A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center Study to Compare Toripalimab Injection (JS001) Combined With Standard Chemotherapy Versus Placebo Combined With Standard Chemotherapy in Treatment of Advanced or Metastatic Esophageal Squamous Cell Cancer (ESCC) Without Previous Systemic Chemotherapy
Phase: PHASE3
Conditions: Advanced or Metastatic Esophageal Squamous Cell Cancer Without Previous Systemic Chemotherapy
Sponsor: Shanghai Junshi Bioscience Co., Ltd.

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
Clinical Study Protocol 
Protocol Title:  
A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled, Multi-Center Study to Compare 
Toripalimab (JS001) Combined with Standard 
Chemotherapy vs Placebo Combined with Standard 
Chemotherapy in the Treatment of Advanced or 
Metastatic Esophageal Squamous Cell Carcinoma 
without Previous Systemic Chemotherapy 
Protocol Number: 
JS001-021-III-ESCC 
Medicinal Product(s):  
Toripalimab (JS001) 
Study Phase:  
Phase 3 
Sponsor:  
Shanghai Junshi Biosciences Co., Ltd. 
Floor 13, Building 2, Haiqu Road No. 36 and 58, Free 
Trade Zone, Shanghai, China, 200120 
Medical Monitor:  
Xusheng Ren, Medical Manager 
Principal Investigator:  
Prof. Ruihua Xu 
Protocol Number: 
4.0 
Protocol Date: 
June 30, 2020 
Previous Versions: 
v1.0, October 25, 2018 
 
v2.0, April 30, 2019 
 
v3.0, August 19, 2019 
 
Confidentiality Statement 
The confidential information provided to you (investigator or consultant) in this document is for review by you, 
your staff, and appropriate institutional review board/independent ethics committee. Acceptance of this 
document means that you agree not to disclose the information contained herein to others without the written 
approval by the Sponsor. 
 
 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
Table of Contents 
 
Sponsor’s Statement ..................................................................................................................................... 7 
Investigator’s Statement ............................................................................................................................... 8 
Protocol Synopsis .......................................................................................................................................... 9 
List of Abbreviations and Definition of Terms ......................................................................................... 25 
1 
Background ......................................................................................................................... 28 
1.1 
Relevant Background for Esophageal Cancer................................................................... 28 
1.1.1 
Targeted Therapy Against Esophageal Cancer ............................................................. 29 
1.1.2 
Relevant Studies of Programmed Death -1 in Esophageal Squamous Cell Cancer ...... 29 
1.2 
Background of Toripalimab ................................................................................................ 30 
1.2.1 
Pharmacodynamics ....................................................................................................... 31 
1.2.2 
Pharmacokinetics/Pharmacodynamics and Immunogenicity in Animals ..................... 31 
1.2.3 
Pre-clinical Toxicology Studies .................................................................................... 32 
1.3 
Toripalimab-related Clinical Experience .......................................................................... 34 
1.3.1 
Ongoing Clinical Studies .............................................................................................. 34 
1.3.2 
Clinical Safety ............................................................................................................... 36 
1.3.3 
Clinical Efficacy ........................................................................................................... 37 
1.3.4 
Clinical Pharmacokinetics, Dose Selection, and Immunogenicity ................................ 39 
1.4 
Rationale for Study Design .................................................................................................. 40 
1.5 
Benefit-Risk Assessment ...................................................................................................... 41 
2 
Study Objectives ................................................................................................................. 43 
2.1 
Efficacy Objectives ............................................................................................................... 43 
2.1.1 
Primary Efficacy Objective ........................................................................................... 43 
2.1.2 
Secondary Efficacy Objectives ............................................................................................ 43 
2.2 
Safety Objective ................................................................................................................... 44 
2.3 
Exploratory Objectives ........................................................................................................ 44 
3 
Study Design ........................................................................................................................ 44 
3.1 
Study Description ................................................................................................................. 44 
3.2 
End of study and Duration of the Study ........................................................................ 48 
4 
Materials and Methods ....................................................................................................... 48 
4.1 
Study Population .................................................................................................................. 49 
4.1.1 
Inclusion Criteria .......................................................................................................... 49 
4.1.2 
Exclusion Criteria ......................................................................................................... 51 
4.1.3 
Considerations for Other Inclusion Criteria .................................................................. 56 
4.1.4 
Additional Patient Requirements for Study Participation ............................................. 56 
4.2 
Treatment Allocation and Blinding .................................................................................... 57 
4.3 
Treatment Plan ..................................................................................................................... 58 
4.3.1 
Formulation, Packaging and Disposal ........................................................................... 58 
4.3.2 
Study Treatment Dosages, Administration and Compliance ........................................ 60 
4.3.3 
Storage, Handling and Retention of the Study Drugs and Chemotherapeutic Drugs.... 62 
4.3.4 
Prophylactic Medications .............................................................................................. 63 
4.3.5 
Access to Toripalimab After Study Closure ................................................................. 64 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
4.4 
Concomitant Medication and Concurrent Therapy ......................................................... 64 
4.5 
Prohibited Therapy .............................................................................................................. 66 
4.6 
Study Assessments ............................................................................................................... 66 
4.6.1 
Informed Consent Form and Screening Evaluation ...................................................... 66 
4.6.2 
Demographic Information and Baseline Disease Characteristics ................................. 67 
4.6.3 
Physical Examination .................................................................................................... 67 
4.6.4 
Vital Signs ..................................................................................................................... 67 
4.6.5 
Electrocardiogram ......................................................................................................... 68 
4.6.6 
Echocardiography ......................................................................................................... 68 
4.6.7 
ECOG Performance Status Score.................................................................................. 68 
4.6.8 
Laboratory Tests ........................................................................................................... 68 
4.6.9 
Analysis of Biological Specimens ................................................................................ 69 
4.6.10 Tumor Assessments ...................................................................................................... 70 
4.6.11 Tumor Tissue Samples .................................................................................................. 72 
4.6.12 Patient-reported Outcomes ............................................................................................ 73 
4.6.13 Schedule of Assessment ................................................................................................ 73 
4.7 
Discontinuation of Study Treatment .................................................................................. 75 
4.7.1 
Discontinuation of Study Treatment  By Patients ......................................................... 75 
4.7.2 
Discontinuation of Study Treatment by Investigators ................................................... 75 
4.7.3 
Termination of the Study and/or Closure of the Research Site ..................................... 77 
5 
Safety Evaluation ................................................................................................................ 77 
5.1 
Safety Plan ............................................................................................................................ 78 
5.1.1 
Risks Associated with Toripalimab .............................................................................. 78 
5.1.2 
Risks Associated with  Paclitaxel ................................................................................. 79 
5.1.3 
Risks Associated with Cisplatin .................................................................................... 79 
5.1.4 
Overall Plan for Safety Management ............................................................................ 79 
5.1.5 
Dose Adjustment and Management of Adverse Events Related to Toripalimab/Placebo 
and Chemotherapeutic Drugs ........................................................................................ 80 
5.2 
Safety Parameters and Definitions ..................................................................................... 87 
5.2.1 
Adverse Events ............................................................................................................. 88 
5.2.2 
Serious Adverse Events ................................................................................................ 88 
5.2.3 
Adverse Events of Special Interest (to be Report to the Sponsor Immediately) ........... 89 
5.3 
Methods and Timing for Capturing and Evaluating Safety Parameters ........................ 90 
5.3.1 
Adverse Event Reporting Period ................................................................................... 90 
5.3.2 
Collection of Adverse Events ....................................................................................... 90 
5.3.3 
Severity Assessment of Adverse Events ....................................................................... 90 
5.3.4 
Causality Analysis of Adverse Events .......................................................................... 91 
5.3.5 
Recording Procedure of Adverse Events ...................................................................... 92 
5.4 
Immediate Reporting Requirements (Within 24 Hours) From Investigators to the 
Sponsor ................................................................................................................................. 98 
5.4.1 
Serious Adverse Event Reporting Requirements .......................................................... 99 
5.4.2 
Reporting Requirements for Pregnancies ...................................................................... 99 
5.5 
Follow-up for Patients Following Adverse Events .......................................................... 100 
5.5.1 
Investigator Follow-up ................................................................................................ 100 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
5.5.2 
Sponsor Follow-up ...................................................................................................... 101 
5.6 
Post-study Adverse Events ................................................................................................ 101 
5.7 
Expedited Reporting to Health Authorities, Investigators, Institutional Review Board, 
and Ethics Committee ....................................................................................................... 101 
6 
Statistical Considerations and Analytical Plan .............................................................. 102 
6.1 
Determination of Sample Size ........................................................................................... 102 
6.2 
Data Analysis Sets .............................................................................................................. 103 
6.3 
Analytical Method .............................................................................................................. 103 
6.3.1 
Demographics and Baseline Disease Characteristics .................................................. 103 
6.3.2 
Efficacy ....................................................................................................................... 104 
6.3.3 
Safety .......................................................................................................................... 106 
6.3.4 
Exploratory Analysis................................................................................................... 106 
6.4 
Interim Analysis ................................................................................................................. 106 
7 
Data Collection and Management ................................................................................... 107 
7.1 
Quality Assurance of Data ................................................................................................ 107 
7.2 
Electronic Case Report Form ........................................................................................... 107 
7.3 
Source Documents .............................................................................................................. 108 
7.4 
Use of Electronic Data Capture Systems ......................................................................... 108 
7.5 
Records Retention .............................................................................................................. 109 
8 
Ethical Considerations ..................................................................................................... 109 
8.1 
Compliance ......................................................................................................................... 109 
8.2 
Informed Consent .............................................................................................................. 109 
8.3 
Ethic Committee ................................................................................................................. 110 
8.4 
Principles of Maintaining Confidentiality ....................................................................... 111 
8.5 
Financial Disclosure ........................................................................................................... 111 
9 
Study Records, Monitoring and Management ............................................................... 111 
9.1 
Study Records ..................................................................................................................... 111 
9.2 
Protocol Deviations ............................................................................................................ 112 
9.3 
Quality Control and Quality Assurance .......................................................................... 112 
9.3.1 
Monitoring .................................................................................................................. 112 
9.3.2 
Auditing ...................................................................................................................... 113 
9.4 
Administrative Management Structure ........................................................................... 113 
9.5 
Publication of the Data and Protection of Commercial Confidential Information/Trade 
Secrets ................................................................................................................................. 113 
9.6 
Protocol Amendment(s) ..................................................................................................... 114 
10 
Independent Data monitoring Committees (IDMC)...................................................... 114 
11 
References .......................................................................................................................... 115 
Appendix 1 
Schedule of Assessments ................................................................................................... 118 
Appendix 2 
Schedule of Biomarkers and Anti-drug Antibody Sampling ........................................ 122 
Appendix 3    Esophageal Cancer Staging of the American Joint Committee on Cancer, v8 (2017) . 123 
Appendix 4    Response Evaluation Criteria in Solid Tumors (RECIST) ............................................ 125 
Appendix 5    Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) ............. 126 
Appendix 6    Recommendations for Treatment of Hypothyroidism .................................................... 133 
Appendix 7    EORTC QLQ-C30 Questionnaire .................................................................................... 135 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
Appendix 8 
EORTC QLQ-OES18 Questionnaire .............................................................................. 137 
Appendix 9 
Eastern Cooperative Oncology Group Performance Status ......................................... 138 
Appendix 10 Management of Allergic Reactions .................................................................................. 139 
Appendix 11 Listing of Autoimmune or Immunodeficiency Disorders to be Considered During 
Screening ........................................................................................................................... 140 
 
 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
List of Tables 
Table 1 
List of Ongoing Clinical Studies of Toripalimab ......................................................................... 34 
Table 2 
Treatment Groups  ........................................................................................................................ 46 
Table 3 
Chemistry and Manufacturing Information for Toripalimab and Placebo .................................... 59 
Table 4 
Administration Procedures for First and Subsequent Infusions of Study Drug  ........................... 60 
Table 5 
Dosage Regimens of Paclitaxel and Cisplatin .............................................................................. 61 
Table 6 
Prophylactic Regimens Administered Prior to Paclitaxel and Cisplatin Administration .............. 63 
Table 7 
Dose Adjustment of Cisplatin for Hematologic Toxicity ............................................................. 81 
Table 8 
Dose Adjustment of Cisplatin for Non-hematologic Toxicity ...................................................... 82 
Table 9 
Dose Adjustment of Cisplatin for Neurologic Toxicity ................................................................ 83 
Table 10 Dose Adjustment Levels for Paclitaxel ........................................................................................ 83 
Table 11 Dose Adjustment of Paclitaxel for Sensory Neuropathya ............................................................. 84 
Table 12 Dose Adjustment of Paclitaxel for Musculoskeletal Pain That Cannot Be Controlled With 
Analgesicsa ................................................................................................................................... 84 
Table 13 Dose Adjustment of Paclitaxel for Hematologic Toxicitya ........................................................... 85 
Table 14 Dose Adjustment of Paclitaxel for Neutropenic Fevera ................................................................ 85 
Table 15 Dose Adjustment of Paclitaxel for Gastrointestinal Toxicity Related to Chemotherapy Other than 
Hepatotoxicitya ............................................................................................................................. 86 
Table 16 Dose Adjustment of Paclitaxel for Hepatotoxicitya ...................................................................... 87 
Table 17 Dose Adjustment of Paclitaxel for Other Clinically Significant AEs a ......................................... 87 
Table 18 Severity Rating Scale for Adverse Events Not Listed in CTCAE ................................................ 91 
 
List of Figures 
Figure 1 
Study Flowchart ......................................................................................................................... 45 
 
 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
Sponsor’s Statement 
Protocol Title: 
A Phase 3, randomized, double-blind, placebo-controlled, 
multi-center study to compare toripalimab (JS001) combined 
with standard chemotherapy vs placebo combined with standard 
chemotherapy in the treatment of advanced or metastatic 
esophageal squamous cell carcinoma without previous systemic 
chemotherapy 
Protocol Number: 
JS001-021-III-ESCC 
Version Number and 
Version Date: 
Version 4.0, June 30, 2020 
 
 
I will conscientiously fulfill the Sponsor’s obligations according to China’s Good Clinical 
Practice (GCP) regulations and be responsible for initiating, conducting, organizing, funding, 
and monitoring this clinical study. I will, in accordance with the relevant national laws and 
regulations, provide active treatments to patients with serious treatment-emergent adverse 
events during the clinical study and cover the corresponding cost of treatment and will also 
provide rational economic compensation for the damage caused by the serious adverse 
reaction that is determined to be related to the study drug. I agree to conduct the clinical study 
in accordance with the design and provisions in this protocol. 
 
 
Sponsor: Shanghai Junshi Biosciences Co., Ltd. 
 
Name of Project Lead: Wei Liu 
Title: Head of the Department of Medical Sciences 
Project Lead (signature):____________ 
Date:____dd____mm____yyyy 
 
 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
 
Investigator’s Statement 
I have read the clinical study protocol (version number: 4.0, dated June 30, 2020), entitled 
“A Phase 3, randomized, double-blind, placebo-controlled, multi-center study to compare 
Toripalimab (JS001) combined with standard chemotherapy vs placebo combined with 
standard chemotherapy in treatment of advanced or metastatic esophageal squamous cell 
carcinoma without previous systemic chemotherapy,” and agree to conduct this clinical study 
in accordance with the study protocol, the current laws and regulations, and the ethical 
principle in the Declaration of Helsinki. 
I agree to comply with the guidelines of GCP and other applicable National Medical Products 
Administration (NMPA) regulations/guidelines on the quality management rules for drug 
clinical studies. 
I agree that the confidential information in this document shall not be used for purposes other 
than the evaluation or conduction of the clinical study, without prior written approval by 
Shanghai Junshi Biosciences Co., Ltd. 
 
Principal investigator name: ____________ 
 
Signature:_______________________ 
Date:____dd____mm____yyyy 
 
 
 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
 
Protocol Synopsis 
Study Title: 
A Phase 3, randomized, double-blind, placebo-controlled, 
multi-center study to compare toripalimab (JS001) combined 
with standard chemotherapy vs placebo combined with 
standard chemotherapy in the treatment of advanced or 
metastatic esophageal squamous cell carcinoma without 
previous systemic chemotherapy  
Protocol Number: 
JS001-021-III-ESCC 
Version Number: 
4.0 
Study Medication: 
Toripalimab (JS001) 
Study Phase 
Phase 3 
Indications: 
Advanced or metastatic esophageal squamous cell carcinoma  
Sponsor: 
Shanghai Junshi Biosciences Co., Ltd. 
 
Objectives and endpoints 
This study is intended to evaluate the efficacy and safety of toripalimab in combination with 
paclitaxel and cisplatin (hereafter referred to as TP regimen) vs placebo in combination with 
TP regimen in patients with advanced or metastatic esophageal squamous cell carcinoma 
(ESCC) who have not received systemic chemotherapy previously. The objectives of this 
study are summarized as follows. 
Study objectives 
Corresponding endpoints 
Primary efficacy objective: 
 
1) To evaluate the differences in PFS (as 
assessed by the BICR per RECIST 1.1 
criteria) and OS following toripalimab in 
combination with TP regimen compared to 
placebo in combination with TP regimen in all 
randomized patient populations with advanced 
or metastatic ESCC who had not previously 
received systemic chemotherapy 
 
PFS is defined as the time from randomization 
to the first progression of disease, or the time 
from randomization to death for any reason, 
whichever comes first, will be determined by 
the BICR in accordance with RECIST 
1.1criteria.  
 
OS is defined as the time from randomization 
to death for any cause. 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
Study objectives 
Corresponding endpoints 
Secondary efficacy objectives: 
 
2) To evaluate the differences between arms in 
ORR, DCR, DOR, and TTR by the 
investigator and by the BICR in accordance 
with RECIST v1.1 
3) To evaluate the differences between arms in 
PFS by the investigator in accordance with 
RECIST v1.1,  
4) To evaluate the differences between arms in 
ORR, DCR, DOR, and TTR by the 
investigator in accordance with irRECIST 
5) To evaluate the 1- and 2-year PFS rates 
between treatment arms 
6) To evaluate the 1- and 2-year OS rates 
between treatment arms 
7) To evaluate the quality of life (QoL) 
following toripalimab in combination with TP 
regimen compared to placebo in combination 
with TP regimen in all randomized population
  
ORR is defined as the proportion of patients 
with the best overall response of CR or PR 
 DOR is defined as the time from first 
documented response to first documented 
evidence of disease progression or death, 
whichever comes first. 
 DCR is defined as the proportion of patients 
with the best efficacy of CR, PR, or SD. 
 TTR is defined as the time from 
randomization to the first documentation of 
objective response (CR or PR).  
 1 year and 2 years PFS rates are defined as the 
proportion of patients who are alive and have 
no documented progression of disease 1 year 
and 2 years after randomization, as evaluated 
in accordance with RECIST 1.1 criteria.  
 OS rate at 1 year and 2 years, defined as the 
proportion of patients who are alive 1 year and 
2 years after randomization.  
 PRO analyzed as mean change from baseline, 
by cycle, in EORTC QLQ-C30 and QLQ-
OES18 score  
Safety objective: 
 
8) To evaluate the safety and tolerability of 
toripalimab in combination with TP regimen 
compared to placebo in combination with TP 
regimen  
 Safety and tolerability characterized by 
incidence and severity of AE and SAE, where 
severity is determined in accordance with 
CTCAE 5.0  
Exploratory objectives: 
 
9) To evaluate predictive or prognostic 
biomarkers (tissue and/or plasma) related to 
the status of disease activity and response to 
treatment  
10) To identify the possible mechanism of the 
drug resistance to the study treatment through 
comparative analysis of the potential 
biomarkers in biopsy tissue samples and blood 
samples prior to treatment and after 
progression of disease  
 Correlation between biomarkers in archival or 
fresh tissue specimen and blood (including but 
not limited to PBMC, PD-L1, MSI, 11q13, 
tumor mutation burden, and other) and disease 
status, mechanism of drug resistance, and/or 
response to toripalimab.  
 The incidence and titer of ADA of toripalimab 
and potential correlation between the 
immunogenicity response and 
pharmacokinetics, safety, and efficacy 
 The feasibility of biopsy of sites with obvious 
increase of tumor volume to differentiate 
between the immunoregulatory effects of 
toripalimab (i.e., pseudoprogression/ tumor 
immune infiltration) and true progression of 
disease.  

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
AE = adverse event; ADA = anti-drug antibody; BICR = blinded independent central review; CR = complete response; 
CTCAE = common terminology criteria for adverse event; DCR = disease control rate; DOR = duration of response; 
EORTC = European Organisation for research and treatment of cancer; QLQ-C3 = quality 
of life instruments for cancer patients; ESCC = esophageal squamous cell carcinoma; irRECIST = immune-related Response 
Evaluation Criteria in Solid Tumors; MSI = microsatellite instability; ORR = objective response rate; OS = overall survival; 
PD-L1 = programmed death receptor – ligand 1; PFS = progression-free survival; PK = pharmacokinetics; PR = partial 
response; PRO = patient-reported outcome; QLQ-OES18 = supplementary scale for esophageal cancer patients; 
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; TTR = time to response.  
 
Study design 
Description of the study 
This is a Phase 3 randomized, double-blind, multi-center, placebo-controlled study. The 
objective of this study is to compare the efficacy and safety of toripalimab in combination 
with the TP regimen and placebo in combination with the TP regimen in patients with 
advanced or metastatic ESCC who have not received systemic chemotherapy previously.  
Eligible patients will be randomized (1:1) into Group A (toripalimab combined with TP 
regimen) or Group B (placebo combined with TP regimen). The stratification factors include 
Eastern Cooperative Oncology Group (ECOG) performance status score (0 or 1) (see 
Appendix 9) and previous radiotherapy (yes or no). The treatment plan will include an 
induction period and a maintenance period in the study as follows: 
 
Toripalimab/placebo dosing (induction period): 240 mg intravenously, once every three 
weeks on Day 1 of each 3-week cycle, in combination with TP, for a maximum of 6 
cycles. 
 
Toripalimab/placebo dosing (maintenance period): 240 mg intravenously, once every 
three weeks, on Day 1 of each 3-week cycle   
Treatment 
group 
Induction period 
(3 weeks/cycle for up to 6 cycles, dosing on 
Day 1 of each cycle) 
Maintenance period 
(3 weeks/cycle, dosing on Day 1 of 
each cycle)  
Group A 
Toripalimab (240 mg) and paclitaxel  
(175 mg/m2) and cisplatin (75 mg/m2) 
Toripalimab (240 mg) 
Group B 
Placebo and paclitaxel (175 mg/m2) and 
cisplatin  
(75 mg/m2) 
Placebo 
 
Study treatment will continue until intolerable toxicity, PD, patient refusal to continue study 
drug treatment, judgment by investigator that the patient needs to be withdrawn from the 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
treatment, or up to two years of treatment, whichever occurs first. During the induction 
period, if one or both chemotherapeutic agent is discontinued due to toxicity, the study drug 
is continued until criteria for discontinuation of treatment are met. For patients with 
progression of disease (PD) in accordance with the Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1; the patient may continue to receive the study drug in blinded 
state after the investigator determines, and the Sponsor agrees, that the patient may benefit 
from continuation of study drug and after the patient signs the corresponding informed 
consent form (ICF) for continuation of treatment after disease progression.  
Planned number of patients 
It is planned to enroll approximately 500 patients with advanced or metastatic ESCC who 
have not previously received systemic chemotherapy for ESCC. They will be randomized at a 
1:1 ratio into the toripalimab in combination with the TP regimen group or the placebo in 
combination with the TP regimen group (i.e., 250 patients each in groups A and B).  
Target population 
Inclusion criteria 
For inclusion in the study, patients must fulfill all the following: 
1. Inclusion criteria for esophageal cancer 
a) Histologically or cytologically confirmed locally advanced/recurrent or metastatic 
ESCC that is not suitable for curative resection; 
b) No prior systemic antitumor therapy for recurrent or metastatic tumor; 
c) No relapse in an interval of at least 6 months after the end of the last dose in the 
patients previously receiving adjuvant, neoadjuvant chemotherapy/radiotherapy/ 
chemoradiotherapy, and radical therapy for non-metastatic disease (no relapse in an 
interval of at least 12 months after the end of the last dose in the patients previously 
receiving adjuvant chemotherapy/chemoradiotherapy with TP regimen); 
d) No risk of major hemorrhage or esophageal fistula, for example, a large ulcer at the 
lesion is considered a risk for major hemorrhage and esophageal fistula, so the 
patient would not be suitable for enrollment. The risk for hemorrhage or fistula 
should be carefully evaluated for patients with direct invasion to adjacent organs, 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
e.g., aorta or trachea (T4b disease), prior to enrollment, and the Sponsor should be 
consulted prior to enrollment. 
2. General criteria for inclusion:  
a) Signed ICF; 
b) Male or female between 18 to 75 years old; 
c) ECOG performance status score of 0 or 1; 
d) Expected survival longer than 3 months; 
e) Agreement upon providing archival tumor tissue specimen or fresh tumor biopsy for 
biomarker analysis; 
f) 
At least 1 measurable lesion in accordance with RECIST 1.1. If a lesion was 
previously irradiated and confirmed PD has occurred at this site, then this lesion can 
be used as a measurable lesion;  
g) Adequate organ function as defined below: 
Hematology: neutrophil ≥1.5×109/L, hemoglobin ≥9 g/dL and platelet ≥100×109/L;  
Hepatic function: bilirubin ≤1.5× upper limit of normal (ULN) (patients who are 
known to have Gilbert’s syndrome’s and a serum bilirubin level ≤3× ULN can be 
enrolled), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5× ULN (in case of hepatic metastasis, AST/ALT≤5× ULN), and alkaline 
phosphatase (ALP) ≤3× ULN (in case of hepatic or bone metastasis, ALP≤5× ULN); 
albumin ≥3 g/dL;  
International normalized ratio or prothrombin time or activated partial 
thromboplastin time ≤1.5× ULN; 
Renal function: serum creatinine ≤1.5× ULN or estimated glomerular filtration rate 
in accordance with Cockcroft-Gault formula: creatinine clearance ≥60 mL/min 
(140 − age)x(weight，kg)x(0.85，for women)
72 x(serum creatinine，mg/dL)
 
or: 

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Toripalimab - Shanghai Junshi Biosciences Co., Ltd. 
Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
(140 − age)x(weight，kg)x(0.85，for women)
0.818 x(serum creatinine，μmol/L)
 
h) Female patients who meet the following criteria are eligible: 
Female patients with no childbearing potential (e.g., physiologically infertile) 
defined as meeting any one of the following conditions:  
• 
Hysterectomy performed;  
• 
Bilateral oophorectomy (oophorectomy) performed;  
• 
Bilateral tubal ligation performed; or 
• 
Postmenopausal (total duration of menopause ≥1 year).  
Female patients with childbearing potential who have a negative serum pregnancy 
test result at screening (within 7 days prior to the first dose of study drug) and to 
initiate adequate contraceptive measure during screening and continue throughout 
the study until 60 days after the last dose of the study drug. Adequate contraceptive 
measures taken continuously, according to the instruction on the contraceptive 
product and physician’s guidance, are defined as follows:  
 
Any intrauterine device confirmed to have a failure rate for contraception lower 
than 1% per year; 
 
Dual-barrier contraception, defined as a condom with spermicidal gel, foam, 
suppository, or film; a diaphragm with spermicide; or a male condom used in 
addition to a diaphragm.  
Exclusion criteria 
Patients who fulfill any of the following criteria are not eligible for this study: 
1. Cancer-specific exclusion criteria:  
a) Active or untreated central nervous system metastasis (e.g., brain or leptomeningeal 
metastasis) confirmed by computerized tomography (CT) or magnetic resonance 
imaging at screening and previous radiological evaluation. Patients who previously 
received treatment of brain or leptomeningeal metastasis, stabilized for ≥2 months 

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Protocol JS001-021-III-ESCC, Version 4.0, Version Date June 30, 2020 
and discontinued systemic hormone therapy (>10 mg/day of prednisone or 
equivalent) for >28 days prior to randomization may participate in the study; 
b) Uncontrolled tumor-related pain;  
c) Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated 
drainage (once per month or more frequently). Indwelling catheter (e.g., PleurX®) is 
allowed;  
d) Uncontrollable or symptomatic hypercalcemia (ionized calcium >1.5 mmol/L or 
calcium >12 mg/dL or corrected serum calcium > ULN);  
e) History of malignant tumors, except for esophageal cancer, within 5 years prior to 
randomization. However, patients with malignant tumors that have a negligible risk 
of metastasis or resulting in death (e.g., an expected 5-year survival rate > 90%) and 
are expected to be cured after treatment can be enrolled, for example, cervical 
carcinoma in situ, basal or squamous cell skin cancer, localized prostate cancer, or 
ductal carcinoma in situ treated by curative resection.  
f) 
Palliative radiotherapy within 28 days prior to enrollment or radiopharmaceutical 
therapy within 8 weeks prior to enrollment, except for localized, palliative 
radiotherapy for metastatic bone lesions. Localized, palliative radiotherapy of a 
symptomatic lesion (such as bone metastasis or cancer invasion of nerves) must be 
completed prior to enrollment and the patient must have recovered from the side 
effects of such palliative radiotherapy prior to enrollment. There is no minimum 
requirement for the period of time from recovery to enrollment/randomization. 
g) Patients with bone metastasis of multiple vertebra that are prone to fractures and 
puts the patient at risk of paraplegia, except patients who are assessed by a specialist 
as stable and not in need of treatment; 
h) Patients with advanced cancer with metastasis to vital organs and who are at risk of 
developing life-threatening complications in the short term (e.g., liver metastases 
involving >50% of total liver volume); 
i) 
Patients with known complete esophageal obstruction per endoscopy who have 
undergone necessary tracheal or esophageal stenting; 

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j) 
Patients who have a body mass index of <17.5, weight loss of >10% within 2 
months prior to the first dose of study treatment (excluding weight loss attributed to 
drainage of massive pleural effusion or ascites), or other manifestations of severe 
malnutrition. 
2. General medical exclusion criteria: 
a) Female patients who are pregnant, lactating, or plan to become pregnant during the 
study; 
b) History of severe allergic, anaphylaxis, or other hypersensitivity reaction to a 
chimeric or humanized antibody or fusion protein; 
c) Known allergy or hypersensitivity to the biological products manufactured from 
Chinese hamster ovary cells or any component of toripalimab drug product;  
d) History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, antiphospholipid syndrome-related vascular thrombosis, 
Wegener’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple 
sclerosis, vasculitis, and glomerulonephritis (see Appendix 11 Listing of Autoimmune 
or Immunodeficiency Disorders to be Considered During Screening);  
• 
Patients with hypothyroidism who are on stable-dose thyroid hormone 
replacement therapy can be enrolled in this study (refer to Appendix 6 for the 
replacement therapy for hypothyroidism); 
• 
Patients with type I diabetes whose blood glucose is controlled through 
stable-dose insulin can be enrolled in this study;  
• 
Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with 
cutaneous manifestations only (e.g., patients with psoriatic arthritis will be 
excluded from the study) are allowed to be enrolled in this study if they meet the 
following conditions:  
 
Rash must be <10% of body surface area;  
 The disease has been fully controlled at baseline, and only low-potency 
topical steroid therapy is needed;  

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 No acute exacerbation of underlying diseases in the past 12 months (no need 
for psoralen plus ultraviolet A radiation (PUVA), methotrexate, retinol, 
biological preparation, oral calcineurin inhibitor, or high-potency systemic 
steroid therapy).  
e) History of idiopathic pulmonary fibrosis, organized pneumonia (e.g., obliterative 
bronchiolitis), drug-induced pneumonia, idiopathic pneumonia, interstitial pneumonia, 
or evidence of active pneumonia found during chest CT screening scan; 
f) Patients with a positive test result of human immunodeficiency virus;  
g) Patients with hepatitis B virus (HBV) (known positive HBV surface antigen hepatitis 
B surface antigen [HBsAg] and HBV deoxyribonucleic acid [DNA] ≥1000 cps/mL or 
200 IU/mL or ≥ULN at each study site) or hepatitis C virus (HCV): 
• 
Patients with a previous HBV infection will be eligible to participate in this 
study only when their HBV DNA is negative (HBV DNA ˂1000 cps/mL or 200 
IU/mL or <ULN) in a required HBV DNA test; 
• 
Patients with a positive HCV antibody can participate in this study only if they 
have negative HCV ribonucleic acid (RNA) by polymerase chain reaction. 
h) Patients with active pulmonary tuberculosis (clinical diagnosis includes clinical 
history, physical examination, and radiological findings, as well as the tuberculosis 
test performed in accordance with local medical procedures);  
i) Serious infection within 28 days prior to randomization, including but not limited to 
the infection complications, bacteremia, and severe pneumonia requiring 
hospitalization;  
j) Treatment with oral or intravenous (iv) antibiotics within 2 weeks prior to 
randomization; patients receiving preventive antibiotic therapy (e.g., for prevention of 
urinary tract infection or prevention of exacerbation of chronic obstructive pulmonary 
disease) can be enrolled;  
k) Serious cardiovascular diseases, e.g., heart disease defined by New York Heart 
Association (Grade 2 or above), myocardial infarction within 3 months prior to 
randomization, unstable arrhythmia, unstable angina pectoris, cerebrovascular 
accident, or transient cerebral ischemic attack. Patients with known coronary artery 

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disease, congestive heart failure not meeting the above criteria, or left ventricular 
ejection fraction <50% must receive the treatment considered by the attending 
physician as the optimal treatment and may consult a cardiologist when necessary;  
l) Major surgery (except for diagnostic operation) within 28 days prior to randomization 
or expected major surgery during the study; 
m) Previous allogeneic bone marrow transplantation or solid organ transplantation. 
n) Use of attenuated live vaccine within 28 days prior to randomization or plan to use 
such attenuated live vaccine during the study; 
o) Any other disease, metabolic disorder, physical examination finding, or abnormal 
laboratory examination that will possibly lead to contraindicated use of the study drug 
affect the interpretation of the study results, or place the patient at high risk of 
treatment-related complications of diseases or conditions;  
3. Exclusion criteria related to medications: 
a) Patients who have previously received any approved anticancer traditional Chinese 
medicine within 2 weeks prior to the first dose of study drug;  
b) Patients who have used other investigational products or participated in other 
clinical studies for therapeutic objectives within 28 days prior to randomization 
(including signing an ICF for other trials and failure of screening); 
c) Previous immune checkpoint blocking therapy, for example, therapeutic antibodies 
of anti-programmed death receptor-1 and anti-PD-antibody; 
d) Previous systemic immunomodulator therapy, including but not limited to interferon 
or interleukin-2, within 2 weeks or 5 half-lives prior to randomization, whichever 
lasts longer. Previous vaccinations with cancer vaccines are allowed;  
e) Use of systemic immunosuppressive drugs within 2 weeks prior to randomization, 
including but not limited to prednisone (>10 mg/day prednisone or equivalent), 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and tumor necrosis 
factor;  
• 
Patients who have received a short-term, low-dose, systemic 
immunosuppressant (e.g., a single dose of dexamethasone for nausea) can participate 

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in this study after discussion between investigators and the medical monitor and 
approval by the medical monitor;  
• 
Patients who use inhaled corticosteroids for treatment of chronic obstructive 
pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for treatment of 
orthostatic hypotension, and low-dose glucocorticoids (≤10 mg/day prednisone or 
equivalent drug) supplement for treatment of hypoadrenocorticism are eligible.  
f) 
Patients who have previously received the hematopoietic growth factors (e.g., 
granulocyte colony-stimulating factor and erythropoietin) or blood transfusion 
within 2 weeks prior to randomization. 
4. Exclusion criteria related to chemotherapy:  
a) History of allergy to cisplatin, carboplatin, or other platinum-based compounds;  
b) Grade 2 or higher peripheral neuropathy according to the Common Terminology 
Criteria for Adverse Events v5.0.  
The end of the study and duration of the study 
The end of the study is defined as the date when approximately 366 deaths required for the 
primary analysis of overall survival (OS) in the intent-to-treat (ITT) population have been 
observed. The duration of the study is estimated to be approximately 39 months from the first 
patient signing the ICF to the end of this study.  
Study drug and administration 
Toripalimab, placebo, and chemotherapeutic agents will be provided by the Sponsor.  
Group A: Toripalimab in combination with TP regimen 
Group B: placebo in combination with TP regimen 
Toripalimab/placebo dosing (induction period): 240 mg iv infusion, day 1, once every 
three 3 weeks (Q3W). 
Toripalimab/placebo dosing (maintenance period): 240 mg iv infusion, day 1, Q3W.  
Paclitaxel: 175 mg/m2 iv infusion over 3 hours or per local clinical practice, day 1, Q3W, for 
up to 6 cycles.  

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In order to prevent allergic reactions, 20 mg dexamethasone can be administered orally 12 
and 6 hours and 50 mg diphenhydramine (or similar product) and an H2 receptor antagonist 
(cimetidine 300 mg or ranitidine 50 mg) can be used within 1 hour prior to paclitaxel. The 
prophylactic premedication for paclitaxel may be adjusted according to the standard practice 
of the site.  
Cisplatin: 75 mg/m2 diluted with 500 mL 0.9% sodium chloride administered as an iv 
infusion at a rate of approximately 1 mg/min or per local clinical practice on Day 1 of each 3-
week treatment cycle for up to 6 cycles. 
It is recommended that the patients be adequately hydrated prior to and for up to 24 hours 
after cisplatin administration. Adequate hydration can be achieved by 500-1000 mL 0.9% 
sodium chloride solution via iv infusion prior to cisplatin administration and then 1000-2000 
mL after administration. Mannitol and furosemide (Lasix) can be administered before and 
after hydration to ensure a urine volume of 2000～3000 mL per day. Attention should be paid 
to fluid and electrolyte balance. Procedures to ensure adequate hydration may be adjusted 
according to the standard practice of the research site. 
During induction period, toripalimab will be administered prior to paclitaxel and cisplatin on 
Day 1 of each cycle.  
When the induction period is completed, toripalimab/placebo will be administered during the 
maintenance period until intolerable toxicity, PD, patient refusal to continue study drug 
treatment, judgment by investigator that the patient needs to be withdrawn from the 
treatment, or up to two years of treatment, whichever occurs first. 
Statistical methods 
Determination of sample size 
Approximately 500 patients with advanced or metastatic ESCC who have not received 
previous systemic chemotherapy for ESCC will be enrolled in this study and randomized 
(1:1) into the toripalimab in combination with TP group (Group A) and placebo in 
combination with TP group (Group B) (i.e., 250 patients each in group). 
The sample size was calculated based on the dual primary efficacy endpoints of 
progression-free survival (PFS), as evaluated by the blinded independent central review 
(BICR) per RECIST 1.1, and OS. A hierarchical testing will be used for PFS and OS analysis 

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at an overall significance level of 2-sided 0.05, i.e., the overall α level (2-sided 0.05) will be 
firstly used for the hypothesis test of PFS; if the null hypothesis of PFS is rejected, the 
hypothesis test of OS will be performed at the two-sided significance level of 0.05.  
For PFS, 283 PFS events are expected to be observed in approximately 500 patients enrolled 
approximately 24 months after randomization of the first patient. This will provide 85% 
statistical power to detect an improvement in PFS for toripalimab in combination with the TP 
regimen vs placebo in combination with the TP regimen in patients with advanced or 
metastatic ESCC who have not previously received systemic chemotherapy at the two-sided 
significance level of 0.05 to detect a corresponding hazard ratio (HR) of 0.7.  
For OS, 366 OS events are expected to be observed in approximately 500 patients enrolled 
approximately 39 months after randomization of the first patient, thereby there is 85% 
statistical power to detect an improved OS for toripalimab in combination with the TP 
regimen vs placebo in combination with the TP regimen in patients with advanced or 
metastatic ESCC who have not previously received systemic chemotherapy at the two-sided 
significance level of 0.05 to detect a corresponding HR of 0.73. One planned interim analysis 
of OS will be performed at the time of the PFS analysis (approximately 24 months after 
randomization of the first patient). 
Efficacy analysis 
Primary efficacy outcome 
The primary efficacy endpoints of the study are PFS (as evaluated by BICR per RECIST 1.1) 
and OS. The hierarchical testing will be used for PFS and OS analysis at the overall 
significance level of 2-sided 0.05. That is, all α levels (2-sided 0.05) will be firstly used for 
the hypothesis test of PFS; if the null hypothesis of PFS is rejected, the hypothesis test of OS 
will be performed at the two-sided significance level of 0.05. 
PFS per RECIST v1.1 is defined as the time from randomization to first recorded PD or to 
death for any cause, whichever is earlier. Patients without PD or death will be censored on the 
day of the last complete tumor evaluation. Patients who have not received any tumor 
evaluation during the study and are not dead will be censored 1 day after randomization. 
Patients who do not report any PD nor start any anticancer therapy unspecified in the protocol 
will be censored on the day of the last evaluable tumor evaluation prior to the start of 
subsequent anticancer therapy. The stratified log-rank test will be used for PFS analysis, 

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stratification factors include ECOG performance status score (0 or 1) and previous 
radiotherapy (yes or no). The Kaplan-Meier (KM) method will be used to estimate the 
median PFS in each treatment group; the 95% confidence interval (CI) of median PFS will be 
estimated through the Brookmeyer-Crowley method using log-log function conversion to 
reach normal approximation. The HR of PFS and its 95% CI will be estimated using the 
stratified Cox proportional hazard model.  
OS is defined as the time from randomization to death for any cause. Patients without death 
recorded will be censored on the last known survival date. Patients without any follow-up 
information will be censored on the day after randomization. The same analytical method for 
PFS will be used for analysis of OS. 
Secondary efficacy outcome 
The secondary efficacy endpoints include ORR, disease control rate (DCR), duration of 
response (DOR), and time to response (TTR) evaluated by BICR and by investigators in 
accordance with RECIST 1.1, PFS evaluated by investigators in accordance with RECIST 
1.1, PFS, ORR, DCR, DOR, and TTR evaluated by investigators in accordance with 
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), as well as the 
PFS and OS rates at 1 year and 2 years. The specific definitions for these endpoints are as 
follows:  
• 
The PFS rate at 1 year or 2 years is defined as the percentage of patients who are alive 
and have no documentation of PD or death within 1 year or 2 years after randomization.  
• 
The OS rate at 1 year and 2 years is defined as the percentage of patients who are alive 
within 1 year or 2 years after randomization.  
• 
The objective response rate (ORR) is defined as the proportion of patients with a best 
overall response of complete response (CR) or partial response (PR). 
• 
DCR is defined as the proportion of patients with a best overall response of CR, PR, or 
stable disease (SD).  
• 
DOR is defined as the time from the first recorded response (CR or PR) to the first 
recorded occurrence of disease progression or death, whichever is earlier. DOR is 
analyzed only for patients with a best overall response of CR or PR. Patients without 
disease progression or death after achieving response will be censored on the date of the 

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last tumor evaluation. If no tumor evaluation is performed after achieving response, 
patients will be censored 1 day after the tumor evaluation documenting response.  
• 
TTR is defined as the time from randomization to first recorded response (CR or PR). 
TTR will be calculated only for patients with a best overall response of CR or PR, 
without censoring.  
The KM method used for the primary efficacy dual endpoints of PFS and OS will be used for 
the secondary efficacy endpoints of DOR and TTR. The percentage of patients in each 
treatment group will be calculated for ORR and DCR. The Clopper-Pearson method will be 
used to calculate their 95% CIs; the 95% CI for the difference in the percentage between 
groups will be estimated using the Newcombe method. The KM method will be used to 
estimate the PFS and OS rates at 1 year and 2 years in each treatment group. The 95% CI will 
be estimated using the Greenwood formula, and the 95% CI for the intergroup difference in 
PFS and OS rate will be estimated using the Newcombe method.  
Interim analysis 
One interim analysis of OS is planned in this study.  
The interim analysis of OS is planned to be conducted at the time of the definitive PFS 
analysis, i.e., when approximately 283 PFS events and 212 OS events have occurred, which 
is expected approximately 24 months after the first patient is randomized. However, the exact 
time of this interim OS analysis will depend on the actual time when the number of required 
events for the PFS analysis is reached. 
The interim analysis will be performed by an independent statistical analysis service 
provider; the result of the interim analysis will be reviewed by independent data monitoring 
committee (IDMC), and advice will be provided to the Sponsor thereafter. 
Independent data monitoring committee 
An IDMC will be established to assess the safety, efficacy, and risk/benefit data from the 
study. The IDMC will include at least 2 clinicians and 1 biostatistician with professional 
knowledge of oncological trials. Prior to the final analysis of PFS, risk/benefit assessments 
will be conducted at regular data review meetings to ensure the safety of the patients. If any 
interim analysis is planned, the IDMC will also review the efficacy data. After review of the 
data, the IDMC will provide advice on continuation of the study, amendment to the protocol 

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or discontinuation of the study. The final decision will be made by the Sponsor. The 
procedures on management of the IDMC will be specified in a separate IDMC charter.

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List of Abbreviations and Definition of Terms 
Abbreviations
Definitions 
AE 
Adverse event 
AESI 
Adverse event of special interest 
aPTT 
Activated partial thromboplastin time 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ADA 
Anti-drug antibody 
BICR 
Blinded independent central review 
BSA 
Body surface area 
CCND1 
Cyclin D 1 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CR 
Complete response 
CrCL 
Creatinine clearance 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T lymphocyte 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
ESCC 
Esophageal squamous cell carcinoma 
FDA 
Food and Drug Administration 
G-CSF 
Granulocyte colony-stimulating factor 

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Abbreviations
Definitions 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HER-2 
Human epidermal growth factor receptor-2 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent data monitoring committee 
IFN 
Interferon 
IMP 
Investigational drug 
INR 
International normalized ratio 
irAE 
Immune-related adverse events 
IRC 
Independent Review Committee 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITT 
Intent to treat 
iv 
intravenous(ly) 
IxRS 
Interactive voice/web response system 
KM 
Kaplan-Meier 
MSI 
Microsatellite instability 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NSG 
NOD scid gamma  
NIMP 
Non-investigational medicinal drugs 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progression of disease 
PD-1 
Programmed death-1 
PD-L1 
Programmed death ligand-1 
PD-L2 
Programmed death ligand-2 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 

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Abbreviations
Definitions 
PRO 
Patient-reported outcome 
PT 
Preferred term 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
QLQ-C30 
Quality of Life - Core Questionnaires 30 
QLQ-OES18 
Quality of Life - Supplementary Scale for Esophageal cancer 18 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SD 
Stable disease 
SOP 
Standard operating procedure 
SS 
Safety set 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Half-life 
TKI 
Tyrosine-kinase inhibitor 
TNF 
Tumor necrosis factor 
TSH 
Thyroid stimulating hormone 
T3 
Total triiodothyronine 
TTR 
Time to response 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
NMPA 
National Medical Products Administration 
 
 

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1 
Background 
1.1 
Relevant Background for Esophageal Cancer 
Esophageal cancer is the 8th most prevalent cancer in the world. The high incidence regions 
include Asia, Southern Africa, and Northern France[1]. China is a high incidence region of 
esophageal cancer. According to the data in the Chinese Cancer Registry Annual Report 
2015, among the top 10 most common malignant tumors, esophageal cancer ranked 3rd in 
males and 5th in females in incidence and ranked 4th in death rate[2]. Esophageal squamous 
cell carcinoma (ESCC) and adenocarcinoma are the 2 main histological subtypes of 
esophageal cancer and are the main subtypes in Chinese ESCC, accounting for 90% of the 
incidence of esophageal cancer[3]. Clinical pathological and epidemiological studies have 
showed that the main risk factors of ESCC are smoking and alcoholism, and the 2 main risk 
factors for adenocarcinoma are gastroesophageal reflux disease and Barrett’s esophagus[4]. 
Occurrence of esophageal cancer is a multi-factor, multi-stage complex process, commonly 
associated with multiple genetic defects. Several studies have demonstrated that the 
occurrence and evolution of esophageal cancer are related to abnormality of multiple 
chromosomes. Some studies have found that chromosome 11q13 amplification is the most 
frequent genetic abnormality in esophageal cancer[41]. Cyclin Dl (CCNDl) is possibly the 
target gene for 11q13 amplification, suggesting that the gene may possibly play a critical role 
in the process of esophageal cancer development[41]. The genome characteristics of 11q13 
region amplification have been reported in many tumor types including breast 
adenocarcinoma (15% to 20%), ovarian cancer (16%), bladder cancer (11%), lung cancer 
(9%), pancreatic adenocarcinoma (14% to 25%), melanoma (9% to 44%), ESCC (33%), and 
head and neck cancer squamous cell cancer (HNSCC) (30% to 62%)[42]. For the population in 
Northeastern China, the cancer genetics study for ESCC found that 7 out of 10 tested patients 
have CCNDl gene overexpression resulting from chromosome 11q13amplication[43]. Another 
study in 134 Chinese patients with ESCC found that 11q13 amplification is associated with 
lymphatic metastasis and advanced disease[44]. The study of genetic mutations in esophageal 
cancer will provide useful information for screening its susceptible genes and may also help 
with early diagnosis and assessment of prognosis. 
For esophageal cancer, the multimodality treatment which may include surgery, radiotherapy, 
and chemotherapy is generally adopted. The selection of treatment depends on disease stage, 
tumor site, and patient’s medical condition. For early esophageal cancer, surgical treatment 

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followed by adjuvant chemotherapy has a high response rate; for advanced esophageal 
cancer, chemotherapy-centered multimodality treatment is the standard care. Commonly used 
systemic anti-cancer treatment includes 5-Fluorouracil, platinum-based chemotherapy, and 
taxanes; however, the clinical benefit of such therapy is limited[5]. 
1.1.1 Targeted Therapy Against Esophageal Cancer 
With progress in molecular biological research in cancer, targeted therapy for the treatment of 
cancer by acting on specific molecules on cancer cells has become an area of great interest in 
current studies due to high specificity and low toxicity of the targeted therapy. 
Presently, some new targeted drugs for treatment esophageal cancer have been clinically 
explored and applied, including epidermal growth factor receptor (EGFR) inhibitors 
(e.g., cetuximab and tyrosine-kinase inhibitor [TKI]), human epidermal growth factor 
receptor-2 (HER-2) inhibitors (e.g., trastuzumab), vascular endothelial growth factor (VEGF) 
inhibitors (e.g., bevacizumab and certain TKIs), and programmed death receptor-1 (PD-1) 
inhibitors (e.g., pembrolizumab or nivolumab).[6] 
Although targeted drugs, including those directed against EGFR, HER, or VEGF have 
achieved good clinical efficacy in other solid tumors, the currently available data from the 
clinical trials in esophageal cancer have showed that the efficacy is not substantial. 
1.1.2 Relevant Studies of Programmed Death -1 in Esophageal Squamous Cell Cancer 
PD-1 is an immunosuppressive receptor mainly expressed in the surface of T cells, B cells, 
monocytes, and NK cells, and its relevant ligands are programmed death ligand-1 (PD-L1) 
and programmed death ligand-2 (PD-L2). Here, PD-L1 is extensively expressed in various 
tumor cells and immune cells, and its expression level may be up-regulated by multiple 
cytokines (e.g., interferon [IFN]-γ), in tumor microenvironment[7]. The persistent activation 
of PD-1 pathway following the binding of PD-L1 with PD-1 on the surface of tumor cells and 
antigen presenting cells may inhibit tumor antigen-specific T cell activation and impair 
antitumor activities of T cells. PD-1/PD-L1 antibodies may interfere with the binding of 
PD-L1 and PD-1 and eliminate the immunosuppression of the pathway, thus restoring 
antitumor immunity of T cells[8]. 
Pembrolizumab, developed by Merck Sharp & Dohme, was the first PD-1 inhibitor and was 
approved by the United States Food and Drug Administration (FDA) in 2014 for the 

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treatment of advanced or unresectable melanoma. The relevant data in the esophageal cancer 
cohort in KEYNOTE-028 was recently published[9]. The results showed that 90 patients with 
PD-L1-positive advanced esophageal cancer were enrolled, of whom 23 patients with PD-L1-
positive cancer were treated, including 17 patients (74%) with squamous cell cancer, 5 
patients with adenocarcinoma, and 1 patient with mucinous adenocarcinoma, whose median 
follow-up was 7.1 months and response rate was 30.4%, which were all partial response (PR), 
including adenocarcinoma 40.4% and squamous cell cancer 29.4%; 52.2% of the patients 
showed evidence of tumor reduction; the median duration of response was 40 weeks; in 6 out 
of 7 patients, tumor response persisted after discontinuation of the treatment. Common 
treatment-related adverse events (AEs) included decreased appetite, decreased lymphocyte 
count, and rashes. There were no treatment-related deaths or AEs requiring discontinuation of 
treatment. Recently, Phase 2 and Phase 3 studies of Pembrolizumab in patients with 
esophageal cancer are ongoing in Japan[10]. 
Nivolumab, developed by Bristol Myers Squibb, was the second PD-1 inhibitor approved by 
the FDA in 2015 for treatment of metastatic melanoma, and recently has also been approved 
for treatment of non-small cell lung cancer (NSCLC). The most recent published results from 
the Study CheckMate-032 of nivolumab showed that the overall response rate of nivolumab 
monotherapy was 14% in patients with local advanced/metastatic gastric cancer, esophageal 
cancer, and esophageal junction cancer. The objective response rates in patients with PD-L1 
expression >1% and >5% were 27% and 33%, respectively, including 1 patient achieving 
complete response (CR). The median survival was 5 months, and the 1-year survival rate was 
36%[11]. An ongoing Phase 2 study in Japan evaluated safety and efficacy of nivolumab in 
patients with advanced esophageal cancer. The recently published results showed 17.2% 
ORR, including 1 patient achieving CR. Twenty-five percent of the patients achieved stable 
disease (SD). The median overall survival (OS) was 12.1 months. The serious adverse events 
(SAEs) observed in this study included pulmonary infection, dehydration, and interstitial lung 
disease[12]. 
1.2 
Background of Toripalimab 
The active ingredient of toripalimab, developed independently by Shanghai Junshi 
Biosciences Co., Ltd. (hereafter referred to as the Sponsor), is a novel recombinant 
humanized (97% homogeneity) anti-PD-1 monoclonal antibody (China Patent Authorization 
Code CN104250302B, PCT Patent Publication No. WO2014/206107A1), which is a human 

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immunoglobin G4/Kappa (IgG4/Kappa) subtype with a point mutation of proline introduced 
at the No. 228 amino acid site (serine to proline, S228P) in the hinge of IgG4 heavy chain to 
increase stability of the antibody and reduce possible IgG4 Fab chain replacement. Compared 
to nivolumab and pembrolizumab which are also anti-PD-1 monoclonal antibodies, 
Toripalimab differs in the complementarity-determining regions (CDR) and has a unique 
binding site to PD-1. Toripalimab binds to PD-1 with high affinity and specificity and can 
effectively block -interaction between PD1 and its ligands, PD-L1 (i.e., B7-H1) and PD-L2 
(i.e., B7-DC), thus activating cytotoxic T lymphocytes (CTLs) and inhibiting tumor growth 
(see the toripalimab Investigator’s Brochure for details on the relevant data from the 
preclinical and clinical studies).[13] 
1.2.1 Pharmacodynamics 
Toripalimab binds to human PD-1 with high affinity and does not induce complement-
dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or 
cytokine storm. The in vitro pharmacodynamic study showed that in an antigen memory 
response experiment, toripalimab could significantly stimulate the proliferation of antigen-
specific T cells and enhance the release of IFN-γ. The in vivo pharmacodynamic study 
showed that toripalimab could effectively increase the proliferation of human cluster of 
differentiation 4 (CD4+) and CD8+ T cells in the adoptive transfer of human peripheral blood 
mononuclear cells (PBMC) in an NSG mouse model, while enhancing the activation of 
human effector/memory T cells, with its stimulation effect obviously more potent than the 
approved same-target drug nivolumab. Toripalimab can eliminate the immunosuppression of 
tumor microenvironment on T cells and enhance the killing effect of CTL on tumor cells. 
In PD-1 humanized mice, toripalimab significantly inhibits the growth of MC38 colon cancer 
implants. 
The PD-1 receptor occupancy test in cynomolgus monkeys showed a dose-effect relationship 
between toripalimab and PD-1 binding on cell surface, the effective dose started from serum 
antibody concentration 0.3 μg/mL and became saturated at 3 μg/mL, when the optimal 
biological effect was exerted. These preclinical data provide justification for dose inference 
for further conduction of toripalimab clinical studies. 
1.2.2 Pharmacokinetics/Pharmacodynamics and Immunogenicity in Animals 

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Following a single intravenous (iv) infusion of toripalimab at different doses (1, 10, and 75 
mg/kg) in cynomolgus monkeys, the serum exposure level increased in a dose-dependent 
manner within the dose range of 1 to 10 mg/kg. The maximum plasma concentrations (Cmax) 
were 27.70±12.29 µg/mL, 216.11±34.52 µg/mL, and 1891.72 ± 270.16 µg/mL in 1, 10 and 
75 mg/kg group, respectively. The in vivo half-lives (t1/2; 134 to 194 hours) were similar to 
the reported pharmacokinetic (PK) data of nivolumab and pembrolizumab, and the 
toripalimab showed low immunogenicity. 
1.2.3 Pre-clinical Toxicology Studies 
As toripalimab does not bind to murine PD-1, the cynomolgus monkey was selected as the 
main animal tested for toxicology studies in accordance with the Guideline on Non-Clinical 
Safety Evaluation for Therapeutic Biologics. National Shanghai Center for New Drug Safety 
Evaluation and Research in China was selected to conduct the preclinical safety toxicology 
strictly in accordance with Good Laboratory Practice (GLP) requirement. General 
pharmacology, acute toxicity, chronic toxicity, hemolysis, histological examination, and local 
irritation studies as well as other nonclinical toxicology studies have been conducted. 
General pharmacology: The study evaluating the safety pharmacology of toripalimab found 
that 10, 30, and 100 mg/kg toripalimab have no obvious effects on cardiovascular system and 
respiratory frequency in cynomolgus monkeys after iv administration. At the same time, 
toripalimab has no effect on the motor coordination and behavioral activity in Sprague-
Dawley rats. 
Acute toxicity: No obvious acute toxicity was observed after a single iv dose of toripalimab 
to cynomolgus monkeys, and the no observed adverse effect level (NOAEL) was 406 mg/kg, 
which was approximately 1350 times of the proposed clinical start dose (0.3 mg/kg). 
Chronic toxicity: Toripalimab showed no obvious toxicity and side effects in the chronic 
toxicity experiment of toripalimab in which cynomolgus monkeys were administered iv at the 
doses of 10, 30, and 100 mg/kg for 4 consecutive weeks. No drug-related abnormal reactions 
were reported in all the animals. No abnormal changes related to toripalimab were reported in 
the animals’ body weight, food consumption, clinical observations, body temperature, 
electrocardiogram (ECG), ophthalmologic examinations, clinical pathology (hematology, 
coagulation function, serum biochemistry, immune function, and urinary and fecal analysis), 
macroscopic pathology, organ weights, or histopathology. No obvious manifestations of local 

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stimulation were reported in muscles and blood vessels at the administration site. The in vivo 
systemic exposure of toripalimab in cynomolgus monkeys was positively correlated to the 
dose and toripalimab exhibited linear pharmacokinetics after administration of the first dose 
and non-linear pharmacokinetics after administration of multiple doses. 
In the chronic toxicity experiment in cynomolgus monkeys after iv injection of 10, 30, and 
100 mg/kg toripalimab for 26 consecutive weeks, no abnormal changes related to toripalimab 
were observed in body weight, food consumption, clinical observations, body temperature, 
ECG, ophthalmologic examinations, clinical pathology (hematology, coagulation function, 
serum biochemistry, immune function, and urinary and fecal analysis), hormone levels 
(testosterone or free testosterone), macroscopic pathology, organ weight or histopathology, or 
immunohistopathology. The NOAEL was 100 mg/kg. The systemic exposure of toripalimab 
was positively correlated with the dose and has a linear kinetic property. After administration 
of toripalimab for 26 consecutive weeks, obvious accumulation was observed at the moderate 
and high doses and not at the low dose. 
Hemolysis: After addition of different doses of toripalimab (the proposed Cmax was 
≤3 mg/mL) to rabbits’ red blood cells, toripalimab, at the dose of 10 mg/mL, did not result in 
hemolysis and condensation of rabbits’ red blood cells. 
Local stimulation: The experiment in cynomolgus monkeys was a concurrent experiment 
consisting of a 4-week iv administration and a 4-week recovery period. The experimental 
results showed that during and after toripalimab administration (2, 6, and 20 mg/mL), no 
swelling, hemorrhage, infection, induration, or necrosis occurred at the injection sites across 
the animal groups. Histopathology examinations showed no obvious pathological changes in 
blood vessels and muscle tissues at the administration sites. 
Genotoxicity: In accordance with the “General Principles for Technical Evaluation of 
Nonclinical Safety of Therapeutic Biological Products” and the Nonclinical Safety 
Evaluation of Drugs for Biotechnology Application (Mar 23, 2012), toripalimab is a 
macromolecular drug and would not interact directly with deoxyribonucleic acid (DNA) or 
other chromosome substances; thus, no genetic toxicity studies were conducted. 
Carcinogenicity: In accordance with the General Principles for Technical Evaluation of 
Nonclinical Safety of Therapeutic biological Products and the Guideline for Nonclinical 
Evaluation of Antineoplastic Drugs (Mar 4, 2010), toripalimab is a drug developed 

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specifically for patients with advanced cancer; thus, no carcinogenicity studies were 
conducted. 
Reproductive and developmental toxicity: In accordance with the General Principles for 
Technical Evaluation of Nonclinical Safety of Therapeutic biological Products, and the 
Nonclinical Safety Evaluation of the Drugs for Biotechnology Application (Mar 23, 2012), 
toripalimab is used in clinical studies for treatment of tumor; thus, no reproductive and 
developmental toxicity study was conducted. According to literature reports, it is known that 
PD-1/PD-L1 signal pathway is critical for maintenance of pregnancy and for fetal tissue 
resistance and embryo-fetal survival via maternal immunity (Guleria et al. 2005; Habicht et 
al. 2007; D’Addio et al. 2011). It is expected that toripalimab has an adverse effect on 
pregnancy and has a risk to human fetuses, including embryonic death. In principle, 
toripalimab is not applicable for pregnant women or women who plan to be pregnant. 
1.3 
Toripalimab-related Clinical Experience 
1.3.1 Ongoing Clinical Studies 
Currently, there are several ongoing and planned studies of toripalimab to evaluate efficacy 
and safety of the monotherapy or in combination with other drugs. By August 31, 2018, 
nearly 900 patients had been enrolled across 18 Phase 1 to 3 clinical studies. The complete 
list of ongoing studies is provided in Table 1. 
Table 1 
List of Ongoing Clinical Studies of Toripalimab 
No. 
Study code 
Trial name 
Progress 
CT1 
HMO-JS001-I-
CRP-01 
A phase 1, open, single-center, dose-escalation study to 
investigate the tolerability and pharmacokinetics of 
single dose and multiple doses of Recombinant 
Humanized Anti-PD-1 Monoclonal Antibody Injection 
in patients with advanced tumors 
Enrollment 
closed 
CT2 
JS001-I-CRP-1.4 
Phase 1a clinical study on the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of single 
dose combined with multiple doses of Recombinant 
Humanized Anti-PD-1 Monoclonal Antibody Injection 
in patients with advanced solid tumors 
Enrollment 
closed 
CT3 
JS001-I-CRP-1.3 
A phase 1 clinical study on the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of single 
dose and multiple doses of Recombinant Humanized 
Anti-PD-1 Monoclonal Antibody Injection in patients 
with advanced malignant tumors 
Enrollment 
closed 
CT4 
HMO-JS001-II-
CRP-01 
An open-label, multi-center, single-arm, phase 2 clinical 
study to investigate the efficacy and safety of 
Enrollment 
closed 

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No. 
Study code 
Trial name 
Progress 
Recombinant Humanized Anti-PD-1 Monoclonal 
Antibody Injection in patients with locally advanced or 
metastatic melanoma after failure of standard of care 
CT5 
JS001-Ib-CRP-1.0
A Phase 1b/2, multi-center, open-label clinical study to 
evaluate JS001 in treatment of advanced gastric 
adenocarcinoma, esophageal squamous cell carcinoma, 
nasopharyngeal carcinoma, and head and neck 
squamous cell carcinoma 
Enrollment 
ongoing 
CT6 
JS001-I 
A phase 1 clinical study on the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of multiple 
doses of Recombinant Humanized Anti-PD-1 
Monoclonal Antibody Injection in patients with 
recurrent refractory malignant lymphoma 
Enrollment 
closed 
CT7-1 
HMO-JS001-I-PK 
-01 
A phase 1 study to investigate the similarity in 
pharmacokinetics and safety of single-dose and parallel 
comparison of Recombinant Humanized Anti-PD-1 
Monoclonal Antibody Injection Before and After the 
Process Change in patients with advanced NSCLC 
before and after process change 
Enrollment 
closed 
CT 7-2 
HMO-JS001-I-PK 
-02 
A phase 1 study to investigate the similarity in 
pharmacokinetics and safety of single-dose and parallel 
comparison of Recombinant Humanized Anti-PD-1 
Monoclonal Antibody Injection Before and After the 
Process Change in patients with advanced melanoma 
before and after process change 
Enrollment 
closed 
CT8 
HMO-JS001-II-
MM-02 
A randomized, controlled, multi-center, phase 2 clinical 
study to investigate Recombinant Humanized Anti-PD-
1 Monoclonal Antibody Injection vs high-dose 
interferon in adjuvant therapy of completely resected 
mucosal melanoma 
Enrollment 
ongoing 
CT9 
HMO-JS001-I-
CRP-03 
An open-label, single-center, dose-escalation, phase 1 
clinical study to investigate the tolerability and 
pharmacokinetics of single and multiple doses of 
Recombinant Humanized Anti-PD-1 Monoclonal 
Antibody Injection in patients with triple negative 
breast cancer 
Enrollment 
closed 
CT10 
HMO-JS001-I-
CRP-1.4 
A prospective phase 1 clinical study on radiotherapy 
combined with Recombinant Humanized Anti-PD-1 
Monoclonal Antibody Injection (JS001) in treatment of 
advanced triple negative breast cancer 
Enrollment 
ongoing 
CT11 
HMO-JS001-I-
CRP-1.5  
A phase 1 clinical trial on Recombinant Humanized 
Anti-PD-1 Monoclonal Antibody Injection (JS001) in 
combination with Gemcitabine plus Cisplatin (GP) as 
the first-line therapy for advanced triple negative breast 
cancer 
Not 
initiated 
but closed 
CT12 
HMO-JS001-II-
CRP-02 
An open-label, multi-center, single-arm, phase 2 clinical 
study to investigate the efficacy and safety of 
Recombinant Humanized Anti-PD-1 Monoclonal 
Antibody Injection in patients with locally advanced or 
Enrollment 
ongoing 

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No. 
Study code 
Trial name 
Progress 
metastatic bladder urothelial carcinoma after failure of 
standard of care 
CT13 
HMO-JS001-Ib-
CRP-01 
An open, single-center, dose-escalation, phase 1b 
clinical study to investigate the tolerability and 
pharmacokinetics of Recombinant Humanized Anti-
PD-1 Monoclonal Antibody Injection combined with 
Axitinib in patients with advanced renal carcinoma and 
melanoma after failure of standard of care 
Enrollment 
ongoing 
CT14 
HMO-JS001-Ib-
NEC-02 
A phase 1b clinical study to investigate the safety and 
efficacy of Recombinant Humanized Anti-PD-1 
Monoclonal Antibody Injection in patients with 
advanced neuroendocrine tumor after failure of standard 
of care 
Enrollment 
ongoing 
CT15 
JS001-NPC-III  
A randomized, double-blind, international, multi-center, 
phase 3 study to evaluate the efficacy and safety of 
JS001/placebo combined with GP regimen 
(Gemcitabine and Cisplatin) in treatment of advanced 
nasopharyngeal carcinoma 
Initiating 
CT16 
JS001-016-II-
HCC 
A randomized, double-blind, multi-center, phase 2 study 
to evaluate the efficacy and safety of recombinant 
humanized anti-PD-1 monoclonal antibody (JS001) as 
the postoperative adjuvant therapy for patients receiving 
radical resection of high-risk recurrent liver cancer 
Initiating 
CT17 
JS001-017-III-
MM 
A randomized, controlled, multi-center, phase 3 clinical 
study to investigate Recombinant Humanized Anti-PD-
1 Monoclonal Antibody Injection (JS001) vs 
Dacarbazine as the 1st-line therapy for unresectable or 
metastatic melanoma 
Enrollment 
ongoing 
CT18 
JS001-018-II-LC  
A multi-center, single-arm phase 2 clinical study to 
evaluate JS001 combined with Pemetrexed and 
carboplatin in treatment of advanced or recurrent non-
small cell lung cancer with EGFR sensitive mutation 
and negative T790M after failure of EGFR-TKI therapy
Enrollment 
ongoing 
 
1.3.2 Clinical Safety 
According to the Investigator’s Brochure (IB), the safety profile of toripalimab is 
summarized for 598 patients with different types of tumors (including melanoma, 
nasopharyngeal carcinoma, ESCC, gastric adenocarcinoma, head and neck squamous cell 
carcinoma, NSCLC, triple negative breast cancer, malignant lymphoma, and soft tissue 
sarcoma, etc.) by August 2018. 
A total of 576 of 598 (96.3%) patients had at least 1 AE, and 556 (93.0%) patients had an AE 
related to toripalimab. The most commonly reported (≥10%) treatment-emergent adverse 
events were anemia, elevated alanine aminotransferase (ALT), elevated aspartate 

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aminotransferase (AST), fever, cough, decreased white blood cell count, rash, decreased 
appetite, weakness, and hypothyroidism. Eighty-eight (14.7%) patients had an SAE related to 
toripalimab that occurred in ≥4 (0.7%) patients, including pulmonary infection in 10 (1.7%) 
patients, death in 8 (1.3%) patients, pneumonia in 6 (1.0%) patients, and decreased platelet 
count in 5 (0.8%) patients. Seventy-eight (13.0%) patients had AEs related to toripalimab that 
led to termination of the drug. Fifty-two (8.7%) patients had AEs related to toripalimab that 
led to interruption of the drug. One hundred forty-two (23.7%) patients had grade 3 and 
above AEs related to toripalimab and those occurred in ≥4 (0.7%) patients included anemia 
and hyponatremia each in 16 (2.7%) patients; elevated lipase in 9 (1.5%) patients; death in 8 
(1.3%) patients; pulmonary infection in 7 (1.2%) patients; elevated amylase and elevated 
AST each in 6 (1.0%) patients; elevated ALT in 5 (0.8%) patients; and decreased platelet 
count, elevated serum triglyceride, elevated γ-glutamyl transferase, hypokalemia, 
hyperuricemia, fatigue, hypertension, and pneumonia each in 4 (0.7%) patients. 
Immune-related adverse reaction was observed in 155 (25.9%) patients and included 
immune-related interstitial lung disease, immune-related hypothyroidism and 
hyperthyroidism, immune-related pancreatitis, immune-related hyperglycemia or diabetes, 
immune-related abnormal hepatic function, and immune-related adrenal cortical 
insufficiency, which were mostly grades 1 to2 and did not lead to termination or interruption 
of toripalimab and were completely relieved for most of them. These adverse reactions were 
consistent with those observed for other similar products and no new immune-related adverse 
reaction was found. 
Overall, the AEs observed in the pooled safety data are mainly abnormalities in various 
examinations, mostly grades 1 to2 in severity or consistent with the characteristics of 
underlying disease. The immune-related adverse reactions are consistent with that reported 
for products in the same class and showed a good tolerability. No new safety signal is seen. 
The AEs are overall controllable. 
Please see the Investigator’s Brochure for the details. 
1.3.3 Clinical Efficacy 
Study HMO-JS001-II-CRP-01 (CT4) was a Phase 2, open-label, multi-center, single-arm 
clinical study to investigate the efficacy and safety of toripalimab 3 mg/kg every 2 weeks 
(Q2W) in the treatment of patients with locally advanced or metastatic melanoma after failure 

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of standard of care. The primary endpoint was the objective response rate evaluated by 
independent radiological data review committee in accordance with the Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1. By the data cutoff date of March 15, 2018, a total of 
128 patients with locally progressed or metastatic melanoma after failure of previous 
treatment had been enrolled. As per RECIST 1.1, the evaluation by the independent third-
party review committee showed that in the efficacy evaluable population, 1 (0.83%) patient 
had CR, 21 (16.54%) patients had PR, 51 (40.16%) patients had SD, and 48 (37.80%) 
patients had progression of disease (PD); the ORR was 17.32% (95% confidence interval 
[CI]: 11.19, 25.04%) and the disease control rate (DCR) was 57.48% (95% CI: 48.40, 
66.20%). An analysis of duration of response (DOR) showed that by the data cutoff date, 21 
out of 22 patients with CR or PR had ongoing responses and the median DOR was not 
reached. The DOR ranged from 1.87+ to 10+ months and all patients were censored for DOR. 
The analysis of time to response (TTR) showed that among the 22 out of 127 patients who 
had CR or PR, the median TTR was 3.45 months (95% CI: 1.74, 3.57) and the TTR ranged 
from 1.61 to 7.34 months. The median progression-free survival (PFS) was 3.61 months 
(95% CI: 2.72, 5.48 months). The longest PFS was 13.61 months, and the 6-month PFS rate 
was 34.89%. The OS data were immature (107 out of 127 patients were censored) and had 
not yet reached the median OS, with the longest survival of 14.52 months, a 6-month survival 
rate of 88.87%, and a 12-month survival rate of 78.97%. 
Study JS001-Ib-CRP-1.0 (CT5) was a multi-center Phase 1b/2 clinical study (basket trial) 
intended to preliminarily evaluate the antitumor activity and tolerability of toripalimab in the 
treatment of advanced gastric adenocarcinoma, ESCC, nasopharyngeal carcinoma, and head 
and neck squamous cell carcinoma and provide a basis for the subsequent Phase 3 clinical 
study. The primary endpoint was the ORR evaluated by the investigator in accordance with 
RECIST 1.1. As of November 30, 2017, the results evaluated by the investigator according to 
the RECIST 1.1 in the interim analysis showed CR in 1 patient (esophageal cancer), PR in 
35 patients, and ORR of 22.4%, based on the evaluable-evaluable population across all 
cohorts. A total of 44 (27.3%) patients had SD and the DCR was 49.7% in the overall 
efficacy-evaluable population. There were 8 patients with PR in the patients with gastric 
adenocarcinoma, and the ORR was 20.0%; there was 1 patient with CR and 9 patients with 
PR among the patients with ESCC, and the ORR was 20.8%; there were 14 patients with PR 
among the patients with nasopharyngeal carcinoma, and the ORR was 28.0%; there were 4 

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patients with PR among the patients with head and neck squamous cell carcinoma, and the 
ORR was 17.4%. 
Please see the Investigator’s Brochure for the details. 
1.3.4 Clinical Pharmacokinetics, Dose Selection, and Immunogenicity 
The preliminary PK data show a linear PK profile of toripalimab within the range of 0.3 to 10 
mg/kg; when the dose is 10 mg/kg, toripalimab shows a non-linear PK profile in some but not 
all clinical studies. The plasma drug concentration basically reached steady state in patients 
after toripalimab iv infusion for 3 to 4 consecutive doses; in vitro experiments showed when 
the concentration of toripalimab was >20 nM or 3 µg/mL, it saturates PD-1 receptors on the T 
cell surface. Peripheral blood concentrations of toripalimab are at 25 µg/mL may ensure entry 
of antibody macromolecules into the tumor microenvironment. At the dose of 3 mg/kg Q2W, 
the minimum plasma drug concentration at steady state ranges from 20 to 40 µg/mL. In 
addition, all Phase 1 studies showed complete occupancy of PD-1 receptors at all dose groups 
(0.3, 1, 3, and 10 mg/kg, once Q2W). The above-stated PK results and data on receptor 
occupancy support the selection of dose regimen of 3 mg/kg once Q2W as the dose for the 
CT4 Phase 2 pivotal study. 
A fixed dose of 360 mg, Q3W, was explored in 2 early studies (CT5 and CT7). The 
preliminary PK results from 9 patients in these 2 studies showed that, compared to 3 mg/kg 
Q2W (from the 11 patients in CT1), the steady-state peak concentration increased by 153% 
(166.53 ug/mL: 95% CI: 121.0, 212.0 vs 108.83 ug/mL: 95% CI: 87.5, 130.0); the steady-
state peak concentration increased by 133% (47.92 ug/mL: 95% CI: 31.8, 64.0 vs 
36.09 ug/mL: 95% CI: 27.7, 44.5), and AUC0-Day85  increased by 138% (164993 ug/mL×h vs 
119814 ug/mL×h). The PK model predicted a similar trough concentration (~32 ug/mL) and 
exposure level for 240 mg Q3W and 3 mg/kg Q2W. Based on a comprehensive consideration 
of the above - results of toripalimab PK, receptor occupancy data and the results from the CT 
4, a phase 2 study in patients with previously treated melanoma, toripalimab 240 mg Q3W 
was recommended as the dose for Phase 3 clinical studies. 
Additionally, the PK data in the single dose and multiple dose periods of CT1 showed that, 
after administration of multiple doses, toripalimab has accumulation in human body, while in 
the previous dose-escalation study, 0.3 to 10 mg/kg showed no dose-limiting toxicity (DLT) 

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and exhibited a good tolerance. These results further supported the recommended dose for 
clinical Phase 3 studies, i.e., toripalimab 240 mg fixed dose, Q3W. 
The use of any recombinant protein has the potential to induce local and systemic immune 
responses. Additional tests, such as autoimmune serology or biopsy, should be used to 
carefully monitor the patient for development of anti-drug antibodies (ADAs) to determine 
the probability of possible immunogenicity and the impact on the patient. 
The results of a pooled analysis from 518 patients showed that ADA development was 
observed in all patients receiving toripalimab at doses ranging from 0.3 to 10 mg/kg and the 
ADA-positive rate of individual patients was 17.2%. The ADA-positive rate of individual 
patients was 18% among 128 melanoma patients who received toripalimab 3 mg/kg. Based 
on PK and exposure-efficacy analyses, no loss of efficacy, change in toxicity profile, or 
change in PK profile were observed in the presence of ADAs, and no difference in efficacy 
and safety was observed between ADA-positive and -negative patients. 
The incidence of ADA is highly dependent on the sensitivity and specificity of the assay. In 
addition, the positive rate of antibodies (including neutralizing antibodies) detected in the 
trial will also be affected by other factors, including analysis methods, sample processing, 
sample collection time, concomitant drug therapy, and other concomitant diseases. For these 
reasons, comparison of ADA rates between different products may be misleading. The current 
amount of data is insufficient to conclude the correlation between ADA and drug exposure, 
safety, and efficacy. In the future, collection and analysis of plasma concentration and ADAs 
should be continued in clinical trials, and subsequent analysis of ADA and its correlation with 
drug exposure, efficacy, and safety should be carried out. 
Please see the IB for details. 
1.4 
Rationale for Study Design 
Rationale for evaluation of toripalimab in combination with the TP regimen in patients with 
esophageal cancer: 
Cisplatin is a first-generation platinum-based antitumor drug. A cisplatin-based regimen is 
generally used for treatment of patients with advanced or metastatic esophageal cancer. 
Cisplatin-based combination regimens generally include combinations with taxanes, 
vinorelbine, and gemcitabine and show good efficacy in the treatment of advanced, relapsed, 
and metastatic esophageal cancer.  

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Paclitaxel is an anti-microtubular drug. It arrests cells at G2 phase and mitotic phase and has 
significant efficacy against multiple cancer cells. The overall response rate of paclitaxel 
monotherapy in treatment of patients with esophageal cancer may be 17% to 31% and 
paclitaxel has no cross resistance with cisplatin.  
In a Phase 2 clinical study, paclitaxel plus cisplatin were used in the treatment of 35 patients 
with advanced esophageal cancer. The results of this study showed that the overall response 
rate was 48.6%, including 45.7% achieving PR, the median PFS was 7 months, the median 
survival was 13 months, and the 1-year survival rate was 39%; no SAEs were reported[18]. In 
another paclitaxel plus cisplatin study to treat patients with advanced esophageal cancer, the 
overall response rate was 37.3%. The response rates in the initial treatment group and the 
retreatment group were 40.5% and 28.6%, and CR rates were 5.4 and 7.1%, respectively. In 
the study, the major toxicity was grades 3 to 4 bone marrow suppression, which resolved in 
all patients [19]. In a study that compared the efficacy and safety of paclitaxel to 5-fluorouracil 
plus cisplatin therapy as first-line therapy in treatment of the patients with advanced 
ESCC[20], the ORR of paclitaxel plus cisplatin and of 5-fluorouracil plus cisplatin were 42.5% 
and 38.4%, median PFS times were 7.85 and 6.53 months that showed statistically significant 
difference, and the median OS times were 13.46 and 12.67 months, respectively. 
Based on the above 2 clinical studies, the combination regimen of paclitaxel plus cisplatin for 
treatment of patients with advanced esophageal cancer has confirmed efficacy and is 
tolerable. It is expected that toripalimab plus paclitaxel and cisplatin in treatment of advanced 
or metastatic ESCC may further increase efficacy and benefit patients. 
Rationale for biomarker assessment: 
In CT5, a Phase 1b/2, open-label, multi-center, clinical study evaluating toripalimab in 
treatment of advanced gastric adenocarcinoma, ESCC, nasopharyngeal cancer, and head and 
neck squamous cell cancer, the whole-exome sequencing found that 24 out of 51 (47.1%) 
patients with ESCC in the toripalimab monotherapy group carried 11q13 segment 
amplification; patients without 11q13 segment amplification achieved better results in terms 
of objective response rate, median PFS, and median OS than the patients with 11q13 segment 
amplification. 
1.5 
Benefit-Risk Assessment 

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Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated 
that a focus on the treatment of improving T cell response to cancer may lead to significant 
survival benefit for patients with advanced malignancies. Therefore, immunomodulation is a 
new and promising cancer therapeutic strategy and may improve anticancer activity. When 
chemotherapeutic drugs are used alone, they may kill tumor cells by cytotoxicity, but can also 
result in exposure of the immune system to high-level tumor antigens. When 
chemotherapeutic drugs and PD-1/PD-L1 inhibitors are used concurrently, they may increase 
immune activities of tumor-specific T cells by inhibiting PD-L1/PD-1 signal pathway to 
produce deeper and longer response effects[16],[17]. 
The results of the preclinical pharmacodynamic study showed that toripalimab can activate 
T lymphocytes and has significant inhibition of tumor growth in NSG mice when combined 
with CTL. In the head-to-head in vitro and in vivo pharmacodynamic studies with nivolumab, 
toripalimab showed favorable pharmacodynamic characteristics (better PD-1 binding) and 
displayed an excellent safety profile in the long-term toxicity trial in primates. No DLT is 
observed from the present toripalimab human study data, and its safety is in the acceptable 
range. With reference to the research results of the same type of drugs, nivolumab and 
pembrolizumab, it is expected that toripalimab has similar risk and benefits. 
Esophageal cancer is a highly prevalent malignancy in China; the risk factors for 
development of esophageal cancer may be different from those in other regions of the world. 
In China, patients with esophageal cancer are generally mostly at advanced stage when 
diagnosed, and the tumor burden are heavier than those in developed countries. Thus, there is 
an urgent clinical need in China. The ongoing Phase 1 to Phase 2 clinical studies in ESCC in 
Chinese patients evaluate safety of toripalimab at different doses. Although toripalimab is 
generally well tolerated (see Section 1.3.2), immune-related adverse events (irAEs) are still 
observed in Study JS001-Ib-CRP-1.0, including hypothyroidism, fever, decreased 
triiodothyronine (T3), and increased thyroid stimulating hormone (TSH), etc. However so far, 
those events may be managed through treatment. The early clinical study of toripalimab 
provides adequate evidence for the further conduction of Phase 3 clinical study of toripalimab 
in patients with esophageal cancer to explore the efficacy of toripalimab in Chinese patients 
with esophageal cancer. 
Through the study design and the toxicity management guideline for chemotherapeutic drugs 
and immune/infusion-related AEs, toxicities of toripalimab, as monotherapy or in 

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combination with other cancer therapy, are usually manageable. Toripalimab maintains good 
benefit-risk characteristics, which supports clinical development for this indication. 
2 
Study Objectives 
This study is intended to evaluate efficacy and safety of toripalimab in combination with 
paclitaxel and cisplatin (hereafter referred to as TP regimen) vs placebo in combination with 
the TP regimen in patients with advanced or metastatic ESCC who have not received 
systemic chemotherapy previously. 
2.1 
Efficacy Objectives 
2.1.1 Primary Efficacy Objective 
The primary objective of this study is: 
1) To evaluate and compare differences in PFS (as assessed by the blinded independent 
central review [BICR] per RECIST 1.1) and OS following toripalimab in combination 
with the TP regimen vs placebo in combination with the TP regimen in all randomized 
patient population with advanced or metastatic ESCC who have not received systemic 
chemotherapy previously. 
2.1.2 Secondary Efficacy Objectives 
The secondary efficacy objectives of the study are: 
2) To evaluate differences in efficacy of toripalimab in combination with the TP regimen vs 
placebo in combination with the TP regimen in terms of measuring indicators ORR, 
DCR, DOR, and TTR as evaluated by the investigator and by the BICR in accordance 
with RECIST 1.1 
3) To evaluate differences in efficacy of toripalimab in combination with the TP regimen vs 
placebo in combination with the TP regimen in terms of measuring indicator PFS as 
evaluated by the investigator in accordance with RECIST 1.1 
4) To evaluate differences in efficacy of toripalimab in combination with the TP regimen vs 
placebo in combination with the TP regimen in terms of measuring indicators ORR, 
DCR, DOR, and TTR as evaluated in accordance with Immune-related Response 
Evaluation Criteria in Solid Tumors (irRECIST) 
5) To evaluate 1- and 2-year PFS rates of the treatment groups 

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6) To evaluate 1- and 2-year OS rates of the treatment groups 
7) To evaluate disease-related symptoms and Health-Related Quality of Life in patients 
receiving toripalimab in combination with the TP regimen vs placebo in combination 
with the TP regimen by the European Organisation for Research and Treatment of 
Cancer (EORTC) Quality of Life - Core Questionnaires 30 (QLQ-C30) and Quality of 
Life - Supplementary Scale for Esophageal cancer 18 (QLQ-OES18) questionnaires. 
2.2 
Safety Objective 
To evaluate safety and tolerance in all randomized patients receiving toripalimab in 
combination with the TP regimen vs placebo in combination with the TP regimen. 
2.3 
Exploratory Objectives 
1) To explore the correlation between the biomarkers in archived or fresh tissue specimen 
and blood (including but not limited to PBMC, PD-L1, Epstein-Barr virus (EBV), 
microsatellite instability (MSI), 11q13, tumor mutation burden, and other) and disease 
status, mechanism of drug resistance, and/or response to toripalimab. 
2) To evaluate the incidence and titer of ADA against toripalimab and to explore the 
potential correlations between the immunogenicity response and PK, safety, and efficacy 
3) To evaluate the feasibility of biopsy in patients with PD to differentiate between an 
increase of tumor volume due to immunoregulatory activity of toripalimab (i.e., 
pseudoprogression/tumor immune infiltration) and the true PD. 
3 
Study Design 
3.1 
Study Description 
This is a randomized, double-blind, multi-center, placebo-controlled, Phase 3 study. The 
objective of this study is to compare the efficacy and safety of toripalimab combined with a 
TP regimen with placebo combined with a TP regimen in approximately 500 patients with 
advanced or metastatic ESCC who have not previously received systemic chemotherapy. The 
detailed study design is shown in Figure 1. For the assessment schedule, please see the Study 
Flow Sheet in Appendix 1 Schedule of Assessments. 

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Figure 1 
Study Flowchart 
 
Eligible patients will be randomized 1:1 into Group A (toripalimab combined with TP 
regimen) or Group B (placebo combined with TP regimen). The stratification factors include 
Eastern Cooperative Oncology Group (ECOG) performance status score (0 or 1) (see 
Appendix 9) and previous radiotherapy (yes or no). The treatment plan will include an 
induction period and a maintenance period in this study. Patients will receive toripalimab or 
placebo combined with a TP regimen in the induction period in 1 treatment cycle of 3 weeks 
for up to 6 cycles. Dosing will occur on Day 1 of each cycle; Day is defined as the first day 
the patient will receive the study drug. Thereafter, patients will enter the maintenance period 
to receive toripalimab or placebo monotherapy on Day 1 of each three--week cycle (Table 2) 
Patients with advanced or metastatic esophageal squamous cell carcinoma who have not 
previously received a systemic chemotherapy 
N = 500 
Randomization in a 1:1 ratio 
Stratification factors: 
a)
ECOG performance status score (0 or 1)
b)
Previous radiotherapy (yes or no) 
Induction 
period 
Maintenance 
period 
Group A 
JS001 + Paclitaxel + Cisplatin
Group B 
Placebo + Paclitaxel + Cisplatin
Receive the treatment until the study 
endpoint specified in the protocol
Placebo 
Receive the treatment until the study 
endpoint specified in the protocol
Follow-up/Survival follow-up 

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Table 2 
Treatment Groups  
Treatment 
group 
Induction period 
(3 weeks/cycle for up to 6 cycles, dosing on Day 1 of 
each cycle) 
Maintenance period 
(3 weeks/cycle, dosing on Day 1 of each cycle) 
Group A 
Toripalimab (240 mg), paclitaxel (175 mg/m2) and  
cisplatin (75 mg/m2) 
Toripalimab (240 mg) 
Group B 
Placebo (240 mg), paclitaxel (175 mg/m2), and 
cisplatin (75 mg/m2) 
Placebo 
 
Study drug will continue until intolerable toxicity, PD, patient refusal to continue study drug 
treatment, judgment by investigator that the patient needs to be withdrawn from the 
treatment, or up to two years of treatment, whichever occurs first. During the treatment, if 
one or both of the chemotherapeutic agents is/are discontinued due to toxicity, the study drug 
treatment will continue. If PD occurs (in accordance with RECIST 1.1) and the patient may 
still clinically benefit from continuation of the drug administration as judged by investigators, 
the patient can continue toripalimab (Group A) or placebo (Group B) treatment after 
discussion between the Investigators and the Sponsor on the comprehensive benefit-risk ratio 
and the patients’ signing of informed consent form. The potential for clinical benefit is based 
on a comprehensive evaluation of radiological findings and clinical status by the investigator 
and the absence of intolerable toxicity or worsening of symptoms due to PD. Patients who 
discontinue study drug administration will be followed for survival (i.e., using the date of the 
last dose as a starting point). Data on any subsequent antitumor therapy and survival will be 
collected every 3 months (±7 days) until death, withdrawal of informed consent, loss to 
follow-up, or termination of the study by the Sponsor, whichever occurs first. 
Patients with stable disease or a complete (CR) or partial response (PR) as determined by the 
investigator will discontinue the study treatment after receiving toripalimab treatment for up 
to 2 years. If PD occurs in these patients after discontinuation of study drug in these patients, 
the investigators should discuss with the medical monitor whether the patient can resume the 
study drug provided that the following criteria are met: 
• 
No other antitumor therapies were administered after the last dose of study drug. 
• 
All general inclusion criteria listed in Section 4.1.1 are met and none of the exclusion 
criteria in Section 4.1.2 are met. 
During the study, investigators will evaluate tumors in accordance with RECIST 1.1 
(see Appendix 4 for details) and irRECIST (see Appendix 5 for details). 

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Regardless of any delay in study treatment dosing, the patient will receive tumor evaluation 
at baseline (screening period) and once every 6 weeks (±7 days) in the first 12 months of 
treatment. After 12 months, the tumor will be evaluated once every 9 weeks (±7 days) until 
intolerable toxicity, PD, patient refusal to continue study drug treatment, judgment by 
investigator that the patient needs to be withdrawn from the treatment, or up to two years of 
treatment, whichever occurs first. Management of all patients will be based on investigator 
assessment. 
Tumor evaluation must be conducted once every 6 weeks (±7 days) in the first 12 months 
after the start of treatment, and thereafter once every 9 weeks (±7 days), for patients who 
terminate the treatment for any reason other than PD (e.g., toxicity), until PD, death, 
withdrawal of consent to remain on study, loss to follow-up, termination of the study by the 
Sponsor, or start of a new antitumor therapy, whichever occurs first. 
Patients who are suspected of having PD prior to the next scheduled tumor evaluation should 
undergo an unscheduled tumor evaluation. 
If a patient withdraws consent to continue study drug therapy for any reason, an imaging 
examination must be during the end-of-treatment visit. If the previous imaging examination 
was performed within 28 days of the request for discontinuation of study drug treatment, it 
does not need to be repeated. The mode of imaging scan (CT or MRI) should be the same as 
that performed at baseline, including scanning layer thickness and contrast media. 
At the time of PD, a tumor biopsy will be obtained (after obtaining patient consent via 
signing of the informed consent form). If a tumor biopsy sample is not collected, the reason 
why the biopsy was not collected must be recorded in the electronic case report form (eCRF).  
Tumor specimens collected at enrollment and disease progression will be tested for 
expression of PD-L1 and other exploratory biomarker studies in the central laboratory. Tumor 
biopsy data obtained at the time of PD will be used during the exploratory investigations to 
ascertain the consistency between radiological findings and evidence of true progression. In 
addition, the data from tumor biopsy will be analyzed to evaluate the correlation between 
changes in biomarkers and the clinical outcome and to understand the mechanisms of PD and 
drug resistance in patients of toripalimab arm by comparing with chemotherapy arm. 
Evaluation of the exploratory biomarkers will not be used for the development of any 
treatment-related strategy.  

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Patients who cannot safely undergo a tumor biopsy nor provide a sample for biopsy but 
otherwise meet the above criteria can continue study drug treatment. Patients who cannot 
safely undergo a tumor biopsy nor provide a sample for biopsy but otherwise meet the above 
criteria can continue study drug treatment. 
The Independent Review Committee (IRC), which is composed of independent experts, will 
conduct a blinded independent review, in accordance with RECIST 1.1 and irRECIST, of all 
radiological scans and determine the PFS, ORR, DOR, and DCR results. Refer to the 
corresponding IRC charter for details on this review. 
Considering the unique responses observed (such as delayed response after pseudo-
progression) with cancer immunotherapy, both RECIST 1.1 and irRECIST will be used to 
evaluate the tumor response. A treatment duration of 2 years is considered as sufficient to 
provide the maximum therapeutic effect. Therefore, in the induction period, patients who 
achieve an objective response (CR or PR) or have stable disease will continue study drug as 
maintenance therapy for up to 2 years. After 2 years, patients should receive best supportive 
caret or start a new anti-cancer treatment according at the time of disease progression.  
This study will be conducted in accordance with national and international ethical standards 
and Good Clinical Practice (GCP). This protocol will be approved by the ethics committee 
(EC) of the participating centers. 
3.2 
End of study and Duration of the Study 
The end of this study is defined as the time needed to observe approximately 366 deaths for 
the primary analysis of OS in the intent-to-treat (ITT) population. The duration of this study 
is estimated to be approximately 39 months from the first patient signing the ICF to the end 
of the study. If there are patients who are still receiving the study drug at the end of study, 
they will be transferred to an extension study to continue to receive toripalimab. 
If there are patients who are still receiving the study drug at the end of the study, they will be 
transferred to an extension study to continue to receive toripalimab until intolerable toxicity, 
PD, patient refusal to continue study drug treatment, judgment by investigator that the patient 
needs to be withdrawn from the treatment, or up to two years of treatment, whichever occurs 
first. The Sponsor may make the decision to terminate the study at any time. 
4 
Study Population, Randomization Scheme, Treatment and Monitoring Plan 

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4.1 
Study Population 
The study plans to enroll approximately 500 patients with advanced or metastatic ESCC who 
have not received previously a systemic chemotherapy. 
4.1.1 Inclusion Criteria 
For inclusion in the study, patients must fulfill all the following criteria: 
1. Inclusion criteria for esophageal cancer: 
a) Histologically or cytologically confirmed, locally advanced/relapsed or metastatic 
ESCC that cannot be eradicated; 
b) No prior systemic antitumor therapy for relapsed or metastatic tumor; 
c) No relapse in an interval of at least 6 months after the end of the last dose in the 
patients previously receiving adjuvant, neoadjuvant chemotherapy/radiotherapy/ 
chemoradiotherapy and radical therapy for non-metastatic disease (no relapse at 
least 12 months after the end of the last dose in patients previously receiving 
adjuvant chemotherapy/chemoradiotherapy with a TP regimen); 
d) No risk of major hemorrhage or esophageal fistula, for example, a patient with a 
large ulcer at the lesion would not be suitable to for enrollment, as the lesion is 
considered a risk for major hemorrhage and esophageal fistula. The enrollment 
eligibility of those patients who are at risk of hemorrhage or fistula due to direct 
ESCC invasion of adjacent organs, e.g., aorta or trachea (T4b disease) should be 
determined in consultation with the Sponsor. The Sponsor will make the final 
decision on eligibility. 
2. General requirements for inclusion: 
a) Signed informed consent; 
b) Male or female aged 18 to 75 years; 
c) ECOG performance status score of 0 or 1; 
d) Expected survival longer than 3 months; 
e) Agreement to provide a previously reserved tumor tissue specimen or biopsied 
tumor lesion tissue for biomarker analysis; 

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f) 
At least 1 measurable lesion in accordance with RECIST 1.1 (only when clear PD 
occurs after radiotherapy for a previously irradiated lesion can a lesion be used as a 
measurable lesion); 
g) Adequate organ function as defined below: 
 Hematology: Neutrophil ≥1.5×109/L, hemoglobin ≥9 g/dL, and platelet 
≥100×109/L; 
 Hepatic function: bilirubin ≤1.5× upper limit of normal (ULN) (patients who 
are known to have Gilbert’s syndrome and have a serum bilirubin level ≤3× 
ULN can be enrolled), AST and ALT ≤2.5× ULN (in case of hepatic 
metastasis, AST /ALT ≤5× ULN), and alkaline phosphatase (ALP) ≤3× ULN 
(in case of hepatic or bone metastasis, ALP ≤5× ULN); albumin ≥3 g/dL;  
 International normalized ratio (INR) or prothrombin time (PT) or activated 
partial thromboplastin time (aPTT) ≤1.5× ULN; 
 Renal function: Serum creatinine ≤1.5× ULN or estimated glomerular 
filtration rate by Cockcroft-Gault formula: Creatinine clearance (CrCL) ≥60 
mL/min 
(140  age)  (body weight, kg)  (0.85, for females) 
72  (serum creatinine, mg/dL) 
or: 
(140  age)  (body weight, kg)  (0.85, for females) 
0.818  (serum creatinine, μmol/L) 
h) Female patients who meet the following criteria are eligible for inclusion in the 
study: 
Female patients with no childbearing potential (e.g., physiologically infertile), based 
on any of the following criteria: 
 Hysterectomy performed; 
 Bilateral oophorectomy (oophorectomy) performed; 
 Bilateral tubal ligation performed; or 

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 Postmenopausal (menopause ≥1 year). 
Female patients with childbearing potential who have a negative serum pregnancy 
test result at screening (within 7 days prior to the first dose of the investigational 
drug) and use adequate contraceptive measures prior to the study until 60 days after 
the last dose of the investigational drug.  
Adequate contraceptive measures taken continuously, according to the instruction 
on the contraceptive product and physician’s guidance, are defined as follows: 
 Any intrauterine device confirmed to have a failure rate for contraception lower 
than 1% per year; 
 Dual-barrier contraception, defined as a condom with spermicidal gel, foam, 
suppository, or film; a diaphragm with spermicide; or a male condom used in 
combination with a diaphragm. 
4.1.2 Exclusion Criteria 
Patients who fulfill any of the following criteria will be excluded from this study: 
1. 
Cancer-specific exclusion criteria: 
a) Active or untreated central nervous system (CNS) metastasis (e.g., brain or 
leptomeningeal metastasis) confirmed by computerized tomography (CT) or 
magnetic resonance imaging (MRI) evaluation at screening and previous 
radiological evaluation. Patients who have previously received treatment of brain or 
leptomeningeal metastases, have stabilized for ≥2 months, and have discontinued 
systemic hormone therapy (>10 mg/d of prednisone or equivalent) for >28 days prior 
to randomization may participate in the study; 
b) Uncontrolled tumor-related pain; 
c) Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated 
drainage (once per month or more frequent). An indwelling catheter (e.g., PleurX®) 
is allowed; 
d) Uncontrollable or symptomatic hypercalcemia (ionized calcium >1.5 mmol/L or 
calcium >12 mg/dL or corrected serum calcium > ULN);  

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e) History of malignant tumors, except esophageal cancer, within 5 years prior to 
randomization. However, patients with malignant tumors that have a negligible risk 
of metastasis or death (e.g., an expected 5-year survival rate >90%) and are expected 
to be cured after treatment can be enrolled, for example, an appropriately treated 
carcinoma in situ, basal or squamous cell skin cancer, local prostate cancer treated 
with by radical operation, and ductal carcinoma in situ treated by radical operation; 
f) Palliative radiotherapy within 28 days prior to enrollment or radiopharmaceutical 
therapy within 8 weeks, except for localized palliative radiotherapy for metastatic 
bone lesions. The localized, palliative radiotherapy of a symptomatic lesion (such as 
bone metastasis or cancer invasion of nerves) shall be completed prior to 
enrollment/randomization and the patient has recovered from the side effects of such 
palliative radiotherapy. There is no minimum requirement for the period of time 
from recovery to enrollment/randomization. 
g) Patients with bone metastasis of multiple vertebra that are prone to fractures and 
puts the patient at risk of paraplegia, except patients who are assessed by a specialist 
as stable and not in need of treatment; 
h) Patients with advanced cancer with metastasis to vital organs and who are at risk of 
developing life-threatening complications in the short term (e.g., liver metastases 
involving >50% of total liver volume); 
i) 
Patients with known complete obstruction under endoscopy who require 
interventions or surgery to remove the obstruction and have undergone tracheal or 
esophageal stenting; 
j) 
Patients who have a body mass index of <17.5, a body weight decrease of >10% 
within 2 months prior to the first dose of the study treatment (considering changes of 
massive pleural effusion and ascites), or severe malnutrition displayed by other 
indicators. 
2. 
General medical exclusion criteria: 
a) Women who are pregnant, lactating, or plan to become pregnant during the study; 
b) History of severe allergy, anaphylactoid, or other hypersensitive reactions to 
chimeric or humanized antibody or fusion protein; 

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c) Known allergy or hypersensitivity to the biological products manufactured from 
Chinese hamster ovary cells or any component of toripalimab; 
d) History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, antiphospholipid syndrome-related vascular 
thrombosis, Wegener’s granulomatosis, Sjogren’s syndrome, Guillain-Barre 
syndrome, multiple sclerosis, vasculitis, and glomerulonephritis; 
 
Patients with hypothyroidism but who receive stable-dose thyroid hormone replacement 
therapy can be enrolled in this study (refer to Appendix 6 for the replacement therapy for 
hypothyroidism); 
 
Patients with type I diabetes whose blood glucose can be controlled through stable-dose 
insulin can be enrolled in this study; 
 
Patients with eczema, psoriasis, chronic lichen simplex, or cutaneous manifestations only 
of vitiligo (e.g., patients with psoriatic arthritis will be excluded from the study) are 
allowed to be enrolled in this study if they meet the following conditions: 
 Rash must be <10% of body surface area (BSA); 
 The disease has been fully controlled at baseline, and only low-potency 
topical steroid therapy is needed; 
 No acute exacerbation of underlying diseases in the past 12 months (no need 
for psoralen plus ultraviolet A radiation, methotrexate, retinol, biological 
preparation, oral calcineurin inhibitor, or high-potency or oral steroid 
therapy). 
e) History of idiopathic pulmonary fibrosis, organized pneumonia (e.g., obliterative 
bronchiolitis), drug-induced pneumonia, idiopathic pneumonia interstitial 
pneumonia, or evidence of active pneumonia found during chest CT screening scan; 
f) 
Patients with a positive test result of human immunodeficiency virus (HIV); 
g) Patients with hepatitis B virus (HBV) (known HBV surface antigen (HBsAg) and 
HBV DNA ≥1000 cps/mL or 200 IU/mL or ≥ULN at each study site) or hepatitis C 
virus (HCV): 

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• 
Patients with a previous HBV infection will be eligible to participate in this 
study only when their HBV DNA is negative (HBV DNA ˂1000 cps/mL or 200 
IU/mL or < ULN); 
• 
Patients with a positive HCV antibody can participate in this study only if they 
have negative polymerase chain reaction HCV ribonucleic acid (RNA). 
h) Patients with active pulmonary tuberculosis (clinical diagnosis includes clinical 
history, physical examination, and radiological findings, as well as the tuberculosis 
test conducted in accordance with local medical routines); 
i) 
Serious infection within 28 days prior to randomization, including but not limited to 
the infection complications, bacteremia, and severe pneumonia requiring 
hospitalization; 
j) 
Oral or iv antibiotics within 2 weeks prior to randomization; patients receiving 
preventive antibiotic therapy (e.g., for prevention of urinary tract infection or 
prevention of exacerbation of chronic obstructive pulmonary disease) can be 
enrolled; 
k) Important cardiovascular diseases, e.g., heart disease defined by the New York Heart 
Association (Grade 2 or above), myocardial infarction within 3 months prior to 
randomization, unstable arrhythmia, unstable angina pectoris, cerebrovascular 
accident, or transient cerebral ischemic attack. Patients with known coronary artery 
disease, congestive heart failure not meeting the above criteria, or left ventricular 
ejection fraction <50% must receive the treatment considered by the attending 
physician as the optimal treatment and may consult a cardiologist when necessary; 
l) 
Major surgery (except for diagnostic operation) within 28 weeks prior to 
randomization or expected major surgery during the study; 
m) Previous allogeneic bone marrow transplantation or solid organ transplantation; 
n) Use of attenuated live vaccine within 28 days prior to randomization or plan to use 
such attenuated live vaccine during the study; 
o) Any other disease, metabolic disorder, physical examination finding, or abnormal 
laboratory examination with the reason to suspect that it can lead to contraindicated 

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use of the investigational drug, affect reliability of the study results, or place the 
patient at high risk of treatment-related complications of diseases or conditions; 
3. 
Exclusion criteria related to medications: 
 Patients who have previously received any approved antitumor proprietary Chinese 
medicine within 2 weeks prior to the first dose of the study drug;  
 Patients who have received treatments using other investigational products or 
participated in other clinical studies for therapeutic objectives within 28 days prior to 
randomization (including signing an ICF for other trials, and failure of screening); 
 Previous immune checkpoint blocking therapy, for example, therapeutic antibodies 
of anti-PD-1 and anti-PD-L1 antibody; 
 Previous systemic immunostimulatory therapy (including but not limited to IFN or 
interleukin-2) within 2 weeks or 5 t1/2 prior to randomization, whichever last longer. 
Previous vaccinations with cancer vaccine are allowed; 
 Use of systemic immunosuppressive drugs within 2 weeks prior to randomization, 
including but not limited to Prednisone (>10 mg/day or equivalent drug), 
Cyclophosphamide, azathioprine, methotrexate, thalidomide, and tumor necrosis 
factor (TNF); 
• 
Patients who have received short-term, low-dose, systemic immunosuppressant 
(e.g., 1 single dose of Dexamethasone for nausea) can participate in this study after 
discussion between investigators and the medical monitor and approval by the 
medical monitor; 
• 
Patients who use inhaled corticosteroids for treatment of chronic obstructive 
pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for treatment of 
orthostatic hypotension and low-dose glucocorticoid (≤10 mg/d Prednisone or 
equivalent drug) supplement for treatment of hypoadrenocorticism are eligible. 
 Patients receiving hematopoietic stimulating factors (e.g., granulocyte 
colony-stimulating factor [G-CSF] and erythropoietin) or blood transfusion within 
2 weeks prior to randomization. 
4. 
Exclusion criteria related to chemotherapy: 

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 History of allergy to cisplatin, carboplatin, or other platinum-based compounds; 
 Grade 2 or higher peripheral neuropathy according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. 
4.1.3 Considerations for Other Inclusion Criteria 
The investigator should refer to the Investigator’s Brochure for details of warnings, 
precautions, contraindications, AEs, and other important data relating to the investigational 
drug to evaluate the impact of any potential safety factors on patient eligibility.  
Following consultation with the Sponsor, rescreening is allowed under certain conditions. For 
example, if a patient’s test result deviates slightly from the laboratory criteria and can be 
corrected and the result is not due to rapid worsening of disease or PD, then rescreening is 
allowed. Multiple attempts for rescreening are not allowed. 
4.1.4 Additional Patient Requirements for Study Participation 
Patients must also meet the following requirements for patients participating in the study: 
 Ability to complete the protocol-specified visits in accordance with the requirements 
of the protocol; 
 Agree to follow the restrictions for concomitant medications as described in Section 
4.4. 
 Female patients with childbearing potential agree to follow protocol-specified 
contraception measures beginning prior to enrollment through at least 60 days after 
the last dose of the study drug. Male patients agree to follow adequate contraception 
measures (complete abstinence or using condoms with spermicide) during the study 
through at least 60 days after the last dose of the study drug.  
 For male patients who have partners with childbearing potential: 
a) Unsterilized male patients who have partners with childbearing potential must use a 
male condom with spermicide beginning during from screening until at least 60 days 
after the last dose of study drug. Complete abstinence is an acceptable contraception 
method; however, occasional abstinence, safe period contraception (rhythm method), 
and coitus interruptus are not acceptable. 

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b) The female partner (of childbearing potential) of a male patient must also adopt 
highly effective contraception measures in this period (the same requirements for 
female patients). 
• 
Strenuous exercise should be avoided for 72 h prior to the scheduled study visits. 
4.2 
Treatment Allocation and Blinding 
After obtaining the patient’s signed ICF and determination of their inclusion eligibility, the 
research site will input patient demographic and baseline characteristics via the interactive 
voice/web response system (IxRS). For patients who meet the criteria, the research site will 
obtain the patients’ randomization number and assigned treatment group via the IxRS. 
The enrolled patients will be randomized in a 1:1 ratio to one of the treatment groups 
(toripalimab or placebo with paclitaxel and cisplatin). Permuted block randomization will be 
adopted to ensure balanced assignment between the treatment groups. Randomized patients 
will be stratified by the following conditions: 
• 
ECOG performance status score (0 or 1) 
• 
Prior radiotherapy (yes or no) 
Patients shall receive the first dose of the investigational drug on the date of randomization if 
possible. If not feasible, the first dose of the investigational drug should be administered 
within 3 calendar days after randomization. 
To maintain the study blind for treatment assignment, blood samples for ADA and trough 
concentration must be collected from the patients in the control group; however, the 
measured results for ADA/trough concentration are generally not required for patient safety 
or to interpret the trial results. The relevant Sponsor staff or the designee responsible for 
determination of ADA/trough concentration may obtain access to patient treatment 
assignments (for details, see the Maintenance of Study Blinding Plan), to determine 
appropriate ADA/trough concentration samples for analysis. Unless required explicitly (e.g., 
for evaluation of possible administration error), the ADA and toripalimab concentration 
samples for patients in the control group will not be analyzed. 
Unblinding of treatment assignment will be conducted via IxRS. It is strongly suggested that 
the investigator should not unblind information for individual patients. If unblinding is 
required for patients’ management (e.g., in the event of an SAE, the information of treatment 

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assignment would possibly influence the treatment measures for the patient), the investigator 
may unblind via IxRS. Unblinding is not allowed for non-emergencies. If an investigator 
desires to know the information of the investigational drug for any other reason, the 
investigator should contact the medical monitor directly.  
The investigator should record and provide the reasons (e.g., accidental unblinding or 
unblinding for evaluation of an SAE) for premature unblinding. If a research site unblinds the 
information inappropriately, the research site may be required to withdraw from the study.  
If unblinding to patients and/or investigator occurs during the study, the Sponsor must be 
notified immediately. The information for unblinding a patient’s treatment code must be 
recorded in the patient’s source documents (medical records) and in the randomization (IxRS) 
system. 
For regulatory reporting purposes, if a local health authority requires it, the Sponsor will 
unblind the treatment code for all unexpected, suspected serious adverse reactions (refer to 
Section 5.7) as considered by the investigator or the Sponsor. 
At end of the study, all patients still receiving the therapy will be unblinded. Only the patients 
randomized into the toripalimab arm may continue the treatment with toripalimab. The 
patients in the placebo arm are not allowed to be crossed over to toripalimab arm. 
4.3 
Treatment Plan 
4.3.1 Formulation, Packaging and Disposal 
4.3.1.1 Study Drug 
Toripalimab is a recombinant humanized antihuman PD-1 IgG4 kappa monoclonal antibody. 
Toripalimab contains a complementary determinant region of murine antibody that may bind 
to human PD-1, as well as a human framework region with limited reverse mutations in the 
parental murine sequence. Introduction of a serine to proline at protein site 228 minimizes 
Fab arm exchange. Toripalimab is produced by recombinant DNA technology using the 
Chinese Hamster Ovary Mammalian Cell Expression System (LONZA). The predicted 
molecular weight of toripalimab is approximately 147 kDa, and it consists of 2 heavy chains 
of 452 amino acids, and 2 light chains of 219 amino acids. Toripalimab has a N-linked 
glycosylation site at Site 302 of the heavy chain. The isoelectric point of toripalimab is 6.4 to 
7.4. The drug product of toripalimab is an aseptic liquid of 6 mL, supplied in a glass bottle 

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(Fluorotech stopper and aluminum-plastic composite lid) and administered via iv infusion. 
Refer to Table 3 for the description of the drug product of toripalimab and placebo; The study 
drug should be stored at 2°C to 8°C and protected from light.  
Table 3 
Chemistry and Manufacturing Information for Toripalimab and Placebo 
Investigational 
drug/control drug  
MFR.  
Supplied concentration and formulation  
Toripalimab  
Suzhou Zhonghe Biosciences 
Co., Ltd.  
Longqiao Roads No. 999, 
Suzhou City, Jiangsu Province, 
China; postal code 215200 
Sterile liquid containing toripalimab 240 mg. 
The nominal concentration is 40 mg/mL, 
containing 20 mM sodium citrate, 2.5% (w/v) 
mannitol, 50 mM NaCl, and 0.02% (w/v) 
polysorbate 80. pH value is 6.0. Each bottle 
contains 6 mL of effective volume.  
Placebo  
Suzhou Zhonghe Biosciences 
Co., Ltd.  
Longqiao Roads No. 999, 
Suzhou City, Jiangsu Province, 
China; postal code 215200  
Sterile liquid containing 20 mM sodium 
citrate, 2.5% (w/v) mannitol, 50 mM NaCl, 
and 0.02% (w/v) polysorbate 80. pH value is 
6.0. Each bottle contains 6 mL of effective 
volume.  
 
The sterile liquid of toripalimab or placebo is supplied in a 6-mL glass vial (Westar® stopper 
and aluminum-plastic composite lid), and is provided to the research site by a separate drug 
box for multiple patients with 1 vial in each drug box. A white label is attached to the drug 
box and vial of toripalimab or placebo. Other codes are not used. 
The main label on the vial contains the following information: protocol number, content of 
toripalimab or placebo, batch number, expiration date, storage conditions, and instructions for 
use. The content of the label is in accordance with Good Manufacturing Practice (GMP) and 
local regulatory requirements. Label text must be translated into the local language, if 
applicable. 
Toripalimab/placebo is provided by the Sponsor. 
4.3.1.2 Chemotherapeutic Drugs 
In the study, the chemotherapeutic drugs are paclitaxel and cisplatin. The marketed dosage 
form of each drug is provided by the Sponsor. Please refer to the corresponding package 
inserts for details regarding the strength, packaging, storage and handling information of 
paclitaxel and cisplatin. Please refer to the package insert for a detailed description of 
preparation for administration of paclitaxel and cisplatin. 

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4.3.2 Study Treatment Dosages, Administration and Compliance 
The study will include an induction period and a maintenance period. Patients will receive 
toripalimab or placebo combined with a TP regimen for combined therapy in the induction 
period in 1 treatment cycle of 3 weeks, and for up to 6 cycles, on Day 1 of each cycle. The 
patients will then enter the maintenance period of toripalimab or placebo monotherapy, which 
will be administered on Day 1 of each cycle (1 treatment cycle consisting of 3 weeks) until 
intolerable toxicity, PD, patient refusal to continue study drug treatment, judgment by 
investigator that the patient needs to be withdrawn from the treatment, or up to two years of 
treatment, whichever occurs first. The protocol allows an excursion of up to ±5% for each 
dose of paclitaxel or cisplatin. 
4.3.2.1 Administration of Study Drugs 
The study drug may be either toripalimab or placebo. The eligible patients will be 
randomized to toripalimab or placebo in combination with TP chemotherapy.  
Toripalimab 240 mg/placebo will be administered on Day 1 of each 3-week cycle (Q3W) via 
iv infusion in a monitored environment. The environment will be equipped with specialized 
staff and adequate devices/drugs to manage any possible serious allergic reactions occurring 
in patients at any time (See Appendix 4 Response Evaluation Criteria in Solid Tumors 
(RECIST)).  
The dose of toripalimab 240 mg/placebo will be diluted in an infusion bag containing 100 mL 
of 0.9% NaCl and administered via iv infusion over ≥ 60 minutes, followed by an observation 
period of 60 min (required in the first 2 cycles only). If no clinically significant, infusion-
related adverse reactions occur in the first 2 cycles, then the study drug may be infused over 
30 (±10) minutes in subsequent cycles. 
The infusion of toripalimab will follow the instructions as shown in Table 4. 
Table 4 
Administration Procedures for First and Subsequent Infusions of Study 
Drug  
First infusion 
Subsequent infusions 
 
Premedication is not allowed. 
 
Within 60 min prior to infusion, the patient’s 
vital signs (pulse rate, respiratory rate, blood 
pressure, and temperature) shall be recorded. 
 
Toripalimab/placebo is infused for ≥60 min. 
 
If a patient develops infusion-related 
reactions in the previous infusion, the 
physician may decide, at his/her discretion, 
to treat the patient with antihistamine in 
cycle 2 and in subsequent cycles thereafter.  

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First infusion 
Subsequent infusions 
 
At 30 (±10) min after infusion, the patient’s 
vital signs (pulse rate, respiratory rate, blood 
pressure, and temperature) shall be monitored. 
At 60 (±10) min after infusion, the patient’s 
vital signs (pulse rate, respiratory rate, blood 
pressure, and temperature) shall be recorded. 
 
Patients will be informed of any delayed 
symptoms that may occur after infusion and 
that they should contact the study physician if 
such symptoms occur. 
 
At 60 (±10) min after the second infusion, 
the patient’s vital signs (pulse rate, 
respiratory rate, blood pressure, and 
temperature) shall be recorded.  
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should be 
recorded during the infusion if indicated 
clinically or if a patient develops symptoms 
in the previous infusion. 
 
If no infusion-related adverse reactions 
occur in the first 2 infusions, the subsequent 
administration is allowed to be completed in 
30 (±10) min, and the 60-min observation 
period may be exempted. 
 
If infusion reactions occur in the previous 
infusions, subsequent toripalimab iv 
infusion time must be at least 60 min. 
 
If infusion reactions or clinical indications 
occur in the prior infusion, the patient’s vital 
signs must also be monitored for 60 min 
(±10 min) after infusion. 
 
Dose adjustment of the study drug is not allowed. Please see Section 5.1.5.2 for dose 
modifications of study drug due to an AE and management of toripalimab-specific AEs. 
4.3.2.2 Administration of Chemotherapy 
Initiation of administration of the chemotherapeutic drugs begins 1 h after the end of infusion 
of the study drug in the first 2 cycles, if and vital signs are normal and stable. The 
chemotherapeutic drugs are infused in the order of first paclitaxel and then cisplatin. See 
Table 5 for the details of the administration of the TP regimen. Chemotherapy must be 
administered as described in Table 5. If the administration of chemotherapy as specified in 
the protocol is significantly different from the procedures at the research site, please contact 
the medical monitor. 
Table 5 
Dosage Regimens of Paclitaxel and Cisplatin 
Chemotherapeutic 
drugs 
Dose/route of 
administration 
Induction period 
(up to 6 cycles) 
Maintenance 
period 
Paclitaxel 
175 mg/m2, iv 
infusion 
iv infusion, over 3 h or per local clinical 
practices, on Day 1 of each cycle (Q3W) 
NA 
Cisplatin 
75 mg/m2, iv 
infusion 
iv infusion at a rate of approximately 
1 mg/min or per local clinical practices on 
Day 1 of each cycle (Q3W) 
NA 

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NA = not applicable 
When patients receive TP chemotherapy, they should receive prophylactic treatment against 
hypersensitivity reactions or vomiting and also receive adequate hydration prior to 
chemotherapy administration. See Section 4.3.4.1 for details of the prophylactic regimen for 
TP. 
Please see Section 5.1.5.3 for dose adjustment of paclitaxel and of cisplatin during the study. 
The computational equation for BSA45 is: 
BSA (m²) = SQRT ([height (cm) × body (kg)]/3600) 
Note: SQRT = square root 
4.3.2.3 Medication Compliance 
The dose and time of administration of the investigational drug and chemotherapeutic drugs 
for each patient in each treatment cycle shall be recorded in the eCRF. The reasons for 
delayed administration, dose adjustment, or missing administration should also be recorded in 
eCRF. 
4.3.3 Storage, Handling and Retention of the Study Drugs and Chemotherapeutic 
Drugs 
All unused investigational drugs will be stored in the designated storage place at the research 
site according to the specified storage conditions (2°C to 8°C, protected from light). The 
Sponsor shall regularly arrange a third party to recover empty vials of used investigational 
drugs. If the study drug is lost or the packaging is damaged, the detailed situation should be 
recorded. 
In the study, the chemotherapeutic drugs include paclitaxel and cisplatin. Please refer to the 
corresponding package insert for the strength, packaging information, and disposal method of 
the chemotherapeutic drugs. The study drug is toripalimab alongside placebo. Paclitaxel and 
cisplatin are non-study drug. All study drugs (toripalimab/placebo) and non-study drugs 
(paclitaxel and cisplatin) required for the study will be provided by the Sponsor. 
The research site will confirm receipt of study drug via IxRS and confirm shipment 
conditions and contents; non-study drug will be managed manually. If the study drug is 
damaged, it will be replaced. 

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The study drug will be disposed of at the site according to the site’s in-house standard 
operating procedures (SOPs) or returned to the Sponsor, which will be appropriately 
recorded. The research site must obtain written permission from the sponsor before study 
drug destruction; study drug destruction must be recorded on the appropriate tracking 
document. 
The receipt, distribution, return, and destruction of all study drug and non-study drug at the 
research site should be accurately recorded on the Drug Inventory Log. 
4.3.4 Prophylactic Medications 
Prophylactic drugs should be given prior to administration of paclitaxel and cisplatin to 
prevent potential allergic reactions and vomiting. The patients must also receive adequate 
hydration prior to administration of chemotherapy. See Table 6 for the recommended 
prophylactic regimen for chemotherapy or refer to local clinical practices. 
Table 6 
Prophylactic Regimens Administered Prior to Paclitaxel and Cisplatin 
Administration 
Pretreatment 
medications 
Dose/route of 
administration 
Time of dosing 
Prophylaxis for allergic reaction 
Dexamethasone 
20 mg, orally 
Dexamethasone 20 mg, orally, 12 and 6 h prior to 
administration of Paclitaxel 
Diphenhydramine (or 
another drug in this 
class) 
50 mg, iv infusion 
Diphenhydramine 50 mg (or a drug of the same 
kind) within 60 min prior to administration of 
Paclitaxel 
Histamine 2 receptor 
antagonist (cimetidine 
or ranitidine) 
Cimetidine 300 mg or 
Ranitidine 50 mg, iv 
infusion 
Histamine 2 receptor antagonist (Cimetidine 300 
mg or Ranitidine 50 mg) within 60 min prior to 
administration of Paclitaxel. 
Hydration 
0.9% sodium chloride
500-1000 mL, iv infusion
500-1000 mL of 0.9% sodium chloride solution is 
first given prior to administration of Cisplatin, and 
1000-2000 mL of the solution is given after 
administration. 
Mannitol and 
furosemide 
Oral or iv 
Mannitol and furosemide (Lasix) may be used 
supportively before and after hydration. 
Anti-emetic Prophylaxis 
5-HT3 antagonist 
(e.g., Ondansetron) 
In accordance with the 
package insert 
It is suggested that the research sites adopt 5-HT3 
antagonist (e.g., Ondansetron) for the prevention 
of vomiting prior to the start of chemotherapy. 
 

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4.3.5 Access to Toripalimab After Study Closure 
After the completion of 2 years of treatment, toripalimab will be provided free of charge to 
patients in the toripalimab arm who meet all the criteria below. 
 
Disease progression occurs after discontinuation of toripalimab. 
 
The investigator judges that the patient may benefit from re-treatment with toripalimab. 
 
The patient requires continued use of toripalimab for his or her well-being.  
 
There is no alternative anti-cancer therapy. 
 
The patient and his or her doctor comply with the corresponding legal or regulatory 
requirements. 
After completion of the study, patients will not receive toripalimab provided by the Sponsor 
for free under any of the following circumstances: 
 
The investigational drug is commercially available and affordable in the country where 
the patient lives (e.g., it is covered by the patient’s insurance, or it does not result in 
economic difficulties for the patient). 
 
The Sponsor has stopped development of toripalimab or the data have demonstrated that 
toripalimab is ineffective on relapsed or metastatic esophageal cancer. 
 
The Sponsor has safety concerns regarding use of toripalimab in the treatment of 
advanced or metastatic esophageal cancer. 
4.4 
Concomitant Medication and Concurrent Therapy 
Concomitant medications include all drugs/concomitant therapies taken by the patient from 
28 days prior to enrollment to the end-of-treatment visit. Any medications taken during the 
study by the patient must be approved by the investigator and used under the direction of the 
investigator. 

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 
Oral contraceptive; 
 
Hormone replacement therapy; 
 
Prophylactic or therapeutic anticoagulation (e.g., a stable dose level of low molecular 
weight heparin or warfarin); 
 
Patients may receive localized, palliative radiotherapy (e.g., for treatment of known bone 
metastases) if the irradiated lesion is not the only site of disease and it does not interfere 
with the evaluation of tumor response in accordance with RECIST 1.1, so that tumor 
response in patients may still be evaluated; 
 
Inactivated influenza vaccine (only to be administered during influenza season); 
 
Megestrol for appetite stimulation;  
 
Inhaled corticosteroids for treatment of chronic obstructive lung disease; 
 
Mineralocorticoids (e.g., fludrocortisone) as hormone replacement therapy; 
 
Low-dose corticosteroids for orthostatic hypotension or adrenocortical insufficiency; 
 
Bisphosphonate for treatment of bone metastasis. 
Generally, the investigator should treat the patient with supportive therapy in accordance with 
local standards and based on clinical indications. Patients with infusion-related reactions are 
treated with acetaminophen, Ibuprofen, diphenhydramine, and/or famotidine or other H2-
receptor antagonists in accordance with the standard medical practices. Patients with serious 
infusion reactions such as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, 
decreased oxygen saturation, or respiratory distress should receive additional medical 
interventions appropriate for the type and severity of symptoms. 
Patients with local bone metastasis are allowed to receive localized radiotherapy prior to the 
first dose of study drug to control symptoms (e.g., palliative therapy for bone metastatic 
lesion). At enrollment, patients must have completed such therapy and recovered from all 
prior therapy-related toxicities. During treatment, palliative therapy for known bone 
metastatic lesion is permitted as long as it does not interfere with evaluation of any tumor 
target lesion (e.g., the lesion to be irradiated is not the only target lesion) in accordance with 
RECIST 1.1. Toripalimab treatment can be continued during palliative therapy. 

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All concomitant medications and concomitant therapies must be recorded in the Concomitant 
Medications page of the eCRF. 
4.5 
Prohibited Therapy 
Unless otherwise indicated, the following drugs are prohibited when patients are receiving 
the investigational therapy: 
• 
Other tumor-related radiotherapies, chemotherapies, immunotherapies, or hormone 
therapies (except antiallergic drugs), as well as other investigational drugs; 
 
Approved traditional Chinese drug products for treatment of cancer; refer to the relevant 
classification and regulations specified in the Expert Consensus on Use of Palliative 
Chinese Patent Medicine in Oncology. 
 
Any attenuated live vaccines are prohibited within 28 days prior to randomization and 
during treatment. 
 
Prophylactic G-CSF is not permitted within the first 2 weeks prior to the first cycle. 
Thereafter, symptomatic or prophylactic therapy should be given in accordance with the 
guidelines or local clinical practices. 
If a patient requires any other specific anticancer therapy as judged by the investigator, then 
the patient should terminate treatment of the investigational drug prematurely prior to 
receiving a new anticancer therapy. 
4.6 
Study Assessments 
See Appendix 1 Schedule of Assessments for the schedule of study visits and assessments 
for this study Flow Sheet. 
All patients will be closely monitored for safety and tolerability of treatment throughout the 
study. Each patient must undergo all required assessments and the results will be recorded in 
the eCRF. 
Prior to treatment on Day 1 of each cycle, the investigator will evaluate the patient for 
eligibility. The study drug and the chemotherapy may be administered only if the clinical 
evaluation of the patient and laboratory test results are within acceptable ranges. 
4.6.1 Informed Consent Form and Screening Evaluation 

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A written ICF for this study, signed by the patient, must be obtained prior to any study 
screening examination or evaluation, within 28 days prior to start of the investigational 
therapy. ICFs for all unenrolled and enrolled patients will be stored at the research site. 
All screening evaluations must be completed and the results must be reviewed to confirm that 
the patient meets all the inclusion criteria prior to randomization. The investigator will record 
the information of all screened patients in the screening log and, if applicable, confirm the 
patient’s eligibility or record the reason for screening failure. 
For patients who develop PD on study and in whom the investigator has determined that the 
potential for clinical benefit exists, may continue to receive study drug (blinded) only after 
they agree to undergo a biopsy of the progressing lesion (if clinically feasible) and sign an 
ICF acknowledging the risks of the delay of administration of other therapeutic regimens. 
4.6.2 Demographic Information and Baseline Disease Characteristics 
Medical history to be collected includes clinically significant diseases, surgery, 
non-esophageal cancer (including prior antitumor therapies and surgeries), fertility status, 
smoking history, alcohol consumption, and drug abuse. 
History of esophageal cancer includes prior antitumor therapies and surgeries for cancer. 
Demographic data will include age, sex, and self-reported ethnicity. 
4.6.3 Physical Examination 
The patients will undergo physical examinations at the specified timepoints in Appendix 1
 
Schedule of Assessments, Study Flow Sheet; see Appendix 1 Schedule of Assessments 
for the specific examination items. Any abnormality at baseline should be recorded in the 
eCRF for General History and Baseline Diseases. 
Symptom-oriented physical examination will be conducted in subsequent visits (and as 
clinically indicated). Any new or worsening, clinically significant physical finding or 
abnormality should be recorded in the eCRF as an AE. 
4.6.4 Vital Signs 
Patients will be assessed for vital signs at the timepoints specified in Appendix 1 Schedule 
of Assessments, Study Flow Sheet; the assessed items include temperature, pulse rate, 
respiratory rate, and blood pressure. Baseline abnormalities are recorded in eCRF for General 

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History and Baseline Diseases. In subsequent visits, any new or aggravated, clinically 
significant abnormality should be recorded in the CRF for Adverse Events.  
4.6.5 Electrocardiogram 
Patients will undergo a 12-lead ECG at the timepoints specified in Appendix 1 Schedule of 
Assessments, Study Flow Sheet. During the study, every effort shall be made to ensure that 
the same machine be used for obtaining the patient’s ECG. The position of leads should be 
consistent as far as possible. The ECG must be conducted after the patient has rested in the 
supine position for at least 10 minutes. 
To monitor safety, the investigator must review, sign, and date all ECGs. The paper copy of 
electrocardiogram will be retained in the permanent study file at the research site. Any 
change in the waveform morphology or other ECG abnormalities must be recorded in the 
appropriate eCRF. 
4.6.6 Echocardiography 
During the study, the patients undergo an echocardiogram to measure left ventricular ejection 
fraction at the timepoints specified in Appendix 1 
Schedule of Assessments, Study Flow 
Sheet. 
4.6.7 ECOG Performance Status Score 
During the study, the patients will be assigned an ECOG performance status score at the 
timepoints specified in Appendix 1Schedule of Assessments, Study Flow Sheet; see 
Appendix 9 for the scoring criteria. 
4.6.8 Laboratory Tests 
During the study, the following laboratory tests will be conducted at the timepoints specified 
in Appendix 1 
Schedule of Assessments, Study Flow Sheet. The samples used for the 
laboratory tests must be sent to the local laboratory of the research site, and the laboratory 
tests in the treatment period should be completed prior to administration of each dose. The 
investigational drug will not be administered until the laboratory test results meet the criteria 
for continued medication as judged by the investigator. The detailed test items are provided 
below (for details, see Appendix 1 Schedule of Assessments, Study Flow Sheet): 

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 Hematology (complete blood cell count, including red blood cell count, hemoglobin, 
hematocrit, white blood cell count and differentials [neutrophils, eosinophils, 
lymphocytes, monocytes, and basophils], and platelet count); 
 Blood biochemistry (glucose, blood urea nitrogen or urea, creatinine, sodium, potassium, 
magnesium, chloride, calcium, phosphorus, total bilirubin, direct bilirubin, ALT, AST, 
ALP, lactate dehydrogenase (LDH), total protein and albumin, serum creatine kinase, and 
serum creatine kinase isoenzymes); 
 Coagulation (INR, PT, aPTT); 
 A serum pregnancy test will be conducted only for female patients of childbearing 
potential in the screening period, including those who have undergone bilateral tubal 
ligation.  
 A female patient of childbearing potential is defined as the one who is not surgical 
sterilized (e.g., hysterectomy, and/or bilateral oophorectomy), or is not postmenopausal 
(amenorrhea ≥1 year);  
 Urinalysis (urine pH, specific gravity, glucose, protein, ketone bodies, occult blood, red 
blood cells, and white blood cells); 
 Thyroid function tests (TSH, free T3, and free total thyroxine); 
 HBV serology (HBsAg, anti-HbsAg antibody, and hepatitis B core antibody [anti-HBc]); 
 If the patients are HbsAg positive or have a prior history of hepatitis B infection, then an 
HBV DNA test should be conducted prior to randomization; 
 HCV serology (anti-HCV antibody); 
 HIV test: All patients must receive an HIV test prior to enrollment into the study, and 
those who are positive for HIV are not eligible for enrollment into the study. 
4.6.9 Analysis of Biological Specimens 
4.6.9.1 Anti-drug Antibody Test 
Patients may develop an immune response to toripalimab, that is, an anti-drug antibody 
(ADA) response. During the study, at the timepoints specified in Appendix 2, blood will be 
collected and analyzed using a sensitive validated screening method to test for ADA in serum 

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samples. Patients who develop signs or adverse events possibly due to ADA shall be 
monitored closely. 
4.6.9.2 Biomarker Analysis 
During the study, blood samples will be collected from all enrolled patients at the timepoints 
specified in Appendix 2 to test for biomarkers (including but not limited to PBMC, PD-L1, 
MSI, 11q13, tumor mutation burden, and others). To measure changes in certain blood 
biomarkers (e.g., for circulating tumor DNA [ctDNA]), the samples are processed to separate 
plasma or serum. Whole blood samples will be processed to assess RNA and DNA and to 
evaluate immune-related biomarkers, cancer type-specific biomarkers and other exploratory 
biomarkers (e.g., change in gene expression or single-nucleotide polymorphism). 
Any remaining samples collected for the analysis of biomarkers and ADA may be used for 
further analysis of exploratory biomarkers, pharmacodynamic analysis, and other safety 
assessments. Any residual patient samples for biomarker and ADA analysis will be stored in 
the central laboratory until the approval certificate by NMPA is obtained, at which point they 
will be destroyed by the central laboratory. 
4.6.10 Tumor Assessments 
Tumor status will be evaluated in accordance with RECIST version 1.1 and irRECIST. 
Baseline tumor evaluation in patients must be conducted within 28 days prior to enrollment 
by contrast-enhanced CT or MRI scans of the neck, chest, abdomen, and pelvis. Tumor 
imaging results conducted at the research site within 28 days prior to enrollment into the 
study can be accepted as baseline assessments. Baseline and subsequent imaging should be 
conducted by the same imaging method (CT or MRI) and evaluated by the same reader, if 
possible. At screening, a contrast-enhanced brain CT or MRI scan is to be conducted in all 
patients to evaluate for the presence of CNS metastases. If CT scan results are inconclusive, 
then a brain MRI scan must be conducted to evaluated for CNS metastases. Patients with 
active or untreated CNS metastasis are not eligible to participate in the study. At screening, 
patients with symptoms of bone metastases, a history of bone metastasis, or suspected bone 
metastasis at baseline must undergo a bone scan (those who undergo a bone scan within 60 
days prior to enrollment do not require another one at baseline). If indicated clinically, an 
appropriate method can be used to examine other known or suspected lesions; radiological 

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examinations conducted for routine evaluation of tumor do not need to be repeated if they are 
done at the same study site and are within 28 days prior to enrollment. 
The patient will undergo a tumor evaluation at baseline (screening period) and every 6 weeks 
(±7 days), regardless of dosing delays, for the first 12 months after the start of treatment. 
After the first 12 months, tumor evaluations should be performed every 9 weeks (±7 days), 
regardless of dosing delays, until intolerable toxicity, PD, patient refusal to continue study 
drug treatment, judgment by investigator that the patient needs to be withdrawn from 
treatment, or up to two years of treatment, whichever occurs first. For patients who continue 
treatment beyond RECIST 1.1-defined PD, treatment will be continued until intolerable 
toxicity, confirmed disease progression on a second assessment per irRECIST, patient refusal 
to continue study drug treatment, judgment by investigator that the patient needs to be 
withdrawn from the treatment, or up to two years of treatment, whichever occurs first. 
For patients who terminate the treatment for any reason other than PD (e.g., toxicity), tumor 
evaluation must be conducted every 6 weeks (±7 days) for the first 12 months and thereafter 
every 9 weeks (±7 days) until PD, loss of clinical benefit, death, withdrawal of informed 
consent, start of a new antitumor therapy, lost to follow-up, termination of study by the 
Sponsor, whichever occurs first. 
Patients who continue study drug after PD in accordance with RECIST 1.1 and choose to 
remain on blinded study treatment will undergo tumor evaluation assessments according to 
the above schedule. 
Patients who are suspected to have PD prior to the next scheduled tumor evaluation should 
undergo an unscheduled tumor evaluation. 
If a patient withdraws from study treatment for any reason, an imaging examination must be 
conducted at the end-of-treatment visit, unless the previous imaging examination is within 28 
days of withdrawal from the study.  
The mode of scan should be the same as baseline, including scanning layer thickness and 
contrast medium. 
All images, including CT or MRI scan, will be collected and retained by the Sponsor for 
potential future evaluation by BICR in accordance with RECIST 1.1. The decision to conduct 
an independent review of radiologic images will be made prior to the analysis of the primary 
efficacy endpoint. 

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4.6.11 Tumor Tissue Samples 
4.6.11.1 Tumor Tissue Samples Archived and Freshly Collected for Screening 
At screening, tumor specimen paraffin blocks (preferred) or at least 8 unstained consecutive 
tissue slices of formalin-fixed paraffin embedded tumor specimens must be submitted. The 
pathology reports for the above specimens must also be provided, to determine PD-L1 status, 
as well as expression information for microsatellite instability (MSI), 11q13 amplification, 
and tumor mutation burden. 
Tumor samples must be of good quality in terms of tumor content (if the submitted tumor 
samples are not sufficient to determine PD-L1 expression, then the research site will be 
notified for re-cut or supplement). 
If there is no archival tumor tissue sample is available for submission, patients must consent 
to and undergo a tumor biopsy during the screening in order to be enrolled in the study. 
The acceptable biopsy specimens include excisional biopsy, core needle biopsy, incisional 
biopsy, and endoscopic biopsy. Patients with less than 8 unstained consecutive tissue slides of 
FFPE tumor specimens at baseline may participate in the study as agreed by investigators 
following discussion with the medical monitor. 
Unacceptable samples include the following: 
• 
Fine needle aspiration sample, brush biopsy sample, and cell mass sample 
(e.g., hydrothorax cell precipitation sample and lavage sample); 
• 
Tumor tissues from bone metastasis. 
4.6.11.2 Collection of Tumor Samples at Radiologically Confirmed PD 
Unless clinically infeasible, it is suggested that tumor biopsy be performed in all patients with 
PD. 
The acceptable biopsy specimens include excisional biopsy, core needle biopsy, incisional 
biopsy, and endoscopic biopsy. Tumor samples may be evaluated for immune—related and 
tumor type-related characteristics, as well as other exploratory biomarkers (including but not 
limited to PBMC, PD-L1, MSI, 11q13, tumor mutation burden, and others). 

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4.6.11.3 Collection of Tumor Samples at Other Timepoints 
During the study, if a patient requires any surgery or procedures (e.g., bronchoscopy, 
esophago-gastroduodenoscopy, and colonoscopy) to possibly obtain tumor tissue, then 
remaining samples or partial samples (remaining tumor tissues) for medical diagnosis should 
be collected for exploratory analysis. Acquisition of the tissue samples collected at different 
timepoints from patients may help better understand the dynamic expression of biomarkers 
and their relationship with antitumor therapy. 
4.6.11.4 Use and Storage of Remaining Samples in the Relevant Procedures of the Study 
The remaining samples obtained from the relevant procedures of the study will be destroyed 
within 5 years after the end of the study or destroyed earlier in accordance with local laws 
and regulations. If patients agree to storage of tumor samples at Shanghai Junshi Biosciences, 
Co., Ltd., for further study, then the samples may be stored in the central laboratory until the 
approval certificate by NMPA is obtained, at which point they can be destroyed by the central 
laboratory. 
4.6.12 Patient-reported Outcomes 
EORTC QLQ-C30 and QLQ-OES18 questionnaires will be used to collect patient-reported 
outcome (PRO) data to determine the clinical characteristics of toripalimab (see Appendices 7 
and 8). 
The questionnaires are translated into local language as required. To ensure collection data 
that is valid and complies with the requirements by the health regulatory authorities, the 
questionnaires should be completed independently during each on-site visit by the patient, 
prior to the conduct of other non-PRO evaluations and administration of study treatment. 
4.6.13 Schedule of Assessment 
4.6.13.1 Screening and Baseline Assessments 
The screening test and evaluation will be conducted within 28 days prior to Cycle 1 Day 1. 
The tumor imaging examination results of patients, conducted at the research site within 28 
days prior to enrollment into the study, are acceptable. 
See Appendix 1 Schedule of Assessments, Study Flow Sheet, for the schedule for screening 
assessments, and Appendix 2 for the collection timepoints of ADA and biomarkers samples. 

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4.6.13.2 Assessments During Treatment 
All treatment visits must be completed within the scheduled dates (±3 days), unless otherwise 
noted (see Appendix 1 
Schedule of Assessments, Study Flow Sheet).  Unless otherwise 
indicated, the scheduled assessment must be completed by Day 1 of each cycle, prior to 
administration of study treatment. 
If administration of the study treatment and the study assessments are not conducted as 
scheduled, i.e., due to holidays, weekends, or other events, then the study drug/study 
treatment should be administered as soon as feasible. Upon resumption, if the delay in 
administration of study treatment is no more than 3 days, the next dose will be administered 
according to the original schedule. If study treatment is delayed more than 3 days but less 
than 56 days, study treatment will be administered every 21 days from resumption of 
treatment.  
See Appendix 1, Study Flow Sheet, for the assessment schedule for the study and Appendix 2 
for the collection timepoints for ADA and biomarkers samples. 
4.6.13.3 Assessments at the End-of-treatment Visit 
Patients are required to return to the research site for the end-of-treatment visit within 30 days 
after discontinuation of study drug treatment, regardless of the reason for the discontinuation 
of study treatment. If the decision to discontinue the treatment is made at a treatment visit, 
this treatment visit can serve as the end-of-treatment visit. If more than 30 days elapse 
between the decision to discontinue treatment and the end-of-treatment visit, the investigator 
should complete the end-of-treatment visit as soon as possible. 
After the end-of-treatment visit, patients will be followed for survival according to the 
follow-up assessment schedule and special laboratory assessment schedule, please see the 
Appendix 1 Schedule of Assessments, Study Flow Sheet and Appendix 2. 
4.6.13.4 Follow-up Assessments 
After end-of-treatment visits, follow-up should be conducted as described in Section 5.5, if 
they have unresolved AEs or begin survival follow-up telephone and/or clinic visit every 
month (±7 days) until death, withdrawal of consent to continue on study, loss to follow-up, or 
termination of the study by the Sponsor. 

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Follow-up will include collection of information on subsequent antitumor therapies and 
survival status.  
Please see Appendix 1 
Schedule of Assessments, Study Flow Sheet, and Appendix 2 for 
the survival follow-up assessment schedule. 
4.6.13.5 Assessments at Unscheduled Visits 
Unscheduled visits should be conducted as clinically indicated, based on new or worsening 
AEs, intercurrent illness, or to evaluate for possible disease progression. The data obtained 
during an unscheduled visit should be recorded on the Unscheduled Visits page in the eCRF. 
4.7 
Discontinuation of Study Treatment  
4.7.1 Discontinuation of Study Treatment By Patients 
Patients may withdraw voluntarily from the study for any reason. The reasons for withdrawal 
from the study include but are not limited to the following items: 
• 
Withdrawal of consent to continue study treatment or protocol-required procedures; 
Information on patients who withdraw from the study should be obtained, if possible. The 
primary reason for withdrawal from the study should be recorded in the corresponding eCRF. 
However, if a patient withdraws consent for to remain on study and complete study visits, the 
patient will not be followed up after withdrawal of such consent. Any patient who withdraws 
consent to remain on the study will not be replaced. 
The investigator should ask the patient why they wish to withdraw from the study and request 
that the patient return to the research site for an end-of-treatment visit, if possible. If the 
patient is unable to return for the scheduled visit, the investigator should do everything 
possible to ensure the patient returns to the research site to complete the end-of-treatment 
visit as soon as they can. 
4.7.2 Discontinuation of Study Treatment by Investigators 
Discontinuation of Study Drug 
The investigator has the right to discontinue treatment or to withdraw a patient from the 
study. The study drug must be terminated for any of the following: 

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• 
PD on imaging according to RECIST 1.1 and the patient does not wish to continue study 
treatment or the investigator determines that the benefit-risk assessment for continued 
treatment is not favorable after comprehensive evaluation of imaging data, tissue biopsy 
results and clinical condition.  
• 
The patient develops intolerable treatment-related AEs, including intolerable immune-
mediated AEs as determined by the investigator. 
• 
Any new or worsening medical condition under which continuation of the study drug 
might be detrimental to the patient’s safety. 
• 
The patient has received another antitumor therapy not specified in the protocol. 
• 
Non-compliance of the patient with the protocol. 
• 
Pregnancy. 
Exceptions: A patient with PD per RECIST 1.1 may continue treatment with study drug if, as 
judged by the Sponsor and the treating doctor, that all of the following criteria are met: 
• 
Evidence of clinical benefit, as evaluated by the investigator; 
• 
No symptoms or signs indicative of life-threatening risks due to PD (including worsening 
laboratory test results, e.g., new or aggravated hypercalcemia); 
• 
No decrease in ECOG performance status score due to PD;  
• 
There is no tumor progression at important anatomical sites (e.g., leptomeningeal 
disease) that present life-threatening risks or morbidity; no progression at disease sites 
requiring medical interventions that are prohibited by the protocol; and the patient is 
clinically stable; 
• 
At the first documentation of PD, if a patient chooses to remain on study treatment, the 
patient must sign an ICF acknowledging that such treatment will delay standard therapy 
and agreeing to continue treatment with toripalimab/placebo.  
In accordance with RECIST 1.1, a patient who develops a further PD on a second assessment 
must permanently terminate study drug treatment. 
 
 

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Discontinuation of chemotherapy 
A patient who develops PD in accordance with RECIST 1.1, must terminate chemotherapy 
without exception. 
The primary reason for termination of the study treatment or withdrawal of a patient from 
study should be recorded in the corresponding eCRF. 
4.7.3 Termination of the Study and/or Closure of the Research Site 
The Sponsor has the right to terminate the study at any time. The reasons for study 
termination may include but are not limited to the following: 
• 
The incidence and severity of AEs in this or other studies suggest study drug poses a 
potential health hazard to patients. 
• 
The rate of enrollment of patients is unsatisfactory (slow accrual rate). 
If the Sponsor decides to terminate the study, investigators will be notified. 
The Sponsor has the right at any time to close a research site at any time. The reasons for 
closure of a research site may include but are not limited to the following: 
• 
Very slow accrual; 
• 
Poor compliance with the trial protocol; 
• 
Inaccurate or incomplete data records; 
• 
Non-compliance with the International Conference on Harmonisation (ICH) GCP 
guidelines; 
• 
Study-related activities are no longer being conducted (i.e., all patients have completed 
the study, and all responsibilities have been performed). 
5 Safety Evaluation 
Toripalimab is marketed in China for the treatment of unresectable or metastatic melanoma 
after failure of prior systemic therapy. The use of toripalimab for esophageal cancer is still in 
the clinical development stage. Currently, the clinical experience of toripalimab in humans is 
limited, and the full safety profile is still not fully evaluated. The following information is 
based on non-clinical and clinical findings, as well as published data of similar drugs. 

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5.1 
Safety Plan 
Various measures will be taken to ensure patient safety while participating in this study, 
including use of strict inclusion and exclusion criteria (see Section 4.1.1 and 4.1.2) and close 
monitoring (see the text below and Section 4.6). Please see Section 5.3 for the complete and 
detailed content of the safety report in this study (method, date, and time of collection of 
safety parameters; evaluation of safety information). 
The study drug will be administered in a setting that has emergency medical equipment and 
staff trained in monitoring and management of medical emergencies.  
During the study, all AEs and SAEs shall be recorded until 60 days after the last dose of study 
drug or initiation of a new antitumor therapy, whichever occurs earlier. The investigator is 
required to report all treatment-related SAEs, regardless of whether or not the AE occurs after 
discontinuation of the study drug. The expected potential safety issues and the measures to be 
taken to avoid or minimize toxicity in this study will be summarized in the sections below. 
5.1.1 Risks Associated with Toripalimab 
Most adverse drug reactions by immune checkpoint inhibitors are due to effects of 
inflammatory cells on normal tissues. Generally, those risks refer to events mediated by 
potential inflammatory or immunity and may require more frequent monitoring and/or 
particular interventional measures, e.g., immune inhibitors and/or endocrine replacement 
therapy, The above immune-mediated effects may occur in almost all organ systems. 
Important identified risks of toripalimab therapy include but are not limited to 
immune-related interstitial lung disease, immune-related hepatic dysfunction, immune-related 
hyperthyroidism and hypothyroidism, immune-related hyperglycemia and diabetes, immune-
related adrenocortical insufficiency, immune-related pituitary insufficiency, immune-related 
pancreatitis, immune-related myocarditis, infusion reactions, and allergic reactions. Important 
potential risks of toripalimab therapy include but are not limited to immune-related ocular 
toxicity and neurotoxicity, and reproductive embryotoxicity, etc. Under the established 
procedures for management of toxicity, the majority of immune-mediated AEs can be 
controlled. 
See the current version of the Investigator’s Brochure for a detailed summary of relevant 
safety data for toripalimab, including AEs, SAEs, and CTCAE Grade ≥3 events related with 
the investigational therapy, reported in the studies. 

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5.1.2 Risks Associated with Paclitaxel 
The most common side effects of paclitaxel include bone marrow suppression, allergic 
reactions, neurotoxicity, cardiovascular toxicity, gastrointestinal reaction, and alopecia. 
For more details on the safety profile of paclitaxel, please refer to the package insert. 
5.1.3 Risks Associated with Cisplatin 
Cisplatin is known to cause bone marrow suppression, ototoxicity and nephrotoxicity. 
Cisplatin-based chemotherapy is considered to cause moderately severe vomiting. Patients 
will be monitored for cisplatin-related AEs. 
For more details on the safety profile of cisplatin, please refer to the package insert. 
5.1.4 Overall Plan for Safety Management 
5.1.4.1 Monitoring 
In this study, the safety will be evaluated through monitoring of all the serious and non-SAEs. 
All AEs will be graded in accordance with National Cancer Institute [NCI] CTCAE 5.0. 
Safety assessments (including laboratory test results) will be carried out according to the 
study flow sheet in Appendix 1 
Schedule of Assessments. Laboratory results must be 
reviewed before each infusion. 
The general safety evaluation includes relevant medical history, physical examinations, and 
specific laboratory investigations, including serum biochemistry and complete blood counts 
(see Appendix 1 Schedule of Assessments and 2 for the schedule of study evaluations). 
During the study treatment period, patients will be closely monitored for any symptoms and 
signs of autoimmune disease and infection. 
All SAEs will be reported promptly (see Section 5.2.2). In addition, the independent data 
monitoring committee (IDMC) and medical monitors will review and evaluate any AEs 
observed on a regular basis. 
The safety follow-up visit will be performed approximately 60 days after the last dose of 
study drug. 
After the completion or early termination of treatment, patients with unresolved study 
treatment-related AEs will be followed until one of the following occurs: the AE resolves to 

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baseline; the AE is assessed as stable by the investigators; the patient starts a new anticancer 
therapy; the patient is lost to follow-up; the patient withdraws consent to remain on study; or 
the study drug or participation in the study is not considered to be the cause of the AE. 
5.1.5 Dose Adjustment and Management of Adverse Events Related to 
Toripalimab/Placebo and Chemotherapeutic Drugs 
5.1.5.1 Dose Adjustment of Study Drug 
The dose of study drug will not be adjusted in this study. If an AE requiring dose interruption 
occurs, the study drug dosing can be interrupted for a maximum of 56 days from the last 
dose. If the AE leads to dose interruption of toripalimab for 56 days from the last dose, the 
study drug will be terminated and the patient will be followed up for safety and efficacy in 
accordance with Section 4.6.13.4. 
If the patient is on treatment with glucocorticoids for treatment of AEs, the dose of study drug 
can be interrupted for more than 56 days to allow sufficient time for dose tapering of 
glucocorticoids until glucocorticoids are discontinued or the dose has tapered 
prednisone≤10 mg/day (or equivalent). The acceptable duration of dose interruption for 
patients requiring therapeutic glucocorticoids for more than 56 days must be agreed upon by 
investigators and medical monitors. 
If the study drug is interrupted due to AE but the patient is otherwise stable without major 
organ dysfunction, chemotherapy can be continued after consultation with the Sponsor or 
their medical monitor. If the investigator judges that chemotherapy must be delayed due to 
chemotherapy-related AEs, administration of toripalimab may also be delayed. 
5.1.5.2 Management of Adverse Events Related to Toripalimab 
Toxicity that are related or possibly related to toripalimab should be managed in accordance 
with standard medical practices. Appropriate tests (e.g., autoimmune serological test or tissue 
biopsy) should be performed to determine possible immune-related causes of the AE. 
Although most immune-mediated AEs observed after use of immunomodulators are mild and 
self-limited, they should be identified as early as possible and treated promptly to avoid 
potential serious complications. Resolution of the AE may not occur after temporary 
suspension or discontinuation of study drug in serious cases, a topical corticosteroid, systemic 

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corticosteroid, mycophenolate, or TNF-α inhibitor may be needed for immediate treatment of 
immune-mediated toxicity. 
Refer to the section for information on management of irAEs and other special AEs in the 
Investigator’s Brochure. 
5.1.5.3 Dose Adjustment of Chemotherapy Drugs 
At the start of each cycle, the absolute neutrophil count (ANC) should be ≥ 1.5×109/L and 
platelet count should be ≥ 100×109/L. The cisplatin or paclitaxel dose will be adjusted at start 
of subsequent cycles, based on the minimum platelet count and neutrophil count in the 
previous cycle. For treatment/retreatment criteria and dose adjustment criteria for paclitaxel 
and cisplatin, refer to Table 7 through Table 17 or adjust dose in accordance with local 
treatment practices at the discretion of the investigator. 
Dose adjustment for chemotherapy is permanent; i.e., once the dose of paclitaxel or cisplatin 
is reduced, the reduced dose will be maintained or will be further reduced in subsequent 
cycles. A maximum of two dose reductions are allowed. 
5.1.5.3.1 Dose Adjustment of Cisplatin 
If patients have Grade 3 or 4 hematologic or non-hematologic toxicity (except for alopecia) 
after 2 dose reductions or if Grade 3 or 4 neurotoxicity is observed, cisplatin should be 
terminated. 
o 
Hematologic Toxicity 
The dose of Cisplatin can be delayed for a maximum of 3 weeks, if it is caused by 
hematological toxicity until ANC ≥ 1.5×10^9/L and platelet count >100×109/L on Day 1. If 
the ANC and platelet count are not recovered within 3 weeks, the dose of cisplatin should be 
reduced or interrupted according to the standard practice of the study site and at investigator’s 
discretion, until appropriate recovery of ANC, otherwise the treatment will be terminated. See 
Table 7 for dose adjustment of cisplatin due to hematological toxicity. 
Table 7 
Dose Adjustment of Cisplatin for Hematologic Toxicity 
Toxicitya 
Dose of Cisplatin 
ANC < 0.5×109/L and platelets ≥ 50×109/L 
75% of previous dose 
Platelets < 50×109/L, irrespective of ANC 
75% of previous dose 
Platelets < 50×109/L with ≥ Grade 2 hemorrhage, irrespective of ANC 
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ANC < 1.0×109/L, with fever ≥ 38.5ºC 
75% of previous dose 
ANC = absolute neutrophil count. 
a 
nadir in previous cycles. 
 
o 
Non-hematologic Toxicity 
In case of ≥ Grade 3 non-hematological toxicity (except alopecia or neurotoxicity [not 
requiring termination of treatment]), cisplatin dosing should be interrupted until it is 
recovered to lower than or equal to pre-treatment level. The dose adjustment of cisplatin for 
non-hematological toxicity (except neurotoxicity, ototoxicity and nephrotoxicity) is detailed 
in Table 8.  
Table 8 
Dose Adjustment of Cisplatin for Non-hematologic Toxicity 
Toxicity (except neurotoxicity, ototoxicity and nephrotoxicity) 
Dose of Cisplatin
Any Grade 3 or 4 toxicity except alopecia 
75% of previous 
dose 
Diarrhea that requires hospitalization (regardless of grade) or  
Grade 3 or 4 diarrhea that requires appropriate antidiarrheals 
75% of previous 
dose 
 
o 
Renal Toxicity 
It has been reported that renal impairment can occur when cisplatin is given alone or 
combined with other cytotoxic drugs. It is recommended that the CrCL must be ≥60 mL/min 
prior to the start of any cisplatin cycle. If CrCL is less than 60 mL/min at any time after day 1 
in a treatment cycle and CrCL is ≥ 60 mL/min on Day 1 of the next cycle, the investigator 
should determine whether to continue cisplatin without dose adjustment, at a reduced dose, or 
to delay treatment based on clinical judgment. If CrCL has not recovered to ≥ 60 mL/min 
within 42 days after the last dose of the study drug, the investigator should consider 
permanent discontinuation of cisplatin. 
o 
Ototoxicity 
Ototoxicity has been observed when cisplatin is given alone or combined with other cytotoxic 
drugs. In case of ototoxicity, cisplatin doses should be interrupted until the results of 
audiometry shows auditory acuity is within a normal range[38].  
o 
Neurologic Toxicity 

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Dose adjustment of cisplatin is recommended when neurotoxicity occurs. See Table 9 for the 
details. 
Table 9 
Dose Adjustment of Cisplatin for Neurologic Toxicity 
Toxicity 
Dose of Cisplatin 
Grade 0 or 1 neurotoxicity 
No dose adjustment  
Grade 2 neurotoxicity 
Reduce dose by 50% of previous dose 
Grade 3 or 4 neurotoxicity 
Permanent discontinuation 
 
5.1.5.3.2 Dose Adjustment for Paclitaxel 
The general principles for dose adjustment of paclitaxel during the study are as follows: 
• 
If Grade 3 or 4 non-hematological toxicity occurs, the dose of paclitaxel can be reduced 
from 175 mg/m2 to 140 mg/m2 and further reduced to 110 mg/m2 if necessary; 
• 
If paclitaxel-related hypersensitivity occurs despite preventive medication, it should be 
treated according to medical indication; 
• 
For CTCAE ≤ Grade 3 hypersensitivity, investigators will decide whether or not to 
continue paclitaxel treatment; 
• 
For Grade 4 hypersensitivity, paclitaxel must be discontinued permanently; 
• 
Paclitaxel-related fluid retention will be treated according to investigator judgment; 
• 
If paclitaxel must be terminated prior to completion of the scheduled cycle, patients will 
continue to receive the study drug and cisplatin. 
Dose adjustment of paclitaxel are displayed in Table 10.  
Table 10 
Dose Adjustment Levels for Paclitaxel 
Chemotherapeutic 
drugs 
Dose level 0 (starting 
dose) 
Reduction by 1 dose 
level 
Reduction by 2 dose 
levels 
Paclitaxel (mg/m2) 
175 
140 
110 
 
Dose adjustment for sensory neuropathy is shown in Table 11. Dose adjustment of paclitaxel 
for musculoskeletal pain that cannot be controlled with analgesics is shown in Table 12. Dose 
adjustment of paclitaxel for hematologic toxicity is shown in Table 13. Dose adjustment of 

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paclitaxel for hematologic toxicity is shown in Table 14. Dose adjustment of paclitaxel for 
non-hepatic gastrointestinal toxicity attributed to chemotherapy is shown in Table 15. Dose 
adjustment of paclitaxel for hepatotoxicity is shown in Table 16. Dose adjustment of 
paclitaxel for other clinically significant AEs is shown in Table 17. 
Table 11 
Dose Adjustment of Paclitaxel for Sensory Neuropathya 
Paresthesias/dysesthesias 
Lasting for 1-7 days 
Lasting for >7 days or leading to delay of 
next cycle 
Grade 1: paresthesia/ 
hypoesthesia that does not 
interfere with function 
No dose adjustment 
Maintaining the dose of paclitaxel 
Grade 2: paresthesia/ 
hypoesthesia that interferes with 
function but does not affect 
activities of daily living 
No dose adjustmentb 
 
InterruptionIf improved to ≤ Grade 1, 
reduce paclitaxel dose (dose of Paclitaxel 
reduced by 1 level, see Table 10 for the 
details);  
 
For persistent Grade 2 requiring a dose 
delay of > 3 weeks, paclitaxel will be 
terminated; 
Grade 3: paresthesia/ 
hypoesthesia with pain or 
functional impairment that 
interferes with the activities of 
daily living d 
 
First occurrence: 
reduce the dose of 
paclitaxel by 1 
dose level 
 
Second 
occurrence: 
permanently 
discontinue 
paclitaxel 
Discontinuation of paclitaxel 
a 
Dose adjustment of cisplatin for neurotoxicity is seen in Table 9; 
b 
It must be resolved to ≤ Grade 1 on Day 1 of the next cycle of therapy; 
d 
Paclitaxel should be terminated for persistent paresthesia/hypoesthesia that causes disability or endangers life.  
 
Table 12 
Dose Adjustment of Paclitaxel for Musculoskeletal Pain That Cannot Be 
Controlled With Analgesicsa 
Musculoskeletal 
pain 
Lasting for 1-7 days 
Lasting for >7 days or leading to 
delay of next cycle 
Grade 1 
No dose adjustment  
No dose adjustment 
Grade 2 
No dose adjustment 
No dose adjustment or delay next dose b
Grade 3 
First occurrence: reduce the dose of 
paclitaxel by 1 dose level 
Second occurrence: permanently 
discontinue paclitaxel 
First occurrence: delay next doseb or 
permanently discontinue paclitaxel 
Second occurrence: permanently 
discontinue paclitaxel 
a 
It is encouraged to use morphine and non-steroidal anti-inflammatory drugs to maintain the dose of Paclitaxel when 
possible; adjustment of the dose level of Paclitaxel is seen in Table 10 in detail;  

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b 
Dose of Paclitaxel will be interrupted when persistent Grade 2 or 3 musculoskeletal pain occurs. If it is relieved to 
≤ Grade 1, the dose of paclitaxel must be reduced when Paclitaxel treatment is resumed (reduction of dose of Paclitaxel 
by 1 level, see Table 10 for the details). If the Grade 2 or 3 toxicity still continues after the dose of Paclitaxel is delayed 
for 3 weeks, Paclitaxe l will be terminated; 
 
Table 13 
Dose Adjustment of Paclitaxel for Hematologic Toxicitya 
CTCAE 5.0 grade 
AE that occurs during 
treatment cycle and 
resolves prior to dose 
next cycle of therapyb 
AE that occurs during treatment cycle and is 
present on the day of administration in next 
cycle of therapy 
Neutropenia  
Grade 2, 3, or 4 
No dose adjustment 
Delay next dosec until ANC ≥1.5×109/L.  
Appendix 1 
If recovery occurs in ≥1-3 weeks 
and G-CSF is not given: maintain previous 
dose and add G-CSF; 
Appendix 2 
If recovery occurs within 1 week 
with G-CSF support, no dose adjustment is 
needed  
Appendix 3 
If recovered occurs in 2-3 weeks 
with G-CSF support, reduce by 1 dose level. 
Thrombocytopenia 
Grade 2 or 3 
No dose adjustment 
Delay next dosec until platelet count ≥100 × 109/L 
[1] If 1 week is needed for recovery: maintain the 
dose; 
[2] If 2-3 weeks is needed for recovery: reduce 1 
dose level. 
Grade 4 
Reduce by 1 dose level 
Reduce by 1 dose level 
AE = adverse event; AGC = granulocyte; ANC = absolute neutrophil count; CTCAE = common terminology criteria for 
adverse event; G-CSF = granulocyte colony-stimulating factor  
a 
The dose must be adjusted based on the AE that occurred during the previous treatment cycles (Column 2) and the AE 
that is still present on Day 1 of subsequent cycles (Column 3). The dose must be adjusted based on the AE requiring 
maximum dose adjustment; adjustment of the dose level of Paclitaxel is seen in Table 10 in detail; 
b 
Resolution is defined as all AEs requiring dose adjustment on Day 1 of subsequent cycles of therapy (i.e., continue 
treatment without delayed dose) are ≤ Grade 1 [except ANC/AGC (must be ≥1500/mm3) and bilirubin (must be 
≤ baseline)]; 
c 
Interrupt dose of Paclitaxel and perform the test once per week. Except for ANC/AGC and bilirubin, the treatment will 
be resumed when the toxicity is ≤ Grade 1. If the toxicity is still not resolved when the dose is delayed for 3 weeks, 
Paclitaxel will be discontinued with cisplatin and study drug continued. 
 
Table 14 
Dose Adjustment of Paclitaxel for Neutropenic Fevera 
CTCAE 5.0 grade 
AE that occurs during 
treatment cycle and resolves 
prior to next cycle of therapyb 
AE that occurs during treatment cycle 
and is present on the day of 
administration in next cycle of therapy 
Neutropenia and fever 
Grade 3 or 4 
Reduce by 1 dose level (see Table 10) and add G-CSF support or 
permanently discontinue paclitaxel. 

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AE = adverse event; AGC = granulocyte; ANC = absolute neutrophil count; CTCAE = common terminology criteria for 
adverse event; G-CSF = granulocyte colony-stimulating factor. 
a 
The dose must be adjusted based on the AE that occurred during the previous treatment cycle (Column 2) and the AE 
that is still present on Day 1 of subsequent cycles (Column 3). Dose adjustment must be based on the AE requiring the 
greatest adjustment. Whether the AE is “clinically significant” is to be determined by the investigator; adjustment of the 
dose level of Paclitaxel is seen in Table 10 in detail; 
b 
Resolution is defined as all AEs requiring dose adjustment on Day 1 of subsequent cycles of therapy (i.e., continue 
treatment without delayed dose) are ≤ Grade 1 [except ANC/AGC (must be ≥1500/mm3) and bilirubin (must be 
≤ baseline)].  
 
Table 15 
Dose Adjustment of Paclitaxel for Gastrointestinal Toxicity Related to 
Chemotherapy Other than Hepatotoxicitya 
CTCAE 
5.0 grade 
AE that occurs during treatment cycle 
and resolves prior to next cycle of 
therapyb 
AE that occurs during treatment cycle and 
is present on the day of administration in 
next cycle of therapy 
Diarrhea 
Grade 2 
No dose adjustment 
Reduce by 1 dose level 
Grade 3 
Reduce by 1 dose level 
Reduce by 1 dose level 
Grade 4 
Reduce by 2 dose levels or discontinue 
paclitaxel 
Reduce by 2 dose levels or discontinue 
palictaxel 
Oral mucositis oral (stomatitis) 
Grade 2 
No dose adjustment 
Reduce by 1 dose level 
Grade 3 
Reduce by 1 dose level 
Reduce by 1 dose level 
Grade 4 
Reduce by 2 dose levels or discontinue 
paclitaxel 
Reduce by 2 dose levels or discontinue 
paclitaxel 
Vomiting (regardless of receiving antiemetics) 
Grade 2 
Reduce by 1 dose level (optional) 
Reduce by 1 dose level 
Grade 3 or 
Grade 4 
Reduce by 1 dose level or discontinue 
paclitaxel 
Reduce by 2 dose levels or discontinue 
paclitaxel 
AE = Adverse event; AGC = granulocyte; ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for 
Adverse Events. 
a 
The dose must be adjusted based on the AE that occurred during the previous treatment cycle (Column 2) and the AE 
that is still present on Day 1 of subsequent cycles (Column 3). The dose must be adjusted based on the AE requiring 
maximum dose adjustment (adjustment of the dose level of Paclitaxel is seen in Table 10 in detail). “Clinical 
significance” of an AE is to be determined by the investigator. 
b 
Resolution is defined as all AEs requiring dose adjustment on Day 1 of subsequent cycles of therapy (i.e., continue 
treatment without delayed dose) are ≤ Grade 1 [except ANC/AGC (must be ≥1500/mm3) and bilirubin (must be 
≤ baseline)].  
 

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Table 16 
Dose Adjustment of Paclitaxel for Hepatotoxicitya 
CTCAE  
5.0 grade
AE that occurs during treatment 
cycle and resolves prior to next cycle 
of therapyb 
AE that occurs during treatment cycle and is 
present on the day of administration in next 
cycle of therapy 
Elevated bilirubin or AST or ALP 
Grade 2 
Reduce by 1 dose level 
Delay dosec until bilirubin is recovered to 
baseline grade, AST and ALP are recovered to ≤ 
Grade 1  
Resume at reduced dose by 1 dose level 
Grade 3 
Reduce by 2 dose levels 
Reduce by 2 dose levels 
Grade 4 
Discontinue paclitaxel 
Discontinue paclitaxel 
AE = adverse event; AGC = granulocyte; ALP = alkaline phosphatase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; CTCAE = common terminology criteria for adverse event. 
a 
The dose must be adjusted based on the AE that occurred during the previous treatment cycle (Column 2) and the AE 
that is still present on Day 1 of subsequent cycles (Column 3). The dose must be adjusted based on the AE requiring 
maximum dose adjustment (adjustment of the dose level of Paclitaxel is seen in Table 10 in detail). “Clinical 
significance” of an AE is to be determined by the investigator. 
b 
Resolution is defined as all AEs requiring dose adjustment on Day 1 of subsequent cycles of therapy (i.e., continue 
treatment without delayed dose) that are ≤ Grade 1 [except ANC/AGC (must be ≥1500/mm3) and bilirubin (must be 
≤ baseline)].  
c 
Interrupt the dose, and perform the test once per week. Except for ANC/AGC and bilirubin, the treatment will be 
resumed when the toxicity is ≤ Grade 1. If the toxicity is still not resolved when the dose is delayed for 3 weeks, 
Paclitaxel will be discontinued and the other planned therapies can be completed continuously. 
 
Table 17 
Dose Adjustment of Paclitaxel for Other Clinically Significant AEs a 
CTCAE 5.0 grade 
AE that occurs during 
treatment cycle and resolves 
prior to next cycle of 
therapyb 
AE that occurs during treatment cycle 
and is present on the day of 
administration in next cycle of therapy 
Grade 3 
Reduce by 1 dose level 
Reduce by 1 dose level 
Grade 4 
Reduce by 2 dose levels or 
discontinue paclitaxel 
Discontinue paclitaxel 
AE = Adverse event; AGC = granulocyte; ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for 
Adverse Events. 
a 
The dose must be adjusted based on the AE that occurred during the previous treatment cycle (Column 2) and the AE 
that is still present on Day 1 of subsequent cycles (Column 3). The dose must be adjusted based on the AE requiring 
maximum dose adjustment (adjustment of the dose level of Paclitaxel is seen in Table 10 in detail). “Clinical 
significance” of an AE is to be determined by the investigator. 
b 
Resolution is defined as all AEs requiring dose adjustment on Day 1 of subsequent cycles of therapy (i.e., continue 
treatment without delayed dose) that are ≤ Grade 1 [except ANC/AGC (must be ≥1500/mm3) and bilirubin (must be 
≤ baseline)].  
 
5.2 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and recording of AEs including SAEs, 
protocol-specified safety laboratory evaluation, measurement of protocol-specified vital 

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signs, and other protocol-specified tests that are deemed critical to the safety evaluation of the 
investigational drug. 
Some types of events need to be reported to the Sponsor immediately, as described in Section 
5.4. 
5.2.1 Adverse Events 
According to the ICH guideline for GCP, an AE is any untoward medical occurrence in a 
clinical investigation patient administering a pharmaceutical product, regardless of causal 
attribution. An AE can therefore be any of the following: 
• 
Any unfavorable and unexpected sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered to be related to the medicinal product. 
• 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition), except as described in Section 5.3.5.9. 
• 
The condition occurs intermittently and repeatedly (e.g., headache) and does not exist at 
baseline. 
• 
Worsening of laboratory test results (e.g., ECG, X-ray) or other clinical findings leading 
to a change in administration of the study drug, including discontinuation of the study 
drug, or the need for concomitant medications to treat the AE. 
• 
AEs that are related to a protocol-mandated intervention, including those that occur prior 
to assignment of the investigational drug (e.g., invasive procedures at screening such as 
biopsies) 
5.2.2 Serious Adverse Events  
An SAE is an AE meeting any of the following criteria: 
• 
Leading to death (i.e., death is definitely caused by or resulted from the AE); 
• 
Life threatening (i.e., the AE, in the view of the investigator, may jeopardize the patient 
at an immediate risk of death);  
• 
Requiring inpatient hospitalization or prolongation of existing hospitalization (see 
Section 5.3.5.11); 

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• 
Leading to permanent or major disability/incapability (i.e., the AE causing substantial 
damage to patient’s normal activities); 
• 
Congenital deformity/birth defect in the newborn/infant of the mother using the 
investigational drug; 
• 
Considered a significant medical event by the investigator (e.g., may jeopardize the 
patient’s life or require medical/surgical intervention to prevent one of the outcomes 
listed above) 
If an adverse event would be considered an SAE only after it worsens or results in death, the 
AE event would not be considered an SAE.  
The terms “serious adverse event” and “severity of adverse event” are not synonyms. 
Severity is defined as intensity of an AE (judged in accordance with CTCAE 5.0); the 
medical significance of the event itself may be relatively small (e.g., severe headache without 
any other findings). 
For each AE recorded on the eCRF, its severity and seriousness must be evaluated separately. 
Investigators should report SAEs to the Sponsor immediately (i.e., within 24 hours after 
awareness of the event; see Section 5.4.1 for the report description). 
5.2.3 Adverse Events of Special Interest (to be Report to the Sponsor Immediately) 
The investigator will be required to report adverse events of special interest (AESIs) to the 
Sponsor immediately (i.e., within 24 hours after awareness of the event) (non-serious AESIs 
need not be reported to the regulatory authorities). AESIs of toripalimab include: 
• 
Suspected immune-related myocarditis: elevated myocardial enzymes, change in ECG 
findings, or clinical symptoms; 
• Events meeting the criteria for Hy’s law, including ALT or AST 3 of baseline 
during treatment, with total bilirubin 2 ULN (where the direct bilirubin ≥35%); or 
ALT or AST  3  of baseline during treatment, with clinical jaundice; provided that 
cholestasis or hyperbilirubinemia caused by other reasons (see Section 5.3.5.7). have 
been excluded as alternative causes.  

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5.3 
Methods and Timing for Capturing and Evaluating Safety Parameters 
Investigators are responsible for ensuring that all the AEs (see Section 5.2.1 for the 
definition) are recorded in the Adverse Event page of the eCRF and reported to the Sponsor 
in accordance with the description in this section and Sections 5.4 to 5.6. 
For each AE recorded in the eCRF of AE, investigators will evaluate its seriousness (see 
Section 5.2.2. for criteria for seriousness), severity (see Section 5.3.3) and causal relationship 
(see Section 5.3.4). 
5.3.1 Adverse Event Reporting Period 
Investigators should contact the patient to obtain information related to the AEs. All AEs, 
regardless of where it is reported by patients or identified by research staff, should be 
recorded in the patient’s medical record and Adverse Event page of the eCRF. 
Following signing of the ICF and prior to the first dose of the study treatment, only 
SAEs are to be reported. 
After the start of study treatment, all the AEs will be reported (regardless of the 
relationship to the study drug) for up to 60 days after the last dose of the study treatment, 
initiation of a new antitumor therapy, patient withdrawal of consent, loss to follow-up, or 
death, whichever occurs first. 
Sixty (60) days after the last dose or after the start of a new antitumor therapy 
(whichever occurs first, the investigator should report SAEs to the Sponsor when the 
investigator considers the SAE to be related to the study drug (refer to Section 5.6). 
5.3.2 Collection of Adverse Events 
A consistent methodology of non-directive questioning AE information should be adopted at 
all patient evaluation time points. Examples of non-directive questions are:  
“How have you felt since your last clinic visit?” 
“Is there any new health issue or change of health issue after your last visit?” 
5.3.3 Severity Assessment of Adverse Events 
The severity of AE will be evaluated with reference to CTCAE 5.0. If the occurrence of AEs 
does not fall within the scope of the criteria, Table 18 will be used to assess the severity. 

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Table 18 
Severity Rating Scale for Adverse Events Not Listed in CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or no 
treatment required 
2 
Moderate; requiring minimal, local or non-invasive intervention; or limited age appropriate 
instrumental ADLa 
3 
Severe or medically significant, but not life-threatening immediately; requiring 
hospitalization or prolonged hospital stay; disability; or limited self-care ADL b, c 
4 
Life-threatening outcomes; requiring emergent treatmentd 
5 
Deaths caused by an AEd 
ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; 
SAE = serious adverse event. 
Note: Based on the latest version of CTCAE 5.0 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
a 
Instrumental ADL refers to cooking, buying groceries or clothes, making telephone calls, and paying bills. 
b 
Examples of self-care ADL include bathing, dressing, eating, going to the toilet, and taking medicines, which are 
activities that ambulatory patients can engage in. 
c 
If an event is assessed as a “significant medical event”, it must be reported as an SAE as described in Section 5.4.1. 
5.3.4 Causality Analysis of Adverse Events  
Investigators should comprehensively assess the causal relationship (related/unrelated) 
between an AE and the study treatment based on their understanding of the patient’s medical 
history and clinical course of AE and after ruling out alternative causes. Related is defined as 
a reasonable relationship exists between the AE and study treatment; unrelated is defined as 
no reasonable relationship exists between AE and the study treatment but there are other 
explanations, for example, complications of underlying disease, PD, and concomitant 
therapy. The causal relationship between the AE and each treatment, i.e., toripalimab/placebo, 
paclitaxel and cisplatin, will be evaluated separately for the patients in the induction phase. 
To determine the causal relationship, the following factors should be comprehensively 
considered: 
• 
Temporal relationship between the occurrence of the event and the administration of 
study treatment 
• 
The course of events, in particular, the impact of dose modification, discontinuation and 
rechallenge (if applicable) of the study drug,  
• 
Known correlation between the event and the drug or products of the same class 
• 
Known correlation between the event and the disease under study 

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• 
Presence of risk factors or use of concomitant medications known to increase the 
incidence of the event 
• 
Presence of non-therapeutic related factors known to be associated with occurrence of 
the event 
• 
The investigator’s assessment of causal relationship is one of the criteria for expedited 
reporting of suspected unexpected serious adverse reaction (SUSAR) by the Sponsor. 
The investigator should provide their medical judgment, in accordance with the 
information in the Investigator’s Brochure for the investigational drug and based on 
comprehensive review of the available clinical evidence. 
5.3.5 Recording Procedure of Adverse Events 
Investigators should use correct medical terms/concepts to record AEs on the AE page of the 
eCRF. Avoid using verbatim or colloquial language and abbreviations. 
In the event column on the AE page of the eCRF, only 1 AE term can be recorded for 1 event. 
5.3.5.1 Infusion-related Reaction 
Any AEs diagnosed as infusion-related reactions that occur during or within 24 hours of iv 
infusion should be recorded as a diagnostic result in the AE page of the eCRF (e.g., infusion-
related reactions). Try to avoid using ambiguous terms such as “systemic reactions”. If the 
patient experiences concurrent local and systemic reactions after administration of the study 
drug, each of the adverse reactions should be recorded, separately, in the AE page of the 
eCRF. In case of a local reaction, the term “injection site pain” or “injection site redness and 
swelling” should be used to clarify it. 
5.3.5.2 Recording of AE Diagnosis, Signs and Symptoms 
In addition to individual signs and symptoms, the diagnostic results (if known) should also be 
recorded in the AE page of the eCRF, such as only liver failure or hepatitis, but not jaundice, 
flapping fremitus, and elevated transaminases. However, if a single set of signs and/or 
symptoms cannot be medically diagnosed or diagnosed as a syndrome at the time of 
reporting, each event should be recorded in the AE page of the eCRF. If the diagnosis is 
subsequently confirmed, all previous events based on the diagnosis of symptoms and signs 
should be withdrawn and replaced with an AE report based on a single diagnosis, and the 
start date of the event is the start date of the initial symptom of the final diagnosis. 

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5.3.5.3 Adverse Events Occurring Secondary to Other Events  
In general, for AEs that are secondary to other events (such as cascade events or clinical 
sequelae), their primary causes should be determined, with the exception of severe secondary 
AEs. If secondary AEs are medically significant with independent occurrence dates, the 
secondary event should be recorded as a separate event in the AE page of the eCRF. The 
following are examples: 
• 
Vomiting should be reported in eCRF if the vomiting results in mild dehydration and no 
other treatment is required. 
• 
If vomiting causes severe dehydration, these secondary events (dehydration) should be 
reported separately in the eCRF. 
• 
If severe gastrointestinal bleeding causes renal failure, these secondary events should be 
reported separately in the eCRF. 
• 
If dizziness leads to a fall and a subsequent fracture, these secondary and tertiary events 
should be reported in the eCRF. 
• 
If neutropenia causes infection, these secondary events should be reported separately in 
the eCRF. 
If it is not clear whether there is causality between the events, all AEs should be recorded 
separately in the AE page of the eCRF. 
5.3.5.4 Persistent or Recurrent Adverse Events 
Persistent AEs refer to the continuance of AEs that are not relieved between the assessment 
time points for each patient. Such events need only be recorded once in the AE page of the 
eCRF. When the event is first reported, the initial severity or grade of the event is recorded. If 
persistent AEs worsen, the maximum severity should be recorded in the AE page of the 
eCRF. If the AE meets the criteria for an SAE, the investigator must immediately report it to 
the Sponsor (i.e., within 24 hours after the awareness of aggravated event) (see Section 5.2.2 
for reporting description) and update the AE page of the eCRF by changing the severity of the 
event from “non-serious” to “serious”, providing the date when the event was severe and 
filling in all the data related to the SAE. 

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Recurrent AEs are defined as the AEs that resolve at the time of the assessment compared 
with the last assessment (completely relieved), but subsequently recurred. Each recurrence of 
AEs should be recorded separately in the AE page of the eCRF. 
5.3.5.5 Abnormal Laboratory Test Values 
Not every laboratory abnormality is an AE. When an abnormal laboratory result meets any of 
the following criteria, it must be reported as an AE: 
• 
Is accompanied with clinical symptoms; 
• 
Leads to changes in study treatment (such as change in dose, treatment interruption, or 
discontinuation of treatment); 
• 
Requires medical intervention (such as potassium supplement for hypokalemia) or a 
change in concomitant medications; 
• 
Is clinically significant based on the investigator’s judgment. 
Note: For oncology studies, certain abnormalities need not be reported as AEs. 
The investigator is responsible for reviewing all laboratory results to correctly judge whether 
an isolated abnormal laboratory test result should be regarded as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., ALP 
and bilirubin 5ULN associated with cholestasis), only the diagnosis (i.e., cholestasis) 
should be recorded in the AE page of the eCRF. 
If an abnormal laboratory result is not a sign of a disease or syndrome, the abnormal result 
itself should be recorded in the AE page of the eCRF with an accompanying description 
specifying whether the test result is above or below the normal range (e.g., “high potassium” 
instead of “abnormal potassium”). If an abnormal laboratory result can be expressed with a 
precise clinical term according to the standard definition, the clinical term should be recorded 
as an AE. For example, if serum potassium elevates to 7.0 mEq/L, it should be recorded as 
“hyperkalemia”. 
If the same clinically significant laboratory abnormality is observed between visits, only 1 AE 
should be counted in the AE page of the eCRF (see Section 5.3.5.4 for details on persistent 
AEs). 

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5.3.5.6 Abnormal Vital Signs 
Not every abnormal vital sign is an AE. When the result of a vital sign meets any of the 
following criteria, it must be reported as an AE: 
• 
Is accompanied with clinical symptoms; 
• 
Leads to changes in investigational therapy (such as dose adjustment, treatment 
interruption, or termination of treatment); 
• 
Requires medical intervention or changing concomitant medications; 
• 
Is clinically significant based on the investigator’s judgment. 
The investigator is responsible for reviewing all vital sign findings to correctly judge whether 
an isolated abnormal vital sign should be regarded as an AE. 
If a clinically significant abnormal vital sign indicates a certain disease or syndrome 
(e.g., hypertension), only the diagnostic result (i.e., hypertension) needs to be recorded in the 
AE page of the eCRF. 
If the same clinically significant abnormal vital signs are observed at each visit, they should 
not be duplicated in the AE page of the eCRF unless the etiology changes (for details on 
recording persistent AEs, see Section 5.3.5.4). 
5.3.5.7 Abnormal Hepatic Function Test Findings 
Elevated ALT or AST (3ULN) accompanied by elevated total bilirubin (2 ULN) or 
clinical jaundice which cannot be explained by cholestasis or other medical conditions should 
be considered as drug-induced liver injury (according to Hy’s Law). Therefore, when any of 
the following occurs, the investigator must report it as an AE: 
• 
ALT or AST 3 ULN during treatment with total bilirubin 2 ULN (direct bilirubin 
35%); 
• 
Treatment-emergent ALT or AST 3 ULN with clinical jaundice. 
The diagnosis or laboratory abnormal results (if no clear diagnosis can be made) will be 
recorded as SAEs in the AE page of the eCRF and immediately reported to the Sponsor (i.e., 
within 24 hours of the awareness of the event). 

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5.3.5.8 Death 
In this protocol, death is the endpoint for the efficacy objective of overall survival. A death 
that occurs within the AE reporting timeframe specified in the protocol (see Section 5.3.1, 
from start of screening until 60 days after the last dose of the investigational drug) and is 
caused only by progression of ESCC, as assessed by the investigator, should be recorded as 
“PD” in the eCRF for AEs. The severity of such AE is recorded as Grade 5 (refer to NCI 
CTCAE 5.0) and the outcome is recorded as fatal. Death should be reported immediately to 
the Sponsor. After the AE reporting period as specified in the protocol (refer to  Section 5.3.1, 
after the period of 60 days after the last dose of the investigational drug), a death resulted 
from PD will not be reported as an AE and should be recorded in the Follow-up eCRF page 
instead. 
All the other events leading to deaths, occurring during the study, irrespective of the 
relationship with the investigational drug, should be recorded in the eCRF for AEs, and 
reported to the Sponsor immediately. Death should be regarded as the outcome of event 
rather than the event itself. The event or disease leading to or facilitating the outcome of 
death should be recorded as 1 single medical concept in the eCRF of AE. Generally, only 1 
such event should be reported. 
The term “sudden death” should only be used for the occurrence of an abrupt and unexpected 
death due to presumed cardiac causes in a patient with or without preexisting heart disease, 
within 1 hour of the onset of acute symptoms or, in the case of an unwitnessed death, within 
24 hours after the patient was last seen alive and stable. If the cause of death is unknown and 
cannot be ascertained at the time of reporting, “unexplained death” should be recorded on the 
Adverse Event CRF. If the cause of death is known afterwards (e.g., following autopsy), the 
confirmed cause of death will be used to replace “death of unknown cause”. 
5.3.5.9 Pre-existing Disease Conditions 
The pre-existing disease means that the disease state already exists at the screening visit of 
this study. The preexisting disease should be recorded in the eCRF as part of medical history 
and baseline condition. See Appendix 11 for a detailed listing of pre-existing autoimmune 
diseases, which may preclude eligibility for the study.  
During the study period, only when the frequency, severity, or nature of the pre-existing 
medical condition has deteriorated should it be recorded as an AE. When such an event is 

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recorded in the AE page of the eCRF, care should be taken to adopt a suitable description to 
convey the concept that the pre-existing medical disease has changed (e.g., “more frequent 
headaches”). 
5.3.5.10 Lack of Efficacy 
Events that are clearly consistent with the expected progression pattern of disease under study 
should not be recorded as AEs. These data will only be collected as efficacy analysis data. 
In most cases, the expected progression pattern will be assessed based on radiological 
evaluation criteria (e.g., RECIST 1.1). In rare cases, it will be determined whether there is 
clinical progression based on the worsening of symptoms. However, objective criteria should 
be used to justify progression. If it is uncertain whether an event is attributed to an AE, the 
event should be reported as an AE. 
5.3.5.11 Hospitalization or Prolongation of Hospitalization 
Any AE leading to hospitalization (i.e., inpatient admission) or prolonged hospitalization 
should be documented and reported as an SAE (as defined in Section 5.2.2, Serious Adverse 
Events), with the following exceptions: 
 
Hospitalization due to temporary medical care; 
 
Hospitalization as scheduled in study protocol (e.g., for investigational drug 
administration or for evaluation of the efficacy of this study); 
 
Hospitalization due to preexisting conditions, but all the following criteria must be met: 
a) Hospitalization is already planned prior to the study, or hospitalization for elective 
surgery is needed due to expected normal disease progression during the study. 
b) The patient has not experienced any AE. 
c) Hospitalization only due to related cancer progression. 
If a patient is hospitalized because they need medical treatment outside of normal outpatient 
business hours, then the hospitalization will not be considered to meet the criterion for an SAE. 
5.3.5.12 Adverse Events in Association With Overdose/Medication Errors 
Overdose refers to accidental or intentional administration at higher doses than those 
currently being studied. Overdose or improper dose of the investigational drug itself will not 

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be regarded as an AE, and the information on the medication should be recorded on the 
medication page of the eCRF. AEs associated with overdose or incorrect administration of the 
investigational drug will be considered as SAEs and will be recorded in the AE page of the 
eCRF and reported immediately to the Sponsor (i.e., within 24 hours after the awareness of 
the event). Please refer to Section 5.4.1. 
5.3.5.13 Data on Patient-reported Outcomes 
The data source of AE reporting does not include the PRO data received by the Sponsor, and 
PRO data will not be used for analysis of safety. However, when any PRO data that is 
possibly indicative of an AE is found in reviewing the PRO data at the research site, 
investigators need to determine whether it meets the criteria of an AE and record this event on 
the AE page of the eCRF if it meets. 
5.4 
Immediate Reporting Requirements (Within 24 Hours) From Investigators to the 
Sponsor 
 Regardless of the causality, investigators must report the following events to the Sponsor 
within 24 hours after being aware of them: 
• 
SAE 
• 
AESI 
• 
Pregnancy 
Investigators must report the important new follow-up data on these events to the Sponsor 
immediately (i.e., within 24 hours after awareness of the events). Important new information 
includes the following: 
• 
New sign or symptom or change in diagnosis; 
• 
Important new results of laboratory tests; 
• 
Change of causality based on the new data; 
• 
Change in the outcome of event, including recovery; 
• 
Other narrative data on the clinical course of the event. 
Investigators also have to follow relevant requirements on SAE reporting according to local 
health regulatory authorities and IRC/EC. 

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5.4.1 Serious Adverse Event Reporting Requirements 
5.4.1.1 SAE Occurring Before the Start of the Study Treatment 
All SAEs occurring after signing informed consent until 60 days after the last dose of study 
drug must be reported. Investigators should complete the SAE report form and submit it to 
the Sponsor or the designated person immediately (i.e., within 24 hours after awareness of the 
event) via fax or email. 
5.4.1.2 SAE Occurring After the Start of Study Treatment 
All serious adverse events occurring at any time after the first dose of study drug through 60 
days after the last dose of study treatment, initiation of a new antitumor therapy, patient 
withdrawal of consent to remain on study, loss to follow-up, or death, whichever occurs first, 
must be reported. Investigators should complete the SAE report form and submit to the 
Sponsor or the designated person immediately (i.e., within 24 hours after awareness of the 
event) via fax or email. 
See Section 5.6 for a description of the required AE reporting after the study. 
5.4.2 Reporting Requirements for Pregnancies 
5.4.2.1 Pregnancy of Female Patients 
The female patients of childbearing potential shall be informed to notify investigators 
immediately if they are pregnant during the study or within 90 days after the last dose of the 
investigational drug. Investigators should fill in the pregnancy report form immediately 
(i.e., within 24 hours after awareness of pregnancy) and submit to the Sponsor. Investigators 
should discontinue dosing of the investigational drug and discuss with the patient about the 
risk of pregnancy and possible effect on the fetus. Monitoring should be continued until 
conclusion of the pregnancy. Pregnancy will not be recorded as an AE, however, a 
pregnancy-related SAE (e.g., fetal event, SAE in the mother during or resulting from the 
pregnancy, or congenital deformity/birth defect in children) should be reported in the AE 
page of the eCRF. In addition, following acquisition of the updated information on the course 
and outcome of pregnancy, investigators will submit the pregnancy report form under this 
trial. 

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5.4.2.2 Pregnancy of Female Partners of Male Patients  
Male patients must also be instructed in the ICF to immediately inform the investigator if 
their female partner becomes pregnant during the study or within 90 days after the last dose 
of the study drug. Investigators should fill in the pregnancy report form immediately 
(i.e., within 24 hours after awareness of pregnancy) and submit to the Sponsor. The 
investigator should make every effort to collect and report detailed information on the course 
and outcome of the pregnancy. The pregnant partner will be asked to a letter authorization 
disclosure of pregnancy-related medical information and to allow follow-up for her 
pregnancy in order to update the pregnancy report form.  Investigators contacted by male 
patient or his pregnant partner can provide the treating physician and/or obstetrician with 
information on the potential risk to the fetus, and make the informed decision jointly. 
If the electronic data capture (EDC) system is not available, it will be reported in accordance 
with the report description provided in Section 5.4.2.1. 
5.4.2.3 Abortion 
Any abortion (except induced abortion) should be classified as an SAE (as the Sponsor 
considers abortion to be an adverse event of medical significance), recorded in the AE page 
of the eCRF, and reported to the Sponsor immediately (i.e., within 24 hours after awareness 
of the event) (see Section 5.4.2). 
5.4.2.4 Congenital Anomaly/Birth Defect 
If the congenital deformity/birth defect occurred in the fetus delivered by the female patient 
using the investigational drug or female partner of male patient using the investigational drug, 
it should be classified as an SAE, recorded in the AE page of the eCRF, and reported to the 
Sponsor immediately (i.e., within 24 hours after awareness of the event; see Section 5.4.2). 
5.5 
Follow-up for Patients Following Adverse Events 
5.5.1 Investigator Follow-up 
Investigators should follow up all AEs, until resolution or stabilization of the AE, patients’ 
loss to follow-up, initiation of a new antitumor therapy, death, termination of the study by the 
Sponsor or patient’s withdrawal of consent to remain on study, whichever occurs first. Every 
effort should be made to follow up all the SAEs related to the investigational drug or study 
procedures, until the final outcome can be reported. 

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During the study, resolution of AE (and the date of recovery) should be recorded on the AE 
page of the eCRF and patient’s medical record, as to facilitate validation of source data. If the 
outcome of the AE is unclear from the information collected by follow-up, it should be stated 
on the AE page of the eCRF. 
All pregnancies reported during the study should be followed up until the termination of 
pregnancy. 
5.5.2 Sponsor Follow-up 
For SAE, AESI, and pregnancy, the Sponsor or the designated person can acquire case-related 
information and its outcome via telephone, fax, email, and/or monitoring visit (e.g., from 
discharge note, consultation report, autopsy report) to facilitate independent medical 
evaluation of these reported cases. 
5.6 
Post-study Adverse Events 
After a period of 60 days after the last dose or start of a new antitumor therapy, whichever 
occurs first, any SAE considered to be related with the previous treatment with 
investigational drug should be reported by the investigator until patients’ withdrawal of the 
informed consent, lost to follow-up, or death. 
If the EDC system is not available, investigators can use the provided fax number or email 
address to send the SAE/AESI report form directly to the Pharmacovigilance Department of 
Shanghai Junshi Biosciences Co. Ltd. or its designated email address. 
5.7 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Board, and Ethics Committee 
Based on the accumulated experiences of products, the Sponsor will evaluate all the SAEs 
and AESIs in real-time, identify SUSAR, and communicate immediately with the 
investigator, the institutional review board, and the health regulatory authorities in 
accordance with regulatory requirements. 
In order to determine the requirement for reporting single AE case, the Sponsor will use the 
Investigator’s Brochure on toripalimab as the reference to evaluate the predictability of these 
events. 

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The Sponsor will compare the severity and cumulative event frequency of each event 
reported in this study with what is recorded in the applicable reference document. 
The reporting requirement will also be based on the evaluation of relationship and 
seriousness by investigators, and the Sponsor is allowed to update it when required. 
The Sponsor shall strictly implement the expedited reporting in accordance with the 
requirements of “Good Clinical Practices (Administration Decree No.3) – Clause 40, the 
applicant and the investigator should investigate rapidly any serious adverse event occurred, 
and adopt essential measures to ensure safety and rights of patients, and to report to the drug 
supervision and administration authorities and health administration authorities immediately 
as well as to circulate to other investigators involved in the clinical trials of the same drug”.  
6 
Statistical Considerations and Analytical Plan 
6.1 
Determination of Sample Size 
Approximately 500 patients with advanced or metastatic ESCC who have not received 
systemic chemotherapy previously will be enrolled in this study and randomized in a ratio of 
1:1 into the toripalimab combined with TP regimen (Group A) and placebo combined with TP 
regimen (Group B). 
The sample size was calculated based on the dual —primary efficacy endpoints of PFS as 
evaluated by BICR per RECIST 1.1 and OS. 
A hierarchical testing will be used for PFS and OS analysis at an overall significance level of 
two-sided 0.05, i.e., all the α levels (two-sided 0.05) will be firstly used for the hypothesis 
test of PFS, and when the null hypothesis of PFS is rejected, the hypothesis test of OS will be 
conducted at the 2-sided 0.05 significance level.  
For PFS, 283 PFS events are expected to be observed in approximately 500 patients enrolled 
approximately 24 months after randomization of the first patient. This will provide 85% 
statistical power to detect an improvement in PFS for toripalimab in combination with TP vs 
placebo in combination with TP in patients with advanced or metastatic ESCC who have not 
previously received systemic chemotherapy at the two-sided significance level of 0.05 to 
detect a corresponding hazard ratio (HR) of 0.7.  
[]For OS, 366 OS events are expected to be observed in approximately 500 patients enrolled 
approximately 39 months after randomization of the first patient, thereby there is 85% 

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statistical power to detect an improved OS for toripalimab in combination with TP vs placebo 
in combination with TP in patients with advanced or metastatic ESCC who have not 
previously received systemic chemotherapy at the two-sided significance level of 0.05 to 
detect a corresponding HR of 0.73. One planned interim analysis of OS will be performed at 
the time of the PFS analysis (approximately 24 months after randomization of the first 
patient). 
Calculation of the above sample size is based on the following assumptions: 
• 
PFS and OS appear exponential distribution; 
• 
The median PFS in Group B is 5 months and the median OS is 10 months; 
• 
α-consumption function of O’Brien-Fleming type (approximation using Lan-DeMets 
method) is used for interim analysis and primary analysis of OS, to control the overall type I 
error rate; 
• 
Approximately 500 patients will be recruited within 22 months; 
• 
For observation of PFS and OS events, the drop-out rate is 5% within 1 year after 
randomization. 
6.2 
Data Analysis Sets 
ITT set: All the randomized patients. 
Safety analysis set (SS): In the ITT set, all the patients who have received any dose of the 
investigational drugs (including toripalimab or chemotherapy). 
6.3 
Analytical Method 
The standard descriptive statistical results include median, mean, standard deviation, 
minimum, and maximum for continuous variables, and number and percentage for 
categorical variables. 
The detailed statistical plan and method shall be described in detail in a separate Statistical 
Analysis Plan. 
6.3.1 Demographics and Baseline Disease Characteristics 
Demographic and baseline disease characteristics data shall be summarized by the above 
descriptive analysis method. 

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6.3.2 Efficacy 
All efficacy data shall be analyzed, based on the ITT analysis set. 
6.3.2.1 Primary Efficacy Endpoints 
The primary efficacy endpoint is the dual endpoint comprised of PFS (as evaluated by BIRC 
in accordance with RECIST 1.1) and OS. In this study, hierarchical testing method will be 
used for the analysis of PFS and OS, i.e., all the α levels (2-sided 0.05) will be firstly used for 
the hypothesis test of PFS, when the null hypothesis of PFS is rejected, the hypothesis test of 
OS will be conducted at the two-sided significance level of 0.05. The null hypothesis and 
alternative hypothesis of PFS and OS analyses can be represented by the corresponding 
survival function SA(t) in Group A and the survival function SB(t) in Group B: 
H0: SA(t) = SB(t) vs H1: SA(t) ≠ SB(t). 
PFS is defined as the time from randomization to first recorded PD or to death for any cause, 
whichever occurs earlier. Patients with no PD or death will be censored on the day of the last 
complete tumor assessment evaluation. Patients who have not undergone any post-treatment 
tumor evaluations during the study and with no death recorded will be censored 1 day after 
randomization. Patients who do not report any PD nor start any anticancer therapy 
unspecified in the protocol will be censored on the day of the last evaluable tumor evaluation 
prior to the start of subsequent anticancer therapy. PFS analysis will be conducted by the 
stratified log-rank test method, and the stratification factors include ECOG performance 
status score (0 or 1) and previous radiotherapy (yes or no). The Kaplan-Meier (KM) method 
will be used to estimate the median PFS in each treatment group; the 95% CI of median PFS 
will be estimated through the Brookmeyer-Crowley method using log-log function 
conversion to reach normal approximation. The HR of PFS and its 95% CI will be estimated 
using the stratified Cox proportional hazard model. 
The OS is defined as the time from randomization to death for any cause. Patients without 
death recorded will be censored on the last known survival date. Patients without any 
follow-up information will be censored on the day after randomization. The same analytical 
method for PFS will be used for analysis of OS. 

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6.3.2.2 Secondary efficacy endpoints 
The secondary efficacy endpoints include ORR, DCR, DOR, and TTR evaluated by BICR or 
by the investigator in accordance with RECIST 1.1; PFS evaluated by the investigator in 
accordance with RECIST 1.1; and PFS, ORR, DCR, DOR and TTR evaluated by the 
investigator in accordance with irRECIST, as well as the 1- and 2-year PFS and OS rates. The 
specific definition is as follows: 
• 
The PFS rate at 1 year or 2 years is defined as the percentage of patients who are alive 
and have no documentation of PD within 1 year or 2 years after randomization.  
• 
The OS rate at 1 year and 2 years is defined as the percentage of patients who are alive 
within 1 year or 2 years after randomization. 
• 
The ORR is defined as the proportion of patients with a best overall response of CR or 
PR. 
• 
DCR is defined as the proportion of patients with a best overall response of CR, PR, or 
SD. 
• 
DOR is defined as the time from first documented objective response (CR or PR) to first 
recorded PD or to death, whichever is earlier. DOR is analyzed only for the patients with 
the best overall response of CR or PR. Patients without progression or death after 
achieving response will be censored on the date of the last tumor assessment. If no tumor 
assessment is performed after achieving response, the patients will be censored 1 day 
after the tumor assessment upon response. 
• 
TTR is defined as the time from randomization to first documented objective response 
(CR or PR). TTR will be calculated only for the patients with the best overall response of 
CR or PR, without censoring. 
The analytic methods used for the primary efficacy endpoints of PFS and OS will be used for 
analysis of the secondary efficacy endpoints of DOR and TTR. The percentage of patients in 
each treatment group will be calculated for ORR and DCR. The Clopper-Pearson method will 
be used to calculate their 95% CIs, and the 95% CI for the difference in the percentage 
between groups will be estimated using the NEWCOMBE method. The KM method will be 
used to estimate the PFS and OS rate at 1 year and 2 years in each treatment group. The 95% 

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CIs will be estimated using the Greenwood formula, and the 95% CI for the intergroup 
difference in PFS and OS rate will be estimated using the Newcombe method. 
6.3.3 Safety 
All safety data will be summarized based on the safety analysis set. 
AEs will be summarized by the system organ class and preferred term (PT) of the Medical 
Dictionary for Regulatory Activities. The summaries for correlations of SAEs and AEs, 
severity of AEs, and irAEs will be tabulated. 
Vital signs data, ECG data, laboratory test data, and physical examination data shall be 
tabulated by time. 
A frequency form will be used to summarize the occurrence of AEs and the number and 
incidence of abnormal laboratory tests. Severity and relationship to the investigational drug 
will be tabulated for each AE and abnormal laboratory value. Descriptive statistics will be 
used to summarize the laboratory test results and vital sign indicators of each visit by group. 
The safety of toripalimab will be evaluated by analyzing the occurrence of AEs in 
combination with the vital signs and laboratory test results during the drug administration. 
6.3.4 Exploratory Analysis 
• 
To explore the correlation between the biomarkers in archived or fresh tissue specimen 
and blood (including but not limited to PBMC, PD-L1, EBV, MSI, 11q13, tumor 
mutation burden, and other) and disease status, mechanism of resistance and/or response 
to toripalimab. 
• 
To evaluate the incidence and titer of ADA of toripalimab and to explore the potential 
correlation between the immunogenicity response and PK, safety, and efficacy 
• 
To evaluate the practicability of biopsy when obvious PD appears to differentiate the 
obvious increase of tumor volume related to the immunoregulatory activity of 
toripalimab (i.e., pseudo-progression/ tumor immune infiltration) and real PD. 
6.4 
Interim Analysis 
One interim analysis of OS is planned to be conducted in this study. 

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The interim analysis of OS is to be conducted at the time of the PFS analysis, i.e., when 
approximately 283 PFS events and 212 OS events have occurred, respectively, which is 
expected approximately 24 months after the first patient is randomized. However, the exact 
timing of this analysis will depend on the actual time when the number of PFS events 
required for PFS analysis is reached. 
The interim analysis will be performed by independent statistical analysis service 
provider, the result of the interim analysis will be reviewed by IDMC and advice will be 
provided to the Sponsor thereafter. 
7 
Data Collection and Management 
7.1 
Quality Assurance of Data 
The Sponsor will entrust a contract research organization (CRO) to conduct data management 
of this study, including verification of the data quality. Patients’ data will be collected through 
EDC system using eCRF. The research site is responsible for data entry to EDC system. If a 
discrepancy is found in the data, the Sponsor will request the research site to clarify, and any 
correction or clarification must be done in EDC system. 
The Sponsor will establish the procedures on how to ensure the quality of data captured in the 
EDC. The central laboratory will transfer the data to the Sponsor directly, and the electronic 
transmission of these data will be conducted according to the Sponsor’s SOP. 
The audit trail control feature of EDC system will be used to keep a record of change and 
corrections made to eCRF. The data backup and study record retention will be conducted by 
the Sponsor according to the Sponsor’s SOP. 
7.2 
Electronic Case Report Form 
eCRF will be filled by the EDC system designated by the Sponsor. The research sites will be 
trained on how to fill out the eCRF. The eCRF will be submitted electronically to the Sponsor 
according to the procedures defined by the Sponsor. 
All eCRFs must be completed by the designated and trained staff of the research site. The 
investigator or designee will review the eCRF, and the investigator will sign electronically. 
At end of the study, the investigator will receive patients’ data of the research sites through a 
read-only disc and will be stored with the study records. The return receipt for the disc must 
be signed. 

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7.3 
Source Documents 
The study monitor will carry out continuous verification of source data to ensure that the key 
data (i.e., source data) from source documents are entered in eCRF accurately and completely 
by authorized staff at the study site and ready to be verified. 
Source documents (paper or electronic) refer to verified first-hand data of patients. Source 
documents include but are not limited to hospital records, clinical and outpatient medical 
records, laboratory records, memos, patients’ log or PRO, list of assessments, pharmacy 
dispensation records, data recorded in the automatic instruments, copies that are verified to be 
true and exact to the original documents, microfiches, photographic plates, microfilms or 
magnetic media, X-ray photography, patients’ documents, and records stored in pharmacies, 
laboratories, and medical technical departments participating in the clinical study. 
Prior to start of the study, the types of source documents that are acceptable must be defined 
clearly in the Study Monitoring Plan, including protocol data directly entered into eCRF (i.e., 
written or electronic data previously not existing) and any other media considered as source 
data. 
Alteration or destruction of the source documents required to verify validity and integrity of 
the data entered in eCRF is prohibited. Source documents must be stored in accordance with 
the record retention policies as described in Section 7.5. 
The investigator and the research site must grant the Sponsor, EC and regulatory authority 
direct access to source documents for audit, review or inspection.  
7.4 
Use of Electronic Data Capture Systems 
When the clinical results are directly entered into the electronic data capture (computer) 
system for medical records for the trial center (i.e., instead of the original hard copy records), 
the electronic records may be used as source documents, if the computer system has been 
validated in accordance with the regulatory requirements for computer system used in clinical 
studies. If the original data are changed, then the system should retain visible audit trails, 
which can show the original data and the reasons for changes, name of the modifier, and the 
date of change. 

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7.5 
Records Retention 
Trial-related records and files, including eCRF, PRO data, ICFs, laboratory test results, and 
study drug inventory records, must be retained by the principal investigator for at least 15 
years after study completion or termination or for a period as required by the national or local 
regulatory authorities, whichever is longer. After the retention period, the above documents 
may be destroyed in accordance with local laws and regulations. 
The records should not be disposed without written permission by the Sponsor. A written 
notice should be submitted to the Sponsor before any records are transferred to a different 
location. 
8 
Ethical Considerations 
8.1 
Compliance 
This study shall be carried out in strict accordance with the laws and regulations for clinical 
studies in China, including GCP, Declaration of Helsinki (edition 2013), and other 
regulations, as well as this study protocol. The specific procedures for implementation of the 
study shall be in accordance with the SOPs of all organizations/collaborators in participating 
the study.  
8.2 
Informed Consent 
The Sponsor’s template of ICF will be provided to each site. Prior to submission to EC, the 
Sponsor or its designated personnel must review and approve any modification to the 
Sponsor’s template of ICF or any alternated consent form provided by the research site 
(collectively referred to as “informed consent form”). As required locally, the final consent 
form approved finally by EC must be provided to the Sponsor for submission to health 
authorities. 
The ICF includes a separate section involving collection of optional samples and use of 
remaining samples (plasma, serum, whole blood, and tissue), which are used for the optional 
exploratory study. The investigator or designee will explain to patients the relevant purposes, 
methods, and potential risks of each optional procedure. The patients are informed that they 
may voluntarily refuse to participate in the study, withdraw the informed consent at any time, 
and/or request to withdraw sample for any reason during the storage. It is required to provide 
a separate signature specifically to record that the patients agree for collection of optional 

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samples and use of any remaining samples for the exploratory study. Patients who refuse to 
participate do not need to provide a separate signature.  
The informed consent shall also contain the following additional signature page: 
• 
If approved by the investigator and the Sponsor’s medical monitor or designated 
representative, patients in the toripalimab/placebo group who choose to continue the 
treatment after the first radiologically documented PD and who meet the criteria 
described in Section 4.7.2 shall sign on this page. Prior to consent, the patients will be 
informed by the investigator of other available treatment options and potential risks of 
continued treatment.  
An optional ICF for collection of tumor tissue sample at the time of PD must be by the 
patient to provide consent for biopsy at the time of disease progression. For details, see 
Section 4.6.11.2. 
The patient or his/her legal representative must sign the ICF and date prior to patient’s 
participation in the study. The process of obtaining informed consent must be recorded in 
each patient’s medical record or clinic record and must be completed before participation in 
the study. 
If the study procedure is changed or new information that may possibly affect patient’s 
willingness to participate in the study is acquired, the ICF should be revised. The revised ICF 
must be approved by IRB/EC before use and submitted to regulatory authorities. 
During participation in the study, all revised versions of consent forms must be re-signed by 
the patients (or consent on important new information/results appendix in accordance with 
applicable laws and EC policies). The process of re-consenting must be documented. 
A copy of the signed consent form must be provided to the patient or his/her legally 
authorized representative. All the signed and dated ICFs must be kept in the patient’s study 
document or site document and can be provided to study monitors for verification at any 
time. 
8.3 
Ethic Committee 
Prior to initiation of the study, the investigator must provide the study protocol, ICF, and any 
information to the patients to the EC for review and approval. In addition, all materials for 
recruitment of patients must be approved by the EC. 

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In accordance with the laws and regulations, policies, and relevant requirements by EC, the 
principal investigator shall submit a written progress report for the study at least annually to 
the EC. The investigator is also responsible in notifying EC for information of any 
amendment of the study protocol (see Section 9.6). 
In addition to reporting all AEs to the Sponsor, the investigator must report SAEs to local 
regulatory authorities and EC in accordance with the requirements. The investigator may 
receive the written safety report for the study drug or other safety related correspondences 
from the Sponsor. The investigator is responsible for reviewing and processing of these 
reports in accordance with the requirements by regulatory authorities and policies and 
procedures established by EC. Safety reports will be archived at the research site. 
8.4 
Principles of Maintaining Confidentiality 
To protect the patients’ privacy, the Sponsor assigns a unique patient ID for each patient 
enrolled into the study. This means that the patient’s name will not be included in the data set 
delivered to the Sponsor. 
The patients’ medical information obtained in the study are confidential and can be disclosed 
to a third party only as allowed in the ICF (or a separate letter of authorization for use of 
personal healthy information) signed by the patients. 
For treatment purposes, the medical information may be provided to the patient’s own doctor 
or other healthcare professionals who are attending the patient. 
The representative of the national or local health regulatory authorities, the medical monitor, 
representative or collaborators of the Sponsor, or EC of each research site may request access 
to the data obtained from the study at any time. 
8.5 
Financial Disclosure 
The investigator will provide adequate and accurate financial information to the Sponsor in 
accordance with the local laws and regulations so that the Sponsor may submit a complete 
and accurate financial proof or disclosure statement to the health regulatory authorities. The 
investigator shall provide the information on financial interests during the study and within 1 
year after completion of the study. 
9 
Study Records, Monitoring and Management 
9.1 
Study Records 

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The investigator must keep adequate and accurate records so that the implementation process 
of the study has complete written records, including but not limited to the study protocol, 
protocol amendments, ICF, and approval documents by EC and government. In addition, the 
investigator will receive patient’s data at the end of study, including audit trails for the 
records for all data changes. 
9.2 
Protocol Deviations 
The investigator should record and explain any deviation from the protocol. In accordance 
with the established EC policies and procedures, the investigator should report any deviation 
that may influence patients’ safety and data integrity to the Sponsor and EC. 
9.3 
Quality Control and Quality Assurance 
In order to ensure quality of the trial, the clinical study plan is discussed and established 
jointly by the Sponsor and the investigators prior to the official initiation of the formal study. 
Relevant investigators participating in the study are trained according to GCP. 
Each research site must manage the study drug according to the SOPs, including receipt, 
storage, dispensation, and retention. 
9.3.1 Monitoring 
The clinical monitor authorized by the Sponsor shall have the right to consult the eCRF, ICF, 
and all original source data. 
The clinical monitor shall be responsible for formulating the plan and procedures that must be 
followed during the study. An on-site visit shall be carried out prior to initiation of the study. 
A regular visit shall be made during performance of the study. If needed, the patient may be 
contacted via telephone, fax, or mail, as supplement to the on-site visit. 
Prior to initiation of the study, the investigator shall be notified of the expected frequency of 
monitoring visits. Additionally, during the study, the investigator shall be notified in advance 
prior to each monitoring visit. The visit is intended to ensure that the clinical study shall be 
carried out in strict accordance with the study protocol and to ensure the integrity and 
accuracy of the case report form, which may be verified from the original documents. 
The clinical monitor shall check that all eCRFs are filled out correctly and completely and are 
consistent with the original data; all the errors and missing data have been modified or noted, 

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signed, and dated by investigators. At each visit, the investigator and the clinical monitor 
shall cooperate closely, to check and verify the case report form, drug supply and inventory 
records, drug distribution and recovery records, and other scheduled additional records. 
The Sponsor or a person authorized by the Sponsor may check the quality of the study; the 
checker has the right to examine all study-related medical records, investigator’s files and 
correspondences, and ICF. 
9.3.2 Auditing 
When appropriate, the auditor shall conduct an audit of the study according to relevant SOPs, 
to ensure that the study is carried out in accordance with the national relevant laws and 
regulations, SOPs, and the protocol. The audit range includes office documents and the 
research site’s documents. After the audit, the auditor shall submit a written report to describe 
any problem found and propose suggestions; relevant persons (investigator and auditor) shall 
adopt corresponding corrective measures and record them in writing. 
9.4 
Administrative Management Structure 
This study is sponsored and managed by Shanghai Junshi Biosciences Co., Ltd. 
Approximately 500 patients will be randomized. 
Randomization is conducted by the IxRS. The site facilities will be used for evaluation (e.g., 
designated laboratory examinations) throughout the study. For routine study examinations, a 
locally certified laboratory will be responsible for implementation; the normal laboratory test 
ranges for the local laboratory will be collected. 
9.5 
Publication of the Data and Protection of Commercial Confidential 
Information/Trade Secrets 
The investigator shall keep information and data related with the study confidential and shall 
not cite or publish study results or data without permission of the Sponsor. 
The Sponsor has the right to issue or publish information or data related to the study or 
submit them to NMPA. The Sponsor shall seek permission of the investigator if the 
investigator’s name will appear in the publication or other content. 

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9.6 
Protocol Amendment(s) 
Protocol amendments will be submitted to the EC in accordance with the provisions of the 
local laws and regulations. 
Prior to implementation of any change in the protocol, the revised protocol must be approved 
by the EC (according to local requirements), unless the change is to eliminate any direct 
hazard to patients or is only a change in logistics or personnel (e.g., change of medical 
monitor or contact information). 
10 
Independent Data monitoring Committees (IDMC) 
An IDMC will be set up to assess safety data and conduct efficacy assessment and benefit-
risk assessment of this study. The IDMC will include at least 2 clinicians and 1 biostatistician 
with professional knowledge on oncological trials. Prior to the final analysis of PFS, 
risk/benefit assessments will be conducted at regular data review meetings to ensure the 
safety of the patients. The IDMC will also review the efficacy data from any planned interim 
analysis. After review of the data, the IDMC will provide advice on continuation of the study, 
amendment to the protocol, or discontinuation of the study. The final decision will be made 
by the Sponsor. The procedures on management of the IDMC will be specified in 1 separate 
IDMC constitutional document. 

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11 
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in China, 2015. CA Cancer J Clin. 2016;66(2):115-32. 
3. Liang H, Fan JH, Qiao YL. Epidemiology, etiology, and prevention of esophageal 
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6. Lai X, Zheng X, Mao W. Research progress in targeted therapy for esophageal cancer. J 
Chinese Oncol. 2015;21(2):142-50. 
7. Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol. 2015;23:32-8. 
8. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. 
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9. Doi T, Piha-Paul SA, Jalal SI, et al. Updated results for the advanced esophageal 
carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475). 
2016 Gastrointestinal Cancers Symposium, Poster Session A Board #F7. 
10. Tanaka T, Nakamura J, Noshiro H. Promising immunotherapies for esophageal cancer. 
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11. Le DT, Bendell JC, Calvo E, et al. Safety and activity of nivolumab monotherapy in 
advanced and metastatic (A/M) gastric or gastroesophageal junction cancer (GC/GEC): 
Results from the CheckMate-032 study. J Clin Onco. 2016;54(1):59-68. 
12. Kojima T, Hara H, Yamaguchi K, et al. Phase II study of nivolumab (ONO-4538/BMS-
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14. Guidance for Nonclinical Safety Evaluation of Biological Products for Therapeutic Use. 
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15. Standards for Quality Control of Drug Clinical Trials. China Food and Drug 
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cytotoxic T-lymphocyte-mediated antitumor immunity in poorly immunogenic murine 
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17. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like 
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18. Zhang X, Shen L, Li J, Li Y, Li J, Jin M. A phase II trial of paclitaxel and cisplatin in 
patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol. 
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19. Chaofeng Tang, Yueqin Ma, et al Observation on the treatment of 102 patients with 
advanced esophageal cancer with paclitaxel combined with cisplatin. Medi Innov China. 
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20. Liu Y, Ren Z, Yuan L, Xu S, Yao Z, Qiao L, et al. Paclitaxel plus cisplatin vs. 5-
fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell 
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Biologics. May 2007.  
22. European Medicines Agency Guideline on the Evaluation of Anticancer Medicinal 
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24. Temel J S, Greer J A, Muzikansky A, et al. Early palliative care for patients with 
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both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised 
trial. Lancet Oncology. 2012;13(5):528. 
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immunotherapy agents. Ann Oncol 2010;21(10):1944. 
27. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads 
to clinical activity in patients with metastatic triple-negative breast cancer [abstract]. San 
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31. Vickery CW, Blazeby JM, Conroy T, Arraras J, Sezer O, Koller M, et al. Development of 
an EORTC disease-specific quality of life module for use in patients with gastric cancer. 
Eur J Cancer. 2001;37(8):966-71. 
32. Horn L, Spigel DR, Gettinger SN, Antonia SJ, Gordon MS, Herbst RS, et al. Clinical 
activity, safety and predictive biomarkers of the engineered antibody MPDL3280A (anti-
PDL1) in non-small cell lung cancer (NSCLC): Update from a phase Ia study. J Clin 
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33. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
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34. Fitzsimmons D, Johnson CD, George S, et al. Development of a disease specific quality 
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Quality of Life. Eur J Cancer, 1999;35(6):939. 
35. Blazeby JM Gettinger SN, Kowanetz M, Soria JC, et al. Molecular correlates of PD-L1 
status and predictive biomarkers in patients with non-small cell lung cancer (NSCLC) 
treated with the anti-PDL1 antibody MPDL3280A [abstract]. International Association 
for the Study of Lung Cancer 15th World Conference 2013:MO19.09. 
36. Conroy T, Hammerlid E, et al. Clinical and psychometric validation of an EORTC 
questionnaire module, the EORTC QLQ-OES18, to assess quality of life in patients with 
oesophageal cancer. Eur J Cancer. 2004, 40(15):2260. 
37. Di G A, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4 antibodies 
across clinical indications. Semin Oncol. 2010, 37(5):499-507. 
38. Adverse reactions of ototoxicity to platinol (generic name: cisplatin). 
http://www.drugs.com/pro/platinol.html. Accessed on 28 October 2017. 
39. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et 
al. Second symposium on the definition and management of anaphylaxis: summary 
report—Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
40. International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use. ICH Harmonized. Integrated Addendum to ICH E6(R2): Guideline for 
Good Clinical Practice E6(R2). 09 November2016. 
41. Chen L, Li F. Chromosome aberrations in esophageal cancer and progress in research 
methods. World Chinese J Digestol. 2006;14(19):1895-9. 
42. Xiaoxia H, Ji WM, Shibo L,Weihong X, Xianfu W Yuanyuan L, Ji-Yun L Amplification 
and overexpression of CTTN and CCND1 at chromosome 11q13 in esophagus squamous 
cell carcinoma (ESCC) of North Eastern Chinese Population. Int J Med Sci. 
2016;13(11):868-74. 
43. Pablo Ramos-García, Isabel Ruiz-Ávila, José Antonio Gil-Montoya, Ángela Ayén, Lucía 
González-Ruiz, Francisco José Navarro-Triviño, Miguel Ángel González-Moles. 
Relevance of chromosomal band 11q13 in oral carcinogenesis: An update of current 
knowledge. Oral Oncol. 2017;72:7-16. 
44. Hao JJ, Shi ZZ, Zhao ZX, et al. Characterization of genetic rearrangements in esophageal 
squamous carcinoma cell lines by a combination of M-FISH and array-CGH: Further 
confirmation of some split genomic regions in primary tumors. BMC Cancer. 
2012;12:367. 
45. Mosteller RD, et al. N Engl J Med. 1987 Oct 22;317(17):1098 
 

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Appendix 1 Schedule of Assessments 
Study Assessment 
Screening 
perioda 
All treatment cycles 
 
 
End of 
treatmentc 
Survival 
follow-upd 
Induction period 
Maintenance period 
Unscheduled 
visitb 
Study Day 
(window) 
-28 to 
-1 
-7 to 
-1 
C1D1
C2D1
(3)
C3-
C6D1
(3) 
C7D1
(3)
From C8D1 to last does of 
study drug (3) 
NA 
 
 
Informed consent signed 
xe 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
Medical history at baseline 
x 
 
 
 
 
 
 
 
 
 
Patient-reported outcomef 
 
 
X 
x 
x 
x 
x 
 
 
 
Vital signsg 
 
x 
X 
x 
x 
x 
x 
x 
X 
 
Body weight 
 
x 
 
x 
x 
 
 
 
X 
 
ECOG performance status 
 
x 
X 
x 
x 
x 
x 
x 
X 
 
Body height 
 
x 
 
 
 
 
 
 
 
 
ECGh1 
x 
 
 
 
x 
x 
x 
 
X 
 
Echocardiographyh2 
x 
 
 
 
x 
 
x 
 
 
 
Complete physical examinationi 
x 
 
 
 
 
 
 
 
 
 
Brief physical examinationj 
 
 
x 
x 
x 
x 
x 
 
x 
 
Hematologyk 
 
x 
 
x 
x 
x 
x 
 
x 
 
Blood biochemistryl 
 
x 
 
x 
x 
x 
x 
 
x 
 
Pregnancy testm 
 
x 
 
 
 
 
 
 
x 
 
Coagulation examination (INR, 
prothrombin time, activated partial 
thromboplastin time)n 
 
x 
 
 
x 
x 
 
 
x 
 

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Study Assessment 
Screening 
perioda 
All treatment cycles 
 
 
End of 
treatmentc 
Survival 
follow-upd 
Induction period 
Maintenance period 
Unscheduled 
visitb 
Study Day 
(window) 
-28 to 
-1 
-7 to 
-1 
C1D1
C2D1
(3)
C3-
C6D1
(3) 
C7D1
(3)
From C8D1 to last does of 
study drug (3) 
NA 
 
 
Thyroid function test (TSH, free T3, 
and free T4)n 
x 
 
 
 
x 
x 
 
 
x 
 
Urinalysiso 
 
x 
 
x 
x 
x 
x 
 
x 
 
HIV, HBV, and HCV serologyp 
x 
 
 
 
 
 
 
 
 
 
Administration of the investigational 
drug 
 
 
x 
x 
x 
x 
x 
 
 
 
Tumor response assessments 
xq 
 
 
 
xr 
xr 
 
 
xr 
 
Serum samples for ADA/trough 
concentrations 
 
 
x 
 
x 
x 
 
 
x 
 
Blood samples for biomarkerst 
 
 
x 
 
x 
x 
 
 
 
 
Concomitant medicationsu 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse eventsv 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA = anti-drug antibody; AE = adverse events; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
C1D1 = Cycle 1 Day 1; CNS = central nervous system; CT = computerized tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case 
report form; HBV = hepatitis B virus; HbsAG = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; INR = international normalized ratio; LDH = 
lactate dehydrogenase; MRI = magnetic resonance imaging; NA = not applicable; PD = progression of disease; PRO = patient-reported outcome; SAE = serious adverse event; TSH = thyroid 
stimulating hormone; T3 = total triiodothyronine. 
Note: Unless otherwise specified, all the scheduled visits must be completed within 28 days. During treatment, all the assessments must be conducted prior to administration of the 
investigational drug, unless otherwise specified.  
A Results from the tests or examinations conducted prior to obtaining signed informed consent and within 28 days before Cycle 1 Day 1 may be used; such tests or examination need not be 
repeated.  
B 
Visits not specified in the trial protocol. They should be conducted when clinically indicated. 
C 
Patients completing the treatment period should return to the research site and complete the end-of-treatment visit within 30 days after the last dose of study drug. The patients permanently 
terminating the study drug should return to the research site and complete the end-of-treatment visit within 30 days after the last dose of study drug. A visit in which the tumor evaluation 

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shows progression of disease may be considered as the end-of-treatment visit. If the study drug is terminated due to a delay of study drug administration and a subsequent decision is made 
that study drug cannot be resumed and the interval from the last dose of study drug infusion to the decision for termination of study drug treatment may be close or more than 30 days, the 
investigator should complete the end-of-treatment visit as far as possible after the patient confirms the termination of the investigational therapy. 
D After end of study drug dosing (using the date of the last dose as starting point), follow-up information will be collected once per month (±7 days) via telephone and/or clinic visit, until 
death, lost to follow-up, or termination of the study by the Sponsor. 
E 
All signatures on the informed consent must be obtained prior to the conduct of any study-specific procedures. 
F 
The patient should complete the EORTC QLQ C30 and QLQ-OES18 questionnaires prior to receiving any information for tumor status, any non-PRO assessment, and administration of the 
investigational therapy. 
G Including patients’ respiratory rate, pulse rate, systolic blood pressure, and diastolic blood pressure, as well as body temperature. Baseline abnormalities are recorded in eCRF for General 
History and Baseline Diseases. In subsequent visits, any new or aggravated, clinically significant abnormality should be recorded in the Adverse Events page in the eCRF. 
H1 A 12-lead ECG is conducted at screening and once every 2 cycles after C1D1 and at the end of treatment visit. During the study, the same instrument should be used as far as possible for 
ECG. The position of leads should be consistent as far as possible. ECG must be conducted after the patient rests in the supine position for at least 10 minutes.  
H2 Echocardiography is conducted at screening and once every 4 cycles after C1D1 to examine left ventricular ejection fraction. 
I 
Including assessments of the head, eyes, ear, nose, and throat, as well as of cardiovascular, skin, musculoskeletal, respiratory, gastrointestinal, urogenital, and nervous systems. Baseline 
abnormalities are recorded in the eCRF pages titled General History and Baseline Diseases. In subsequent visits, any new or aggravated, clinically significant abnormality should be 
recorded in the CRF page titled Adverse Events. 
J 
Some examinations are conducted based on the symptoms, as indicated clinically at specified timepoints or as indicated clinically. Any new or aggravated, clinically significant abnormality 
should be recorded in the eCRF titled Adverse Events. 
K Hematology tests involve complete blood counts that include white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count, and white blood cell differential counts 
(neutrophils, eosinophils, basophils, monocytes, and lymphocytes). Results for whole blood count must be available before start of infusion (after C1, samples must have been obtained 
within 3 days prior to the infusion). 
L 
Blood biochemistry (serum or plasma), including glucose, BUN or urea, creatinine, sodium, potassium, magnesium, chloride, calcium, phosphorus, total bilirubin, direct bilirubin, ALT, 
AST, alkaline phosphatase, LDH, total protein and albumin, serum creatine kinase, and serum creatine kinase isoenzymes. Results for blood biochemistry must be available before start of 
infusion (after C1, samples must have been obtained within 3 days prior to the infusion). 
M At screening, all women of childbearing potential, including those who have undergone a bilateral tubal ligation, must receive a serum pregnancy test and subsequent test per patients’ 
condition. 
N The results for coagulation test (INR, PT, and aPTT) and thyroid function test (TSH, free T3, and free T4) are collected at screening, and once per 2 cycles after C1D1 (after C1, the samples 
must be obtained within 3 days prior to infusion), and at the end-of-treatment visit. 
O Urinalysis includes urine pH, specific gravity, glucose, protein, ketone bodies, occult blood, red blood cells, and white blood cells (after C1, samples must be obtained within 3 days prior to 
infusion). 
P 
Prior to enrollment into the study, all the patients must undergo testing for HBV serology and HCV and HIV tests. HBV serology includes HbsAg, anti-HbsAg antibody, and hepatitis B 
core antibody [anti-HBc]. Patients who are HCV seropositive and/or HIV seropositive are not eligible for this study. In patients who are HbsAg positive or have a prior history of hepatitis B 
infection, then an HBV DNA test should be conducted prior to randomization. 
Q At screening, a contrast-enhanced CT or MRI scans of the neck, chest, abdomen, and pelvic cavity must be performed (a plain scan may be adopted if the patients are allergic to the contrast 
medium). At screening, enhanced CT or MRI scan of the head must be conducted to evaluate CNS metastasis in all patients. If CT scan results are unclear, then brain MRI scan must be 
conducted to confirm or rule out CNS metastasis. 
R 
Whether treatment delay occurs or not, tumor assessment evaluation is conducted once every 6 weeks (±7 days, approximately once per 2 cycles) in the first 12 months after Cycle 1 Day 1, 
and thereafter once every 9 weeks (±7 days) until progression of disease, loss of clinical benefit, withdrawal of the consent to remain on study, loss to follow-up, death, termination of the 

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study by the Sponsor, or start of a new antitumor therapy, whichever occurs first. If progression of disease is suspected, then CT scan may be repeated at any time; if a patient withdraws 
from the investigational therapy for any reason, an imaging examination must be conducted as soon as possible. If the previous tumor evaluation is within 28 days of the date of withdrawal 
from the study, then it would not need to be repeated.  The same imaging modality (CT or MRI), including scanning layer thickness and contrast medium, should be used consistently during 
the study. 
s 
For the detailed plan, see 0. 
t 
For the detailed plan, see 0. 
u 
Including all drugs/concomitant therapies used in patients from 28 days prior to administration of the investigational drug to the end-of-treatment visit. After the end-of-treatment visit, 
concomitant medication/concomitant therapies for treatment of AEs/SAEs should also be collected. 
v 
All serious adverse events that occur After obtaining the signed informed consent but prior to the first dose of study drug, should be captured on the CRF. All adverse events occurring after 
the first dose of study drug through 60 days after the last dose of study drug or start of a new antitumor therapy (whichever occurs first), should be captured on the CRF. After this period, 
the Sponsor should be notified of any serious adverse event considered to be related to the study drug by the investigator (see Section 0). The investigator should follow up on all the adverse 
events, until the adverse event has resolved to baseline, becomes stable per the investigator, patient is lost to follow-up, or patient’s withdraw informed consent form (whichever occurs 
first). Every effort should be made to follow up on all the serious adverse events that are considered to be related to the study drug or study-related procedures until the final outcome can be 
reported. 
 

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Appendix 2 Schedule of Biomarkers and Anti-drug Antibody Sampling 
Visit 
Timepoint 
Sample type 
Volume of whole 
blood collected 
Screening period 
(Days -28 to -1) 
NA 
Tumor tissue specimens (if 
possible, paraffin block or 8 
FFPE sections are 
preferable) 
Fresh or archived tissues 
may be acceptable 
NA 
Day 1 of every 2 
cycles from Cycle 1 
in the 1st year 
Prior to administration 
(administration date of 
the investigational drug)
Toripalimab ADA/trough 
concentration 
3 mL 
Prior to administration 
(administration date of 
the investigational drug)
Biomarkers 
10 mL 
Day 1 of every 6 
cycles after the 1st 
year 
Prior to administration 
(administration date of 
the investigational drug)
Toripalimab ADA/trough 
concentration 
3 mL 
Prior to administration 
(administration date of 
the investigational drug)
Biomarkers 
10 mL 
Fresh biopsy (during 
treatment or at 
progression, 
including follow-up 
period) 
NA 
Tumor tissue specimen 
NA 
First progression of 
disease 
NA 
Biomarkers 
10 ml 
End of treatment 
NA 
Toripalimab ADA/trough 
concentration 
3 ml 
ADA = anti-drug antibody; FFPE = formalin-fixated paraffin embedded; NA = not applicable. 
 
 

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Appendix 3 Esophageal Cancer Staging of the American Joint Committee on Cancer, v8 
(2017) 
Cancer staging categories for Squamous Cell cancer of the Esophagus and 
Esophagogastric junction 
T category  
 
Tx - The primary tumor cannot be determined 
 
T0 - No evidence for primary tumor 
 
Tis – High-grade dysplasia, defined as malignant cells confined by the basement 
membrane 
 
T1 - Tumor invades the lamina propria, muscularis mucosae or submucosa 
 
T1a - Tumor invades the lamina propria or muscularis mucosa 
 
T1b - Tumor invades the submucosa 
 
T2 - Tumor invades the esophageal muscularis propria 
 
T3 - Tumor invades the adventitia  
 
T4 - Tumor invades adjacent structures 
 
T4a - Tumor invades the pleura, peritoneum, pericardium, or diaphragm 
 
T4b - Tumor invades other adjacent structures, e.g., aorta, trachea, or vertebral 
body 
N – Category  
 
Nx - Regional lymph node metastasis cannot be assessed 
 
N0 – No regional lymph node metastases 
 
N1 - Metastasis to 1 to 2 regional lymph nodes 
 
N2 - Metastasis to 3 to 6 regional lymph nodes 
 
N3 - Metastasis to ≥7 regional lymph nodes 
M Category  

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 
M0 - No distant metastasis 
 
M1 - Distant metastasis 
Squamous cell carcinoma G category 
 
Gx - Differentiation cannot be assessed 
 
G1 – Well-differentiated 
 
G2 - Moderately differentiated.  
 
G3 - Poorly differentiated.  
AJCC v8, Staging of Squamous Cell Cancer.Esophageal Cancer  

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Appendix 4 Response Evaluation Criteria in Solid Tumors (RECIST) 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
Please refer to: http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf. 
 
 

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Appendix 5 Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) 
 
Objective 
AIM: RECIST 1.1 has its shortcomings for targeted immunotherapy in oncology. Using 
RECIST 1.1 in immunotherapy trials would lead to declaration of progressive disease (PD) 
too early, when the treatment effect is not yet fully evident. RECIST also neglects the 
importance of the ‘flare effect’ -pseudo-progression effect within the so-called flare time 
window. 
Immune related Response Criteria (irRC) based on WHO criteria were published with an aim 
to provide better assessment of the effect of immunotherapeutic agents. With this poster we 
introduce irRECIST based on RECIST 1.1, irRC and Nishino et al., 2013 findings. Our aim is 
to define criteria that better capture antitumor activity and reduce irRC criteria ambiguity. 
Consistent implementation of irRECIST by both investigators and blinded independent 
readers will help reduce site: central discordance. 
METHODS: The adaptations from irRC and WHO criteria, as applicable in immunotherapy 
clinical studies, are documented in the “irRECIST Modifications and Clarifications” column 
in a comparative table format within our Blinded Independent Central Review (BICR) 
Charter.  
The modifications we introduce represent adaptations of published criteria based on 
radiology practice and clinical trial experience, and they provide more objective and 
reproducible response assessments for investigators and for the central independent image 
review.  
RESULTS: irRECIST criteria are based on irRC criteria adapted for unidimensional 
measurements, as outlined in Nishino et al., 2013. To further align the criteria with RECIST 
1.1 we outline the approach for the assessment of baseline selected non-target lesions and 
new non-measurable lesions, and discuss the impact of those lesions on the overall tumor 
response assessment.  
Guidelines for the evaluation of patients with non-target disease only and patients in adjuvant 
setting is provided. 
 

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CONCLUSIONS: irRECIST criteria as outlined here introduce the needed clarifications and 
adjustments to irRC criteria and Nishino et al., 2013 publication to allow for treatment 

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evaluations that better meet both investigators’ and patients’ needs and with that better reflect 
sponsors’ demands for more reliable and reproducible study data in targeted immunotherapy 
in oncology studies. The main adaptation of the existing immune-response criteira lies in the 
assessment of all detected lesions. Unequivocal and substantial increase of non-target and 
new non-measurable lesions prevents irCR and may also lead to irPD. Reduction of the tumor 
burden in patients in an adjuvant setting may lead to irPR and such patients may therefore be 
enrolled in studies with response endpoints. Clinical relevance of these adaptations needs to 
be confirmed. 
SUMMARY AND ADDITIONAL GUIDANCES 
1. TMTB: Baseline-selected target lesions and new measurable lesions should NOT be 
assessed separately. Measurements of those lesions should be combined into the Total 
Measured Tumor Burden (TMTB), and one combined assessment provided. 
2. New Measurable Lesions: According to irRC a measurable new lesion has to be at least 5 
mm x 5 mm to be selected as an index lesion. For bidimensional measurements this 
threshold was acceptable. In irRECIST, criteria for unidimensional lesion measurement 
apply to both target and new measurable lesions: a minimum 10 mm in the longest diameter 
for non-nodal lesions, and a minimum 15 mm in short axis for lymph nodes. Smaller 
lesions contribute to the non-target or new non- measurable tumor burden, but do not get 
measured. 
3. irPR if no Target Lesions: If new measurable lesions appear in patients with no target 
lesions at baseline, irPD will be assessed. That irPD timepoint will be considered a new 
baseline, and all subsequent timepoints will be compared to it for response assessment. 
irPR is possible if the TMTB of new measurable lesions decreases by ≥ 30% compared to 
the first irPD documentation. 
4. irPR in Adjuvant Studies: irRECIST can be used in the adjuvant setting, in patients with no 
visible disease on CT/MRI scans. The appearance of new measurable lesion(s) 
automatically leads to an increase in TMTB by 100% and leads to irPD. These patients can 
achieve a response if the TMTB decreases at follow-up, as a sign of delayed response. 
Considering 3 and 4, sponsors may consider enrolling patients with no measurable disease 
and/or patients with no visible disease at all in studies with response related endpoints. 
5. Non-Target Lesions: In alignment with RECIST 1.1, baseline selected non-target lesions 
can never convert to measurable lesions, not even if they increase in size at subsequent 
timepoints and become measurable. Only true new lesions can be measured and contribute 
to the TMTB. 

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6. Example: A patient has multiple lung metastases, all smaller than 10 mm and selected as 
non-target lesions at baseline. If, at a subsequent timepoint some of these non-target lesions 
increase and become > 10 mm, and one new lesion >10 mm appears, only the new 
measurable lesion will contribute to the TMTB, and not the baseline selected non-target 
lesion that increased in size. Otherwise, such an increase would make persisting non-target 
lesions switch into the new measurable lesion category which would be inaccurate, as the 
lesion existed at baseline. 
7. irPD Based on Non-Target Lesions: Unlike irRC that neglect non-target lesions for the 
assessment of irPD, in irRECIST a substantial and unequivocal increase of non-target 
lesions is indicative of progression. 
8. irPD Based on New Non-Measurable Lesions: According to irRC, a patient with multiple 
new lesions of 9 mm would be considered non-PD, whereas a patient with just one new 
lesion of 10 mm may be assessed as irPD if the TMTB of such a patient increases ≥ 20% 
compared to nadir. According to irRECIST, the reviewer may assign irPD for the patient 
with multiple new lesions of 9 mm if they are considered to be a sign of unequivocal, 
massive worsening (see 2.3) 
9. irPD Confirmation: Progression confirmation no less than 4 weeks after the initial irPD 
assessment is recommended especially in case of marginal disease growth and if the first 
irPD assessment is within the compound-specific tumor flare window. 
 
REFERENCES 
1. JD Wolchok, A Hoos, O Bohnsack, et.al., Guidelines for the Evaluation of Immune Therapy 
Activity in Solid Tumors: Immune-Related Response Criteria, Clin Cancer Res 2009;15(23) 
December 1, 2009 
2. Nishino M et al. Developing a common language for tumor response to immunotherapy: 
immune-related response criteria using unidimensional measurements. Clin Cancer 
Res. 2013 Jul 15;19(14):3936-43 
3. Therasse P, Arbuck SG, et al.: New Guidelines to Evaluate the Response to Treatment in 
Solid Tumors. Journal of the National Cancer Institute 2000 92(3):205-216] 
4. Eisenhauer EA, Therasse P, Bogaerts J, et al.: New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). In: Eur. J. Cancer. 45, Nr. 2, Januar 2009, 
S. 228–47. 
5. Therasse P, Eisenhauer EA, Verweij J: RECIST revisited: a review of validation studies on 
tumour assessment. In: Eur. J. Cancer. 42, Nr. 8, Mai 2006, S. 1031–9. 

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6. WHO handbook for reporting results of cancer treatment. Geneva (Switzerland): World 
Health Organization Offset Publication No. 48; 1979. 
[Source: https://www.parexel.com/application/files_previous/7914/2186/7838/irrecist-path-
PDF.pdf] 
 
 

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Appendix 6 Recommendations for Treatment of Hypothyroidism 
Levothyroxine sodium (common brandname: Euthyrox) is recommended for patients who 
develop drug-related hypothyroidism. 
The dose of levothyroxine sodium recommended in this appendix is a general 
recommendation; a patient’s daily dose should be determined from the results of laboratory 
tests and clinical examinations. As total thyroxine and thyroxine free levels in many patients 
would be increased, the baseline concentration of serum thyroid stimulating hormone (TSH) 
is a reliable basis to determine a therapeutic method. Generally, thyroid hormone replacement 
therapy should be started at a low dose and increased gradually in dose every 2 to 4 weeks 
until the replacement dose is sufficient. Generally speaking, patients with hypothyroidism 
requires a lifelong oral administration of the drug. 
Special attention should be exercised in the initiation phase of thyroid hormone replacement 
therapy in elderly patients or patients with coronary heart disease or chronic hypothyroidism. 
A low initial dose (such as 12.5 μg/d) should be selected, and the oral dose should be 
increased slowly (such as increase of 12.5 μg/d every 2 weeks). 
If the maintenance dose is lower than the optimal dose, then hypothyroidism cannot be 
corrected completely based on TSH level. 
Clinical experience has demonstrated that a low dose of levothyroxine is effective for patients 
with a low body weight or patients with macronodular goiter. 
Levothyroxine sodium should be taken under a fasted state (e.g., half an hour prior to 
breakfast) as a single daily dose with an adequate amount of liquid (such as half glass of 
water). 
List of Recommended Doses 
 
Dose 
50 μg tablets
100 μg tablets
Administration 
frequency 
Initial dose 
(After the initial dose, 
increase the dose by 25-50 μg 
per day, every 2-4 weeks, 
until the maintenance dose is 
reached) 
25～50 μg 
½~1 tablet 
¼~½ tablet 
QD 
Maintenance dose 
100～200 μg 
2~4 tablets 
1~2 tablets 
QD 
 

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Confirm the cause of secondary hypothyroidism prior to initiation of treatment. 
Glucocorticoids should be administered as necessary. Once the levothyroxine maintenance 
dose is determined, adjust the thyroid hormone replacement dose based on the patient’s 
clinical responses and laboratory test results or if the patient is switched to another thyroid 
hormone replacement drug. 
For details, please refer to the package insert of the respective thyroid hormone replacement 
product. 
 
 

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Appendix 7 EORTC QLQ-C30 Questionnaire 
EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health. Please answer all of the 
questions yourself by circling the number that best applies to you. There are no "right" or 
"wrong" answers. The information that you provide will remain strictly confidential. 
Please fill in your initials: 
 
 
Your birthdate (Day, Month, Year): 
 
 
Today’s date (Day, Month, Year): 
 
 
 
 
Not at 
all 
A 
little
Quite 
big 
Very 
big 
1. Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside of the 
house? 
1 
2 
3 
4 
4. 
Do you have to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing yourself or 
using the toilet? 
1 
2 
3 
4 
During the past week: 
Not at 
all 
A 
little
Quite 
big 
Very 
big 
6. 
Were you limited in doing either your work or other daily 
activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other leisure 
time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
table continues on next page… 
 

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Appendix 7 - EORTC QLQ-C30 Questionnaire (continued) 
English 
During the past week: 
Not at 
all 
A 
little
Quite 
big 
Very 
big 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things like reading 
a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment interfered 
with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment interfered 
with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment caused you 
financial difficulties? 
1 
2 
3 
4 
 
For the following questions, please circle the number between 1 and 7 that best applies to 
you 
29. How would you rate your overall health condition in the past week? 
1 
2 
3 
4 
5 
6 
7 
Very poor 
 
 
 
 
 
Excellent 
30. How would you rate your overall quality of life in the past week? 
1 
2 
3 
4 
5 
6 
7 
Very poor 
 
 
 
 
 
Excellent 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. All Rights Reserved. Version 3.0 
 
 

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Appendix 8 EORTC QLQ-OES18 Questionnaire 
EORTC Quality of Life Questionnaire, QLQ-OES18  
Patients sometimes report that they have the following symptoms or problems. Please 
indicate the extent to which you have experienced these symptoms or problems during the 
past week. Please answer by circling the number that best applies to you.  
In the past 1 week: 
Not at 
all 
Some
what 
Quite
Very 
31. Could you eat solid food? 
1 
2 
3 
4 
32. Could you eat liquid or semiliquid food? 
1 
2 
3 
4 
33. Could you drink liquids? 
1 
2 
3 
4 
34. Have you had trouble with swallowing your saliva? 
1 
2 
3 
4 
35. Have you choked when swallowing? 
1 
2 
3 
4 
36. Have you had trouble enjoying your meals? 
1 
2 
3 
4 
37. Have you felt full up too quickly? 
1 
2 
3 
4 
38. Have you had trouble with eating? 
1 
2 
3 
4 
39. Have you had trouble with eating in front of other 
people? 
1 
2 
3 
4 
40. Have you had a dry mouth? 
1 
2 
3 
4 
41. Did food and drink taste different from usual? 
1 
2 
3 
4 
42. Have you had trouble with coughing? 
1 
2 
3 
4 
43. Have you had trouble with talking? 
1 
2 
3 
4 
44. Have you had acid indigestion or heartburn? 
1 
2 
3 
4 
45. Have you had trouble with acid or bile coming into your 
mouth? 
1 
2 
3 
4 
46. Have you had pain when you eat? 
1 
2 
3 
4 
47. Have you had pain in your chest? 
1 
2 
3 
4 
48. Have you had pain in your stomach? 
1 
2 
3 
4 
 
© QLQ-OES18 Copyright 1999 EORTC Quality of life Group. All rights reserved. 
 
 

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Appendix 9 Eastern Cooperative Oncology Group Performance Status 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, 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 more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. 
 
 

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Appendix 10 Management of Allergic Reactions 
Required Equipment 
• 
Tourniquet 
• 
Oxygen 
 
Epinephrine for subcutaneous injection, intravenous injection, and/or tracheal 
administration according to the standard practices for treatment 
• 
Antihistamine agents 
• 
Corticosteroids 
• 
Solution for intravenous infusion, infusion tube, catheter, and adhesive tape 
Procedures 
In cases of suspected allergic reactions occurred during infusion of the investigational drug, 
the following procedures should be implemented: 
 
Discontinue the study drug infusion 
 
Use a tourniquet at the proximal end of the injection site to delay systemic absorption of 
the study drug; do not occlude arterial blood stream of affected limbs 
 
Maintain airway patency 
 
Administer antihistamine, epinephrine, or other drugs, as directed by the doctor on duty 
 
Maintain patient under continued observation and record observations  
 
 

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Appendix 11 Listing of Autoimmune or Immunodeficiency Disorders to be Considered 
During Screening 
Carefully inquire regarding the patient’s history of acquired or congenital immunodeficiency 
or autoimmune disease. Patients with a history of immunodeficiency or autoimmune disease, 
as listed in the table below, are ineligible for enrollment into the study. The possible 
exception to this exclusion criteria is patients with a history of atopic disease or childhood 
arthritis, in which the clinical likelihood of exacerbation of autoimmune disease is low. The 
patients with a history of autoimmune-related hypothyroidism who are receiving a stable dose 
of thyroid hormone can be enrolled in the study. In addition, transient autoimmune 
manifestations of acute infectious diseases that are relieved during treatment for infectious 
pathogens (for example, acute Lyme arthritis) are not excluded. For any uncertainty regarding 
the autoimmune disease exclusion criteria, please contact the medical monitor. 
Autoimmune Disease and Immunodeficiency 
Acute disseminated 
encephalomyelitis 
Acquired epidermolysis bullosa 
Ord’s thyroiditis 
Addison disease 
Gestational pemphigoid 
Pemphigus 
Ankylosing spondylitis 
Giant cell arteritis 
Pernicious anemia 
Antiphospholipid antibody 
syndrome 
Goodpasture syndrome 
Polyarteritis nodosum 
Aplastic anemia 
Graves’ disease 
Arthritis 
Autoimmune hemolytic 
anemia 
Guillain-Barre syndrome 
Polyglandular autoimmune 
syndrome 
Hepatitis autoimmune 
Hashimoto disease 
Primary biliary cirrhosis 
Autoimmune 
hypoparathyroidism 
IgA nephropathy 
Psoriasis 
Autoimmune hypophysitis 
Inflammatory bowel disease 
Reiter’s syndrome 
Autoimmune myocarditis 
Cystitis interstitial 
Rheumatoid arthritis 
Autoimmune oophoritis 
Kawasaki disease 
Sarcoidosis 
Autoimmune orchitis 
Lambert-Eaton myasthenic 
syndrome 
Dermatosclerosis 
Autoimmune 
thrombocytopenic purpura 
Lupus erythematosus 
Sjögren syndrome 
Behcet’s disease 
Lyme disease - chronic 
Stiff-Person syndrome 
Bullous pemphigoid 
Meniere syndrome 
Aorto-arteritis 
Chronic fatigue syndrome 
Mooren’s ulcer 
Ulcerative colitis 
Chronic inflammatory 
demyelinating 
polyneuropathy 
Circumscribed scleroderma 
Vitiligo 
 
Sclerosis multiple 
Vogt-Kovanagi-Harada disease 
Chung-Strauss syndrome 
Myasthenia gravis 
Wegener granulomatosis 
Crohn disease 
Neuromyotonia 
 

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Dermatomyositis 
Oculo-cerebello-myoclonic 
syndrome 
 
Type 1 diabetes 
Neuritis optic 
 
Familial dysautonomia