Clinical trial NCT03777657
Conditions: Gastric, or Gastroesophageal Junction Adenocarcinoma
Sponsor: BeiGene
Start date: 2018-12-13; Completion date: 2024-08-27
Enrollment: 997 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was designed to compare the efficacy and safety of tislelizumab plus chemotherapy versus placebo plus chemotherapy as the first treatment (first-line) for adults diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Detailed description:

Arms: arm 1: Participants received 200 mg of tislelizumab intravenously with investigator's choice of chemotherapy once every 3 weeks for up to six treatment cycles. Chemotherapy consisted of 1000 mg/m² capecitabine twice daily on Days 1-14 and 130 mg/m² oxaliplatin on Day 1, or 800 mg/m² 5-fluorouracil (5-FU) on Days 1-5 and 80 mg/m² cisplatin on Day 1 of each 21-day cycle. Thereafter, participants continued treatment with 200 mg tislelizumab, with optional maintenance capecitabine (only permitted for participants who initially received capecitabine and oxaliplatin) once every 3 weeks until disease progression or unacceptable toxicity. arm 2: Participants received placebo intravenously with investigator's choice of chemotherapy once every 3 weeks for up to six treatment cycles. Chemotherapy consisted of 1000 mg/m² capecitabine twice daily on Days 1-14 and 130 mg/m² oxaliplatin on Day 1, or 800 mg/m² 5-FU on Days 1-5 and 80 mg/m² cisplatin on Day 1 of each 21-day cycle. Thereafter, participants continued treatment with placebo with optional maintenance capecitabine (only permitted for participants who initially received capecitabine and oxaliplatin) once every 3 weeks until disease progression or unacceptable toxicity.
Interventions: intervention 1: Tislelizumab intervention 2: Placebo intervention 3: Cisplatin intervention 4: Oxaliplatin intervention 5: Capecitabine intervention 6: 5-Fluorouracil
Intervention descriptions: intervention 1: 200 mg intravenously (IV) on Day 1 of each 21-day cycle intervention 2: Placebo to match tislelizumab IV on Day 1 of each 21-day cycle intervention 3: 80 mg/m² IV on Day 1 of each 21-day cycle intervention 4: 130 mg/m² IV on Day 1 of each 21-day cycle intervention 5: 1000 mg/m² orally twice daily (BD) Days 1 through 14 (14 days total) of each 21-day cycle intervention 6: 800 mg/m²/day IV using continuous infusion on Days 1 to 5 of each 21-day cycle

Protocol documents:
Prot_000.pdf: 
BGB-A317-305 
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Protocol Amendment 3.0 
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CONFIDENTIAL 
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CLINICAL STUDY PROTOCOL 
Protocol Title: 
Protocol Identifier: 
Phase: 
Investigational 
Medicinal Product(s): 
Indication: 
EudraCT Number: 
Sponsor: 
Sponsor Medical 
Monitor: 
Original Date: 
Amendment 1.0: 
Amendment 2.0: 
Amendment 3.0: 
TITLE PAGE 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Clinical Study Comparing the Efficacy and Safety of 
Tislelizumab (BGB-A317) plus Platinum and Fluoropyrimidine 
Versus Placebo plus Platinum and Fluoropyrimidine as First-Line 
Treatment in Patients with Locally Advanced Unresectable or 
Metastatic Gastric or Gastroesophageal Junction 
Adenocarcinoma BGB-A317-305 
3 
Tislelizumab (BGB-A317) 
Advanced Gastric or Gastroesophageal Junction Adenocarcinoma 
2018-000312-24   
 BeiGene, Ltd.  
c/o BeiGene USA, Inc. 
1840 Gateway Drive, 3rd Floor 
San Mateo, California 94404, USA 
12 February 2018 
20 August 2018 
03 April 2020 
17 April 2023 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd. 
and its affiliates. This document is for use by individuals and their designated representatives for 
their confidential review, consideration, and/or participation in investigational trial(s). This 
document may not be copied or distributed for review by any unauthorized individuals without 
the prior written authorization of BeiGene, Ltd. or one of its affiliates. Your acceptance of this 
document constitutes agreement that you will not disclose the information contained herein to 
others without the prior written authorization from BeiGene, Ltd. or one of its affiliates. 
NCT Number: 
        NCT03777657


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FINAL PROTOCOL APPROVAL SHEET  
 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Clinical Study 
Comparing the Efficacy and Safety of Tislelizumab (BGB-A317) plus Platinum and 
Fluoropyrimidine Versus Placebo plus Platinum and Fluoropyrimidine as First-Line Treatment in 
Patients with Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction 
Adenocarcinoma 
 
BeiGene, Ltd. Approval: 


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INVESTIGATOR SIGNATURE PAGE  
 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Clinical Study 
Comparing the Efficacy and Safety of Tislelizumab (BGB-A317) plus Platinum and 
Fluoropyrimidine Versus Placebo plus Platinum and Fluoropyrimidine as First-Line Treatment in 
Patients with Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction 
Adenocarcinoma 
 
Protocol Identifier: BGB-A317-305 
 
This protocol is a confidential communication of BeiGene, Ltd and its affiliates. I confirm that I 
have read this protocol, I understand it, and I will work according to this protocol and the terms 
of the clinical study agreement governing the study. I will also work consistently with the ethical 
principles that have their origin in the Declaration of Helsinki and that are consistent with good 
clinical practices and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd or one of its affiliates. 
 
Instructions for Investigator: Please SIGN and DATE this signature page prior to 
implementation of this sponsor-approved protocol. PRINT your name, title, and the name 
and address of the center in which the study will be conducted. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:  
 
_______________________________   Date:  _____________ 
Printed Name:  
 
 
 
 
_______________________________ 
Investigator Title:  
 
 
 
_______________________________ 
Name/Address of Center:  
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................11 
SYNOPSIS ....................................................................................................................................12 
LIST OF ABBREVIATIONS AND TERMS ................................................................................21 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Advanced and Metastatic Gastric Cancer ...................................................................24 
1.2. 
Immunotherapy of Gastric Cancer ..............................................................................24 
1.2.1. 
Pembrolizumab ...........................................................................................................25 
1.2.2. 
Nivolumab ..................................................................................................................27 
1.2.3. 
Avelumab ....................................................................................................................28 
1.2.4. 
Summary of Immuno-Oncology in Gastric Cancer ....................................................29 
1.3. 
Background Information on Tislelizumab ..................................................................31 
1.3.1. 
Pharmacology .............................................................................................................31 
1.3.2. 
Toxicology ..................................................................................................................31 
1.3.3. 
Clinical Pharmacology ................................................................................................32 
1.3.4. 
Prior Clinical Experience of Tislelizumab .................................................................32 
1.3.4.1. 
Pooled Safety Assessment of Monotherapy Studies ..................................................32 
1.3.4.2. 
Efficacy Assessment of Tislelizumab .........................................................................33 
1.3.4.3. 
Safety and Efficacy Assessment of Study BGB-A317-205 (Combination 
therapy) .......................................................................................................................34 
1.4. 
Study Rationales .........................................................................................................36 
1.4.1. 
Rationale for Tislelizumab in the Treatment of Gastric Cancer .................................36 
1.4.2. 
Rationale for Selection of Tislelizumab Dose ............................................................37 
1.4.3. 
Rationale for Selection of Chemotherapies ................................................................37 
1.5. 
Benefit-Risk Assessment ............................................................................................38 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................40 
2.1. 
Study Objectives .........................................................................................................40 
2.1.1. 
Primary Objective .......................................................................................................40 


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2.1.2. 
Secondary Objectives .................................................................................................40 
2.1.3. 
Exploratory Objectives ...............................................................................................40 
2.2. 
Study Endpoints ..........................................................................................................41 
2.2.1. 
Primary Endpoint ........................................................................................................41 
2.2.2. 
Secondary Endpoints ..................................................................................................41 
2.2.3. 
Exploratory Endpoints ................................................................................................41 
3. 
STUDY DESIGN .......................................................................................................43 
3.1. 
Summary of Study Design ..........................................................................................43 
3.2. 
Screening Period .........................................................................................................46 
3.3. 
Treatment Period ........................................................................................................46 
3.4. 
Safety Follow-up ........................................................................................................48 
3.5. 
Survival Follow-up .....................................................................................................49 
3.6. 
Patient, Treatment, Study, and Site Discontinuation ..................................................49 
3.6.1. 
Discontinuation from Study Treatment ......................................................................49 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........50 
3.6.3. 
Withdrawal of Consent ...............................................................................................50 
3.6.4. 
Lost to Follow-Up.......................................................................................................50 
3.6.5. 
End of Study ...............................................................................................................51 
4. 
STUDY POPULATION .............................................................................................53 
4.1. 
Inclusion Criteria ........................................................................................................53 
4.2. 
Exclusion Criteria .......................................................................................................54 
5. 
STUDY TREATMENT ..............................................................................................57 
5.1. 
Formulation, Packaging, and Handling ......................................................................57 
5.1.1. 
Tislelizumab and Placebo ...........................................................................................57 
5.1.1.1. 
Tislelizumab ...............................................................................................................57 
5.1.1.2. 
Placebo ........................................................................................................................57 
5.1.2. 
Chemotherapy .............................................................................................................57 
5.2. 
Dosage, Administration, and Compliance ..................................................................58 
5.2.1. 
Tislelizumab or Placebo .............................................................................................59 
5.2.2. 
Chemotherapy .............................................................................................................60 
5.2.3. 
Supportive Care ..........................................................................................................61 
5.3. 
Overdose or Incorrect Administration ........................................................................61 


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5.4. 
Investigational Medicinal Product Accountability .....................................................61 
5.5. 
Dose Modification ......................................................................................................61 
5.5.1. 
General Guidance Regarding Dose Modifications .....................................................62 
5.5.2. 
Dose Modification for Tislelizumab or Placebo .........................................................63 
5.5.3. 
Dose Modifications of Chemotherapy ........................................................................64 
5.5.4. 
Blinding ......................................................................................................................64 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................66 
6.1. 
Concomitant Therapy .................................................................................................66 
6.1.1. 
Permitted Concomitant Medications/Procedures .......................................................66 
6.1.2. 
Prohibited or Restricted Concomitant Medications ....................................................67 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................69 
7.1. 
Screening ....................................................................................................................69 
7.1.1. 
Demographic Data and Medical History ....................................................................69 
7.1.2. 
Females of Childbearing Potential and Contraception ...............................................70 
7.1.3. 
Informed Consent and Screening Log ........................................................................70 
7.1.4. 
Pulmonary Function Tests ..........................................................................................70 
7.2. 
Enrollment ..................................................................................................................70 
7.2.1. 
Confirmation of Eligibility .........................................................................................70 
7.2.2. 
Patient Numbering ......................................................................................................71 
7.2.3. 
Enrollment/Randomization .........................................................................................71 
7.3. 
Tislelizumab, Placebo and Chemotherapy Dispensing ..............................................71 
7.4. 
Safety Assessments .....................................................................................................71 
7.4.1. 
Vital Signs ..................................................................................................................71 
7.4.2. 
Physical Examinations ................................................................................................72 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status ........................................72 
7.4.4. 
Laboratory Safety Tests ..............................................................................................72 
7.4.4.1. 
Cardiac Enzyme Monitoring .......................................................................................72 
7.4.5. 
Electrocardiograms .....................................................................................................72 
7.4.6. 
Adverse Events ...........................................................................................................73 
7.4.7. 
Ophthalmologic Examination .....................................................................................73 
7.4.8. 
Hepatitis B and C Testing ...........................................................................................73 
7.5. 
Tumor and Response Evaluations ..............................................................................73 


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7.6. 
Pharmacokinetic and Antidrug Antibody Testing ......................................................75 
7.7. 
Biomarkers ..................................................................................................................75 
7.7.1. 
Tissue Biomarkers ......................................................................................................75 
7.7.2. 
Blood Biomarkers .......................................................................................................76 
7.8. 
Patient-reported Outcomes .........................................................................................76 
7.9. 
Visit Windows ............................................................................................................76 
7.10. 
Unscheduled Visits .....................................................................................................77 
8. 
SAFETY MONITORING AND REPORTING .........................................................78 
8.1. 
Risks Associated with Tislelizumab and Chemotherapy ............................................78 
8.1.1. 
Risks Associated With Tislelizumab ..........................................................................78 
8.1.2. 
Risks Associated with Platinum and Fluoropyrimidine .............................................78 
8.2. 
General Plan to Manage Safety Concerns ..................................................................78 
8.2.1. 
Eligibility Criteria .......................................................................................................78 
8.2.2. 
Safety Monitoring Plan ...............................................................................................78 
8.3. 
Adverse Events ...........................................................................................................79 
8.3.1. 
Definitions and Reporting ...........................................................................................79 
8.3.2. 
Assessment of Severity ...............................................................................................79 
8.3.3. 
Assessment of Causality .............................................................................................80 
8.3.4. 
Following Adverse Events ..........................................................................................81 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................81 
8.4. 
Definition of a Serious Adverse Event .......................................................................82 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................83 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................83 
8.6.1. 
Adverse Event Reporting Period ................................................................................83 
8.6.2. 
Reporting Serious Adverse Events .............................................................................84 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................84 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................84 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................85 
8.6.3. 
Eliciting Adverse Events ............................................................................................85 
8.6.4. 
Disease Progression ....................................................................................................85 
8.6.5. 
Deaths .........................................................................................................................85 
8.6.6. 
Pregnancies .................................................................................................................85 


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8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................86 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................86 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................86 
8.7. 
Management of AE of Special Interest .......................................................................86 
8.7.1. 
Infusion-Related Reactions and Hypersensitivity Reactions ......................................87 
8.7.2. 
Immune-Mediated Adverse Events ............................................................................87 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................89 
9.1. 
Statistical Analysis ......................................................................................................89 
9.1.1. 
Randomization Methods .............................................................................................89 
9.1.2. 
Analysis Sets ...............................................................................................................89 
9.1.3. 
Patient Disposition ......................................................................................................89 
9.1.4. 
Demographic and Other Baseline Characteristics ......................................................89 
9.1.5. 
Prior and Concomitant Medications ...........................................................................90 
9.2. 
Efficacy Analyses .......................................................................................................90 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................90 
9.2.2. 
Secondary Efficacy Analysis ......................................................................................92 
9.2.3. 
Exploratory Efficacy Analysis ....................................................................................93 
9.3. 
Safety Analyses ..........................................................................................................93 
9.3.1. 
Extent of Exposure .....................................................................................................93 
9.3.2. 
Adverse Events ...........................................................................................................93 
9.3.3. 
Laboratory Analyses ...................................................................................................94 
9.3.4. 
Vital Signs ..................................................................................................................94 
9.3.5. 
Ophthalmologic Examination .....................................................................................94 
9.3.6. 
Pulmonary Function Test ............................................................................................94 
9.4. 
Pharmacokinetic Analysis ..........................................................................................95 
9.5. 
Immunogenicity Analyses ..........................................................................................95 
9.6. 
Sample Size Consideration .........................................................................................95 
9.7. 
Interim Analyses .........................................................................................................95 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................97 
10.1. 
Independent Data Monitoring Committee ..................................................................97 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................98 


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11.1. 
Access to Information for Monitoring ........................................................................98 
11.2. 
Access to Information for Auditing or Inspections ....................................................98 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................99 
12.1. 
Regulatory Authority Approval ..................................................................................99 
12.2. 
Quality Assurance .......................................................................................................99 
12.3. 
Study Site Inspections.................................................................................................99 
12.4. 
Drug Accountability ...................................................................................................99 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ................................................101 
13.1. 
Ethical Standard ........................................................................................................101 
13.2. 
Institutional Review Board/Independent Ethics Committee ....................................101 
13.2.1. 
Protocol Amendments ..............................................................................................101 
13.3. 
Informed Consent .....................................................................................................101 
13.4. 
Patient and Data Confidentiality ...............................................................................102 
13.5. 
Financial Disclosure .................................................................................................104 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................105 
14.1. 
Data Collection and Management Responsibilities ..................................................105 
14.1.1. 
Data Entry in the Electronic Case Report Form .......................................................105 
14.1.2. 
Data Collection .........................................................................................................105 
14.1.3. 
Data Management/Coding ........................................................................................105 
14.2. 
Data Integrity and In-house Blinding .......................................................................106 
14.3. 
Study Records Retention ..........................................................................................106 
14.4. 
Protocol Deviations ..................................................................................................107 
14.5. 
Study Report and Publications..................................................................................107 
14.6. 
Study and Study Center Closure ...............................................................................108 
14.7. 
Information Disclosure and Inventions ....................................................................108 
15. 
REFERENCES .........................................................................................................110 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................117 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ..............................................123 
APPENDIX 3. ECOG PERFORMANCE STATUS.................................................................124 
APPENDIX 4. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................125 
APPENDIX 5. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................135 


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APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................136 
APPENDIX 7. INFUSION-RELATED REACTIONS, HYPERSENSITIVITY 
REACTIONS AND IMMUNE-MEDIATED ADVERSE EVENTS: 
EVALUATION AND MANAGEMENT .................................................................137 
APPENDIX 8. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................150 
APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................151 
APPENDIX 10. DOSE MODIFICATION OF CHEMOTHERAPY .......................................153 
APPENDIX 11. EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30 .................................................................................156 
APPENDIX 12. EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE GASTRIC CANCER 
MODULE QLQ-STO22 ...........................................................................................158 
APPENDIX 13. EUROPEAN QUALITY OF LIFE 5-DIMENSIONS 5-LEVELS 
HEALTH QUESTIONNAIRE .................................................................................159 
APPENDIX 14. PRINCIPLES OF PATHOLOGIC REVIEW AND HER2-NEU 
TESTING ..................................................................................................................161 
 
LIST OF TABLES  
Table 1: 
KEYNOTE-059 Study Cohort 1 and Cohort 3: Pembrolizumab Alone.....................26 
Table 2: 
KEYNOTE-059 Study Cohort 2 .................................................................................26 
Table 3: 
CheckMate-032: Nivolumab Alone ............................................................................27 
Table 4: 
Selection and Timing of Dose Administration of Tislelizumab or Placebo in 
Combination with Oxaliplatin and Capecitabine ........................................................58 
Table 5: 
Selection and Timing of Dose Administration of Tislelizumab or Placebo in 
Combination with Cisplatin and 5-FU ........................................................................59 
Table 6: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
Both Treatment Arms .................................................................................................83 
Table 7: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................84 
Table 8: 
Examples of Immune-Mediated Adverse Events .......................................................88 
Table 9: 
Stopping Boundaries (in p-value and Z score) of Primary Analysis of OS................92 


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Table 10: Hazard Ratio and Median OS Assumption, Number of Events, Alpha And 
Power in The Primary Hypothesis Tests ....................................................................95 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................44 
 


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SYNOPSIS  
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Medicinal Product: Tislelizumab 
Title of Study: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Clinical Study Comparing 
the Efficacy and Safety of Tislelizumab (BGB-A317) plus Platinum and Fluoropyrimidine Versus 
Placebo plus Platinum and Fluoropyrimidine as First-Line Treatment in Patients with Locally 
Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma 
Protocol Identifier: BGB-A317-305 
Phase of Development: 3 
Number of Patients: Approximately 980 
Study Centers: Approximately 180 centers globally  
Study Objectives: 
Primary: 
• 
To compare overall survival of tislelizumab plus chemotherapy versus placebo plus 
chemotherapy in the programmed cell death protein ligand-1 positive (PD-L1+) and intent-to-
treat analysis sets 
Secondary: 
• 
To compare progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1 as 
assessed by investigators of tislelizumab plus chemotherapy versus placebo plus chemotherapy 
in the programmed cell death protein ligand-1 positive and intent-to-treat analysis sets 
• 
To evaluate overall response rate, and duration of response, per Response Evaluation Criteria 
in Solid Tumors 1.1 as assessed by investigators  
• 
To evaluate European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Gastric Cancer Module QLQ-STO22 Score, European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Score, and European 
Quality of Life 5-Dimensions 5-Levels Health Questionnaire Score 
• 
To evaluate the safety and tolerability profile of tislelizumab or placebo plus chemotherapy 
• 
To evaluate disease control rate, clinical benefit rate, and time to response per Response 
Evaluation Criteria in Solid Tumors 1.1 as assessed by investigators  
Exploratory: 
• 
To evaluate progression-free survival after next line of treatment (PFS2)  
• 
To characterize the pharmacokinetics of tislelizumab  
• 
To determine host immunogenicity to tislelizumab  


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• 
To assess predictive, prognostic, exploratory biomarkers including but not limited to 
programmed cell death protein ligand-1 (PD-L1) expression, Epstein-Barr virus (EBV) 
infection, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) status, 
genomically stable (GS) or chromosomal instability (CIN), immune-related gene expression 
profiling, tumor infiltrated lymphocytes (TILs) and tumor mutation burden in tumor tissues 
and/or blood samples and the association with response to study treatment, mechanisms of 
resistance, and/or disease status 
Study Endpoints: 
Primary: 
• 
Overall survival – defined as the time from the date of randomization to the date of death due 
to any cause 
Secondary: 
• 
Progression-free survival as assessed by investigators – defined as the time from the date of 
randomization to the date of the first objectively documented tumor progression, assessed by 
investigators per Response Evaluation Criteria in Solid Tumors v1.1, or death, whichever 
occurs first 
• 
Overall response rate as assessed by investigators – defined as the proportion of patients whose 
best overall response is complete response or partial response per Response Evaluation Criteria 
in Solid Tumors v1.1  
• 
Duration of response as assessed by investigators – defined as the time from the first 
determination of an objective response per Response Evaluation Criteria in Solid Tumors v1.1, 
until the first documentation of progression or death, whichever occurs first  
• 
Change from baseline in European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire Gastric Cancer Module QLQ-STO22 Score and change from baseline in 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 Score and European Quality of Life 5-Dimensions 5-Levels Health 
Questionnaire Score 
• 
The incidence and severity of adverse events according to National Cancer Institute Common 
Terminology Criteria for Adverse Events v5.0 
• 
Disease control rate (ie, proportion of complete response + partial response + stable disease), 
clinical benefit rate (ie, proportion of complete response + partial response + durable stable 
disease), and time to response (ie, time from randomization to the first determination of an 
objective response) per Response Evaluation Criteria in Solid Tumors 1.1 as assessed by 
investigators 
Exploratory: 
• 
Progression-free survival after next line of treatment (PFS2) – defined as the time from 
randomization to the objective disease progression after next line of treatment, or death from 
any cause, whichever occurs first 
• 
Summary of serum concentration of tislelizumab  
• 
Assessments of immunogenicity of tislelizumab by determining the incidence of antidrug 
antibodies 
• 
Status of programmed cell death protein ligand-1 (PD-L1) expression, immune or 


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gastric-related, and other exploratory biomarkers including but not limited to Epstein-Barr 
virus (EBV) infection, microsatellite instability-high (MSI-H) or mismatch repair deficient 
(dMMR), genomically stable (GS) or chromosomal instability (CIN), immune-related gene 
expression profiling, tumor infiltrated lymphocytes (TILs) and tumor mutation burden in tumor 
tissues and/or blood samples obtained before treatment with tislelizumab and/or at progression, 
and the association with disease status and/or response to tislelizumab in combination with 
chemotherapy or chemotherapy alone 
Study Design: 
This is a randomized (1:1), double-blind, placebo-controlled, Phase 3 study designed to compare the 
efficacy and safety of tislelizumab or placebo plus chemotherapy as first-line (1L) therapy for locally 
advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.  
After providing written informed consent, completing all screening assessments, and being confirmed 
as eligible for study participation, approximately 980 patients will be randomized 1:1 to receive either 
tislelizumab plus chemotherapy or placebo plus chemotherapy.  
At randomization, patient enrollment will be stratified by the following factors: 
• 
Regions of enrollment: China (including Taiwan) vs. Japan and S. Korea vs. US and Europe 
and other regions. NOTE: other regions include other western countries/populations. 
• 
Programmed cell death protein ligand-1 (PD-L1) expression (positive or negative): PD-L1+ 
patients are patients with tumor and immune cell score (TIC score) ≥ 5% using VENTANA 
PD-L1 (SP263) Cdx Assay*. TIC score is the total percentage of the tumor area covered by 
tumor cells with PD-L1 membrane staining and tumor-associated immune cells with PD-L1 
staining at any intensity. 
• 
*During enrollment, the proportion of patients of multiple PD-L1 expression levels will be 
monitored. Hence, study assumptions could be adjusted accordingly if it is deemed appropriate. 
• 
Presence of peritoneal metastasis (yes or no) 
• 
Investigator’s choice of chemotherapy (oxaliplatin + capecitabine versus cisplatin + 
5-fluorouracil [5-FU])  
After randomization, patients will be treated on the following arms. Cross-over between the treatment 
arms will not be allowed.  
• 
Arm A: Tislelizumab 200 mg intravenously once every 3 weeks (Q3W) + chemotherapy  
• 
Arm B: Placebo intravenously Q3W + chemotherapy 
Oxaliplatin + capecitabine or cisplatin + 5-FU regimens are used as the backbone chemotherapy. The 
chemotherapy backbone regimen needs to be decided on an individual patient basis before 
randomization. There is no switching between regimens throughout the entire course of the study. 
Oxaliplatin + 
Capecitabine 
 
Day 1: Oxaliplatin 130 mg/m² intravenously 
Day 1 (evening) – Day 15 (morning) or Day 1 (morning) – Day 14 
(evening): capecitabine 1000 mg/m2 orally twice daily 
Every 3 weeks as a cycle 
Cisplatin + 5-FU 
 
Day 1: Cisplatin 80 mg/m² IV 
Days 1–5: 5-FU 800 mg/m2/day intravenous continuous infusion over 
24 hours daily 
Every 3 weeks as a cycle  


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The oxaliplatin + capecitabine or cisplatin + 5-FU doublet regimen is administered up to 6 cycles. 
Capecitabine as maintenance therapy is optional only for those patients who received capecitabine and 
oxaliplatin and may be administered until disease progression, intolerable toxicity, withdrawal of 
consent, or another treatment discontinuation criterion is met. Tislelizumab (or placebo) will be 
administered until disease progression, intolerable toxicity, withdrawal of consent, or another treatment 
discontinuation criterion is met. Treatment beyond initial investigator-assessed Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 defined progression will be permitted provided that the patient 
has investigator-assessed clinical benefit and is tolerating study drug. The following criteria must be 
met to treat patients after initial evidence of radiological disease progression: absence of clinical 
symptoms and signs of disease progression; stable Eastern Cooperative Oncology Group Performance 
Status (ECOG PS)  1; absence of rapid progression of disease or progressive tumor at critical 
anatomical sites that require urgent alternative medical intervention; and additional written informed 
consent. The medical monitor must agree, in writing, with the investigator’s decision to continue study 
drugs beyond initial investigator-assessed progression, and the decision must be documented in the 
study records. 
Study Assessments: 
Tumor assessments will be performed by investigator using RECIST v1.1 criteria (Eisenhauer EA 
2009). Tumor imaging (computed tomography [CT] with or without contrast or magnetic resonance 
imaging [MRI]) must be performed within 28 days prior to randomization. On-study tumor 
assessments will occur every 6 weeks (± 7 days) during the first 48 weeks and every 9 weeks (± 7 
days) thereafter until disease progression. If a patient discontinues study treatment due to any reasons 
other than disease progression, tumor assessments will continue to be performed as scheduled until 
disease progression, loss to follow up, withdrawal of consent, death, or until the study terminates, 
whichever occurs first. 
Patient reported outcomes will be collected using the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire Gastric Cancer Module QLQ-STO22 (EORTC 
QLQ-STO22), European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30), and European Quality of Life 5-Dimensions 5-Levels 
Health Questionnaire (EQ-5D-5L) at screening or baseline, at every cycle through Cycle 6, then every 
other cycle thereafter until progressive disease (PD), and at the End of Treatment Visit. 
Patients will be evaluated for any adverse events (AEs) and serious adverse events (SAEs) occurring up 
to 30 days after the last dose of study drug (all severity grades), per National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI-CTCAE] v5.0 or until initiation of new anticancer 
therapy, whichever occurs first, and for immune-mediated AEs (imAEs) occurring up to 90 days after 
the last dose of tislelizumab or placebo regardless of whether or not the patient starts a new anticancer 
therapy. All SAEs considered related to the study drug(s) that are brought to the attention of the 
investigator should be reported regardless of time since the last dose of treatment until patient death, 
withdrawal of consent, or loss to follow-up, whichever occurs first. All study drug-related SAEs will be 
followed until they resolve to baseline or ≤ Grade 1, the investigator assesses the AE as stable and 
unlikely to improve, or the patient is lost to follow-up, whichever occurs first. 
Safety and efficacy monitoring will be performed by an Independent Data Monitoring Committee 
(IDMC). The IDMC may recommend modifications to the study, including termination due to safety 
and/or efficacy concerns. The functions and membership of the IDMC will be described in an IDMC 
Charter. 
Duration of Patient Participation: 
Approximately 48 months duration of study 


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Study Population:  
Patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, and no prior 
systemic therapy for advanced disease. 
Key Eligibility Criteria: 
Adult patients (≥ 18 years of age or acceptable age according to local regulations, whichever is older) 
at the time of voluntarily signing informed consent with histologically confirmed diagnosis of gastric 
or GEJ adenocarcinoma who have not received previous systemic therapy for locally advanced 
unresectable or metastatic gastric/GEJ cancer. All patients are also required to have ≥ 1 measurable or 
non-measurable lesion per RECIST v1.1, an Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) score of ≤ 1, and adequate organ function. 
Investigational Medicinal Product, Dose, and Mode of Administration:  
Tislelizumab will be administered at a dose of 200 mg intravenously on Day 1, given every 3 weeks. 
Reference Therapy, Dose, and Mode of Administration:  
Please refer to Study Design above. 
Statistical Methods: 
Overall survival (OS) within the 2 primary analysis sets (ie, PD L1+ and intent-to-treat [ITT]) of the 
study are 2 primary endpoints of the study. The type I error is strongly controlled at 0.025 in the 2 
primary hypotheses. A hierarchical testing procedure will be adopted in this study and the OS analysis 
in ITT analysis set will be performed only if the OS analysis in the PD-L1+ analysis set is statistically 
significant favoring tislelizumab + chemotherapies. 
Hypothesis testing of PFS in the PD-L1+ and ITT analysis sets will be performed at the same time as 
the interim analysis of OS if OS analyses are significant in both PD-L1+ and ITT analysis sets. Only 
when the superiority of both PFS and ORR in PD-L1+ are demonstrated, its alpha will be shifted to the 
hypothesis testing of the secondary endpoints PFS, overall response rate (ORR) in the ITT analysis set. 
The inferential test will be stopped at the first non-significant endpoint. Nominal p-values may be 
computed for other efficacy analysis but should be interpreted with caution.  
Analysis Sets: 
• 
ITT analysis set – Includes all randomized patients. Patients will be analyzed according to their 
randomized treatment arm. This will be the dual primary analysis set for efficacy analyses. 
• 
PD-L1+ analysis set (≥ 5% of area with PD-L1 staining cells [including tumor cells and 
tumor-associated immune cells]/total tumor area) – Includes all randomized patients whose 
tumors were PD-L1+. Patients will be analyzed according to their randomized treatment arms. 
This will be the dual primary analysis set for efficacy analyses. 
• 
Per-Protocol (PP) analysis set – Includes all randomized patients who received at least 1 dose 
of the assigned study drug and had no major protocol deviations. Major protocol deviations 
will be determined and documented before the database lock for the primary analyses. 
• 
Safety analysis set – Includes all patients who received at least 1 dose of study drugs. This will 
be the analysis set for the safety analyses. 


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Primary Efficacy Endpoint Analysis: 
OS in the PD-L1+ analysis set: 
The null hypothesis to be tested is: 
H0:  OS in Arm A = OS in Arm B 
against the alternative: 
H1:  OS in Arm A ≠ OS in Arm B 
The primary analysis of OS will be carried out once the targeted number of death events is reached. In 
absence of confirmation of death, patients will be censored either at the date that the patient was last 
known to be alive or the date of data cutoff, whichever comes earlier.  
OS will be compared between Arm A and Arm B using stratified log-rank test at 1-sided 0.025 level of 
significance stratified by pooled stratification factors of regions of enrollment (east Asia versus rest of 
the world [ROW]) and presence of peritoneal metastasis.  
The median OS and the cumulative probability of OS at every 6 months if estimable, will be calculated 
for each treatment arm and presented with 2-sided 95% CIs. Kaplan-Meier survival probabilities for 
each arm will be plotted over time. OS rate at 12 and 24 months based on Kaplan-Meier estimate will 
be compared between 2 treatment arms for landmark analysis. 
The treatment effect will be estimated by fitting a Cox regression model to the OS times including 
treatment arm as a factor and region of enrollment (east Asia versus ROW) and presence of peritoneal 
metastasis as strata. From this model, the hazard ratio (HR) of OS will be estimated and presented with 
a 2-sided 95% CI. 
These analyses will be performed in the PD-L1+ analysis set as the primary analysis. Outcomes in the 
Per Protocol analysis set will be evaluated as a sensitivity analysis. 
OS in the ITT analysis set: 
Analysis of OS in the ITT analysis set will be performed only if superiority of OS favoring 
tislelizumab + chemotherapy is demonstrated in the PD-L1+ analysis set. The hypothesis testing of OS 
in the ITT analysis set will be carried out similarly at a significance level of 0.025 (1-sided in the 
stratified analysis [ie log-rank and Cox regression]), stratified by pooled stratification factors of regions 
of enrollment (east Asia versus ROW), PD-L1 expression and presence of peritoneal metastasis.  
There will be one interim analysis of OS using the O’Brien-Fleming boundary approximated by 
Hwang-Shih-DeCani spending function with the gamma parameter set at -4. The non-binding lower 
(futility) boundary is defined by Hwang-Shih-DeCani spending function with the gamma parameter set 
at -12. The interim analysis of OS will be performed when approximately 269 deaths in the PD-L1+ 
analysis set and 538 deaths in the ITT analysis set (70% of the target number of OS events in each 
analysis set) among the 2 treatment arms have been observed which is estimated to occur 
approximately 30 months after the first patient is randomized. The final analysis of OS will take place 
after approximately 384 and 768 death events have been observed in the 2 analysis sets, respectively, 
which is estimated as 48 months after the first patient is randomized. Stopping boundaries in p-value 
and Z score for primary analyses of OS are shown in Table a. The boundaries will be updated 
according to the actual numbers of events in the interim and final analyses, using the above pre-
specified alpha spending function. 
 
 
 
 
 


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Table a: Stopping Boundaries (in p-value and Z score) of Primary Analysis of OS 
Analysis 
Set 
Analysis 
Time 
(m) 
# 
Events 
p-value a 
(Z score) 
for 
Efficacy 
p-value a 
(Z score) 
for 
Interim 
Futility 
Approximate 
HR 
Threshold 
Cumulative 
Prob of 
Crossing 
Under H1 
PD-L1+b 
Interim 
analysis 
30 
269 
< 0.0072 
(> 2.45) 
> 0.5731 
(< -0.18) 
0.742 
0.47 
Final 
analysis 
48 
384 
< 0.0228 
(> 2.00) 
- 
0.815 
0.80 
ITT 
Interim 
analysis 
30 
538 
< 0.0072 
(> 2.45) 
> 0.5384 
(<-0.1) 
0.810 
0.56 
Final 
analysis 
48 
768 
< 0.0228 
(> 2.00) 
- 
0.866 
0.87 
a: 1-sided, b: PD-L1+ is 50% of the ITT 
Secondary Efficacy Endpoint Analyses: 
The distribution of PFS as determined by investigators will be estimated using the Kaplan-Meier (KM) 
method; the median PFS along with 95% confidence intervals (CIs) will be presented by treatment arm; 
the comparison of the distribution of PFS between treatment groups will be performed using a stratified 
log-rank test; A Cox regression stratified by the factors same as the ones used in the OS analyses will 
be used to estimate the hazard ratio (HR) of PFS, along with 95% CI. 
The null hypotheses of no difference in ORR per RECIST 1.1 assessed by investigators will be tested 
in a Cochran-Mantel-Haenszel (CMH) test adjusting for pooled stratification factors in the ITT and 
PD-L1+ analysis sets. Patients with no post-baseline response assessment (for any reason) will be 
considered non-responders. The 2-sided 95% CIs for the odds ratio in ORR will be calculated, as well 
as Clopper-Pearson 95% CIs of ORR for each treatment arm. 
Duration of response (DOR) assessed by investigators will be analyzed similarly to PFS in the 
responders. 
Change from baseline of EORTC QLQ-STO22, EORTC QLQ-C30, and EQ-5D-5L will be compared 
between Arms A and B.  
Both EORTC scales and single items will be scored on a categorical scale and transformed to a 
0-100 scale. In addition to change from baseline scores, minimal important differences defined as 
10-point change from baseline will be used to calculate the proportion of patients with clinically 
meaningful deterioration over time. Descriptive statistics will be used to show the changes from 
baseline and percentage of patients with deterioration at each time point in each arm, unless otherwise 
specified.  
Best overall response (BOR) is defined as the best response per RECIST v1.1 recorded from 
randomization till data cut, progressive disease or start of new anticancer treatment. The proportion and 
its corresponding Clopper-Pearson 95% CI for each of the response categories (complete response 
[CR], partial response [PR], stable disease [SD] and PD) will be presented by treatment arm. Time to 
response will be summarized using descriptive statistics, such as mean, median, and standard deviation. 
Only patients who have achieved an objective response will be included in the analysis of time to 
response. 
Disease control rate (DCR) and clinical benefit rate (CBR) assessed by investigators will be analyzed 
similarly to ORR in the ITT and PD-L1+ analysis sets. 


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Exploratory Efficacy Analyses: 
To calculate PFS2, data from patients without disease progression after next-line of treatment or death 
at the time of analysis will be censored at the last time known to be alive. Kaplan-Meier (KM) method 
as described in the PFS and OS analyses will be used in the analysis of PFS2. 
Safety Analyses: 
Extent of exposure to each study drug will be summarized descriptively as the number of doses 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity, and relative dose intensity. 
Verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory Activities 
(MedDRA®) terms and graded per NCI-CTCAE v5.0. All treatment emergent AEs (TEAEs) will be 
summarized. A TEAE is defined as an AE that had an onset date or a worsening in severity from 
baseline (pre-treatment) on or after the first dose of study drug and up to 30 days following study drug 
discontinuation or initiation of new anticancer therapy, whichever occurs first. The TEAE classification 
also applies to imAEs that are recorded up to 90 days after discontinuation from tislelizumab or 
placebo, regardless of whether or not the patient starts a new anticancer therapy. SAEs, deaths, TEAEs 
with Grade 3 or above, treatment-related TEAEs, TEAEs that led to treatment discontinuation, dose 
reduction, dose interruption or dose delay, and imAEs will be summarized. 
Clinical laboratory data with values outside of the normal ranges will be identified. Select laboratory 
data will be summarized by grade. Changes in vital signs will also be summarized by visit. 
Pharmacokinetic Analysis: 
Pharmacokinetic (PK) samples will be collected in this study as outlined in the schedule of assessments 
(Appendix 1).  
Tislelizumab serum concentration data, including but not limited to trough serum concentration 
(Ctrough), will be tabulated and summarized by visit/cycle at which these concentrations are collected. 
Descriptive statistics will include means, medians, ranges, and standard deviations, as appropriate. 
Additional PK analyses may be conducted, as appropriate. Exposure-response (efficacy or safety 
endpoints) analysis may be carried out if supported by data. 
Immunogenicity Analysis: 
Immunogenicity samples will be collected in this study as outlined in the schedule of assessments.  
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable antidrug antibodies (ADAs). The incidence of positive 
ADA and neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on 
PK, efficacy, and safety may be evaluated if data allow. 
Sample Size Considerations: 
The sample size calculation is based on the primary efficacy analyses of OS in the comparison between 
Arms A and B in the PD-L1+ and ITT analysis sets. The number of events needed is based on the 
assumption of an exponential distribution. The 1-sided overall type I error in the study is set at 0.025. 
Table b summarizes the statistical assumption and power in the sample size calculation. Assuming a 
50% PD-L1+ prevalence rate, a total of 928 patients including approximately 464 (ie, 50%) in the PD-
L1+ subset will be enrolled in a 1:1 randomization to observe targeted OS events at the defined time 
periods as shown in Table a. Assuming a roughly 5% dropout rate, approximately 980 patients will be 
enrolled over 24 months at enrollment rates of 17 patients/month in the first 2 months, 34 
patients/month in the next 2 months, and 44 patients/month in the last 20 months. The enrollment 
assumptions, including percentage of PD-L1+ patients, will be monitored during the enrollment; 
therefore, the sample size and timeline could be adjusted accordingly. Enrollment of patients whose 
tumors are PD-L1- might be stopped if necessary, to ensure that the percentage of PD-L1+ is no less 
than 50% of the ITT analysis set. The primary analyses will be performed when the target number of 


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events is observed. An interim analysis of OS (see Table a) is planned after approximately 70% of the 
total planned death events have occurred in both ITT and PD-L1+ analysis sets. 
Table b: Hazard ratio and median OS assumption, number of events, alpha and power in the 
primary hypothesis tests 
Analysis Set 
HR 
Median in 
Arm A (in 
months) 
Median in 
Arm B (in 
months) 
# Events 
Alpha 
Power 
PD-L1+ 
0.75 
15.3 
11.5 
384 
0.025 
80% 
ITT 
0.8 
14.4 
11.5 
768 
0.025 
87% 


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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma or serum concentration-time curve 
CI 
confidence interval 
Cmax 
maximum observed plasma concentration 
CPS 
combined positive score 
CR 
complete response 
CT 
computed tomography 
Ctrough 
trough serum concentration 
DCR 
disease control rate 
dMMR 
mismatch repair deficient 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EORTC QLQ-
C30 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 
ESMO 
European Society for Medical Oncology 
EORTC QLQ-
STO22 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Gastric Cancer Module QLQ-STO22 
EOT 
end of treatment 
EQ-5D-5L 
European Quality of Life 5-Dimensions 5-Levels Health Questionnaire  
Fc 
fragment crystallizable region (typically, of immunoglobulin G) 
FcγR 
gamma Fc receptor (eg, Fcγ-RI, Fcγ-RIII) 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FFPE 
Formalin-fixed paraffin-embedded 
GC 
Gastric cancer 
GEJ 
gastroesophageal junction 


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Abbreviation 
Definition 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G (eg, IgG1, IgG2, IgG3, IgG4); other types of immunoglobulins 
include IgD and IgM  
INR 
international normalized ratio 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-treat 
KD 
dissociation constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability-high 
NCCN 
National Comprehensive Cancer Network  
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein ligand-1 
PD-L2 
programmed cell death protein ligand-2 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
Q3W 
once every 3 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROW 
Rest of the world 


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Abbreviation 
Definition 
SAE 
serious adverse event 
SD 
stable disease 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
Tislelizumab 
BGB-A317 
TTR 
time to response 
ULN 
upper limit of normal 
Vd 
volume of distribution  
1L 
first-line 
5-FU 
5-fluorouracil 


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1. 
INTRODUCTION  
1.1. 
Advanced and Metastatic Gastric Cancer  
There were an estimated 17.5 million cancer cases and 8.7 million cancer deaths in 2015 
worldwide. Gastric cancer (GC) alone contributed about 1.3 million cases with 800,000 deaths. It 
is the fifth most common cancer worldwide and the second leading cause of cancer death 
together with colorectal and liver cancer (Global Burden of Disease Cancer Collaboration 2017). 
More than half of gastric cancer cases and deaths are estimated to occur in China, with 
approximately 680,000 cases and approximately 500,000 deaths in 2015 (Chen et al 2016a). 
Predicted GC deaths for the European Union in 2017 are approximately 55,000 (Malvezzi et al 
2017). For the United States (US), estimates for GC in 2017 are approximately 28,000 cases with 
11,000 deaths (Stomach Cancer: Statistics 2017). 
Adenocarcinoma is the major histologic subtype representing approximately 90% of GC (Smyth 
et al 2016). About two-thirds are true GCs (non-cardia) and the remainder are gastroesophageal 
junction (GEJ) cancers (cardia) (Colquhoun et al 2015). The most common anatomical subsites 
differ in world regions due to differences in risk factors. Distal and antral GCs are more common 
in East Asia and tumors of the proximal stomach or GEJ are more common in non-Asian 
countries (Forman and Burley 2006; World Cancer Research Fund International/American 
Institute for Cancer Research 2017).  
Patients with newly diagnosed, inoperable, locally advanced or metastatic disease generally 
receive chemotherapy regimens containing a platinum and a fluoropyrimidine (Smyth et al 2016; 
NCCN 2017). Triplet regimens may provide additional clinical benefit, as suggested in a 
meta-analysis for the addition of an anthracycline (Okines et al 2009). Because of their added 
toxicities, however, they have not been uniformly adopted and are recommended only for 
medically fit patients with good performance status and access to frequent toxicity evaluations. 
Response rates for first-line (1L) chemotherapy regimens are around 30% to 50% with median 
progression-free survival (PFS) ranging from 5 to 7 months. Median overall survival (OS) is less 
than 12 months, and less than 10% of patients are still alive after 5 years (Chau et al 2004; 
Cunningham et al 2008; Kang et al 2009; Van Cutsem et al 2006; Wagner et al 2006). 
Approximately 12% to 20% of gastric adenocarcinomas are HER2-positive (Van Cutsem et al 
2015). For these patients, a unique treatment paradigm has been established that combines 1L 
platinum- and fluoropyrimidine-based chemotherapy with the anti-HER2 antibody trastuzumab 
(Bang et al 2010). The reference chemotherapy regimen for 1L treatment of HER2 negative 
metastatic gastric and GEJ adenocarcinoma is a fluoropyrimidine (5-fluorouracil [5-FU] or 
capecitabine) in combination with a platinum. 
1.2. 
Immunotherapy of Gastric Cancer  
The presence of tumor infiltrating lymphocytes (TILs) has been associated with an improved 
prognosis for different tumor types, including GC (Fridman 2012). On the contrary, high 
programmed cell death protein ligand-1 (PD-L1) expression plays a leading role as immune 
inhibitory mechanism and has been identified as a negative prognostic marker in GC (Zheng et al 
2014). Nevertheless, more studies are needed to improve the understanding of the prognostic role 
of PD-L1 expression and immune cell activity. Interesting recent data from a small cohort of 
resected GCs showed that patients with higher CD8+ T-cell density have higher PD-L1 


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expression and worse outcome (Thompson et al 2016). Categorization of tumor according to the 
mechanism of immune-surveillance escape includes type I (high PD-L1 with TILs driving 
adaptive immune resistance), type II (low PD-L1 with no TIL, indicating immune ignorance), 
type III (high PD-L1 with no TIL, indicating intrinsic induction), and type IV (low PD-L1 with 
TIL, indicating the role of other suppressor(s) in promoting immune tolerance). While the 
predictive role of PD-L1 expression is still controversial in the clinic, the tumor stratification 
based on the presence of T cells and PD-L1 might be a promising predictive tool to define 
optimal therapy for patients with advanced cancer (Teng et al 2015). Indeed, interest in 
characteristics of tumor environment is not only in prognostic terms but also in predicting 
response to immune checkpoint inhibition. In GC, it seems that infiltration of CD8+ T-cells is 
associated with high expression of PD-L1 (adaptive immune resistance type mechanism), 
suggesting potential efficacy of anti-PD-1/PD-L1. Of note, CTLA-4 is only expressed by a small 
subset of patients with GC, whereas programmed cell death protein-1 (PD-1) as well as PD-L1 
are expressed by approximately 50% of tumor-infiltrating lymphocytes (Schlößer et al 2016).  
1.2.1. 
Pembrolizumab  
Pembrolizumab is a selective humanized monoclonal antibody that was designed to directly 
block the interaction between PD-1 and PD-L1 or programmed cell death protein ligand-2 
(PD-L2). The safety and efficacy of pembrolizumab alone or in combination with chemotherapy 
in patients with GCs have been evaluated in the following studies.   
KEYNOTE-012 study (ClinicalTrials.gov ID: NCT01848834) is a multicenter open-label Phase 
1b study, in which pembrolizumab was administered to patients with advanced GC, urothelial 
cancer, triple-negative breast cancer, and head and neck cancer, have recently become available. 
To be eligible, patients needed at least 1% PD-L1 expression in tumor cells, immune cells, or 
both cell types. Thirty-nine patients were enrolled in the GC Cohort. In this cohort, partial 
responses (PRs) were observed in 22% of cases (according to central review) and disease 
stabilization in 14% (according to central review). Of note, median overall survival (OS) was 
11 months in a population in which most of the patients had received 2 or more previous lines of 
therapy. The overall response rate (ORR) was very similar across the countries, regardless of the 
Asian ethnicity (ORR 24% in Asian patients and 21% in non-Asian patients) (Muro et al 2016).  
KEYNOTE-059 study (ClinicalTrials.gov ID: NCT02335411) is a Phase 2 study evaluating the 
efficacy and safety of pembrolizumab alone or in combination with chemotherapy in patients 
with advanced GC and GEJ cancer (Wainberg et al 2017). In Cohort 1 of this study, patients with 
≥ 2 prior lines of chemotherapy were treated with pembrolizumab (200 mg once every 3 weeks 
[Q3W]). The preliminary efficacy data for Cohort 1 are summarized in Table 1.  
Based on the efficacy (tumor response rate and durability of response) and safety data from this 
cohort, the FDA (Food and Drug Administration) has approved pembrolizumab for the treatment 
of patients with PD-L1+ recurrent or advanced gastric or GEJ adenocarcinoma who have 
received 2 or more lines of chemotherapy, including fluoropyrimidine- and platinum-containing 
chemotherapy, and, if appropriate, HER2/neu-targeted therapy. 
In Cohort 3 of KEYNOTE-059 (ClinicalTrials.gov ID: NCT02335411), PD-L1+ patients without 
prior therapy were treated with pembrolizumab alone. The preliminary efficacy data for Cohort 3 
are also summarized in Table 1. 


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Table 1: 
KEYNOTE-059 Study Cohort 1 and Cohort 3: Pembrolizumab Alone  
Parameter 
Cohort 1 (≥ 2L prior treatment) 
Cohort 3 (1L 
GC) 
 _ 
All patients 
(n=259) 
PD-L1+ (n=148) 
PD-L1- (n=109) 
PD-L1+ (n=31) 
ORR (95% CI), % 
12 (8-17) 
16 (11-23) 
6 (3-13) 
26 (12-45) 
mPFS (95% CI), mo 
2.0 (2.0-2.1) 
2.1 (2.0-2.1) 
2.0 (1.9-2.0) 
3.3 (2.0-6.0) 
6-mo PFS Rate 
14.6% 
18.2% 
9.9% 
34.9% 
mOS (95% CI) 
5.5 (4.2-6.5) 
5.8 (4.4-7.8) 
4.6 (3.2-6.5) 
20.7 (9.2-20.7) 
6-mo OS Rate 
45.7% 
48.4% 
42.9% 
72.9% 
In Cohort 2 of KEYNOTE-059, patients without any prior therapy was treated with 
pembrolizumab in combination with chemotherapy (cisplatin + 5-FU or capecitabine, Q3W). 
The preliminary efficacy data are summarized in Table 2.  
Table 2: 
KEYNOTE-059 Study Cohort 2  
 Parameter 
All patients (n=25) 
PD-L1+ (n=16) 
PD-L1- (n=8) 
ORR (95% CI), % 
60 (39-79) 
69 (41-89) 
38 (9-76) 
mPFS (95% CI), mo 
6.6 (5.9-10.6) 
- 
- 
6-mo PFS Rate 
68.0% 
- 
- 
mOS (95% CI) 
13.8 (8.6-NR) 
- 
- 
6-mo OS Rate 
76.0% 
- 
- 
Two Phase 3 studies (KEYNOTE-062 [ClinicalTrials.gov ID: NCT02494583] and 
KEYNOTE-063 [ClinicalTrials.gov ID: NCT03019588]) (www.clinicaltrials.gov) are on-going 
to evaluate pembrolizumab alone or in combination with chemotherapy in patients with 
PD-L1(+) GC in various geographic regions. 
KEYNOTE-061 is a randomized, open-label, Phase 3 study to compare pembrolizumab with 
paclitaxel as second-line treatment in patients with advanced GC or GEJC that progressed on 1L 
chemotherapy with a platinum and fluoropyrimidine. Eligible patients were randomized (1:1) in 
blocks of 4 per stratum to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years 
or standard-dose paclitaxel. As of Oct 26, 2017, 326 patients in the population with combined 
positive score (CPS) of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab 
group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 
9.1 months (95% confidence interval [CI] 6.2-10.7) with pembrolizumab and 8.3 months 
(7.6-9.0) with paclitaxel (hazard ratio [HR] 0.82, 95% CI 0.66-1.03; 1-sided p=0.0421). Median 
progression-free survival was 1.5 months (95% CI 1.4-2.0) with pembrolizumab and 4.1 months 
(3.1-4.2) with paclitaxel (HR 1.27, 95% CI 1.03-1.57). In the total population, Grade 3-5 
treatment-related adverse events (AEs) occurred in 42 (14%) of the 294 patients treated with 
pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. In summary, 
Pembrolizumab did not significantly improve overall survival compared with paclitaxel as 


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second-line therapy for advanced gastric or gastro-esophageal junction cancer with PD-L1 CPS 
of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. However, 
protocol-specified and post-hoc exploratory subgroup analyses suggest that the treatment effect 
of pembrolizumab might be more pronounced in patients with a better performance status, 
greater levels of PD-L1 expression (CPS ≥ 10, HR = 0.64), and tumors with high levels of 
microsatellite instability. These data support further exploration to identify patients who are 
likely to benefit from pembrolizumab monotherapy and the ongoing development of 
pembrolizumab as part of combination therapy regimens (Shitara et al 2018). 
KEYNOTE-062 is a randomized, active-controlled, partially blinded, phase 3, 1L treatment 
study patients with advanced GC or GEJC. Eligible patients were randomized (1:1:1) to 
pembrolizumab 200 mg every 3 weeks for up to 2 years, or pembrolizumab + chemotherapy 
(cisplatin 80 mg/m2 once every 3 weeks + 5-FU 800 mg/m2 on Day 1 to Day 5 of each cycle), or 
placebo once every 3 weeks + chemotherapy (cisplatin + 5-FU); 5-FU may be replaced by 
capecitabine 1000 mg/m2 twice a day on Day 1 to Day14 of each cycle per local guideline. As of 
cutoff date 26 March 2019, 763 patients (281 patients with CPS ≥ 10) were randomized to 
receive pembrolizumab + chemotherapy (257 patients), pembrolizumab (256 patients), or 
placebo + chemotherapy (250 patients). Median follow-up was 11.3 months. Pembrolizumab 
prolonged OS in CPS ≥ 10 compared with chemotherapy (median 17.4 versus 10.8 months; HR 
0.69; 95% CI 0.49-0.97). Pembrolizumab + chemotherapy was not superior to chemotherapy for 
OS (12.5 versus 11.1 months; HR 0.85; 95% CI 0.70-1.03) and PFS (6.9 versus 6.4 months; HR 
0.84; 95% CI 0.70-1.02) in CPS ≥ 1 or OS (12.3 versus 10.8 months; HR 0.85; 
95% CI 0.62-1.17) in CPS ≥ 10. ORR was higher in pembrolizumab + chemotherapy group than 
placebo + chemotherapy group in CPS ≥ 1 (48.6% versus 37.2%) and CPS ≥ 10 (52.5% versus 
37.8%). Grade 3-5 drug-related AE rates were 17% in pembrolizumab group, 73% in 
pembrolizumab + chemotherapy group, and 69% in placebo + chemotherapy group. These data 
support further exploration to identify patients who are likely to benefit from pembrolizumab + 
chemotherapy (Shitara et al 2019). 
1.2.2. 
Nivolumab  
Nivolumab is a fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the 
negative immunoregulatory human cell surface receptor programmed death-1 (PD-1). The safety 
and efficacy of nivolumab alone or in combination with chemotherapy in patients with GC have 
been evaluated in the following studies.   
CheckMate-032 evaluated the efficacy and safety of nivolumab in patients with advanced 
chemotherapy-refractory esophago-gastric cancer according to microsatellite instability status 
(Ott et al 2017). The preliminary efficacy results are summarized in Table 3. The authors 
concluded that nivolumab alone demonstrated clinical activity in chemotherapy-refractory 
patients. Numerically higher response rates were observed in microsatellite instability-high 
patients.   
Table 3: 
CheckMate-032: Nivolumab Alone  
  
All patients 
(n=59) 
MSI-H (n=7) Non-MSI-H 
(n=18) 
MSI-U 
(n=34) 
ORR (95% CI), % 
12 (5-23) 
29 (4-71) 
11 (1-35) 
9 (2-24) 


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mOS (95% CI) 
6.2 (3.4-12.4) 
15 (2-NE) 
6 (3-12) 
5 (3-16) 
12-mo OS Rate 
39% 
57% (17-84) 
33 (14-55) 
39 (22-56) 
ATTRACTION-2 is a randomized, double-blind, placebo-controlled, Phase 3 study conducted in 
Japan, South Korea, and Taiwan to evaluate safety and efficacy of nivolumab in patients with 
advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least 
2 previous chemotherapy regimens (ONO-4538-12) (Kang et al 2017a). The study met its 
primary endpoint: median OS was 5.26 months (95% CI 4.60–6.37) in the nivolumab group and 
4.14 months (3.42–4.86) in the placebo group (hazard ratio 0.63, 95% confidence interval [CI] 
0.51–0.78; p < 0.0001). Twelve-month OS rates were 26.2% (95% CI 20.7–32.0) with 
nivolumab and 10.9% (6.2–17.0) with placebo. No new safety signals were observed. 
Checkmate 649 (ClinicalTrials.gov ID: NCT02872116) (www.clinicaltrials.gov) is a 
randomized, multicenter, open-label, Phase 3 study of nivolumab plus ipilimumab or nivolumab 
in combination with oxaliplatin plus fluoropyrimidine versus oxaliplatin plus fluoropyrimidine in 
patients with previously untreated advanced or metastatic gastric (G) or GEJ cancer. In this 
study, of 2687 patients assessed for eligibility, 1581 patients are randomized to treatment 
(nivolumab plus chemotherapy [n = 789, 50%] or chemotherapy alone [n = 792, 50%]). The 
median follow-up for OS was 13.1 months (interquartile range [IQR]: 6.7 to 19.1) for nivolumab 
plus chemotherapy and 11.1 months (IQR: 5.8 to 16.1) for chemotherapy alone. Nivolumab plus 
chemotherapy resulted in significant improvements in OS (hazard ratio [HR]: 0.71 
[98.4% CI: 0.59 to 0.86]; p < 0.0001) and PFS (HR: 0.68 [98 % CI: 0.56 to 0.81]; p < 0.0001) 
versus chemotherapy alone in patients with a PD-L1 CPS ≥ 5 (minimum follow-up time of 
12.1 months). Additional results showed significant improvement in OS, along with PFS benefit, 
in patients with a PD-L1 CPS ≥ 1 and all randomly assigned patients. Among all treated patients, 
462 of 782 patients (59%) in the nivolumab plus chemotherapy group and 341 of 767 patients 
(44%) in the chemotherapy alone group had Grade 3 or 4 treatment-related adverse events. The 
most common (≥ 25%) treatment-related adverse events were nausea, diarrhoea, and peripheral 
neuropathy across both groups. Sixteen deaths (2%) in the nivolumab plus chemotherapy group 
and 4 deaths (1%) in the chemotherapy alone group were considered to be treatment-related. No 
new safety signals were identified. (Janjigian et al 2021). 
1.2.3. 
Avelumab  
Avelumab, a fully human anti-PD-L1 immunoglobulin G (IgG)1 antibody (MSB0010718C), 
showed an acceptable safety profile and clinical activity in GC patients. The safety and efficacy 
of avelumab in patients with GC have been evaluated in the following studies.   
The Phase 1b JAVELIN study enrolled 2 cohorts of patients: the first encompassing 62 patients 
who had progressed on prior therapy (second-line group) and a second with 89 patients who had 
previously received chemotherapy without disease progression (maintenance group) (Chung et al 
2016). Objective responses and disease stabilization were observed in both groups. PD-L1 
expression was evaluable in 74 patients; the cutoff for defining positivity was ≥ 1%. In the 
maintenance cohort, median PFS was 17.6 weeks for PD-L1(+) and 11.6 weeks for PD-L1(−). In 
the second-line cohort, median PFS was longer for PD-L1(−) (10.4 vs. 6.3 weeks).  


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The JAVELIN Gastric 100 trial is Phase 3 open-label study of maintenance therapy with 
avelumab (MSB0010718C) vs. continuation of 1L chemotherapy in patients with unresectable, 
locally advanced or metastatic, adenocarcinoma of the stomach, or of GEJ (Moehler et al 2016).   
The JAVELIN Gastric 300 trial is a Phase 3 study in patients with GC or GEJ adenocarcinoma 
who have been previously treated with 1L combination chemotherapy and second-line 
ramucirumab, alone or in combination. The primary endpoint is best overall response (according 
to Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria). Secondary objectives 
include assessment of PFS, OS, and immune-related efficacy evaluations. Association between 
tumor PD-L1 expression and efficacy will be also evaluated (Oh et al 2016). In November 2017, 
Merck KGaA/Pfizer announced that the Phase 3 JAVELIN Gastric 300 trial did not meet its 
primary endpoint of superior OS with avelumab vs. physician’s choice of chemotherapy 
(paclitaxel or irinotecan monotherapy) (Avelumab Nov 2017). 
1.2.4. 
Summary of Immuno-Oncology in Gastric Cancer  
Gastric (including GEJ) cancer is a very aggressive tumor and the second leading cause of cancer 
death together with colorectal and liver cancer worldwide (Global Burden of Disease Cancer 
Collaboration 2017). Radical surgery remains the first curative choice, while perioperative 
chemotherapy is a standard treatment in early GC (Waddell et al 2013; Shen et al 2013). 
However, 50% of advanced GC patients suffer from local or systemic recurrence even after 
standard adjuvant treatment, and only 10–15% of all GC patients achieve 5-year OS (Chen et al, 
2016b; Choi et al 2015). Today, immunotherapy has important clinical applications with 
potential favorable outcomes.  
GC cells acquire the ability to elude the host immune responses by several mechanisms such as 
the loss of antigen presentation and by recruitment of immune suppressive cells (eg, 
up-regulation of PD-L1). GC microenvironment is infiltrated with tumor infiltrating lymphocytes 
(TILs), which have a more pronounced cytolytic activity than stromal T-cells in chronic gastritis, 
and the high levels of TILs could be considered a good prognostic factor (Amedeo et al 2011). 
Thus, PD-1/PD-L1 inhibitors are showing very promising results in GC. 
In GC patients, tumors with PD-L1 expression have been reported to be positively associated 
with depth of muscle invasion, tumor size, and lymph node metastasis. The survival of patients 
with PD-L1 or PD-L2 expressing tumors is significantly worse than for those patients without 
PD-L1/PD-L2 expressing tumors. PD-L1 or PD-L2 expressing tumors have been reported in 
approximately 22% to 40% of GC and PD-L1 expression has been suggested as a prognostic 
marker (Wu et al 2006; Ohigashi et al 2005). Thus, blockage of PD-1/PD-L1/PD-L2 might 
improve the survival of GC patients. Anti PD-1 and PD-L1 inhibitors (eg, nivolumab, 
pembrolizumab, and avelumab) have been investigated in GC treatment and have demonstrated 
anti-tumor activity (Le et al 2016; Muro et al 2015; Chung et al 2015).  
Treatment with pembrolizumab achieved a 33% ORR by investigator assessment and 22% by 
central data review in advanced GC patients with PD-L1 expressing tumors. The 6-month PFS 
rate was 26% and median PFS was 1.9 months (95% CI: 1.8, 3.5). The 6-month OS rate was 
66% and mOS was 11.4 months (95% CI: 5.7, NR). PD-L1 expressing tumors (cutoff 1%) were 
reported in 40% of GC patients in this study, which is consistent with previous reports (Muro et 
al 2015). 


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Preliminary data for second-line use of pembrolizumab in advanced GC have been reported in 
the KEYNOTE-061 study. Although pembrolizumab did not significantly improve overall 
survival compared with paclitaxel in PD-L1 CPS ≥ 1 GC patients, protocol-specified and 
post-hoc exploratory subgroup analyses suggest that the treatment effect of pembrolizumab 
might be more pronounced in patients with a better performance status, greater levels of PD-L1 
expression (CPS ≥ 10, HR=0.64), and tumors with high levels of microsatellite instability. The 
KEYNOTE-062 trial showed that pembrolizumab plus chemotherapy as first-line treatment 
achieved a higher ORR than the chemotherapy group in CPS ≥ 1 (48.6% versus 37.2%) and CPS 
≥ 10 (52.5% versus 37.8%).  
Preliminary data for second line (2L) and switch maintenance use of avelumab in advanced GC 
have been recently reported. The ORRs were 15% and 7.3%, the 6-month PFS rates were 19% 
and 34%, and the median PFS were 2.9 months and 3.5 months, respectively (Chung et al 2015).  
The preliminary safety data of pembrolizumab plus 5-FU and cisplatin in chemotherapy 
treatment-naive patients with advanced GC has been reported recently (Wainberg et al 2017). 
The safety profile reflected additive toxicity of the individual agents with 72% experiencing 
Grade 3/4 treatment-related AEs and was considered manageable using established safety 
guidelines. No treatment-related discontinuation attributed to pembrolizumab nor treatment-
related deaths were reported. A study of nivolumab in combination with oxaliplatin and 
fluoropyrimidine in chemotherapy-naive GC or GEJ in an Asian population is ongoing (Kang et 
al 2017b). 
As of May 2020, the Phase 3 CheckMate‑649 study reported superior OS, along with PFS 
benefit and an acceptable safety profile of nivolumab in combination with chemotherapy versus 
chemotherapy alone, in previously untreated patients with gastric or gastroesophageal junction or 
esophageal adenocarcinoma (Janjigian et al 2021). 
Cancer therapeutics such as chemotherapy may modulate tumor/immune-system interactions in 
favor of the immune system. Chemotherapy can result in tumor cell death with a resultant 
increase in tumor antigen delivery to antigen-presenting cells. Tumor cell death may also lead to 
a reduction in soluble and membrane-bound factors inhibiting tumor-infiltrating T-cells. 
Chemotherapy may also disrupt immune system regulatory networks by decreasing numbers of 
T-regulatory cells. Immunogenic chemotherapy such as oxaliplatin in combination with an 
immune checkpoint inhibitor can: trigger T-cell infiltration into tumor; provide additive or 
synergistic anti-tumor activity in-vivo; and may be expected to contribute to durable anti-tumor 
responses (Pfirschke and Engblom 2016).  
In summary, PD-1/PD-L1 inhibitors combined with chemotherapy provide a basis for potential 
beneficial immunologic effects, which include inhibition of suppressive immune cells, induction 
of immunogenic cell death, enhanced presentation of tumor antigens, induction of maturation/ 
activation of dendritic cells, and enhancement of effector T-cell function. Moreover, 
chemotherapy can induce PD-L1 expression on tumor cells, providing a strong rationale for 
specific use in combination with a PD-1 inhibitor (Emens and Middleton 2015). 
Thus, preclinical and clinical data suggest that tislelizumab in combination with platinum and 
fluoropyrimidine may be expected to bring clinical benefits to advanced GC/GEJ patients with a 
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1.3. 
Background Information on Tislelizumab  
Refer to the most recent edition of the Tislelizumab Investigator’s Brochure for additional 
background on tislelizumab. 
1.3.1. 
Pharmacology  
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against PD-1 under clinical development for the treatment of several 
human malignancies.  
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as 
well as high affinity (dissociation constant [KD]=0.15 nM). It competitively blocks binding 
efforts by both PD-L1 and PD-L2, thus inhibiting PD-1-mediated negative signaling in T cells. 
In in vitro cell-based assays, tislelizumab was observed to consistently and dose-dependently 
enhance the functional activity of human T cells and pre-activated, primary peripheral blood 
mononuclear cells. In addition, tislelizumab has demonstrated in vivo antitumor activity in 
several allogeneic xenograft models, in which peripheral blood mononuclear cells were 
co-injected with human cancer cells (A431 [epidermoid carcinoma]) or tumor fragments 
(BCCO-028 [colon cancer]) into immunocompromised mice.  
In addition, tislelizumab is an IgG4-variant antibody to gamma fragment crystallizable region 
(Fc) receptors (FcγR) such as FcγRI and FcγRIIIA and it has very low binding affinity to 
complement 1q (C1q), a subunit of complement 1. In vitro assays with tislelizumab suggest 
either low or no antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular 
phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC) effects in humans (Zhang 
et al 2018). Tislelizumab was specifically engineered to minimize these potential mechanisms of 
T-cell clearance. Preserving T cells may slow tumor resistance to anti-PD-1 therapy. 
1.3.2. 
Toxicology  
The nonclinical toxicity and toxicokinetic profile of tislelizumab was characterized in 
single-dose studies in mice and cynomolgus monkeys and in a repeated-dose study in 
cynomolgus monkeys dosed once every 2 weeks for 13 weeks. Tissue cross-reactivity in normal 
human and cynomolgus monkey frozen tissues was also evaluated. In addition, the potential 
off-target binding of tislelizumab was screened using the Retrogenix microarray assay. The 
single-dose regimens spanned from the intended human dose to 10-fold higher than the 
maximum of the intended human dose, and the repeated-dose regimens spanned to 3-fold higher 
than the maximum of the intended human dose. Cynomolgus monkey was the only relevant 
species based on the target sequence homology and binding activity.  
Overall, no apparent toxicity was noted in mice or monkey toxicity studies. No tissue 
cross-reactivity was found in either human or monkey tissues, nor was any effect on cytokine 
release observed in human whole blood assay. Based on the Retrogenix cell microarray 
screening of more than 6400 different proteins, tislelizumab clearly exhibited relatively high 
selective binding to the intended target, PD-1 protein, and had weakly binding to only one 
off-target protein. The toxicokinetic profile was well characterized with dose proportional 
increases in systemic exposure without apparent accumulation or sex difference. 
Immunogenicity was observed without apparent immunotoxicity or effect on the systemic 


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exposure. The no observed adverse effect level of tislelizumab in the 13-week monkey toxicity 
study was considered to be 30 mg/kg. The toxicity profile of tislelizumab is considered adequate 
to support the current study BGB-A317-305.   
Refer to the Tislelizumab Investigator’s Brochure for detailed information regarding toxicology 
studies. 
1.3.3. 
Clinical Pharmacology  
Tislelizumab exhibited a dose-proportional increase in exposure over the entire dose range 
(0.5 to 10 mg/kg) tested in study BGB-A317-001. A population PK analysis was performed 
based on pooled data (PK, dosing information, demographics, and patient or disease 
characteristics) from 2596 patients across 12 clinical studies. The PK of tislelizumab was best 
characterized using a 3-compartmental model with linear clearance mechanism. No time-varying 
clearance was observed in tislelizumab PK. The typical estimates of clearance (CL), central 
volume of distribution (Vc), and peripheral volumes 2 and 3 (V2 and V3, respectively), were 
0.153 L/day, 3.05 L, 1.27 L, and 2.10 L, respectively, with interindividual variability in CL 
(26.3%), Vc (16.7%), V2 (74.7%), and V3 (99.9%). The terminal half-life (t1/2) was estimated to 
be approximately 23.8 days. The accumulation ratios are estimated to be 2.14 and 2.49 for area 
under the serum concentration-time curve at steady state (AUCss) and minimum concentration at 
steady-state (Cmin,ss), respectively. Steady state is expected to be reached in approximately 
12 weeks. 
The population PK analyses demonstrated that race, baseline aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), bilirubin, lactate dehydrogenase, estimated glomerular filtration 
rate, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and sum of products 
of perpendicular diameters of classical Hodgkin lymphoma did not have statistically significant 
influences on tislelizumab PK. Baseline body weight, tumor size of solid tumors, albumin level, 
age, sex, immunogenicity, and tumor type were found to be statistically significant covariates on 
the PK of tislelizumab; however, the exposure changes by these covariates were relatively small 
compared to the overall range estimated for the PK exposures, and hence are not considered 
clinically meaningful. 
1.3.4. 
Prior Clinical Experience of Tislelizumab  
The overall safety experience with tislelizumab, as a monotherapy or in combination with 
chemotherapy, is based on experience in 3220 patients (2173 patients treated with monotherapy 
and 1047 patients treated with chemotherapy) in clinical studies as of the cutoff date 
20 July 2022. 
For more detailed information on the safety and efficacy of tislelizumab when given as 
monotherapy or in combination with chemotherapy, refer to the most recent edition of the 
Tislelizumab Investigator's Brochure. 
1.3.4.1. 
Pooled Safety Assessment of Monotherapy Studies  
A pooled analysis of 7 monotherapy studies was conducted to provide a comprehensive safety 
assessment separate from the combination therapy. Data from patients with solid tumors were 
analyzed separately from patients with hematologic malignancies. 


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Data are available from 1992 patients treated in 7 pooled solid tumor monotherapy studies. The 
median treatment exposure duration was 4.07 months (range: 0.10 to 55.46) and median study 
follow-up duration was 11.65 months (range: 0.07 to 58.91). The median age of these patients 
was 60 years, and 72.1% were men. 
Of the 1992 patients in the solid tumor monotherapy pool, 1925 (96.6%) experienced ≥ 1 TEAE. 
The most commonly occurring TEAEs were Anaemia (25.3%), Aspartate aminotransferase 
increased (18.4%), Alanine aminotransferase increased (17.1%), Decreased appetite (16.7%), 
and Cough (15.3%). Of the 1992 patients, 712 patients (35.7%) experienced at least 1 
treatment-emergent SAE. The most commonly occurring SAEs were Pneumonia (4.8%), 
Pneumonitis (1.4%), Dysphagia (1.2%), Pyrexia (1.1%), and Pleural effusion (1.0%). 
Of the 1992 patients in the solid tumor monotherapy pool, 55 (2.8%) experienced ≥ 1 
infusion-related reaction of any grade. 
Of the 1992 patients in the adjudicated solid tumor group the pooled monotherapy studies, 
312 (16.3%) experienced at least 1 imAE of any grade. The most commonly occurring imAEs of 
any grade were Hypothyroidism (6.3%), Pneumonitis (2.1%), Hyperthyroidism (0.9%), Rash 
(0.9%), Alanine aminotransferase increased (0.7%), and Immune-mediated lung disease (0.7%). 
Within the solid tumor group, imAEs ≥ Grade 3 in severity were reported in 83 patients (4.3%). 
The most commonly occurring ≥ Grade 3 imAEs were Pneumonitis (0.8%), Interstitial lung 
disease (0.4%), Alanine aminotransferase increased (0.4%), Aspartate aminotransferase 
increased (0.3%), and Hepatitis (0.3%). 
For more detailed information on the safety of tislelizumab when given as monotherapy, refer to 
the most recent edition of the Tislelizumab Investigator's Brochure. 
1.3.4.2. 
Efficacy Assessment of Tislelizumab  
Efficacy data from 2 monotherapy studies (BGB-A317_Study_001 and BGB-A317-102) and 
1 combination therapy study (BGB-A317-205) in solid tumors are available and are summarized 
below. 
1.3.4.2.1. Study BGB-A317_Study_001  
Study BGB-A317_Study_001 is a 2-stage study consisting of a Phase 1a dose-escalation 
(0.5-10 mg/kg) and dose-finding component with 3 parts (2 and 5 mg/kg given either once every 
2 or 3 weeks, and a fixed dose of 200 mg given once every 3 weeks) to establish the maximum 
tolerated dose (MTD), if any, a recommended Phase 2 dose (RP2D), and followed by a Phase 1b 
component to investigate efficacy in select tumor types at the RP2D to further evaluate safety 
and tolerability of tislelizumab. Indication specific cohorts included esophageal (EC), gastric 
(GC), hepatocellular (HCC), and non-small cell lung (NSCLC) cancer. 
Responses were assessed by the investigator per the RECIST v1.1 criteria. 
There were 451 patients treated in the study and 441 patients were included in the efficacy 
evaluable set. The Efficacy Evaluable Analysis Set includes all treated patients who had at least 
1 measurable baseline target lesion and had at least 1 evaluable post-baseline tumor assessment. 
This set included 52 patients in the gastric cancer (GC) cohort. 


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Across all disease cohorts, there were 5 patients (1.1%) with a CR. A total of 55 patients (12.5%) 
had a confirmed PR. The resulting overall clinical response rate was 13.6%. Additionally, there 
were 142 patients (32.2%) with a best overall response of stable disease (SD). A total of 
199 patients (45.1%) had a best response of PD in this study. 
Of the 52 patients in the GC cohort, no patients (0%) had a CR. A total of 7 patients (13.5%) had 
a confirmed PR. Additionally, there were 9 patients (17.3%) with a best overall response of 
stable disease (SD). A total of 31 patients (59.6%) had a best response of PD in this cohort, and 
the assessment for 5 patients (9.6%) were missing. 
1.3.4.2.2. Study BGB-A317-102  
Study BGB-A317-102 is a non-randomized, Phase 1/2 study of tislelizumab monotherapy in 
Chinese patients with advanced solid tumors. Phase 1 includes a dose verification substudy and a 
substudy of PK evaluation of the products derived from 2 manufacturing processes and scales.  
Phase 2 evaluates the activity and safety of tislelizumab at its recommended Phase 2 dose of 
200 mg given once every 3 weeks in indication specific expansion cohorts. 
Responses were assessed by the Investigator per the RECIST v1.1 criteria. 
Overall, of the 300 patients treated in Study BGB-A317-102, 249 patients were included in the 
Efficacy Evaluable Analysis Set as of the data cutoff date of 31 May 2020. The Efficacy 
Evaluable Analysis Set includes all treated patients who had at least 1 measurable baseline target 
lesion and had at least 1 evaluable post-baseline tumor assessment. This set included 16 patients 
in the GC cohort. 
The tumor responses in the efficacy evaluable analysis set of Study BGB-A317-102 across all 
disease cohorts and study phases was 1 patient (0.4%) with a CR and 50 patients (20.1%) with 
confirmed PR. The resulting objective response rate was 20.5%. Additionally, there were 
83 patients (33.3%) with a best overall response of stable disease. A total of 115 patients (46.2%) 
had a best response of PD in this study. 
The tumor responses in the Efficacy Evaluable Analysis Set of Study BGB-A317-102 in the GC 
cohort (16 patients) was no patients (0%) had a CR and 4 patients (25.0%) had a confirmed PR. 
Additionally, there were 2 patients (12.5%) with a best overall response of SD. A total of 10 
patients (62.5%) had a best response of PD in this cohort. 
1.3.4.3. 
Safety and Efficacy Assessment of Study BGB-A317-205 (Combination therapy)  
Study BGB-A317-205 is a multi-cohort, Phase 2 study of tislelizumab in combination with 
standard chemotherapy (cisplatin/5-fluorouracil or oxaliplatin/capecitabine) as first-line 
treatment in esophageal squamous cell carcinoma (ESCC) and GC/GEJ conducted in Chinese 
patients. 
As of 31 March 2019, of the 30 patients treated (15 patients each from the ESCC and GC/GEJ 
adenocarcinoma, respectively), 7 (46.7%) patients in each cohort remained on study; 4 patients 
(26.7%) in each cohort were still receiving tislelizumab treatment. In the GC/GEJ 
adenocarcinoma cohort, the median duration was 26.1 weeks (range: 3 to 75 weeks) for 
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All 15 patients (100.0%) treated in GC/GEJ cohort experienced at least 1 TEAE. For the 
GC/GEJ adenocarcinoma cohort, TEAEs reported in at least 30% of patients included aspartate 
aminotransferase increased, asthenia (9 patients each, 60.0%), platelet count decreased 
(8 patients, 53.3%), alanine aminotransferase increased, blood bilirubin increased, nausea, 
vomiting (7 patients each, 46.7%), anaemia, decreased appetite, neutrophil count decreased 
(6 patients each, 40.0%), diarrhoea, hypoalbuminaemia, leukopenia, and pyrexia (5 patients each, 
33.3%).  
Serious TEAEs were reported in 5 patients (33.3%). All these serious TEAEs were considered 
both tislelizumab-related and chemotherapy-related. 
Tislelizumab-related TEAEs were reported for all 15 (100%) patients in the GC/GEJ 
adenocarcinoma cohort. For the GC/GEJ adenocarcinoma cohort, treatment-related TEAEs 
reported in at least 30% of patients included aspartate aminotransferase increased, asthenia 
(9 patients each, 60.0%), platelet count decreased (8 patients, 53.3%), alanine aminotransferase 
increased, blood bilirubin increased, nausea, vomiting (7 patients each, 46.7%), anaemia, 
decreased appetite, neutrophil count decreased (6 patients each, 40.0%), diarrhoea, pyrexia, 
hypoalbuminaemia, and leukopenia (5 patients each, 33.3%). Ten patients (66.7%) experienced a 
severe (≥ Grade 3) tislelizumab-related TEAE. In the GC/GEJ adenocarcinoma cohort, 
10 patients (66.7%) experienced at least 1 TEAE of Grade 3 or 4; all the events were reported for 
single patients by Preferred Term. 
In the GC/GEJ adenocarcinoma cohort, 11 patients (73.3%) experienced at least 1 
immune-mediated TEAE. The most frequently reported categories of immune-mediated TEAE 
were immune-mediated endocrinopathies and immune-mediated hepatitis (4 patients each, 
26.7%), followed by immune-mediated colitis and immune-mediated pneumonitis (3 patients 
each, 20.0%), and other immune-mediated reactions (2 patients, 13.3%). Grade 3 or 4 
immune-mediated TEAEs were reported in 7 patients (46.7%).  
No patient experienced infusion-related reactions due to tislelizumab infusion.  
In the GC/GEJ adenocarcinoma cohort, TEAEs leading to tislelizumab treatment discontinuation 
were reported in 3 patients (20.0%). All TEAEs that led to tislelizumab treatment discontinuation 
were assessed as ≥ Grade 3 and were reported in single patients.  
In the GC/GEJ adenocarcinoma cohort, 6 patients (40.0%) died during the study. Five deaths 
occurred > 30 days after the last dose of study drugs and one death occurred within 30 days of 
receiving the last dose of study drugs. The cause of all deaths was disease progression. 
The Efficacy Evaluable Analysis Set includes all the GC/GEJ patients who have received at least 
1 dose of the study drug, had measurable or evaluable disease at baseline according to RECIST 
v1.1, and had at least 1 post baseline tumor response assessment unless any clinical PD or death 
occurred within 10 weeks after the first dose. The tumor responses in the efficacy evaluable 
analysis set of GC/GEJ patients (13 patients) was no patients (0%) with a CR and 7 patients 
(53.8%) with confirmed PR. Additionally, there were 3 patients (23.1%) with a best overall 
response of SD. Only 1 patient (7.7%) had a best response of PD. 


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1.4. 
Study Rationales  
1.4.1. 
Rationale for Tislelizumab in the Treatment of Gastric Cancer  
Immunotherapeutic approaches with anti-PD-1 have demonstrated clinical efficacy in several 
advanced cancer types, including melanoma (Weber et al 2015), non-small cell lung cancer 
(NSCLC) (Borghaei et al 2015), and renal cell carcinoma (RCC) (Motzer et al 2015) and have 
been approved in the US, Europe, Japan and other countries (Raedler 2015; Kazandjian et al 
2016; Xu et al 2017; News of Nivolumab on AJMC 2014; News of Nivolumab on Targeted 
Oncology 2017).  
Preclinical data indicate that PD-1 targeted therapies may improve antitumor activity and 
increased IFN-gamma production levels as well as increased proportion of PD-1-expressing 
CD4/CD8 tumor-infiltrating T-effector cells (Curran et al 2010). 
In addition, high levels of FcγR-expressing myeloid derived cells (eg, M2 macrophage, MDSC) 
in tumor tissues predict a poor survival of tumor-bearing animals after anti-PD-1 monoclonal 
antibody treatment; this is possibly due to Fc-FcγR-mediated ADCC or antibody-dependent 
cellular phagocytosis (ADCP) depletion of effector T-cells (Gül et al 2015; Prieto et al 2015; 
Makarova-Rusher et al 2015; Beers et al 2016; Dahan et al 2015). As a no-to low-FcγR-binding 
agent (thus causing minimal ADCC/ADCP effect), tislelizumab theoretically may show superior 
efficacy and lower toxicity in GC.  
Available data from clinical trials with other anti-PD-1 monoclonal antibodies, such as 
pembrolizumab and nivolumab, have shown that anti-PD-1 antibodies have both manageable 
safety profile and promising antitumor activity in patients with unresectable GC/GEJ 
(Section 1.2). 
Data for a GC Cohort of tislelizumab treated patients was presented at European Society for 
Medical Oncology (ESMO) in 2017 (Desai et al 2017). As of 8 Jun 2017, 46 patients with 
heavily pretreated GC have been enrolled in BGB-A317_Study_001 Phase 1a/1b totally. A total 
of 34 GC patients were evaluable. Four patients achieved a confirmed PR, and 3 patients 
achieved a best overall response of SD. The disease control rate (DCR) was 21%. Treatment-
related adverse events (TRAEs) occurred in 15 patients. Decreased appetite (n=4, 27%), 
abdominal pain (4, 27%), fatigue (3, 20%) and nausea (n=3, 20%) were the most commonly 
reported TRAEs. The majority of these TRAEs were ≤ Grade 2 in severity. One patient 
experienced proteinuria that was ≥ Grade 3. Treatment with tislelizumab was generally well 
tolerated in pretreated patients with advanced GC. Adverse events reported were consistent with 
the overall safety profile observed in the BGB-A317_Study_001 Phase 1a/1b study, and were 
generally of low severity, manageable and reversible. The preliminary safety profile and 
antitumor activity support continued development of tislelizumab in patients with 
advanced/metastatic GC. 
The BGB-A317-205 Phase 2, single arm study is investigating the safety, pharmacokinetics and 
preliminary antitumor activity of the anti-PD-1 monoclonal antibody tislelizumab in combination 
with chemotherapy as 1L treatment in adults with inoperable, locally advanced or metastatic 
esophageal, gastric, or gastroesophageal junction carcinoma. The first Safety Monitoring 
Committee (SMC) evaluation demonstrated that tislelizumab + oxaliplatin and capecitabine has a 


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manageable safety profile. The safety data summary will be available before the study initiation 
of BGB-A317-305. 
Finally, according to the latest data collected from the Phase 1 study BGB-A317_Study_001, 
tislelizumab monotherapy has established a manageable safety profile, with the most common 
side effects consistent with known class effects of other anti-PD-1 antibodies (Section 1.3.4). 
This is a randomized (1:1), double-blind, placebo-controlled, Phase 3 study of tislelizumab plus 
chemotherapy verses placebo plus chemotherapy as 1L treatment in patients with locally 
advanced unresectable or metastatic gastric or GEJ adenocarcinoma, based on the research 
hypothesis that tislelizumab given in addition to SOC chemotherapy will have superior efficacy 
as demonstrated by PFS and/or OS and acceptable tolerability profile as compared with 
chemotherapy alone and the PD-L1+ patients will be enriched for responsive to tislelizumab plus 
chemotherapy. 
1.4.2. 
Rationale for Selection of Tislelizumab Dose  
The dosage of 200 mg intravenously once every 3 weeks was selected based on safety, efficacy, 
and PK assessments in the first-in-human study BGB A317_Study_001. A wide range of dosages 
were investigated in this study, including 2 mg/kg or 5 mg/kg on schedules of once every 2 
weeks or once every 3 weeks. For the once every 3 weeks schedule, a fixed dose of 200mg was 
also investigated, and was ultimately selected for the following reasons: 
• All dosages tested, including 200 mg once every 3 weeks, were tolerated. The 
maximum tolerated dose was not reached with dosages up to 10 mg/kg once every 2 
weeks. The observed serum concentration after 200 mg dosing was within the range 
seen after 2 mg/kg and 5 mg/kg dosing. 
• Preliminary clinical activity was observed at this dosage. 
• Exposure-response relationships were flat for ORR and safety endpoints across a 
variety of tumor types (data from studies BGB A317_Study_001, BGB A317 102, 
and BGB A317 203). In addition, no clinically significant covariates were identified 
in population PK analysis. 
• Compared with doses based on patient weight, a fixed dose simplifies dose 
administration and reduces the chance of medical errors. 
• Compared with a once every 2 weeks schedule, a once every 3 weeks schedule allows 
for more convenient integration with common chemotherapeutic regimens and 
increases patient convenience. 
1.4.3. 
Rationale for Selection of Chemotherapies  
Platinum compounds and fluoropyrimidines are generally considered as 1L, standard-of-care 
treatment options in metastatic GC and GEJ cancer across geographic regions. In Western 
countries and Asia, the reference chemotherapy regimen for 1L treatment of metastatic gastric 
and GEJ adenocarcinoma is a fluoropyrimidine (5-FU or capecitabine) in combination with a 
platinum agent (cisplatin or oxaliplatin) with or without a third cytotoxic drug (usually epirubicin 
or docetaxel) (Van Cutsem et al 2011).  


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National Comprehensive Cancer Network (NCCN) guideline suggests the 2-drug chemotherapy 
as the preferred regimen in the 1L setting; the 3-drug regimen, due to its toxicity profile, should 
be considered only for use in patients with good performance status. In addition, the triplet 
regimen is not common in Asia due to its high toxicity profile (NCCN guideline v3 2016; 
Japanese gastric cancer treatment guidelines v4 2014).  
The comparator selected in this study is a platinum doublet regimen (ie oxaliplatin plus 
capecitabine and cisplatin plus 5-FU). 
Several Phase 3 studies and meta-analyses, oxaliplatin and capecitabine have both been shown to 
be non-inferior to cisplatin and 5-FU, respectively with a favorable safety profile (Wagner et al 
2010; Al-Batran et al 2008; Cunningham et al 2010).  
Based on these observations, platinum- and fluoropyrimidine-based doublet regimens, 
oxaliplatin + capecitabine and cisplatin + 5-FU (Ajani et al 2017; Kang et al 2009; Dank et al 
2008; Van Cutsem et al 2006) are considered to be reasonable comparators in this Phase 3 study, 
and the investigators can choose either regimen per their local standard. The dose level used in 
this Phase 3 study is also consistent with prevailing clinical practice. 
Maintenance chemotherapy is an evolving concept in medical oncology. The role of maintenance 
therapy has been demonstrated in non–small-cell lung cancer and colorectal cancer (Luis et al 
2013; Aprile et al 2016). Although data are limited, it has been shown that capecitabine 
maintenance may be feasible in treatment of advanced/metastatic GC and GEJ cancer (Eren et al 
2016; Qiu et al 2014). The efficacy and safety of capecitabine as maintenance treatment after 1L 
chemotherapy in GC has been evaluated in 287 Chinese patients who had previously received 6 
cycles of oxaliplatin and capecitabine as 1L chemotherapy, without disease progression but with 
documented Grade 2 or higher neuropathy.  
Overall, 222 patients interrupted the treatment and 64 patients received capecitabine as 
maintenance. The median PFS was 11.4 months (95% CI 10.2-12-2 months) for patients who 
received maintenance therapy versus 7.1 months (95%CI 6.1-8.0 months) for those in the control 
group (p < 0.001). A multivariate analysis showed that the maintenance treatment was an 
independent prognostic factor. Moreover, the safety profile was consistently mild in the phase of 
maintenance treatment (Qiu et al 2014). Capecitabine may be a viable option as maintenance 
treatment of GC and GEJ cancer if no progression occurs after a predefined number of cycles of 
chemotherapy. In the present study, those patients receiving oxaliplatin + capecitabine regimen 
who experience a complete response, partial response, or stable disease have the option to 
continue with capecitabine as maintenance therapy. 
1.5. 
Benefit-Risk Assessment  
Available data from clinical trials of other anti-PD-1 antibodies, such as nivolumab and 
pembrolizumab, have demonstrated favorable efficacy in metastatic or unresectable GC and GEJ 
adenocarcinoma patients previously treated with 2 or more prior chemotherapy regimens. 
Available data has also indicated that combined treatment of chemotherapy and anti-PD-1 
antibodies has a manageable safety profile when administered as 1L therapy in patients with 
advanced gastrointestinal malignancies. 
According to the latest data collected from the Phase 1 studies of BGB-A317_Study_001 and 
BGB-A317-102, tislelizumab has demonstrated a favorable safety profile that is consistent with 


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known class effects. Anti-tumor activity with tislelizumab has been demonstrated in patients 
with esophageal squamous cell carcinoma (ESCC) and GC.  
As noted in Section 1.3.4.3, the incidence and type of treatment-related AEs of patients from 
Phase 2 BGB-A317-205 study were similar to the AEs known to be associated with 
chemotherapy regimens combined with other PD-1 products. Tislelizumab in combination with 
oxaliplatin + capecitabine demonstrated manageable safety profiles. 
Given the unmet medical need and limited treatment options for these patients, the benefit/risk 
assessment of BGB-A317-305 is considered favorable based on available data from tislelizumab 
Phase 1 studies data (BGB-A317_Study_001 and BGB-A317-102), Phase 2 study in GC (BGB-
A317-205), and the primary efficacy by anti-PD-1 antibodies in GC and GEJ adenocarcinoma.    
An Independent Data Monitoring Committee (IDMC) will be established to regularly monitor 
the safety of patients in this study. An interim analysis for OS superiority test is planned in the 
study (Section 9.7).  


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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives  
2.1.1. 
Primary Objective  
• To compare overall survival of tislelizumab plus chemotherapy versus placebo plus 
chemotherapy in the programmed cell death protein ligand-1 positive and intent-to-
treat analysis sets 
2.1.2. 
Secondary Objectives  
• To compare progression-free survival per Response Evaluation Criteria in Solid 
Tumors 1.1 as assessed by investigators of tislelizumab plus chemotherapy versus 
placebo plus chemotherapy in the programmed cell death protein ligand-1 positive 
and intent-to-treat analysis sets  
• To evaluate overall response rate, and duration of response, per Response Evaluation 
Criteria in Solid Tumors 1.1 as assessed by investigators  
• To evaluate European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Gastric Cancer Module QLQ-STO22 Score, European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-
Core 30 Score and European Quality of Life 5-Dimensions 5-Levels Health 
Questionnaire Score 
• To evaluate the safety and tolerability profile of tislelizumab or placebo plus 
chemotherapy 
• To evaluate disease control rate, clinical benefit rate, and time to response per 
Response Evaluation Criteria in Solid Tumors 1.1 as assessed by investigators  
2.1.3. 
Exploratory Objectives  
• To evaluate progression-free survival after next line of treatment (PFS2)  
• To characterize the pharmacokinetics of tislelizumab  
• To determine host immunogenicity to tislelizumab  
• To assess predictive, prognostic, exploratory biomarkers including but not limited to 
programmed cell death protein ligand-1 (PD-L1) expression, Epstein-Barr virus 
(EBV) infection, microsatellite instability-high (MSI-H) or mismatch repair deficient 
(dMMR) status, genomically stable (GS) or chromosomal instability (CIN), 
immune-related gene expression profiling, tumor infiltrated lymphocytes (TILs) and 
tumor mutation burden in tumor tissues and/or blood samples and the association with 
response to study treatment, mechanisms of resistance, and/or disease status 


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2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoint  
• Overall survival – defined as the time from the date of randomization to the date of 
death due to any cause 
2.2.2. 
Secondary Endpoints  
• Progression-free survival as assessed by investigators – defined as the time from the 
date of randomization to the date of the first objectively documented tumor 
progression, assessed by investigators per Response Evaluation Criteria in Solid 
Tumors v1.1, or death, whichever occurs first 
• Overall response rate as assessed by investigators – defined as the proportion of 
patients whose best overall response is complete response or partial response per 
Response Evaluation Criteria in Solid Tumors v1.1  
• Duration of response (DOR) as assessed by investigators – defined as the time from 
the first determination of an objective response per Response Evaluation Criteria in 
Solid Tumors v1.1, until the first documentation of progression or death, whichever 
occurs first  
• Change from baseline in European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Gastric Cancer Module QLQ-STO22 Score and 
change from baseline in European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-Core 30 Score and European Quality of Life 5-
Dimensions 5-Levels Health Questionnaire Score 
• The incidence and severity of adverse events according to National Cancer Institute 
Common Terminology Criteria for Adverse Events v5.0 
• Disease control rate (ie, proportion of complete response + partial response + stable 
disease), clinical benefit rate (ie, proportion of complete response + partial response + 
durable stable disease), and time to response (ie, time from randomization to the first 
determination of an objective response) per Response Evaluation Criteria in Solid 
Tumors 1.1 as assessed by investigators  
2.2.3. 
Exploratory Endpoints  
• Progression-free survival after next line of treatment (PFS2) – defined as the time 
from randomization to the objective disease progression after next line of treatment, 
or death from any cause, whichever occurs first  
• Summary of serum concentration of tislelizumab 
• Assessments of immunogenicity of tislelizumab by determining the incidence of 
antidrug antibodies (ADAs) 
• Status of programmed cell death protein ligand-1 (PD-L1) expression, immune or 
gastric-related, and other exploratory biomarkers including but not limited to Epstein-
Barr virus (EBV) infection, microsatellite instability-high (MSI-H) or mismatch 


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repair deficient (dMMR), genomically stable (GS) or chromosomal instability (CIN), 
immune-related gene expression profiling, tumor infiltrated lymphocytes (TILs) and 
tumor mutation burden in tumor tissues and/or blood samples obtained before 
treatment with tislelizumab and/or at progression, and the association with disease 
status and/or response to tislelizumab in combination with chemotherapy or 
chemotherapy alone 


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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is a randomized (1:1), double-blind, placebo-controlled, Phase 3 study of tislelizumab plus 
platinum and fluoropyrimidine versus placebo plus platinum and fluoropyrimidine in patients 
with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Patients must 
have not received previous systemic therapy for locally advanced unresectable or metastatic 
gastric/GEJ cancer. All patients are also required to have ≥ 1 measurable or non-measurable 
lesion per RECIST v1.1, an ECOG PS score of ≤ 1, and adequate organ function. 
The study procedures will occur over a Screening Phase (up to 28 days); Treatment Phase (until 
the investigator determines that study drugs will no longer be used); Safety Follow-up Phase 
(30 days [± 7 days] after the last dose of study drugs, or before the initiation of a new anticancer 
treatment, whichever occurs first); and a Survival Follow-up Phase (continuing until death, loss 
to follow-up, withdrawal of consent, or study termination by sponsor). 
In addition, immune-mediated adverse events (imAEs) will be recorded up to 90 days after the 
last dose of tislelizumab or placebo, regardless of whether or not the patient starts a new 
anticancer therapy. 
The study design schematic is presented in Figure 1.


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Figure 1: 
Study Schema  
Initial up to 6 Treatment 
Cycles 
Cycle 7 and Beyond* 
Locally advanced 
unresectable or 
metastatic gastric or 
GEJ adenocarcinoma 
(N=980) 
 
Stratification: 
• Regions: China 
(including Taiwan) 
vs. Japan and 
S.Korea vs. US and 
Europe and other 
regions 
• PD-L1 expression 
(positive or negative) 
• Presence of 
peritoneal metastasis 
(yes or no) 
• Investigator’s choice 
of chemotherapy 
Arm A 
Tislelizumaba +Chemotherapy 
• Tislelizumab 200 mg IV, 
Day 1, every 3 weeks 
• Chemotherapy Backbone 
Regimen (investigator’s 
choice):  
o
Oxaliplatin + 
Capecitabine : 
–
Oxaliplatin 130 mg/m² 
IV, Day 1, AND 
Capecitabine 1000 
mg/m2 orally twice daily 
for consecutive 14 days, 
repeated every 3 weeks 
Or 
o
Cisplatin + 5-FU : 
–
Cisplatin 80 mg/m² IV, 
Day 1, AND 5-FU 
800 mg/m2/day IV 
continuous infusion over 
24 hours daily on 
Day 1-5, repeated every 
3 weeks 
Arm B 
Placebo + Chemotherapyb 
Chemotherapy is the same with that 
presented on Arm A 
Tislelizumab 
200 mg IV Day1 
every 3 weeks  
+ Capecitabine 
1000 mg/m2 
orally twice daily 
for consecutive 
14 days, repeat 
every 3 weeks 
Placebo 
+ 
Capecitabine 
1000 mg/m2 orally 
twice daily for 
consecutive 
14 days, repeat 
every 3 weeks 
Continuec until: 
 
• Disease 
progression 
• Intolerable 
toxicity or 
withdrawal of 
consent or 
another treatment 
discontinuation 
criterion is met 
Follow 
Up 


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* Capecitabine as maintenance therapy is optional and only for oxaliplatin + capecitabine regimen  
Abbreviations: GEJ, gastroesophageal junction; IV, intravenously; 5-FU, 5-fluorouracil; vs, versus 
a. 
The initial infusion (Cycle 1, Day 1) will be administered over a period of 60 minutes. If this infusion is well tolerated, subsequent infusions may be 
administered over 30 minutes. After tislelizumab or placebo infusion, patients will be further monitored for a period of 1 hour during Cycles 1 and 2. 
From Cycle 3 onward, a post-infusion monitoring period of at least 30 minutes will be required. 
b. The oxaliplatin + capecitabine or cisplatin + 5-FU doublet regimen is administered up to 6 cycles, capecitabine as optional maintenance therapy only for 
oxaliplatin + capecitabine regimen may be administered until disease progression, intolerable toxicity, withdrawal of consent, or another treatment 
discontinuation criterion is met. Tislelizumab (or placebo) will be administered until disease progression, intolerable toxicity, withdrawal of consent, or 
another treatment discontinuation criterion is met. 
c. 
Treatment beyond initial investigator-assessed RECIST v1.1 defined progression will be permitted provided that the patient has investigator-assessed 
clinical benefit and is tolerating the study drug. The following criteria must be met to treat patients after initial evidence of radiological disease 
progression: absence of clinical symptoms and signs of disease progression; stable ECOG PS ≤ 1; absence of rapid progression of disease or progressive 
tumor at critical anatomical sites that require urgent alternative medical intervention; and additional written informed consent. The medical monitor 
must agree, in writing, with the investigator’s decision to continue study drugs beyond initial investigator-assessed progression, and the decision must be 
documented in the study records.  
For all study procedures see Section 7 and Appendix 1. 
 


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3.2. 
Screening Period  
Screening evaluations will be performed within 28 days prior to randomization. Patients who 
agree to participate in this study will sign the informed consent form (ICF) prior to undergoing 
any study-specific screening procedure. Patients who are suspected to have serious respiratory 
concurrent illness or exhibit significant respiratory symptoms unrelated to underlying cancer will 
also take a pulmonary function test (refer to Section 7.1 and Appendix 1 for details). Screening 
evaluations may be repeated as needed within the screening period; the investigator is to assess 
preliminary patient eligibility according to the latest screening assessment results. 
Tumor tissues must be collected for the purpose of PD-L1 assessment and other biomarker 
analyses. A fresh biopsy sample is highly preferred if feasible in clinic. If no archival samples 
are available, a fresh tumor biopsy at baseline is mandatorily required. For patients with 
unavailable MSI/MMR status, an MSI or MMR assessment will be performed in investigational 
sites, third-party local lab or designated central laboratory. For MMR testing, 5 formalin-fixed 
paraffin-embedded [FFPE] slides required; for MSI testing, 5 FFPE slides and approximately 
2 mL blood samples will be collected. Patients with unknown HER2 status must undergo an 
HER2 test at the investigational sites, third-party local lab or designated central laboratory prior 
to enrollment. Refer to Section 7.7 for details. 
3.3. 
Treatment Period  
After completing all screening activities, patients confirmed to be eligible by the investigator will 
be randomized in a 1:1 ratio to receive either tislelizumab or placebo plus chemotherapy 
treatment. The choice of chemotherapy regimen must be decided prior to randomization and the 
interchange of chemotherapy regimen is not permitted during the study period. 
At randomization, patient enrollment will be stratified by the following factors: 
• Regions of enrollment: China (including Taiwan) vs. Japan and S. Korea vs. US and 
Europe and other regions. NOTE: other regions include other western 
countries/populations. 
• PD-L1 expression (positive or negative): PD-L1+ patients are patients with tumor and 
immune cell score (TIC score) ≥ 5% using VENTANA PD-L1 (SP263) Cdx Assay*. 
TIC score is the total percentage of the tumor area covered by tumor cells with PD-L1 
membrane staining and tumor-associated immune cells with PD-L1 staining at any 
intensity. 
*During enrollment, the proportion of patients of multiple PD-L1 expression 
levels will be monitored. Hence, study assumptions (see Section 9.6) could be 
adjusted accordingly if it is deemed appropriate.  
• Presence of peritoneal metastasis (yes or no) 
• Investigator’s choice of chemotherapy (oxaliplatin + capecitabine versus cisplatin + 
5-FU) 
After randomization, patients will be treated on the following arms. Cross-over between the 
treatment arms will not be allowed.   


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• Arm A: Tislelizumab 200 mg intravenously Q3W + chemotherapy  
• Arm B: Placebo intravenously Q3W + chemotherapy 
Oxaliplatin + capecitabine or cisplatin + 5-FU regimens are used as the backbone chemotherapy. 
The chemotherapy backbone regimen needs to be decided on an individual patient basis before 
randomization. There is no switching between regimens throughout the entire course of the 
study. 
Oxaliplatin + 
Capecitabine 
 
Day 1: Oxaliplatin 130 mg/m² intravenously 
Day 1 (evening) – Day 15 (morning) or Day 1 (morning) – Day 14 
(evening): Capecitabine 1000 mg/m2 orally twice daily 
Every 3 weeks as a cycle 
Cisplatin + 5-FU 
 
Day 1: Cisplatin 80mg/m² intravenously 
Days 1–5: 5-FU 800mg/m2/day intravenously continuous infusion 
over 24 hours daily 
Every 3 weeks as a cycle 
The oxaliplatin + capecitabine or cisplatin + 5-FU doublet regimen is administered up to 6 
cycles. Capecitabine as maintenance therapy is optional only for the oxaliplatin + capecitabine 
regimen and may be administered until disease progression, intolerable toxicity, withdrawal of 
consent, or another treatment discontinuation criterion is met (whichever occurs first; see 
Section 3.6.1). Tislelizumab (or placebo) will be administered until disease progression, 
intolerable toxicity, withdrawal of consent, or another treatment discontinuation criterion is met 
(whichever occurs first; see Section 3.6.1).  
In both arms, treatment beyond the initial investigator-assessed RECIST v1.1-defined 
progression is permitted provided that the patient has investigator-assessed clinical benefit and is 
tolerating study drug. 
Specific requirements for post-progression continuation of patients treated with tislelizumab or 
placebo and capecitabine are described in Section 3.6.1. 
Radiological assessment of tumor-response status will be performed approximately every 
6 weeks (± 7 days) for the first 48 weeks and every 9 weeks (± 7 days) after 48 weeks based on 
RECIST v1.1 from randomization. Tumor response will be assessed by investigators. Details are 
provided in Section 7.5. 
Safety will be assessed throughout the study by monitoring AEs/SAEs (toxicity grades assigned 
per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] 
v5.0), and laboratory results. Vital signs, physical examinations, ECOG PS change, 
electrocardiogram (ECG) results, and other examinations will also be used for safety assessment. 
Safety assessments are further detailed in Section 7.4 and the Schedule of Assessments 
(Appendix 1). 
When a patient reaches 2 years of treatment (as measured from Cycle 1 Day 1): 
• Patients may continue on study therapy beyond 2 years if the investigator considers 
this to be in the best interest of the patient based on an assessment of clinical benefit 


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and potential risks. Continuation of study therapy beyond 2 years must be explicitly 
approved by the sponsor and will be contingent on the continued availability of 
tislelizumab. The study assessment and procedure schedule will remain the same. 
• Patients with confirmed CR, PR, or SD may stop treatment after 2 years if the patient 
wishes. The decision should be based on the investigator’s evaluation, with the 
patient’s clinical benefit and risk taken into consideration. The investigator should 
notify the sponsor that treatment will be stopped prior to stopping the treatment. In 
these cases, the study assessments and procedures will be performed every 12 weeks 
(in conjunction with repeat radiographic imaging, as described in Section 7.5) rather 
than every cycle. If new information becomes available indicating the patient should 
restart treatment, the patient must sign a new ICF, meet (continued) treatment 
eligibility, and the investigator must receive approval before the patient can restart 
treatment. 
− If a patient has evidence of PD within 1 year of treatment interruption, the 
investigator can consider restarting tislelizumab therapy after discussion with the 
sponsor, contingent on the continued availability of tislelizumab. 
Optional blood samples of approximately 10 mL will be taken at baseline (predose at Day 1 of 
Cycle 1), at the time of first tumor response (predose at Day1 of the following Cycle) and at end 
of treatment (EOT) after disease progression (10 mL each timepoint) for all randomized patients 
to explore the association of blood-based biomarkers with response, prognosis and resistance to 
tislelizumab in combination with chemotherapy or chemotherapy alone. Written informed 
consent is required for blood sample collections.  
3.4. 
Safety Follow-up  
Patients who discontinue treatment for any reason will be asked to return to the clinic for the 
Safety Follow-up Visit (to occur on 30 days [± 7 days] after the last dose of study drugs, or 
before the initiation of a new anticancer treatment, whichever occurs first). (N.B. a patient may 
unintentionally miss the Safety Follow-up Visit window if the decision of discontinuation is 
made more than 30 days [± 7days] after the actual last dose date. In this scenario, it will not be 
regarded as a protocol deviation and the EOT visit can be used as Safety Follow-up.) 
In addition, telephone contacts with patients should be conducted to assess imAEs and 
concomitant medications (if appropriate, ie, associated with an imAE or is a new anticancer 
therapy) at 60 days (± 14 days) and 90 days (± 14 days) after the last dose of tislelizumab or 
placebo, regardless of whether or not the patient starts a new anticancer therapy. If patients 
report a suspected imAE at a telephone follow-up contact, the investigator should arrange an 
unscheduled visit if further assessment is indicated.  
All adverse events, including SAEs, will be collected as described in Section 8.6.   
The EOT visit at which a response assessment showed progressive disease, resulting in patient 
discontinuation, may be used as the Safety Follow-up visit, provided that it occurred 
approximately 30 days (± 7 days) after the last study treatment. Patients who discontinue study 
treatment prior to disease progression will have their tumors assessed as outlined in Section 7.5. 
See Appendix 1 for assessments to be performed at the Safety Follow-up Visit. 


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3.5. 
Survival Follow-up  
Patients who discontinue study drug for reasons other than disease progression (eg, toxicity) will 
continue to undergo tumor assessments according to Section 7.5 and the Schedule of 
Assessments (Appendix 1) until the patient experiences disease progression, withdraws consent, 
loss to follow-up, death, or until the study terminates, whichever occurs first.  
Patients will be followed for survival and to obtain information on subsequent anticancer therapy 
after discontinuation of study treatment via telephone calls, patient medical records, and/or clinic 
visits approximately every 3 months (± 14 days) after the EOT/Safety Follow-up visit or as 
directed by the sponsor until death, loss to follow-up, withdrawal of consent, or the end of the 
study (see Section 3.6.5). 
3.6. 
Patient, Treatment, Study, and Site Discontinuation  
Patients who discontinue study treatment early should be followed for assessments of antitumor 
activity (Section 7.5), safety (Section 7.4) and survival (Section 3.5), if possible. 
3.6.1. 
Discontinuation from Study Treatment  
Patients have the right to voluntarily withdraw from the study or discontinue study treatment at 
any time for any reason. In addition, the investigator has the right to discontinue a patient from 
the study treatment at any time. Patients who discontinue study treatment early should be 
followed for assessments of antitumor activity, safety, and survival, if possible. 
Every effort should be made to obtain information on patients who discontinue the study 
treatment. The primary reason for discontinuation from the study treatment should be 
documented on the appropriate electronic case report form (eCRF).  
Patients may discontinue study treatment for reasons which may include, but are not limited to, 
the following:  
• Patient withdrawal of consent 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety, if he or she were to continue the study treatment 
• Use of any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese herbal 
medicine and Chinese patent medicines] for the treatment of cancer) 
• Patient noncompliance. Investigative site staff should first counsel patients who are 
significantly noncompliant (eg, missing 2 treatment cycles) on the importance of 
study drug compliance and drug accountability. The investigator may, in consultation 
with the medical monitor, discontinue patients from treatment who are consistently 
noncompliant. 
Patients in both treatment arms will be permitted to continue study drugs beyond initial 
investigator-assessed RECIST v1.1-defined progression provided that the patient has 


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investigator-assessed clinical benefit and is tolerating study drug. The following criteria must be 
met to treat patients after initial evidence of radiological disease progression: 
• Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening of laboratory values)  
• Stable ECOG PS ≤ 1 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, spinal cord compression) that requires urgent alternative medical 
intervention 
• The investigator must obtain written informed consent for treatment beyond 
radiologic disease progression and inform patients that this practice is not considered 
standard in the treatment of cancer. Patients must be informed that by continuing 
treatment beyond progression they may be forgoing other treatment that has shown 
benefit.  
• The medical monitor must agree, in writing, with the investigator’s decision to 
continue study drugs beyond initial investigator-assessed progression, and the 
decision must be documented in the study records. 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient)  
Patients may discontinue study for reasons which include, but are not limited to, the following:  
• Patient withdrawal of consent 
• Death 
• Lost to follow-up 
3.6.3. 
Withdrawal of Consent  
Patients who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
patient specifically withdraws consent for any further contact with him/her or persons previously 
authorized by patient to provide this information. Patients should notify the investigator of the 
decision to withdraw consent from future follow-up verbally or in writing. The withdrawal of 
consent should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is from further treatment with study drug only or also from study procedures and/or 
post treatment study follow-up and entered on the appropriate CRF page. In the event that 
survival status (whether the patient is alive or dead) is being measured, publicly available 
information should be used to determine survival status only as appropriately directed in 
accordance with local law. 
3.6.4. 
Lost to Follow-Up  
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status. This includes follow-up with persons authorized by the patient as noted above. Lost to 
follow-up is defined by the inability to reach the patient after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by patient to one registered mail letter. 


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All attempts should be documented in the patient’s medical records. If it is determined that the 
patient has died, the site will use permissible local methods to obtain the date and cause of death. 
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the patient’s informed consent, then the investigator may use a sponsor-
retained third-party representative to assist site staff with obtaining patient’s contact information 
or other public survival status data necessary to complete the follow-up portion of the study. The 
site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. If the patient’s survival 
status is determined, the survival status will be documented, and the patient will not be 
considered lost to follow-up. If after all attempts, the patient remains lost to follow-up, then the 
last known alive date as determined by the investigator should be reported and documented in 
the patient’s medical records. 
3.6.5. 
End of Study  
The end of the study is defined as the timepoint when the final data point is collected from the 
last patient in the study. The primary analyses will be conducted when the predefined death 
events have been observed (see Section 9.2.1) for the efficacy and safety evaluation. The study 
will continue until the last patient dies, is lost to follow-up, or withdraws consent.  
The sponsor has the right to terminate this study at any time. Reasons for early terminating the 
study may include but are not limited to the following:  
• The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients  
• Overall patient enrollment is unsatisfactory 
• A rollover study becomes available 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients should be seen as soon as possible for an EOT 
visit/Safety Follow-up Visit.  
At the end of study, any patients who, in the opinion of the investigator, continues to benefit 
from tislelizumab will be offered the option to continue treatment in a company-sponsored 
rollover study until it is commercially available or post-study drug supply program in the country 
of the patient’s residence. 
The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigators will 
be responsible for informing Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) of the early termination of the study.  
The sponsor has the right to close a site at any time. The decision will be notified to the site in 
advance. Reasons for closing a site may include but are not limited to the following:  
• Excessively slow recruitment  
• Poor protocol adherence  
• Inaccurate or incomplete data recording  


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• Good Clinical Practice (GCP) noncompliance 
• Study activity is completed (ie, all patients have completed, and all obligations have 
been fulfilled) 


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4. 
STUDY POPULATION  
The specific eligibility criteria for selection of patients are provided in Section 4.1 and Section 
4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all of the following criteria: 
1. Able to provide written informed consent and can understand and comply with the 
requirements of the study 
2. Adult patients (≥ 18 years of age or acceptable age according to local regulations, 
whichever is older) at the time of voluntarily signing informed consent  
3. Locally advanced unresectable or metastatic GC or GEJ carcinoma and have 
histologically confirmed adenocarcinoma 
4. At least 1 measurable or non-measurable lesion per RECIST v1.1 as determined by 
investigator assessment. 
5. No previous systemic therapy for locally advanced unresectable or metastatic gastric/GEJ 
cancer. NOTE: Patients may have received prior neoadjuvant or adjuvant therapy as long 
as it was completed and have no recurrence or disease progression for at least 6 months. 
6. Patients must be able to provide tumor tissues (FFPE blocks or approximately 15 [≥ 7 if 
MSI/MMR and HER2 results are available] freshly cut unstained FFPE slides) with an 
associated pathological report. A fresh biopsy sample is highly preferred if feasible in 
clinic. If no archival samples are available, a fresh tumor biopsy at baseline is 
mandatorily required and slides requirement is the same with that in archival tumor 
tissues. PD-L1 expression will be assessed centrally, and patients who have evaluable 
PD-L1 results are eligible. 
7. ECOG PS ≤ 1 within 7 days prior to randomization 
8. Adequate organ function as indicated by the following laboratory values ≤ 7 days prior to 
randomization: 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin 
≥ 90 g/L. NOTE: Patients must not have required a blood transfusion or growth factor 
support ≤ 14 days before sample collection 
b. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated Glomerular 
Filtration Rate ≥ 60 mL/min/1.73 m2. (Appendix 8) 
c. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN 
d. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients 
with Gilberts syndrome) 
e. International normalized ratio (INR) or prothrombin time (PT) (or prothrombin time 
ratio) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy and PT values are 
within the intended therapeutic range of the anticoagulant 
f. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN 
g. Albumin ≥ 3.0 g/dL or 30 g/liter 


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9. Patients with inactive/asymptomatic carrier, chronic, or active HBV infection must meet 
the following criteria: HBV deoxyribonucleic acid (DNA) < 500 IU/mL (or 
2500 copies/mL) at screening. Patients with cured hepatitis C virus (HCV) infection at 
screening can be enrolled. 
 
 
Eligible 
HBV 
HB sAg (-) 
HB sAg (+) and 
HBV DNA < 500 IU/mL (or 2500 copies/mL) 
HCV 
HCV Ab (-) 
 
HCV Ab (+) and HCV RNA (-) 
10. Females of childbearing potential must have a negative urine or serum pregnancy test 
within 7 days of randomization and must be willing to use a highly effective method of 
birth control (Appendix 9) for the duration of the study, and ≥ 120 days after the last dose 
of tislelizumab or placebo and 180 days after the last dose of chemotherapy. 
11. Non-sterile males must be willing to use a highly effective method of birth control 
(Appendix 9) for the duration of the study and for ≥ 120 days after the last dose of 
tislelizumab or placebo and 180 days after the last dose of chemotherapy. 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria must be excluded from this study: 
1. Patient has squamous cell or undifferentiated or other histological type GC 
2. Active leptomeningeal disease or uncontrolled brain metastasis. Patients with equivocal 
findings or with confirmed brain metastases are eligible for enrollment provided that they 
are asymptomatic and radiologically stable without the need for corticosteroid treatment 
for ≥ 4 weeks before randomization.  
3. Active autoimmune diseases or history of autoimmune diseases that may relapse 
(Appendix 5).   
NOTE: Patients with the following diseases are not excluded and may proceed to further 
screening:  
a. Controlled Type I diabetes 
b. Hypothyroidism (provided it is managed with hormone replacement therapy only) 
c. Controlled celiac disease 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
4. Any active malignancy ≤ 2 years before randomization, with the exception of the specific 
cancer under investigation in this study and any locally recurring cancer that has been 


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treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder 
cancer, carcinoma in situ of the cervix or breast).  
5. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (at least once a week) and/or diuretics within 7 days prior to randomization (the 
cytological confirmation of any effusion is permitted). 
6. Have clinically significant bleeding (CTCAE ≥ Grade 2) from the gastrointestinal (GI) 
tract within 1 month prior to randomization  
7. Have a history of ≥ Grade 2 (CTCAE) GI perforation and/or fistulae (including prior 
gastric fistula operation) within 6 months prior to randomization 
8. Have a clinically significant bowel obstruction (CTCAE ≥ Grade 2) 
9. Diagnosed with gastric or GEJ adenocarcinoma with positive HER2 
10. Any condition that requires systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
randomization 
NOTE: Patients who are currently or have previously been on any of the following 
steroid regimens are not excluded: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)  
b. Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with minimal 
systemic absorption 
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast 
dye allergy or antiemetic therapy for specific chemotherapy) or for the treatment of a 
non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by 
contact allergen) 
11. With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled 
systemic diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung 
diseases, etc. 
NOTE: Patients with radiation pneumonitis may be randomized if the radiation 
pneumonitis has been confirmed as stable (beyond acute phase) without any concerns 
about recurrence. Patients with severe but stable radiation-induced pneumonitis may be 
required to undergo routine pulmonary function studies   
12. With severe chronic or active infections requiring systemic antibacterial, antifungal or 
antiviral therapy, including tuberculosis infection, etc. 
13. A known history of HIV infection 
14. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days before randomization  
b. Symptomatic pulmonary embolism ≤ 28 days before randomization 
c. Any history of acute myocardial infarction ≤ 6 months before randomization 
d. Any history of heart failure meeting New York Heart Association Classification III or 
IV (Appendix 6) ≤ 6 months before randomization 


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e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
randomization  
f. Any history of cerebrovascular accident ≤ 6 months before randomization 
15. Patients with weight loss ≥ 20% within 2 months prior to randomization and/or CTCAE 
≥ Grade 2 anorexia within 7 days prior to randomization  
16. Within 28 days or 5 half-lives (whichever is shorter but at least 14 days) prior to 
randomization: any immunotherapy (eg, interleukin, interferon, thymoxin, etc) or any 
investigational therapies; Within 28 days prior to randomization for investigational 
devices. 
17. Within 14 days prior to randomization: any Chinese herbal medicine or Chinese patent 
medicines used to control cancer or boost immunity  
18. Palliative radiation treatment within 14 days prior to randomization 
19. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways 
20. Have undergone major surgery within 28 days prior to randomization, except if the 
procedure is minimally invasive (for example, introduction of peripherally inserted 
central catheter [PICC]) 
21. Prior allogeneic stem cell transplantation or organ transplantation 
22. A history of severe hypersensitivity reactions to other monoclonal antibodies or any 
components of study treatment 
23. Known dihydropyrimidine dehydrogenase (DPD) deficiency 
24. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered 
to baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, 
specific laboratory abnormalities) 
25. Administered a live vaccine within 4 weeks before randomization. 
NOTE: Seasonal vaccines for influenza are generally inactivated vaccines and are 
allowed. Intranasal vaccines are live vaccines and are not allowed. 
26. Underlying medical conditions or alcohol or drug abuse or dependence that, in the 
investigator’s opinion, will be unfavorable for the administration of study drug or affect 
the explanation of drug toxicity or adverse events; or insufficient compliance during the 
study according to investigator’s judgement.  
27. Have an estimated life expectancy < 3 months, in the judgment of the investigator. 


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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Tislelizumab and Placebo  
5.1.1.1. 
Tislelizumab  
Tislelizumab is a monoclonal antibody formulated for intravenous infusion in a single-use vial 
(20R glass, United States Pharmacopeia [USP] Type I), containing a total of 100 mg of antibody 
in 10 mL of isotonic solution. Tislelizumab has been aseptically filled in single-use vials with a 
rubber stopper and capped by an aluminum flip-off seal cap. Each vial is packaged into a single 
carton box.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature and light conditions as specified on the label and 
in the Pharmacy Manual.  
Refer to the Pharmacy Manual for details regarding reconstitution, intravenous administration, 
accountability, and disposal. Refer to the Tislelizumab Investigator’s Brochure for other details 
regarding tislelizumab. 
5.1.1.2. 
Placebo  
Placebo is a sterile, preservative-free solution for infusion formulated in the same buffer as 
tislelizumab. All excipients used for the manufacture of placebo are of pharmacopeial grade. No 
animal-derived components are used in the manufacture of placebo. Each vial is packaged into a 
single carton box. 
As with tislelizumab, the contents of the label will be in accordance with all applicable local 
regulatory requirements. 
The study drug must be kept at the temperature and light conditions as specified on the label and 
in the Pharmacy Manual.  
Refer to the Pharmacy Manual for details regarding reconstitution, intravenous administration, 
accountability, and disposal.   
5.1.2. 
Chemotherapy  
Management (ie, handling, storage, administration, and disposal) of cisplatin, 5-FU, capecitabine 
and oxaliplatin will be in accordance with relevant local guidelines and/or prescribing 
information. For sites where the sponsor is required to provide all study drugs including standard 
of care drugs: cisplatin, 5-FU, capecitabine, and oxaliplatin will either be supplied or reimbursed 
by the sponsor or designee. 
For further details, see the manufacturer’s prescribing information for the respective 
chemotherapies. 


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5.2. 
Dosage, Administration, and Compliance  
Dosing schedules for tislelizumab or placebo and chemotherapy are provided in Table 4 and 
Table 5. All patients will be monitored continuously for AEs. Treatment modifications (eg, dose 
delay, reduction, interruption, or discontinuation) will be based on specific laboratory and 
adverse event criteria, as described in Section 5.5. 
Abbreviations: IV, intravenous. 
a. 
These products may be obtained by the investigational sites as local commercial products in certain countries 
if allowed by local regulations. These products should be prepared/stored/administered in accordance with the 
package inserts or summaries of product characteristics (SmPCs) or Pharmacy Manual. 
b. Reduction of tislelizumab infusion time from 60 minutes to 30 minutes is based on the 60-minute infusion 
time being well tolerated.  
 
Table 4: 
Selection and Timing of Dose Administration of Tislelizumab or Placebo in 
Combination with Oxaliplatin and Capecitabine        
Order of 
Administration 
on Day 1 
Study Druga 
Dose (Route) 
Initial 6 Treatment Cyclesb 
Cycle 7 and 
Beyond 
First 
Tislelizumab 
or placebo 
200 mg (IV) 
Day 1 of each 21-day cycle: 
Cycle 1: infuse over 
60 minutes (wait 1 hour before 
chemotherapy) 
Cycles 2 to 6: infuse over 
30 minutes (wait 1 hour before 
chemotherapy at cycle 2 and 
thereafter wait 30 minutes 
before chemotherapy) 
Day 1 of each 
21-day cycle, 
infusion over 
30 minutes (wait 
30 minutes before 
chemotherapy, if 
applicable) 
Second 
Oxaliplatin 
130 mg/m
2 
(IV) 
Day 1 of each 21-day cycle 
Discontinue 
treatment 
Third 
Capecitabine 
1000 mg/m
2 
(Oral) 
Twice daily, from the morning 
of Day 1 to the evening of Day 
14 OR from the evening of 
Day 1 to the morning of Day 
15 of each 21-day cycle  
Twice daily, from 
the morning of 
Day 1 to the 
evening of 
Day 14 OR from 
the evening of 
Day 1 to the 
morning of 
Day 15 during 
each 21-day cycle 
(Optional) 


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Table 5: 
Selection and Timing of Dose Administration of Tislelizumab or Placebo in 
Combination with Cisplatin and 5-FU        
Order of 
Administration on 
Day 1 
Study 
Druga 
Dose (Route) 
Initial 6 Treatment Cyclesb 
Cycle 7 and 
Beyond 
First 
Tislelizumab 
or placebo 
200 mg (IV) 
Day 1 of each 21-day cycle: 
Cycle 1: infuse over 
60 minutes (wait 1 hour 
before chemotherapy) 
Cycles 2 to 6: infuse over 
30 minutes (wait 1 hour 
before chemotherapy at cycle 
2 and thereafter wait 
30 minutes before 
chemotherapy) 
Day 1 of each 
21-day cycle, 
infusion over 
30 minutes  
Second 
Cisplatin 
80 mg/m² (IV) 
Day 1 of each 21-day cycle 
Discontinue 
treatment 
Third 
5-FU 
800 mg/m
2/day
  
(IV, using 
continuous 
pumping 
system) 
Day 1 through Day 5 of each 
21-day cycle  
Discontinue 
treatment 
Abbreviations: 5-FU, 5-fluorouracil; IV, intravenous. 
a. 
These products may be obtained by the investigational sites as local commercial products in certain countries 
if allowed by local regulations. These products should be prepared/stored/administered in accordance with the 
package inserts or summaries of product characteristics (SmPCs) or Pharmacy Manual. 
b. Reduction of tislelizumab infusion time from 60 minutes to 30 minutes is based on the 60-minute infusion 
time being well tolerated in previous cycles. 
5.2.1. 
Tislelizumab or Placebo  
Tislelizumab or placebo will be administered on Day 1 of each 21-day cycle (once every 
3 weeks).  
Tislelizumab or placebo will be administered by intravenous infusion through an intravenous line 
containing a sterile, nonpyrogenic, low-protein-binding 0.2- or 0.22-micron in-line or add-on 
filter. Specific instructions for product preparation, storage, and administration are provided in 
the Pharmacy Manual. 
As a routine precaution, after infusion of tislelizumab or placebo on Day 1 of Cycle 1 and Cycle 
2, patients must be monitored for at least 1 hour afterwards in an area with resuscitation 
equipment and emergency agents before chemotherapy. From Cycle 3 onward, at least a 
30-minute monitoring period is required in an area with resuscitation equipment and emergency 
agents before chemotherapy. 
The initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes; if this is well tolerated, 
then the subsequent infusions may be administered over 30 minutes, which is the shortest time 


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period permissible for infusion. Tislelizumab or placebo must not be concurrently administered 
with any other drug (refer to Section 6). 
Guidelines for dose modification, treatment interruption or discontinuation and for the 
management of imAEs and infusion-related reactions are provided in detail in Section 5.5.2, 
Section 8.7, and Appendix 7.  
Details of tislelizumab or placebo and chemotherapy dose administration are summarized in 
Table 4 and Table 5. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration.  
5.2.2. 
Chemotherapy  
When the oxaliplatin and capecitabine regimen is used as chemotherapy, patients will be treated 
with tislelizumab 200 mg or placebo intravenously on Day 1, followed by oxaliplatin 130 mg/m² 
intravenously on Day 1, and capecitabine 1000 mg/m² orally twice daily for 14 consecutive days 
from Day 1 during each 21-day cycle (Q3W). Oxaliplatin will be administered for up to 6 cycles 
and capecitabine as maintenance therapy may be administered until disease progression, 
intolerable toxicity, or another treatment discontinuation criterion is met. Tislelizumab (or 
placebo) will be administered until disease progression, intolerable toxicity, or treatment 
discontinuation for another reason.  
NOTE: The capecitabine can be dosed either from the morning of Day 1 to the evening of Day 
14 OR from the evening of Day 1 to the morning of Day 15 of each cycle. 
When the cisplatin and 5-FU regimen is used as chemotherapy, patients will be treated with 
tislelizumab 200 mg or placebo intravenously on Day 1, followed by cisplatin 80 mg/m² 
intravenously on Day 1, and 5-FU 800 mg/m²/day intravenously continuous infusion using 
pumping system over 24 hours daily on Day 1 through Day 5 during each 21-day cycle (Q3W). 
Cisplatin and 5-FU will be given for up to 6 cycles, and tislelizumab or placebo will be 
administered until disease progression, intolerable toxicity, or treatment discontinuation for 
another reason.  
Each drug in the regimen should be administered sequentially. Details of tislelizumab or placebo 
and chemotherapy dose administration, including order of dosing and time between doses, are 
summarized in Table 4 and Table 5.  
If the patient is unable to resume chemotherapy treatment within 6 weeks after the last dose of 
chemotherapy, then the patient should be discontinued from treatment. If the patient is not able 
to resume chemotherapy within 6 weeks after the last dose for unforeseen non-drug-related 
reasons, continued treatment may be allowed if approved by the medical monitor. 
All subsequent chemotherapy doses must be rescheduled according to the last chemotherapy 
dose administration date. 
Recommended guidelines for dosage modification and treatment interruption or discontinuation 
are provided in Section 5.5.3 and Appendix 10. For commercially available drugs, please refer to 
SmPC or Pharmacy Manual as a resource. If there is a significant difference between the 


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protocol specified-guidelines and institutional standards of care, the investigator or designee 
should discuss this with the sponsor’s medical monitor or its designee. 
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any AEs. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of each therapy.   
5.2.3. 
Supportive Care  
Patients should receive full supportive care, including epoetin and other hematopoietic growth 
factors (eg, colony-stimulating factors [CSFs]), transfusions of blood and blood products, 
antibiotics, antiemetics, other applicable medications, as needed according to local standard of 
care guidelines or practices. 
5.3. 
Overdose or Incorrect Administration  
Any overdose (defined as ≥ 600 mg of tislelizumab or placebo in a 24-hour period) or incorrect 
administration of study drug (for chemotherapy, doses > 120% of targeted total dose specified in 
this protocol represent an incorrect administration) should be noted in the patient’s chart and on 
the appropriate eCRF. AEs associated with an overdose or incorrect administration of study drug 
will be recorded on the adverse event eCRF. Any SAEs associated with an overdose or incorrect 
administration are required to be reported within 24 hours of awareness via SAE reporting 
process as described in Section 8.6. Supportive care measures should be administered as 
appropriate. 
5.4. 
Investigational Medicinal Product Accountability  
The investigational medicinal products (IMPs) required for completion of this study 
(tislelizumab and placebo) will be provided by the sponsor, as required by local or 
country-specific guidance. The investigational site will acknowledge receipt of tislelizumab and 
placebo. Any damaged shipments will be replaced, as appropriate.  
Accurate records of all IMP received, dispensed, returned, and disposed should be recorded on 
the site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of IMP management. 
5.5. 
Dose Modification  
Every effort should be made to administer the study drugs according to the planned dose and 
schedule. In the event of significant toxicities or logistical reasons not related to study therapy, 
dosing may be delayed and/or reduced based on the guidelines provided below. Reasons for dose 
reductions or delays, the supportive measures taken, and the outcome will be documented in the 
patient’s chart and recorded in the eCRF. 
The dose modification guidelines in this section are not intended to be a substitute for clinical 
judgment. Investigators may delay or reduce doses for other reasons (eg, AEs or laboratory 
findings) as appropriate. 


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5.5.1. 
General Guidance Regarding Dose Modifications  
Reasons for dose modifications or delays, the supportive measures taken, and the outcome will 
be documented in the patient's chart and recorded in the eCRF. The severity of adverse events 
will be graded according to the NCI-CTCAE v5.0 grading system. 
The chemotherapy-related toxicities should be managed according to the prescribing information 
for the approved product or institutional standard practices. The details in this section are for 
reference of this study: 
• Baseline body weight is used to calculate the required chemotherapy doses. The 
Mosteller formula is recommended for BSA calculation.  
BSA (m2) = √ℎ𝑖𝑔ℎ𝑡 (𝑐𝑚) ×𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
3600
 OR BSA (m2) = √ℎ𝑖𝑔ℎ𝑡 (𝑖𝑛) ×𝑤𝑒𝑖𝑔ℎ𝑡 (𝑙𝑏𝑠)
3131
 
• Dose modifications are required if the patient’s body weight changes by ≥ 10% from 
baseline (or the newly referred body weight). Chemotherapy doses should not be 
modified for any body weight change of less than 10%, unless there is an ongoing 
toxicity requiring dose modification. When several toxicities with different grades of 
severity occur at the same time, the dose modifications should be according to the 
highest grade observed. 
• If any component of chemotherapy is temporarily interrupted, both chemotherapeutic 
agents will be delayed until doublet chemotherapy can be given as planned. 
• In case of chemotherapy-related toxicity, chemotherapy will be delayed until it was 
resolved to baseline or ≤ Grade 1 prior to administering the next dose of 
chemotherapy, with the exception of alopecia, Grade 2 fatigue, or other AEs, which, 
in the opinion of the investigator, would not affect the safety evaluation of the study 
drugs. Tislelizumab or placebo should continue as scheduled. If the AE is resolved to 
baseline or ≤ Grade 1 within 10 days, chemotherapy will be administrated. The 
administration of chemotherapy and tislelizumab or placebo will be resynchronized at 
the subsequent cycle, which will be rescheduled according to the chemotherapy dose 
administration date. If the AE is not resolved within 10 days, chemotherapy will be 
omitted. If AE is resolved to baseline or ≤ Grade 1 within 21 days, chemotherapy and 
tislelizumab or placebo will be administered on Day 1 of the next planned cycle.  
• In case of tislelizumab or placebo related toxicity, tislelizumab or placebo will be 
delayed until it resolves to baseline or ≤ Grade 1 prior to administering the next dose 
of tislelizumab or placebo, with the exception of alopecia, Grade 2 fatigue, or other 
AEs, which, in the opinion of the investigator, would not affect the safety evaluation 
of the study drugs. Chemotherapy should continue as scheduled. If the AE is resolved 
to baseline or ≤ Grade 1 within 10 days, tislelizumab or placebo will be 
administrated. The administration of chemotherapy and tislelizumab or placebo will 
be resynchronized at the subsequent cycle, which will be scheduled according to the 
chemotherapy dose administration date. If the AE is not resolved within 10 days, 
tislelizumab or placebo will be omitted. If AE is resolved to baseline or ≤ Grade 1 
within 21 days, tislelizumab or placebo and chemotherapy will be administered on 
Day 1 of the next planned cycle.  


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• The tumor assessment schedule will not be altered if chemotherapy and/or 
tislelizumab or placebo are delayed or discontinued.  
• Every effort should be made to continue treatments in combination when patient’s 
condition allows, also taking into consideration patient’s convenience for the 
treatment schedule. 
• Following either completion of or discontinuation from chemotherapy, tislelizumab 
or placebo should be continued as scheduled, if clinically appropriate. Capecitabine 
maintenance after completion of oxaliplatin + capecitabine doublet chemotherapy is 
also permitted. 
• Reasons for dose modifications or delays, the supportive measures taken, and the 
outcomes will be documented in the patient’s chart and recorded on the eCRF. 
The severity of adverse events will be graded according to the NCI-CTCAE v5.0 
grading system. 
• If one component of chemotherapy is discontinued permanently during the initial 
6 cycles of treatment for reasons other than progressive disease (PD), the other 
component of chemotherapy could be continued per the study protocol or local 
practice. 
• If tislelizumab or placebo is discontinued permanently during the initial 6 cycles of 
treatment, the patient may continue the chemotherapy per the study protocol or local 
practice.  
Dose modification guidelines for chemotherapy are described in Section 5.5.3 depending on the 
severity of toxicity and an assessment of the risk versus benefit for the patient, with the goal of 
maximizing patient compliance and access to supportive care. 
5.5.2. 
Dose Modification for Tislelizumab or Placebo  
There will be no dose reduction for tislelizumab or placebo in this study.  
Patients may temporarily suspend study treatment if they experience toxicity that is considered 
related to tislelizumab or placebo that requires a dose to be withheld, or if they have logistical 
reasons not related to study therapy. If a dose of tislelizumab or placebo is delayed for ≤ 10 days 
for a planned dosing cycle (eg, Cycle 3, Day 1), tislelizumab or placebo should be administered 
in the current cycle. If the delay is more than 10 days, patients should skip the tislelizumab or 
placebo dose at this cycle and will be dosed at the start of the next planned cycle (see 
Section 5.5.1). 
The patients should resume tislelizumab or placebo treatment as soon as possible after the AEs 
recover to baseline or Grade 1 (whichever is more severe) within 12 weeks after last dose of 
tislelizumab or placebo. If the patient is unable to resume tislelizumab or placebo within 
12 weeks after the last dose of tislelizumab or placebo, then the patient should be discontinued 
from treatment.  
In case a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with sponsor medical 
monitor. 


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If a scheduled dose coincides with logistical reasons not related to study therapy (eg, elective 
surgery, unrelated medical events, patient vacation, and holidays) that precludes dosing, dosing 
should commence on the nearest following date and subsequent dosing can continue on a new 
21-day schedule based on the infusion date.  
If tislelizumab or placebo is discontinued because of tolerability concerns during the first 
6 cycles of treatment, the patient may continue on the chemotherapy regimen (cisplatin + 5-FU 
or oxaliplatin + capecitabine) or 1 component of these regimens if agreed upon by the 
investigator and patient. 
Patients who discontinue treatment for tislelizumab (or placebo) and/or chemotherapy toxicity in 
the absence of disease progression should continue on tumor assessment until an objective 
disease progression event occurs. 
Specific treatment modifications to manage tislelizumab-related toxicities, such as imAEs and 
infusion-related reactions, are described Appendix 7 and Section 8.7.1, respectively.   
5.5.3. 
Dose Modifications of Chemotherapy  
Toxicities related to chemotherapy must be resolved to baseline or ≤ Grade 1 prior to 
administering the next dose of chemotherapy, with the exception of alopecia, Grade 2 fatigue, or 
other AEs, which, in the opinion of the investigator, would not affect the safety evaluation of the 
study drugs. A maximum of 2 dose reductions per chemotherapeutic agent are permitted. If 
additional reductions are required, that chemotherapeutic agent must be discontinued. Once the 
dose has been decreased, it should remain reduced for all subsequent administrations or further 
reduced if necessary. There will be no dose escalations in this study.   
If the patient is unable to resume chemotherapy treatment within 6 weeks after the last dose of 
chemotherapy, then the patient should be discontinued from treatment. If the patient is not able 
to resume chemotherapy within 6 weeks after the last dose for unforeseen non-drug-related 
reasons continued treatment may be allowed if approved by the medical monitor. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (eg, elective surgery, unrelated medical events, patient vacation, and 
holidays). Patients should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the sponsor. The reason for interruption should be 
documented in the patient's study record. 
Patients may also discontinue chemotherapy following multiple cycles if, in the investigator’s 
judgment, cumulative toxicity is likely to increase over time and become problematic. 
Recommended guidance regarding dose modifications of chemotherapy for certain toxicities is 
presented in Appendix 10. For toxicities not listed, dose modifications are permitted per local 
standards. 
5.5.4. 
Blinding  
This is a randomized, double-blind, Phase 3 study. Patients will be randomized to receive 
tislelizumab or matching placebo in a double-blind fashion such that neither the investigator, nor 
the patient, nor medical or ancillary medical staff, nor the sponsor or its designees, will know 
which drug is being administered in addition to chemotherapy.  


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• Emergency unblinding  
Emergency unblinding for AEs may be performed through an Interactive Web 
Response System (IWRS). 
All AEs should be evaluated and determined whether they are related to tizlelizumab 
plus chemotherapy or chemotherapy alone and treatment provided accordingly. 
Therefore, emergency unblinding should not be required to manage the patient’s care. 
If knowledge of the investigational medicinal product is critical to the patient's 
management and the investigator decides that unblinding is required to manage an 
adverse reaction (eg, some ≥ Grade 3 imAEs or the event of a medical emergency or 
pregnancy), the investigator should make every effort to contact the sponsor medical 
monitor prior to unblinding a patient’s treatment assignment unless this could delay 
emergency treatment of the patient. If a patient’s treatment assignment is unblinded 
due to an emergency treatment, the sponsor must be notified immediately. 
• Inadvertent unblinding  
Every effort will be made to blind both the patient and the investigator to the identity 
of tislelizumab or placebo, but the inadvertent unblinding of a patient may occur. If 
an investigator, site personnel performing assessments, or patient is unblinded, the 
unblinding will not be sufficient cause (in and of itself) for that patient to be 
discontinued from study therapy or excluded from any safety or efficacy analyses. 
• Unblinding for serious adverse reaction reporting 
The sponsor will unblind patients who experience an unexpected serious adverse 
reaction, for the purpose of reporting to the regulatory authorities. In such a case, the 
medical monitors will not be informed of the treatment allocation, according to the 
sponsor’s standard procedures. 
• Unblinding after final analysis 
Investigators, site personnel, and patients will be unblinded to treatment arms and 
PD-L1 result at the time of final analysis. Placebo administration will be discontinued 
after the unblinding. Crossover between the treatment arms will not be allowed. 
Bioanalytical labs may not be blinded as long as there are no means for the investigators or 
blinded sponsor team to know which samples will be analyzed or not. 


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6. 
PRIOR AND CONCOMITANT THERAPY   
6.1. 
Concomitant Therapy  
6.1.1. 
Permitted Concomitant Medications/Procedures  
All treatments that the investigator considers necessary for a patient’s health and safety may be 
administered at the discretion of the investigator in keeping with the local standards of medical 
care. All concomitant medication, including all prescription and over-the-counter medications, 
herbal supplements and remedies, and intravenous medications and fluids, will be recorded on 
the eCRF. Patients may continue to receive hormone replacement if it was initiated prior to 
enrollment. Bisphosphonates and RANK-L inhibitors, if initiated prior to enrollment, are allowed 
for bone metastases. 
All concomitant medications received within 30 days before the first dose of study drug and 
30 days after the last infusion or dose of study drug should be recorded.  
Systemic corticosteroids required for the control of imAEs are suggested to be tapered over at 
least 1 month and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) 
before the next study drug administration. The use of steroids as prophylactic treatment for 
patients with contrast allergies to diagnostic imaging contrast dyes or antiemetic therapy for 
specific chemotherapy is permitted. 
Patients with active hepatitis B, defined as either detectable HBsAg or HBV DNA at baseline 
must initiate treatment 2 weeks prior to randomization or the first dose of study drug, and 
continue until 6 months after the last dose of study drug or per local guideline (eg, AASLD 
guidelines). Patients should continue effective antiviral treatment during the study to decrease 
potential viral re-activation risk. Tenofovir and entecavir are recommended in the American 
Association for the Study of Liver Disease (AASLD) guideline because they lack resistance with 
long-term use (Terrault et al, 2016; AASLD/IDSA HCV Guidance Panel, 2015). The 
investigator might use other antiviral agents, if appropriate, following local guidelines. 
Management of antiviral therapy is at the discretion of the investigator; however, reason(s) must 
be provided in the CRF if a patient with active hepatitis B is not treated with antiviral 
prophylaxis.  
However, interferon-based therapy for HBV or HCV is not permitted on study. 
Hematopoietic growth factors (ie, G-CSF or GM-CSF) may be used according to institutional or 
other specific guidelines (eg, country or regional guidelines or guidelines of oncology 
organizations, such as the American Society of Clinical Oncology [ASCO]) to treat febrile 
neutropenia but should not be used as primary prophylaxis. The use of any growth factor support 
must be documented in the patient’s record and eCRF. Growth factors must be discontinued at 
least 48 hours prior to initiation of the next cycle of chemotherapy.  
According to NCCN 2014 guidelines (https://www.nccn.org/), erythropoiesis-stimulating agents 
(ESAs) may be considered for the treatment of cancer-related anemia in patients undergoing 
palliative treatment. Erythropoietic therapy may be considered for treatment of 
chemotherapy-induced anemia in cases where hemoglobin is < 11 g/dL or a decrease of ≥ 2 g/dL 
from baseline, but only after the patient has been counseled about the risks and benefits of ESA 
use. 


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The use of prophylactic medication such as magnesium/calcium infusions or others for 
prevention of oxaliplatin-induced neuropathy is at the discretion of the investigator; however, 
these treatments are not recommended for use in this study, as their benefits have not been 
clearly established. 
Whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) are permitted for 
patients with progressive central nervous system metastasis. Patients with symptomatic brain 
metastases are not eligible for participation in the study (refer to Section 4). Palliative 
(limited-field) radiation therapy is permitted, but only for pain control to sites of bone disease 
present at baseline provided that the following criteria are met: 
• Repeat imaging demonstrates no new sites of bone metastases 
• The lesion being considered for palliative radiation is not a target lesion for RECIST 
v1.1 
• The case is discussed with the sponsor’s medical monitor, and the medical monitor 
agrees that the conditions required to receive palliative radiation have been met 
Additionally, palliative radiation or other focally ablative therapy for other nontarget sites of the 
disease is permitted if the investigator determines that it is clinically indicated. These patients 
should have a tumor assessment of the lesion(s) before receiving the radiotherapy in order to rule 
out progression of disease. 
6.1.2. 
Prohibited or Restricted Concomitant Medications  
The following medications are prohibited or restricted at screening and during the study: 
• Immunosuppressive agents (except to treat a drug-related AE) are restricted 
• Systemic corticosteroids > 10 mg daily (prednisone or equivalent), except to treat or 
control a drug-related AE (per protocol) or for short-term use as prophylactic 
treatment (eg, antiemetic therapy for specific chemotherapy) are restricted 
• Any concurrent systemic anticancer therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese herbal 
medicine and Chinese patent medicines] for the treatment of cancer) is not allowed 
• Radiation therapy is not allowed, except for palliative radiation therapy described in 
Section 6.1.1. 
• Live vaccines within 28 days before the first dose of study drugs and 60 days 
following the last dose of study drugs are prohibited. (NOTE: seasonal vaccines for 
influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are 
live vaccines and are not allowed.) 
• Concomitant use of drugs with a potential ototoxic or nephrotoxic effect (eg, 
aminoglycosides, cefalotine, furosemide, amphotericin B) should be avoided or 
adequately monitored 
• Allopurinol use in patients administered 5-FU should be avoided. Interactions with 
allopurinol have been observed with 5-FU that possible decrease efficacy of 5-FU. 


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• Antivirals and antiprotozoals: 5-FU should not be administered together with the 
antiviral drug sorivudine or its chemically related analogues, such as brivudine. A 
clinically significant drug-drug interaction between sorivudine and 5-FU, resulting 
from the inhibition of dihydropyrimidine dehydrogenase (DPD) by sorivudine, has 
been described in the literature (Diasio, 1998). This interaction, which leads to 
increased fluoropyrimidine toxicity, is potentially fatal. 
• Metronidazole has been shown to increase the toxicity of 5-FU in patients with 
colorectal cancer, apparently by reducing the clearance of the antineoplastic 
(Bardakji, 1986). As it has been described in the literature, caution should be 
exercised in the cancer populations participating in this study. 
• Phenytoin has been observed to have toxicity associated with elevated phenytoin 
concentrations in patients concomitantly taking capecitabine. Concentrations of 
phenytoin should be carefully monitored in patients taking capecitabine and 
phenytoin. 
• Altered coagulation parameters and/or bleeding have been reported in patients taking 
capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin 
and phenprocoumon. Caution should be exercised with use of coumarin-derivative 
anticoagulants in the cancer populations participating in this study. 
• Refer to the approved product labeling complete information regarding drug-drug 
interactions 
The following are also prohibited during the study:  
• Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or known 
to potentially interfere with liver or other major organ function (eg, hypericin)  
• Herbal remedies for the treatment of cancer or Chinese patent medicines with 
approval from the China NMPA for use as an anticancer treatment (regardless of 
cancer type) 
• Patients should not abuse alcohol or other drugs during the study 
Patients must notify the investigator of all herbal remedies used during the study. 


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7. 
STUDY ASSESSMENTS AND PROCEDURES  
A table of scheduled study assessments is provided in Appendix 1. Patients will be closely 
monitored for safety and tolerability throughout the study. All assessments must be performed 
and documented in the medical record for each patient. 
Treatment assignment in IRT and dosing will occur only if the clinical assessment and local 
laboratory test values (that must be available before any dosing) have been reviewed and found 
to be acceptable per protocol guidelines.  
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
events, the visit should be scheduled on the nearest feasible date (the visit window is provided in 
Appendix 1), with subsequent visits rescheduled accordingly. 
7.1. 
Screening  
Screening evaluations will be performed within 28 days prior to randomization. Patients who 
agree to participate will sign the ICF prior to undergoing any screening procedure unless 
otherwise specified. ICF signature alone does not define the start of the screening period, instead, 
date of the first study related procedure is to be used as date of screening visit. Patients who are 
suspected or known to have serious respiratory concurrent illness or exhibit significant 
respiratory symptoms unrelated to underlying cancer should take a pulmonary function test (refer 
to Appendix 1 for details). Screening evaluations may be repeated as needed within the screening 
period; the investigator is to assess patient eligibility according to the latest screening assessment 
results.  
Results of standard of care tests or examinations performed prior to obtaining informed consent 
and ≤ 28 days prior to randomization may be used for the purposes of screening rather than 
repeating the standard of care tests unless otherwise indicated. 
Procedures conducted during the Screening Visit only are described in this section. For the 
description of other assessments that are conducted during screening, as well as throughout the 
study, refer to Safety Assessments (Section 7.4), Tumor and Response Evaluations (Section 7.5) 
and Biomarkers (Section 7.7). The PK sampling schedule is shown in Appendix 1. 
Rescreening under limited conditions may be allowed after consultation with BeiGene. 
Rescreening is allowed only once. If the patient was rescreened, the patient must be re-
consented. Any new result will override the previous one (ie, the most recent result prior to 
randomization) and is the value by which study inclusion will be assessed, as it represents the 
patient’s most current clinical state. 
7.1.1. 
Demographic Data and Medical History  
Demographic data will include age or year of birth, gender, and self-reported race/ethnicity.  
Medical history includes any history of clinically significant disease, surgery, or cancer related 
symptoms or signs; reproductive status (ie, of childbearing potential or no childbearing 
potential); history of alcohol consumption and tobacco (ie, former or current or never); and all 
medications (eg, prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 30 days before the first dose of study drugs. 


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If appropriate, clinically significant disease should be graded according to NCI-CTCAE v5.0 and 
reported in the Medical History eCRF. 
Cancer history will include pathologic diagnosis, stage at screening, tumor location, location of 
metastatic disease at study baseline, an assessment of prior surgery, prior radiotherapy, prior 
drug therapy, including start and stop dates, best response and reason for discontinuation. 
Radiographic studies performed prior to study entry may be collected for review by the 
investigator. 
7.1.2. 
Females of Childbearing Potential and Contraception  
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer 
to Appendix 9 for contraception guidelines and definitions of “women of childbearing potential” 
and “no childbearing potential”. 
7.1.3. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures unless otherwise specified. ICF signature alone does 
not define the start of the screening period, instead, date of the first study related procedure is to 
be used as date of screening visit. Informed consent forms for enrolled patients and for patients 
who are screened but not enrolled will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization. The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable. 
7.1.4. 
Pulmonary Function Tests  
Patients who are suspected or known to have serious/severe respiratory conditions or exhibit 
significant respiratory symptoms unrelated to the underlying cancer will undergo pulmonary 
function testing which may include but is not limited to spirometry and assessment of diffusion 
capacity done during the Screening period to assist the determination of suitability on the study. 
7.2. 
Enrollment  
7.2.1. 
Confirmation of Eligibility  
The investigator will assess and confirm the eligibility of each patient. All screening procedure 
results and relevant medical history must be available before eligibility can be determined. All 
inclusion criteria must be met and none of the exclusion criteria may apply. No eligibility 
waivers will be granted.   
After a patient is screened and the investigator determines the patient is eligible for 
randomization, study site personnel will complete an Eligibility Authorization Packet and send it 
to the medical monitor or designee to approve the enrollment. Study site personnel should ensure 
that a medical monitor-approved Eligibility Authorization Packet is received before 
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Once enrolled in the IRT, patients that have met all eligibility criteria will be ready to be 
randomized through the IRT. The following information is required for patient randomization: 
• Patient number 
• Year of birth 
• Gender: male versus female 
• Region: China (including Taiwan) vs. Japan and S. Korea vs. US and Europe and 
other regions. NOTE: other regions include other western countries/populations. 
• PD-L1 expression (positive or negative): PD-L1+ patients are patients with tumor and 
immune cell score (TIC score) ≥ 5% using VENTANA PD-L1 (SP263) Cdx Assay. 
TIC score is the total percentage of the tumor area covered by tumor cells with PD-L1 
membrane staining and tumor-associated immune cells with PD-L1 staining at any 
intensity. 
• Presence of peritoneal metastasis (yes or no) 
• Investigator’s choice of chemotherapy  
7.2.2. 
Patient Numbering  
After obtaining informed consent, study site personnel will access the Interactive Response 
Technology (IRT) system to assign a unique patient number to a potential study participant.   
7.2.3. 
Enrollment/Randomization  
Site personnel will access the IRT system to assign study drugs which is supplied centrally by 
sponsor. The choice of chemotherapy regimen must be decided prior to randomization and the 
interchange of chemotherapy regimen is not permitted during study period. Study treatment must 
commence within 3 days after randomization/treatment assignment.   
7.3. 
Tislelizumab, Placebo and Chemotherapy Dispensing  
Tislelizumab or placebo and chemotherapy will be dispensed and administered as described in 
Section 5.2. 
7.4. 
Safety Assessments  
7.4.1. 
Vital Signs  
Vital signs will include measurements of pulse rate, and blood pressure (systolic and diastolic) 
while the patient is in a seated position after resting for 10 minutes, and body temperature (˚C).  
For the first infusion of tislelizumab or placebo, the patient’s vital signs are required to be 
recorded within 60 minutes before, during, and within 30 minutes after the infusion. For 
subsequent infusions, vital signs will be collected within 60 minutes before infusion and, if 
clinically indicated, during and within 30 minutes after the infusion. Patients will be informed 
about the possibility of delayed post-infusion symptoms and instructed to contact their study 
physician if they develop such symptoms. Refer to Section 5.2.1 regarding precautionary 
monitoring of patients post infusion of tislelizumab or placebo. 


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7.4.2. 
Physical Examinations  
A complete physical examination including an evaluation of 1) head, eyes, ears, nose, throat, 2) 
cardiovascular, 3) dermatological, 4) musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) 
neurological systems is required to be performed at screening. Any abnormality identified at 
baseline will be graded according to NCI-CTCAE v5.0 and recorded on the Medical History 
eCRF with appropriate disease/condition terms.  
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations will be performed. New or worsened clinically significant abnormalities are to be 
recorded as AEs on the Adverse Event eCRF. Refer to Section 8.3 regarding AE definitions and 
reporting and follow-up requirements. 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG PS (Appendix 3) will be assessed during the study.  
7.4.4. 
Laboratory Safety Tests  
Local and/or central laboratory assessments on serum chemistry, hematology, thyroid function, 
coagulation, and urinalysis will be conducted, of which certain elements will be collected as 
specified in Appendix 2. If serum chemistry, hematology, coagulation, or urinalysis at screening 
are not performed within 7 days prior to the administration of study drugs on Cycle 1 Day 1, 
these tests should be repeated and reviewed before study drugs administration. Hematology and 
serum chemistry (including liver function tests) as specified in Appendix 2 should be performed 
weekly for the first 3 cycles and at the beginning of each subsequent cycle. After Cycle 1, results 
are to be reviewed within 72 hours before study drug administration.  
If a patient experiences elevated ALT/AST ≥ 5 x ULN and/or elevated total bilirubin ≥ 3 x ULN, 
the sponsor should be notified as soon as possible. Clinical and laboratory monitoring should be 
initiated by the investigator.    
Details about sample collection and shipment will be provided in a separate instruction manual. 
Investigators may use results from local laboratories for assessing eligibility, safety monitoring 
and dosing decision.   
7.4.4.1. 
Cardiac Enzyme Monitoring  
Although immune-mediated myocarditis is a rare complication of immune checkpoint inhibitors, 
serum creatinine kinase (CK) and CK cardiac isoenzyme (CK-MB) is monitored in all 
tislelizumab studies to protect study participants and to quantify the risk of muscle inflammation 
(see Appendix 1 for the blood collection schedule and Appendix 7 for guidelines for 
management of suspected immune-mediated myocarditis). Serum troponins may be substituted 
per local guidelines if CK-MB fractionation is not available. 
7.4.5. 
Electrocardiograms  
A 12-lead ECG is required at screening, safety follow-up, and as clinically indicated. ECGs 
should be obtained on the same machine for all study assessments, if possible. Lead placement 
should be as consistent as possible. The ECG recordings should be performed after the patient 
has been resting for at least 10 minutes. 


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For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient's permanent study 
file at the site. 
When coinciding with blood draws, ECG assessment should be performed prior to blood draws. 
Patients should rest in semi-recumbent supine position for at least 10 minutes prior to ECG 
collection.  
7.4.6. 
Adverse Events  
Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, 
version 5.0 (NCI-CTCAE). Characterization of toxicities will include severity, duration, and 
time to onset.  
All adverse events, including SAEs, will be collected as described in Section 8.6.  
7.4.7. 
Ophthalmologic Examination  
Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test) 
will be assessed by an appropriate specialist at the Screening Visit for all patients. Eye exam, 
visual acuity test, and optical coherence tomography (or equivalent diagnostic test for retinal 
examination) captured as standard of care prior to obtaining written informed consent and within 
28 days of randomization may be used for the Screening evaluation. Patients will undergo repeat 
assessments by an appropriate specialist approximately every 15 weeks (± 7 days) during study 
treatment and at either the EOT or during safety follow-up.   
In addition, investigators should solicit patients regarding changes in vision, visual disturbance, 
or ocular inflammation at each scheduled study visit during tislelizumab or placebo treatment. 
For any change in vision, referral to an appropriate specialist will be made for further 
management guidance (see Appendix 7). 
7.4.8. 
Hepatitis B and C Testing  
Testing will be performed by local and/or central laboratory at Screening and will include 
HBV/hepatitis C virus (HCV) serology (HB sAg, HB sAb, hepatitis B core antibody [HB cAb], 
and HCV antibody) and viral load assessment (HBV and HCV) will be required if clinically 
indicated.  
Patients who have detectable HBV DNA at screening will perform a viral load test at least every 
4 cycles (ie, Day 1 of Cycle 5, 9 and 13, etc). 
7.5. 
Tumor and Response Evaluations  
Tumor imaging will be performed within 28 days prior to randomization. Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent and 
≤ 28 days prior to randomization may be used for the purposes of screening rather than repeating 
the standard-of-care tests. During the study, tumor imaging will be performed approximately 
every 6 weeks (± 7 days) during the first 48 weeks and thereafter approximately every 9 weeks 
(± 7 days). 


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Screening assessments and each subsequent assessment must include computed tomography 
(CT) scans (with oral and/or intravenous contrast, unless contraindicated) or magnetic resonance 
imaging (MRI) of the chest, abdomen, and pelvis. Other known or suspected sites of disease 
must be included in the imaging assessments (eg, neck, brain, etc.). 
Tumor assessments must include CT scans (with oral/intravenous contrast, unless 
contraindicated) or MRI, with preference for CT, of the chest, abdomen, and pelvis. All 
measurable and evaluable lesions should be assessed and documented at the Screening Visit and 
reassessed at each subsequent tumor evaluation. The same radiographic procedure as used to 
assess disease sites at screening is required to be used throughout the study (eg, the same contrast 
protocol for CT scans). 
• An MRI (or CT scan if MRI is contraindicated or not readily available) of the brain 
may be required at screening based on clinical judgement. 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a non-contrast CT of the chest plus a 
contrast-enhanced MRI (if possible) of abdomen and pelvis should be performed.  
• If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan. 
• Bone scans (technetium-99m [TC-99m]) or 18F-sodium fluoride (NaF) positron-
emission tomography (PET) should be performed at Screening if clinically indicated. 
If bone metastases are present at Screening and cannot be seen on CT or MRI scans 
afterwards, TC-99m or 18F-NaF PET bone scans should be conducted when a CR is 
suspected. In addition, TC-99m or 18F-NaF PET bone scans may be conducted when 
progression in bone is suspected. 
• CT scans of the neck or extremities should also be performed if clinically indicated 
and followed throughout the study, if there is evidence of metastatic disease in these 
regions at Screening. At the investigator’s discretion, other methods of assessment of 
target lesion and nontarget lesions per RECIST v1.1 may be used.  
Response will be assessed by the investigator using RECIST v1.1 (see Appendix 4).   
Tumor assessment should continue as planned in patients receiving study drug(s) beyond initial 
investigator-assessed progression. Tumor assessment in such patients should continue until study 
treatment discontinuation. 
Patients who discontinue study treatment early for reasons other than disease progression (eg, 
toxicity) will continue to undergo tumor assessments following the original plan until the patient 
begins a subsequent anticancer treatment, experiences disease progression, withdraws consent, is 
lost to follow-up, dies, or until the study terminates, whichever occurs first.  
Tumor assessments are required to be performed on schedule regardless of whether study 
treatment has been administered or held. That is, assessments should not be adjusted for delays 
in cycles.  


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7.6. 
Pharmacokinetic and Antidrug Antibody Testing  
Pharmacokinetic samples will be collected in patients randomized to receive tislelizumab or 
placebo at the time points presented in Appendix 1. Procedures for collection of PK samples are 
described in the Laboratory Manual. 
Tislelizumab may elicit an immune response. Patients with signs of any potential immune 
response to tislelizumab will be closely monitored. Validated screening and confirmatory assays 
will be employed to detect ADAs at multiple time points throughout the study (see Appendix 1). 
The immunogenicity evaluation will utilize a risk-based immunogenicity strategy (Koren et al, 
2008; Worobec and Rosenberg, 2004a; Worobec and Rosenberg, 2004b) to characterize ADA 
responses to tislelizumab in support of the clinical development program.  
The following assessments will be performed at a central laboratory:  
• ADA assays: serum samples will be tested for the presence of ADAs to tislelizumab 
using a validated immunoassay 
• PK assay: serum samples will be assayed for tislelizumab concentration with use of a 
validated immunoassay 
PK and ADA samples collected from patients randomized to receive placebo will not be 
analyzed. 
Shipping, storage, and handling of samples for the assessment of tislelizumab PK and ADA 
assays will be managed through a central laboratory. Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
7.7. 
Biomarkers  
Shipping, storage, and handling of blood, archival tumor, fresh tumor, and leftover tumor tissue 
for the assessment of biomarkers will be managed through investigational sites and/or a central 
laboratory. Refer to the laboratory manual for details of sample handling.  
7.7.1. 
Tissue Biomarkers  
See Appendix 1 for the tissue biomarker sample collection schedule. 
Tumor tissues (FFPE blocks or approximately 15 [≥ 7 if MSI/MMR and HER2 results are 
available; additional 5 if MSI/MMR result is not available; and additional 3 to 6 if HER2 status 
is not identified] freshly cut unstained FFPE slides) need to be sent to investigational site or 
central laboratory for biomarker analysis, including central immunohistochemistry assay of 
PD-L1 status. For patients with unavailable MSI/MMR status, an MSI or MMR assessment will 
be performed in investigational sites, third-party local lab or designated central laboratory. For 
MMR testing, 5 FFPE slides required; for MSI testing, 5 FFPE slides and approximately 2 mL 
blood samples will be collected. Patients with unknown HER2 status must undergo a HER2 test 
at the investigational sites (or other designated sites), third-party local lab or sponsor designated 
central laboratory prior to enrollment. Refer to Section 4.1 for inclusion criteria and Appendix 14 
for HER2 pathological review guideline. 
In addition to PD-L1 expression, MSI/MMR and HER2 status, status of EBV infection, GS, and 
CIN will be collected if available. Other exploratory predictive biomarkers, such as gene 


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expression profiling (GEP), tumor infiltrating lymphocytes (TILs), and tumor mutation burden 
(TMB) that are related to response or clinical benefit of tislelizumab may also be evaluated from 
remaining tumor tissue obtained at baseline. A fresh biopsy sample is highly preferred if feasible 
in clinic. If no archival samples are available, a fresh tumor biopsy at baseline is mandatorily 
required. Acceptable fresh biopsy samples include core needle biopsies for deep tumor tissue or 
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal 
lesions. 
Optional biopsy will also be taken at the EOT visit for the patients who have confirmed disease 
progression during the study from accessible tumor sites to obtain samples, which could be used 
for exploratory study including but not limited to the resistance mechanism. If feasible, any 
follow up biopsy should be ideally taken from the same tumor lesion as the baseline biopsy. 
Written informed consent is required for fresh tumor biopsies at EOT. 
Tumor tissue should be of good quality based on total and viable tumor content. Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, lavage samples, or bone/bone marrow 
aspirates are not acceptable.  
7.7.2. 
Blood Biomarkers  
See Appendix 1 for the blood biomarkers sample collection schedule. 
Optional blood samples of approximately 10 mL will be taken at baseline (predose at Day 1 of 
Cycle 1), at the time of first tumor response (predose at Day 1 of the following Cycle) and at 
EOT after disease progression (10 mL each timepoint) for all randomized patients to explore the 
association of blood-based biomarkers with response, prognosis and resistance to tislelizumab in 
combination with chemotherapy or chemotherapy alone. Written informed consent is required 
for optional blood sample collection. 
7.8. 
Patient-reported Outcomes  
Patients will be asked to complete the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) (Appendix 11), European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire Gastric 
Cancer Module QLQ-STO22 (EORTC QLQ-STO22) (Appendix 12), and European Quality of 
Life 5-Dimensions 5-Levels Health Questionnaire (EQ-5D-5L) (Appendix 13) questionnaires 
before any clinical activities are performed during on-study clinic visits apart from blood draw 
according to the schedule in Appendix 1. The questionnaires will be provided in the patient’s 
preferred language. 
7.9. 
Visit Windows  
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see 
Appendix 1). All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed prior to study treatment infusion/dose 
unless otherwise noted. Laboratory results are required to be reviewed prior to dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
events, the visit should be scheduled on the nearest feasible date (the visit window is provided in 


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Appendix 1), with subsequent visits conducted according to a new 21-day schedule based on the 
date of the patient’s last study treatment. 
7.10. 
Unscheduled Visits  
Unscheduled visits may be performed at any time at the patient’s or investigator’s request and 
may include vital signs/focused physical examination; ECOG performance status; AE review; 
concomitant medications and procedures review; radiographic assessments; physical 
examination of liver, spleen, and lymph nodes; review of disease-related constitutional 
symptoms; and hematology and chemistry laboratory assessments. The date and reason for the 
unscheduled visit must be recorded in the source documentation.   
If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, then 
diagnostic tests may be performed based on investigator assessment as appropriate, and the 
results of these tests should be entered on the unscheduled visit eCRF. 


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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol.  
8.1. 
Risks Associated with Tislelizumab and Chemotherapy  
8.1.1. 
Risks Associated With Tislelizumab  
Tislelizumab is an investigational agent that is currently in clinical development.  
The following recommendation is based on results from nonclinical and clinical studies with 
tislelizumab and published data on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions. AEs observed with anti-PD-1 therapy are presented in Section 8.7.2.  
An imAE may occur at any time during or after treatment. Often, the etiology of imAEs is not 
clear, and other causes should be ruled out. This may require diagnostic testing and consultation 
with a specialist. Suggested evaluation and management guidelines for suspected imAEs are 
provided in Appendix 7. 
8.1.2. 
Risks Associated with Platinum and Fluoropyrimidine  
Refer to the most recent, locally approved package insert for information on the risk associated 
with a particular platinum- or fluoropyrimidine-based chemotherapy. 
8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria  
Eligibility criteria were selected to guard the safety of patients in this study. Results from the 
nonclinical toxicology studies and clinical data with tislelizumab, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were taken into account. 
Specifically, patients at risk for study-emergent active autoimmune diseases, or with a history of 
autoimmune diseases that may relapse, patients who have undergone allogenic stem cell or organ 
transplantation and patients who have received a live viral vaccine within 28 days before 
randomization are excluded from the study. Patients with contraindications for chemotherapy 
treatment are also excluded from the study (see Section 4.2 for the full list of exclusion criteria). 
8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all adverse events, defined and 
graded according to NCI-CTCAE v5.0 (except as noted in Section 8.6.4). Patients will be 
assessed for safety (including laboratory values) according to the schedule in Appendix 1. 
Clinical laboratory results must be reviewed prior to the start of each cycle.  
In this study, all enrolled patients will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study. Safety evaluations will 
consist of medical interviews, recording of AEs, physical examinations, laboratory 


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measurements (hematology, chemistry, etc.), imaging, consultations (as needed), and other 
assessments including those listed in Appendix 1. In addition, patients will be closely monitored 
for the development of any signs or symptoms of autoimmune conditions and infections.  
Serum samples will be drawn for determination of ADAs to tislelizumab in patients randomized 
to tislelizumab arm. Administration of tislelizumab or placebo will be performed in a setting 
where emergency medical equipment and staff who are trained to respond to medical 
emergencies are available (see Section 5.2.1).   
Investigators are instructed to report all AEs (including pregnancy-related AEs). 
The potential safety issues anticipated in this study, as well as measures intended to avoid or 
minimize such toxicities, are outlined in the following sections. 
8.3. 
Adverse Events  
8.3.1. 
Definitions and Reporting  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not.   
Examples of AEs include:  
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome  
• New conditions detected or diagnosed after study drug administration even though it 
may have been present before the start of the study  
• Signs, symptoms, or the clinical sequelae of a suspected interaction  
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor. In this instance, all patient identifiers will be blinded or 
redacted on the copies of the medical records prior to submission to the sponsor. 
8.3.2. 
Assessment of Severity  
The investigator will make an assessment of severity for each AE and SAE reported during the 
study. AEs and SAEs should be assessed and graded based upon the NCI-CTCAE v5.0. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
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• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL  
• Grade 4: Life-threatening consequences; urgent intervention indicated  
• Grade 5: Death related to AE  
NOTE: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions. Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.6.2.3. 
8.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE, using best clinical judgment. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the AE or SAE to the study drug should be considered and investigated. The investigator should 
consult the tislelizumab Investigator’s Brochure in the determination of his/her assessment.  
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always makes an assessment of causality for every SAE prior to transmission of the 
SAE report to the sponsor, since the causality assessment is one of the criteria used when 
determining regulatory reporting requirements. The investigator may change his/her opinion of 
causality in light of follow-up information, amending the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related”. An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drug (ie, there are facts, evidence, or arguments to suggest 
possible causation). A number of factors should be considered in making this assessment, 
including:  
• Temporal relationship of the AE to the administration of study treatment/study 
procedure  
• Whether an alternative etiology has been identified  
• Mechanism of action of the study drug  
• Biological plausibility  
• An AE should be considered “related” to study drug if any of the following are met, 
otherwise the event should be assessed as “not related”: 
− There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out  


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− There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely  
− There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of the study drug). However, the 
influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs).  
8.3.4. 
Following Adverse Events  
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up or the patient 
withdraws consent. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities  
Only abnormal laboratory findings (eg, clinical chemistry, complete blood count [CBC] 
coagulation, or urinalysis) or other abnormal assessments (eg, ECGs, X-rays, or vital signs) that 
are judged by the investigator as clinically significant will be recorded as AEs or SAEs. This 
includes clinically significant abnormal laboratory findings or other abnormal assessments that 
are present at baseline and significantly worsen during the study. The definition of clinically 
significant is left to the judgment of the investigator. In general, these are the laboratory test 
abnormalities or other abnormal assessments that:  
• are associated with clinical signs or symptoms, or  
• require active medical intervention, or  
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or  
• require further diagnostic investigation. 


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 x ULN associated with cholestasis), only the diagnosis (ie, 
cholestasis) should be recorded on the Adverse Event eCRF. If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should be 
recorded as the AE. For example, an elevated serum potassium level of 7.0 mEq/L (or mmol/L) 
should be recorded as “hyperkalemia.” 
8.4. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose, meet any of the following criteria:  
• Results in death 
• Is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE, 
which hypothetically might have caused death, if it were more severe.  
• Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
• Results in disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere or prevent everyday life functions, but do not constitute a substantial 
disruption.  
• Is a congenital anomaly/birth defect 
• Is considered a significant medical AE by the investigator based on medical 
judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above) 
The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 


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8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets 
the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is 
not consistent with those noted in the Investigator’s Brochure. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
8.6.1. 
Adverse Event Reporting Period  
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until either 30 days after last dose of study drugs or initiation of new anticancer therapy, 
whichever occurs first. Immune-mediated AEs (serious or non-serious) should be reported until 
90 days after the last dose of tislelizumab or placebo, regardless of whether or not the patient 
starts a new anticancer therapy. All SAEs considered related to the study drug(s) that are brought 
to the attention of the investigator should be reported regardless of time since the last dose of 
treatment.  
AEs and SAEs should be recorded according to the details in Table 6. For the follow-up period 
for AEs, see Section 8.3.4. For the definition of TEAEs, see Section 9.3.2. 
Table 6: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
Both Treatment Arms  
Event type 
Record new or worsening events that occur during 
this period 
Begin 
End 
SAEs  (not 
treatment-related) 
Signing of 
informed consent 
Up to 30 days after last dose, 
initiation of new anticancer 
therapy, death, withdrawal of 
consent, or loss to follow-up, 
whichever occurs first 
Treatment-related 
SAEs 
Signing of 
informed consent 
Patient death, withdrawal of 
consent, or loss to follow-up, 
whichever occurs first 
Nonserious AEs due to 
PD 
Do not record (see Section 8.6.4) 
Nonserious AEs other 
than those due to PD 
First dose of study 
drug 
Up to 30 days after last dose, 
initiation of new anticancer 
therapy, death, withdrawal of 
consent, or loss to follow-up, 
whichever occurs first 


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Event type 
Record new or worsening events that occur during 
this period 
Begin 
End 
Immune-mediated AEs 
(serious or nonserious) 
First dose of study 
drug 
Up to 90 days after last dose 
(regardless of initiation of new 
anticancer therapy), death, 
withdrawal of consent, or loss to 
follow-up, whichever occurs first 
Abbreviations: AE, adverse event; PD, progressive disease; SAE, serious adverse event. 
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 7.  
Table 7: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee        
 
Timeframe for 
Sending Initial 
Report 
Documentation 
Method 
Timeframe for 
Making Follow-
up Report 
Documentation 
Method 
Reporting 
Method 
All 
SAEs  
Within 24 h of 
first knowledge 
of the SAE 
SAE Report 
As expeditiously 
as possible 
SAE Report 
Electronic 
submission of 
SAE form to 
portal a 
Abbreviations: h, hours; SAE, serious adverse event. 
a SAE reports should be submitted to the sponsor safety database electronically from within the electronic data 
capture system. If the electronic submission is not available for any reason, a paper SAE form should be 
submitted by email or fax. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 8.6.2.1. The SAE Report 
will always be completed as thoroughly as possible with all available details of the event and 
forwarded to the sponsor or designee within the designated time frames. Treatment assignment 
revealed through unblinding (see Section 5.5.4) must not be included in the SAE report. 
If the investigator does not have all information regarding an SAE, he/she must not wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 


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8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will report all SAEs to the sponsor in accordance with the procedures detailed in 
Section 8.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation.  
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
All SUSARs (as defined in Section 8.5), will be submitted to all applicable regulatory authorities 
and investigators for tislelizumab studies. 
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC. The investigator should place copies of 
Safety Reports from the sponsor in the Investigator Site File. 
8.6.3. 
Eliciting Adverse Events  
The investigator or designee will ask patients about AEs by asking the following standard 
questions:  
• How are you feeling?  
• Have you had any medical problems since your last visit?  
• Have you taken any new medicines since your last visit?  
8.6.4. 
Disease Progression  
Disease progression, which is expected in this study population and measured as an efficacy 
endpoint, should not be recorded as an AE term. Similarly, nonserious AEs that are clearly 
consistent with the pattern of progression of the underlying disease and are considered 
unequivocally due to disease progression should not be recorded. However, if there is any 
uncertainty as to whether a nonserious AE is due to disease progression, it should be recorded as 
an AE. All SAEs and deaths regardless of relatedness to disease progression should be recorded 
and reported (see Section 8.6.2.1). 
8.6.5. 
Deaths  
When a patient dies, if the only information available is death and the cause of death is unknown, 
then the death is reported as an AE, eg, “death NOS”. In all other cases, death is captured as an 
outcome. 
8.6.6. 
Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy or within 120 days after the last dose of tislelizumab or placebo or within 
180 days after the last dose of chemotherapy, a pregnancy report form is required to be submitted 
to the sponsor. The pregnancy report must follow the same prompt reporting guidelines 


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described in Section 8.6.2.1. The outcome of the pregnancy, including any premature termination 
of the pregnancy must also be reported to the sponsor.  
While pregnancy itself is not considered to be an adverse event, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE.  
An abortion, whether accidental, therapeutic, or spontaneous should be always reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as an SAE. 
Patients who become pregnant must immediately discontinue treatment (see Section 3.6.1). For 
patients who are no longer pregnant, resumption of treatment may be discussed with the medical 
monitor. 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees  
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation.  
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information (RSI) documents: 
• Tislelizumab Investigator’s Brochure 
• The prescribing information of chemotherapy 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events  
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-mediated (see Section 8.7.2) should be classified as imAEs and 
identified as such in the eCRF AE page. 
8.6.9. 
Recording Infusion-Related Reactions  
The signs and symptoms of an infusion-related reaction should be recorded as the adverse terms 
for those individual signs and symptoms. In assessing whether an adverse event is infusion 
related, note that the symptoms of infusion-related reactions may include, but are not limited to, 
fever, chills/rigor, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, 
urticaria, rash, vomiting, myalgia, dizziness, or hypertension. Severe reactions may include acute 
respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic 
shock. 
8.7. 
Management of AE of Special Interest  
Infusion-related reactions, severe hypersensitivity reactions and imAEs according to the 
NCI-CTCAE criteria are outlined below. 


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8.7.1. 
Infusion-Related Reactions and Hypersensitivity Reactions  
Patients should be closely monitored during and after study drug administration for 
infusion-related reactions and hypersensitivity reactions. See Section 5.2.1 for the monitoring 
periods required. Immediate access to an Intensive Care Unit (ICU) or equivalent environment 
and appropriate medical therapy (including epinephrine, corticosteroids, intravenous 
antihistamines, bronchodilators, and oxygen) must be available to treat infusion-related 
reactions.   
See Appendix 7 for management of infusion-related reactions and hypersensitivity reactions as 
well as treatment modifications. 
8.7.2. 
Immune-Mediated Adverse Events  
In this study, imAEs are of special interest. Potential imAEs are listed in Table 8 below. All AEs 
similar to those listed in the table should be evaluated in patients receiving tislelizumab or 
placebo to determine whether the AE is immune-mediated. The investigator should exclude 
alternative explanations (eg, combination drugs, infectious disease, metabolic causes, toxins, 
disease progression, or other neoplastic causes) with appropriate diagnostic tests that may 
include but are not limited to serologic, immunologic, and histologic (biopsy) data (see 
Appendix 7). If alternative causes have been ruled out and the AE required the use of systemic 
steroids, other immunosuppressants, or endocrine therapy, and it is consistent with an 
immune-mediated mechanism of action, the imAE indicator in the eCRF AE page should be 
checked. 
Recommendations for managing imAEs are detailed in Appendix 7.  


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Table 8: 
Examples of Immune-Mediated Adverse Events        
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; 
Sweet’s syndrome 
Skin (severe-rare) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or 
endoscopic/radiographic evidence of inflammation); pancreatitis; 
hepatitis; aminotransferase (ALT/AST) elevation; bowel perforation 
Endocrine 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with 
features of hypopituitarism, eg, fatigue, weakness, weight gain; 
insulin-dependent diabetes mellitus; diabetic ketoacidosis; adrenal 
insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Musculoskeletal 
arthritis; arthralgia; myalgia; myasthenic syndrome/myasthenia 
gravis, myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Neurologic 
encephalitis; Guillain-Barre syndrome; meningitis; 
meningoradiculitis; meningoencephalitis; neuropathy 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 


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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
The statistical analyses will be performed by the sponsor or designee after data collection is 
completed and the database is locked and released. Details of the statistical analyses will be 
included in a separate Statistical Analysis Plan (SAP).  
9.1. 
Statistical Analysis  
9.1.1. 
Randomization Methods  
As discussed in Section 7.2.3, patients will be randomized using the IRT system for this study by 
permuted block stratified randomization.  
The stratified randomization will be produced, reviewed, and approved by an independent 
statistician. 
9.1.2. 
Analysis Sets  
Intent-to-Treat (ITT) analysis set – Includes all randomized patients. Patients will be analyzed 
according to their randomized treatment arm. This will be the dual primary analysis set for all 
efficacy analyses. 
PD-L1+ analysis set (with tumor and immune cell score [TIC score] ≥ 5% using VENTANA 
PD-L1 [SP263] Cdx Assay. TIC score is the total percentage of the tumor area covered by tumor 
cells with PD-L1 membrane staining and tumor-associated immune cells with PD-L1 staining at 
any intensity) – Includes all randomized patients whose tumors were PD-L1+. Patients will be 
analyzed according to their randomized treatment arms. This will be the dual primary analysis 
set for efficacy analyses. 
Per-Protocol (PP) analysis set – Includes all randomized patients who received at least 1 dose of 
the assigned study drug and had no major protocol deviations. Major protocol deviations will be 
determined and documented before the database lock for the primary analyses. 
Safety analysis set – Includes all patients who received at least 1 dose of study drugs. This will 
be the analysis set for the safety analyses. 
9.1.3. 
Patient Disposition  
The number of patients randomized, treated, discontinued from study drug and/or study and 
those with major protocol deviations will be counted. The primary reason for study drug and/or 
study discontinued will be summarized according to the categories in the eCRF. The end of study 
status (alive, dead, withdrew consent or lost to follow-up) at the data cutoff date will be 
summarized using the data from the eCRF.  
Major protocol deviations will be summarized and listed by each category. 
9.1.4. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized in the ITT analysis set using 
descriptive statistics. Continuous variables include age, weight, vital signs, time since initial 
cancer diagnosis, and time since advanced/metastatic disease diagnosis; categorical variables 


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include, PD-L1 expression, gender, ECOG, geographical region, race, tumor staging, number of 
metastatic sites, metastatic site (eg liver, peritoneal, lung bone, etc.), previous gastrectomy, 
weight loss (< 10% versus ≥ 10%), age (< 65 years versus ≥ 65 years), primary tumor location 
(GEJ vs. gastric), histologic type (well differentiated, moderately differentiated, poorly 
differentiated, unknown differentiated). The histologic type (Lauren Classification) including the 
diffuse-type, intestinal-type, mixed type and unknown status are also collected if available. 
9.1.5. 
Prior and Concomitant Medications  
Prior and concomitant medications will be coded using the WHO Drug Dictionary drug codes. 
Prior and concomitant medications will be further coded to the appropriate Anatomical 
Therapeutic Chemical (ATC) code indicating therapeutic classification. Prior and concomitant 
medications will be summarized and listed by drug and drug class in the Clinical Study Report 
(CSR) for this protocol. Prior medications will be defined as medications that stopped before the 
day of first dose of study drug. Concomitant medications will be defined as medications that 1) 
started before the first dose of study drug and were continuing at the time of the first dose of 
study drug, or 2) started on or after the date of the first dose of study drug up to 30 days after the 
patient’s last dose (as of Safety Follow-up visit). A listing of prior and concomitant medications 
will be included in the CSR for this protocol. 
9.2. 
Efficacy Analyses  
The type I error will be strongly controlled at 0.025 (1-sided) in the primary analysis of OS in 
PD-L1+ and ITT analysis sets using sequential testing method. OS analysis in ITT analysis set 
will be performed only if the OS analysis in the PD-L1+ analysis set is statistically significant 
favoring tislelizumab + chemotherapy. 
Hypothesis testing of the secondary endpoints PFS and ORR in the PD-L1+ and ITT analysis 
sets will be performed at the same time as the interim analysis of OS. Only when the superiority 
of OS in both PD-L1+ and ITT analysis sets have been demonstrated, its alpha of 0.025 (1-sided) 
will be shifted sequentially to the hypothesis testing of the secondary endpoints in order of PFS 
in PD-L1+, ORR in the PD-L1+ analysis set, followed by PFS and ORR in ITT analysis set. The 
inferential test will be stopped at the first non-significant endpoint. Nominal p-values may be 
computed for other efficacy analysis but should be interpreted with caution.   
9.2.1. 
Primary Efficacy Analysis  
OS in the PD-L1+ analysis set: 
The null hypothesis to be tested is: 
H0:  OS in Arm A = OS in Arm B 
against the alternative: 
H1:  OS in Arm A ≠ OS in Arm B 
The primary analysis of OS will be carried out once the targeted number of death events is 
reached. In absence of confirmation of death, patients will be censored either at the date that the 
patient was last known to be alive or the date of data cutoff, whichever comes earlier.  


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OS will be compared between Arm A and Arm B using stratified log-rank test at 1-sided 0.025 
level of significance, stratified by pooled stratification factors of regions of enrollment (east Asia 
versus rest of the world [ROW]), and presence of peritoneal metastasis.  
The median OS and the cumulative probability of OS at every 6 months if estimable, will be 
calculated for each treatment arm and presented with 2-sided 95% CIs. Kaplan-Meier survival 
probabilities for each arm will be plotted over time. OS rate at 12 and 24 months based on 
Kaplan-Meier estimate will be compared between 2 treatment arms for landmark analysis. 
The treatment effect will be estimated by fitting a Cox regression model to the OS times 
including treatment arm as a factor and region of enrollment (east Asia versus ROW) and 
presence of peritoneal metastasis as strata. From this model, the hazard ratio (HR) of OS will be 
estimated and presented with a 2-sided 95% CI. 
These analyses will be performed in the PD-L1+ analysis set as the primary analysis. Outcomes 
in the Per Protocol analysis set will be evaluated as a sensitivity analysis. 
OS in the ITT analysis set: 
Analysis of OS in the ITT analysis set will be performed only if superiority of OS favoring 
tislelizumab + chemotherapy is demonstrated in the PD-L1+ analysis set.   
The hypothesis testing of OS in the ITT analysis set will be carried out similarly at a significance 
level of 0.025 (1-sided) in the stratified analysis (ie, log-rank and Cox regression) stratified by 
pooled stratification factors of regions of enrollment (east Asia versus ROW), PD-L1 expression, 
and presence of peritoneal metastasis. There will be one interim analysis of OS using the 
O’Brien-Fleming boundary approximated by Hwang-Shih-DeCani spending function with the 
gamma parameter set at -4. The non-binding lower (futility) boundary is defined by Hwang-
Shih-DeCani spending function with the gamma parameter set at -12. The interim analysis of OS 
will be performed when approximately 269 deaths in the PD-L1+ analysis set and 538 deaths in 
the ITT analysis set (70% of the target number of OS events in each analysis set) among the 
2 treatment arms have been observed which is estimated to occur approximately 30 months after 
the first patient is randomized. The final analysis of OS will take place after approximately 384 
and 768 death events have been observed in the 2 analysis sets, respectively, which is estimated 
as 48 months after the first patient is randomized. Stopping boundaries in p-value and Z score for 
primary analyses of OS are shown in Table 9. The boundaries will be updated according to the 
actual numbers of events in the interim and final analyses, using the above pre-specified alpha 
spending function.  
 
 
 


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Table 9: 
Stopping Boundaries (in p-value and Z score) of Primary Analysis of OS       
Analysis 
Set 
Analysis 
Time 
(m) 
# 
Events 
p-valuea 
(Z score) 
for 
Efficacy 
p-valuea (Z 
score) for 
Interim 
Futility 
Approxima
te HR 
Threshold 
Cumulative 
Prob of 
Crossing 
Under H1 
PD-L1+ b 
Interim 
analysis 
30 
269 
< 0.0072 
(>2.45) 
> 0.5731 
(< -0.18) 
0.742 
0.47 
Final 
analysis 
48 
384 
< 0.0228 
(> 2.00) 
- 
0.815 
0.80 
ITT 
Interim 
analysis 
30 
538 
< 0.0072 
(>2.45) 
> 0.5384 
(< -0.1) 
0.810 
0.56 
Final 
analysis 
48 
768 
< 0.0228 
(> 2.00) 
- 
0.866 
0.87 
a. 
1-sided 
b. PD-L1+ is 50% of the ITT 
9.2.2. 
Secondary Efficacy Analysis  
PFS assessed by investigators per RECIST v1.1 will be estimated using the Kaplan-Meier (KM) 
method in the PD-L1+ and ITT analysis set. The PFS censoring rule will follow United States 
(US) FDA Guidance for Industry, Clinical Trial Endpoints for Approval of Cancer drugs and 
Biologics (2007) (FDA Guidance for Industry 2007). Data for patients without disease 
progression or death at the time of analysis will be censored at the time of the last adequate 
tumor assessment. Data for patients who are lost to follow-up prior to documented disease 
progression will be censored at the last adequate tumor assessment date when the patient is 
known to be progression free. Data for patients who start to receive new anticancer therapy will 
be censored at the last adequate tumor assessment date prior to the introduction of new therapy.  
The median PFS and the cumulative probability of PFS at every 3 months including PFS-6m and 
PFS-12m if estimable, will be calculated for each treatment arm and presented with 2-sided 95% 
CIs. Kaplan-Meier survival probabilities for each arm will be plotted over time.  
The treatment effect will be estimated by fitting a Cox regression model to the PFS times 
including treatment arm as a factor and region of enrollment (east Asia versus ROW), PD-L1 
expression (only when testing PFS in the ITT analysis set), and presence of peritoneal metastasis 
as strata. From this model, the hazard ratio (HR) of PFS will be estimated and presented with a 
2-sided 95% CI. 
The null hypotheses of no difference in ORR per RECIST 1.1 assessed by investigators will be 
tested in a Cochran-Mantel-Haenszel (CMH) test adjusting for pooled stratification factors in the 
ITT and PD-L1+ analysis sets. Patients with no post-baseline response assessment (for any 
reason) will be considered non-responders. The 2-sided 95% CIs for the odds ratio in ORR will 
be calculated, as well as Clopper-Pearson 95% CIs of ORR for each treatment arm. 
Duration of response (DOR) assessed by investigators will be analyzed similarly to PFS in the 
responders. 


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Change from baseline of EORTC QLQ-STO22, EORTC QLQ-C30 and EQ-5D-5L will be 
compared between Arms A and B.  
Both EORTC scales and single items will be scored on a categorical scale and transformed to a 
0-100 scale. In addition to change from baseline scores, minimal important differences defined 
as 10-point change from baseline will be used to calculate the proportion of patients with 
clinically meaningful deterioration over time. Descriptive statistics will be used to show the 
changes from baseline and percentage of patients with deterioration at each time point in each 
arm, unless otherwise specified. 
BOR is defined as the best response per RECIST v1.1 recorded from randomization till data cut, 
progressive disease or start of new anticancer treatment. The proportion and its corresponding 
Clopper-Pearson 95% CI for each of the response categories (CR, PR, SD, and PD) will be 
presented by treatment arm. Time to response (TTR) will be summarized using descriptive 
statistics, such as mean, median, and standard deviation. Only patients who have achieved an 
objective response will be included in the analysis of TTR. 
DCR and clinical benefit rate (CBR) assessed by investigators will be analyzed similarly to ORR 
in the ITT and PD-L1+ analysis sets. 
9.2.3. 
Exploratory Efficacy Analysis  
To calculate progression-free survival after next line of treatment (PFS2), data from patients 
without disease progression after next-line of treatment or death at the time of analysis will be 
censored at the last time known to be alive. Kaplan-Meier (KM) method as described in the PFS 
and OS analyses will be used in the analysis of PFS2. 
9.3. 
Safety Analyses  
Safety will be assessed by the monitoring and recording of all AEs graded by NCI-CTCAE v5.0. 
Laboratory values (eg, hematology, clinical chemistry, coagulation and urinalysis), dosing, vital 
signs, ECGs, and physician examinations will also be evaluated in defining the safety profile of 
each treatment arm. Descriptive statistics will be used to analyze all safety data in the Safety 
analysis set. 
9.3.1. 
Extent of Exposure  
Extent of exposure to each study drug will be summarized descriptively as the number of doses 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose reduction, interruption, dose delay, and drug 
discontinuation due to AEs will be summarized for each study drug. Frequency of the above dose 
adjustments and discontinuation will be summarized by category.  
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.3.2. 
Adverse Events  
The AE verbatim descriptions (investigator’s description from the eCRF) will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA). Adverse events will be coded to 


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MedDRA (Version 20.0 or higher) lower level term, preferred term and primary system organ 
class (SOC). 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the date of first dose of study drug and up to 30 days following study 
drug discontinuation (Safety Follow-up visit) or initiation of new anticancer therapy, whichever 
comes first. The TEAE classification also applies to imAEs that are recorded up to 90 days after 
the last dose of tislelizumab or placebo, regardless of whether or not the patient starts a new 
anticancer therapy. Only those AEs that were treatment emergent will be included in summary 
tables. All AEs, treatment-emergent or otherwise, will be presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and Preferred Term. A patient will be counted only once by the highest severity grade per 
NCI-CTCAE v5.0 within an SOC and Preferred Term, even if the patient experienced more than 
1 TEAE within a specific SOC and preferred term. The number (percentage) of patients with 
TEAEs will also be summarized by relationship to the study drug. Treatment-related AEs include 
those events considered by the investigator to be related to a study drug or with missing 
assessment of the causal relationship. SAEs, deaths, TEAEs with ≥ Grade 3 severity, imAEs, 
treatment-related TEAEs and TEAEs that led to treatment discontinuation, dose interruption, 
dose reduction, or dose delay will be summarized. 
9.3.3. 
Laboratory Analyses  
Clinical laboratory (eg, hematology, serum chemistry, urinalysis) values will be evaluated for 
each laboratory parameter as appropriate. Abnormal laboratory values will be flagged and 
identified as those outside (above or below) the normal range. Reference (normal) ranges for 
laboratory parameters will be provided. Descriptive summary statistics (eg, n, mean, standard 
deviation, median, minimum, maximum for continuous variables; n [%] for categorical 
variables) for laboratory parameters and their changes from baseline will be calculated. 
Laboratory values will be summarized by visit and by worst postbaseline visit. 
Laboratory parameters that are graded by NCI-CTCAE v5.0 will be summarized by 
NCI-CTCAE grade. In the summary of laboratory parameters by NCI-CTCAE grade, parameters 
with NCI-CTCAE grading in both high and low directions (eg, glucose, potassium, sodium) will 
be summarized separately. 
9.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, heart rate, 
and temperature) and changes from baseline will be presented by visit for all visits. Vital signs 
will be listed by patient and visit. 
9.3.5. 
Ophthalmologic Examination  
Ophthalmologic examination results will be listed by patient. 
9.3.6. 
Pulmonary Function Test  
Pulmonary function test results will be listed by patient if available. 


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9.4. 
Pharmacokinetic Analysis  
Individual tislelizumab serum concentrations will be tabulated by scheduled time of collection.  
Additional PK analyses may be conducted as appropriate. Exposure-response (efficacy or safety 
endpoints) analysis such as population PK, PK/pharmacodynamic analyses may be carried out if 
supported by data. Any such analysis will be reported separately from the main study report. 
9.5. 
Immunogenicity Analyses  
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidence of positive ADA and 
neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy and safety may be evaluated if data allow. 
9.6. 
Sample Size Consideration  
The sample size calculation is based on the primary efficacy analyses of OS in the comparison 
between Arms A and B in the ITT and PD-L1+ analysis sets. The number of events needed is 
based on the assumption of an exponential distribution. The 1-sided overall type I error in the 
study is set at 0.025. Table 10 summarizes the statistical assumption and power in the sample 
size calculation. Assuming a 50% PD-L1+ prevalence rate, a total of 928 patients including 
approximately 464 (ie, 50%) in the PD-L1+ subset is required in order to observe targeted 
numbers of OS events at the defined time periods as shown in Table 9 above. Assuming a 
roughly 5% dropout rate, approximately 980 patients will be enrolled in a 1:1 randomization 
ratio over 24 months period at enrollment rates of 17 patients/month in the first 2 months, 34 
patients/month in the next 2 months and 44 patients/month in the last 20 months. The enrollment 
assumptions including percentage of PD-L1+ patients will be monitored during the enrollment; 
thus sample size and timeline could be adjusted accordingly. Enrollment of patients whose 
tumors are PD-L1- might be stopped if necessary, to ensure that the percentage of PD-L1+ is no 
less than 50% of the ITT analysis set. The primary analyses will be performed when the target 
number of events is observed. An interim analysis of OS (see Table 9) is planned after 
approximately 70% of the total planned death events have occurred in both ITT and PD-L1+ 
analysis sets. 
Table 10: 
Hazard Ratio and Median OS Assumption, Number of Events, Alpha And 
Power in The Primary Hypothesis Tests  
Analysis Set 
HR  
Median in 
Arm A (in 
months)  
Median in 
Arm B (in 
months) 
# Events 
Alpha 
Power 
PD-L1+ 
0.75 
15.3 
11.5 
384 
0.025 
80% 
ITT 
0.8  
14.4 
11.5 
768 
0.025 
87% 
9.7. 
Interim Analyses  
This is a randomized, double-blind, placebo-controlled, Phase 3 clinical study. Data summary by 
actual treatment assignment and PD-L1 status will be limited and documented. Study team at the 


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sponsor will not have access to the summary or individual patient reports by actual treatment 
group during the study.  
An interim analysis for OS superiority (see Section 9.2.1) will be performed by an independent 
statistician external to the sponsor. The independent statistician will work with the blinded study 
statistician to provide statistical outputs to the IDMC as described in the IDMC charter and 
perform any ad-hoc analyses requested by the IDMC. 
Safety monitoring will be conducted continuously through end of treatment visit. 


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10. 
STUDY COMMITTEES AND COMMUNICATION  
10.1. 
Independent Data Monitoring Committee  
Regular safety monitoring (at least every 6 months), and efficacy monitoring will be performed 
by an IDMC. The first IDMC safety review will occur after at least 50 patients have been 
randomized to study treatment (ie, approximately 25 patients per treatment arm) and have been 
on treatment for ≥1 month in order to determine if the proposed dosing schedule of tislelizumab 
or placebo plus chemotherapy is safe and tolerable. The IDMC will also be responsible for 
reviewing the unblinded results of interim analysis of OS and making recommendations for 
discontinuation or modification of the study. The function and membership of the IDMC will be 
described in the IDMC charter. 
In addition to the planned IDMC review(s), ad hoc reviews may take place based on new 
information.  
Following IDMC review and discussion, the sponsor will make all final decisions regarding any 
change in study conduct. Please see the details in the IDMC charter. 


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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study may be fully documented. Such records include, but are not limited to, the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals. In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data. 
11.1. 
Access to Information for Monitoring  
In accordance with International Council for Harmonization (ICH) GCP guidelines, the study 
monitor must have direct access to the investigator’s source documentation in order to verify the 
data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during the course of these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections  
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by a regulatory authority the investigator agrees to notify the sponsor or its designee 
immediately. The investigator agrees to provide to the representatives of a regulatory agency or 
representatives of the sponsor with access to records, facilities, and personnel for the effective 
conduct of any inspection or audit. 


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12. 
QUALITY ASSURANCE AND QUALITY CONTROL  
12.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements. Alternatively, the 
sponsor will file the protocol to the appropriate regulatory agency before the study is initiated at 
a study center in that country. 
12.2. 
Quality Assurance  
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Site Inspections  
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study. 
12.4. 
Drug Accountability  
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledging the receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records and returned or 
destroyed study product. Dispensation records will document quantities received from the 
sponsor’s designated depot or its designee and quantities dispensed to patients, including 
batch/lot number, date dispensed, patient identifier number, and the initials of the person 
dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with the sponsor’s requirements specified in 
the Pharmacy Manual. At appropriate times during the conduct of the study or at the end of the 
study, after final drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures. If the site cannot meet the sponsor’s requirements specified in the Pharmacy Manual 
for disposal, arrangements will be made between the site and the sponsor or its representative for 
destruction or return of unused study drug supplies. 


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All drug supplies and associated documentation will be reviewed periodically and verified by the 
study monitor over the course of the study. 


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13. 
ETHICS/PROTECTION OF HUMAN PATIENTS  
13.1. 
Ethical Standard  
This study will be conducted by the investigator and the study center in full conformance with 
the guidelines for Good Clinical Practice (ICH E6) and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the patient. The study will also comply with the Definitions and 
Standards for Expedited Reporting (ICH E2A). 
13.2. 
Institutional Review Board/Independent Ethics Committee  
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted, reviewed, and approved by the IRB/IEC before the study is 
initiated. In addition, any patient recruitment materials must be approved by the IRB/IEC. Copies 
of the IRB/IEC correspondence and approval of the amended ICF or other information and the 
approved amended ICF/other information must be forwarded to the sponsor promptly. 
The investigator is responsible for providing written summaries of the status of the study to the 
IRB/IEC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC. Investigators are also responsible for promptly informing 
the IRB/IEC of any protocol amendments. In addition to the requirements for reporting all AEs 
to the sponsor, investigators must comply with requirements for reporting SAEs to the local 
health authority and the IRB/IEC. Investigators may receive written investigational new drug 
(IND) safety reports or other safety-related communications from the sponsor. Investigators are 
responsible for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/IEC and 
archived in the site’s study file.  
13.2.1. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements. Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and /or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand and sign each revised ICF 
confirming their willingness to remain in the study. 
13.3. 
Informed Consent  
The sponsor’s sample ICF will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. The final IRB/IEC-approved ICFs must be provided to 
the sponsor for health authority submission purposes according to local requirements.  


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The ICFs must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained before participation in the study.  
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate. The 
final revised IRB/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes.  
Patients must reconsent to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study, if the updated information may be relevant to the patient’s 
willingness to continue participation in the study. For any updated or revised ICFs, the case 
history or clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained using the updated/revised ICFs for continued 
participation in the study. All patients in the Long-term/Survival Follow-up will reconsent to the 
updated ICF if the updates may be relevant to the patient’s willingness to continue participation 
in the study, either during on-site visits or by phone/video-call/mail, according to local 
regulations. The IRB/IEC submission letters, if applicable, should specify the approach taken 
(phone, video-call, or mail) according to local regulations. The process by which the consent is 
obtained from a patient during the Long-term/Survival Follow-up should be documented in the 
patient’s case history or clinical records. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time.  
13.4. 
Patient and Data Confidentiality  
The investigator, institution, sponsor, and site will maintain confidentiality and privacy standards 
for the collection, storage, transmission, and processing of patients’ personal and medical 
information by following applicable laws and regulations related to the confidentiality, use, and 
protection of such information, including the ICH Good Clinical Practice Guideline, as 
implemented locally. Such laws may be more stringent than the requirements in this protocol. 
The investigator and site shall code the personal and medical information obtained during the 
study with a unique patient identification number assigned to each patient enrolled in the study. 
The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Unless required to be provided by laws or 
regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the investigator and site must ensure that any personal and medical information 
transmitted to sponsor or its service providers is: 1) required by the protocol, and 2) 
appropriately de-identified (eg, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients are NOT shared: 
• names or initials (full or partial); 
• full dates of birth; 


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• contact information (such as phone numbers or home or email addresses);  
• numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part 
of this study; 
• geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  
• information about marital status, family, or household members; employment, sex 
life, sexual preference, or other sensitive data that is not relevant to the study. 
Patient personal and medical information obtained during this study is confidential and may only 
be disclosed to third parties as permitted by the signed ICF (or a separate authorization for the 
use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law. 
In limited circumstances, such as in connection with insurance purposes or patient support 
services ancillary to certain study sites (eg, for patient travel or reimbursement), the investigator 
and site may provide certain of this personal information to the sponsor or its representatives. 
Such personal information may not be provided as part of the study protocol (eg, as part of the 
eCRF, on samples or reports submitted to the central lab, on safety reporting forms [except in 
China], or on product dispensing logs provided to the sponsor, etc). 
Investigator and site must use only the specific forms and clinical trial systems, (eg, the 
electronic data capture [EDC] system and any secure file transfer platforms [SFTPs]) designated 
by sponsor for sharing and transfers of personal and medical information.  
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
investigator, site, and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable laws. If the sponsor identifies personal or medical information that 
was not properly de-identified, it may be required to report the disclosure under local applicable 
laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes where allowed by local 
law or the patient’s signed ICF.  
Information generated during this study must be available for inspection upon request by 
representatives of the United States Food and Drug Administration (US FDA), the China 
National Medical Products Administration (China NMPA), and all other national and local 
health authorities; by sponsor monitors, representatives, and collaborators; and by the IRBs/IECs 
for each study site, as appropriate.  
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator's Brochure, this protocol, eCRFs, the investigational drugs, and any other 
study information, are confidential and remain the sole and exclusive property of the sponsor 
during the conduct of the study and thereafter. This information is not to be disclosed to any third 
party (except employees or agents directly involved in the conduct of the study or as required by 
law) without prior written consent from the sponsor. The investigator further agrees to take all 


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reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
Demographic factors such as age, gender, race, and ethnicity could influence the effects (safety 
and efficacy) of medicines and the risk/benefit assessment in different populations. Race and 
ethnicity data are collected in accordance with ICH guidance (ICH E5 1998, ICH E17 2017) 
adopted by the EMA and US FDA, to understand whether race/ethnicity could influence the PK, 
safety, and/or efficacy of the study drug. For example, population PK analysis is a 
well-established, quantitative method that can quantify and explain the variability in drug 
concentrations among patients. Such variability can be attributed to intrinsic factors (eg, body 
weight, age, gender, race/ethnicity), or to extrinsic factors (eg, concomitant medications), and 
can lead to clinically relevant changes in drug concentrations that require a change in the dose or 
dosing regimen. Results from race/ethnicity and other demographic analyses will be incorporated 
into drug product labeling to provide guidance on safety and efficacy variations (if any) linked to 
certain populations (eg, race or ethnic group) as well as any potential dose adjustment needed for 
those populations. Therefore, collecting race/ethnicity data in the study is essential to understand 
whether race/ethnicity could influence the PK, safety, and/or efficacy. 
13.5. 
Financial Disclosure  
Investigators (including any subinvestigators and coinvestigators) are required to provide the 
sponsor with sufficient accurate financial information in accordance with regulations to allow the 
sponsor to submit complete disclosure or certification to the absence of certain financial interest 
of the clinical investigators and/or disclose those financial interests, as required to the 
appropriate health authorities. This is intended to ensure financial interests and arrangements of 
the clinical investigators with the sponsor that could affect reliability of data submitted to health 
authorities are identified and disclosed by the sponsor. Investigators are responsible for 
providing information about their financial interests before participation in the study, and to 
update this information if any relevant changes occur during the study and for 1 year after 
completion of the study (ie, last patient, last visit). 


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14. 
DATA HANDLING AND RECORD KEEPING  
14.1. 
Data Collection and Management Responsibilities  
14.1.1. 
Data Entry in the Electronic Case Report Form  
All study-related data collected or received by the investigator or study team shall be promptly 
entered into the eCRFs. In no event should the entry of the study data into the eCRF be later than 
what is stipulated in the site contract after the data is collected or received by the investigator or 
study team without prior communication with and approval by the sponsor. 
14.1.2. 
Data Collection  
Data required by the protocol will be entered into an electronic data capture (EDC) system.  
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The e-signature of the investigator or designee must be 
provided in the EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of the sponsor and should not be made 
available in any form to third parties without written permission from the sponsor, except for 
authorized representatives of the sponsor or appropriate regulatory authorities.  
14.1.3. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol, will be stored by the sponsor at the end of the study.  
Standard procedures (including following data review guidelines, computerized validation to 
produce queries and maintenance of an audit file that includes all database modifications) will be 
followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. Checking the 
eCRFs for completeness, clarity and cross checking with source documents is required to 
monitor the progress of the study. Direct access to source data is also required for inspections 
and audits and will be carried out with due consideration given to data protection and medical 
confidentiality. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA by the lowest-level term, Preferred Term, and primary 
SOC. Concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary. Concomitant diseases/medical history will be coded using MedDRA. 


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14.2. 
Data Integrity and In-house Blinding  
In this double-blind, placebo-controlled study, all patients and personnel involved in the conduct 
and interpretation of the study, including the investigators, BeiGene study team, and site 
personnel, will be blinded to the treatment assignment. Randomization data will be kept strictly 
confidential; filed securely by the appropriate groups for BeiGene, the IRT and the IDMC; and 
will be accessible only to authorized persons per SOPs until the time of unblinding.  
PD-L1 status of each individual patient will be blinded to BeiGene study team in order to avoid 
unwanted bias. PD-L1 expression status in the IRT will not be accessible to anyone except for 
independent statistician, BeiGene IRT manager, and IDMC. PD-L1 expression status will not be 
included in the listings generated for data review either. Granted study teams from BeiGene and 
BeiGene’s cooperator can only review the summarized proportions of patients with different PD-
L1 expression levels in order to monitor PD-L1 prevalence in the study. 
14.3. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least 1 of the following categories: 1) investigator’s study file, and 2) patient 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC, and governmental approval with correspondence, ICFs, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include documents such as 
(although not be limited to) the following: patient hospital/clinic records, physician’s and nurse’s 
notes, appointment book, original laboratory reports, ECG, electroencephalogram, x-ray, 
pathology and special assessment reports, consultant letters, screening and enrollment logs, etc.  
After closure of the study, the investigator must maintain all study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval, when needed (eg, 
audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel. Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating a hard copy, if required. Furthermore, the investigator must 
ensure that there is an acceptable backup of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements, local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to ≥ 15 years. 


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The investigator must notify the sponsor of any changes in the archival arrangements, including, 
but not limited to the following: archival at an offsite facility, or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 
store these in sealed containers away from the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage away from the site. 
Subject to patient consent, or as otherwise allowed under applicable law, biological samples at 
the conclusion of this study may be retained ≤ 10 years or as allowed by your IRB/IEC, 
whichever is shorter. 
14.4. 
Protocol Deviations  
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert that they will apply 
due diligence to avoid protocol deviations and shall report all protocol deviations to the sponsor. 
The investigator is to document and explain any deviations from the approved protocol. Any 
major deviations that might impact patient safety and/or data integrity must be promptly reported 
by the investigator to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures. 
14.5. 
Study Report and Publications  
A clinical study report will be prepared and provided to the regulatory agency(ies). The sponsor 
will ensure that the report meets the standards set out in the Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance, and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study. The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential. As this is a multicenter study, the first publication or disclosure 
of study results shall be a complete, joint multicenter publication or disclosure coordinated by 
the sponsor. Thereafter, any secondary publications will reference the original publication(s). 
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of Medical 
Journal Editors, 2018). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 


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from this study will be presented in the investigator’s clinical study agreement. Each investigator 
agrees that, in accordance with the terms of the clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 
14.6. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Collection of all study documents for the trial master file filing according to GCP and 
local regulation 
• Shipment of samples (including, but not limited to, those for PK, ADA, and 
biomarkers) to the assay laboratory for central laboratory analysis according to 
protocol and laboratory manual requirements  
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for any reason. 
Potential reasons for suspension or discontinuation include but are not limited to, safety or 
ethical issues or noncompliance with this protocol, GCP, the sponsor’s written instructions, the 
clinical study agreement, or applicable laws and regulations. If the sponsor determines such 
action is needed, the sponsor will discuss this with the investigator (including the reasons for 
taking such action) at that time. When feasible, the sponsor will provide advance notification to 
the investigator of the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons. The sponsor will also inform the 
regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action. If required by applicable regulations, the investigator must inform the IRB/IEC promptly 
and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor. In 
addition, arrangements will be made for the return of all unused study drug(s) in accordance with 
the applicable sponsor procedures for the study.  
Financial compensation to the investigators and/or institutions will be in accordance with the 
clinical study agreement established between the investigator and/or institutions and the sponsor. 
14.7. 
Information Disclosure and Inventions  
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights that are conceived or reduced to practice by the study center personnel during the 


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course of or as a result of the study are the sole property of the sponsor, and are hereby assigned 
to the sponsor. 
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel. This 
information and data will not be used by the investigator or other study center personnel for any 
purpose other than conducting the study without the prior written consent of the sponsor.  
These restrictions do not apply to the following: 
• Information that becomes publicly available through no fault of the investigator or 
study center personnel 
• Information that is necessary to disclose in confidence to an IRB/IEC solely for the 
evaluation of the study 
• Information that is necessary to disclose to provide appropriate medical care to a 
patient 
• Study results that may be published as described in Section 14.5 
If a written contract for the conduct of the study is executed and it includes provisions 
inconsistent with this statement, that contract’s provisions shall apply rather than this statement. 
 


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15. 
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intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol. 
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Al-Batran SE, Hartmann JT, Probst S, et al. Phase III trial in metastatic gastroesophageal 
adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the 
Arbeitsgemeinschaft Internistische Onkologie.  J Clin Oncol. 2008 Mar 20;26(9):1435-42. doi: 
10.1200/JCO.2007.13.9378.  
Amedeo A, Niccolai E, and D'Elios MM. T cells and adoptive immunotherapy: recent 
developments and future prospects in gastrointestinal oncology. Clinical and Developmental 
Immunology, 2011:17.  
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APPENDIX 1. SCHEDULE OF ASSESSMENTS  
Assessment 
Screening1 
Treatment Cycles 
Safety Follow-
up3 
Survival 
Follow-
up4 
Cycles 1 to 3  
(every 21 days) 
Cycle 4 and 
Subsequent 
Cycles 
(Every 21 
Days) 
End of 
Treatment  
Visit2 
Days (Window) 
-28 to ~ -1 
1 
8 (± 2)  
15 (± 2) 
1 (± 3) 
0 to 7 Days 
30 ± 7 Days 
After Last 
Dose 
Every 
3 Months 
± 14 days 
Informed consent1 
x 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
Randomization5 
x 
 
 
 
 
 
 
 
Demographics/medical 
history/prior medications 
x 
 
 
 
 
 
 
 
Cancer history6 
x 
 
 
 
 
 
 
 
Vital signs/ 
height and weight7 
x 
x 
x 
x 
x 
x 
x 
 
Physical examination8 
x 
x 
 
 
x 
x 
x 
 
ECOG Performance 
Status 
x 
x 
 
 
x 
x 
x 
 
12-lead ECG9 
x 
As clinically indicated 
x 
 
Adverse events10 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
 
Hematology11 
x 
x 
x 
x 
x 
x 
x 
 


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Assessment 
Screening1 
Treatment Cycles 
Safety Follow-
up3 
Survival 
Follow-
up4 
Cycles 1 to 3  
(every 21 days) 
Cycle 4 and 
Subsequent 
Cycles 
(Every 21 
Days) 
End of 
Treatment  
Visit2 
Days (Window) 
-28 to ~ -1 
1 
8 (± 2)  
15 (± 2) 
1 (± 3) 
0 to 7 Days 
30 ± 7 Days 
After Last 
Dose 
Every 
3 Months 
± 14 days 
Serum chemistry11 
x 
x 
x  
x  
x 
x 
x 
 
Coagulation parameters 
11,12 
x 
x 
 
 
x 
x 
x 
 
Urinalysis11 
x 
As clinically indicated  
 
Pregnancy test13 
x 
x 
 
 
x 
 
Thyroid function14 
x1 
 
 
 
x14 
 
x 
 
HBV/HCV tests15 
x 
Once at least every 4 cycles for patients who have detectable HBV DNA at Screening  
 
Pulmonary function 
tests16 
x 
 
 
 
 
 
 
 
Optical coherence 
tomography (or 
equivalent diagnostic 
test) and visual acuity 
tests17 
x 
 
 
 
x 
x18 
x18 
 
Pharmacokinetics19 
 
x 
 
 
x 
 
x 
 
Anti-tislelizumab 
antibodies20 
 
x 
 
 
x 
 
x 
 
Tumor assessment21 
x 
 
 
 
x 
x2 
 
x 
Archival tumor tissue22 
x 
 
 
 
 
 
 
 


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Assessment 
Screening1 
Treatment Cycles 
Safety Follow-
up3 
Survival 
Follow-
up4 
Cycles 1 to 3  
(every 21 days) 
Cycle 4 and 
Subsequent 
Cycles 
(Every 21 
Days) 
End of 
Treatment  
Visit2 
Days (Window) 
-28 to ~ -1 
1 
8 (± 2)  
15 (± 2) 
1 (± 3) 
0 to 7 Days 
30 ± 7 Days 
After Last 
Dose 
Every 
3 Months 
± 14 days 
Fresh tumor tissue 23 
x 
 
 
 
 
x 23 
 
 
Tislelizumab or placebo 
administration24 
 
x 
 
 
x 
 
 
 
Chemotherapy 
administration25 
 
x 
 
 
x 
 
 
 
EORTC-QLQ-C3026 
/EQ-5D-5L 
x 
x 
 
 
x 
x 
 
 
EORTC-QLQ-STO2226 
x 
x 
 
 
x 
x 
 
 
Survival status 
 
 
 
 
 
 
 
x 
Blood sample collection27 
x 
x 
x 
x 
 
 
Abbreviations: AE, adverse event; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EORTC QLQ-STO22, QLQ Module for Gastric Cancer; FFPE, formalin-fixed 
paraffin-embedded; HBcAb, hepatitis B core antibody; HB sAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HB sAb, hepatitis B 
surface antibody; imAE, immune-mediated adverse event; IRT, interactive response technology; IV, intravenous; MRI, magnetic resonance imaging; 
NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PK, pharmacokinetic; PO, orally; Q3W, once every 3 weeks; 
RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; TSH, thyroid stimulating hormone; v, version. 
 
1. Written informed consent is required prior to performing any study-specific tests or procedures. Informed consent may be obtained prior to the screening 
window allowing the acquisition of tumor biopsy sample and submission of fresh or archived tumor sample, which must be analyzed prior to randomization. 
Results of standard of care tests or examinations performed prior to obtaining informed consent and within 28 days prior to randomization may be used for 
Screening assessments rather than repeating such tests. Please refer to Appendix 14 for HER2 assessment pathological review guideline. 


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2. The End of Treatment Visit is conducted when the investigator determines that study drug(s) will no longer be used. If routine laboratory tests (eg, 
hematology, serum chemistry) are completed within 7 days before the End of Treatment Visit, tests need not be repeated. Tumor assessment is not required 
at the End of Treatment Visit provided that fewer than 6 weeks have passed since the last assessment. 
3. The Safety Follow-up Visit is required to be conducted 30 days (± 7 days) after the last dose of study drug(s), or before the initiation of a new anticancer 
treatment, whichever occurs first. In addition, telephone contacts with patients should be conducted to assess imAEs and concomitant medications (if 
appropriate, ie, associated with an imAE or is a new anticancer therapy) at 60 days (±14 days), and 90 days (±14 days) after the last dose of tislelizumab or 
placebo, regardless of whether or not the patient starts a new anticancer therapy. If patients report a suspected immune-related AE at a telephone follow-up 
contact, the investigator should arrange an unscheduled visit if further assessment is indicated.  
4. Survival Follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (± 14 days) 
after the Safety Follow-up Visit until death, loss to follow-up, withdrawal of consent, or study termination by sponsor. All patients will be followed for 
survival and subsequent anticancer therapy information unless a patient requests to be withdrawn from follow-up. 
5. Patients will be randomized via IRT. All patients are required to receive study treatment within 3 days of randomization. 
6. Include pathologic diagnosis, stage at screening, tumor location, location of metastatic disease at study baseline, an assessment of prior surgery, prior 
radiotherapy, prior drug therapy, including start and stop dates, best response and reason for discontinuation. Radiographic studies performed prior to study 
entry may be collected for review by the investigator. 
7. Vital signs collected on study include temperature, pulse rate, and blood pressure. For the first infusion of tislelizumab or placebo, the patient’s vital signs 
are required to be recorded within 60 minutes before, during, and within 30 minutes after the infusion of tislelizumab. For subsequent infusions, vital signs 
will be collected within 60 minutes before infusion and if clinically indicated, during and within 30 minutes after the infusion. The height is only measured 
at screening. 
8. Physical examination: A complete physical examination should include an evaluation of the head, eyes, ears, nose, throat, cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems at screening. At subsequent visits (or as clinically indicated), limited, symptom-
directed physical examinations should be performed. 
9. The ECG recordings will be obtained during Screening, the Safety Follow-up Visit, and as clinically indicated at other time points. Patients should be resting 
for at least 10 minutes prior to each ECG collection. 
10. The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0. All AEs will also be evaluated for seriousness. After the informed consent form 
has been signed, but prior to the administration of study drug, only SAEs should be reported. After the first dose of study drug, all AEs and SAEs, regardless 
of their assessed relationship to study drug, are to be reported until either 30 days after the last dose of study treatment or the initiation of new anticancer 
therapy, whichever occurs first. All imAEs will be reported for 90 days after the last dose of tislelizumab or placebo, regardless of whether or not the patient 
starts a new anticancer therapy. All drug-related SAEs will be recorded by the investigator after treatment discontinuation until patient death, withdrawal of 
consent, or loss to follow-up, whichever occurs first. 
11. Local and/or central laboratory assessments on serum chemistry, hematology, coagulation, and urinalysis will be conducted, of which certain elements will 
be collected as specified in Appendix 2. If laboratory tests at screening are not performed within 7 days prior to the administration of study drugs, these tests 
should be repeated and reviewed before study drugs administration. Hematology and serum chemistry (including liver function tests) will be performed 
weekly for the first 3 cycles and then at the beginning of each subsequent cycle (data collected as specified in Appendix 2). After Cycle 1, results are to be 
reviewed within 72 hours before study drug administration. Urinalysis is to be conducted during the treatment period and Safety Follow-up period as 
clinically indicated. Refer to Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities.  
12. Includes international normalized ratio, prothrombin time (or prothrombin time ratio), and activated partial thromboplastin time. 
13. Urine pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative 
within 7 days prior to randomization. Urine pregnancy tests will be performed at each visit prior to dosing (exception for China but should be implemented if 


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clinically indicated, and at end of treatment or safety follow up visit). A serum pregnancy test must be performed if the urine pregnancy test is positive or 
equivocal. 
14. Analysis of FT3, FT4, and TSH will be performed by a central laboratory or the local study site laboratory. Thyroid function tests will be performed at 
Screening and every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc), and at Safety Follow-up Visit. 
15. Testing will be performed by local and/or central laboratory at Screening and will include HBV/HCV serology (HB sAg, HB sAb, HB cAb, and HCV 
antibody) and viral load assessment (HBV and HCV) will be required if clinically indicated. Patients who have detectable HBV DNA at Screening will 
perform a viral load test at least every 4 cycles (ie, Day 1 of Cycle 5, 9, 13, etc). 
16. Patients who are suspected or known to have serious/severe respiratory conditions or exhibit significant respiratory symptoms unrelated to the underlying 
cancer will have pulmonary function testing which may include but is not limited to spirometry and assessment of diffusion capacity done during the 
Screening period to assist the determination of suitability on the study. 
17. Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test for retinal examination) captured as standard of care prior to 
obtaining written informed consent and within 28 days of randomization may be used rather than repeating tests. Eye exam, visual acuity test, and optical 
coherence tomography (or equivalent diagnostic test) will be assessed at the Screening Visit. Patients will undergo repeat assessments approximately every 
15 weeks (± 7 days) 
18. The ophthalmologic assessments including eye exam, visual acuity test, and OCT (or equivalent diagnostic test) should only be performed once at either the 
EOT or during safety follow-up. 
19. Procedures for collection of PK samples are described in the Laboratory Manual. Predose (within 60 minutes before starting infusion) samples are required 
to be collected at Day 1 of Cycles 1, 2, 5, 9 and 17; A postdose (within 30 minutes after completing tislelizumab or placebo infusion) sample is required to 
be collected at Day 1 of Cycles 1 and 5. An additional PK sample is required to be collected at the Safety Follow-up. Should a patient present with any 
≥ Grade 3 imAE, an additional blood PK sample may be taken to determine the serum concentration of tislelizumab or placebo. These tests are required 
when it is allowed by local regulations/IRBs/ECs. In the event of dose delay or dose discontinuation, please refer to the Laboratory Manual for PK/ADA 
sample collection.  
20. Blood used to test for anti-tislelizumab antibodies should be collected within 60 minutes before beginning the Day 1 infusion of Cycles 1, 2, 5, 9, and 17 and 
at the mandatory Safety Follow-up Visit. All samples should be drawn at the same time as blood collection for predose PK analysis. These tests are required 
when it is allowed by local regulations/IRBs/ECs. 
21. Radiological images captured as standard of care prior to obtaining written informed consent and within 28 days of randomization may be used rather than 
repeating tests. All measurable and evaluable lesions are required to be assessed and documented at the Screening Visit. An MRI (or CT scan if MRI is 
contraindicated or not readily available) of the head may be required at screening based on clinical judgement; bone scan or 18F-NaF PET is required if 
clinically indicated. The same radiographic procedure must be used throughout the study for each patient. 
 
The investigator must review radiograph results before dosing at the next cycle. Patients will undergo tumor assessments approximately every 6 weeks 
(±7 days) during the first 48 weeks and every 9 weeks (±7 days) after 48 weeks (based on RECIST v1.1 assessment) from randomization. The investigator 
may perform additional scans or more frequent assessments if clinically indicated. See Section 7.5 for more information. Patients who discontinue study 
treatment early for reasons other than disease progression (eg, toxicity) will continue to undergo tumor assessments following the original plan until the 
patient experiences disease progression, withdraws consent, dies, is lost to follow-up, or until the study terminates, whichever occurs first. Treatment beyond 
initial investigator-assessed RECIST v1.1 defined progression (Section 3.6.1) will be permitted provided that the patient has investigator-assessed clinical 
benefit and is tolerating study drug. The following criteria must be met to treat patients after initial evidence of radiological disease progression: absence of 
clinical symptoms and signs of disease progression; stable ECOG PS ≤ 1; absence of rapid progression of disease or progressive tumor at critical anatomical 
sites that require urgent alternative medical intervention; and additional written informed consent. The medical monitor must agree, in writing, with the 
investigator’s decision to continue study drugs beyond initial investigator-assessed progression, and the decision must be documented in the study records. 


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22. Patients are required to provide archival tumor tissues (FFPE blocks or approximately 15 unstained slides [≥ 7 if MSI/MMR and HER2 status are available, 
additional 5 if MSI/MMR status is not available, and additional 3 to 6 if HER2 status is not identified]) for biomarker analysis.  
23. Fresh biopsy: A fresh biopsy sample is highly preferred if feasible in clinic. If no archival samples are available, a fresh tumor biopsy at baseline is 
mandatorily required. Optional biopsy will also be taken for the patients who have confirmed disease progression during the study from accessible tumor 
sites to obtain samples to explore resistance mechanism (written informed consent is required prior to fresh tumor biopsies). See Section 7.7 for more 
information.  
24. Tislelizumab or placebo will be given intravenously Q3W. The initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes, and then can be 
administered over 30 minutes for subsequent infusions if well tolerated. Patients must be monitored for 1 hour after infusion of tislelizumab or placebo on 
Day 1 of Cycle 1 and Cycle 2, from Cycle 3 onward, at least a 30-minute monitoring period is required. The first dose will be given on C1D1 and subsequent 
dosing will continue at the scheduled 21-day intervals. Each cycle has a (±) 3-day window. 
25. Chemotherapy will be dosed every 3 weeks. Each cycle has a (±) 3-day window. 
26. EORTC QLQ-C30, EORTC QLQ-STO22 and EQ-5D-5L will be completed at Screening or baseline, at every cycle through Cycle 6, then every other cycle 
thereafter until PD, and at EOT. QoL will be completed prior to any clinical activities apart from blood draw during on-study site visits. 
27. If MSI assessment is required, a blood sample of approximately 2 mL will be taken at screening. An optional blood sample of approximately 10 mL will be 
taken at baseline (predose, on Cycle 1 Day 1), at the time of first tumor response (predose at Day 1 of the following Cycle) and at EOT after disease 
progression (10 mL each timepoint) for all randomized patients to explore the association of blood-based biomarkers with response, prognosis, and 
resistance to tislelizumab in combination with chemotherapy or chemotherapy alone. Written informed consent is required for optional blood sample 
collection. 


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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS  
Serum Chemistry 
Hematology 
Thyroid Function 
Coagulation 
Urinalysis 
 
Alkaline 
phosphatase 
 
Alanine 
aminotransferase 
 
Aspartate 
aminotransferase 
 
Albumin 
 
Total bilirubin 
 
Direct bilirubin 
 
Blood urea 
nitrogen or urea 
 
Potassium 
 
Sodium 
 
Creatinine 
 
Glucose 
 
Lactate 
dehydrogenase 
 
Total protein 
 
Chloride 
 
Creatine Kinase 
(CK) a 
 
CK-MB a 
 
Hematocrit  
 
Hemoglobin  
 
Platelet 
counts 
 
WBC count  
 
Lymphocyte 
count 
 
Neutrophil 
count 
 
Free 
triiodothyronine 
 
Free thyroxine 
 
Thyroid 
stimulating 
hormone 
 
Prothrombin time (or 
prothrombin time ratio) 
 
Partial thromboplastin 
time or activated 
partial thromboplastin 
time 
 
 
International 
normalized ratio  
 
Glucose 
 
Protein  
 
Blood  
 
Ketones 
Abbreviations: CK-MB, creatine kinase-cardiac muscle isoenzyme; pH, negative of the logarithm to base 10 of the 
activity of the (solvated) hydronium ion; WBC, white blood cell. 
a In the event that CK-MB fractionation is not available, please assess troponin I and/or troponin T instead. 


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APPENDIX 3. ECOG PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
As published by (Oken et al, 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 


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APPENDIX 4. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1  
Source: Eisenhauer et al 2009. 
Definitions  
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (v1.1). Changes in 
only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria.  
 
Note: Lesions are either measurable or nonmeasurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) and magnetic resonance imaging (MRI) (no 
less than double the slice thickness and a minimum of 10 mm). Assumes a scan slice 
thickness no greater than 5 mm. 
• 10 mm caliper measurement by clinical exam (when superficial) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered nonmeasurable 
disease. Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all nonmeasurable. 
Bone lesions: 
• Bone scan, positron-emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered measurable lesions if the soft tissue component meets the 
definition of measurability described above 
• Blastic bone lesions are nonmeasurable 


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Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor nonmeasurable) since they are, 
by definition, simple cysts 
• Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• The concept of cystic metastases also applies to metastatic lesions with a necrotic 
component. Hence, measurable lesions with a necrotic component may be selected as 
target lesions. However, if non-necrotic lesions are present, these are preferred for 
selection as target lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. A maximum of 2 measurable 
lymph nodes, inclusive of all lymphatic chains involved, may be chosen as target lesions (ie, the 
lymphatic system is considered one organ). Target lesions should be selected based on size 
(lesions with the longest diameter), how representative they are of all involved organs, and 
whether they lend themselves to reproducible repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 perpendicular dimensions in the plane in 
which the image is obtained (for CT scan, this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, sagittal, or coronal, but the axial plane is recommended for 
measurements). The smaller of these measures is the short axis. For example, an abdominal node 
which is reported as being 20 mm by 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should 
be considered nontarget lesions. Nodes that have a short axis < 10 mm are considered 
nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 


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Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present”, “absent”, or in rare cases “unequivocal 
progression” (more details to follow). In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”). If a nontarget lymph node normalizes 
(< 10 mm in short axis) after baseline, the respective evaluation should be “absent.” 
Guidelines for Evaluation of Measurable Disease  
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules). For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. As noted above, when lesions can be 
evaluated by both clinical examination and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the 
study. 
• Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than x-ray, particularly in 
identifying new lesions. However, lesions on chest x-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
• CT, MRI: Target lesion measurements should be performed in the axial plane. CT is 
the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. MRI is also acceptable in certain situations (eg, for body 
scans). If there is a change from CT to MRI or the reverse, target lesions should 
continue to be measured provided the imaging parameters do not render 
measurements incomparable. 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in 


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the course of the study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in studies 
where recurrence after complete response (CR) or surgical resection is an endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in CR. Because tumor markers are disease 
specific, instructions for their measurement should be incorporated into protocols on a 
disease specific basis. Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and prostate-specific antigen response (in recurrent prostate cancer), 
have been published. In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line studies in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between partial 
response (PR) and CR in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain). When effusions are known to be a potential adverse effect of treatment 
(eg, with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
Response Criteria 
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes must have reduction in short axis to < 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance 
of 1 or more new lesions is also considered progression).  
• Both PR and PD: If the change in sum of diameters is consistent with both PR and PD 
at a tumor assessment visit, PD should take precedence. 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study 


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• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study. This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if CR criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm. Case report form may be designed to have target 
nodal lesions recorded in a separate section where, to qualify for CR, each node must 
achieve a short axis < 10 mm. For PR, SD and PD, the actual short axis measurement 
of the nodes is to be included in the sum of target lesions. 
• Target lesions that become “too small to measure”. While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (eg, 2 mm). However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure”.  
When this occurs, it is important that a value be recorded on the electronic case report 
form (eCRF). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned (Note: It is less likely that this rule will be used for lymph nodes 
since they usually have a definable size when normal and are frequently surrounded 
by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well). This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially nonreproducible, therefore providing this 
default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that measurement should be recorded, even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment”, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion”. 
Evaluation of Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the timepoints specified in the protocol. 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker level. 
All lymph nodes must be nonpathological in size (< 10 mm short axis). 
• PD: Unequivocal progression (as detailed below) of existing nontarget lesions. (Note: 
The appearance of 1 or more new lesions is also considered progression.) 


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• Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
• When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the nontarget disease, there must be an overall level of 
substantial worsening in nontarget disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in the size of 1 or more nontarget 
lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in nontarget disease 
in the face of SD or PR of target disease will therefore be extremely rare. 
• When the patient has only nonmeasurable disease: This circumstance arises in some 
Phase 3 studies when it is not a criterion of study entry to have measurable disease. 
The same general concept applies here as noted above, however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
nonmeasurable disease burden. Because worsening in nontarget disease cannot be 
easily quantified (by definition: if all lesions are truly nonmeasurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in nonmeasurable 
disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: ie, an increase in tumor burden representing an additional 
73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion).  
• Examples include an increase in a pleural effusion from “trace” to “large”, an 
increase in lymphangitic disease from localized to widespread, or it may be described 
in protocols as “sufficient to require a change in therapy”. If “unequivocal 
progression” is seen, the patient should be considered to have had overall PD at that 
point. While it would be ideal to have objective criteria to apply to nonmeasurable 
disease, the very nature of that disease makes it impossible to do so, therefore the 
increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of preexisting lesions). This is particularly important 
when the patient’s baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain scan 
ordered that reveals metastases. The patient’s brain metastases are considered evidence of PD 
even if he or she did not have brain imaging at baseline. 


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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible “new” disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a 
preexisting site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
• Timepoint Response: It is assumed that at each protocol specified timepoint, a 
response assessment occurs. The following table provides a summary of the overall 
response status calculation at each timepoint for patients who have measurable 
disease at baseline: 
Target Lesions 
Nontarget Lesions 
New Lesions Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated No 
PR 
SD 
Non-PD or not all evaluated No 
SD 
Not all evaluated Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease. 
When patients have nonmeasurable (therefore nontarget) disease only, the following table is to 
be used: 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
SD (Non-CR/non-PD) 


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Nontarget Lesions 
New Lesions 
Overall Response 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; SD, stable 
disease. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study drug treatment 
until the end of treatment considering any requirement for confirmation. On occasion a response 
may not be documented until after the end of therapy, so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the findings 
of both target and nontarget disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in nonrandomized studies where response 
is the primary endpoint, confirmation of PR or CR is needed to deem either one the “best overall 
response”. 
The best overall response is determined once all the data for the patient is known. Best response 
determination in studies where confirmation of complete or partial response IS NOT required: 
Best response in these studies is defined as the best response across all timepoints (for example, 
a patient who has SD at first assessment, PR at second assessment, and PD on last assessment 
has a best overall response of PR). When SD is believed to be best response, it must also meet 
the protocol specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best timepoint response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same patient lost to 
follow-up after the first SD assessment would be considered inevaluable. 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of “zero”.  
In studies where confirmation of response is required, repeated “NE” (not evaluable) timepoint 
assessments may complicate best response determination. The analysis plan for the studies must 
address how missing data/assessments will be addressed in determination of response and 
progression. For example, in most studies it is reasonable to consider a patient with timepoint 
responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document objective progression 


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even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR. FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication. However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
progression is confirmed at the next scheduled assessment, the date of progression should be the 
earlier date when progression was suspected. 
Confirmation of Measurement/Duration of Response  
Confirmation 
In nonrandomized studies where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such studies. However, in all other circumstances, ie, in 
randomized studies (phase 2 or 3) or studies where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of study results. However, elimination of the requirement for response 
confirmation may increase the importance of central review to protect against bias, in particular 
in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks). 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 


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Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular study, the protocol should specify the minimal time interval 
required between 2 measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity, and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between studies are to be made. 


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APPENDIX 5. PRE-EXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES  
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease.  
Please contact the sponsor medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions.  
Acute disseminated encephalomyelitis 
Addison’s disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn’s disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture’s syndrome  
Granulomatosis with polyangiitis  
Graves’ disease  
Guillain-Barré syndrome 
Hashimoto’s disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki’s disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
Mooren’s ulcer  
Morphea  
Multiple sclerosis  
Myasthenia gravis 
Neuromyotonia  
Opsoclonus myoclonus syndrome  
Optic neuritis  
Ord’s thyroiditis  
Pemphigus  
Pernicious anemia  
Polyarteritis nodusa  
Polyarthritis  
Polyglandular autoimmune syndrome  
Primary biliary cirrhosis  
Psoriasis  
Reiter’s syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren’s syndrome  
Stiff person syndrome 
Takayasu’s arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 


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APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
 
Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart 
failure at rest. If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin et al 1994. 
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood 
Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 


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APPENDIX 7. INFUSION-RELATED REACTIONS, 
HYPERSENSITIVITY REACTIONS AND IMMUNE-
MEDIATED ADVERSE EVENTS: EVALUATION AND 
MANAGEMENT  
Management of Infusion-Related Reactions and Hypersensitivity Reactions 
Management and treatment modifications for symptoms of infusion-related reactions associated 
with study drug(s) administration are provided in the table below. 
If a hypersensitivity reaction occurs, the patient must be managed according to the best available 
medical practice, as described in the guideline for emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (UK) (Soar et al 2008). Patients 
should be instructed to report any delayed reactions to the investigator immediately. 
Treatment Modifications for Symptoms of Infusion-Related or Hypersensitivity Reactions 
Associated with Study Drug(s) Administration 
NCI-CTCAE Grade 
Treatment Modification for study drug(s) 
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Closely monitor 
for worsening signs or symptoms. Medical 
management as needed. 
Subsequent infusions should be given after 
appropriate premedication and at the reduced 
infusion rate. 
Grade 2 - moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, corticosteroids, and/or intravenous 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reaction has 
resolved or decreased to Grade 1 in severity. 
Closely monitor for worsening signs or 
symptoms. Appropriate medical management 
should be instituted, as described below. 
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
observation or clinical management. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Grade 4 – life threatening 
Life-threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Hospitalization is recommended. 
Abbreviations: NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Event. 


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If the infusion rate of study drug(s) has been decreased by 50% or suspended due to an 
infusion-related reaction, this decreased rate must be maintained for all subsequent infusions and 
be administered with premedication. If the patient has a second infusion-related reaction 
(≥ Grade 2) on the slower infusion rate, infusion should be discontinued, and the patient should 
be withdrawn from tislelizumab treatment. 
For the prophylaxis of mild events (eg, nasal congestion or flu-like symptoms), a dose of 25 mg 
indomethacin or a comparable dose of nonsteroidal anti-inflammatory drugs (eg, 600 mg 
ibuprofen or 500 mg naproxen sodium) may be administered 2 hours before and 8 hours after the 
start of each dose of study drugs(s) infusion. Alternative treatments for fever (eg, paracetamol) 
may be given to patients at the discretion of the investigator. 
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be instituted 
as indicated per the type of reaction. This includes, but is not limited to, an antihistamine (eg, 
diphenhydramine), an antipyretic (eg, paracetamol), and if considered indicated, oral or 
intravenous glucocorticoids, epinephrine, bronchodilators, and oxygen. In subsequent cycles, the 
patient should receive oral premedication with an antihistamine (eg, diphenhydramine) and an 
antipyretic (eg, paracetamol), and should be closely monitored for clinical signs and symptoms 
of an infusion reaction. 
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes, but is not limited 
to, oral or intravenous antihistamines, antipyretics, glucocorticoids, epinephrine, bronchodilators, 
and oxygen. 
In the event of a systemic anaphylactic/anaphylactoid reaction the infusion must be stopped 
immediately, and the patient discontinued from study treatment. Systemic 
anaphylactic/anaphylactoid reactions typically manifest within minutes following administration 
of the drug/antigen and are characterized by respiratory distress; laryngeal edema; and/or intense 
bronchospasm; and often followed by vascular collapse or shock without antecedent respiratory 
difficulty; cutaneous manifestations such as pruritus and urticaria (with or without edema); and 
gastrointestinal manifestations such as nausea, vomiting, crampy abdominal pain, and diarrhea. 
The patient will be administered epinephrine injection and dexamethasone infusion if severe 
hypersensitivity reaction is observed. The patient should be closely monitored, and ICU should 
be alerted for possible transfer as indicated. 
Evaluation of Immune-Mediated Adverse Events 
The recommendations below for the diagnosis and management of any immune-mediated AE 
(imAE) are intended as guidance. This document should be used in conjunction with expert 
clinical judgement (by specialist physicians experienced in the treatment of cancer using 
immunological agents), and individual institutional guidelines or policies. 
The recommendations for diagnostic evaluation and management of imAEs are based on 
European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology 
(ASCO) guidelines (Haanen et al 2017, Brahmer et al 2018). For any AEs not included in the 
tables below, refer to the ASCO Clinical Practice Guideline (Brahmer et al 2018) for further 
guidance on diagnostic evaluation and management of immune-mediated toxicities. 


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Criteria used to diagnose imAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, 
and adverse effects of concomitant drugs. In addition to the results of these tests, the following 
factors should be considered when making an imAE diagnosis:  
• What was the temporal relationship between initiation of tislelizumab and the AE? 
• How did the patient respond to withdrawal of tislelizumab? 
• Did the event recur when tislelizumab was reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the imAE field 
associated with the AE in the eCRF should be checked. If further diagnostic evaluations change 
the assessment, the eCRF should be updated accordingly. 
Recommended Diagnostic Tests in the Management of Possible Immune-Mediated Adverse 
Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeated thyroid function tests (TSH and T4).  
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such 
as an upper respiratory infection, new cough, shortness of breath or hypoxia should 
be assessed by high-resolution CT. Consider pulmonary function test including 
DLCO.  
Radiographic appearance is often nonspecific. Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered. Consult with a respiratory medicine physician for cases of uncertain 
cause.  
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications. Conduct a diabetic 
screen, and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology. Consider the need for brain/spine MRI/MRA and nerve conduction study 
for peripheral neuropathy. Consult with a neurologist if there are abnormal 
findings. 
Colitis 
Review dietary intake and exclude steatorrhea. Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, and cryptosporidia (drug-resistant 
organism).  


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Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan. If a patient 
experiences bleeding, pain or distension, consider colonoscopy with biopsy and 
surgical intervention, as appropriate.  
Eye Disorders 
If patient experiences acute, new onset, or worsening of eye inflammation, blurred 
vision, or other visual disturbances, refer the patient urgently to an ophthalmologist 
for evaluation and management.   
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend on 
severity of the AE (eg, daily if Grade 3 to 4; every 2 to 3 days if Grade 2, until 
recovering). Review medications (eg, statins, antibiotics) and alcohol history. 
Perform liver screen including Hepatitis A/B/C serology, Hepatitis E PCR and 
assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies. Consider imaging (eg, 
ultrasound scan for metastases or thromboembolism). Consult with a hepatologist 
and consider liver biopsy.  
Renal toxicity 
Review hydration status, and medication history. Test and culture urine. Consider 
renal ultrasound scan, protein assessment (dipstick/24-hour urine collection), or 
phase-contrast microscopy. Refer to a nephrologist for further management 
assistance.  
Dermatology 
Consider other causes by conducting a physical examination. Consider 
dermatology referral for skin biopsy 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination. Consider joint X-ray and other imaging as required to exclude 
metastatic disease. Perform autoimmune serology and refer to rheumatology for 
further management assistance.  
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and refer to a 
cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CK-MB, creatine kinase-cardiac isoenzyme; CNS, central nervous system; 
CRP, C-reactive protein; CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; ECG, 
electrocardiogram; ESR, erythrocyte sedimentation rate; FBC, full blood count; HIV, human immunodeficiency 
virus; INR, international normalized ratio; LCI, liver cytosolic antigen; LFT, liver function test; LKM, liver kidney 
microsomal antibody; LP, liver pancreas antigen; MRA, magnetic resonance angiogram; MRI, magnetic resonance 
imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, 
thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC, urea electrolytes and creatinine. 
Management of Immune-Mediated Adverse Events 
Immune-mediated AEs can escalate quickly; study treatment interruption, close monitoring, 
timely diagnostic work-up and treatment intervention, as appropriate, is required 
Immune-mediated AEs should improve promptly after introduction of immunosuppressive 
therapy. If this does not occur, review the diagnosis, seek further specialist advice and contact 
the study medical monitor 
For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be considered 
if there is evidence of a clinical response to study treatment, after consultation with the study 
medical monitor 


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Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. Equivalent 
dosages of other corticosteroids can be substituted. For steroid-refractory imAEs, consider use of 
steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
Consider prophylactic antibiotics for opportunistic infections if the patient is receiving long-term 
immunosuppressive therapy 
Management of Immune-Mediated Adverse Events 
Autoimmune Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
Thyroid Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
 
Replace thyroxine if 
hypothyroid, until TSH/T4 
levels return to normal range. 
Thyrotoxic patients should be 
referred to an endocrinologist. In 
cases with systemic symptoms: 
withhold study treatment, treat 
with a beta blocker and consider 
oral prednisolone 0.5 mg/kg/day 
for thyroid pain. Taper 
corticosteroids over 2-4 weeks. 
Monitor thyroid function 
regarding the need for hormone 
replacement. 
Continue study 
treatment or withhold 
treatment in cases 
with systemic 
symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an 
endocrinologist.  
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for 
the elderly or those with 
comorbidities, the suggested 
starting dose is 0.5 µg/kg/day). 
Add oral prednisolone 
0.5 mg/kg/day for thyroid pain. 
Thyrotoxic patients require 
treatment with a beta blocker 
and may require carbimazole 
until thyroiditis resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
Hypophysitis 
1-2 
Mild-moderate symptoms 
Refer patient to an 
endocrinologist for hormone 
replacement. Add oral 
prednisolone 0.5-1 mg/kg/day 
for patients with pituitary 
inflammation. Taper 
corticosteroids over at least 
1 month. If there is no 
improvement in 48 hours, treat 
as Grade 3-4.   
Continue study 
treatment. 


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Autoimmune Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe or life-threatening 
symptoms 
Refer patient to an 
endocrinologist for assessment 
and treatment. Initiate pulse 
intravenous methylprednisolone 
1 mg/kg for patients with 
headache/visual disturbance due 
to pituitary inflammation. 
Convert to oral prednisolone and 
taper over at least 1 month. 
Maintain hormone replacement 
according to endocrinologist's 
advice.  
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary 
inflammation until 
resolved/improved to 
Grade 2 or less. 
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-
3 days.  
If appearance worsens, treat as 
Grade 2. 
Consider holding 
study treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if 
infection suspected. Add oral 
prednisolone 1 mg/kg/day if 
symptoms/appearance persist for 
48 hours or worsen. Consider 
Pneumocystis infection 
prophylaxis. Taper 
corticosteroids over at least 
6 weeks. 
Consider prophylaxis for 
adverse steroid effects: eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Hold study treatment. 
Retreatment is 
acceptable if 
symptoms resolve 
completely or are 
controlled on 
prednisolone 
≤ 10 mg/day. 
Discontinue study 
treatment if 
symptoms persist 
with corticosteroid 
treatment. 
3-4 
Severe or life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with intravenous 
methylprednisolone 
2-4 mg/kg/day. If there is no 
improvement, or worsening after 
48 hours, add infliximab 
5 mg/kg (if no hepatic 
involvement). Convert to oral 
prednisolone and taper over at 
least 2 months. Cover with 
empiric antibiotics and consider 
prophylaxis for Pneumocystis 
infection and other adverse 
steroid effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Discontinue study 
treatment. 
Neurological Toxicity 
1 
Mild symptoms 
— 
Continue study 
treatment. 


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Autoimmune Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-
1 mg/kg/day. Taper over at least 
4 weeks. Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
3-4 
Severe/life-threatening 
symptoms 
Initiate treatment with oral 
prednisolone or intravenous 
methylprednisolone 1-
2 mg/kg/day, depending on 
symptoms. Taper corticosteroids 
over at least 4 weeks.  
Consider azathioprine, MMF, 
cyclosporine if no response 
within 72-96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: < 4 liquid 
stools per day over 
baseline and feeling well 
Symptomatic management: 
fluids, loperamide, avoid high 
fiber/lactose diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event 
Continue study 
treatment. 
2 
Moderate symptoms: 4-6 
liquid stools per day over 
baseline, or abdominal 
pain, or blood in stool, or 
nausea, or nocturnal 
episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic 
tests to start treatment. Taper 
steroids over 2-4 weeks. 
Consider endoscopy if 
symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe 
symptoms: > 7 liquid 
stools per day over 
baseline, or if episodic 
within 1 hour of eating 
Initiate intravenous 
methylprednisolone 1-
2mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks. 
Consider prophylaxis for 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
If no improvement in 72 hours 
or symptoms worsen, consider 
infliximab 5 mg/kg if no 
perforation, sepsis, TB, hepatitis, 
NYHA Class III/IV CHF or 
other immunosuppressive 
treatment: MMF or tacrolimus. 
Consult gastroenterologist to 
conduct colonoscopy/ 
sigmoidoscopy. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and 
after discussion with 
the study medical 
monitor. 
4 
Life-threatening 
symptoms 
Discontinue study 
treatment. 
Skin reactions 
1 
Skin rash, with or without 
symptoms, < 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
 
Continue study 
treatment. 


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Autoimmune Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
2 
Rash covers 10%-30% of 
BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate 
strength cream once a day or 
potent cream twice a day) ± oral 
or topical antihistamines for itch. 
Consider a short course of oral 
steroids. 
Continue study 
treatment. 
3 
Rash covers > 30% BSA 
or Grade 2 with 
substantial symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows based 
on clinical judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day 
for 3 days then taper over 
2-4 weeks. 
For severe symptoms: 
intravenous methylprednisolone 
0.5-1 mg/kg/day; convert to oral 
prednisolone and taper over at 
least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved 
to mild rash 
(Grade 1-2) after 
discussion with the 
study medical 
monitor. 
 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, erythema, 
purpura, epidermal 
detachment) 
Initiate intravenous 
methylprednisolone 1-
2 mg/kg/day. Convert to oral 
prednisolone and taper over at 
least 4 weeks. 
Admit to a hospital and seek 
urgent dermatology consultation. 
Discontinue study 
treatment. 
 
Hepatitis 
1 
ALT or AST > ULN to 3 
x ULN 
Check LFTs within 1 week and 
before the next dose check LFTs 
to verify that there has been no 
worsening. 
If LFTs are worsening, recheck 
every 48-72 hours until 
improvement is seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment 
if LFTs are worsening 
until improvement is 
seen. 


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Grade 
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to Clinical Judgement) 
Study Drug 
Management 
2 
ALT or AST 3 to 5 x 
ULN 
Recheck LFTs every 48-72 
hours:  
For persistent ALT/AST 
elevation: consider oral 
prednisolone 0.5-1 mg/kg/day 
for 3 days then taper over 2-
4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and 
taper over 2-4 weeks; re-escalate 
dose if LFTs worsen, depending 
on clinical judgement.  
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline Grade and 
prednisolone tapered 
to ≤ 10 mg. 
3 
ALT or AST 5 to 20 x 
ULN 
ALT/AST < 400 IU/L and 
normal bilirubin/INR/albumin: 
Initiate oral prednisolone 
1 mg/kg and taper over at least 
4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: 
Initiate intravenous 
(methyl)prednisolone 
2 mg/kg/day. When LFTs 
improve to Grade 2 or lower, 
convert to oral prednisolone and 
taper over at least 4 weeks.  
If ALT and AST ≤ 10 
x ULN: Hold study 
treatment until 
improved to baseline 
grade; reintroduce 
only after discussion 
with the medical 
monitor. 
If ALT or AST > 10 x 
ULN: Discontinue 
study treatment. 
4 
ALT or AST > 20 x ULN 
Initiate intravenous 
methylprednisolone 
2 mg/kg/day. Convert to oral 
prednisolone and taper over at 
least 6 weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
• 
If on oral prednisolone change to pulsed intravenous methylprednisolone 
• 
If on intravenous add mycophenolate mofetil (MMF) 500 to 1000 mg twice a 
day 
• 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5 x baseline 
or > ULN to 1.5 x ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as 
per criteria below. 
Continue study 
treatment. 
 
2 
Creatinine > 1.5-3 x 
baseline or > 1.5-3 x ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-
hour urine collection. Discuss 
with nephrologist the need for 
kidney biopsy. 
If attributed to study drug, 
initiate oral prednisolone 0.5-
Hold study treatment. 
If not attributed to 
drug toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: 
Restart study drug if 


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Autoimmune Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
1 mg/kg and taper over at least 
2 weeks. 
Repeat creatinine/U&E every 
48-72 hours. 
tapered to < 10 mg 
prednisolone. 
3 
Creatinine > 3 x baseline 
or > 3-6 x ULN 
Hospitalize patient for 
monitoring and fluid balance; 
repeat creatinine every 24 hours; 
refer to a nephrologist and 
discuss need for biopsy. If 
worsening, initiate intravenous 
(methyl)prednisolone 1-2 mg/kg. 
Taper corticosteroids over at 
least 4 weeks. 
Hold study treatment 
until the cause is 
investigated.  
If study drug 
suspected: 
Discontinue study 
treatment. 
4 
Creatinine > 6 x ULN 
As per Grade 3, patient should 
be managed in a hospital where 
renal replacement therapy is 
available. 
Discontinue study 
treatment. 
Diabetes/ 
Hyperglycemia* 
1 
Fasting glucose value 
ULN to 160 mg/dL; ULN 
to 8.9 mmol/L 
Monitor closely and treat 
according to local guideline. 
Check for C-peptide and 
antibodies against glutamic acid 
decarboxylase and islet cells are 
recommended 
Continue study 
treatment. 
2 
Fasting glucose value 
160-250 mg/dL; 8.9-13.9 
mmol/L 
Obtain a repeat blood glucose 
level at least every week. 
Manage according to local 
guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening. Resume 
treatment when blood 
glucose is stabilized 
at baseline or 
Grade 0-1. 
3 
Fasting glucose value 
250-500 mg/dL; 13.9- 
27.8 mmol/L 
Admit patient to hospital and 
refer to a diabetologist for 
hyperglycemia management. 
Corticosteroids may exacerbate 
hyperglycemia and should be 
avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has 
been stabilized at 
baseline or Grade 0-1. 
4 
Fasting glucose 
value > 500 mg/dL; > 27.8 
mmol/L 
Admit patient to hospital and 
institute local emergency 
diabetes management. Refer the 
patient to a diabetologist for 
insulin maintenance and 
monitoring. 
Ocular Toxicity 
1 
Asymptomatic eye 
examination/test 
abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 


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Autoimmune Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an 
ophthalmologist for assessment 
and topical corticosteroid 
treatment. Consider a course of 
oral steroids. 
Continue study 
treatment or hold 
treatment if 
symptoms worsen or 
if there are symptoms 
of visual disturbance. 
3 
Posterior uveitis/ 
panuveitis or significant 
symptoms 
Refer patient urgently to an 
ophthalmologist. Initiate oral 
prednisolone 1-2 mg/kg and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1; 
reintroduce only after 
discussion with the 
study medical 
monitor. 
4 
Blindness (at least 20/200) 
in the affected eyes 
Initiate intravenous 
(methyl)prednisolone 
2 mg/kg/day. Convert to oral 
prednisolone and taper over at 
least 4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood test 
abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, nausea 
and vomiting 
Admit to hospital for urgent 
management. Initiate 
intravenous 
(methyl)prednisolone 1-
2 mg/kg/day. Convert to oral 
prednisolone when 
amylase/lipase improved to 
Grade 2, and taper over at least 
4 weeks 
Hold study treatment; 
reintroduce only after 
discussion with the 
study medical 
monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate 
referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.  Continue study 
treatment. 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental (fine 
motor) activities 
Management as per local 
guideline. Consider referring 
patient to a rheumatologist. If 
symptoms worsen on treatment 
manage as a Grade 3 event. 
Continue treatment 
or, if symptoms 
continue to worsen, 
hold study treatment 
until symptoms 
improve to baseline 
or Grade 0-1. 
3 
Severe pain with 
inflammation or 
permanent joint damage, 
daily living activity 
Refer patient urgently to a 
rheumatologist for assessment 
and management. Initiate oral 
prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; 
reintroduce only after 
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Autoimmune Toxicity 
Grade 
Treatment Guidelines (Subject 
to Clinical Judgement) 
Study Drug 
Management 
limited 
study medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat 
with analgesics, topical 
treatments and oral hygiene care. 
Ensure adequate hydration. If 
symptoms worsen or there is 
sepsis or bleeding, manage as a 
Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited food 
and fluid intake, daily 
living activity limited 
Admit to hospital for appropriate 
management. Initiate 
intravenous 
(methyl)prednisolone 
1-2 mg/kg/day. Convert to oral 
prednisolone when symptoms 
improve to Grade 2 and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care. Consider intravenous 
corticosteroids if not 
contraindicated by infection. 
Discontinue study 
treatment. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated 
and patient has symptoms, 
consider oral steroids and treat 
as Grade 2  
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3 x ULN or worse, 
initiate oral prednisolone 
0.5-1 mg/kg and taper over at 
least 4 weeks 
Hold study treatment 
until improved to 
Grade 0-1 
3-4 
Severe weakness, limiting 
self-care 
Admit to hospital and initiate 
oral prednisolone 1 mg/kg. 
Consider bolus intravenous 
(methyl)prednisolone and 1-
2 mg/kg/day maintenance for 
severe activity restriction or 
dysphagia. If symptoms do not 
improve add 
immunosuppressant therapy. 
Taper oral steroids over at least 
4 weeks 
For Grade 3: Hold 
study treatment until 
improved to Grade 0-
1. Discontinue upon 
any evidence of 
myocardial 
involvement 
Myocarditisa 
< 2 
Asymptomatic but 
significantly increased 
CK-MB or increased 
Initiate cardiac evaluation under 
close monitoring with repeat 
serum testing and including 
ECG, cardiac echo/MUGA, 
 


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Autoimmune Toxicity 
Grade 
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to Clinical Judgement) 
Study Drug 
Management 
troponin OR clinically 
significant intraventricular 
conduction delay 
and/or other interventions per 
institutional guidelines; consider 
referral to a cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2 
Hold study treatment. 
 
If a diagnosis of 
myocarditis is 
confirmed and 
considered immune-
mediated, 
permanently 
discontinue study 
treatment in patients 
with moderate or 
severe symptoms. 
Patients with no 
symptoms or mild 
symptoms may not 
restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline 
and after discussion 
with the study 
medical monitor. 
2 
Symptoms on mild-
moderate exertion 
Admit to hospital and initiate 
oral prednisolone or intravenous 
(methyl) prednisolone at 
1-2 mg/kg/day. Consult with a 
cardiologist and manage 
symptoms of cardiac failure 
according to local guidelines. 
If no immediate response change 
to pulsed doses of 
(methyl)prednisolone 1 g/day 
and add MMF, infliximab or 
anti-thymocyte globulin 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; ECG, 
electrocardiogram; INR, international normalized ratio; LFT, liver function test; MMF, mycophenolate mofetil; 
MUGA, multigated acquisition scan; NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, 
thyroid function test; TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 
a If clinically significant cardiac enzyme abnormalities are detected during laboratory assessment and serial cardiac 
enzyme assessments pose logistical hardship for the patient, then patient hospitalization should strongly be 
considered until immune-mediated myocarditis has been ruled out. 


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APPENDIX 8. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION  
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation1 and the Modification of Diet in Renal Disease (MDRD) Study equation. The National 
Kidney Disease Education Program (NKDEP) calculators rely on creatinine determinations 
which are isotope dilution mass spectrometry (IDMS) traceable. All laboratories should be using 
creatinine methods calibrated to be IDMS traceable. Read more about creatinine standardization. 
This CKD-EPI equation calculator should be used when Scr reported in mg/dL. This equation is 
recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 x min (Scr /κ, 1) α x max (Scr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if 
black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
 
The online calculator for CKD-EPI can be found here: www.niddk.nih.gov/health-
information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-
calculators  


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APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group recommendations related to contraception and pregnancy 
testing in clinical studies include the use of highly effective forms of birth control. These 
methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
Note: Oral birth control pills are not considered a highly effective form of birth 
control, and if they are selected, they must be used with a second, barrier method of 
contraception such as condoms with or without spermicide. 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
Note: This is only considered a highly effective form of birth control when the 
vasectomized partner is the sole partner of the study participant and there has been a 
medical assessment confirming surgical success. 
− A sterile male is one for whom azoospermia, in a semen sample, has been 
demonstrated as definitive evidence of infertility. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment). 
− NOTE: Total sexual abstinence should only be used as a contraceptive method if 
it is in line with the patients’ usual and preferred lifestyle. Periodic abstinence (eg, 
calendar, ovulation, symptom-thermal, post-ovulation methods), declaration of 
abstinence for the duration of exposure to study drug, and withdrawal are not 
acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
used in combination with one of the highly effective forms of birth control listed above. 
Definitions of “Women of Childbearing Potential” AND “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant.  


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Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
− < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone (FSH) concentration > 30 IU/mL 
and all alternative medical causes for the lack of spontaneous menses for ≥ 12 
months have been ruled out, such as polycystic ovarian syndrome, 
hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
Adapted from Clinical Trials Facilitation Group (CTFG). Recommendations related to 
contraception and pregnancy testing in clinical trials. September 15, 2014. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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APPENDIX 10. DOSE MODIFICATION OF CHEMOTHERAPY  
Recommended Dose Modifications for Hematologic Toxicity of Chemotherapy 
Dose adjustments are based on nadir blood counts since the preceding chemotherapy 
administration. Dose level adjustments are relative to that of the preceding administration. 
Recommended dose modifications for hematologic and non-hematologic toxicity are provided in 
Table 2 and Table 3 as below. Toxicities related to chemotherapy must be resolved to baseline or 
≤ Grade 1 prior to administering the next dose of chemotherapy, with the exception of alopecia, 
Grade 2 fatigue, or other AEs, which, in the opinion of the investigator, would not affect the 
safety evaluation of the study drugs. 
Table 1 
: BGB-A317-305 Dose Reduction Level of Chemotherapy 
Drug Dose  
Standard Level 
(Every 3 weeks as a cycle) 
1st Level 
2nd Level 
Capecitabine 
1000 mg/m2, BID (total 
14 days) 
Reduce dose to 75% 
Reduce dose to 50% 
Oxaliplatin  
130 mg/m2 (Day 1) 
Reduce dose to 100 mg/m2 Reduce dose to 
80 mg/m2 
5-FU 
800 mg/m2(Day 1 to Day 5) 
Reduce dose to 75%  
Reduce dose to 50% 
Cisplatin 
80 mg/m2 (Day 1) 
Reduce dose to 75%  
Reduce dose to 50% 
 
Table 2: 
BGB-A317-305 Dose Modifications for Hematologic Toxicities of 
Chemotherapy  
AE 
Grade  
Dose Modifications  
Febrile Neutropenia 
3 
1st occurrence: 1st reduced dose level 
2nd occurrence: Stop treatment permanently unless it 
is in the best interest of the patient to treat with 2nd 
reduced dose level 
4 
1st occurrence: Stop treatment permanently unless it 
is in the best interest of the patient to treat with 2nd 
reduced dose level 
2nd occurrence: Stop treatment permanently  
Neutrophil count decreased  
1/2 
Maintain dose level 
3/4 
1st occurrence: 1st reduced dose level 
2nd occurrence: 2nd reduced dose level 
3rd occurrence: Stop treatment permanently 
Platelet count decreased 
1 
Maintain dose level 
 
≥ 2 
1st occurrence: 1st reduced dose level 


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2nd occurrence: 2nd reduced dose level 
3rd occurrence: Stop treatment permanently 
NOTE: If considered in the best interest of the patient and consistent with local practice, investigators may decide to 
use supportive measures / treatment and/or secondary prophylaxis instead of dose reductions for the next cycle. 
The provided triggers for dose modifications are recommendations only. 
 
Table 3: 
BGB-A317-305 Dose Modifications for Non-hematologic Toxicities of 
Chemotherapy  
AE 
Grade  
Dose Modifications  
Capecitabine 
Diarrhea  
 2 
Immediately interrupted, 1st reduced dose level 
3 or 4 
Immediately interrupted, 2nd reduced dose level  
Nausea/vomiting 
2  
Immediately interrupted, 1st reduced dose level 
3 or 4 
Immediately interrupted, 2nd reduced dose level  
Hand/foot syndrome 
2 or 3  
Immediately interrupted, 1st reduced dose level 
Stomatitis 
2 or 3 
Immediately interrupted, 1st reduced dose level 
4 
Immediately interrupted, 2nd reduced dose level 
Cardiac toxicity 
≥ 2 
Stop capecitabine permanently 
Oxaliplatin 
Respiratory symptoms indicative of 
pulmonary fibrosis 
any 
Interrupt treatment and investigate cause of symptoms 
Nausea and/or vomiting  
3 or 4 
1st reduced dose level 
Diarrhea  
3 or 4 
1st reduced dose level 
Peripheral neuropathy (Paresthesia) 
 
2 
Last < 21 days: Maintain dose level 
Last ≥ 21 days: Delay
 then 1st reduced dose level 
3 
Last < 7 days: Maintain dose level 
Last ≥ 7 days: 1st reduced dose level 
Last ≥ 21 days: Stop Oxaliplatin permanently  
4 
Stop Oxaliplatin permanently 
5-FU 
Nausea and/or Vomiting 
3 or 4 
1st reduced dose level 
Diarrhea 
3 or 4 
1st reduced dose level 
Stomatitis 
 
3 
1st reduced dose level 
4 
2nd reduced dose level 
Cardiac toxicity  
≥ 2 
Stop 5-FU permanently 


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Skin toxicities 
3 or 4 
2nd reduced dose level 
Cisplatin  
eGFR: ≥ 60 mL/min  
1 
Maintain dose level 
eGFR: 51-59 mL/min 
2 
1st reduced dose level 
eGFR: 41-50 mL/min 
2 
2nd reduced dose level 
eGFR: ≤ 40 mL/min1 
2 
Stop cisplatin permanently 
Nausea or Vomiting 
3 or 4 
1st reduced dose level 
Ototoxicity  
2 
1st reduced dose level 
3 or 4 
Stop cisplatin permanently  
Sensory neuropathy 
2 
1st reduced dose level 
3 or 4 
Stop cisplatin permanently  
NOTE: If considered in the best interest of the patient and consistent with local practice, investigators may decide to 
use supportive measures / treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle. 
The provided triggers for dose modifications are recommendations only 
Obtained from http://ascopubs.org/doi/abs/10.1200/jco.2010.28.18_suppl.lba4007. Accessed Jan 22nd, 2018. 


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APPENDIX 11. EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30  
 


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APPENDIX 12. EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE 
GASTRIC CANCER MODULE QLQ-STO22  
 


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APPENDIX 13. EUROPEAN QUALITY OF LIFE 5-DIMENSIONS 5-
LEVELS HEALTH QUESTIONNAIRE  
 


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APPENDIX 14. PRINCIPLES OF PATHOLOGIC REVIEW AND HER2-
NEU TESTING  
Assessment of overexpression of HER2-neu in gastric cancer for patients with inoperable locally 
advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastroesophageal junction 
(GEJ), assessment for tumor HER2-neu overexpression using immunohistochemistry (IHC) and 
fluorescence in situ hybridization (FISH) or other in situ hybridization method is recommended. 
The following criteria used in the ToGA trial are recommended:  
 
Table 1: 
Immunohistochemical Criteria for Scoring HER2-neu Expression in Gastric 
and Esophagogastric Carcinoma* 
 
 
Surgical Specimen Expression 
Pattern, Immunohistochemistry  
Biopsy Specimen Expression 
Pattern, Immunohistochemistry  
HER2-neu 
Overexpression 
Assessment 
0 
No reactivity or membranous reactivity 
in < 10% of cancer cells  
No reactivity or no membranous 
reactivity in any cancer cell  
Negative 
1+ 
Faint or barely perceptible 
membranous reactivity in ≥ 10% of 
cancer cells; cells are reactive only in 
part of their membrane  
Cancer cell cluster with a faint or 
barely perceptible membranous 
reactivity irrespective of percentage 
of cancer cells positive  
Negative 
2+ 
Weak to moderate complete, 
basolateral, or lateral membranous 
reactivity in ≥ 10% of cancer cells  
Cancer cell cluster with a weak to 
moderate complete, basolateral, or 
lateral membranous reactivity 
irrespective of percentage of cancer 
cells positive  
Equivocal 
3+ 
Strong complete, basolateral, or lateral 
membranous reactivity in ≥ 10% of 
cancer cells  
Cluster of five or more cancer cells 
with a strong complete, basolateral, 
or lateral membranous reactivity 
irrespective of percentage of cancer 
cells positive  
Positive 
*The NCCN Guidelines panel recommends that cases showing 2+ expression of HER2-neu by 
immunohistochemistry should be additionally examined by FISH or other in situ hybridization methods. Cases 
with 3+ overexpression by IHC or FISH positive (HER2:CEP17 ratio ≥ 2) are considered positive. 
 


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SAP_001.pdf: 
BeiGene USA, Inc 
   BGB-A317-305 
     (Statistical Analysis Plan) 
Version 2.0:  11/18/2021 
Page 1 of 44 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-A317-305 
Study Protocol 
Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Clinical 
Study Comparing the Efficacy and Safety of Tislelizumab (BGB-A317) 
plus Platinum and Fluoropyrimidine Versus Placebo plus Platinum and 
Fluoropyrimidine as First-Line Treatment in Patients with Locally 
Advanced Unresectable or Metastatic Gastric or Gastroesophageal 
Junction Adenocarcinoma 
Date: 
 Nov 18, 2021 
Version: 
Final version 2.0 
NCT Number:  
 NCT03777657


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Version 2.0:  11/18/2021
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CONFIDENTIAL
SIGNATURE PAGE
Author:
              
 
               
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Version 2.0:  11/18/2021 
Page 3 of 44  
CONFIDENTIAL 
 
TABLE OF CONTENTS 
1 
INTRODUCTION 
10 
2 
STUDY OVERVIEW 
10 
2.1 
Study Design 
10 
2.2 
Study Assessments 
11 
3 
STUDY OBJECTIVES 
12 
3.1 
Primary Objectives 
12 
3.2 
Secondary Objectives 
12 
3.3 
Exploratory Objectives 
12 
4 
DEFINITION OF PRIMARY ESTIMAND 
13 
4.1 
Primary Estimand 1 – Survival Benefit in Gastric or GEJ Adenocarcinoma 
with PD-L1 Positive 
13 
4.2 
Primary Estimand 2 – Survival Benefit in Gastric or GEJ Adenocarcinoma 
14 
5 
STUDY ENDPOINTS 
15 
5.1 
Primary Endpoints 
15 
5.2 
Secondary Endpoints 
15 
5.3 
Exploratory Endpoints 
15 
6 
SAMPLE SIZE CONSIDERATIONS 
16 
7 
STATISTICAL METHODS 
17 
7.1 
Analysis Populations 
17 
7.2 
Data Analysis General Considerations 
17 
7.2.1 
Definitions and Computations 
17 
7.2.2 
Conventions 
18 
7.2.3 
Handling of Missing/partial Data 
18 
7.2.4 
Adjustments for Covariates/Stratification 
19 
7.2.5 
Multiplicity Adjustment 
19 
7.2.6 
Data Integrity 
19 
7.3 
Subject Characteristics 
20 
7.3.1 
Subject Disposition 
20 
7.3.2 
Protocol Deviations 
20 
7.3.3 
Demographic and Other Baseline Characteristics 
20 
7.3.4 
Disease History and Baseline Disease Characteristics 
21 
7.3.5 
Prior Anti-Cancer Therapies and Surgeries 
21 
7.3.6 
Prior and Concomitant Medication and Therapy 
22 
7.3.7 
Medical History 
22 
7.4 
Efficacy Analysis 
22 
7.4.1 
Primary Efficacy Endpoints 
22 
7.4.2 
Secondary Efficacy Endpoints 
25 
Objective Response Rate by investigators 
26 
Duration of Response 
26 
Disease control rate (DCR), clinical benefit rate (CBR) 
27 
Health-Related Quality of Life 
27 


 
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7.4.3 
Subgroup Analyses 
31 
7.4.4 
Exploratory Efficacy Endpoints 
31 
7.4.5 
Post and during-treatment Anti-Cancer Therapy 
32 
7.5 
Safety Analyses 
32 
7.5.1 
Extent of Exposure 
33 
7.5.2 
Adverse Events 
34 
7.5.2.1 
Treatment Emergent Adverse Event 
34 
7.5.2.2 
Immune-mediated Adverse Event 
35 
7.5.2.3 
Infusion-related Adverse Event 
36 
7.5.3 
Death 
36 
7.5.4 
Laboratory Values 
36 
7.5.5 
Vital Signs 
36 
7.5.6 
Electrocardiograms (ECG) 
37 
7.5.7 
ECOG 
37 
7.5.8 
Antidrug Antibody 
37 
7.5.9 
Other Safety Measurements 
38 
7.6 
Pharmacokinetic Analyses 
38 
7.7 
Other Analysis 
38 
8 
INTERIM ANALYSIS 
38 
9 
CHANGES IN THE PLANNED ANALYSIS 
39 
10 
REFERENCES 
39 
11 
APPENDIX 1  IMPUTATION RULES FOR PARTIAL DATES 
41 
11.1 
Impute partial dates for concomitant medication 
41 
11.2 
Impute partial dates for adverse events 
41 
11.3 
Impute partial dates for subsequent anti-cancer systematic 
therapy/surgery/procedure 
42 
11.4 
Impute partial dates for prior anti-cancer therapy (drug, surgery/procedure, 
radiotherapy) 
42 
12 
APPENDIX 2  RULES FOR IDENTIFYING MISSING TUMOR 
ASSESSMENTS 
44 
 
 
 
 
 
 
 
 
 
 
 
 


 
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DOCUMENT REVISION HISTORY 
Version 
number 
Finalization date  
summary of change 
1.0  
Sept 12, 2021 
 
2.0 
Nov 18, 2021 
- 
Update “TAP score” to more general term “PD-L1+ 
score” throughout the document. The change does not 
impact the original PD-L1+ subgroup definition per 
protocol  
- 
Introduction section: Refine wording to introduce TAP 
- 
Section 7.1: Replace PD-L1 scores with TAP when 
defining PD-L1 + analysis set 
Replace immunogenicity with Antidrug antibody 
(ADA) when defining ADA analysis set 
- 
Section 7.2.5: Clarify that PFS and ORR testing will be 
conducted based on the date up to interim analysis after 
positive OS testing in both PD-L1 + analysis set and 
ITT analysis set (either at interim or final analysis).   
- 
Section 7.3.6: Update definition for concomitant 
medication to align with definition update in TEAE. 
Delete the summary of systemic Corticosteroid 
/immunosuppressant 
- 
Section 7.4.3: Clarify subgroup analysis for geography 
and PD-L1 expression  
- 
Section 7.4.5 Clarify the new anticancer therapy flags 
for efficacy and safety analysis 
- 
Section 7.5.2: To streamline the logic of deriving 
TEAE, TEAE definition is updated  
- 
Section 7.5.2.1: Clarify that TEAE overview will not 
include imAE; Overview of TEAE will be summarized 
by region in safety analysis set Section 7.5.2.2: add 
sentence to emphasize all imAE up to last dose of 
tislelizumab/placebo will be summarized, clarity that 
imAE 
will 
be 
summarize 
in 
tislelizumab 
+ 
chemotherapy arm only 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BID 
Twice daily 
BIRC 
Blinded Independent Review Committee 
BOR 
Best overall response 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration 
COVID-19 
Coronavirus disease of 2019 
CR 
Complete response 
CSR 
Clinical Study Report 
CT 
Computed tomography 
Ctrough 
Trough serum concentration 
DCR 
Disease control rate 
dMMR 
mismatch repair deficient 


 
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DOR 
Duration of response 
EBV  
Epstein-Barr Virus  
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30 
EORTC QLQ-STO22 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Gastric Cancer Module QLQ-
STO22 
EQ-5D-5L 
European Quality of Life 5-Dimensions 5-Levels Health 
Questionnaire  
FDG-PET 
Fluorodeoxyglucose-position emission tomography 
FFPE 
Formalin-fixed paraffin-embedded 
GC 
Gastric cancer 
GCP 
Good Clinical Practice 
GEJ 
gastroesophageal junction 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
iDMC 
Independent Data Monitor Committee  
INR 
International Normalized Ratio 
imAE 
Immune-mediated adverse event 


 
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ITT 
Intent-to-Treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LLN 
Lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite Instability 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NA 
Not assessable 
NE 
Not evaluable 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed cell death protein-1 
PD-L1 
programmed cell death ligand-1 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PO 
Orally 
PP 
Per-Protocol  
PR 
Partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RMST 
Restricted Mean Survival Time 


 
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RPSFT 
Rank Preserving Structural Failure Time 
ROW 
Rest of world 
Q3W 
Once every 3 weeks 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SOC 
System Organ Class 
T1/2 
Elimination half-life 
TCM 
Tradition Chinese Medicine 
Tmax 
Time to maximum plasma concentration 
TA 
Tumor assessment 
TAP 
Tumor Area Positivity  
TEAE 
Treatment-emergent adverse event 
TIC  
tumor and immune cell  
QTcF 
Fridericia’s correction formula 
ULN 
Upper limit of normal 
Vd 
Volume of distribution 
5-FU 
5-fluorouracil 
 


 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and statistical 
methods that will be used to analyze and report results for study BGB-A317-305: A Randomized, 
Double-Blind, Placebo-Controlled, Phase 3 Clinical Study Comparing the Efficacy and Safety of 
Tislelizumab (BGB-A317) plus Platinum and Fluoropyrimidine Versus Placebo plus Platinum and 
Fluoropyrimidine as First-Line Treatment in Patients with Locally Advanced Unresectable or 
Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma.  This SAP is based on BGB-
A317-305 Protocol Amendment 2.0, dated on April 03, 2020.  The focus of this SAP is the planned 
interim and final analysis specified in the study protocol. The analysis details for Pharmacokinetic 
(PK), Pharmacodynamics, Pharmacogenomics and Biomarker analyses are not described within 
this SAP. Separate analysis plans will be completed for these analyses as needed and will be 
attached to the clinical study report. 
PD-L1 expression is determined by PD-L1 score assessed by tumor area positive score (TAP) 
(previously referred to Tumor Immune Cell (TIC) score in protocol), which is defined as the total 
percentage of the tumor area covered by tumor cells with any membrane staining above 
background and tumor-associated immune cells with any staining above background, using 
Ventana PD-L1 (SP263) assay.  
2 
STUDY OVERVIEW 
2.1 
STUDY DESIGN 
This is a randomized (1:1), double-blind, placebo-controlled, Phase 3 study of tislelizumab plus 
platinum and fluoropyrimidine versus placebo plus platinum and fluoropyrimidine in patients with 
locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.   
 
The study procedures will occur over a Screening Phase (up to 28 days); Treatment Phase (until 
the investigator determines that none of the study drugs will no longer be used); Safety Follow-up 
Phase (30 days ± 7 days after the last dose of study drugs, or before the initiation of a new 
anticancer treatment, whichever occurs first); and a Survival Follow-up Phase (continuing until 
death, loss to follow-up, withdrawal of consent, or study termination by sponsor). 
 
In addition, immune-mediated AEs will be recorded up to 90 days after the last dose of 
tislelizumab or placebo, regardless of whether or not the patient starts a new anticancer therapy. 
 
At randomization, patients will be stratified by the following 4 factors: 
x Regions of enrollment: China (including Taiwan) vs. Japan and S. Korea vs. US and 
Europe and other regions. NOTE: other regions include other western 
countries/populations. 
x Programmed cell death protein ligand-1 (PD-L1) expression: positive or negative. PD-L1 
positive patients are the ones with PD-L1 score ≥ 5% using VENTANA PD-L1 (SP263) 
Cdx Assay.  
x Presence of peritoneal metastasis (yes or no) 


 
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x Investigator’s choice of chemotherapy (Oxaliplatin + capecitabine versus cisplatin + 
5-fluorouracil [5-FU])  
After randomization, patients will be treated on the following arms. Cross-over between the 
treatment arms will not be allowed.   
x Arm A: Tislelizumab 200 mg intravenously (IV) once every 3 weeks (Q3W) + 
chemotherapy  
x Arm B: Placebo IV Q3W + chemotherapy 
 
2.2 
STUDY ASSESSMENTS 
Tumor assessments will be performed by investigator using RECIST v1.1 criteria (Eisenhauer EA 
2009). Baseline tumor imaging (computed tomography [CT] with or without contrast or magnetic 
resonance imaging [MRI]) must be performed within 28 days prior to randomization. On-study 
tumor assessments will occur every 6 weeks (±7 days) during the first 48 weeks and every 9 weeks 
(±7 days) thereafter from the randomization until disease progression. If a patient discontinues 
study treatment due to any reasons other than disease progression, tumor assessments will continue 
to be performed as scheduled until disease progression, loss to follow up, withdrawal of consent, 
death, or until the study terminates, whichever occurs first. 
Patients will be evaluated for any adverse events (AEs) and serious adverse events (SAEs) 
occurring up to 30 days after the last dose of study drug (all severity grades), per National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] v5.0 or until initiation 
of new anticancer therapy, whichever occurs first, and for immune-mediated AEs (imAEs) 
occurring up to 90 days after the last dose of tislelizumab or placebo regardless of whether or not 
the patient starts a new anticancer therapy. All drug-related SAEs will be recorded by the 
investigator after treatment discontinuation until patient death, withdrawal of consent, or loss to 
follow-up, whichever occurs first. All study drug-related SAEs will be followed until they resolve 
to baseline or ≤ Grade 1, the investigator assesses the AE as stable and unlikely to improve, or the 
patient is lost to follow-up, whichever occurs first. 
In this double-blind, placebo-controlled study, all patients and personnel involved in the conduct 
and interpretation of the study, including the investigators, BeiGene study team, and site 
personnel, will be blinded to the treatment assignment. Randomization data will be kept strictly 
confidential; filed securely by the appropriate groups for BeiGene, the IRT and the IDMC; and 
will be accessible only to authorized persons per SOPs until the time of unblinding.  
Safety and efficacy monitoring will be performed by an Independent Data Monitoring Committee 
(IDMC). The IDMC may recommend modifications to the study, including termination due to 
safety and/or efficacy concerns. The functions and membership of the IDMC will be described in 
the IDMC Charter. 
PD-L1 status of each individual patient will be blinded to BeiGene study team in order to avoid 
unwanted bias. PD-L1 expression status in the IRT will not be accessible to anyone except for 
independent statistician, BeiGene IRT manager, and IDMC. PD-L1 expression status will not be 


 
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included in the listings generated for data review either. Study teams from BeiGene and BeiGene’s 
cooperator (e.g.Novartis) can only review the summarized proportions of patients with different 
PD-L1 expression levels in order to monitor PD-L1 prevalence in the study.  
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES  
x To compare overall survival of tislelizumab plus chemotherapy versus placebo plus 
chemotherapy in the programmed cell death protein ligand-1 positive (PD-L1+) and 
intent-to-treat analysis set 
3.2 
SECONDARY OBJECTIVES  
x To compare progression-free survival per Response Evaluation Criteria in Solid Tumors 
1.1 as assessed by investigators of tislelizumab plus chemotherapy versus placebo plus 
chemotherapy in the programmed cell death protein ligand-1 positive and intent-to-treat 
analysis set 
x To evaluate overall response rate, and duration of response, per Response Evaluation 
Criteria in Solid Tumors 1.1 as assessed by investigators  
x To evaluate European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Gastric Cancer Module QLQ-STO22 Score, European Organization 
for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Score, and 
European Quality of Life 5-Dimensions 5-Levels Health Questionnaire Score 
x To evaluate the safety and tolerability profile of tislelizumab or placebo plus 
chemotherapy 
x To evaluate disease control rate, clinical benefit rate, and time to response per Response 
Evaluation Criteria in Solid Tumors 1.1 as assessed by investigators  
 
3.3 
EXPLORATORY OBJECTIVES 
x To evaluate progression-free survival after next line of treatment (PFS2)  
x To characterize the pharmacokinetics of tislelizumab  
x To determine host immunogenicity to tislelizumab  
x To assess predictive, prognostic, exploratory biomarkers including but not limited to 
programmed cell death protein ligand-1 (PD-L1) expression, Epstein-Barr virus (EBV) 
infection, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) 
status, genomically stable (GS) or chromosomal instability (CIN), immune-related gene 
expression profiling, tumor infiltrated lymphocytes (TILs) and tumor mutation burden in 
tumor tissues and/or blood samples and the association with response to study treatment, 
mechanisms of resistance, and/or disease status 


 
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4 
DEFINITION OF PRIMARY ESTIMAND 
4.1 
PRIMARY ESTIMAND 1 – SURVIVAL BENEFIT IN GASTRIC OR GEJ 
ADENOCARCINOMA WITH PD-L1 POSITIVE  
The primary analysis was written in estimand framework per study design as described in the 
protocol. 
The primary scientific question of interest is: will the addition of tislelizumab to chemotherapy 
doublet (platinum and fluropyrimidine) prolong survival in first line gastric or GEJ 
adenocarcinoma with PD-L1 score ≥ 5%, regardless whether to receive anticancer therapy 
subsequently. 
The primary estimand described by the following attributes:  
1. Treatment of interest:  
The experimental treatment regimen constitutes tislelizumab plus chemotherapy (either 
cisplatin + 5-FU or oxaliplatin + capecitabine). Patients receive capecitabine may be 
further administrated capecitabine as maintenance therapy.  The control treatment regimen 
is chemotherapy (either cisplatin + 5-FU or oxaliplatin + capecitabine, with capecitabine 
as maintenance therapy afterwards). 
2. Population:  
Adult patients with locally advanced unresectable or metastatic gastric or GEJ 
adenocarcinoma, who have not received previous systemic therapy for advanced disease 
and PD-L1 score ≥ 5% using VENTANA PD-L1[SP263] Cdx Assay. 
3. Primary variable:  
Overall survival defined as the time from the date of randomization to the date of death 
due to any cause. Further details on OS are provided in Section 7.4.1. 
4. Handling of intercurrent events:  
x New anticancer therapy started prior to death: any incidence will be ignored, i.e., any 
death or patients’ data collected after the new anticancer therapy will be considered 
for analysis. (treatment policy strategy)  
x Discontinuation of treatment: any death or patients’ data collected after the 
discontinuation of treatment will be considered for analysis. (treatment policy 
strategy) 
x Death due to COVID-19 infection: it will be counted as an event in the analysis of 
overall survival. (composite strategy)   
x Treatment interruption/discontinuation due to COVID-19 infection: any incidence 
will be ignored. Any death or patients’ data collected after the treatment 
interruption/discontinuation due to COVID-19 infection will be considered for 
analysis. (treatment policy strategy) 
x Any other unforeseen intercurrent events: OS will take into account all deaths and 
any patients’ data after any unforeseen intercurrent events   
 
5. Population-level summary: 


 
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Hazard ratio (HR) of OS comparing tislelizumab plus platinum and fluoropyrimidine versus 
placebo plus platinum and fluoropyrimidine estimated using Cox proportional hazard model 
stratified by regions of enrollment (east Asia versus rest of the world) and presence of peritoneal 
metastasis (yes or no).   
4.2 
PRIMARY ESTIMAND 2 – SURVIVAL BENEFIT IN GASTRIC OR GEJ 
ADENOCARCINOMA 
The definition of  primary estimand 2 components is similar to the one described in Section 4.1.  
The application to the specific one in ITT analysis set only is straightforward with minor 
modification.   
The primary scientific question of interest is: will the addition of tislelizumab to chemotherapy 
doublet (platinum and fluropyrimidine) prolong survival in first line gastric or GEJ 
adenocarcinoma, regardless whether to receive anticancer therapy subsequently. 
The primary estimand described by the following attributes:  
1. Treatment of interest:  
The experimental treatment regimen constitutes tislelizumab plus chemotherapy (either 
cisplatin + 5-FU or oxaliplatin + capecitabine). Patients receive capecitabine may be further 
administrated capecitabine as maintenance therapy.  The control treatment regimen is 
placebo plus chemotherapy (either cisplatin + 5-FU or oxaliplatin + capecitabine , with 
capecitabine as maintenance therapy afterwards). 
2. Population:  
Adult patients with locally advanced unresectable or metastatic gastric or GEJ 
adenocarcinoma, who have not received previous systemic therapy for advanced disease.  
3. Primary variable:  
Overall survival defined as the time from the date of randomization to the date of death 
due to any cause. Further details on OS are provided in Section 7.4.1. 
4. Handling of remaining intercurrent events:  
x New anticancer therapy started prior to death: any incidence will be ignored, ie. Any 
death or patients’ data collected after the new anticancer therapy will be considered 
for analysis. (treatment policy)  
x Discontinuation of treatment: any death or patients’ data collected after the 
discontinuation of treatment will be considered for analysis. (treatment policy) 
x Death due to COVID-19 infection will be counted as an event in the analysis of 
overall survival. (composite strategy)   
x Treatment interruption/discontinuation due to COVID-19 infection: any incidence 
will be ignored. Any death or patients’ data collected after the treatment 
interruption/discontinuation due to COVID-19 infection will be considered for 
analysis.  (treatment policy) 
x Any other unforeseen intercurrent events: OS will take into account all deaths and 
any patients’ data after any unforeseen intercurrent events   


 
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5. Population-level summary: 
Hazard ratio (HR) of OS comparing tislelizumab plus platinum and fluoropyrimidine versus 
placebo plus platinum and fluropyrimidine, estimated using Cox proportional hazard model 
stratified by regions  (east Asia versus rest of the world), presence of peritoneal metastasis (yes 
or no) and PD-L1 expression (positive:  PD-L1 score≥ 5% or negative: PD-L1 score < 5%).   
 
5 
STUDY ENDPOINTS 
5.1 
PRIMARY ENDPOINTS 
x Overall Survival – defined as the time from the date of randomization to the date of death 
due to any cause 
5.2 
SECONDARY ENDPOINTS 
x Progression-free survival as assessed by investigators– defined as the time from the date 
of randomization to the date of the first objectively documented tumor progression, 
assessed by investigators per Response Evaluation Criteria in Solid Tumors v1.1, or death, 
whichever occurs first. 
x Overall response rate as assessed by investigators – defined as the proportion of patients 
whose best overall response is complete response or partial response per Response 
Evaluation Criteria in Solid Tumors v1.1  
x Duration of response as assessed by investigators – defined as the time from the first 
determination of an objective response per Response Evaluation Criteria in Solid Tumors 
v1.1, until the first documentation of progression or death, whichever occurs first  
x Change from baseline in European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Gastric Cancer Module QLQ-STO22 Score and change from 
baseline in European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 Score and European Quality of Life 5-Dimensions 5-Levels Health 
Questionnaire Score 
x The incidence and severity of adverse events according to National Cancer Institute 
Common Terminology Criteria for Adverse Events v5.0 
x Disease control rate (ie, proportion of complete response + partial response + stable 
disease), clinical benefit rate (ie, proportion of complete response + partial response + 
durable stable disease) and time to response (ie, time from randomization to the first 
determination of an objective response) per Response Evaluation Criteria in Solid Tumors 
1.1 by investigators  
5.3 
EXPLORATORY ENDPOINTS 
x Progression-free survival after next line of treatment (PFS2) – defined as the time from 
randomization to the objective disease progression after next line of treatment, or death 
from any cause, whichever occurs first 


 
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x Summary of serum concentration of tislelizumab  
x Assessments of immunogenicity of tislelizumab by determining the incidence of antidrug 
       antibodies 
x Status of programmed cell death protein ligand-1 (PD-L1) expression, immune or 
gastric-related, and other exploratory biomarkers including but not limited to Epstein-Barr 
virus (EBV) infection, microsatellite instability-high (MSI-H) or mismatch repair deficient 
(dMMR), genomically stable (GS) or chromosomal instability (CIN), immune-related gene 
expression profiling, tumor infiltrated lymphocytes (TILs) and tumor mutation burden in 
tumor tissues and/or blood samples obtained before treatment with tislelizumab and/or at 
progression, and the association with disease status and/or response to tislelizumab in 
combination with chemotherapy or chemotherapy alone 
6 
SAMPLE SIZE CONSIDERATIONS 
The sample size calculation is based on the primary efficacy analyses of OS in the comparison 
between Arms A and B in the PD-L1 positive (PD-L1+)  and ITT analysis sets. The OS is assumed 
to follow  an exponential distribution. Sequential testing procedure is implemented to control 
overall alpha at 2.5% one-sided.  OS analysis in the PD-L1+ analysis set will be performed first 
and OS analysis in the ITT analysis set will be carried out only if the OS analysis in the PD-L1+ 
analysis set is statistically significant favoring tislelizumab + chemotherapy arm.  Table 1 
summarizes the statistical assumption and power in the sample size calculation. Assuming a 50% 
PD-L1+ (PD-L1score ≥ 5%) prevalence rate, a total of 928 patients including approximately 
464 (ie, 50%) in the PD-L1+ subset will be enrolled in a 1:1 randomization to observe targeted OS 
events at the defined time periods as shown in Table1. Assuming a roughly 5% dropout rate, 
approximately 980 patients will be enrolled over 24 months at enrollment rates of 17 
patients/month in the first 2 months, 34 patients/month in the next 2 months, and 44 patients/month 
in the last 20 months. The enrollment assumptions, including percentage of PD-L1+ patients, will 
be monitored during the enrollment; therefore, the sample size and timeline could be adjusted 
accordingly. Enrollment of patients whose tumors are PD-L1- might be stopped if necessary, to 
ensure that the percentage of PD-L1+ (PD-L1 score ≥ 5%) is no less than 50% of the ITT analysis 
set. The primary analyses will be performed when the target number of events in both ITT and 
PD-L1+ analysis set are observed. An interim analysis of OS is planned after approximately 70% 
of the total planned death events have occurred in both ITT and PD-L1+ analysis sets (Section 8 
for more details). 
 
Table 1: Hazard ratio and median OS assumption, number of events, alpha and power in the 
primary hypothesis tests 
Analysis Set 
HR 
Median in Arm 
A (in months) 
Median in Arm 
B (in months) 
# Events 
Alpha 
Power 
PD-L1+ 
0.75 
15.3 
11.5 
384 
0.025 
80% 
ITT 
0.8 
14.4 
11.5 
768 
0.025 
87% 


 
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7 
STATISTICAL METHODS 
7.1 
ANALYSIS POPULATIONS 
Intent-to-Treat (ITT) analysis set – Includes all randomized patients. Patients will be analyzed 
according to their treatment assigned at randomization. This will be one of the dual primary 
analysis sets for demography and efficacy analyses. 
PD-L1 positive analysis set (PD-L1 score ≥ 5% using VENTANA PD-L1 (SP263) assay). – 
Includes all randomized patients whose tumors were PD-L1 positive (PD-L1 score ≥ 5%). Patients 
will be analyzed according to their treatment assigned at randomization. This will be one of the 
dual primary analysis sets for demography and efficacy analyses. 
Safety analysis set – Includes all patients who received at least 1 dose of study drugs. This will be 
the analysis set for the safety analyses.  Patients will be analyzed according to the study treatment 
they actually received. Patients will be classified according to treatment received, where treatment 
received is defined as (i) the intended treatment if it was received at least once, or (ii) the first 
treatment received when starting therapy with study medication if intended treatment is never 
received. Each patient will be classified into and analyzed consistently within one (and only one) 
treatment arm. 
PD-L1 positive safety analysis set – Includes patients in the safety analysis set whose PD-L1 score 
≥ 5% using VENTANA PD L1 [SP263] Cdx Assay. This will be analysis set for the safety analyses 
in patients with  PD-L1 score≥ 5%.   
PK Analysis Set included all patients who received ≥ 1 dose of tislelizumab per the protocol for 
whom any post dose PK data were available. 
Antidrug antibody (ADA) Analysis Set included all patients who received ≥ 1 dose of 
tislelizumab for whom both baseline ADA and ≥1 postbaseline ADA results were available. 
7.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
7.2.1 Definitions and Computations 
Study day:  
Study day will be calculated in reference to the first dose date for safety analysis. For 
assessments conducted on or after the date of first dose date, study day will be calculated as 
(assessment date –first dose date + 1). For assessments conducted before first dose date, study 
day is calculated as (assessment date – first dose date). If no dose is given, then the date of first 
randomization will be used.  There is no study day 0.  
To derive the duration of any efficacy endpoint, the reference date will be date of randomization.   
Baseline Measurements: 
x For efficacy evaluation: a baseline value is defined as the last non-missing value 
collected prior to the randomization.  


 
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x For safety: a baseline value is defined as the last non-missing value prior to the first study 
drug administration. 
x For toxicity grade of certain laboratory tests: two baseline toxicity grades should be derived 
according to the directions (lower (Hypo) or higher (Hyper)). For example, a baseline 
hemoglobin with value between 10.0 g/dL and LLN, two baseline toxicity grades: Grade 1 
for Hypo and Grade 0 for Hyper will be derived.  
Study Follow-up Duration (SFD): Study follow-up duration is defined as the duration from  
the randomization date to the study discontinuation date (e.g. death, consent withdrawal, lost 
to follow-up) or to cutoff date if a patient is still ongoing. 
Minimum study follow up is defined as a difference between the date of analysis cut-off and the 
date of last patient randomized. 
All calculations and analyses will be conducted using SAS version 9.2 or higher. 
7.2.2 Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
 
x 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
significant digit. 
x 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up 
to 1 significant digit. 
x Age will be calculated as the integer part of (date of informed consent – date of birth + 
1)/365.25 
x P-values will be rounded to 4 decimal places.  P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as ‘> 0.9999’.   
x Time-to-event or duration of event endpoints will be based on the actual date when the 
radiograph was obtained rather than the associated visit date. 
x Missing efficacy or safety data will not be imputed unless otherwise specified. 
x For laboratory results collected as < or >, a numeric value, 0.0000000001 will be 
subtracted or added, respectively, to the value. 
x For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with non-missing data as the denominator, unless otherwise specified. 
x For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median, Q1, Q3 and range (minimum and maximum). 
7.2.3 Handling of Missing/partial Data 
Handling of missing data related to primary estimand will be further elaborated in Section 7.4.1.  
Missing dates or partially missing dates will be imputed conservatively for adverse events and 
prior/concomitant medications/procedures.  Specific rules for handling of missing or partially 


 
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missing dates for adverse events and prior/concomitant medications/procedures are provided in 
Section 11 Appendix 1. Other missing data will not be imputed unless otherwise specified in the 
SAP. 
By-visit endpoints will be analyzed using observed data, unless otherwise specified. For observed 
data analyses, missing data will not be imputed and only the observed records will be included.  
7.2.4 Adjustments for Covariates/Stratification 
The value of the stratification factors used at randomization (IVRS), including region of 
enrollment, PD-L1 expression [in ITT only] and presence of peritoneal metastasis will be used in 
stratified log-rank test and stratified Cox proportional hazard model for primary endpoint OS, 
secondary endpoint, PFS. Similarly these stratification factors will be used in Cochran-Mantel-
Haenszel method to analyze ORR.  
The actual value of the stratification factors (collected in eCRF) and other baseline covariates may 
be used in statistical models as covariates as sensitivity analyses for endpoints.  
7.2.5 Multiplicity Adjustment 
The type I error will be strongly controlled at 0.025 (1-sided) in the primary analysis of OS in 
PD-L1+ and ITT analysis sets using sequential testing method. OS analysis in ITT analysis set will 
be performed only if the OS analysis in the PD-L1 positive analysis set is statistically significant 
favoring tislelizumab + chemotherapy arm. 
Hypothesis testing of the secondary endpoints PFS and ORR in the PD-L1 positive and ITT 
analysis sets will be performed at the same time as the interim analysis of OS. Only when the 
superiority of OS in both PD-L1+ and ITT analysis sets have been demonstrated (either at interim 
or final analysis), full alpha of 0.025 (1-sided) will be shifted sequentially to the hypothesis testing 
of the secondary endpoints in order of PFS in PD-L1+, ORR in the PD-L1+ analysis set, followed 
by PFS in ITT and ORR in ITT analysis set based on the data up to interim analysis. The hypothesis 
test will be stopped at the first non-significant endpoint. Nominal p-values may be computed for 
other efficacy analysis but should be interpreted with caution.   
Inferential tests of efficacy outcomes will be carried out as described above. Type I error is not 
controlled in the safety analysis and safety summary will be performed in the safety analysis set 
regardless of the results in primary efficacy endpoint testing, unless otherwise specified. 
7.2.6 Data Integrity 
The data set for analysis should be an accurate and complete representation of the patients' 
relevant outcomes from the clinical database. All data should be complete and reviewed up to a 
pre-specified cutoff date as specified in the Data Extract and Snapshot Plan. Consistency checks 
and appropriate source data verification should be completed as specified in the Site Monitoring 
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7.3 
SUBJECT CHARACTERISTICS 
7.3.1 Subject Disposition 
The number (percentage) of patients who signed informed consent, enrolled in the study, died 
before enrollment, and screen-failure including re-screened will be summarized. The number 
(percentage) of screen failure reason will also be summarized. 
The number (percentage) of patients randomized, treated, discontinued from treatment (or 
completed chemotherapies) and discontinued from the study will be summarized. The primary 
reason for end of treatment (treatment discontinuation) and end of study (study discontinuation) 
will be summarized by categories. The reasons for treatment/study discontinuation related to 
COVID-19 impact will also be summarized. Study follow up duration will be summarized 
descriptively. 
Patient disposition will also be summarized by region (China (including Taiwan) vs. Japan and 
S. Korea vs. US and Europe and other regions) for ITT and PD-L1 positive analysis set.  
7.3.2 Protocol Deviations 
Protocol deviation criteria will be established together with its category/term of important and 
not important. Patients with important protocol deviations will be identified and documented 
before the database lock. Important protocol deviations will be summarized for all patients in the 
ITT analysis set.  
Critical protocol deviation that significantly impacts efficacy or safety evaluation will be 
reviewed prior to data base lock according to the criteria defined in protocol deviation 
specification.  
Protocol deviations that are related to COVID-19 will be summarized and all patients affected by 
COVID-19-related protocol deviations will be listed along with site information and specific 
deviation description. 
7.3.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the ITT and PD-L1 positive 
analysis set using descriptive statistics. Continuous variables will be summarized using number of 
patients, mean, standard deviation, median, minimum and maximum. Categorical variables will 
be summarized using number of patients and percentage in relevant categories.  
 
Demographic and other baseline characteristics include: 
 
x Age 
x Age group (≤ 65 vs > 65 years) 
x Sex 
x Race 
x Ethnicity 
x Weight (kg) 
x BMI 
x ECOG 


 
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x Smoking status 
x Alcohol consumption 
 
In addition, the stratification factors per Interactive Response Technology (IRT) and per eCRF 
will be summarized based on ITT population: 
x Regions of enrollment: China (including Taiwan) vs. Japan and S. Korea vs. US and 
Europe and other regions. 
x PD-L1 expression (PD-L1 score ≥ 5% vs PD-L1 score < 5%): 
x Presence of peritoneal metastasis (yes or no) 
x Investigator’s choice of chemotherapy (Oxaliplatin + capecitabine versus cisplatin + 5 
fluorouracil [5-FU])  
 
7.3.4 Disease History and Baseline Disease Characteristics 
The following disease history and baseline disease characteristics will be summarized in ITT 
population: 
x Time since initial cancer diagnosis to study entry 
x Disease stage at screening 
x Location of tumor 
x PD-L1 expression (<1%, ≥1%,  ≥5% and ≥10%) 
x HER2 status 
x Histological Tumor differentiation grade 
x Histologic type (Lauren classification) 
x MSI or MMR status 
x EBV status 
x Genomically stable type 
x Chromosomal instability type 
x Patients with non-target lesion only 
x Prior gastrostomy/ esophagectomy 
x Previous adjuvant or neoadjuvant therapy 
x Number of metastatic sites, 0-2 vs >=3  
 
Disease history and baseline disease characteristics will also be summarized by region (China, 
Japan & South Korea and ROW) for ITT and PD-L1 positive analysis set. In addition, Disease 
history and baseline disease characteristics will also be summarized in all randomized patients 
with PD-L1 score < 5%.   
7.3.5 Prior Anti-Cancer Therapies and Surgeries   
The number of patients receiving prior anti-cancer drug therapies, prior anti-cancer radiotherapy, 
prior anti-cancer surgery will be summarized. The therapies with the same sequence/regimen 
number are counted as one prior therapy.     


 
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7.3.6 Prior and Concomitant Medication and Therapy 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD) drug codes, and will be further classified to the appropriate Anatomical 
Therapeutic Chemical (ATC) code.  
The number (percentage) of patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred term by phase in the safety 
population. Prior medications are defined as medications that stopped before the first dose date. 
Concomitant medications will be defined as medications that (1) started before the first dose of 
study drug and were continuing at the time of the first dose of study drug, or (2) started on or after 
the date of the first dose of study drug up to 30 days after the subject’s last dose.  
Medication to treat COVID-19 related adverse events will also be summarized separately.   
Patient data listings of prior and concomitant medication will be provided.  
7.3.7 Medical History 
Medical History will be coded Medical history/current medical conditions are coded using the 
latest version of Medical Dictionary for Regulatory Activities (MedDRA) terminology available 
at the time of the analyses. The number (percentage) of patients reporting a history of any medical 
condition, as recorded on the CRF, will be summarized by system organ class and preferred term 
in the safety population. A listing of medical history will be provided. 
7.4 
EFFICACY ANALYSIS 
OS is the primary endpoint in this study.  OS analysis will be carried out in the PDL1+ analysis 
set first.  A formal statistical test of OS in the ITT analysis set will be performed only if the OS 
analysis 
in 
the 
PD-L1+ 
analysis 
set 
is 
statistically 
significant 
favoring 
tislelizumab + chemotherapy.  There is one interim analysis of OS for both efficacy and futility 
planned. The interim analysis of OS will be performed when approximately 269 deaths in the PD-
L1+ analysis set and 538 deaths in the ITT analysis set (70% of the target number of OS events in 
each analysis set) among the 2 treatment arms have been observed. The final analysis of OS will 
take place after approximately 384 and 768 death events have been observed in the 2 analysis sets, 
7.4.1 Primary Efficacy Endpoints 
The primary estimand is defined in Section 4. Details of the statistical methods used in OS 
derivation and analysis are provided in this section including pre-defined sensitive analyses of the 
primary estimand and supplementary analyses of OS.      
Variable  
Overall survival is defined as time from randomization date to the documented death date for 
patients who died prior to or on the clinical cutoff date. For patients who are alive by the clinical 
cutoff date, OS will be censored at the last known alive date (LKADT). The last known alive date 
will be defined as either the clinical data cutoff date for patients who are still on treatment, or last 
available date showing patients alive or cut-off date whichever comes first for other alive patients.  


 
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Every effort should be made to ensure complete death dates. In the rare case, if day of death date 
is missing, death date is imputed as the max (last available date showing patients alive + 1, first 
day of year/month of death date). The patient with imputed death date will be considered as an 
event for OS analysis.  
 
Primary efficacy analyses 
OS in PD-L1+ and ITT analysis sets: 
The null hypothesis to be tested is: 
H0:   HR ≥ 1 
against the alternative: 
H1:   HR < 1 
The primary efficacy analyses of OS will be performed using the stratified log-rank test on the 
PD-L1+ analysis set and ITT analysis set separately according to the treatment arm and 
randomization strata (region of enrollment, PD-L1 expression [in ITT only] and presence of 
peritoneal metastasis) to which patients are assigned at randomization.  
 
The survival distribution of OS will be estimated using Kaplan-Meier method. The results will be 
plotted graphically (Kaplan-Meier curves) by treatment. The plots will display the number of 
patients at risk at equidistant time point. The median OS for each treatment group will be provided 
along with the approximate 95% confidence intervals using the method of Brookmeyer and 
Crowley (Brookmeyer & Crowley, 1982). Additionally, 25% and 75% percentiles will also be 
provided. The cumulative probability of OS at every 6 months if estimable, will be calculated for 
each treatment arm and presented with 2--sided 95% CIs. The CIs will be constructed using the 
standard errors derived from Greenwood’s formula (Collett 1994).
 
The treatment effect will be estimated by fitting a stratified Cox proportional hazard model to the 
OS times including treatment arm as a covariate and region of enrollment (east Asia versus ROW), 
PD-L1 expression (for ITT only) and presence of peritoneal metastasis as strata. From this model, 
the hazard ratio (HR) of OS will be estimated and presented with a 2-sided 95% CI. In this analysis 
the baseline hazard function will be allowed to vary across strata. SAS PHREG procedure with 
TIES=Efron option will be used to carry out this analysis in which the model statement will include 
treatment group variable as the only covariate and the STRATA statement will include the 
stratification variable as obtained via IRT.  
 
Sensitivity analysis and supportive analysis 
Sensitivity analysis 1 “Unstratified OS analysis”: To assess the impact of stratifiction factors, OS 
will be analyzed using a unstratified Cox model, and the treatment effect will be summarized by 
the hazard ratio with its 95% confidence interval.    
 


 
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Sensitivity analysis 2: “OS analysis with stratification factors from the eCRF”: OS will be analyzed 
using stratified Cox model and the distribution of OS will be compared between the treatment 
group using stratified log-rank test, with stratification factors obtained from the CRF.   
 
Supportive analysis 3: “OS analysis to check Proportional hazard assumption” Analyses to assess 
proportional hazard assumption including Schoenfeld residual plot and time dependent covariate 
in the Cox model will be explored.  
 
Supplementary analysis 
Supplementary analysis 1 “OS analysis based on Max-Combo method”: This analysis targets an 
estimand which has the same attributes as the primary estimand except the population level 
summary will be Weighted hazard ratio of OS (combo of G(0,0), G(0,1), G(1,0) and G(1,1)) 
from Max-combo test to account for the possible non-proportional hazards effects . (Satrajit R, 
Keaven A, Jiabu Y, Pralay M, 2019). 
 
Supplementary analysis 2 “OS analysis based on Restricted mean survival time method”:  This 
analysis targets an estimand which has the same attributes as the primary estimand except the 
population level summary will be difference in Restricted mean survival time (RMST) between 
two treatment groups. In order to account for the possible non-proportional hazard effect, the 
restricted mean survival time (RMST) (RMST, Uno H, Claggett B, Tian L, Inoue E, et al. 2014) 
will be computed for OS separately using the area under the curve from baseline to the minimum 
of the largest observed time on each of the two treatment groups. RMST will be computed for each 
treatment arm and the difference with its 95% CI will be displayed.  
 
Supplementary analysis 3 “OS analysis adjusted for baseline covariates”: OS will be also analyzed 
by adjusting multivariate covariates at baseline.  The analysis addresses a different scientific 
question. i.e., will the addition of tislelizumab to chemotherapy doublet prolong survival, adjusting for 
covariates (ECOG PS, liver metastasis, number of metastatic organs, prior gastrostomy) Covariate 
adjusted multivariate Cox regression provides a conditional treatment effect rather than marginal 
treatment effect. A stratified Cox regression model will be performed adjusted key baseline 
prognostic factors (ECOG PS, live metastasis, number of metastatic organs, prior gastrostomy).  
 
Supplementary analysis 4 “COVID-19 OS supplementary analysis”: this analysis will aim at 
assessing the treatment effect based on OS had COVID-19 pandemic not occurred.  The primary 
variable is defined as the time from the date of randomization to the date of death due to non-
COVID-19 pandemic reasons. The remaining intercurrent events will be handled as follows:  
o Discontinuation of study treatment due to any non-COVID-19 pandemic reasons: 
OS will take into account all deaths irrespective of the study treatment discontinuation 
reasons (treatment policy strategy) 
o Discontinuation of study treatment due to COVID-19 pandemic reasons: OS will 
be censored on the date of discontinuation of treatment due to COVID-19 pandemic. 


 
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The discontinuation reason due to COVID-19 pandemic will be identified from the 
eCRF (hypothetical strategy). 
o Medications used for treating COVID-19 cases: OS will be censored on the date of 
administration of COVID-19 medication (hypothetical strategy) 
o Death due to COVID-19: OS will be censored on the date of death due to COVID-19 
(hypothetical strategy) 
Additional supplementary analyses may be carried out to explore the impact of next-line 
anticancer therapy to OS evaluation.  
7.4.2 Secondary Efficacy Endpoints 
Progression Free Survival (PFS) by investigators 
PFS is defined as the time from the randomization date to disease progression or death, whichever 
occurs first. PFS will be censored at the last adequate tumor assessment if one of the following 
occurs: absence of event; the event occurred after a new anticancer therapy is given; the event 
occurred after two or more consecutive missing/non-evaluable  tumor assessments.  The table 2 
shows the derivation rules for PFS.  The algorithm to identify missing TAs are presented in 
Appendix 2.   
Table 2:  Censoring Rules for Progression-free Survival Per RECIST Version 1.1 
 
Derivation rules 
Outcome  
No progression at the time of data 
cut-off or withdrawal from study or 
lost to follow up  
Date of last adequate radiologic assessment prior 
to or on date of data cut-off or withdrawal from 
study or lost to follow up 
Censored  
New anticancer therapy started 
prior to disease progression or 
death 
Last adequate radiological assessment before the 
new anticancer therapy (hypothetical strategy) 
 
Censored  
No baseline or post-baseline tumor 
assessments without death within 
13 weeks after randomization 
Date of randomization  
Censored  
No baseline or post-baseline tumor 
assessments with death within 13 
weeks after randomization 
Date of death 
Event  
Death or progression after more 
than one missed visit 
Date of last adequate radiologic assessment 
before missed tumor assessments 
Censored  
The methods used to analyze OS will be applied to the analysis for PFS. The primary analysis of 
comparing PFS as assessed by investigators between two treatment groups in the PD-L1 analysis 
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(east Asia versus rest of the world [ROW]), presence of peritoneal metastasis. The primary analysis 
of comparing PFS as assessed by investigators between two treatment groups in the ITT analysis 
set will be stratified log-rank test, stratified by pooled stratification factors of regions of enrollment 
(east Asia versus rest of the world [ROW]), presence of peritoneal metastasis and PD-L1 
expression.   
The median PFS and the cumulative probability of PFS estimated at every 3 months will be 
calculated using Kaplan-Meier estimates for each treatment arm and presented with 2-sided 95% 
CIs computed by Brookmeyer and Crowley method using the log-log transformation. The 
treatment effect will be estimated by fitting a Cox regression model to the PFS times including 
treatment arm as a covariate and beforementioned stratification factors as strata. From this model, 
the hazard ratio (HR) of PFS will be estimated and presented with a 2-sided 95% CI. 
The following sensitivity analyses are planned: 
x The first sensitivity analysis is the same as primary analysis for PFS except including any 
tumor assessments/death after more than one missing visits when deriving PFS.  Missing 
more than one visit is not considered as a reason for PFS censoring. This analysis is to 
address the impact of PFS comparison due to missing TAs. 
One supplementary analysis is planned: 
x This analysis is the same as the primary analysis except excluding the start of new 
anticancer therapy as a reason for PFS censoring.  Any tumor assessments after the start of 
new anticancer therapy including PD or death will be considered when deriving PFS. This 
analysis is to address the impact of the new anticancer therapy received prior to 
progression.    
Objective Response Rate by investigators 
Best overall response (BOR), defined as the best response recorded from randomization until data 
cut or the start of new anticancer treatment. Patients with no post-baseline response assessment 
(due to any reason) will be considered non-responders for BOR.  ORR is defined as the number of 
patients whose BOR is confirmed CR or PR divided by the number of randomized patients in each 
arm.  The null hypotheses of no difference in ORR per RECIST 1.1 assessed by investigators will 
be tested in a Cochran-Mantel-Haenszel (CMH) test adjusting for region of enrollment (east Asia 
versus ROW), PD-L1 expression (for ITT only) and presence of peritoneal metastasis as strata in 
the PDL1+ and ITT analysis sets. Patients with no post-baseline response assessment (for any 
reason) will be considered as non-responders. The 2-sided 95% CIs for the odds ratio in ORR will 
be calculated, as well as Clopper-Pearson 95% CIs for ORR and its corresponding Clopper-
Pearson 95% CI for each of the response categories (CR, PR, SD, and PD) will be presented by 
treatment arm.  
Duration of Response  
Duration of Response (DOR) is defined as progression/death event free time counted from the first 
objective response date to the first documented radiological PD date/or death date, whichever 
occurred first. All the censoring rules for PFS should be applied to DOR.  Duration of response 
(DOR) assessed by investigators will be analyzed in the responders only. The median DOR and 


 
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the cumulative probability of DOR estimated at every 3 months will be calculated using Kaplan-
Meier estimates for each treatment arm and presented with 2-sided 95% CIs computed by 
Brookmeyer and Crowley method using the log-log transformation.  No formal testing will be 
performed to compare DOR between two treatment group as it would be based on a non-
randomized subgroup.   
Disease control rate (DCR), clinical benefit rate (CBR)  
Disease control rate (DCR) defined as the proportion of patients whose best overall response 
(BOR) is CR, PR, or SD including non-CR/non-PD. Clinical benefit rate (CBR) defined as the 
proportion of patients who have CR, PR, or SD including non-CR/non-PD of ≥ 24 weeks in 
duration. DCR and clinical benefit rate (CBR) assessed by investigators will be analyzed similarly 
to ORR in the ITT and PD-L1+ analysis sets. 
Time to response (TTR) will be summarized using descriptive statistics, such as mean, median, 
and standard deviation. Only patients who have achieved an objective response will be included 
in the analysis of TTR. 
Waterfall plots will be provided for the maximum tumor shrinkage based on target lesion. In 
addition, patients will be marked out in the plot for those who had tumor reduction in target lesion 
assessments but contradicted to the PD results in overall response due to new-lesion or non-target 
lesion. The maximum tumor shrinkage based on target lesion used in the plots will be listed. These 
analyses will be performed based on RECIST1.1. 
Health-Related Quality of Life 
The EORTC QLQ-C30 (QlQ-C-30) consists of thirty questions that are specific to cancer and 
cancer treatment (Aaronson NK, et al., 1993; Fayers PM, et al., 2001). It includes global health 
status (GHS/Qol) scale that consists of 2 items, and five functional scales measuring Physical (5 
items), Role (2 items), Cognitive (2 items), Emotional (4 items), and Social (2 items), three 
symptom scales measuring Fatigue (3 items), Pain (2 items), and Nausea and Vomiting (2 items) 
and six single items measuring Dyspnoea, Insomnia, Appetite Loss, Constipation, Diarrhea, and 
Financial Difficulties.  QLQ-C30 scores are based on 4-point Likert scales from 1 = “Not At All” 
to 4 = “Very Much” with lower score indicating better HRQoL; except for the GHS/Qol that is 
scored on a 7-point scale ranging from 1 = “Very Poor” to 7 = “Excellent” with higher scores 
indicating better health status. The QLQ-STO22 consists of 22 questions in 6 subscales: 
Dysphagia/odynophagia (4 items), Pain/discomfort (3 items), Dietary restrictions (5 items), Upper 
gastro-intestinal symptoms (3 items), Specific emotional problems (3 items) and 4 single items. 
Scores are based on 4-level Likert scales (0= Not at all to 4=Very Much); with lower scores 
indicating lower symptoms/better HRQoL. 
The EQ-5D-5L comprises a descriptive module and a Visual Analogue scale (VAS). The 
descriptive module comprises of 5 dimensions: mobility, self-care, usual activities, pain/ 
discomfort, and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2 = slight 
problems, 3 = moderate problems, 4 = severe problems, and 5 = extreme problems. Higher scores 
indicate lower quality of life. The EQ VAS measures respondent’s self-rated health status on a 0 
to 100 scale, with 100 = ‘the best health you can imagine’ and 0 = ‘the worst health you can 
imagine’. Higher scores on VAS indicate higher health status.  


 
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EORTC Scoring Derivation 
The principle for scoring applies to all scales/scores. The derived scales are obtained from the raw 
scores as defined in the EORTC manual.  If at least half of the items for a scale are answered, then 
the remaining completed items are used to calculate the score for that scale; however, if more than 
half are missing, the scale score is set to missing. 
Raw Score (RS) 
Raw scores are calculated as the average of the items that contribute to the scale: 
RS=(I1+I2+…+ In)/n 
Derived Scale (S) 
A linear transformation to standardize the raw scores is utilized, so that the scores are ranged from 
0 to 100. The derived scales have a more intuitive interpretation: higher scores in functional scales 
and the global health status/QoL(GHS/Qol) indicate improvements while higher scores in 
symptom scales and items indicate deteriorations. The derivation formulas are computed as 
follows: 
Functional scales: 
S=[1- (RS-1)/range]*100 
Symptom scales and global health status: 
      S=[(RS-1)/range]*100 
QLQ-STO22 Index score = [∑(domain scores + single item scores)]÷number of available 
domains and single items  
Scales/Items:  QLQ-C30 
GHS and Functional Scales: Higher scores = Better HRQoL 
Symptom Scales: Lower Scores = Better HRQoL 
Table 3 QLQ-30 scores 
 
Scale 
Number 
of items 
Item 
range 
Item Numbers 
Global health status/ QoL 
 Global health status/QOL 
QL2 
2 
6 
29,30 
Functional Scales 
 
 
 
 
Physical functioning  
PF2 
5 
3 
1, 2, 3, 4, 5  
Role functioning  
RF2 
2 
3 
6, 7  
Emotional functioning  
EF 
4 
3 
21, 22, 23, 24  


 
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Cognitive functioning  
CF 
2 
3 
20, 25  
Social functioning  
SF 
2 
3 
26, 27  
Symptom Scales/ items 
 
 
 
 
Fatigue 
FA 
3 
3 
10, 12, 18 
Nausea and vomiting 
NV 
2 
3 
14, 15 
Pain* 
PA 
2 
3 
9, 19 
Dyspnoea 
DY 
1 
3 
8 
Insomnia 
SL 
1 
3 
11 
Appetite loss 
AP 
1 
3 
13 
Constipation 
CO 
1 
3 
16 
Diarrhoea 
DI 
1 
3 
17 
Financial Difficulties 
FI 
1 
3 
28 
*questions regarding Pain in QlQ-C30 are more general whereas for HCC & LC13 the pain questions are 
very specific to the disease. In some of the analysis, there were not significant correlations between them, 
and in some other studies they were. For simplicity, I suggest for the 317-208 and 307 using the disease 
specific pain scales; however, for the 311-302 using pain scale from the C-30 scale.      
 
QLQ – STO22  
Lower scores = Better HRQoL 
Table 4 QLQ-STO22 scores 
Symptom Scales 
Number of 
items 
Item range 
Item Numbers 
Scales 
 
 
 
Dysphagia/odynophagia  
4 
4 
31, 32, 33, 34 
Pain/discomfort 
3 
4 
35, 36, 37 
Upper gastro-intestinal symptoms  
3 
4 
38, 39, 40 
Dietary restrictions  
5 
4 
41, 42, 43, 45, 46 
Anxiety/ emotional problems  
3 
4 
47, 49, 50 
Hair Loss 
2 
4 
51, 52 


 
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Single items  
 
 
 
Dry Month 
1 
 
44 
Taste problem 
1 
 
45 
Body image 
1 
 
49 
 
All HRQoL measures will be summarized in PD-L1+ and ITT analysis set.  
Any unscheduled QoL assessments will be mapped into the scheduled QoL visits (screening or 
baseline, every cycle up to cycle 6, then every other cycle thereafter) prior to or after this visit if 
no QoL assessments are available at the scheduled QoL visits.   
A questionnaire module is considered complete if at least one question is answered.  The adjusted 
completion rate is defined as percentages of patients who completed the questionnaire at each visit 
divided by the number of patients still in treatment who were expected to complete the 
questionnaire. Completion rates and adjusted completion rate for the EORTC QLQ C30, EORTC 
QLQ -STO22, and EQ-5D-5L will be summarized separately at each visit.   
The derived scores (functional scales/symptom scales/single items and the GHS/QoL scale) of 
QLQ C30, and index and symptom scales/items of QLQ-STO22 will be summarized as well as 
change from baseline at each cycle using descriptive statistics. For EQ-5D-5L, descriptive modules 
will be summarized by visit and dimension in an ordinal scale.  The plots of the mean values and 
their standard errors at each visit over time for each sub domain and overall QLQ-STO22 and EQ-
5D-5L by treatment arm will be presented.  
Time to deterioration analysis will be performed to the compare key quality of life scores between 
two treatment groups. Time to deterioration is defined as time from randomization to the first 
occurrence of an decrease of ≥10 scores in global health status/QoL (GHS/QoL) and physical 
function and fatigue of the QLQ-C30, and ≥10 increase in the index score and scores of dysphagia, 
pain, dietary restrictions and upper gastro of QLQ-STO22. The primary definition of 10 points is 
derived from the published 10-point EORTC threshold (Osaoba 1992, Osaba 2002, Osaba et al 
1998). Sensitivity analysis may explore a secondary deterioration threshold defined using anchor 
based meaningful-within patient change (MWPC) framework. A deterioration is not counted as an 
event if a subsequent improvement returned the overall worsening from baseline to less than 10 
points. If a patient does not have an event (10% deterioration), they are censored at their last clinic 
visit at which HRQoL is measured. A nonparametric Kaplan-Meier method will be used to 
estimate the deterioration curve in each group.  The log-rank test and hazard ratio will be provided 
to show the magnitude of treatment effect and are only used for descriptive purpose only. 
In addition, a mixed effect model analysis for measuring clinically meaningful changes post-
baseline will be performed using the GHS/QoL, physical function and fatigue domains of QLQ-
C30, and dysphagia, pain, dietary restrictions and upper gastro of QLQ-STO22. Difference in 
change from baseline to cycle 4 and cycle 6 between arms of before-mentioned parameters will be 
assessed in the mixed models which include baseline score, stratification factors, treatment arm, 
visit, and treatment arm by visit interaction as fixed effects and visit as a repeated measure with 
an unstructured covariance structure.  


 
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7.4.3 Subgroup Analyses 
To determine if the treatment effect is consistent across various subgroups, the median OS in each 
subgroups along with unstratified OS hazard ratio  and its 95% CI will be estimated and plotted 
within each category of the following variables:  
x geography 1 (Asia vs Rest of World) 
x geography 2 (China (including Taiwan vs Japan and S. Korea vs Rest of World) 
x race  
x age (< 65 vs  ≥ 65 years) 
x gender (Female vs Male) 
x ECOG PS (0 vs 1) 
x Liver metastasis  
x MSI or MMR status 
x Presence of peritoneal metastasis (yes or no) 
x Investigator’s choice of chemotherapy (Oxaliplatin + capecitabine versus cisplatin + 5 
fluorouracil [5-FU])  
x Prior gastrostomy 
x Previous adjuvant or neoadjuvant therapy 
x Number of metastatic sites, 0-2 vs >=3  
x PD-L1 expression (<5%, ≥5%) 
 
Country-specific subgroups may also be summarized per local regulatory requirements. Subgroup 
analysis of PD-L1 expression (<1%, ≥1% and < 10%, ≥10%) maybe explored.   
 
7.4.4 Exploratory Efficacy Endpoints 
Progression-free survival after next line of treatment (PFS2) is defined as time from the 
randomization date to the first documented disease progression on next-line therapy or death from 
any cause, whichever occurs first. The first documented progression on next-line treatment will be 
recorded by investigator (i.e. captured on the post treatment discontinuation anti-cancer systemic 
therapy CRF page).  
x Next-line therapy is defined as the first new (systemic) anti-neoplastic therapy initiated 
after discontinuation of study treatment regardless of EOT reason. Drugs given as part of 
the same regimen should be grouped as one line (i.e. part of the next-line therapy). In 
addition, continuation of the study treatment after the initial radiologic disease progression 
will not be considered as next-line therapy.  
x PFS2 will be censored if no PFS2 event (progression or death) is observed during next-line 
therapy before the analysis cut-off date; the censoring date will be the date of last known 
to be alive.    
x In case a second new anti-cancer therapy is introduced without progression on the first next 
anti-cancer therapy, then PFS2 will be censored at the end date of the first new anti-cancer 
therapy (i.e. next line therapy).  


 
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x PFS2 will be censored at the date of last known to be alive.  if a patient is still ongoing on 
study treatment irrespective of the disease progression status or second progression while 
being on study treatment, or patient has discontinued study treatment but has not started 
next-line therapy and is still alive.  
x Any death prior to initiation of next-line therapy will be considered as an event for PFS2  
Kaplan-Meier (KM) method as described in the PFS and OS analyses will be used in the analysis 
of PFS2. The median PFS2 and the cumulative probability of PFS2 estimated at every 3 months 
will be calculated using Kaplan-Meier estimates for each treatment arm and presented with 2-
sided 95% CIs computed by Brookmeyer and Crowley method using the log-log transformation. 
The hazard ratio (HR) of PFS2 from stratified Cox model will be estimated and presented with a 
2-sided 95% CI. 
7.4.5 Post and during-treatment Anti-Cancer Therapy 
Post treatment anti-cancer therapy is defined as the anti-cancer therapy started after the last dose 
of study drug(s). A summary of number and percentage of patients who received subsequent 
systematic anticancer therapy/immune checkpoint inhibitors (single treatment), and combination 
therapy of immune checkpoint inhibitors and tyrosine kinase inhibitors will be provided by arm 
based on ITT analysis set and PD-L1 positive analysis set. 
Separate flags of start date of new anti-cancer therapy for efficacy and safety analyses are derived 
individually.   
- 
As for efficacy analysis, start date of new anti-cancer therapy will be the earlist date of 
prohibited anti-cancer therapy taken during treatment, date of the post-treatment systemic 
anti-cancer therapy and date of other anti-cancer therapy such as post-treatment surgery 
and radiotherapy as deemed appropriate.   
- 
The start date of new anti-cancer therapy in defining TEAE for safety is always the first 
date of new systemic anti-cancer therapy taken after the last study treatment.   
 
Tumor response per RECIST or event driven endpoints have not been commonly used for the 
efficacy evaluation of TCM. ORR, PFS or OS benefit of Chinese herbal medicines or Chinese 
patent medicines has not yet been established. Therefore, they will not be taken into account as 
new anti-cancer therapy in the efficacy and safety analyses.  
 
Patient data listings of post-treatment anti-cancer therapy, procedure, radiotherapy, or surgery 
will be provided. 
7.5 
SAFETY ANALYSES 
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE v5.0. 
Laboratory values (e.g., hematology, clinical chemistry), vital signs, ECGs, and PEs, will also be 
used in determining safety. Descriptive statistics (e.g., n, mean, standard deviation, median, Q1, 
Q3, minimum, maximum for continuous variables; n [%] for categorical variables) will be used to 
analyze all safety data in the safety analysis set.  


 
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7.5.1 Extent of Exposure 
The following exposure parameters will be summarized with descriptive statistics for each study 
drug. One cycle is defined as 21 days of treatment. Specifically: 
Treatment duration (TD) for tislelizumab/placebo, cisplatin, 5-FU, oxaliplatin, capecitabine: The 
treatment duration will be calculated as (last date of exposure – date of first dose + 1)  
x If patients discontinued treatment (with non-missing EOT date), using min 
(CUOFFDT, death date, last dose date + 20) as the “last date of exposure” for 
tislelizumab, cisplatin and oxaliplatin; using min (CUOFFDT, death date, last dose 
date + 16) as the “last date of exposure” for 5-FU; using min (CUOFFDT, death date, 
last dose date + 7) as the “last date of exposure” for capecitabine.  
x otherwise if patient has treatment ongoing, using cutoff date as the “last date of 
exposure” for calculation of TD 
 
Total Cumulative Dose: sum (all actual dosages per administration at all visits prior to the cutoff 
date) 
Actual dose intensity (ADI), planned dose and relative dose intensity (RDI) 
Actual Dose Intensity (ADI) for tislelizumab (mg/cycle) = 21*total cumulative dose (mg) / (last 
dose date prior to cut off date+ 21 - first dose date). 
Planned Dose Intensity for tislelizumab (mg/cycle) = 200 mg/cycle. 
Relative Dose Intensity (%) for tislelizumab = Actual Dose Intensity/200 *100% 
The derivations of ADI planned dose and RDI for Chemotherapy are shown in Table 5.   
Table 5  ADI, planned dose and RDI for Chemotherapy 
 
 
                                          ADI(mg/m2/cycle) 
Planned dose 
per cycle  
RDI 
cisplatin 
∑
ܽܿݐݑ݈ܽ ݀݋ݏ݁
ܤܵܣ∗
× 21
#௢௙ ௖௬௖௟௘௦
ଵ
݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 21 −݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁ 
 
80 mg/m2 
 
ܣܦܫ
80  
 
Oxaliplatin 
∑
ܽܿݐݑ݈ܽ ݀݋ݏ݁
ܤܵܣ∗
× 21
#௢௙ ௖௬௖௟௘௦
ଵ
݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 21 −݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁ 
    
130 mg/m2 
 
 
ܣܦܫ
130  
 
5-FU 
∑
ܽܿݐݑ݈ܽ ݀݋ݏ݁
ܤܵܣ∗
#௢௙ ௖௬௖௟௘௦
ଵ
max( ݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 17 −݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁
21
,
݊ݑܾ݉݁ݎ ݋݂ ܿݕ݈ܿ݁ݏ ݅݊ ݈ܽݏݐ ݀݋ݏ݅݊݃ ܥܴܨ ݌ܽ݃݁)
       
800 * 5 
mg/m2 
ܣܦܫ
4000  
 
capecitabine 
∑
ܽܿݐݑ݈ܽ ݀݋ݏ݁
ܤܵܣ∗
#௢௙ ௖௬௖௟௘௦
ଵ
max( ݀ܽݐ݁ ݋݂ ݈ܽݏݐ ݀݋ݏ݁ ݑ݌ ݐ݋ ܿݑݐ݋݂݂+ 8 −݂݅ݎݏݐ ݀݋ݏ݁ ݀ܽݐ݁
21
,
݊ݑܾ݉݁ݎ ݋݂ ܿݕ݈ܿ݁ݏ ݅݊ ݈ܽݏݐ ݀݋ݏ݅݊݃ ܥܴܨ ݌ܽ݃݁)
 
 
2000*14 
mg/m2 
ܣܦܫ
28000 
 


 
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The number of patients with dose reductions, dose delays, dose interruptions, and treatment 
discontinuation and their reasons will be summarized by counts and percentages according to study 
drug.  
Patient data listings will be provided for all dosing records, and for the above calculated summary 
statistics. 
7.5.2 Adverse Events  
The AE verbatim descriptions (Investigator’s description from the eCRF) will be classified into 
standardized medical terminology using Medical Dictionary for Regulatory Activities (MedDRA). 
Adverse events will be coded to MedDRA (Version 24 or higher) lower level term closest to the 
verbatim term. The linked MedDRA System Organ Class (SOC) and Preferred Term are also 
classified. All adverse event summaries are based on safety analysis set. 
In this trial, a TEAE is defined as an AE that had an onset date or a worsening in severity from 
baseline (pretreatment) on or after the first dose of study drug up to 30 days following study drug 
discontinuation or initiation of the first new systemic anti-cancer therapy after the last study 
treatment, whichever occurs first. Only those AEs that were treatment-emergent will be included 
in TEAE summary tables. All AEs, treatment-emergent or otherwise, will be presented in patient 
data listings.  COVID-19 related adverse events will be summarized separately.   
 
It is noteworthy that the definitions of TEAE in the protocol is different from the one in this SAP, 
while the definition of imAE remains the same. The update of TEAE window streamlines the 
TEAE derivation so all TEAEs can be identified programmatically instead of relying on the 
manual medically review of imAE.  imAE occurs outside of the above mentioned TEAE window 
will not be classified as treatment-emergent adverse events.  All imAE will be reported separately. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and Preferred Term. A patient will be counted only once by the highest severity grade per 
NCI-CTCAEv.5.0 within an SOC and Preferred Term, even if the patient experienced more than 
1 TEAE within a specific SOC and Preferred Term. The number (percentage) of patients with 
TEAEs will also be summarized by relationship to the study drug.  
7.5.2.1 Treatment Emergent Adverse Event 
An overall summary of TEAEs will summarize (in the safety analysis set and PD-L1+ safety 
analysis set, as well as by region) the number (%) of patients with  
x At least one TEAE 
x At least one TEAE with NCI-CTCAE grade ≥3 
x At least one treatment-related TEAE 
x At least one serious TEAE 
x At least one TEAE leading to death 
x At least one TEAE leading to discontinuation of study drug 


 
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x At least one TEAE leading to dose modification of study drug 
x At least one infusion-related reaction 
x At least one infusion-related reaction with NCI-CTCAE grade ≥3 
Summaries of the following TEAEs will be provided in the PD-L1+ analysis set and safety analysis 
set:  
x All TEAEs  
o All TEAEs by SOC 
o All TEAEs by SOC and PT 
o Most frequently reported (incidence ≥10% in any treatment arm) TEAE by SOC 
and PT 
o Treatment-related TEAE by SOC and PT 
o Most frequently reported (incidence ≥10% in any treatment arm) Treatment-related 
TEAE by SOC and PT 
x Serious TEAEs by SOC and PT 
o Most frequently reported (incidence ≥ 5% in any treatment arm) serious TEAE by 
SOC and PT 
o Treatment-related Serious TEAE by SOC and PT 
x TEAEs with NCI-CTCAE grade ≥3 by SOC and PT 
o Treatment-related TEAE with NCI-CTCAE grade ≥ 3 by SOC and PT 
x Most frequently reported (incidence ≥ 5 % in any treatment arm) TEAE with NCI-CTCAE 
grade ≥ 3 by SOC and PT. 
x TEAEs leading to death by SOC and PT 
o Treatment-related TEAE Leading to Death by SOC and PT 
x TEAEs leading to treatment discontinuation by SOC and PT 
o Treatment-related TEAE Leading to Treatment Discontinuation by SOC and PT 
x TEAEs leading to dose modification by SOC and PT 
o Treatment-related TEAE Leading to Dose Modification by SOC and PT 
7.5.2.2 Immune-mediated Adverse Event 
Immune-mediated adverse events are of special interest and summarized by category within a pre-
defined list. The identification of immune-mediated adverse events is described in immune-
mediated adverse event charter.  All imAE up to 90 days of last dose of tislelizumab/placebo will 
be summarized.  
Summaries of the following incidence of immune-mediated adverse events will be provided in 
tislelizumab + chemotherapy arm: 


 
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x Immune-mediated adverse events by category and maximum severity  
x Immune-mediated adverse events with NCI-CTCAE grade ≥3 by category 
x Immune-mediated adverse events leading to treatment discontinuation by category 
x Immune-mediated adverse events leading to death by category 
x Immune-mediated adverse events leading to dose modification by category 
x Immune-mediated adverse events treated with systematic corticosteroid by category 
x Time to Immune-mediated adverse events and resolution 
x Duration of resolved Immune-mediated adverse events 
7.5.2.3 Infusion-related Adverse Event 
For infusion related reaction (IRR)s, a summary of incidence by SOC, PT and maximum severity 
will be provided, sorted by descending order of incidence within each SOC and PT based on 
tislelizumab column. Summaries of IRRs, IRRs with NCI-CTCAE grade ≥3 and IRRs leading to 
treatment discontinuation will also be provided by PT only, in descending order. 
7.5.3 Death 
All deaths and causes of death will be summarized by treatment group, including those occurred 
during the study treatment period and those reported during the survival follow-up period after 
treatment completion/discontinuation. 
7.5.4 Laboratory Values 
Clinical laboratory (e.g., hematology, serum chemistry, Coagulation and Urinalysis) values will 
be evaluated for each laboratory parameter by patient. Abnormal laboratory values will be flagged 
and identified as those outside (above or below) the normal range. Reference (normal) ranges for 
laboratory parameters will be included in the CSR for this protocol. Descriptive summary statistics 
(e.g., n, mean, standard deviation, median, minimum, maximum for continuous variables; n [%] 
for categorical variables) for laboratory parameters and their changes from baseline will be 
calculated. Laboratory values will be summarized by visit and by worst postbaseline visit.  The 
summary tables will report lab assessments up to 30 days of the last dose date.   
Laboratory parameters that are graded in NCI-CTCAEv.5.0 will be summarized by NCI-CTCAE 
grade. In the summary of laboratory parameters by NCI-CTCAE grade, parameters with NCI-
CTCAE grading in both high and low directions (e.g., calcium, glucose, magnesium, potassium, 
sodium) will be summarized separately.  
Hy’s Law for liver injury will also be summarized.  
7.5.5 Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic BP, heart rate, temperature, 
weight) and changes from baseline will be presented by visit. For tislelizumab, the change from 


 
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post-dose (end of infusion) to pre-dose also need to be summarized for all vital sign parameters 
except for height and weight. Vital signs will be listed by patient and visit.  
7.5.6 Electrocardiograms (ECG) 
12-lead ECG recordings are required at Screening, Safety Follow-up, and as clinically indicated. 
Patient listing of ECG will be provided for all ECG recordings. 
The actual value and the change from baseline for QTcF intervals will be summarized by visit 
and treatment group using descriptive statistics.   
 
Abnormal post-baseline QTcF results will be summarized with the following categories: increase 
of >30 msec, increase of > 60 msec, value of > 450 msec, value of > 480 msec, value of > 500 
msec for each visit by treatment group. 
7.5.7 ECOG 
ECOG performance status will be summarized by treatment arm and by visit. 
A shift table from baseline to worst post-baseline in ECOG performance score will be summarized.  
Patient listing of ECOG will be provided for all ECOG findings. 
7.5.8 Antidrug Antibody 
Samples to assess anti tislelizumab antibodies will be collected only in patients randomized to 
receive tislelizumab and in sites that are able to adequately perform sampling, handling, and 
processing procedures outlined in the laboratory manual. 
ADA attributes: 
Treatment boosted ADA is defined as ADA positive at baseline that was boosted to a 4-fold 
or higher-level following drug administration.  
Treatment-induced ADA is defined as ADA negative at baseline and ADA positive post-
baseline.  
Transient ADA response is defined as Treatment-emergent ADA detected only at 1 time 
point during treatment or follow-up, excluding last time point; or detected at 2 or more 
time points during treatment or follow-up, where the first and last positive samples are 
separated by less than 16 weeks and the last time point is negative. 
Persistent ADA response is defined as Treatment-induced ADA detected at 2 or more time 
points during treatment or follow-up, where the first and last ADA positive samples are 
separated by 16 weeks or longer; or detected only in the last time point or at a time point 
less than 16 weeks before a negative last sample. 
Neutralizing ADA is defined as ADA that inhibits or reduces the pharmacological activity. 
ADA response endpoints: 
x ADA incidence is defined as sum of treatment-induced and treatment-boosted ADA-
positive patients as a proportion of the ADA evaluable population.  


 
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x ADA prevalence is defined as proportion of all patients that are ADA positive, including 
pre-existing ADA, at any time point. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidence of positive ADA and 
neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy and safety may be evaluated if data allow, and may be reported separately from the main 
study report 
7.5.9 Other Safety Measurements 
Other safety measurements including pulmonary function, ophthalmology exam, digital pulse 
oximetry, and abnormal physical exam findings, will be listed by patient and visit. 
7.6 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic samples will be collected in this study as outlined in appendix 1 of the protocol, 
and only from patients randomized to receive tislelizumab in sites that are able to adequately 
perform PK sampling, handling, and processing procedures as outlined in the Laboratory Manual. 
Tislelizumab post-dose and trough serum concentration data (Ctrough) will be tabulated and 
summarized by visit/cycle at which these concentrations are collected. Descriptive statistics will 
include means, medians, ranges, and standard deviations, as appropriate. PK analysis by subgroup 
(e.g. region) may be performed as needed.   
Additional PK analyses, including population PK analyses and exposure-response (efficacy, safety 
endpoints) analyses may be conducted as appropriate and the results of such analysis may be 
reported separately from the CSR. Concentrations of tislelizumab will be summarized 
descriptively. 
7.7 
OTHER ANALYSIS 
Distribution of PD-L1 expression will be examined in the ITT Population. Potential association 
between PD-L1 expression and tislelizumab treatment combined with chemotherapy effect over 
chemotherapy will be explored.  
Other potential predictive markers may be assessed. 
 
8 
INTERIM ANALYSIS 
There will be one interim analysis of OS using the O’Brien-Fleming boundary approximated by 
Hwang-Shih-DeCani spending function with the gamma parameter set at -4. The non-binding 
lower (futility) boundary is defined by Hwang-Shih-DeCani spending function with the gamma 
parameter set at -12. The interim analysis of OS will be performed when approximately 269 deaths 
in the PD-L1+ analysis set and 538 deaths in the ITT analysis set (70% of the target number of OS 
events in each analysis set) among the 2 treatment arms have been observed which is estimated to 
occur approximately 30 months after the first patient is randomized. The final analysis of OS will 
take place after approximately 384 and 768 death events have been observed in the 2 analysis sets, 


 
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respectively, which is estimated as 48 months after the first patient is randomized. Stopping 
boundaries in p-value and Z score for primary analyses of OS are shown in Table6. The boundaries 
will be updated according to the actual numbers of events in the interim and final analyses, using 
the above pre-specified alpha spending function. In the event that only OS in PD-L1+ analysis set 
is positive at IA, all the planed analyses in PD-L1+ analysis set will be reported. The study will 
continue until 768 deaths events have been observed in the ITT analysis set.  
Table 6: Stopping Boundaries (in p-value and Z score) of Primary Analysis of OS 
Analysis 
Set 
Analysis 
Time (m) 
# 
Events 
p-valuea (Z 
score) for 
Efficacy 
p-valuea (Z 
score) for 
Interim 
Futility 
Approximate 
HR 
Threshold for 
efficacy 
Cumulative 
Prob of 
Crossing 
Under H1 
PD-L1+b 
Interim 
analysis 
30 
269 
< 0.0072 
(>2.45) 
> 0.5731 
(< -0.18) 
0.742 
0.47 
Final 
analysis 
48 
384 
< 0.0228 
(> 2.00) 
- 
0.815 
0.80 
ITT 
Interim 
analysis 
30 
538 
< 0.0072 
(>2.45) 
> 0.5384 
(< -0.1) 
0.810 
0.56 
Final 
analysis 
48 
768 
< 0.0228 
(> 2.00) 
- 
0.866 
0.87 
 
a. 
1-sided 
b. PD-L1+ is 50% of the ITT 
An interim analysis for OS will be performed by an independent statistician external to the 
Sponsor. The independent statistician will work with the blinded study statistician to provide 
statistical outputs to the IDMC as described in the IDMC charter and perform any ad-hoc analyses 
requested by the IDMC.  
 
9 
CHANGES IN THE PLANNED ANALYSIS 
If the SAP needs to be revised, the sponsor will determine how the revision impacts the study and 
how the revision should be implemented.  The details of the revision will be documented and 
described in the clinical study report. 
 
10 REFERENCES 
Common Terminology Criteria for Adverse Events (CTCAE).  Version 4.0.  United States 
Department of Health and Human Services, National Institutes of Health, National Cancer Institute, 
Washington, DC, USA, June 14, 2010. 
Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R, et al.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer. 
2009;45:228-47. 


 
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Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.  
Washington, DC: United States Food and Drug Administration; 2007. 
Robins JM, Tsiatis A. Correcting for non-compliance in randomized trials using rank-preserving 
structural failure time models. Communications in Statistics. 1991;20: 2609-31. 


 
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11 APPENDIX 1  IMPUTATION RULES FOR PARTIAL DATES 
11.1  IMPUTE PARTIAL DATES FOR CONCOMITANT MEDICATION  
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute partial dates for medications.   
If start date of a medication/therapy/procedure is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
x If the imputed start date > death date, then set to death date 
If end date of a medication/therapy/procedure is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed end date > death date, then set to death date 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
11.2 IMPUTE PARTIAL DATES FOR ADVERSE EVENTS 
If year of the start date is missing or start date is completely missing, do not impute. Impute AE 
end date first if both AE start date and end date are partially missing. 
If end date of an adverse event is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed end date > death date, then set to death date 
If year of the end date is missing or end date is completely missing, do not impute. If start date 
of an adverse event is partially missing, impute as follows: 
x If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
x If both month and day are missing and year ≠ year of treatment start date, then set to 
January 01 
x If day is missing and month and year = month and year of treatment start date, the set 
to treatment start date 
x If day is missing and month and year ≠ month and year of treatment start date, the set 
to first of the month 
x If the imputed AE start date is after AE end date (maybe imputed), then update AE 
start date with AE end date as final imputed AE start date. If the imputed end date > 


 
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min (death date, end of study date), then set to min (death date, end of study date). 
11.3 IMPUTE PARTIAL DATES FOR SUBSEQUENT ANTI-CANCER SYSTEMATIC 
THERAPY/SURGERY/PROCEDURE 
When the start date of subsequent anti-cancer therapy is partially missing, the following rules 
will be applied to impute partial dates. 
If start date of is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed start date > min (death date, study discontinuation date, data cutoff 
date, start date of the next subsequent therapy), then set to min (death date, study 
discontinuation date, data cutoff date, start date of the next subsequent therapy) 
x The imputed start date must be before or equal to the end date 
If stop date of is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed stop date > min (death date, study discontinuation date, data cutoff 
date, start date of the next subsequent therapy), then set to min (death date, study 
discontinuation date, data cutoff date, start date of the next subsequent therapy) 
x The imputed stop date must be after or equal to the end date 
If year of the start date/stop date is missing, do not impute.  
 
11.4 IMPUTE PARTIAL DATES FOR PRIOR ANTI-CANCER THERAPY (DRUG, 
SURGERY/PROCEDURE, RADIOTHERAPY) 
Impute end date first. If end date is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to the last day of the month 
x For start date of prior systemic therapy for cancer, if imputed end date > 
randomization date – 6 months, then set to randomization date – 6 months 
x For start date of prior radiotherapy/surgery, if imputed end date > randomization date, 
then set to randomization date - 1 
 If start date is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 


 
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x If the imputed start date > end date, then set to the end date 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute.  
 
 
 
 
 
 


 
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12 APPENDIX 2  RULES FOR IDENTIFYING MISSING TUMOR 
ASSESSMENTS 
Identifying two missing tumor assessment 
1) Input scheduled TA visit list for each study 
a. (eg. 6wk-12wk-18wk-27wk-36wk…;    9wk-18wk-27wk-36wk-45wk-54wk-
66wk- 78wk…) 
2) Identify last evaluable TA before PD or death (--LPTADT) and map it to the closest 
scheduled visit (--LPTADT_WK). 
a. In the event of unscheduled TA, choose the closest scheduled visit number (e.g. 
6wk or 27wk) as –LPTADT_WK. It can be achieved programmatically by 
following the classification rule (e.g. defining thresholds) depicted in table 7 
below.   
b. Otherwise, assign the scheduled visit number (assuming it is coded correctly) to --
LPTADT_WK 
3) Find the 2nd TA visit after LPTADT_WK according to the list in step 1 (--
LPTADT_WK_2) 
a. If LPTADT_WK_2+1wk < earliest of PD/death date, then censor PFS at the –
LPTADT 
Table 7 shows how to assign unscheduled TA to a schedule visit.  The Threshold column is defined 
as the mid-point between current and next visit (except for baseline); it is the upper limit for 
LPTADT to be mapped to the prior scheduled assessment (step 2a above). For example, if 
LPTADT is Week 44 for an unscheduled visit, it will be mapped to Week 42 TA since it is within 
the Thredshold for Week 42. Assuming it is SD and the subsequent TA of the patient is PD after 
Week 58, PFS will be censored at LPTADT (Week 44); had the PD occurred prior to Week 58, it 
would be counted as an PFS event 
 
Table 7 Example of scheduled tumor assessments with time window  
 
Weeks 
Scheduled week -1 
Scheduled week 
Scheduled week+1 Threshold  
Baseline 
  
Baseline 
  
  
Every 6 weeks 
for the first 48 
weeks 
  
  
  
Week 5 
Week6 
Week 7 
Week 9 
Week 11 
Week 12 
Week 13 
Week 15 
Week 17 
Week 18 
Week 19 
Week 21 
Week 23 
Week 24 
Week 25 
Week 27 
Week 29 
Week 30 
Week 31 
Week 33 
Week 35 
Week 36 
Week 37 
Week 39 
Week 41 
Week 42 
Week 43 
Week 45 
Week 47 
Week 48 
Week 49 
Week 52 
 Every 9 weeks 
afterwards 
  
Week 56 
Week 57 
Week 58 
Week 61 
Week 65 
Week 66 
Week 67 
Week 70 
Week 74 
Week 75 
Week 76 
…