Non-CR/non-PD" is preferred over SD for non-target disease. Since SD is increasingly used as an endpoint 
for efficacy evaluation, non-CR/non-PD response is developed to address the absence of lesion measurability. 
4.4.2 Missing assessments and unevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient 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 patient had a baseline sum of 50 mm with three measured lesions and only two 
lesions were assessed at subsequent follow-up, but those gave a sum of 80 mm, the patient will 
have achieved PD status, regardless of the contribution of the missing lesion. 
4.4.3 Best overall response: all time points 
The BOR is determined once all the data for the patient are known. 
BOR determination in studies 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 patient 
who has SD in evaluation at Cycle 1, PR at Cycle 2, and PD at 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 


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calculated from baseline. If the minimum time is not met when SD is otherwise the BOR, the 
patient's BOR depends on the subsequent assessments. For example, a patient 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 patient lost to follow-up after the first SD assessment would be considered not 
evaluable. 
BOR determination in studies 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 best overall response can be interpreted as in Table 3. 
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 
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 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable. 
a: If a CR is truly met at first time point, then efficacy of any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline, will still evaluated as PD at that point (since disease will 
reappear 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 were likely still present and in fact 
the patient had 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. 
4.4.4 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to "normal" 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the 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 patients with CR may 
not have "zero" recorded on the case report form (CRF). 


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In trials where confirmation of response is required, repeated "NE" time point evaluations may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/evaluations will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a 
confirmed response. 
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 patients is to be determined 
by evaluation of target and non-target disease 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 to 
perform a biopsy before evaluating the efficacy of complete remission of local lesions. 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. 
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. 
4.5 
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 studies 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 can 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) 


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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 treatment, the need for tumor re-evaluations depends on whether the trial has as made the 
response rate or the time to an event (progression/death) an endpoint. If "time to an event" 
(e.g. TTP/DFS/PFS) is the main endpoint of the study, then routine scheduled re-evaluation of 
protocol specified sites of disease is warranted. In randomized comparative trials 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. 
4.6 
Confirmatory Measurement/Duration of Response 
4.6.1 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 
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. 
4.6.2 Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). The duration of overall complete response is measured from the time criteria 
are first met for CR until the first date that recurrent or progressive disease is truly documented. 


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4.6.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). The clinical 
relevance of the duration of stable disease varies in different studies and diseases. If the 
proportion of patients achieving SD for a minimum period of time is an endpoint in a particular 
study, the protocol should 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 precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made. 
4.7 
PFS/TTP 
4.7.1 Phase II clinical trials 
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 anticancer activity of new agents/regimens. In such cases, PFS/PPF at landmark time 
points might 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 trials 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. 

SAP_001.pdf: 
Title: A Randomized, Open-Label, Active-Controlled, Multi-Center, Phase III Clinical 
Study of Anti-PD-1 Antibody SHR-1210 vs. Investigator's Choice of Chemotherapy in 
Subjects with Locally Advanced or Metastatic Esophageal Cancer 
NCT number: NCT03099382 
Date: 28 Jun., 2017 


PAREXEL International 
Statistical Analysis Plan 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
SHR-1210-III-301-ESC 
Statistical Analysis Plan 
 
 
TP-GDO-WW-016-06 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  28 Jun 17 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 1 of 39 
 
 
PAREXEL International 
 
 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
SHR-1210-III-301-ESC 
 
 
A Randomized, Open-Label, Active-Controlled, Multi-Center, Phase III Clinical Study of Anti-
PD-1 Antibody SHR-1210 vs. Investigator's Choice of Chemotherapy in Subjects with Locally 
Advanced or Metastatic Esophageal Cancer 
 
 
Statistical Analysis Plan 
 
 
PAREXEL Project No.: 236104 
 
Translated from Original Document 


Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
SHR-1210-III-301-ESC 
Statistical Analysis Plan 
 
 
TP-GDO-WW-016-06 
CONFIDENTIAL 
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Effective Date:  28 Jun 17 
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Related to:  SOP-GDO-WW-019 
Page 2 of 39 
 
SPONSOR SIGNATURE PAGE 
 
 
 
 
Approved by:  
_________________________ 
_______________ 
 
 
Date 
 
Director of Statistics 
 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
 
 
_________________________ 
_______________ 
 
 
Date 
 
Medical Director 
 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 


Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
SHR-1210-III-301-ESC 
Statistical Analysis Plan 
 
 
TP-GDO-WW-016-06 
CONFIDENTIAL 
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PAREXEL SIGNATURE PAGE 
 
 
Signatures below confirm that the review process has been completed in accordance with SOP-
GDO-WW-019. 
 
This document has been approved and signed electronically on the final page by the 
following: 
 
Signatory 
Author  
[Name] 
 
Project Role: Biostatistics Lead  
 
Signatory 
Reviewer 
[Name] 
 
Project Role: Biostatistics Reviewer 
[Name] 
 
Project Role: Statistical Programming Lead 


Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
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Statistical Analysis Plan 
 
 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION ................................................................................................................. 9 
2 
OBJECTIVES AND ENDPOINTS ...................................................................................... 9 
2.1 Study Objectives ............................................................................................................... 9 
2.1.1 Primary objective .................................................................................................. 9 
2.1.2 Secondary objectives ............................................................................................ 9 
2.1.3 Exploratory objective ............................................................................................ 9 
2.2 Study Endpoints ................................................................................................................ 9 
2.2.1 Primary endpoint................................................................................................... 9 
2.2.2 Secondary endpoints ............................................................................................. 9 
2.2.3 Exploratory endpoint .......................................................................................... 10 
3 
STUDY DESIGN ................................................................................................................. 10 
4 
STATISTICAL METHODS ............................................................................................... 13 
4.1 General Principles ........................................................................................................... 13 
4.1.1 Baseline ............................................................................................................... 13 
4.1.2 Visit/analysis time window ................................................................................. 13 
4.1.3 Study days ........................................................................................................... 14 
4.1.4 Descriptive statistics ........................................................................................... 15 
4.1.5 Number of decimal places .................................................................................. 15 
4.1.6 Analysis software ................................................................................................ 15 
4.2 Analysis Set/Population .................................................................................................. 15 
4.2.1 Informed consent set (ICS) ................................................................................. 15 
4.2.2 Randomized set (RAN) ....................................................................................... 16 
4.2.3 Full analysis set (FAS) ........................................................................................ 16 
4.2.4 Per-protocol set (PPS) ......................................................................................... 16 
4.2.5 Safety set (SS) ..................................................................................................... 16 
4.2.6 QLQ-C30 analysis set ......................................................................................... 16 
4.2.7 QLQ-OES18 analysis set .................................................................................... 17 
4.3 Subject ............................................................................................................................ 17 


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4.3.1 Subject distribution ............................................................................................. 17 
4.3.2 Protocol deviations ............................................................................................. 18 
4.4 Demographics and Baseline Data ................................................................................... 18 
4.4.1 Demographics ..................................................................................................... 18 
4.4.2 Tumor diagnosis ................................................................................................. 18 
4.4.3 Medical history ................................................................................................... 19 
4.4.4 History of cancer treatment................................................................................. 19 
4.4.5 History of allergies, medical history, and concomitant medication ................... 20 
4.4.6 New anti-tumor treatment ................................................................................... 20 
4.5 Treatment Compliance .................................................................................................... 20 
4.5.1 SHR-1210 ........................................................................................................... 20 
4.5.2 Docetaxel ............................................................................................................ 20 
4.5.3 Irinotecan ............................................................................................................ 20 
4.6 Efficacy Analysis ............................................................................................................ 20 
4.6.1 Handling of dropouts and missing data .............................................................. 20 
4.6.2 Multiple comparison/multiplicity ....................................................................... 21 
4.6.3 Subgroup analysis ............................................................................................... 21 
4.6.4 Primary efficacy endpoint – OS.......................................................................... 22 
4.6.4.1 Primary analysis ................................................................................... 22 
4.6.4.2 Secondary analysis ............................................................................... 22 
4.6.5 Secondary efficacy endpoints ............................................................................. 23 
4.6.5.1 PFS ....................................................................................................... 23 
4.6.5.2 ORR ..................................................................................................... 24 
4.6.5.3 DoR ...................................................................................................... 25 
4.6.5.4 Quality of life score ............................................................................. 25 
4.6.5.4.1 EORTC QLQ-C30 scale ...................................................... 25 
4.6.5.4.2 EORTC QLQ-OES18 scale ................................................. 26 
4.6.6 Exploratory analysis ........................................................................................... 26 
4.6.6.1 Expression level of PD-L1 in tumor tissues ........................................ 26 
4.6.6.2 Other biomarkers ................................................................................. 26 


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4.7 Safety Analysis ............................................................................................................... 27 
4.7.1 Adverse events .................................................................................................... 27 
4.7.2 Laboratory measurements ................................................................................... 32 
4.7.3 ECOG (performance status)................................................................................ 33 
4.7.4 Vital signs ........................................................................................................... 33 
4.7.5 12-lead ECG ....................................................................................................... 34 
4.7.6 Echocardiography ............................................................................................... 34 
4.7.7 Physical examination .......................................................................................... 34 
4.8 Determination of Sample Size ........................................................................................ 34 
4.9 Updates for Study Implementation or Planned Analysis ................................................ 35 
5 
REFERENCES .................................................................................................................... 35 
6 
APPENDICES ..................................................................................................................... 36 
6.1 Appendix 1 ...................................................................................................................... 36 
6.2 Appendix 2 ...................................................................................................................... 37 
6.3 Appendix 3 ...................................................................................................................... 38 
6.4 Appendix 4 ...................................................................................................................... 39 
  


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ABBREVIATIONS 
Abbreviation 
Full Name 
ADR 
Adverse drug reaction 
AE 
Adverse event 
CI 
Confidence interval 
CR 
Complete response 
eCRF 
Electronic case report form 
CRO 
Contract research organization 
D 
Day 
DoR 
Duration of response 
ECG 
Electrocardiogram 
EDC 
Electronic data collection 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organisation for Research and Treatment of Cancer 
FAS 
Full analysis set 
HR 
Hazard ratio 
ICS 
Informed consent set 
IDMC 
Independent Data Monitoring Committee 
irAE 
Immune-related adverse event 
irRECIST 
Immune-related response evaluation criteria in solid tumors 
ITT 
Intention-to-treat 
kg 
Kilogram 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
NCI-CTC 
National Cancer Institute Common Terminology Criteria 
ORR 
Objective response rate 
OS  
Overall survival 
P 
P value 
PR 
Partial response 
PD 
Progressive disease 
PFS 
Progression-free survival 
PPS 
Per-protocol set 
PT 
Preferred term 


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Abbreviation 
Full Name 
QLQ 
Quality of life questionnaire 
RAN 
Randomized set 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOC 
System organ class 
SS 
Safety set 
TEAE 
Treatment-emergent adverse event 
TLF 
Table, Listing, Figure 
 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) details the methods of statistical analysis that will be used in 
the analysis of this study. This SAP does not include tables, listings, and figures (TLFs). TLFs 
will be shown in another article. Changes to the methods of statistical analysis will require 
amendments to the SAP. 
This SAP is based on the following documents: 
• 
Study Protocol, version 5.0 (12 Apr., 2018) 
• 
Electronic Case Report Form (eCRF), version 7.0 (18 Feb., 2019) 
2 
OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 Primary objective 
To evaluate the efficacy of SHR-1210 vs. investigator’s choice of chemotherapy in patients with 
locally advanced or metastatic esophageal cancer who are refractory to the first-line 
chemotherapy. 
2.1.2 Secondary objectives 
To evaluate the safety of SHR-1210 vs. investigator’s choice of chemotherapy in patients with 
locally advanced or metastatic esophageal cancer who are refractory to the first-line 
chemotherapy. 
2.1.3 Exploratory objective 
To evaluate the relationship between biomarkers in tumor tissue and/or blood (such as PD-L1) 
and the efficacy of SHR-1210. 
2.2 
Study Endpoints 
2.2.1 Primary endpoint 
Overall survival (OS): defined as the time from the start of randomization to the death of the 
subject caused by any reason.  
2.2.2 Secondary endpoints 
Progression-free survival (PFS): defined as the time from the start of randomization to the first 
documented objective tumor progression or death caused by any reason, whichever occurs first. 
Objective response rate (ORR): the proportion of subjects who achieve CR and PR. 


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Duration of response (DoR): defined as the time from the date of the first recording of tumor 
response to the date of the first recording of objective tumor progression or death caused by any 
reason. 
Quality of life score: As a core scale for all cancer patients, the EORTC QLQ-C30 scale 
comprises 30 items, 5 functional scales (physical, role, cognitive, emotional and social), 3 symptom 
scales (fatigue, pain and nausea/vomiting), 1 global health status/quality of life scale and 6 single-
item scales (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). 
The EORTC QLQ-OES18 scale is mainly used for patients with esophageal cancer and contains 
18 symptom items. The assessment should be completed at various time points based on the 
schedule of activities, starting from the first cycle until 30 days after the last dose. 
2.2.3 Exploratory endpoint 
To evaluate the relationship of the expression of PD-L1 and/or other biomarkers with the 
efficacy of SHR-1210. 
Tumor tissues and/or blood obtained during the study may also be used in the future to 
determine tumor mutation burden, proteomics, or other analytes. 
3 
STUDY DESIGN 
This is a randomized, open-label, active-controlled, multi-center study. A total of 438 eligible 
subjects with locally advanced or metastatic squamous cell carcinoma of the esophagus who are 
refractory to first-line chemotherapy will be randomized to investigational treatment group or 
control group in a 1:1 ratio and stratified by: 1. locally advanced lesion vs. distant metastasis; 
2. ECOG PS (0 vs. 1). 
Subjects in the investigational treatment group will receive SHR-1210 (200 mg/dose, on Day 1 of 
each 2-week cycle) and those in the control group will receive the investigator's choice of 
chemotherapy, either docetaxel (75 mg/m2, on Day 1 of each 3-week cycle) or irinotecan (180 mg/m2, 
on Day 1 of each 2-week cycle). Both investigational treatment group and control group will 
continue treatment until the occurrence of progressive disease (PD), intolerable toxicity, 
voluntary withdrawal by the subject, or treatment discontinuation determined by the 
investigator. 
Based on SHR-1210 being an immune checkpoint inhibitor and the experience of similar drugs, 
some subjects may experience delayed or early tumor pseudoprogression after receiving the 
immunotherapy. Therefore, the use of RECIST v1.1 alone may underestimate the benefits of the 
immunotherapy. As a result, it is suggested in this study to carry out a comprehensive imaging 
assessment based on both RECIST v1.1 and iRECIST, i.e., for subjects experiencing progressive 
disease for the first time but whose clinical symptoms are stable, the investigator may decide to 


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allow the subjects to continue using SHR-1210 and take the imaging assessment again after 4 weeks 
(± 7 days); when the subsequent imaging assessment confirms progressive disease, the subjects 
need to discontinue SHR-1210 unless the investigator believes that the subjects can continue to 
gain clinical benefits from SHR-1210 and makes the decision following the discussion with the 
sponsor. 
The study procedure is divided into three stages. The screening period is 28 days. After 
completing the screening examination and evaluation, the eligible subjects enter the treatment 
period and undergo visits by the dosing frequency. Relevant examinations and assessments must 
be completed before each dose. In particular, tumor imaging will be assessed once every 8 weeks 
(± 7 days) (including the chemotherapy control group). All subjects mu st complete safety 
examinations and tumor assessments before the end of treatment. The subjects then enter the 
follow-up period. The follow-up visits of all subjects should be carried out 90 days after the last 
dose; the follow-up visits scheduled for 30 days after the last dose should be carried out at the 
study site, while those scheduled for 60 days and 90 days after the last dose via telephone; 
subjects ending the treatment due to reasons other than progressive disease should continue to 
undergo imaging assessments once every 8 weeks (± 7 days) until progressive disease, initiation 
of new anti-cancer treatments or death; subjects ending the treatment due to progressive disease 
and subjects without progressive disease who complete the follow-up visits will enter the survival 
follow-up period, and they will be followed up once a month. 


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The schedule of study procedures is detailed in the protocol. The diagram of study design is 
shown as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients with 
locally advanced 
or metastatic 
esophageal cancer 
refractory to first-
line chemotherapy 
Investigational treatment 
group (n = 219) 
SHR-1210, 200 mg, 
administered on Day 1 of each 
2-week cycle. Treated until 
withdrawal due to confirmed 
PD or intolerable toxicity. 
Control group (n = 219) 
Docetaxel: 75 mg/m2, 
administered on Day 1 of 
each 3-week cycle. 
or 
Irinotecan: 180 mg/m2, 
administered on Day 1 of 
each 2-week cycle. 
Treated until withdrawal due to 
PD or intolerable toxicity. 
Observations 
OS, PFS, ORR, 
quality of life 
score, and safety 
1:1 randomization,  
stratified by: 
Locally advanced lesion vs. 
distant metastasis 
ECOG 0 VS 1 


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4 
STATISTICAL METHODS 
4.1 
General Principles 
4.1.1 Baseline 
Unless otherwise stated, the "baseline" in this study is defined as the last non-missing measurement 
value obtained prior to the first use of study drug, including the measurements obtained on the 
day of and prior to the first dose. 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 planned and unplanned visits are present, the value obtained from the planned 
visit will be considered as the last non-missing measurement. 
• 
If there are multiple planned visits, the value obtained from the visit with the largest 
visit number will be considered as the last non-missing measurement. 
• 
If there is no planned visit but there are multiple unplanned visits, the value obtained 
from the visit with the largest number of the unplanned visit will be considered as the 
last non-missing measurement. 
See Section 4.1.2 for the quality of life score at baseline. 
4.1.2 Visit/analysis time window 
The time window will be used for the analysis summarized by visits. In the analysis carried out 
by visits, the statistical analysis will be performed according to the planned time points in the 
protocol, i.e., the time points of unplanned visits do not need to be shown. 
For the analysis of quality of life scores, the analysis time window is defined as shown in the 
following table (calculated by the number of days of study): 
Table 4.1.2-1. Analysis time window for quality of life score. 
 
Planned Visit Time 
Analysis Time Window 
Baseline 
1 
-7 to 1 
Week 8 
57 
50-64 
Week 16 
103 
96-110 
Week 24 
169 
162-176 
Week 32 
225 
218-232 
Week 40 
281 
274-288 
Week 48 
337 
330-344 
… 
… 
… 
End of Treatment (EOT)* 
EOT 
EOT ± 7  
30 Days After the Last Dose 
Day of the last dose + 30 
Day of the last dose + 23 to day of the last dose + 37 
*End of Treatment (EOT) = day of treatment termination/withdrawal from study visit. 


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For the quality of life score, when the planned protocol visit is missing and there is an unplanned 
visit in the analysis time window of the planned visit, the unplanned visit will be used as the visit 
for analysis. If there are 2 or more unplanned visits in the analysis time window, the unplanned 
visit that is the closest to the time of planned visit will be used for visit analysis. If the time of 
two unplanned visits is equal to the time of the planned visit, the later unplanned visit will be 
used for visit analysis. 
Analyses other than that of quality of life scores that should be summed up by visits (e.g. laboratory 
test, vital signs, ECG, physical examination, and tumor response evaluation) will be summarized 
by the protocol-proposed visits shown in eCRF (excluding baseline; see Section 4.1.1 for the 
definition of baseline) with no need to check whether the time of visit exceeds the corresponding 
time window specified in the protocol. 
For examinations other than the quality of life score, when the visit planned in the protocol is 
missing, or one of the test items in the planned protocol visit is missing or its results are invalid, 
the unplanned visit that is the closest to the time of the planned one will be considered as the 
protocol-proposed visit. If the time of two unplanned visits is equally close to the time of 
planned visit, the later unplanned visit will be selected as the protocol visit. All visits in the 
protocol will be sorted in chronological order. In addition, once defined as a protocol visit, an 
unplanned visit will no longer be defined as other protocol visits. 
For the PD-L1 expression in tumor tissues, when one subject has two or more valid tests, the 
result summaries will be based on the earliest one. 
4.1.3 Study days 
The date of administration of the first dose is defined as the start day of the study (Day 1). Then, 
based on the start day of the study, the number of days of study corresponding to test or event is 
calculated by the following formula: 
• 
If an examination/event occurs before the start of the study, days = examination date - 
study start date; 
• 
If an examination/event occurs after the start of the study, days = examination date - 
study start date + 1. 
 
 


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4.1.4 Descriptive statistics 
Unless otherwise stated, all data will be summarized by treatment group and appropriate 
descriptive statistics based on data types. Descriptive statistics for measurement data will include 
number of subjects, mean, standard deviation, median, minimum, and maximum. Descriptive 
statistics for count data will include frequency and percentage. As for time-to-event data, the 
median time and its 95% confidence interval will be estimated using the Kaplan-Meier method, 
and the survival curve will be plotted when necessary. Meanwhile, the 95% confidence interval 
for the median time will be calculated using the Brookmeyer-Crowley method based on log-log 
transformation, and its standard error will be calculated using the Greenwood formula. 
4.1.5 Number of decimal places 
Unless otherwise stated, the rounding of decimal places will follow the rules below. 
• 
The decimal places of minimum and maximum should be consistent with that of the 
raw data recorded on the CRF. Mean and median have one more decimal place than 
those of the raw data, and the standard deviation has 2 more decimal places than that of 
the raw data. However, there can only be at most 4 decimal places. If the value from 
the raw data is less than 0.0001, it will be recorded as "< 0.0001". 
• 
The percentage will be rounded to 2 decimal places. If the frequency is 0, the 
percentage is not displayed. 
• 
The P value will retain 4 decimal places. If the P value is < 0.0001, it will be expressed 
as "< 0.0001"; if the P value is > 0.9999, it will be reported as "> 0.9999". 
• 
The 95% confidence interval will have one more decimal place than that of the raw 
data. If the raw data have no decimal place, the 95% confidence interval will retain 
2 decimal places; if the raw data have 4 or more decimal places, the 95% confidence 
interval will retain at most 4 decimal places. 
4.1.6 Analysis software 
All statistical analyses will be conducted using SAS® (v9.4). 
4.2 
Analysis Set/Population 
The following analysis sets will be involved in this study: 
4.2.1 Informed consent set (ICS) 
All subjects who have signed the informed consent form will be included in this analysis set. 


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4.2.2 Randomized set (RAN) 
All subjects who have been randomized, whether or not they have received study drug, will be 
included in this analysis set. These subjects will be analyzed by group assigned by randomization 
(regardless of the actual treatment they receive). 
4.2.3 Full analysis set (FAS) 
All randomized subjects who have received study drug at least once will be included in FAS. 
The full analysis set is the primary analysis set used for the efficacy analysis of this study. In the 
FAS-based analysis, subjects will be analyzed by group assigned by randomization (regardless of 
the actual treatment they receive). 
4.2.4 Per-protocol set (PPS) 
PPS is a subset of FAS and defined as subjects experiencing no protocol deviations that exert 
major impacts on the efficacy analysis results during the study. These subjects will be analyzed 
by group assigned by randomization (regardless of the actual treatment they receive). 
Protocol deviations with major impacts on study results may include, but are not limited to, the 
following three points: 
• 
Violation of the inclusion and exclusion criteria; 
• 
Administration of drugs prohibited by the study; 
• 
The drugs actual used are inconsistent with the randomized assignment; 
The screening and determination of subjects with protocol deviations that have major impacts on 
study results will be carried out before database locking, and these subjects (if any) will be 
removed from PPS. The PPS-based analysis will serve as a secondary/supportive analysis. 
4.2.5 Safety set (SS) 
All subjects who have received study drug at least once (whether they have participated in 
randomized grouping or not) constitute the safety set. The SS is the primary analysis population 
used for the safety analysis. The SS-based analysis will be performed by the treatment actually 
received by patients. 
4.2.6 QLQ-C30 analysis set 
The QLQ analysis set is a subset of FAS. It is defined as the subject population who have 
completed the QLQ-C30 baseline assessment and at least one post-baseline assessment. This 
analysis set will be used for the analysis of QLQ-C30. 


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4.2.7 QLQ-OES18 analysis set 
The QLQ analysis set is a subset of FAS. It is defined as the subject population who have 
completed the QLQ-OES18 baseline assessment and at least one post-baseline assessment. 
This analysis set will be used for the analysis of QLQ-OES18. 
4.3 
Subject 
4.3.1 Subject distribution 
The descriptive statistics of the screening status of subjects, including number of screened 
subjects, number and percentage of subjects that have failed the screening, number and 
percentage of subjects that have undergone randomization, and number and percentage of 
subjects that have received treatment, will be summarized based on ICS and categorized by the 
reasons for screening failure (number and percentage of subjects). 
The descriptive statistics of number of subjects undergoing randomization, number and 
percentage of subjects that have received study drug, number and percentage of subjects that 
have terminated the treatment, number and percentage of subjects that have withdrawn from the 
study, and number and percentage of subjects that have completed the study will be summarized 
based on RAN and the treatment groups assigned by randomization and categorized by the 
reasons for terminating the treatment and withdrawing from the study (number and percentage of 
subjects). 
The descriptive statistics of number and percentage of subjects included in FAS, PPS, SS, QLQ-
C30 analysis set, and QLQ-OES18 analysis set and number and percentage of subjects rejected 
from various analysis sets will be summarized based on RAN and treatment groups assigned by 
randomization and categorized by the reasons of rejection (number and percentage of subjects). 
Since the control group will receive two different chemotherapy regimens, i.e., docetaxel or 
irinotecan, the above-mentioned summary by treatment group will be further subdivided by the 
chemotherapy regimen received in the control group. 
A detailed listing of reasons for screening failure, randomization of subjects, withdrawal from 
the treatment and the reasons will be provided based on ICS. 
A detailed listing of subjects included into and rejected from FAS, PPS, SS, QLQ-C30 analysis 
set, and QLQ-OES18 analysis set will be provided based on RAN. The listing will include 
rejected analysis sets and reasons for rejection at least. 
 
 


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4.3.2 Protocol deviations 
The Hengrui project team will be responsible for recording all protocol deviations. Before the 
database is locked, PAREXEL will discuss with members of the Hengrui project team to 
determine the impact of protocol deviations on the analysis set/population. Protocol deviations 
can be classified as "major" or "minor". Major protocol deviation refers to protocol deviation that 
may have significant impacts on subjects. 
A descriptive summary of major protocol deviations will be provided for all randomized subjects 
by treatment group and category of protocol deviations (number and percentage of subjects will 
be provided). In addition, a detailed listing of protocol deviations will be provided. The listing 
will include all major and minor protocol deviations. 
4.4 
Demographics and Baseline Data 
The descriptive statistics of demographics and baseline data will be summarized based on FAS 
and by treatment and overall groups. 
4.4.1 Demographics 
The summary of descriptive statistics of demographics (gender, age, age stratification [< 65 years 
old and ≥ 65 years old] (of which, < 65 years old can be further divided into < 45, 45 to < 55, 
and 55 to < 65 years old), ethnicity, height [cm], body weight [kg], BMI [kg/m2]), BMI 
stratification (< 18.5 kg/m2 and ≥ 18.5 kg/m2), smoking, and alcohol use will be provided along 
with detailed listings. 
Age will be calculated with the number of full years between date of birth and signing date of the 
informed consent form. Please refer to Appendix 1 for the rules of age calculation. 
Formula of BMI calculation: Baseline weight (kg)/Baseline height (m2). 
4.4.2 Tumor diagnosis 
Primary tumor site, pathological grade, cumulative number of organ with metastasis, location of 
metastasis, and course of disease will be summarized using descriptive statistics. 
Course of disease (month) is defined as the time from date of the first pathological diagnosis to 
date of randomization, and its formula of calculation is as follows: (Date of randomization – 
Date of first pathological diagnosis)/30.4375. If the "day" in the date of pathological diagnosis is 
missing, the course of disease will be calculated based on imputation with day 15. 
A detailed listing of subjects for tumor diagnosis will be provided. 


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4.4.3 Medical history 
Medical history will be coded by MedDRA (v20.0), and the statistics for the number and 
percentage of subjects under each SOC and PT will be provided. In addition, a detailed listing of 
subjects will be provided. 
4.4.4 History of cancer treatment 
History of cancer treatment mainly includes history of neoadjuvant chemotherapy, history of 
adjuvant chemotherapy, history of rescue therapy, history of radiotherapy, and history of tumor 
surgery. 
For the history of cancer treatment, the following descriptive statistics will be provided: 
• 
Number and percentage of subjects who have received neoadjuvant chemotherapy 
• 
Number and percentage of subjects who have received adjuvant chemotherapy 
• 
Number and percentage of subjects who have received rescue therapy 
• 
Number and percentage of subjects who have received first-line platinum-based 
chemotherapy 
• 
Number and percentage of subjects who have received radiotherapy 
• 
Number and percentage of subjects who have received radical concurrent 
chemoradiotherapy. Radical concurrent chemoradiotherapy is defined as the presence 
of radical radiotherapy in the "History of Radiotherapy" page of eCRF and the 
presence of concurrent chemotherapy in the page of "Rescue Therapy", "History of 
Neoadjuvant Chemotherapy" or "History of Adjuvant Chemotherapy". Specifically, the 
concurrent chemotherapy in the "Rescue Therapy" page is defined as the treatment that 
shares at least one day with the radiotherapy. There is no time limit for "History of 
Neoadjuvant Chemotherapy" and "History of Adjuvant Chemotherapy". 
• 
Number and percentage of subjects who have received tumor surgery 
In addition, the duration between end date of the last tumor treatment and date of randomization 
(month) will be provided using the following formula: (Date of randomization – End date of the 
last tumor treatment)/30.4375. 
In addition, the duration between end date of first-line chemotherapy and date of randomization 
(month) will be provided using the following formula: (Date of randomization – End date of 
first-line chemotherapy)/30.4375. 


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If the end date of the last tumor treatment or the end date of first-line chemotherapy is 
incomplete and only the "day" is missing, the aforementioned duration will be calculated based 
on an imputation with day 15. 
A detailed listing of cancer treatment history will be provided. 
4.4.5 History of allergies, medical history, and concomitant medication 
The detailed listings of subjects with history of allergies, medical history, and concomitant 
medication will be provided separately. 
4.4.6 New anti-tumor treatment 
The number and percentage of subjects who have received new anti-cancer treatment after 
ending treatment will be summarized by the treatment type, and a detailed listing will be 
provided. 
4.5 
Treatment Compliance 
The descriptive statistics of treatment compliance will be analyzed using SS. 
4.5.1 SHR-1210 
Dosing frequency of SHR-1210 in subjects, frequency and reasons of dose discontinuation, and 
frequency and reasons of treatment interruption will be summarized using descriptive statistics. 
A detailed listing of SHR-1210 administration will be provided. This listing will include the 
reasons for dose discontinuation and treatment interruption. 
4.5.2 Docetaxel 
Dosing frequency of docetaxel in subjects, number and reasons of dose modifications, frequency 
and reasons of dose discontinuation, and frequency and reasons of treatment interruption will be 
summarized using descriptive statistics. 
A detailed listing of docetaxel administration will be provided. The listing will include the 
reasons for dose modification, dose discontinuation, and treatment interruption. 
4.5.3 Irinotecan 
Descriptive statistics will be provided in a manner similar to that for docetaxel. 
4.6 
Efficacy Analysis 
4.6.1 Handling of dropouts and missing data 
The handling of missing data will be described separately in sections corresponding to study 
endpoints. 


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4.6.2 Multiple comparison/multiplicity 
This study only involves 1 final analysis of the primary endpoint OS and multiplicity will not be 
involved. 
The secondary analysis in this study will be only used to provide supportive conclusions for the 
primary analysis and no  adjustments will be made for multiplicity. 
4.6.3 Subgroup analysis 
The subgroup analysis is exploratory and will only be performed based on FAS. This study will 
perform the following subgroup analyses on OS and PFS: 
First category of subgroup factors: 
• 
Gender: male/female 
• 
Expression of PD-L1 in tumor tissues: < 1% vs. ≥ 1% 
• 
Cumulative organ with metastatic lesion: 1 vs. ≥ 2. 
• 
Baseline ECOG PS: 0 vs. 1 
• 
Clinical staging: locally advanced lesion vs. distant metastasis 
• 
Liver metastasis: yes vs. no 
Second category of subgroup factors: 
• 
Age: < 65 years vs. ≥ 65 years 
• 
BMI: < 18.5 kg/m2 vs. ≥ 18.5 kg/m2 
• 
Smoking: Never smoke vs. Smoking vs. Quitted smoking 
• 
Alcohol use: Never drink alcohol vs Drinking alcohol vs Quitted alcohol 
To investigate the effects of subgroup factors on OS and PFS, the hazard ratios of OS and PFS of 
the investigational treatment group to the control group under various factors will be estimated 
using the Cox proportional hazards model and their 95% confidence intervals will be calculated 
based on the profile likelihood method. In addition, forest plots will be produced. The model will 
be fitted using treatment group as the only fixed effect with the randomized stratification factors 
being considered. If the subgroup analysis itself is one of the randomized stratification factors, 
the model should be equivalent to a Cox model stratified using the remaining randomized 
stratification factors. 


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4.6.4 Primary efficacy endpoint – OS 
4.6.4.1 
Primary analysis 
The primary analysis is to evaluate the efficacy difference between investigational treatment 
group and control group based on the FAS. In the primary analysis, the null hypothesis that the 
distributions of OS are identical between the two groups will be tested using the stratified log-
rank test based on randomized stratification factors (locally advanced lesion vs. distant 
metastasis; baseline ECOG PS (0 vs. 1). 
The median survival time and its 95% confidence interval will be calculated using the Kaplan-
Meier product limit method, and the survival curve will also be plotted. In addition, the number 
and percentage of subjects experiencing OS events and the number and percentage of censored 
subjects will be summarized and categorized by the reasons for censoring. 
Missing data: In this study, subject survival will be tracked where possible 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 such cases, 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). 
OS will be calculated in months using the following formula: (Date of OS event or censored date 
– Date of randomization + 1)/30.4375. If the complete death date cannot be obtained, e.g. the 
"day" is missing, the survival time will be calculated based on day 15. 
The above analysis for the primary efficacy endpoint will be repeated in FAS and PPS. 
4.6.4.2 
Secondary analysis 
The OS secondary analysis will include: 
• 
The 6-month, 1-year, and 2-year OS rates and their 95% confidence intervals for the 
two treatment groups will be estimated using the Kaplan-Meier product limit method. 
• 
The 1-year and 2-year restricted mean survival time, its difference between treatment 
groups, and the corresponding 95% confidence intervals will be calculated for the two 
groups based on the Kaplan-Meier survival curves (regardless of the randomized 
stratification factors). 
• 
The Kaplan-Meier product limit method will also be used to calculate the OS median 
survival time and its 95% confidence interval without the randomized stratification 
factors being considered, and the log-rank test method will be used to test the 
difference in survival distribution between groups. In addition, the differences in 


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survival distributions of the two groups will be compared using the Max-Combo test. 
The Max-Combo test will use three different Fleming-Harrington (FH) weights, 
namely FH (0,1), FH (1,0), and FH (1,1). 
• 
The hazard ratio of OS of the investigational treatment group to the control group will 
be estimated using the Cox proportional hazards model and its 95% confidence interval 
will be calculated based on the profile likelihood method. The model will be fitted 
using the treatment group as the only fixed effect with the randomized stratification 
factors being considered. In addition, to explore the effects of other factors on the 
efficacy, the model will also include the first category of subgroup factors (except 
randomized stratification factors) defined in Section 4.6.3, in addition to the treatment 
group, as covariates to participate in the fitting, so as to test the hazard ratio of the 
investigational treatment group to the control group following covariate-based 
adjustments. The above Cox proportional hazards model will use the Efron method to 
process the tied data. 
The above analysis for the primary efficacy endpoint will be repeated in FAS and PPS. Missing 
data will be recorded as right-censored data and the rules of censoring are the same as those in 
the primary analysis. 
4.6.5 Secondary efficacy endpoints 
The analysis of secondary efficacy endpoints in this study will be based on FAS only and will be 
carried out for all efficacy endpoints except OS (PFS, ORR, and quality of life score EORTC 
QLQ-C30 and EORTC QLQ-OES18). 
4.6.5.1 
PFS 
For PFS, the inter-group differences will be compared using the log-rank test, and meanwhile, 
HR of PFS will be estimated and the effects of factors (identical to those for OS) other than 
treatment group on the differences in PFS will be investigated using a Cox proportional hazards 
model; both test and model are identical to those used in the OS-related analysis. 
Subjects experiencing progressive disease or death (PFS events), will be censored when the 
following conditions occur: 
• 
If subjects have begun new anti-cancer treatment before the PFS event, they will be 
censored based on the date of the last tumor assessment carried out before the start of 
the new anti-cancer treatment (if there is no post-baseline cancer assessment, the date 
of randomization will be used for censoring). 


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• 
Deaths or progressive diseases occurring after two or more planned tumor assessments 
are missing will be censored based on the date of the last tumor efficacy assessment 
carried out before deaths or progressive diseases. The missing of two or more planned 
tumor evaluations is defined as a situation when the interval between the event and the 
last tumor assessment is more than 126 days. If there is no tumor assessment after 
randomization, the interval from the date of baseline tumor assessment to the date of 
event will be calculated. If the interval exceeds 126 days, it will be recorded as 
censored data with censoring to the date of randomization. 
If the start date of the new anti-cancer treatment is incomplete, it will be imputed with the 
earliest possible date. 
The rules of censoring for subjects experiencing no progressive disease or death are: 
• 
If there is no baseline tumor assessment, the date of randomization will be used for 
censoring. 
• 
If subjects have not experienced a PFS event at the end date of study/analysis or before 
dropout, the censoring will be carried out using the date of the last tumor efficacy 
evaluation. 
• 
If there is no post-baseline tumor efficacy assessment, the date of randomization will 
be used for censoring. 
The date of progressive disease of tumor 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  
• 
Date of the last imaging assessment of observed lesions (when progressive disease 
occurs based on the increased total observed lesions) 
If there is no progressive disease (including PR, CR, SD, and NE), the date of tumor assessment 
will be the latest one recorded for target and non-target lesions (theoretically, there will be no 
new lesions). 
4.6.5.2 
ORR 
Descriptive statistics will be summarized by treatment group (number and percentage of 
subjects). The 95% confidence interval of ORR for a single treatment group will be estimated 
using the Clopper-Pearson method. The 95% confidence interval of inter-group ORR difference 
will be estimated using the Newcombe method. 


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In addition, the ORR of post-treatment best overall response (BOR, the best assessment among 
all tumor efficacy evaluations will not include tumor efficacy evaluations carried out after 
progressive disease or after the start of new anti-cancer treatment) will be summarized using the 
same method described above. 
The analytical methods identical to those described above will be used for CR, PR, SD, DCR 
(defined as the sum of the proportions of subjects with CR, PR, and SD in the overall tumor 
efficacy assessment), and PD. 
In addition, the number and percentage of subjects who continue to use SHR-1210 after 
progressive disease and BOR of drug treatment following progressive disease will also be 
summarized. 
Handling of missing data: When calculating CR, missing data were considered as cases not 
achieving CR, while the handling method for PR, SD, DCR and PD was the same as that for CR. 
4.6.5.3 
DoR 
DoR will only be calculated for subjects who have experienced tumor response after treatment. 
The censoring rules for DoR are the same as those for PFS, and the end date of response of 
subjects must be consistent with that of progressive disease or death of subjects with PFS. For 
DoR, the median survival time and 6-month, 9-month, and 12-month objective response rates, as 
well as their 95% confidence intervals, in each treatment group will be calculated using the 
Kaplan-Meier product limit method, while the survival curves will be plotted. In addition, the 
differences between groups will be analyzed by a log-rank test using randomized stratification 
factors. A descriptive summary will be provided for DoR without the state of censoring being 
considered. 
4.6.5.4 
Quality of life score 
4.6.5.4.1 EORTC QLQ-C30 scale 
The analysis of EORTC QLQ-C30 will be performed using the QLQ-C30 analysis set. 
The EORTC QLQ-C30 scale comprises 30 items, 5 functional scales (physical, role, cognitive, 
emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), 1 global health 
status/quality of life, and 6 single-item scales (dyspnea, insomnia, appetite loss, constipation, 
diarrhea, and financial difficulties). 
For the calculation of the above scores and the handling of missing data, please refer to 
Appendix 3. For more information and SAS procedures, please refer to the EORTC QLQ-C30 
scoring manual[1]. 


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The descriptive statistics of the above scores at each assessment time point and their changes 
from baseline will be provided by treatment group along with a detailed listing. 
4.6.5.4.2 EORTC QLQ-OES18 scale 
The analysis of EORTC QLQ-OES18 will be performed using the QLQ-OES18 analysis set. 
The EORTC QLQ-OES18 scale contains 18 symptom items. Specifically, 12 symptom items can 
be further categorized into 4 subscales, including dysphagia (functional scale), eating (symptom 
scale), reflux (symptom scale), and pain (symptom scale). 
For the calculation of the scores of the above-mentioned subscales and the scores of 6 symptom 
items (single-item scale) and the handling of missing data, please refer to Appendix 4. 
The descriptive statistics of the above scores at each assessment time point and their changes 
from baseline will be provided by treatment group along with a detailed listing. 
4.6.6 Exploratory analysis 
The exploratory analysis will be carried out based solely on FAS. 
4.6.6.1 
Expression level of PD-L1 in tumor tissues 
For the expression of PD-L1 in tumor tissues at baseline, the relationships between the 
expression of PD-L1 and the OS, PFS and ORR (BOR) will be explored with cut-off points of 
< 1% and ≥ 1%, < 5% and ≥ 5%, and < 10% and ≥ 10%, respectively. 
For the analysis of OS and PFS, please refer to the subgroup analysis method as shown in 
Section 4.6.3. The hazard ratios of OS and PFS of the investigational treatment group to the 
control group under various factors will be estimated using the Cox proportional hazards model 
and their 95% confidence intervals will be calculated based on the profile likelihood method. In 
addition, forest plots will be produced. Furthermore, the survival curves under various cut-off 
points of PD-L1 will also be plotted for OS and PFS separately based on the Kaplan-Meier 
product limit method. 
The effects of PD-L1 expression on ORR (BOR) will be explored using a Logistic regression 
model. The model will include treatment group, expression of PD-L1, and interaction term 
between the two thereof. 
4.6.6.2 
Other biomarkers 
This SAP will not involve the analysis of other biomarkers. 


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4.7 
Safety Analysis 
The safety analysis will be summarized by the actual treatment based on SS. Unless otherwise 
stated, safety will be summarized using descriptive statistics. Missing data will not be imputed. 
4.7.1 Adverse events 
An adverse event (AE) refers to any untoward medical condition in a clinical trial subject who 
receives a pharmaceutical product, and the condition does not necessarily have a causality with 
the treatment. AEs will be documented starting from signing of the informed consent form to 
90 days after the last administration of study drugs. From 30 days after the end of treatment, only 
treatment-related AEs will be collected. 
A treatment-emergent AE (TEAE) is defined as an AE that occurs or becomes aggravated on the 
same day or after the first dose of the study drug but no later than 90 days after the last use of the 
study drug. If the start/end date of an AE is incomplete or missing, TEAE will be judged 
according to the "TEAE Judgment Rules" in Appendix 2. 
A treatment-related TEAE, i.e., adverse drug reaction (ADR), is defined as a TEAE whose 
causal relationship with the study drug is definitely related, possibly related, undeterminable, or 
unlikely related. If the relationship between AE and study drug is missing, the AE will be 
considered as an ADR. 
Significant AE is defined as AE, other than serious adverse event (SAE), and significant 
abnormality in blood routine or other laboratory tests (significant abnormality in laboratory test 
will be reported as an AE) that result in the use of targeted medical measures (e.g. drug holiday, 
dose reduction, and symptomatic treatment). 
Immune-related TEAEs of special interest include reactive capillary endothelial proliferation, 
immune-related pneumonitis, immune-related colitis, immune-related hepatitis, immune-related 
myocarditis, immune-related nephritis and renal dysfunction, immune-related endocrine 
diseases, immune-related cutaneous adverse drug reactions, and infusion reactions. 
For the summary statistics on the incidence of AE, each subject will be counted at most once 
under each SOC and PT. One AE that occurs multiple times in one subject will be counted based 
on its most severe level for the summary statistics of severity. When the severity of AEs is 
calculated, one AE that occurs multiple times in one subject will be counted based on its most 
severe level. If the severity of the AE that occurs once or multiple times in one subject is 
missing, no imputation will be made and summary will be carried out with "missing" as the 
category. 


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PT and SOC of AEs will be coded using MedDRA (v20.0), and the dictionary version will be 
updated once at the end of the project without in-project version alteration. The severity of AEs 
will be graded by NCI CTCAE (v4.03). 
First, the number and percentage of subjects who have experienced at least one of the following 
TEAEs throughout the study will be summarized: 
• 
Any TEAE 
• 
Treatment-related TEAE (ADR) 
• 
Grade ≥ 3 TEAE 
• 
Grade ≥ 3 ADR 
• 
TEAE leading to treatment interruption/discontinuation 
• 
ADR leading to treatment interruption/discontinuation 
• 
TEAE leading to death 
• 
ADR leading to death 
• 
Any TESAE (including death) 
• 
Treatment-related TESAE (including death) 
• 
TESAE leading to treatment interruption/discontinuation 
• 
TESAE leading to death 
• 
Treatment-related TESAE leading to death 
• 
TEAE of special interest 
• 
Investigator-judged immune-related TEAE 
• 
Investigator-judged immune-related TEAE leading to death 
• 
Significant TEAE 
• 
Treatment-related significant AE (significant ADR) 
• 
Event with the highest CTC grade: grade 1-5 
Second, the number and percentage of subjects under each category of the following AEs 
will be summarized: 
• 
TEAE (at least one) by SOC and PT 
• 
ADR (at least one) by SOC and PT 


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• 
Grade ≥ 3 TEAE (at least one) by SOC and PT 
• 
Grade ≥ 3 ADR (at least one) by SOC and PT 
• 
TEAE by SOC and PT (at least one, categorized by the most severe level) 
• 
Treatment-related TEAE (at least one, categorized by the most severe level) 
• 
TEAE leading to treatment suspension by SOC and PT 
• 
TEAE leading to treatment termination by SOC and PT 
• 
ADR leading to treatment suspension by SOC and PT 
• 
ADR leading to treatment termination by SOC and PT 
• 
TEAE leading to death by SOC and PT 
• 
ADR leading to death by SOC and PT 
• 
TESAE (at least one) by SOC and PT 
• 
Treatment-related TESAE (at least one) by SOC and PT 
• 
TESAE leading to treatment suspension by SOC and PT 
• 
TESAE leading to treatment termination by SOC and PT 
• 
TESAE leading to death by SOC and PT 
• 
Treatment-related TESAE leading to death by SOC and PT 
• 
TEAE of special interest by SOC and PT 
• 
TEAE of special interest leading to treatment suspension by SOC and PT 
• 
TEAE of special interest leading to treatment termination by SOC and PT 
• 
TEAE of special interest by SOC and PT (including outcome and corrective treatment) 
• 
Investigator-judged immune-related TEAE by SOC and PT 
• 
Investigator-judged immune-related TEAE leading to treatment suspension by SOC 
and PT 
• 
Investigator-judged immune-related TEAE leading to treatment termination by SOC 
and PT 
• 
Investigator-judged immune-related TEAE leading to death by immune-related TEAE 
and PT 


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• 
Investigator-judged immune-related TEAE by SOC and PT (including outcome and 
corrective treatment) 
• 
Significant TEAE by SOC and PT 
• 
Significant ADR by SOC and PT 
Then, the following AEs will be summarized by SOC and PT, and the number and 
percentage of subjects under each PT will be provided: 
• 
TEAE by SOC and PT with an incidence of ≥ 5% 
• 
ADR by SOC and PT with an incidence of ≥ 2% 
• 
TEAE by SOC and PT with incidence of ≥ 10% in the treatment group and inter-group 
incidence difference of ≥ 5% 
• 
ADR by SOC and PT with incidence of ≥ 10% in the treatment group and inter-group 
incidence difference of ≥ 5% 
• 
Grade ≥ 3 TEAE by SOC and PT with incidence of ≥ 10% in the treatment group and 
inter-group incidence difference of ≥ 2% 
• 
Grade ≥ 3 ADR by SOC and PT with incidence of ≥ 10% in the treatment group and 
inter-group incidence difference of ≥ 2% 
Meanwhile, the following AEs will be summarized based on immune-related TEAE of 
special interest, and the number and percentage of these AEs will be provided. 
• 
Immune-related TEAE of special interest (at least one) by immune-related TEAE and 
PT, as well as the most severe CTCAE grade 
• 
Immune-related TEAE of special interest leading to treatment 
interruption/discontinuation by immune-related TEAE 
• 
Immune-related TEAE of special interest by immune-related TEAE (including the 
alleviated number and percentage) 
In addition, for immune-related TEAE of special interest (by immune-related TEAE), time to the 
occurrence of AE, time to the occurrence of grade ≥ 3 AE, duration of AE, duration of grade ≥ 3 AE, 
response time of AE, response time of grade ≥ 3 AE, incidence of AE calculated by exposed 
person-year, and incidence of grade ≥ 3 AE calculated by exposed person-year will be 
summarized. The incidences of TESAE and treatment-related TESAE will also be calculated by 
exposed person-year and summarized by SOC and PT. 


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The time (day) to the occurrence of AE is defined as the time from the date of the first study drug 
administration to the date of the first occurrence of the AE. If one subject has experienced 
multiple times of one AE, the date of the first occurrence of the AE will be used for calculation 
regardless of the AE grading. The formula is as follows: Start date of AE – Date of the first dose 
of study drug + 1. 
The time (day) to the occurrence of grade ≥ 3 AE is defined as the time from the date of the first 
study drug administration to the date of the first occurrence of the grade ≥ 3 AE. The calculation 
method is similar to the time to the occurrence of AE. 
The response time of AE (day) is defined as the date from the start to the end of the AE, and the 
calculation formula is as follow: End date of AE – Start date of AE + 1. If one subject has 
experienced multiple times of one AE, the cumulative time of the AE will be calculated, but the 
time overlapping of multiple times of the AE should be excluded in the calculation. If an AE is 
not relieved by the cut-off time point of analysis or the end of the study (the response of the AE 
will be judged by the last outcome information of the AE, and the response include AE outcome 
of recovered/resolved, recovered/resolved with sequelae, and alleviated), the end date of the AE 
will be used for censoring. If the end date of the AE is missing, the date of the last follow-up 
visit or the date of death (whichever is earlier) will be used for censoring. If one AE category 
(such as the category of immune-related AE) contains more than one AE (by PT) and one of 
these AEs is not relieved, this AE category will be judged as not relieved. 
The duration of AE is defined similarly to the response time of AE, with the difference that the 
duration of AE does not need to consider the state of censoring. 
Time to the occurrence of AE, time to the occurrence of grade ≥ 3 AE, response time of AE, and 
response time of grade ≥ 3 AE will only be calculated for the population who have experienced 
AE, and the corresponding median time and 95% confidence interval will be estimated by the 
Kaplan-Meier product limit method. For duration of AE and duration of grade ≥ 3 AE, a 
descriptive summary will be provided as measurement data. 
The incidence of AE calculated by exposed person-year is the ratio of the number of subjects 
experiencing this AE to the total exposed time by person-year. The total exposed time by person-
year is defined as the sum of time from the first dose of the study drug to 90 days after the end of 
study drug treatment for all subjects. For subjects who have withdrawn from the study, died 
within 90 days after the end of study drug treatment, or been lost to follow-up, the time between 
the date of the first drug administration to the date of the last follow-up visit or death, whichever 
is earlier, will be calculated. The total exposed time by person-year will be calculated in years, 
and the number of days will be converted into the number of years by dividing 365.25. 
 


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For immune-related TEAE of special interest (by immune-related TEAE), the descriptive 
summary of the number and percentage of subjects receiving high dose of corticosteroids 
(defined as at least one dose or a single daily dose of ≥ 40 mg of the equivalent dose of 
prednisone), the starting dose of corticosteroids, and the duration of dosing will also be provided. 
The dosage of different hormonal drugs will be converted into the equivalent dose of prednisone 
according to the following formula: 0.75 mg of dexamethasone = 5 mg of prednisone = 5 mg of 
prednisolone = 4 mg of methylprednisolone = 20 mg of hydrocortisone = 0.8 mg of betamethasone. 
If one subject experiences one AE and receives two or more hormones during the presence of the 
AE, the starting dose of the hormone used first will be involved in the statistics of starting doses 
(i.e., the starting dose(s) of subsequent hormone therapy/therapies will not be involved in the 
statistics of starting doses). Then, the cumulative duration of the use of multiple hormones 
(time overlapping of hormone therapies should be excluded in the calculation) will be 
summarized as the duration of dosing. If one AE category (such as the category of immune-
related AE) contains more than one AE (by PT), this AE category will be treated as one AE 
when being summarized. When the starting dose is summarized, if the dosing frequency of 
hormones is more than once a day, it will be converted into a single daily dose before being 
summarized. When the duration of dosing is summarized, if the end date of hormone drug treatment 
is unknown, it will be imputed with the start date of the last dose of the hormone drug treatment. 
The corrective treatment will also be summarized for immune-related endocrine diseases. 
Corrective treatment, incidence of bleeding, and incidence of infection will also be summarized 
for reactive capillary endothelial proliferation. 
A detailed listing of AE, SAE, AE leading to treatment suspense/termination, and death will be 
provided. 
4.7.2 Laboratory measurements 
For blood routine, blood biochemistry, urinalysis, and thyroid functions, a shift table will be used 
to descriptively summarize the number and percentage of subjects showing most significant 
changes from baseline after the first administration. Among them, the statistics of the most 
severe grading will be calculated for indicators whose toxicity grading can be carried out by 
CTCAE. The statistics of the most severe clinical significance (grading of clinical severity: 
abnormal with clinical significance > abnormal with no clinical significance > normal) will also 
be provided for the above indicators. In addition, the most severe grade 3/4 conditions occurring 
after the first administration will be summarized for the CTCAE grading. 
In addition, for the judgment of clinical significance of blood routine, blood biochemistry, 
urinalysis, and thyroid functions, a shift table by treatment group and test/analysis time points 
will be used to descriptively summarize the number and percentage of subjects showing changes 


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from baseline. For quantitative test/analysis indicators such as blood routine, blood biochemistry, 
and thyroid functions, the measurements of various indicators and their change from baseline 
will be descriptively summarized by treatment group and test/analysis time point. 
The judgment of clinical significance of test indicators such as blood routine, blood 
biochemistry, urinalysis, thyroid function, coagulation function, fecal occult blood, and virology 
will be provided with a detailed listing of various laboratory test items. The listing will include at 
least name of visit, date of sampling, number of days of study, measurement and unit (if applicable), 
judgment of clinical significance (if applicable), and CTCAE severity grading (if any). 
4.7.3 ECOG (performance status) 
ECOG PS will be treated as a categorical variable, and the number and percentage of subjects 
with various ECOG PS will be summarized by treatment group and assessment time point. In 
addition, a detailed listing of ECOG will also be provided. The listing will include at least name 
of visit, date of scoring, study day, and ECOG PS. 
4.7.4 Vital signs 
The vital signs to be collected in this study will include body temperature, heart rate, respiration, 
diastolic blood pressure, and systolic blood pressure. The number and incidence of subjects with 
clinically significant abnormalities after the first administration will be descriptively summarized 
by treatment group (refer to the following criteria for determining clinically significant 
abnormalities in vital signs), along with the results obtained at various time points and their 
changes from baseline. 
In addition, a detailed listing of vital signs will also be provided. The listing will include at least 
the name of the visit, the date of the examination, the study day, the results of various 
examination items of vital signs, and the signs of clinically significant abnormalities. 
The criteria for determining clinically significant abnormalities of vital signs are as follows: 
Test Item 
Unit 
Low 
High 
Body Temperature °C  
≤ 35 ˚C and change from baseline  
≤ -1.1 ˚C 
≥ 38.3 ˚C and change from baseline  
≥ 1.1 ˚C 
Heart Rate 
bpm 
< 40 bpm 
> 120 bpm 
Respiration 
resp/min 
< 12 times/min 
> 24 times/min 
Systolic Blood 
Pressure 
mmHg 
< 90 mmHg  
or 
change from baseline ≤ -30 mmHg 
change from baseline ≥ 30 mmHg 
Diastolic Blood 
Pressure 
mmHg 
< 50 mmHg  
or 
change from baseline ≤ -20 mmHg 
change from baseline ≥ 20 mmHg 


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4.7.5 12-lead ECG 
The descriptive summary of the number and percentage of subjects based on the most severe 
cases after the first administration will be provided by clinical significance judgment, i.e., 
normal, abnormal with no clinical significance, and abnormal with clinical significance (grading 
of clinical severity: abnormal with clinical significance > abnormal with no clinical 
significance > normal). The clinical significance judgment will also be descriptively summarized 
by test time points. 
For PR interval and QTcF, the incidence of each category defined in the table below after the 
first administration will be summarized. In addition, the incidence will be summarized by test 
time points. 
Classification criteria of PR and QTcF 
Test Item 
Unit 
 
Criteria for Abnormality 
PR 
ms 
Absolute value 
max. ≥ 300 
 
 
Change from baseline 
Baseline > 200 and change from baseline ≥ 25%, or, 
baseline ≤ 200 and change from baseline ≥ 50% 
QTcF 
ms 
Absolute value 
450 ≤ max. < 480 
480 ≤ max. < 500 
max. ≥ 500 
 
 
Change from baseline 
30 ≤ max. < 60 
max. ≥ 60 
For ECG parameters such as heart rate, PR interval, QT interval, and QTcF, the results obtained 
at various time points and their changes from baseline will be descriptively summarized. 
A detailed listing will be provided for the results of ECG. 
4.7.6 Echocardiography 
A detailed listing of echocardiogram will be provided. 
4.7.7 Physical examination 
A shift table by treatment group and time points will be used to descriptively summarize the 
number and percentage of subjects showing changes from baseline in various investigations 
(normal, abnormal), and a detailed listing will be provided. 
4.8 
Determination of Sample Size 
This is parallel study with its primary endpoint being OS. Subjects will be randomized in a 1:1 ratio. 
Assuming that the median OS of the control group is 7 months and the median OS of the 
treatment group is 9.5 months (the treatment group will be extended by 2.5 months compared 
with that of the control group), the inter-group OS distribution will be compared using a 


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stratified log-rank test at an overall significance level  = 0.025 (one-sided); when the duration 
of enrollment is assumed to be 18 months and the entire study lasts for 36 months, at least 365 
OS events need to be collected to obtain a power of 80% according to the calculation by East 
(v6.3). Furthermore, assuming a drop-out rate of 20%, a total of 438 subjects need to be enrolled 
in this study (219 in the investigational treatment group and 219 in the control group). 
4.9 
Updates for Study Implementation or Planned Analysis 
Since the immunogenicity data are not collected during the study implementation, the 
immunogenicity analysis mentioned in Section 11.4.4 of the protocol will no longer available. 
A DoR analysis is added for the secondary endpoints. 
5 
REFERENCES 
[1] EORTC. The EORTC QLQ-C30 Scoring Manual. 3rd edition. 2001. 
[2] EORTC. Scoring Procedure for the EORTC-QLQ-OES18. 
 


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6 
APPENDICES 
6.1 
Appendix 1 
Rules of Age Calculation: 
Date of Informed Consent 
Date of Birth 
Algorithm 
Complete 
Complete 
When the "month" and "day" in the date of the informed consent 
are equal to or later than those in the date of birth, age = number 
of years in the date of informed consent – number of years in the 
date of birth. 
When the "month" and "day" in the date of the informed consent 
are earlier than those in the date of birth, age = number of years 
in the date of informed consent – number of years in the date of 
birth – 1. 
 
Incomplete 
When the "day" in the date of birth is missing, the calculation 
will be carried out using the 15th day of the corresponding month. 
The rules of calculation are the same as those applicable to the 
calculation of complete date. 


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6.2 
Appendix 2 
Rules of Imputing Incomplete Date: 
Date 
Earliest Possible Date 
Latest Possible Date 
Missing "Day" 
The first day of the month 
The last day of the month 
Missing "Month" and "Day" 
1 Jan. 
31 Dec. 
TEAE Judgment Rules 
Start/Aggravation Date 
End Date 
Rule 
Complete 
Complete 
When "start date" ≥ "date of first study drug administration" and 
"start date" ≤ "date of last study drug administration" + 90, it is 
judged as a TEAE. 
 
Incomplete 
TEAE is judged based on "start date", and "end date" is imputed with 
the latest possible date. 
 
Missing 
TEAE is judged based on the "start date". 
Incomplete, but it can be 
determined from the 
known part of the date that 
the AE is impossible to 
occur on the same day of 
or after the first study drug 
administration 
Complete 
It's not a TEAE. "Start date" is imputed with the earliest possible 
date. 
Incomplete 
It's not a TEAE. "Start date" is imputed with the earliest possible 
date. "End date" is imputed with the latest possible date. 
Missing 
It's not a TEAE. "Start date" is imputed with the earliest possible 
date. 
Incomplete, but AE may 
occur on the same day of 
or after the first study drug 
administration 
Complete 
When "end date" ≥ "date of first study drug administration", it is 
judged as a TEAE. The earliest possible date is used as "start date". 
When the earliest possible date is earlier than "date of first study 
drug administration", "date of first study drug administration" will be 
used for imputation. 
When "end date" < "date of first study drug administration", it is not 
judged as a TEAE; "start date" is imputed with the earliest possible 
date. 
Incomplete 
It is judged as a TEAE. "Start date" is imputed with the earliest 
possible date; when the earliest possible date is before "date of first 
study drug administration", "date of first study drug administration" 
will be used for imputation; "end date" is imputed with the latest 
possible date. 
Missing 
It is judged as a TEAE. "Start date" is imputed with the earliest 
possible date; when the earliest possible date is before "date of first 
study drug administration", "date of first study drug imputation" will 
be used for imputation. 
Missing 
Complete 
When "end date" ≥ "date of first study drug administration", it is 
judged as a TEAE. 
 
Incomplete 
When "end date" is incomplete, the latest possible date will be used 
for imputation; when the latest possible date ≥ "date of first study 
drug administration", it is judged as a TEAE. 
 
Missing 
It is judged as a TEAE. 


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6.3 
Appendix 3 
EORTC QLQ-C30 (v3) Scoring Guideline 
 
Scale 
Number of 
Items 
Item Range 
eCRF Item 
Numbers 
Functional 
Scales 
Global Health Status 
QL2 
2 
6 
29, 30 
 
Functional Scales 
 
 
 
 
 
  
PF2 
5 
3 
1 to 5 
F 
  
RF2 
2 
3 
6, 7 
F 
  
EF 
4 
3 
21 to 24 
F 
  
CF 
2 
3 
20, 25 
F 
  
SF 
2 
3 
26, 27 
F 
Symptom Scales 
 
 
 
 
 
  
FA 
3 
3 
10, 12, 18 
 
  
NV 
2 
3 
14, 15 
 
  
PA 
2 
3 
9, 19 
 
Single-Item Scale 
 
 
 
 
 
  
DY 
1 
3 
8 
 
  
SL 
1 
3 
11 
 
  
AP 
1 
3 
13 
 
  
CO 
1 
3 
16 
 
  
DI 
1 
3 
17 
 
  
FI 
1 
3 
28 
 
For all scales, the calculation of the scores is divided into the following steps: 
• 
Step 1: Calculate the RawScore = RS = I1 + I2 + … + In) / n of each scale, where n is 
the number of items answered in each scale, and I represents the score of each item in 
this scale. 
• 
Step 2: For Functional scales, the final score is calculated by the following formula: 
Score = (1 – (RS – 1)/range) × 100, where range is the value range of RS, equivalent to 
the value range of a single item in the functional scales. For Global health status, 
Symptom scales, and 6 Single-item scales, the final score is calculated using the 
following formula: Score = ((RS – 1)/range) × 100.  
Handling of missing data: For the global health status, functional scale, and symptom scale, if at 
least half of the items from the scale have been answered, the score is calculated using the above 
steps; otherwise, the score of this scale is considered missing. 


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6.4 
Appendix 4 
EORTC QLQ-OES18 Scoring Guideline 
 
Scale 
Number of Items 
Item Range 
eCRF Item 
Numbers 
Functional Scales 
 
 
 
 
  
OESDYS 
3 
3 
31 to 33 
Symptom Scales 
 
 
 
 
  
OESEAT 
4 
3 
36 to 39 
  
OESRFX 
2 
3 
44, 45 
  
OESPA 
3 
3 
46 to 48 
Single-Item Scale 
 
 
 
 
  
OESSV 
1 
3 
34 
  
OESCH 
1 
3 
35 
  
OESDM 
1 
3 
40 
  
OESTA 
1 
3 
41 
  
OESCO 
1 
3 
42 
  
OESSP 
1 
3 
43 
The calculation methods and handling of missing data of Functional scales, Symptom scales, and 
Single-item scales are the same as those shown in Appendix 3.