Clinical trial NCT03358875
Conditions: Non-small Cell Lung Cancer
Sponsor: BeiGene
Start date: 2017-11-30; Completion date: 2024-01-18
Enrollment: 805 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to show that tislelizumab will improve overall survival in participants with Stage IIIB or IV non-small cell lung cancer when compared to docetaxel in second or third-line treatment setting.

Detailed description:
This is a randomized, open-label, multicenter Phase 3 study in adult participants with histologically confirmed, locally advanced or metastatic (Stage IIIB or IV), NSCLC (squamous or non-squamous) who have disease progression during or after a platinum-containing regimen.

Arms: arm 1: Participants received tislelizumab 200 mg intravenously (IV) once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of informed consent, whichever occurred first. arm 2: Participants received docetaxel 75 mg/m² IV once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of informed consent, whichever occurred first.
Interventions: intervention 1: Tislelizumab intervention 2: Docetaxel
Intervention descriptions: intervention 1: Tislelizumab administered by intravenous (IV) infusion intervention 2: Docetaxel administered as an IV infusion over 1 hour

Protocol documents:
Prot_000.pdf: 
BGB-A317-303 
BeiGene 
Protocol Amendment 3.0 
09 March 2020 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 3, Open-Label, Multicenter, Randomized Study to 
Investigate the Efficacy and Safety of BGB-A317 (Anti−PD1 
Antibody) Compared with Docetaxel in Patients with Non−Small 
Cell Lung Cancer Who Have Progressed on a Prior Platinum-
Containing Regimen 
Protocol Identifier: 
BGB-A317-303 
Phase: 
3 
Investigational Product: 
Tislelizumab (BGB-A317) 
Indication: 
Treatment of Non−Small Cell Lung Cancer in the second- or third-
line setting 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, California 94403 
USA 
BeiGene (Shanghai) Co., Ltd.* 
Floor 4, Building D 
No. 780, Cailun Road 
Pilot Free Trade Zone 
Shanghai 201203, China  
* BeiGene (Shanghai) Co., Ltd., is China sponsor for the study.
Reference Number 
EudraCT 2018-000245-39 
Sponsor Medical Monitors 
 
22nd Floor, Tower D Central International Trade Center 
6A Jianguomenwai Avenue, Chaoyang District 
Beijing 100022, China 
Email:  
 
Phone: 
  
  
22nd Floor, Tower D Central International Trade Center 
6A Jianguomenwai Avenue, Chaoyang District 
Beijing 100022, China 
Email:  
 
Phone: 
  
 
55 Challenger Road, Suite 501, Ridgefield Park 
New Jersey 07660, USA 
Email: 
 
Phone:  
 
NCT Number:  
 
     NCT03358875


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Original Protocol: 
12 July 2017  
Amendment 1.0: 
14 February 2018 
Amendment 2.0: 
20 July 2018  
Amendment 3.0: 
09 March 2020 
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 subsidiaries. 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 subsidiaries. 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 subsidiaries. 


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FINAL PROTOCOL APPROVAL SHEET 
Title: A Phase 3, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and 
Safety of BGB-A317 (Anti−PD1 Antibody) Compared with Docetaxel in Patients with 
Non−Small Cell Lung Cancer Who Have Progressed on a Prior Platinum-Containing Regimen 
 
BeiGene, Ltd. Approval: 
 
___________________________________ 
 
____________________________________ 
Date 


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INVESTIGATOR SIGNATURE PAGE 
Title: A Phase 3, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and 
Safety of BGB-A317 (Anti−PD1 Antibody) Compared with Docetaxel in Patients with 
Non−Small Cell Lung Cancer Who Have Progressed on a Prior Platinum-Containing Regimen 
 
Protocol Identifier: BGB-A317-303 
 
This protocol is a confidential communication of BeiGene, Ltd. 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. 
Instructions for Investigator: Please SIGN and DATE this signature page. PRINT your name, title, 
and the name and address of the center in which the study will be conducted.  
 
I have read the 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 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................3 
INVESTIGATOR SIGNATURE PAGE .........................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
SYNOPSIS ....................................................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................22 
1. 
INTRODUCTION ......................................................................................................25 
1.1. 
Lung Cancer ................................................................................................................25 
1.2. 
Treatment Options for Locally Advanced or Metastatic NSCLC ..............................25 
1.2.1. 
Chemotherapy for Locally Advanced or Metastatic NSCLC .....................................25 
1.2.1.1. 
First-line Treatment for Advanced NSCLC Without an EGFR Mutation or 
ALK Rearrangement ...................................................................................................25 
1.2.1.2. 
Second-line Treatment for Advanced NSCLC Without an EGFR Mutation or 
ALK Rearrangement ...................................................................................................26 
1.2.2. 
Targeted Therapy for Locally Advanced or Metastatic Lung Cancers ......................27 
1.3. 
Anti-PD-1/PD-L1 Therapy for Locally Advanced or Metastatic Lung 
Cancers .......................................................................................................................28 
1.4. 
Background Information on Tislelizumab ..................................................................33 
1.4.1. 
Pharmacology .............................................................................................................33 
1.4.2. 
Toxicology ..................................................................................................................33 
1.4.3. 
Clinical Pharmacology ................................................................................................34 
1.4.4. 
Summary of Relevant Clinical Experience with Tislelizumab ...................................34 
1.4.4.1. 
BGB-A317_Study_001 (Data Cutoff 28 August 2017) .............................................34 
1.4.4.2. 
Study BGB-A317-102 (Data Cutoff 28 August 2017) ...............................................35 
1.4.4.3. 
Immune-Related Reactions .........................................................................................36 
1.5. 
Study Rationales .........................................................................................................36 
1.5.1. 
Rationale for Tislelizumab in NSCLC as Second-or Third-Line Treatment ..............36 
1.5.2. 
Rationale for Docetaxel as the Active Control for Second- and Third-Line 
Treatment ....................................................................................................................37 
1.5.3. 
Rationale for Stratification Factors .............................................................................37 


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1.5.4. 
Rationale for Randomization at 2:1 Ratio ..................................................................38 
1.5.5. 
Rationale for Choosing Overall Survival in ITT and PD-L1-positive Subset 
as Dual Primary Endpoint ...........................................................................................38 
1.5.6. 
Rationale for Patient Population Excluding Patients with EGFR Mutation 
and ALK Translocation ..............................................................................................39 
1.5.7. 
Rationale for Tislelizumab Dose Selection ................................................................40 
1.6. 
Benefit-Risk Assessment ............................................................................................40 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................42 
2.1. 
Objectives ...................................................................................................................42 
2.1.1. 
Primary Objective .......................................................................................................42 
2.1.2. 
Secondary Objectives .................................................................................................42 
2.1.3. 
Exploratory Objectives ...............................................................................................42 
2.2. 
Endpoints ....................................................................................................................42 
2.2.1. 
Primary Endpoints ......................................................................................................42 
2.2.2. 
Secondary Endpoints ..................................................................................................42 
2.2.3. 
Exploratory Endpoints ................................................................................................43 
3. 
STUDY DESIGN .......................................................................................................44 
3.1. 
Summary of Study Design ..........................................................................................44 
3.2. 
Screening Period .........................................................................................................46 
3.3. 
Treatment Period ........................................................................................................46 
3.4. 
Safety Follow-Up ........................................................................................................47 
3.5. 
Survival Follow-up .....................................................................................................47 
3.6. 
Discontinuation From the Study Treatment or From the Study .................................47 
3.6.1. 
Patient Discontinuation from Study Treatment ..........................................................47 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........48 
3.7. 
End of Study ...............................................................................................................48 
4. 
STUDY POPULATION .............................................................................................50 
4.1. 
Inclusion Criteria ........................................................................................................50 
4.2. 
Exclusion Criteria .......................................................................................................51 
5. 
STUDY TREATMENT ..............................................................................................55 
5.1. 
Packaging, Handling, and Storage ..............................................................................55 
5.1.1. 
Tislelizumab ...............................................................................................................55 
5.1.2. 
Docetaxel ....................................................................................................................55 


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5.2. 
Dosage, Administration, and Compliance ..................................................................55 
5.2.1. 
Tislelizumab ...............................................................................................................56 
5.2.2. 
Docetaxel ....................................................................................................................56 
5.3. 
Overdose .....................................................................................................................56 
5.4. 
Investigational Medicinal Product Accountability .....................................................56 
5.5. 
Dose Delay or Modification .......................................................................................57 
5.5.1. 
Dose Delay or Modification for Tislelizumab ............................................................57 
5.5.2. 
Dose Delay or Modifications of Docetaxel ................................................................57 
5.6. 
Disposal and Destruction ............................................................................................58 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................59 
6.1. 
Prior Therapy ..............................................................................................................59 
6.2. 
Concomitant Therapy .................................................................................................59 
6.2.1. 
Permitted Concomitant Medications/Procedures .......................................................59 
6.2.2. 
Prohibited Concomitant Medications/Procedures ......................................................60 
6.2.3. 
Restricted Concomitant Medications/Procedures .......................................................60 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................62 
7.1. 
Screening ....................................................................................................................62 
7.1.1. 
Demographic Data and Medical History ....................................................................62 
7.1.2. 
Females of Childbearing Potential and Contraception ...............................................63 
7.1.3. 
Informed Consent Forms and Screening Log .............................................................63 
7.1.4. 
Pulmonary Function Tests ..........................................................................................63 
7.2. 
Enrollment ..................................................................................................................63 
7.2.1. 
Confirmation of Eligibility .........................................................................................63 
7.2.2. 
Patient Numbering ......................................................................................................63 
7.2.3. 
Enrollment/Randomization .........................................................................................64 
7.3. 
Tislelizumab and Docetaxel Dispensation ..................................................................64 
7.4. 
Safety Assessments .....................................................................................................64 
7.4.1. 
Vital Signs ..................................................................................................................64 
7.4.2. 
Physical Examinations ................................................................................................64 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status ........................................64 
7.4.4. 
Laboratory Safety Tests ..............................................................................................65 
7.4.5. 
Electrocardiogram .......................................................................................................66 


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7.4.6. 
Adverse Events ...........................................................................................................66 
7.4.7. 
Ophthalmologic Examination .....................................................................................66 
7.5. 
Tumor and Response Evaluations ..............................................................................67 
7.6. 
Pharmacokinetic Blood Sampling ..............................................................................68 
7.7. 
Anti-Drug Antibody Testing.......................................................................................69 
7.8. 
Tumor Tissues Samples and Biomarkers Assessment Procedures .............................69 
7.9. 
Health-Related Quality of Life Assessment ...............................................................71 
7.10. 
Visit Windows ............................................................................................................71 
7.11. 
Unscheduled Visits .....................................................................................................71 
8. 
SAFETY MONITORING AND REPORTING .........................................................72 
8.1. 
Risks Associated with Tislelizumab ...........................................................................72 
8.2. 
Risks Associated with Docetaxel ................................................................................72 
8.3. 
General Plan to Manage Safety Concerns ..................................................................72 
8.3.1. 
Eligibility Criteria .......................................................................................................72 
8.3.2. 
Safety Monitoring Plan ...............................................................................................73 
8.4. 
Adverse Events ...........................................................................................................74 
8.4.1. 
Definition and Reporting ............................................................................................74 
8.4.2. 
Assessment of Severity ...............................................................................................74 
8.4.3. 
Assessment of Causality .............................................................................................75 
8.4.4. 
Following Adverse Events ..........................................................................................75 
8.4.5. 
Laboratory Test Abnormalities ...................................................................................76 
8.5. 
Definition of a Serious Adverse Event .......................................................................76 
8.6. 
Suspected Unexpected Serious Adverse Reaction .....................................................77 
8.7. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................77 
8.7.1. 
Adverse Event Reporting Period ................................................................................77 
8.7.2. 
Reporting Serious Adverse Events .............................................................................78 
8.7.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................78 
8.7.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................78 
8.7.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................78 
8.7.3. 
Eliciting Adverse Events ............................................................................................79 
8.7.4. 
Disease Progression ....................................................................................................79 
8.7.5. 
Deaths .........................................................................................................................79 


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8.7.6. 
Pregnancies .................................................................................................................79 
8.7.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards and Ethics Committees ......................................................................80 
8.7.8. 
Assessing and Recording Immune-Related Adverse Events ......................................80 
8.8. 
Management of AE of Special Interest .......................................................................80 
8.8.1. 
Infusion-Related Reactions .........................................................................................80 
8.8.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................82 
8.8.3. 
Immune-Related Adverse Events ...............................................................................82 
8.8.4. 
Renal Function Abnormalities ....................................................................................83 
9. 
STATISTICAL METHODS AND ANALYSIS PLAN .............................................85 
9.1. 
Statistical Analysis ......................................................................................................85 
9.1.1. 
Randomization Methods .............................................................................................85 
9.1.2. 
Analysis  Sets ..............................................................................................................85 
9.1.3. 
Patient Disposition ......................................................................................................85 
9.1.4. 
Demographic and Other Baseline Characteristics ......................................................86 
9.1.5. 
Prior and Concomitant Medication .............................................................................86 
9.2. 
Efficacy Analysis ........................................................................................................86 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................87 
9.2.1.1. 
Overall Survival ..........................................................................................................87 
9.2.2. 
Secondary Efficacy Analysis ......................................................................................88 
9.2.2.1. 
Objective Response Rate ............................................................................................88 
9.2.2.2. 
Progression-Free Survival and Duration of Response ................................................88 
9.2.2.3. 
Health-Related Quality of Life ...................................................................................89 
9.2.3. 
Exploratory Efficacy Analysis ....................................................................................89 
9.3. 
Safety Analysis ...........................................................................................................89 
9.3.1. 
Extent of Exposure .....................................................................................................90 
9.3.2. 
Adverse Events ...........................................................................................................90 
9.3.3. 
Clinical Laboratory Analyses .....................................................................................90 
9.3.4. 
Vital Signs Analyses ...................................................................................................91 
9.3.5. 
Ophthalmologic Examination .....................................................................................91 
9.4. 
Pharmacokinetic Analyses ..........................................................................................91 
9.5. 
Immunogenicity Analyses ..........................................................................................91 
9.6. 
Other Exploratory Analyses .......................................................................................91 


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9.7. 
Sample Size Considerations .......................................................................................92 
9.8. 
Interim Analyses .........................................................................................................92 
9.9. 
Statistical Strategy for ITT-ROW ...............................................................................93 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................94 
10.1. 
Independent Data Monitoring Committee ..................................................................94 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................95 
11.1. 
Access to Information for Monitoring ........................................................................95 
11.2. 
Access to Information for Auditing or Inspections ....................................................95 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................96 
12.1. 
Regulatory Authority Approval ..................................................................................96 
12.2. 
Quality Assurance .......................................................................................................96 
12.3. 
Study Site Inspections.................................................................................................96 
12.4. 
Drug Accountability ...................................................................................................96 
13. 
ETHICAL CONSIDERATIONS................................................................................98 
13.1. 
Ethical Standard ..........................................................................................................98 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................98 
13.2.1. 
Protocol Amendments ................................................................................................98 
13.3. 
Informed Consent .......................................................................................................98 
13.4. 
Patient and Data Confidentiality .................................................................................99 
13.5. 
Financial Disclosure .................................................................................................100 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................101 
14.1. 
Data Collections and Management Responsibilities ................................................101 
14.1.1. 
Data Collection .........................................................................................................101 
14.1.2. 
Data Management/Coding ........................................................................................101 
14.2. 
Data Integrity and In-house Blinding .......................................................................101 
14.3. 
Study Records Retention ..........................................................................................102 
14.4. 
Protocol Deviations ..................................................................................................103 
14.5. 
Publication and Data Sharing Policy ........................................................................103 
14.6. 
Study and Study Center Closure ...............................................................................104 
14.7. 
Information Disclosure and Inventions ....................................................................104 
15. 
REFERENCES .........................................................................................................106 
16. 
APPENDICES ..........................................................................................................112 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................113 
APPENDIX 2. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................118 
APPENDIX 3. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................127 
APPENDIX 4. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL”, “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................128 
APPENDIX 5. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................130 
APPENDIX 6. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................131 
APPENDIX 7. IMMUNE-RELATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................132 
 


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LIST OF TABLES 
Table 1: 
Anti-PD-1/PD-L1 Monoclonal Antibody Clinical Trial Outcomes ...........................31 
Table 2: 
Selection and Timing of Dose for Each Patient ..........................................................55 
Table 3: 
Guidelines for Docetaxel Dose Modifications ...........................................................58 
Table 4: 
Guidelines for Management of Hepatotoxicity in Patients Receiving 
Docetaxel ....................................................................................................................58 
Table 5: 
Eastern Cooperative Oncology Group Performance Status ........................................65 
Table 6: 
A Summary of the Commonly Reported Toxicities of Docetaxel .............................72 
Table 7: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................78 
Table 8: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) ..............................................................................................................81 
Table 9: 
Immune-Related Adverse Events ...............................................................................83 
Table 10: Stopping Boundaries (p-value and Z score) and Approximate HR Threshold 
of Interim and Final Analyses of OS ..........................................................................88 
 
LIST OF FIGURES 
Figure 1: 
Phase 3 Study Schema for Tislelizumab Versus Docetaxel as Second-or 
Third-Line Therapy for NSCLC .................................................................................45 
Figure 2: 
Screening tests for Squamous Cell NSCLC ...............................................................70 
Figure 3: 
Screening tests for Non-Squamous Cell NSCLC .......................................................70 
 


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SYNOPSIS 
Name of Sponsor: BeiGene (Shanghai) Co., Ltd. 
Investigational Product: Tislelizumab (BGB-A317) 
Title of Study: A Phase 3, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and 
Safety of BGB-A317 (Anti−PD1 Antibody) Compared with Docetaxel in Patients with Non−Small 
Cell Lung Cancer Who Have Progressed on a Prior Platinum-Containing Regimen 
Protocol Identifier: BGB-A317-303 
Phase of Development: 3 
Planned Number of Patients: Approximately 800 
Study Centers: Approximately 40 centers in Asia Pacific countries and approximately 60 to 80 centers 
in approximately 15 other countries  
Study Objectives: 
Primary: 
 
To compare the efficacy, as measured by overall survival (OS), of tislelizumab with docetaxel 
in the second- or third-line setting in patients with non-small cell lung cancer (NSCLC) who 
have progressed on a prior platinum-containing regimen. A comparison of the treatment arms 
will be performed in: 
o The intent-to-treat (ITT) Analysis Set 
o The programmed cell death protein ligand-1 (PD-L1) positive Analysis Set, where PD-
L1 positive is defined as ≥25% of tumor cells (TCs) with PD-L1 membrane staining 
via the Ventana SP263 assay 
Secondary: 
 
To compare the efficacy of tislelizumab and docetaxel as measured by objective response rate 
(ORR), duration of response (DoR), and progression-free survival (PFS) per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 in: 
o The ITT Analysis Set 
o The PD-L1 positive Analysis Set 
 
To compare health-related quality of life (HRQoL) between tislelizumab and docetaxel arms 
 
To evaluate the safety and tolerability of tislelizumab versus docetaxel 
Exploratory: 
 
To compare tumor assessment outcomes (ie, disease control rate [DCR] and clinical benefit 
rate [CBR]) between tislelizumab and docetaxel assessed by investigator per RECIST v1.1 
 
To explore potential predictive biomarkers for efficacy including but not limited to PD-L1 
expression, tumor mutational burden (TMB), gene expression profile (GEP), and tumor-
infiltrating immune cells 
 
To characterize the pharmacokinetics (PK) of tislelizumab in patients with NSCLC 
 
To determine host immunogenicity to tislelizumab in patients with NSCLC 


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Study Endpoints: 
Primary: 
 
OS – defined as the time from the date of randomization to the date of death due to any cause 
in the ITT and PD-L1 positive Analysis Set 
Secondary: 
 
ORR – defined as the proportion of patients in the ITT and PD-L1 positive Analysis Set who 
had a complete response (CR) or partial response (PR) as assessed by the investigator per 
RECIST v1.1 
 
DoR – defined as the time from the first occurrence of a documented objective response to the 
time of relapse, as determined by the investigator per RECIST v1.1, or death from any cause, 
whichever comes first in the ITT and PD-L1 positive Analysis Set 
 
PFS – defined as the time from the date of randomization to the date of the first objectively 
documented tumor progression as assessed by the investigator per RECIST v1.1 or death from 
any cause, whichever occurs first, in the ITT and PD-L1 positive Analysis Set 
 
HRQoL – measured using European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire-Lung Cancer (EORTC QLQ-LC13), Core 30 (EORTC QLQ-
C30), and European Quality of Life 5-Dimensions, 5-level (EQ-5D-5L) scale 
 
Incidence and severity of treatment-emergent adverse events (TEAEs) graded according to 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
v4.03 
Exploratory: 
 
DCR – defined as the proportion of patients whose best overall response (BOR) is CR, PR or 
stable disease (SD) per RECIST v1.1 
 
CBR - defined as the proportion of patients who have CR, PR and SD that is ≥24 weeks in 
duration per RECIST v1.1 
 
PD-L1 expression, TMB, GEP, and tumor-infiltrating immune cells as predictive biomarkers 
for response 
 
Summary of serum concentrations of tislelizumab in the pharmacokinetic Analysis Set 
 
Assessments of immunogenicity of tislelizumab by determining the incidence of anti-drug 
antibodies (ADAs) in the ADA Analysis Set 
Study Design: 
This is a randomized, open-label multicenter Phase 3 study designed to compare the efficacy and safety 
of tislelizumab versus docetaxel as treatment in the second- or third-line setting in patients with 
NSCLC. The primary endpoint of the study is measured by OS in both the ITT and PD-L1 positive 
Analysis Sets. 


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Abbreviations: BGB-A317 = tislelizumab; BID = twice daily; ECOG = Eastern Cooperative Oncology Group; IV 
= intravenous; NSCLC = Non-small cell lung cancer; PD = progressive disease; Q3W = once every 3 weeks, TC 
= tumor cells. 
a. 
Randomization will be stratified by histology (squamous versus non-squamous), lines of therapy (second 
versus third), and PD-L1 expression (≥25% TC versus <25% TC). 
b. 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 infusion, 
patients will be further monitored for a period of at least 1 hour during Cycles 1 and 2. From Cycle 3 
onward, a post infusion monitoring period of > 30 minutes will be required. 
c. 
At the discretion of the investigator, patients in the tislelizumab arm may be treated beyond disease 
progression under protocol-defined conditions (Section 7.5). 
Patients must have histologically confirmed, locally advanced or metastatic NSCLC (squamous or non-
squamous). Histology of NSCLC (squamous or non-squamous) will be confirmed at the investigator’s 
site. Patients with known epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma 
kinase (ALK) rearrangement are ineligible for the study. Documentation of wild type EGFR by tissue-
based test is required for non-squamous patients to enter the study. Archival tumor tissues (not 
restricted to pretreatment) will be collected for biomarker analysis at a central laboratory. If archived 
formalin-fixed paraffin-embedded (FFPE) tissue is not sufficient, a fresh biopsy sample will be 
mandatory. 
Patients must have been treated with at least one platinum-containing regimen but not more than 
2 prior lines of systemic chemotherapy and have disease progression during or following chemotherapy 
treatment. Patients who progressed or have disease recurrence during or after neo-adjuvant or adjuvant 
therapy with platinum-containing regimen (counted as one line of therapy) within 6 months are eligible 
to enroll into the study. 
After signing an informed consent form and screening for eligibility, patients will be randomized in a 
2:1 ratio to receive tislelizumab or docetaxel in the following 2 arms: 
Arm A:  
Tislelizumab 200 mg intravenously (IV) once every 3 weeks 
Arm B:  
Docetaxel 75 mg/m2 IV once every 3 weeks 
Randomization will be 2:1 (Arm A:Arm B) stratified by histology (squamous versus non-squamous), 
lines of therapy (second versus third), and PD-L1 expression (≥25% TC versus <25% TC). 
Administration of docetaxel and tislelizumab will continue until disease progression, as assessed by 
investigator per RECIST v1.1, unacceptable toxicity, or withdrawal of informed consent, whichever 
occurs first. Patients receiving tislelizumab will be permitted to continue tislelizumab treatment beyond 
radio-imaging progression if clinical benefit is seen in the absence of symptomatic deterioration and 
unacceptable toxicity per investigator’s discretion.  
Stage IIIB or IV 
NSCLC with PD 
after at least  
1 platinum 
containing 
regimen,  
ECOG 0 or 1 
Randomize 
2:1a 
Treatment 
until 
Unacceptable 
toxicity or 
Disease 
progressionc 
BGB-A317b  
200 mg IV 
Q3W 
Safety  
Follow-up & 
Survival 
Follow-up 
Docetaxel 
75 mg/m2 IV 
Q3W 


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Study Assessments: 
Tumor response will be evaluated by investigators every 9 weeks (± 7 days) during Year 1 and every 
12 weeks (± 7 days) from Year 2 onwards based on RECIST v1.1. If a patient discontinues study 
treatment due to reasons other than disease progression, then tumor assessments should continue to be 
performed as scheduled until the start of new anticancer therapy, disease progression, death, loss to 
follow-up, or withdrawn consent. Any new anticancer therapy after discontinuation of study treatment 
from both arms will be documented. 
To determine the PK properties of tislelizumab and host immunogenic response to tislelizumab, blood 
samples will be collected at various time points as outlined in Appendix 1. 
Patients will be evaluated for adverse events (AEs) and serious adverse events (SAEs) occurring up to 
30 days after the last dose of either study drug or initiation of new anticancer therapy, whichever 
occurs first, (all severity grades according to NCI-CTCAE v4.03) and all immune-related AEs (irAEs) 
(tislelizumab arm only) occurring up to 90 days after the last dose of tislelizumab, 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. 
Duration of Patient Participation: 
Total duration of study participation will vary by patient. 
Study Population:  
Patients with locally advanced or metastatic non−small cell lung cancer with disease progression 
during or following treatment with at least one prior platinum-containing regimen.  
Key Eligibility Criteria: 
The population under study is adult patients (≥ 18 years of age on the day the patient voluntarily agrees 
to participate in the study) with locally advanced or metastatic (Stage IIIB or IV) NSCLC with disease 
progression during or following treatment with at least one platinum-containing regimen. Patients with 
known EGFR sensitizing or driver mutation or ALK rearrangement are ineligible for the study. For 
patients with non-squamous NSCLC, documentation of wild type EGFR by tissue-based test is 
required to enter the study. For patients without documented wild type EGFR, fresh or archival tumor 
tissues (FFPE blocks or 6 freshly cut unstained FFPE slides) are required for central EGFR mutation 
assessment. In addition, all patients are required to have fresh or archival tumor tissues (FFPE blocks 
or approximately 11 [a minimum of 5] freshly cut unstained FFPE slides for biomarker analysis 
including PD-L1 expression, have adequate hematologic and end-organ function, and an Eastern 
Cooperative Oncology Group Performance Status score of ≤1. 
Test Product, Dose and Mode of Administration: 
Tislelizumab will be administered at a dose of 200 mg IV once every 3 weeks 
Reference Therapy, Dose, and Mode of Administration: 
Docetaxel will be administered at a dose of 75 mg/m2 IV once every 3 weeks 


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Statistical Methods: 
This trial was originally designed to enroll patients from China and Asia Pacific (CAP) region. After 
amendment 1, it has been expanded to enroll patients from the rest of the world (ROW) as well. The 
primary and secondary objectives of the trial have not been changed due to this expansion. As of 
amendment 3.0, the number of death events that triggers interim analysis has been changed to 426 
(approximately 76% of total number of 560 deaths) in the ITT Analysis Set. All analyses and testing 
discussed in Section 9 pertaining to study Analysis Set include both the CAP and ROW regions of 
patients.  
Statistical Analysis: 
The overall type I error will be strongly controlled at a one-sided α of 0.025 within the 2 dual primary 
hypotheses and 4 secondary efficacy hypotheses. Initially, α of 0.02 and 0.007 will be assigned to the 
primary hypothesis testing in the ITT and PD-L1 positive Analysis Sets, respectively. The α allocation 
accounts for the positive correlation between the test statistics in the 2 Analysis Sets (ie, PD-L1 
positive is a subset of the ITT Analysis Set). The overall type I error is controlled at 0.025 when at least 
30% of the deaths in the ITT Analysis Set are from the PD-L1 positive subset. The α of 0.007 in the 
PD-L1 testing will be adjusted downwards if the final observed percentage is lower. When the trial 
proceeds to the final analysis, the OS hypothesis in the ITT Analysis Set will be tested first. 
If the OS hypothesis in ITT Analysis Set is rejected, the unused α will be passed on to the OS 
hypothesis test in the PD-L1 positive Analysis Set; followed by the second efficacy hypothesis testing 
in the sequential order of ORR in the PD-L1 positive Analysis Set, DoR in the PD-L1 positive Analysis 
Set, PFS in the PD-L1 positive Analysis Set, PFS in the ITT Analysis Set, ORR in the ITT Analysis 
Set, DoR in the ITT Analysis Set, lung cancer symptom scale measured by QLQ-LC13 and QLQ-C30 
global health status/Quality of Life (QoL) in the ITT and PD-L1 Analysis Sets. Otherwise, if the OS 
hypothesis in the ITT Analysis Set cannot be rejected, hypothesis testing will be carried out 
sequentially only in the PD-L1 positive Analysis Set for OS, ORR, DoR, PFS, lung cancer symptom 
scale measured by QLQ-LC13 and QLQ-C30 global health status/QoL scale  at α of 0.007. The testing 
will continue until the first non-significant outcome occurs following the methodology of 
Glimm et al (2010).  
Analysis Sets: 
 
The ITT Analysis Set includes all randomized patients. Patients will be analyzed according to 
their randomized treatment arms. This will be the primary Analysis Set for efficacy analysis. 
The ITT Analysis Set will be summarized for both the China and Asia Pacific (ITT-CAP) 
Analysis Set and the rest of world (ITT-ROW) Analysis Set. 
 
The PD-L1 positive Analysis Set (≥25% of TC with PD-L1 membrane staining) includes all 
randomized patients whose tumors were PD-L1 positive. Patients will be analyzed according to 
their randomized treatment arms. This will be the dual primary analysis population for efficacy 
analysis. 
 
Safety Analysis Set includes all patients who received at least one dose of study drug. It will be 
the population for the safety analyses. 
 
The PK Analysis Set includes patients who contributed at least one quantifiable postdose PK 
sample. 
 
The ADA Analysis Set includes all patients who have received at least 1 dose of tislelizumab 
for whom non-missing baseline ADA and at least 1 non-missing postbaseline ADA results are 
available. 


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Primary Efficacy Analysis: 
Overall Survival 
OS in ITT Analysis Set: 
OS will be compared between tislelizumab (Arm A) and docetaxel (Arm B) in a stratified log-rank test 
using a significance level of 0.02 (one-sided). 
The null hypothesis to be tested is: 
 
H0: OS in Arm A = OS in Arm B 
against the alternative hypothesis: 
 
Ha: OS in Arm A ≠ OS in Arm B 
This will be the primary analysis once the targeted numbers of deaths are reached in the ITT Analysis 
Set.  
The p-value from a stratified log-rank test will be presented using stratification factors. 
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 two-sided 95% confidence intervals (CIs). Kaplan-Meier 
(KM) survival probabilities for each arm will be plotted over time. 
The hazard ratio (HR) between tislelizumab and docetaxel (HRA/B) and its 95% CI will be estimated 
using a Cox proportional hazard model with treatment arm as a factor and stratified by the actual value 
of the stratification factors. 
OS in the PD-L1 Positive Analysis Set: 
The hypothesis testing of OS in the PD-L1 positive Analysis Set will be carried out at a significance 
level of 0.007. If the OS hypothesis in the ITT Analysis Set is rejected, its corresponding α will be 
shifted to the testing in the PD-L1 positive Analysis Set (ie a total α of 0.025). Similar statistical 
methods as described above will be applied with histology and line of therapy as strata in the stratified 
analyses. 
Timing and Stopping Boundary in the Interim and Final Analyses of OS: 
There will be one interim analysis of OS performed in the ITT Analysis Set. The interim analysis will 
be performed when approximately 426 deaths (76% of the target number of 560 deaths) among the 2 
treatment arms are observed in the ITT Analysis Set. It is estimated that it will take approximately 
23.1 months to observe 426 events. The final analysis of OS will take place after 560 and 207 deaths 
are observed in the ITT Analysis Set and its subgroup of patients with positive PD-L1 tumors, 
respectively. Thus, the predefined number of deaths in the ITT Analysis Set will trigger the interim and 
final analyses. The information fraction used in α spending function will be based on the observed 
number of deaths in the ITT Analysis Set at the corresponding time points. A Hwang-Shih-DeCani 
spending function with γ parameter of -2 will be used in setting up the upper (efficacy) boundary.  
Stopping boundaries (p-value and Z score) of superiority test for OS at the interim and final analyses in 
the ITT Analysis Set, as well as OS at the final analysis in the PD-L1 positive Analysis Set are shown 
in the table below. The boundaries of hypothesis testing in OS will be updated according to the actual 
numbers of death events in the interim and final analyses, using the pre-specified α spending function. 


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Stopping Boundaries (in Terms of P-value and Z Score) and Approximate HR Threshold  
of Interim and Final Analyses of OS 
 
Time 
(months) 
# Deaths 
p-value  
(Z score) for 
Efficacy 
Approximate 
HR Threshold 
for Efficacy 
Interim analysis in ITT 
23.1 
426 
<0.0112 (>2.28) 
<0.791 
Final analysis in ITT 
31.0 
560 
<0.0153 (>2.16) 
<0.824 
Final analysis in PD-L1 positive 
31.0 
207 
<0.007 (>2.46) 
<0.696 
Abbreviations: HR = hazard ratio; ITT = intent-to-treat (Analysis Set); PD-L1 – programmed cell death protein 
ligand 1  
Secondary Efficacy Analysis: 
The statistical significance of the difference in ORR between arms in the ITT Analysis Set will be 
evaluated using the Cochran-Mantel-Haenszel chi-square test with the actual stratification factors as 
strata. The two-sided 95% CIs for the odds ratio and the difference in ORR will be calculated, as well 
as Clopper-Pearson 95% CIs for the ORR within each arm. 
The PFS will be compared between 2 arms in the ITT Analysis Set using a stratified log-rank test using 
actual stratification factors as strata. 
The median PFS and the cumulative probability of PFS at every 3 months will be calculated for each 
treatment arm and presented with two-sided 95% CIs. PFS will be estimated using the Kaplan-Meier 
method. The PFS censoring rule will follow the Food and Drug Administration (FDA) Guidance for 
Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007). 
DoR will be analyzed similarly as PFS. It will be summarized within responders. 
Efficacy outcomes (ie, ORR, DoR, and PFS) in the PD-L1 positive Analysis Set will be summarized 
similarly. 
EORTC QLQ-LC13, EORTC QLQ-C30, and EQ-5D-5L post-baseline scores will be compared 
between the 2 treatment arms, using a mixed model. In addition, changes from baseline in global health 
status/QoL of QLQ-C30 and the functional and symptom scales of QLQ-C30, QLQ-LC13 and EQ-5D-
5L (descriptive scores and visual analog scales) will be summarized descriptively. 
Exploratory Efficacy Analysis: 
Exploratory efficacy endpoints assessed by investigator per RECIST v1.1, including DCR, and CBR, 
will be analyzed in the exploratory analysis. 
BOR will be defined as the best response recorded from start of study drug until data cut or start of new 
anticancer treatment. Patients with no postbaseline response assessment (due to any reason) will be 
considered non-responders for BOR. The proportion and its corresponding Clopper-Pearson 95% CI 
for each of the response categories (CR, PR, SD, and progressive disease [PD]) will be presented by 
treatment arm. 
DCR and CBR will be analyzed similarly as ORR in the ITT and PD-L1 positive Analysis Sets. 
Analysis of the relationship of response to exploratory biomarker expression (eg, PD-L1 expression) 
may be carried out. 


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Safety Analysis: 
Drug exposure will be summarized as number of cycles received, duration, dosage, and dose intensity 
by treatment arm. 
Verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory Activities 
(MedDRA®) terms and graded per NCI-CTCAE v.4.03. All TEAEs will be summarized. 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 new 
anticancer therapy. TEAEs also includes all irAEs and drug-related SAEs recorded up to 90 days after 
the last dose of tislelizumab regardless of whether or not the patient starts a new anticancer therapy. 
The SAEs, deaths, irAEs, TEAEs of Grade 3 or above, treatment related TEAE and TEAEs that led to 
treatment discontinuation, dose interruption dose reduction, or dose delay will be summarized. Multiple 
grades of the same event will be counted once per patient at the maximum severity within a System 
Organ Class (SOC) and Preferred Term (PT). 
Clinical laboratory data with values outside of the normal ranges will be identified. Select laboratory 
data will be summarized by NIC-CTCAE grade. Vital signs will also be summarized. 
Pharmacokinetic Analysis: 
PK samples will be collected in this study as outlined in Appendix 1. 
Tislelizumab serum concentration data, including but not limited to minimum observed plasma 
concentration (Ctrough) will be tabulated and summarized for each cycle at which PK are to be measured. 
Descriptive statistics will include means, medians, ranges, and SDs, as appropriate. 
Additional PK analyses will 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 Appendix 1. 
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. 
Sample Size Considerations: 
The original sample size calculation (ie, approximately 640 patients in China and Asia Pacific region) 
is based on the number of events required to demonstrate the OS superiority of Arm A to Arm B in 
ITT-CAP and ITT-CAP patients with PD-L1 positive tumors. The sample size has been increased to 
include an additional 160 patients from ROW hence a total of approximately 800 patients will be 
recruited into the trial. 
Six hundred and forty patients in ITT-CAP will be enrolled over a 16-month period at a constant 
enrollment rate and randomized in a 2:1 ratio to Arms A and B. The enrollment of 160 patients in ITT-
ROW is expected to start approximately 8 months after that for the ITT-CAP and to last about 12 
months. The median OS is assumed as 10 months in Arm B. 
An interim analysis is planned when approximately 426 deaths in the ITT Analysis Set have been 
observed, which represents 76% of the planned number of events (ie 560) in the ITT for the final 
analysis. There is an approximately 87% power to detect an OS HR (Arm A/Arm B) of 0.75 with a 
one-sided type I error of 0.02 in the ITT.  
A Hwang-Shih-DeCani spending function with γ parameter of -2 based on the information fraction in 
the ITT Analysis Set is used in setting up the upper (efficacy) boundary. The stopping boundaries in 


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Table 10 will be updated based on the actual death events observed in the ITT Analysis Set at the 
interim and final analyses. 
The superiority test of OS in the PD-L1 positive Analysis Set will be performed only in the final 
analysis. Two hundred and seven deaths in the ITT patients with PD-L1 positive tumors are required to 
have approximately 86% power to detect an OS HR of 0.60 with a one-sided type I error of 0.007. 
Assuming the prevalence of PD-L1 positivity is 40% in the ITT Analysis Set, it will take 
approximately 31.0 months to accumulate the required approximately 207 events in approximately 320 
patients with PD-L1 positive tumors in the ITT Analysis Set. 
The PD-L1 expression status will be closely monitored and enrollment of patients whose tumors are 
PD-L1 negative will be stopped as necessary through Interactive web response technology upon 
reaching ~60%, that is to ensure that the percentage of PD-L1 positive patients is no less than 40% of 
the ITT Analysis Set. The capping of PD-L1 negative patients to ~60% will be implemented in both 
ITT-CAP and ITT-ROW independently.  
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration time curve 
BGB-A317 
Code name for Monoclonal Antibody tislelizumab  
BOR 
Best overall response  
BSC 
Best supportive care 
CAP 
China Asia Pacific cohort 
CI 
Confidence interval 
Cmax 
Maximum observed plasma concentration 
CNS 
Central nervous System 
CR 
Complete response 
CT 
Computed tomography 
Ctrough 
Minimum observed plasma concentration 
DCR 
Disease control rate 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor  
EORTC QLQ-LC13 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire-Lung Cancer 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire-Core 30 
EQ-5D-5L 
5-level version of European Quality of Life 5-Dimensional 
Questionnaire 


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Abbreviation 
Definition 
Fc 
Fragment crystallizable region (typically, of immunoglobulin G) 
FcR 
Gamma Fc receptor, such as Fc-RI, Fc-RIII, etc. 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FFPE 
Formalin-fixed paraffin-embedded 
GEP 
Gene expression profile 
GFR 
Glomerular filtration rate 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HRA/B 
Hazard ratio between tislelizumab and docetaxel  
HRQoL 
Health-related quality of life 
ICH 
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee  
IEC 
Independent Ethics Committee 
IgG4 
Immunoglobulin G4 
IND 
Investigational New Drug 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous(ly) 
IWRT 
Interactive web response technology 
KD 
Dissociation constant 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network  
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 


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Abbreviation 
Definition 
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 
PS 
Performance status  
PT 
Preferred term 
QoL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
ROS1 
ROS proto-oncogene 1 
ROW  
Rest of world cohort 
SAE 
Serious adverse event 
SD 
Stable disease (or standard deviation in statistical sections) 
SCLC 
Small cell lung cancer 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse events 
T1/2 
Terminal elimination half-life  
TC 
Tumor cells 
TCR 
T-cell receptor 
TEAE 
Treatment-emergent adverse event 
TMB 
Tumor mutational burden 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 


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1. 
INTRODUCTION 
1.1. 
Lung Cancer 
Lung cancer has been the most common cancer worldwide for many decades. In 2012, there 
were an estimated 1.8 million new diagnoses of lung cancer worldwide, representing 12.7% of 
all new cancers. It is also the most common of cancer-related deaths, with 1.59 million deaths 
worldwide, corresponding to 18.2% of total deaths (GLOBOCAN, 2012). Among all lung cancer 
cases, 605,900 or 35.8% of new cases were in China, and 486,600 or 37.6% of lung cancer-
related deaths were in China. Lung cancer is the most common cancer and leading cause of 
cancer-related death in both males and females, with increasing incidences in both males and 
females during the past decades. A recent publication indicates there were 733,300 new cases 
and 610,200 deaths from lung cancer in 2015 (Chen et al, 2016). The risk for lung cancer is 
higher in males than females (2.27:1) (Chen and Zou, 2010). 
The major histological types of lung cancer are non-small cell lung cancer (NSCLC), the most 
common type; small cell lung cancer (SCLC), the second most common type; and lung carcinoid 
tumors. NSCLC accounts for 80% to 85% of all lung cancers and originates from the epithelial 
cells of the lung with the following major histological subtypes: adenocarcinoma, squamous cell 
carcinoma, and large cell carcinoma (PDQ Adult Treatment Editorial Board, 2017). The SCLCs 
account for approximately 10% to 15% of all lung cancers (PDQ Adult Treatment Editorial 
Board, 2017). 
The prognosis for lung cancer patients is relatively poor. However, the prognosis depends greatly 
on the stage at which the cancer is detected. Currently, lung cancer staging is performed 
worldwide according to the 7th edition of tumor, node, metastasis (TNM) Classification of 
Malignant Tumors (Goldstraw et al, 2007). If the lung cancer is diagnosed in its earliest stages, 
cure is possible through surgery or chemo-radiation therapy. Unfortunately, cases of lung cancer 
are most often detected relatively late in the illness, which makes cure less likely. However, with 
appropriate treatment, survival and prognosis can be improved considerably. For patients with 
locally advanced or metastatic NSCLC, 5-year survival rates are approximately 14% for Stage 
IIIA, 5% for Stage IIIB, and 1% for Stage IV (American Cancer Society). 
Management of patients with advanced NSCLC is individualized on the basis of molecular and 
histologic features of the tumor, and is discussed in Section 1.2 (Chemotherapy), Section 1.2.2 
(Targeted therapy) and Section 1.3 (Immunotherapy). 
1.2. 
Treatment Options for Locally Advanced or Metastatic NSCLC 
1.2.1. 
Chemotherapy for Locally Advanced or Metastatic NSCLC 
1.2.1.1. 
First-line Treatment for Advanced NSCLC Without an EGFR Mutation or ALK 
Rearrangement 
For previously untreated patients with advanced NSCLC who do not harbor epidermal growth 
factor receptor (EGFR) sensitizing mutation or anaplastic lymphoma kinase (ALK) gene 
translocation, platinum-containing doublet chemotherapy regimens are recommended 


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(NCCN, 2017). No advantage has been noted with addition of a third cytotoxic drug 
(Delbaldo et al, 2004). A meta-analysis of randomized trials comparing either cisplatin or 
carboplatin with a third-generation drug revealed that there was no apparent difference between a 
carboplatin-based or cisplatin-based chemotherapy when assessing overall survival (OS) or 1-
year survival rates (American Cancer Society). However, some differences in adverse event (AE) 
profiles were noted, so the authors recommend factoring which therapy is more appropriate for a 
given patient into decisions (NCCN, 2017). 
For patients with non-squamous NSCLC that does not have a sensitizing mutation in EGFR or an 
ALK fusion oncogene, standard first-line therapy includes a chemotherapy doublet of cisplatin 
and pemetrexed, which has been shown to have a superior efficacy and reduced toxicity 
compared to cisplatin and gemcitabine (NCCN, 2017; Alimta package insert; 
Al- Farsi and Ellis, 2014). The median (95% confidence interval [CI]) OS was 11.0 (10.1 to 
12.5) months for pemetrexed plus cisplatin compared to 10.1 (9.3 to 10.9) months for 
gemcitabine plus cisplatin. 
Bevacizumab is a recombinant monoclonal antibody that blocks the vascular endothelial growth 
factor (Roviello et al, 2017). Though a combined analysis of the Eastern Cooperative Oncology 
Group (ECOG) 4599 and POINTBREAK trials found survival benefit with the addition of 
bevacizumab to carboplatin/paclitaxel in patients younger than 75 years (de Castria et al, 2013), 
the ECOG and National Comprehensive Cancer Network (NCCN) only recommend 
bevacizumab/chemotherapy for select patients with advanced non-squamous NSCLC because 
more significant toxicities were observed with bevacizumab/chemotherapy compared to 
chemotherapy alone (NCCN, 2017). Doublet chemotherapy regimens are recommended in the 
NCCN guideline and the Chinese guideline for patients with non-squamous NSCLC who are 
lacking the certain gene dysregulation; bevacizumab/chemotherapy is a treatment option for this 
population. 
For patients with squamous NSCLC, cisplatin and gemcitabine or cisplatin and paclitaxel are 
broadly accepted as standard treatment regimen (NCCN, 2017; Al- Farsi and Ellis, 2014). 
1.2.1.2. 
Second-line Treatment for Advanced NSCLC Without an EGFR Mutation or 
ALK Rearrangement 
Patients clinically or radiologically progressing after first-line chemotherapy should be offered 
second-line therapy if their ECOG performance status (PS) is 0 to 2. In the second-line setting, 
combination chemotherapy regimens failed to show any OS benefit over single-agent treatments 
(Di Maio et al, 2009). Single agents improve disease-related symptoms and OS. There are 
currently 4 chemotherapeutic and targeted agents approved that are commonly used in the 
second-line setting: docetaxel, pemetrexed, erlotinib, and afatinib. The choice of agents depends 
upon a number of factors, including tumor histology, the patient’s comorbidities, toxicity from 
previous treatments, risk of neutropenia, smoking history, and patient preference. Patients with a 
good PS in second-line trials have a median survival duration of approximately 8 to 9 months 
and may receive 2 salvage therapies during the course of their treatment 
(Stinchcombe and Socinski, 2008). 
Docetaxel was the first agent to demonstrate a survival benefit in comparison with best 
supportive care (BSC) in patients with relapsed NSCLC following platinum-containing therapy. 
In the first randomized Phase 3 study (TAX317), 103 eligible patients were stratified by PS and 


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best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 
100 mg/m2 or 75 mg/m2 (55 patients) or BSC. Time to progression was longer for 
docetaxel-treated patients than for BSC-treated patients (10.6 versus 6.7 weeks, respectively; 
P <.001), as was median OS (7.0 versus 4.6 months; log-rank test, P=.047). The difference was 
more significant for patients treated with docetaxel 75 mg/m2 than with docetaxel 100 mg/m2 and 
there was less toxicity with docetaxel 75 mg/m2 than with docetaxel 100 mg/m2 
(Shepherd et al, 2000). Subsequent studies comparing other treatment options with docetaxel in a 
second-line setting showed a response rate of 6% to 11% and median OS of 5 to 10 months 
(Barnfield et al, 2016). 
Pemetrexed appears to be a non-inferior agent compared with docetaxel. A Phase 3 study 
demonstrated non-inferiority for OS between pemetrexed and docetaxel (8.3 versus 7.9 months, 
hazard ratio [HR] 0.99, 95% CI: 0.8 to 1.2). However, pemetrexed showed a better toxicity 
profile with a significantly lower rate of neutropenia and alopecia as well as lower rates of 
gastrointestinal AEs (Hanna et al, 2004). However, use of pemetrexed is limited to patients with 
non-squamous histology. In addition, its use as a first-line agent has become much more 
prevalent, thus limiting its administration in the second-line setting. 
Erlotinib was shown to improve survival as compared with BSC in a randomized study that 
included patients with poor PS (ECOG PS of 2 or 3) (Shepherd et al, 2005). Therefore, erlotinib 
is the preferred option for patients who cannot receive cytotoxic chemotherapy because of poor 
PS. 
Afatinib was compared with erlotinib in a Phase III trial in squamous-type NSCLC and showed 
better efficacy in progression-free survival (PFS) and OS. Thus, afatinib could be an additional 
option for the treatment of patients with ECOG PS 0 to 2 and locally advanced or metastatic 
squamous cell carcinoma progressing on or after platinum-based chemotherapy 
(Soria et al, 2015). 
1.2.2. 
Targeted Therapy for Locally Advanced or Metastatic Lung Cancers 
Advances in understanding of the molecular pathogenesis of lung cancer have led to the 
identification of several specific targets for therapeutic agents. Targeting EGFR and ALK has 
played a central role in advancing NSCLC research, treatment, and patient outcome over the last 
several years. Several small molecular targeted agents have been approved globally for patients 
with NSCLC harboring certain gene dysregulation (Schettino et al, 2013). 
Such small molecule tyrosine kinase inhibitors including drugs that inhibit EGFR (eg, erlotinib, 
gefitinib, icotinib, afatinib, osimertinib) and that target rearranged ALK (eg, crizotinib, certinib, 
alectinib) are especially effective in patients whose tumors harbor a sensitizing EGFR mutation 
or an ALK fusion gene. In Asian population, the EGFR mutation rate among adenocarcinoma is 
around 40%, and can be up to 65% such as in non-smoking Chinese female patients with 
adenocarcinoma of lung, which is significantly higher than that in the western countries, ~10 -
15% (Shi et al, 2014). And a small number (approximately 5%) of NSCLCs express the fusion 
form of ALK in China, which is similar to that reported in Caucasian population 
(Zhou and Zhou, 2015). 
The ROS proto-oncogene 1 (ROS1) oncogene encodes an orphan receptor tyrosine kinase related 
to ALK (Shaw et al, 2014). Crizotinib was approved for metastatic NSCLC whose tumors are 


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ROS1-positive. Crizotinib monotherapy showed marked antitumor activity with the objective 
response rate (ORR) of 72% in patients with advanced ROS1 rearranged NSCLC in an 
expansion cohort of the Phase 1 study. However, no head-to-head clinical trial of crizotinib 
versus first-line doublet chemotherapy demonstrating superiority is available in this population. 
Doublet chemotherapy as first-line treatment is still an option for this population. 
1.3. 
Anti-PD-1/PD-L1 Therapy for Locally Advanced or Metastatic Lung 
Cancers 
Lung cancer has been historically considered poorly immunogenic, with no established benefit 
from cytokine modulation or vaccines. However, the recent development of checkpoint 
inhibitors provided a promising new approach for immunotherapy in patients with NSCLC. 
Immune check point-inhibitory receptor, programmed cell death protein-1 (PD-1) is mainly 
expressed in activated T cells including CD8+ cytotoxic T-lymphocytes and CD4+ T-helper 
lymphocytes (Topalian et al, 2012; Bersanelli and Buti, 2017). It is presumed that PD-1 plays an 
important role in immune modulation of tumor progression by regulating the key inhibitory 
signaling in the T cells when engaged by its ligands. The PD-1 signaling cascade negatively 
regulates T-cell receptor (TCR) and attenuates T-cell proliferation and functional activities, 
leading to T-cell exhaustion. Expression by PD-1 is markedly up-regulated in tumor-infiltrating 
lymphocytes, while the expression of PD-1 ligand, programmed cell death protein ligand-1 (PD-
L1), is significantly increased in tumor cells (TCs) and tumor-associated immune cells in the 
presence of stimulating cytokines, such as interferon-alpha and interferon-gamma in the tumor 
microenvironment. Furthermore, increased PD-1 expression in tumor-infiltrating lymphocytes 
and/or PD-L1 expression in tumor and tumor-associated stromal cells have been observed in 
many types of solid tumors including NSCLC (Jin and Yoon, 2016; Patel and Kurzrock, 2015; 
Van Der Kraak et al, 2016; McDaniel et al, 2016; Gong et al, 2011). Based on these 
observations, monoclonal antibodies blocking the interaction between PD-1 and PD-L1 have 
been developed and have recently been shown to be promising anticancer immunotherapeutic 
agents in a variety of tumor types including NSCLC. 
The PD-1 inhibitors, pembrolizumab and nivolumab, are both immunoglobulin G4 (IgG4) 
antibodies, which bind to PD-1 to disrupt the interaction between PD-1 and its ligands (PD-L1 
and programmed cell death protein ligand -2 [PD-L2]) and thereby impede inhibitory signals in 
T cells (Wang et al, 2014; Garon et al, 2015). Nivolumab is Food and Drug Administration 
(FDA)-approved for treatment as a single agent or in combination with ipilimumab (Cytotoxic T 
Lymphocyte-Associated Antigen 4 [CTLA-4] antagonist) of unresectable or metastatic 
melanoma, metastatic NSCLC that progresses on or after platinum-based chemotherapy, and 
advanced renal cell carcinoma after anti-angiogenic therapy, classical Hodgkin’s lymphoma that 
has relapsed or progressed after autologous hematopoietic stem cell transplantation and post-
transplantation brentuximab vedotin, and head and neck squamous cell cancer with disease 
progression on or after a platinum-based therapy (Antonia et al, 2016b; 
United States FDA, 2017; Motzer et al, 2015; Gettinger et al, 2015; Weber et al, 2015; 
Hodi et al, 2016; Rizvi et al, 2015a, Hellmann et al, 2017). 
The Phase III Checkmate-057 trial compared nivolumab with docetaxel in 582 pretreated 
patients with non-squamous type NSCLC. It showed a significant prolongation of OS in the 
nivolumab group (median OS 12.2 versus 9.4 months, HR=0.73, 95% CI: 0.59 to 0.89; P=0.002), 


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although a small excess of early progression and/or death events were observed for nivolumab 
compared with docetaxel. In addition, ORR (19% versus 12%, P = 0.021) and duration of 
response (DoR) (17.2 versus 5.6 months) were in favor of nivolumab, and no significant 
difference has been reported for PFS (median PFS 2.3 versus 4.2 months, HR=0.92, 95% CI: 
0.77 to 1.1). An exploratory retrospective analysis revealed an association of efficacy by 
nivolumab and the level of tumor membrane expression of PD-L1. However, this analysis is 
limited by the retrospective and unplanned nature of this biomarker assessment 
(Borghaei et al, 2015). In the Phase III Checkmate 017 trial, nivolumab was compared with 
docetaxel in 272 pretreated patients with squamous cell lung cancer; significant prolongation of 
OS was shown in the nivolumab group compared with the docetaxel group (median OS was 
9.2 versus 6.0 months) and the risk of death was 41% lower with nivolumab than with docetaxel 
(HR=0.59; 95% CI: 0.44 to 0.79; P<0.001). At 1 year, the OS rate was 42% (95% CI: 34 to 50) 
with nivolumab versus 24% (95% CI: 17 to 31) with docetaxel. The response rate was 20% with 
nivolumab versus 9% with docetaxel (P = 0.008). The median PFS was 3.5 months with 
nivolumab versus 2.8 months with docetaxel (HR for death or disease progression, 0.62; 95% CI: 
0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor 
predictive of benefit (Brahmer et al, 2015). 
Pembrolizumab is another anti-PD-1 monoclonal antibody (IgG4) that has received FDA 
approval for the treatment of any histological type of NSCLC after failure of first-line therapy in 
patients with tumors expressing PD-L1. In the Phase 3 KEYNOTE-010 trial, 1034 patients with 
previously treated NSCLC with PD-L1 expression on at least 1% of TCs were randomized to 
receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 once every 
3 weeks. The primary end points were OS and PFS both in the total population and in the 
patients with PD-L1 expression on at least 50% of TCs. In the entire population, OS was 
significantly longer for pembrolizumab 2 mg/kg versus docetaxel (HR=0.71, 95% CI: 0.58 to 
0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (HR=0.61, 95% CI: 0.49 to 
0.75; p <0.0001), with median OS of 10.4, 12.7 and 8.5 months in the 3 arms, respectively. 
Pembrolizumab achieved a better outcome for those patients with high PD-L1 expression 
(>50%) (Herbst et al, 2016). 
Atezolizumab is a humanized anti-PD-L1 monoclonal antibody that interrupts PD-L1 binding to 
PD-1 and B7-1. Atezolizumab is FDA-approved for the treatment of patients with locally 
advanced or metastatic urothelial carcinoma who have disease progression during or following 
platinum-containing chemotherapy and for treatment of patients with metastatic NSCLC who 
have disease progression during or following platinum-containing chemotherapy 
(Tecentriq package insert). In the Phase III OAK study, 850 patients were randomized to receive 
atezolizumab or docetaxel. The OS was significantly longer with atezolizumab than with 
docetaxel in the intent-to-treat (ITT) and PD-L1 positive populations. In the ITT population, OS 
was improved with atezolizumab compared with docetaxel (median OS was 13.8 months [95% 
CI: 11.8 to 15.7] versus 9.6 months [8.6 to 11.2 months]; HR=0.73 [95% CI: 0.62 to 0.87], 
p=0.0003). The OS in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab 
(n=241) compared with docetaxel (n=222; median OS was 15.7 months [95% CI: 12.6 to 18.0] 
with atezolizumab versus 10.3 months [8.8 to 12.0] with docetaxel; HR=0.74 [95% CI: 0.58 to 
0.93], p=0.0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had 
improved survival with atezolizumab (median OS was12.6 months versus 8.9 months; HR=0.73 
[95% CI: 0.59 to 0.96]). The OS improvement was similar in patients with squamous (HR=0.73 


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[95% CI: 0.54 to 0.98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or 
non-squamous (0.73 [0.60 to 0.89]; n=313 and n=315) histology (Rittmeyer et al, 2017). 
A summary of anti-PD-1/PD-L1 monoclonal antibody (mAb) clinical trial outcomes in the 
second- or third-line setting is presented in Table 1. 
 


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Table 1: 
Anti-PD-1/PD-L1 Monoclonal Antibody Clinical Trial Outcomes 
Publication 
Population 
Name 
Primary 
Endpoint 
Therapy 
N 
mOS 
(months) 
HR 
mPFS 
(months) 
HR 
Brahmer 
New England 
Journal of Medicine 
373: 123 (2015) 
Squamous 
 
CHECKMATE-
017 
OS 
Nivolumab 
135 
9.2 
0.59 
3.5 
0.62 
Docetaxel 
137 
6.0 
2.8 
Borghaei 
New England 
Journal of Medicine 
373: 1627 (2015) 
Non-squamous 
 
CHECKMATE-
057 
OS 
Nivolumab 
292 
12.2 
0.73 
2.3 
0.92 
Docetaxel 
290 
9.4 
4.2 
Herbst 
Lancet 
387: 1540 (2016) 
PD-L1 ≥1% 
Squamous and 
non-squamous 
 
KEYNOTE-010 
OS and PFS 
 
All and PD-L1 
≥50% 
Pembrolizumab 
2 mg/kg 
345 
10.4 
0.71 
(ITT) 
0.54 
(Dx) 
 
3.9 
0.88 
 
Docetaxel 
343 
8.5 
0.61 
(ITT) 
0.50 
(Dx) 
4.0 
0.79 
Pembrolizumab 
10 mg/kg 
346 
12.7 
 
4.0 
 
Rittmeyer 
Lancet 389: 255 
(2017) 
Squamous and 
non-squamous 
 
OAK 
OS 
 
All and 
TC1/2/3 or 
IC1/2/3 
Atezolizumab 
425 
13.8 
0.73 (ITT) 
0.74 (1+2+3+) 
0.67 (2+3+) 
0.41 (3+) 
2.8 
0.95 
Docetaxel 
425 
9.6 
4.0 
Abbreviations: Dx = programmed cell death protein ligand-1 positive population; HR = hazard ratio; ITT = intent-to-treat (population); IC1/2/3 = programmed 
cell death protein ligand-1 membrane staining on immune cell; mOS = overall survival duration in months; mPFS = progression-free survival duration in months; 
OS = overall survival; PD-1 = programmed cell death protein-1; PD-L1, programmed cell death protein ligand-1; PFS, progression-free survival; 
TC1/2/3 = programmed cell death protein ligand-1 membrane staining on tumor cell. 


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Avelumab, is the second FDA-approved anti-PD-L1 antibody, with its first indication approved 
for advanced urothelial bladder cancer as second-line therapy (Apolo et al, 2017; United States 
FDA, 2017) and other registration trials ongoing including in NSCLC. Durvalumab is the third 
FDA-approved anti-PD-L1 antibody with its first indication for second-line treatment of 
advanced urothelial bladder cancer. In addition, positive interim analysis results were released 
for the PACIFIC trial of durvalumab as maintenance therapy of inoperable Stage III NSCLC 
after curative chemo-radiation therapy (Antonia et al, 2017). 
In the first-line setting, pembrolizumab monotherapy was associated with significantly longer 
progression-free and OS and with fewer AEs than was platinum-based chemotherapy in chemo-
naïve, PD-L1+ (>50% TCs), EGFR and ALK wild type NSCLC patients (Reck et al, 2016). The 
KEYNOTE-024 study randomly assigned 305 patients to receive either pembrolizumab or the 
investigator's choice of platinum-based chemotherapy. Median PFS was 10.3 months versus 
6.0 months in the pembrolizumab and chemotherapy group (HR 0.50; 95% CI, 0.37 to 0.68; 
P<0.001). The estimated rate of OS at 6 months was 80.2% in the pembrolizumab group versus 
72.4% in the chemotherapy group (HR 0.60; 95% CI, 0.41 to 0.89; P=0.005). The ORR was 
higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), and 
treatment related AEs of any grade were less frequent, as were Grade 3, 4, or 5 treatment related 
AEs (26.6% vs. 53.3%). Based on these results, FDA-approved pembrolizumab in metastatic 
NSCLC for first-line treatment of patients whose tumors have high level of PD-L1 expression. In 
contrast, in Checkmate 026, it was reported that nivolumab failed to show any benefit compared 
with standard platinum-based chemotherapy in metastatic NSCLC patients with PD-L1 
expression >1% TC. Study was stratified by PD-L1 expression (<5% vs ≥5% TC) and histology. 
Median PFS in the PD-L1 ≥5% NSCLC group was 4.2 months (nivolumab) versus 5.9 months 
(chemotherapy; HR, 1.15; 95% CI: 0.91 to 1.45, P=0.25). No benefit was observed in the PD-L1 
≥50% subgroup either (Socinski et al, 2016). 
Also in the first-line setting, pembrolizumab was recently FDA-approved in combination with 
pemetrexed and carboplatin for the first-line treatment of metastatic non-squamous NSCLC, 
irrespective of PD-L1 expression (Keytruda package insert). This is based on the positive results 
of the Phase II study KEYNOTE-021 Cohort G1, in which 123 previously untreated patients 
with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations were 
randomized in the pembrolizumab plus pemetrexed/carboplatin or the chemotherapy only group. 
ORR was nearly double in the immune-chemo group than pemetrexed/carboplatin alone: 55% 
(95% CI = 42–68) compared to 29% (95% CI = 18–41), respectively; all responses were partial 
responses (PRs). Among patients who received pembrolizumab plus pemetrexed/carboplatin, 
93% had a DoR of 6 months or more (range = 1.4+ to 13.0+ months) compared to 81% who 
received pemetrexed/carboplatin alone (range = 1.4+ to 15.2+ months). In addition, findings 
demonstrated an improvement in PFS (HR = 0.53; 95% CI = 0.31–0.91, P =.0205), with a 
median PFS of 13.0 months (95% CI = 8.3–not estimable) for patients treated with 
pembrolizumab plus pemetrexed/carboplatin compared to 8.9 months (95% CI = 4.4–10.3) with 
pemetrexed/carboplatin alone (Langer, 2016). 


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1.4. 
Background Information on Tislelizumab 
1.4.1. 
Pharmacology 
Tislelizumab is a humanized IgG4 variant monoclonal antibody against programmed cell death 
protein-1 (PD-1). It is being developed for the treatment of human malignancies. 
Tislelizumab binds 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 the binding of both 
programmed cell death protein ligand-1 (PD-L1) and programmed cell death protein ligand-2 
(PD-L2), inhibiting PD-1 mediated negative signaling in T cells. In in vitro cell-based assays, 
tislelizumab consistently and dose-dependently enhanced the functional activity of human T cells 
and pre-activated, primary peripheral blood mononuclear cells. In addition, tislelizumab 
demonstrated antitumor activity in several allogeneic xenograft models in which peripheral 
blood mononuclear cells were co-injected with human cancer cells (A431 [epidermoid 
carcinoma]) or tumor fragments (BCCO-028 [colon cancer] and BCLU-054 [NSCLC]) into 
immunocompromised mice. 
The IgG4 variant antibody has very low binding affinity to gamma fragment crystallizable region 
receptor IIIA (Fc RIIIA) and complement 1q, a subunit of complement 1, by in vitro assays, 
suggesting a low to no antibody-dependent cellular cytotoxicity or complement-dependent 
cytotoxicity effect in humans (Labrijn et al 2009). Unlike natural IgG4 antibody, tislelizumab 
has no observable fragment antigen-binding (Fab)-arm exchange activity by the in vitro assay, 
predicting the antibody would be stable in vivo and unlikely to form bispecific antibodies. 
Tislelizumab binds to cynomolgus monkey and human PD-1 with similar affinity, but does not 
bind to mouse PD-1 due to the significant sequence divergence from human and monkey PD-1. 
Therefore, cynomolgus monkeys were considered to be the relevant species for nonclinical 
safety evaluation. 
Please refer to the Tislelizumab Investigator’s Brochure for additional details regarding 
nonclinical studies of tislelizumab. 
1.4.2. 
Toxicology 
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology 
studies in mice and monkeys and in a 13-week, repeat-dose toxicology study in cynomolgus 
monkeys. The tissue cross-reactivity was evaluated in the normal frozen tissues from both 
humans and monkeys. The cytokine release assays were also evaluated using fresh human whole 
blood cells. The pivotal toxicology studies were conducted following Good Laboratory Practice 
(GLP) regulations. The single dosing regimens spanned from the intended human doses to 10-
fold higher than the maximum of the intended human doses, and the repeat dosing regimens 
spanned to 3-fold higher than the maximum of the intended human doses. Cynomolgus monkey 
was the only relevant species based on the target sequence homology and binding activity. 
Overall, no apparent toxicity was noted in mice or monkey toxicity studies. No tissue cross-
reactivity was found in either human or monkey tissues, nor was any effect on cytokine release 
observed in human whole blood assay. The 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 


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systemic exposure. The No Observed Adverse Effect Level (NOAEL) of tislelizumab in the 
13-week monkey toxicity study was considered to be 30 mg/kg. The safety profile of 
tislelizumab is considered adequate to support the current study. 
Please refer to the tislelizumab Investigator’s Brochure for more detailed information on the 
toxicology of tislelizumab. 
1.4.3. 
Clinical Pharmacology 
In the Phase 1 BGB-A317_Study_001 and Study BGB-A317-102, interim pharmacokinetic 
analysis (data cutoff date of 28 August 2017) was conducted  using noncompartmental analysis 
methods, using serum concentrations from patients who received doses of tislelizumab 0.5, 2.0, 
5.0, and 10 mg/kg once every 2 weeks and patients who received doses of 2.0 mg/kg, 5.0 mg/kg, 
and 200 mg once every 3 weeks  (Phase 1a, Parts 1, 2, and 3, and Phase 1b in BGB-
A317_Study_001), and patients who received doses of 200 mg once every 3 weeks in Phase 1 of 
Study BGB-A317-102 (n=19). The maximum observed plasma concentration (Cmax) and the area 
under the plasma or serum concentration time curve [AUC]) increased in a nearly dose-
proportional manner from 0.5 mg/kg to 10 mg /kg, both after single-dose administration and at 
steady-state. Preliminary PK data from 27 patients who were administered 1 dose of 200 mg 
once every 3 weeks (Phase 1a, Part 3 and Study BGB-A317-102) showed tislelizumab 
concentrations between the range of concentrations observed for patients who were administered 
2 mg/kg and 5 mg/kg doses. 
Preliminary population PK analysis using a 2-compartment model with first order elimination 
shows a systemic plasma clearance (CL) of tislelizumab was 0.173 L/day, volume of distribution 
(Vd) in the central and peripheral compartments of 2.89 L and 1.76 L respectively, and half-life 
(T1/2) was approximately 19 days. Race, gender, and body weight were not significant covariates 
on the CL of tislelizumab, which supports fixed-dosing across different ethnic groups. 
1.4.4. 
Summary of Relevant Clinical Experience with Tislelizumab 
As of 28 February 2018, there are 13 ongoing studies with tislelizumab, including monotherapy 
and combination studies in solid tumors and hematological malignancies. Of the ongoing 
monotherapy studies in solid tumors, available data from BGB-A317_Study_001, and BGB-
A317-102 are summarized below (with a data cutoff date of 28 August 2017).  
Please refer to the Tislelizumab Investigator's Brochure for more detailed information on 
efficacy and safety of tislelizumab.  
1.4.4.1. 
BGB-A317_Study_001 (Data Cutoff 28 August 2017)   
Study BGB-A317_Study_001 is a 2-stage study consisting of a Phase 1a dose-escalation and 
dose-finding component with 3 parts to establish the maximum tolerated dose, if any, a 
recommended Phase 2 dose for the Phase 1b, and a flat dose (fixed dose) followed by a Phase 1b 
component to investigate efficacy in select tumor types in indication expansion arms and to 
further evaluate safety and tolerability of tislelizumab.  
As of 28 August 2017, in Phase 1a, 116 patients had received tislelizumab at dose regimens 
including: 0.5 mg/kg, 2 mg/kg, 5 mg/kg, or 10 mg/kg once every 2 weeks; 2 mg/kg or 5 mg/kg 


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once every 3 weeks; and 200 mg once every 3 weeks.  In Phase 1b, 323 patients had received 
tislelizumab in Phase 1b across 9 indication-expansion cohorts.  
Overall, for the 439 patients in the study, the median age was 60.0 years, 53.8% of the 
population was male, and 65.6% of patients were white.  The median number of prior anticancer 
therapy regimens was 2 (range: 0 to 12).  The median treatment exposure duration was 2.50 
months (range: 0 to 23.0), and the median study follow-up duration was 5.56 months (range: 0.0 
to 26.9).  As of 28 August 2017, there were 210 patients (47.8%) remaining on study in Study 
BGB A317_Study_001.   
Preliminary Safety 
Of the 439 total patients in the Safety Population for BGB-A317_Study_001, 240 (54.7%) 
experienced at least 1 treatment-emergent adverse event (TEAE) assessed as related to 
tislelizumab by the investigator and 34 (7.7%) experienced at least 1 ≥ Grade 3 related TEAE.  
The most commonly occurring related TEAEs for patients treated with the tislelizumab 
monotherapy in BGB A317_Study_001 were fatigue (12.8%), rash (7.7%), nausea (6.8%), 
diarrhoea (6.6%), and hypothyroidism (4.8%).  The ≥ Grade 3 related TEAEs occurring in ≥ 2 
patients were pneumonitis (6 patients, 1.4%); colitis and alanine aminotransferase (ALT) 
increased (4 patients each, 0.9%); fatigue, type 1 diabetes mellitus, and aspartate 
aminotransferase (AST) increased (3 patients each, 0.7%); and diarrhoea, gamma 
glutamyltransferase (GGT) increased, and diabetic ketoacidosis (2 patients each, 0.5%).  All 
other events occurred in single patients.  Lastly, 18 patients (4.1%) experienced an infusion-
related reaction; all were mild/moderate in severity. 
Preliminary Efficacy 
 For patients in Phase 1a (n=116, evaluable), there were 20 patients with a confirmed 
response and 42 patients with a best overall response (BOR) of stable disease.  
 For patients in Phase 1b (n=286 evaluable), a total of 26 patients had a confirmed 
response.  Additionally, there were 101 patients with a BOR of stable disease. 
 Preliminary efficacy from the NSCLC cohort (with a data cutoff of 26 December 
2017) include a response rate of 14.3% (6/42 patients, 4 confirmed PR +2 
unconfirmed PR, all ongoing) with responses seen regardless of PD-L1 expression 
status, and stable disease in 23 patients (55%) and lasting for ≥6 months in 9 patients.  
1.4.4.2. 
Study BGB-A317-102 (Data Cutoff 28 August 2017)  
This Phase 1/2 study was a dose verification of tislelizumab and an indication-expansion study of 
tislelizumab conducted in Chinese patients with advanced solid tumors.   
Overall, for the 123 patients in Study BGB-A317-102, the median age was 54.0 years, 66.7% of 
the population was male, and 100% of patients were Asian (Chinese).  The median number of 
prior anti-cancer therapy regimens was 2 (range: 0 to 9).  The median treatment exposure 
duration was 1.78 months (range: 0 to 8.0), and the median study follow-up duration was also 
1.78 months (range: 0.0 to 8.0).  As of 28 August 2017, there were 113 patients (91.9%) 
remaining on study in Study BGB-A317-102. 


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Preliminary Safety 
Of the 123 total patients in the Safety Population for Study BGB-A317-102, 69 (56.1%) 
experienced at least 1 TEAE assessed as related to tislelizumab by the investigator and 10 (8.1%) 
were ≥ Grade 3 in severity.  The most commonly occurring related TEAEs were AST increased 
(20 patients, 16.3%), ALT increased (17 patients, 13.8%), and blood bilirubin increased and 
anaemia (13 patients each, 10.6%).  The ≥ Grade 3 related TEAEs occurring in ≥ 2 patients were 
AST increased (3 patients, 2.4%) and ALT increased (2 patients, 1.6%).  All other events 
occurred in single patients, including a case of retinal detachment (Grade 4). 
Preliminary efficacy data from the NSCLC cohort (08 December 2017 data cutoff) include an 
ORR of 10% (4/39 patients with confirmed PR, 2 each PD-L1 positive and negative), and stable 
disease in 20 patients (51%).  
1.4.4.3. 
Immune-Related Reactions  
In patients treated with tislelizumab monotherapy, the following immune-related adverse events 
(irAEs) were observed: 
 Acute hepatitis and abnormal liver function have been reported, including 1 patient 
with fatal hepatitis.  Additionally, 3.2% of patients experienced treatment-related 
abnormal liver function tests, and 1.4% of patients experienced immune-related 
hepatitis or hyperbilirubinaemia. 
 Pneumonitis has been reported in 2.1% of patients, including 1 patient with fatal 
pneumonitis.   
 Colitis has been reported in approximately 2% of patients treated.  Diarrhoea has been 
reported in 6.6% of patients.  
 Endocrinopathies have been reported including diabetes mellitus (hyperglycemia and 
ketoacidosis).  In addition, thyroiditis, including thyrotoxicosis and hypothyroidism 
has been reported.  Furthermore, hypophysitis has been reported in < 1% of patients 
treated.  
 Other immune-related events (< 1% of patients with tislelizumab monotherapy except 
where noted): skin reactions (20.5%, including rash and pruritus); arthralgia (2.5%); 
haemolytic anaemia, nephritis, proteinuria (1.8%); encephalitis, neuropathy, arthritis, 
pancreatitis, stomatitis, uveitis, and dry eye (1.4%).   
Beyond patients treated with tislelizumab monotherapy, one case of fatal myocarditis and 
polymyositis was reported in 1 patient who received a single dose of tislelizumab, in 
combination with paclitaxel and cisplatin.  
Please refer to the tislelizumab Investigator's Brochure for more detailed information.  
1.5. 
Study Rationales 
1.5.1. 
Rationale for Tislelizumab in NSCLC as Second-or Third-Line Treatment 
Despite recent improvements in treatments, the prognosis for patients with advanced NSCLC 
remains dismal, with median OS of approximately 12.5 months (Sandler, 2006). Patients who 


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receive second-line treatment for their disease have an even more limited prognosis, with median 
survival duration of only 8 months (Stinchcombe and Socinski, 2008). Currently approved 
therapies are associated with significant toxicities (eg, neuropathy, febrile neutropenia, 
myelosuppression, and alopecia) that negatively impact quality of life. 
Approved anti-PD-1/PD-L1 mAbs have shown superior efficacy to docetaxel by increasing the 
OS about 2 to 3 months in the second- or third-line setting in advanced NSCLC patients who 
have disease progression during or after a platinum-containing regimen. Tislelizumab is a novel 
anti-PD-1 mAb for which IgG gamma Fc Receptors (FcγRs) binding ability has been specifically 
engineered out. High levels of FcγR-expressing myeloid derived cells (eg, M2 macrophage, 
myeloid derived suppressor cells [MDSCs], etc.) in tumor tissues predict a poor survival of 
tumor-bearing animals after anti-PD-1 mAb treatment, possibly via Fc-FcγR mediated antibody-
dependent cellular cytotoxicity or antibody-dependent cellular phagocytosis depletion of effector 
T cells (Gül et al 2015; Prieto et al 2015; Makarova-Rusher et al 2015; Dahan et al 2015). Large 
numbers of immunosuppressive myeloid derives supperessor cells expressing high levels of 
FcγRs in NSCLC is known to dampen immune response by depleting antitumor effector cells 
with PD-1 expression (Antonia et al, 2016a). Given absent FcγR binding and thereby minimal 
antibody-dependent cellular cytotoxicity/antibody-dependent cellular phagocytosis effect, 
tislelizumab may show better efficacy and lower toxicity in NSCLC patients. 
According to the latest preliminary data outlined in Section 1.4.4, tislelizumab monotherapy 
exhibits a manageable safety profile, with the most common side effects consistent with known 
class effects of other anti-PD-1 antibodies (Section 1.6) 
1.5.2. 
Rationale for Docetaxel as the Active Control for Second- and Third-Line 
Treatment 
In the second- and third-line treatment setting for NSCLC, docetaxel remains a commonly used 
standard treatment option for both squamous and non-squamous histologies in China and 
worldwide. It has demonstrated a survival benefit relative to BSC in patients with relapsed 
NSCLC following first-line therapy and is associated with a response rate between 6% and 11% 
and a median OS of 5 to 10 months (see Section 1.2.1.2). In Checkmate-057/-017, Keynote-010 
and OAK studies, the pivotal trials for nivolumab, pembrolizumab and atezolizumab registration 
in the United States and Europe, docetaxel was chosen as active control in the second-or third-
line setting to anti-PD-1/PD-L1mAbs (Borghaei et al, 2015; Brahmer et al, 2015; Herbst 
et al, 2016; Rittmeyer et al, 2017). A median OS of 7 to 10 months was observed in the docetaxel 
arms across these studies, which is in the range with efficacy reports of docetaxel in a Phase 3 
study comparing docetaxel with pemetrexed as second-line treatment in Chinese NSCLC 
patients (Sun et al, 2013). Based on the above mentioned studies, docetaxel has been chosen as 
the active control in the current study with an assumption of 10 months median OS. The use of 
docetaxel as the active control is consistent with other pivotal trials of anti-PD-1 mAb and will 
make this study more interpretable when comparing the results with the published data. 
1.5.3. 
Rationale for Stratification Factors 
After screening for eligibility and signing of informed consent, approximately 800 eligible 
patients will be randomized in a 2:1 ratio to receive tislelizumab or docetaxel. A stratified 
randomization will be implemented in which patients will be stratified by histology (squamous 


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versus non-squamous), line of therapy (2 versus 3) and PD-L1 expression level on tumor cell 
membrane (<25% versus ≥25%). Among the 3 proposed stratification factors, the first 2 are 
important prognostic factors in NSCLC. Histology has been a clinical feature driving therapeutic 
decision; while line of therapy is also included in NSCLC treatment guidelines for the 
consideration of therapy selection. Patients with one prior line of systemic therapy and/or non-
squamous tumor generally have better prognosis (eg, longer PFS/OS) than patients in the other 
categories. PD-L1 expression as a predictive marker in immunotherapy has been investigated in 
previous second-line NSCLC trials. It has been reported that expression of PD-L1 on TCs 
correlates with response to anti-PD-1 or anti-PD-L1 therapy (Borghaei et al, 2015; 
Herbst et al, 2016; Rittmeyer et al, 2017). Based on these observations, PD-L1 was selected as a 
stratification factor in this study, and it is the Sponsor’s hypothesis that patients with higher PD-
L1 expression may achieve greater clinical benefit from tislelizumab. The PD-L1 expression 
status will be measured by immunohistochemistry assay in a central laboratory and using the 
Ventana PD-L1 (SP263) antibody. PD-L1 is defined as positive if ≥25% of TCs express PD-L1, 
and PD-L1 is defined as negative if <25% of TCs express PD-L1 (Rebelatto et al, 2015). 
Therefore, the proposed stratified randomization will achieve better treatment assignment 
balance. It will help to increase the precision of the estimate of treatment effect and to make the 
results more interpretable. 
1.5.4. 
Rationale for Randomization at 2:1 Ratio 
Published data shows superior efficacy is achieved with anti-PD-1/PD-L1 mAb treatment as 
compared with docetaxel in advanced NSCLC patients who experienced disease progression 
during or after treatment with a platinum-containing regimen. A 2:1 ratio will not weaken the 
statistical power of the study because the numbers of deaths in the interim and final analyses are 
adjusted upwards by 13% from a 1:1 randomization so the power is at least 80% for the 
hypothesis testing in ITT Analysis Set and PD-L1 positive subset. Compared with a 1:1 ratio, 
eligible patients will have 17% higher chance to benefit from tislelizumab treatment based on the 
medical assumption made for this study which will make the trial more attractive. The Sponsor 
believes a 2:1 randomization is unlikely to compromise the safety of patients in the trial given 
the safety data observed in other tislelizumab trials so far and the safety monitoring plan 
proposed in the trial. The randomization ratio could provide more information from the 
tislelizumab treated patients with high PD-L1 expression, a subset of special interest. 
1.5.5. 
Rationale for Choosing Overall Survival in ITT and PD-L1-positive Subset as 
Dual Primary Endpoint 
Anti-PD-1/L1 mAbs monotherapy has been approved in second- and third-line NSCLC based on 
Phase 3 trials showing an OS benefit in the ITT population compared to docetaxel (Table 1). 
Subgroup analyses for different PD-L1 expression indicate a trend for longer OS and higher 
ORR in the higher PD-L1 expression group than the low/intermediate or negative groups, 
especially in non-squamous lung cancer pathological types (Table 1). As NSCLC tumors with 
low PD-L1 expression are less likely to respond to anti-PD-1/ PD-L1 mAb treatment and given 
that multiple ongoing first or second-line trials limit enrollment to only patients with high tumor 
PD-L1 expression (Antonia, 2017), this may lead to an over-representation of patients with PD-
L1 low tumors in this study. To mitigate the risk of obtaining skewed PD-L1 distribution toward 
low expression due to competing trials enrolling only patients whose tumor PD-L1 expression is 


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high, adjustment to enrollment will be made by capping the PD-L1 negative and low population 
to ~60% of ITT. This will be accomplished through the Interactive Web Response Technology 
(IWRT) system, when necessary, such that the percentage of PD-L1 positive patients is no less 
than 40% of the ITT Analysis Set, based on the reported prevalence of PD-L1 positivity is ~40% 
in the NSCLC population (Rebelatto, 2015, Antonia, 2017). The OS will be tested in both the 
ITT Analysis Set and PD-L1 positive subsets while the overall type I error is controlled at 0.05 
(two-sided). It should be noted that the patient enrollment criteria (ie, PD-L1 cutoff) are 
determined prior to the randomization (see Section 3.1); as well as other key design elements (ie, 
α spent in the PD-L1 positive subset, timing and number of deaths included in the final analysis 
of the PD-L1 positive subset (see Section 9.2.1 and Section 9.7), testing sequence of the 
secondary endpoints in the PD-L1 positive subset). Therefore, the statistical inference made with 
respect to the PD-L1 positive subset is held to the same standard as trials with a single primary 
hypothesis in terms of statistical rigor. 
The Sponsor believes that a statistically significant result from the proposed OS test in the PD-
L1 positive subset alone would provide convincing evidence of survival benefit of tislelizumab 
over docetaxel in this population, and thus it would support full approval of the indication in the 
second- and third-line therapy of NSCLC patients with high PD-L1 expression. 
1.5.6. 
Rationale for Patient Population Excluding Patients with EGFR Mutation and 
ALK Translocation 
Patients harboring EGFR sensitizing mutation or ALK translocation have better prognoses than 
those with wild type EGFR and ALK. EGFR and ALK inhibitors are standard care for patients 
harboring the respective genetic disorders. Second- or third-generation tyrosine kinase inhibitors 
are available for patients who developed resistance to first-line treatment. For those patients with 
acquired resistance to EGFR TKIs by mechanisms other than T790M mutation, clinical trials 
investigating compounds targeting alternative mechanisms such as cMet amplification are 
underway. The percentage of EGFR sensitizing mutations is higher in Chinese NSCLC patients 
as compared with Caucasian population, 40% versus 15%, respectively. In Chinese female 
patients with lung adenocarcinoma, the EGFR mutation rate is up to approximately 65% 
(Shi et al, 2014). A similar frequency for ALK gene transfusion is observed in Chinese NSCLC 
patients (~4 to 5 %) as in the Caucasian population (Li et al, 2013). 
Published data suggest the efficacy of anti-PD-1 mAb therapy was not superior to docetaxel in 
patients with EGFR mutant tumors. Subset analysis in EGFR mutant patients, albeit small 
numbers, did not show benefit from checkpoint inhibitor monotherapy over docetaxel 
(Lee et al, 2017). It was confirmed that mutation burden as well as presence of mutations in 
DNA repair genes were correlated with anti-PD-1 response in NSCLC, which has been 
considered as another predictive biomarker for response of checkpoint inhibition (Rizvi et 
al, 2015b). It is known that EGFR mutation is associated with adenocarcinoma in patients with 
none or light smoking history (Shi et al, 2014). It is suspected that mutation load in these patients 
may be lower compared with EGFR wild type NSCLC patients, which underline the lower 
response rate and shorter OS to anti-PD-1 mAb treatment. In addition, low PD-L1 expression is 
correlated with the presence of EGFR mutations in Chinese patients (Ji et al, 2016). Due to the 
low likelihood for EGFR mutant NSCLC patients to benefit from anti-PD-1 mAb treatment, the 
present study will exclude this subpopulation of patients. There were not enough patients with 


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ALK translocation for subgroup analysis in the completed trials testing anti-PD-1/PD-L1 mAbs. 
However, these patients are managed well with targeted therapy at first-line or second-line 
setting, thus they will be excluded from this study. 
1.5.7. 
Rationale for Tislelizumab Dose Selection 
The PK, safety, and efficacy data obtained from the first-in-human study 
BGB-A317_Study_001, as well as other clinical study data, were analyzed in aggregate to 
determine the recommended dose for pivotal studies of tislelizumab.  The flat dose of 200 mg IV 
once every 3 weeks was selected for further evaluation. 
Rates of treatment-related adverse events (AEs) and serious adverse events (SAEs) observed in 
patients receiving 2 mg/kg and 5 mg/kg once every 2 weeks and once every 3 weeks were 
comparable, suggesting no clear dose-dependence across these regimens.  Similarly, confirmed 
overall response rates (ORRs) in patients treated with tislelizumab 2 mg/kg and 5 mg/kg once 
every 2 weeks ranged between 10% and 15%, compared to a range of 15% to 38% for patients 
treated at 2 mg/kg and 5 mg/kg once every 3 weeks. 
According to PK data from BGB-A317_Study_001, Phase 1a, the CL of tislelizumab was found 
to be independent of body weight, ethnicity, and gender, and the observed serum exposure of a 
200 mg dose fell between serum exposure observed after 2 mg/kg and 5 mg/kg doses (dose range 
with comparable safety and efficacy rates).  
Additionally, no unexpected treatment related AEs occurred in the 200 mg fixed dose cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared to body weight-based cohorts. Of the 
evaluable patients treated (n=13), 3 patients (23%) had a BOR of partial response (PR), 4 
patients (31%) had a BOR of SD and 6 patients (46%) had BORs of progressive disease (PD). 
Therefore, clinical activity with a manageable and tolerable safety profile is expected to be 
maintained in patients receiving tislelizumab 200 mg once every 3 weeks.  
In conclusion, tislelizumab 200 mg once every 3 weeks is the recommended dose for pivotal 
studies . 
1.6. 
Benefit-Risk Assessment 
Available data from clinical trials of other anti-PD-1 antibodies, such as nivolumab, and 
pembrolizumab, have demonstrated favorable efficacy/safety profiles. Other immunotherapy 
targeting PD-1s/PD-L1s, such as atezolizumab and avelumab, showed manageable safety 
profiles and approved antitumor activity in patients with advanced lung cancer (refer to 
Section 1.3). The efficacy data with tislelizumab in NSCLC patients is preliminary but consistent 
with other anti-PD1/PD-L1 monoclonal antibodies. 
According to the latest data collected from the Phase 1 trial of BGB-A317_Study_001, 
tislelizumab has demonstrated a favorable safety profile that is consistent with known class 
effects of other anti-PD-1 antibodies (refer to Section 1.3). Antitumor activity with tislelizumab 
monotherapy has been observed in a range of tumor types (refer to Section 1.4.4). 
The present study is a randomized study designed to compare the safety and efficacy of A317 
with docetaxel in patients with advanced non-squamous NSCLC with wild type EGFR or 
squamous NSCLC. The benefit/risk assessment based on available tislelizumab Phase 1 data and 


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the publication from Phase 3 trials of other anti-PD-1 antibodies is considered as positive; the 
trial design, which randomizes patients to tislelizumab and docetaxel at a 2:1 ratio, is considered 
as justified for risk management. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
 To compare the efficacy, as measured by OS, of tislelizumab with docetaxel in the 
second- or third-line setting in patients with NSCLC who have progressed on a prior 
platinum-containing regimen. A comparison of the treatment arms will be performed 
in: 
 The ITT Analysis Set 
 The PD-L1 positive Analysis Set, where PD-L1 positive is defined as ≥25% of 
TCs with PD-L1 membrane staining via the Ventana SP263 assay 
2.1.2. 
Secondary Objectives 
 To compare the efficacy of tislelizumab and docetaxel as measured by ORR, DoR, 
and PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in: 
 The ITT Analysis Set 
 The PD-L1 positive Analysis Set 
 To compare health-related quality of life (HRQoL) between tislelizumab and 
docetaxel arms 
 To evaluate the safety and tolerability of tislelizumab versus docetaxel 
2.1.3. 
Exploratory Objectives 
 To compare tumor assessment outcomes (ie, DCR, and clinical benefit rate [CBR]) 
between tislelizumab and docetaxel assessed by investigator per RECIST v1.1 
 To explore potential predictive biomarkers for efficacy including but not limited to 
PD-L1 expression, tumor mutational burden (TMB), gene expression profile (GEP), 
and tumor-infiltrating immune cells 
 To characterize the PK of tislelizumab in patients with NSCLC 
 To determine host immunogenicity to tislelizumab in patients with NSCLC  
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
 OS - defined as the time from the date of randomization to the date of death due to 
any cause in the ITT and PD-L1 positive Analysis Set 
2.2.2. 
Secondary Endpoints 
 ORR – defined as the proportion of patients in the ITT and PD-L1 positive Analysis 
Set who had a CR or PR as assessed by the investigator per RECIST v1.1 


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 DoR – defined as the time from the first occurrence of a documented objective 
response to the time of relapse, as determined by the investigator per RECIST v1.1, 
or death from any cause, whichever comes first, in the ITT and PD-L1 positive 
Analysis Set 
 PFS – defined as the time from the date of randomization to the date of the first 
objectively documented tumor progression as assessed by the investigator per 
RECIST v1.1 or death from any cause, whichever occurs first, in the ITT and PD-L1 
positive Analysis Set 
 HRQoL – measured using European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire-Lung Cancer (EORTC QLQ-LC13) and Core 
30 (EORTC QLQ-C30), and European Quality of Life 5-Dimensions, 5-level 
(EQ-5D-5L) scale 
 Incidence and severity of TEAEs graded according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE), v4.03 
2.2.3. 
Exploratory Endpoints 
 DCR – defined as the proportion of patients whose best overall response (BOR) is 
CR, PR or stable disease (SD) per RECIST v1.1 
 CBR - defined as the proportion of patients who have CR, PR and SD that is ≥24 
weeks in duration per RECIST v1.1 
 PD-L1 expression, TMB, GEP, and tumor-infiltrating immune cells as predictive 
biomarkers for response 
 Summary of serum concentrations of tislelizumab in the PK Analysis Set 
 Assessments of immunogenicity of tislelizumab by determining the incidence of 
ADAs in the ADA Analysis Set 


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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is a randomized, open-label, multicenter Phase 3 study in adult patients with histologically 
confirmed, locally advanced or metastatic (Stage IIIB or IV), EGFR wild type NSCLC 
(squamous or non-squamous) who have disease progression during or after a platinum-
containing regimen. Histology of NSCLC (squamous or non-squamous) will be confirmed at the 
investigator’s site. Patients with known EGFR mutation or ALK rearrangement are ineligible for 
the study. For non-squamous NSCLC patients, documentation of wild type EGFR by tissue-
based test is required to enter the study. 
Patients must have been treated with at least 1 platinum-containing regimen but not more than 2 
chemotherapy regimens and have disease progression during or following chemotherapy 
treatment. Patients who progressed or have disease recurrence during or after neo-adjuvant or 
adjuvant therapy with platinum-containing regimen (counted as one line of therapy) within 
6 months are eligible to enroll into the study. 
Tumor specimens from eligible patients will be prospectively tested for PD-L1 expression by a 
central laboratory (see Section 7.5). The study will enroll all eligible patients whose tissue is 
evaluable for expression testing, regardless of PD-L1 expression status. The PD-L1 expression 
status remains to be blinded to the Sponsor, patients and investigators and only open to 
Independent Data Monitoring Committee (IDMC). In the case that continued monitoring of 
patient enrollment would project the prevalence of PD-L1 negative or low patients on study to be 
higher than 60%, enrollment may be limited to PD-L1-selected patients whose tumors show 
expression of ≥25% on tumor cells (TCs) by SP263 immunohistochemistry for the remainder of 
the study to ensure adequate enrollment in PD-L1 positive and negative patients (see also 
Section 1.5.5 and Section 10.1). 
The study procedures will occur over a Screening Phase (up to 28 days prior to randomization); 
Treatment Phase (until disease progression, intolerable toxicity, or withdrawal of informed 
consent, whichever occurs first); Safety Follow-up Phase (up to 30 days following last study 
treatment or initiation of new anticancer therapy, whichever occurs first for any AEs and up to 
90 days following last dose of tislelizumab for irAEs, regardless of whether or not the patient 
starts a new anticancer therapy); and a Survival Follow-up Phase. 
A schedule of efficacy and safety assessments is presented in Appendix 1. 
The study schematic is provided in Figure 1. 


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Figure 1: 
Phase 3 Study Schema for Tislelizumab Versus Docetaxel as Second-or 
Third-Line Therapy for NSCLC 
 
Abbreviations: AE = adverse event; ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; 
irAE = immune-related adverse event; IV = intravenously; NSCLC = non-small cell lung cancer; PD-
L1 = programmed cell death protein ligand-1; Q3W = once every 3 weeks; SAE = serious adverse event; 
TC = tumor cells; vs = versus; WT = wild type; yr = year. 


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3.2. 
Screening Period 
Screening evaluations will be performed within 28 days prior to randomization. Patients who 
agree to participate will sign the informed consent form prior to undergoing any screening 
procedure (refer to Appendix 1 for details). Pulmonary function testing including spirometry and 
assessment of oxygenation, at a minimum pulse oximetry at rest and with exercise, or 
alternatively, assessment of diffusion capacity, are to be performed for all patients during the 
Screening Period to assist the determination of suitability on the study, as described in 
Section 7.1.4. Respective test results need to be submitted to the Sponsor. Tests may be repeated 
as clinically indicated while on study (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. 
Patients with EGFR mutation or ALK rearrangement are ineligible for the study. Patients with 
wild type or unknown status of ALK are eligible to enroll. For patients with non-squamous 
NSCLC, documentation of wild type EGFR by tissue-based test is required to enter the study. 
For undocumented cases, fresh or archival tumor tissues are required for central EGFR mutation 
assessment. Archival tumor tissues (not restricted to pretreatment) will be collected for 
biomarker analysis at a central laboratory. If archived formalin-fixed paraffin-embedded (FFPE) 
tissue is not sufficient, a fresh biopsy sample will be needed. Refer to Section 7.8 for details. 
3.3. 
Treatment Period 
After completing all screening activities, eligible patients will be randomized in a 2:1 ratio to 
receive either tislelizumab or docetaxel treatment. Randomization will be stratified by histology 
(squamous versus non-squamous), lines of therapy (second versus third), and PD-L1 expression 
(≥25% TC versus <25% TC). 
Patients will receive open-label treatment with one of the following: 
Arm A:  
Tislelizumab 200 mg IV  once every 3 weeks until disease progression 
assessed by the investigator per RECIST v1.1, unacceptable toxicity, or withdrawal of 
informed consent, whichever occurs first. 
Arm B:  
Docetaxel 75 mg/m2 IV  once every 3 weeks until disease progression 
assessed by the investigator per RECIST v1.1, unacceptable toxicity, or withdrawal of 
informed consent, whichever occurs first. 
Patients receiving tislelizumab will be permitted to continue tislelizumab treatment beyond 
radio-imaging progression if clinical benefit is seen in the absence of symptomatic deterioration 
and unacceptable toxicity per investigator’s discretion. Specific requirements for post-
progression continuation of patients treated with tislelizumab are described in Section 7.5.  
Radiological assessment of tumor response status will be evaluated by investigators every 9 
weeks (± 7 days) for the first  12 months, then every 12 weeks (± 7 days) from Year 2 onwards. 
Response will be assessed by the investigator using RECIST v1.1. Details are provided in 
Appendix 2. 
Safety will be assessed throughout the study by monitoring AEs/serious adverse events (SAEs) 
(toxicity grades assigned per National Cancer Institute Common Terminology Criteria for 
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examinations, Eastern Cooperative Oncology Group (ECOG) performance status change, and 
electrocardiogram (ECG) results will also be used for safety assessment. Safety assessments are 
further detailed in Section 7 and the Schedule of Assessments (Appendix 1). 
The End of Treatment Visit is conducted when the Investigator determines that tislelizumab or 
docetaxel will no longer be administered to the patient.  If routine laboratory tests (eg, 
hematology, serum chemistry) are completed within 7 days before the End of Treatment Visit, 
these tests do not need to  be repeated.  Tumor assessment is not required at the End of 
Treatment Visit provided that fewer than 6 weeks have passed since the last tumor assessment. 
3.4. 
Safety Follow-Up 
Patients who discontinue treatment for any reason will be asked to return to the clinic for the 
Safety Follow-up Visit (to occur within 30 days [± 7 days] after the last dose of either study 
drug, or before the initiation of a new anticancer treatment, whichever occurs first). In addition, 
telephone contacts with patients should be conducted to assess immune-related AEs and 
concomitant medications (if appropriate, ie, associated with an immune-related AE) at 60 days 
(±14 days), and 90 days (± 14 days) after the last dose of tislelizumab, 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. 
All AEs, including SAEs, will be collected as described in Section 8.7. 
The End of Treatment visit at which a response assessment showed progressive disease, resulting 
in patient discontinuation, may be used as the Safety Follow-up Visit, if it occurred 30 days 
(± 7 days) after the last study treatment. Patients who discontinue study treatment prior to disease 
progression will have their tumors assessed as outlined in Section 7.5. 
See Appendix 1 for assessments to be performed at the Safety Follow-up Visit. 
3.5. 
Survival Follow-up 
Patients who discontinue study drug for reasons other than disease progression (eg, toxicity) or 
death will continue to undergo tumor assessments according to Section 7.4.4 and the Schedule of 
Assessments (Appendix 1), until the patient experiences disease progression, withdraws consent, 
loss to follow-up, death or until the study completes, whichever occurs first. 
Patients will be followed for survival and further anticancer therapy information after 
discontinuation of the study treatment via phone contact (with either the patient or the patient’s 
guardian, if applicable), review of patient medical records, and/or in-person clinic visits 
approximately every 3 months (± 14 days) after the Safety Follow-up Visit or as directed by the 
Sponsor until death, loss to follow-up, withdrawal of consent, or study completes by the Sponsor. 
3.6. 
Discontinuation From the Study Treatment or From the Study 
3.6.1. 
Patient Discontinuation from Study Treatment 
Patients have the right to discontinue the study at any time for any reason. In addition, the 
investigator has the right to discontinue a patient from the study at any time. Patients who 


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discontinue study treatment for reasons other than disease progression should be followed for 
assessments of antitumor activity (Section 7.5), safety, (Section 3.4) and survival (Section 3.5), if 
possible. 
The primary reason for discontinuation from the study treatment should be documented on the 
appropriate eCRF. 
Reasons a patient may be discontinued from the study may include, but are not limited to the 
following: 
 Patient withdrawal of consent 
 Pregnancy 
 Any medical condition that the investigator determines may jeopardize the patient’s 
safety, if he or she were to continue in the study 
 Use of any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese (or other 
Country) herbal medicine and Chinese (or other Country) patent medicines] for the 
treatment of cancer) 
 Patient noncompliance 
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 
 Patients have completed all study assessments 
3.7. 
End of Study 
Study termination is defined as the time point when data collection will stop. The primary 
analyses will be conducted when the predefined death events have been observed (see 
Sections 9.2 and 9.3) for the efficacy and safety evaluations. The study will continue until the 
last patient has died, becomes lost to follow-up, or withdraws from study, or until Sponsor 
decides to terminate the study. 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include but are not limited to the following: 
 The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
 Overall patient enrollment is unsatisfactory. 
The Sponsor will notify each investigator if a decision is made to terminate the study. Should 
this be necessary, prematurely discontinued patients should be seen as soon as possible for an 
EOT Visit and Safety Follow-up Visit. 


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The investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing Institutional Review Boards (IRBs) and/or Independent Ethics 
Committees (IECs) of the early termination of the trial. 
The Sponsor has the right to close a site at any time. The decision will be communicated to the 
site in advance. Reasons for closing a site may include, but are not limited to, the following: 
 Excessively slow recruitment 
 Poor protocol adherence 
 Inaccurate or incomplete data recording 
  Noncompliance with Good Clinical Practice, applicable laws and regulations  
 Study activity is completed (ie, all patients have completed and all obligations have 
been fulfilled) 


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4. 
STUDY POPULATION 
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for the study. 
1. Able to provide written informed consent and can understand and comply with the 
requirements of the study and the schedule of assessments. 
2. Age ≥ 18 years on the day of signing the informed consent form (or the legal age of 
consent in the jurisdiction in which the study is taking place). 
3. Histologically confirmed disease which is currently locally advanced or metastatic 
NSCLC of either squamous or non-squamous histology. 
4. With disease progression during or following treatment with at least one platinum-
containing regimen. 
 Patients who received prior neo-adjuvant or adjuvant chemotherapy but progressed 
within 6 months after last dose are eligible provided the target lesion(s) have not been 
previously treated with local therapy (radiation) or the target lesion(s) within the field 
of local therapy have subsequently progressed as defined per RECIST v1.1 
 Note: No more than 2 prior lines of systemic chemotherapy for advanced or 
metastatic disease 
 Chemotherapy regimens will be counted on the basis of interval disease 
progression and not the number of agents or switches in agents (eg, a first-line 
therapy that consists of several cycles of a platinum doublet and subsequent 
maintenance therapy that introduces or switches to a new chemotherapy agent 
without interval disease progression will all be considered one chemotherapy 
regimen). 
 Adjuvant/neo-adjuvant chemotherapy or chemo-radiation counts as a prior 
chemotherapy regimen if ≤ 6 months have elapsed between the last dose and the 
date of recurrence. Combined treatment with chemotherapy and radiation 
constitutes a single regimen; surgery is not considered a regimen. 
 Anti-EGFR treatment with disease progression as the treatment outcome is counted as 
a line of therapy. 
 Anticancer agents used for pleurodesis are not counted as a line of therapy. 
5. Patients must be able to provide archival/fresh tumor tissues (FFPE blocks or 
approximately 11 [at least 5] freshly cut unstained FFPE slides) for biomarker analysis to 
assess PD-L1 expression and, provided sufficient tissue, including tumor mutational 
burden (TMB), and gene expression profiling (GEP). Documentation of wild type status 
of EGFR by tissue-based test must be provided for patients with non-squamous NSCLC 
prior to enrollment. For undocumented cases, archival/fresh tumor tissues (FFPE blocks 
or 6 freshly cut unstained FFPE slides) are required for central assessment of EGFR 


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mutation. In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at 
baseline (within 42 days before Cycle 1 Day 1) is mandatory (written informed consent is 
required prior to fresh tumor biopsies). 
6. ECOG PS ≤ 1 (Table 5). 
7. Adequate hematologic and end-organ function, as defined by the following laboratory 
results (obtained ≤ 28 days prior to randomization): 
 Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, and 
hemoglobin ≥ 90 g/L. Note: Patients must not have required a blood transfusion or 
growth factor support within the 14 days before sample collection 
 Estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73m2 by Chronic Kidney 
Disease Epidemiology Collaboration equation (Appendix 6) 
 Total serum bilirubin  1.5 × upper limit of normal (ULN) 
 ≤ 3 × ULN, if Gilbert’s syndrome or if indirect bilirubin concentrations are 
suggestive of extrahepatic source of the elevation 
 Aspartate and alanine aminotransferase (AST and ALT)  3 × ULN 
  5 × ULN, if liver metastases 
8. Females of childbearing potential must be willing to practice highly effective method of 
birth control (Appendix 4) for the duration of the study, and, for patients in Arm A, for at 
least 120 days after the last dose of tislelizumab, and have a negative urine or serum 
pregnancy test within 7 days of randomization. 
9. Non-sterile males must be willing to use a highly effective method of birth control for the 
duration of the study and, for patients in Arm A, for at least 120 days after the last dose 
of tislelizumab. 
10. Expected life span > 12 weeks. 
4.2. 
Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons. 
1. Received prior docetaxel treatment for metastatic disease or prior immune checkpoint 
inhibitor therapies targeting PD-1, PD-L1 or CTLA-4. 
2. Diagnosed with NSCLC that harbors EGFR sensitizing or driver mutation or ALK gene 
translocation. 
 Patients with a known EGFR mutation are ineligible. Patients with non-squamous 
histology and unknown EGFR mutational status will be required to be tested prior to 
enrollment. Testing can either be performed locally and results submitted for 
eligibility review or submitted for central laboratory evaluation during the Screening 
Period; if EGFR mutation status is found to be positive, the patient will be ineligible 
for the study. For patients with squamous histology, given that testing for EGFR 
mutation is not considered standard in this patient population due to its low 


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frequency, patients with an unknown status will not be required to be tested at 
screening (Chiu, et al, 2014). 
 Patients with a known ALK fusion oncogene are excluded. Patients (non-squamous or 
squamous histology) with unknown ALK fusion oncogene status will not be required 
to be tested at screening given that testing for ALK fusion is not considered standard 
in squamous type patient population and a low frequency in non-squamous type. 
 If local testing results for EGFR mutation is not available for patients with non-
squamous histology, an additional 6 unstained tumor specimen sections may be 
required for central evaluation of these biomarkers. 
3. Patients with toxicities (as a result of prior anticancer therapy including radiation) which 
have not recovered to baseline or stabilized, except for AEs not constituting a likely 
safety risk (including but not limited to alopecia, rash, pigmentation, specific laboratory 
abnormalities etc). 
4. Received chemotherapy, immunotherapy (eg, interleukin, interferon, thymoxin), or 
investigational agent, used to control cancer ≤ 28 days (or ≤ 5 half-lives, whichever is 
shorter) prior to randomization 
5. Received any herbal medicine used to control cancer within 14 days prior to 
randomization. 
6. History of severe hypersensitivity reactions to other mAbs. 
7. History of interstitial lung disease, non-infectious pneumonitis or uncontrolled systemic 
diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung diseases, etc. 
8. Patients with significantly impaired pulmonary function, or who require supplemental 
oxygen at baseline. 
 An assessment of pulmonary function is to be conducted at screening (see 
Section 7.1.4) 
9. Clinically significant pericardial effusion. 
10. Clinically uncontrolled pleural effusion or ascites that requires pleurocentesis or 
abdominal tapping for drainage within 2 weeks prior to randomization. 
11. Active Leptomeningeal disease or uncontrolled, untreated brain metastasis: 
 Patients with a history of treated and, at the time of screening, asymptomatic CNS 
metastases are eligible, provided they meet all the following: 
 Brain imaging at screening shows no evidence of interim progression 
 Have measurable disease outside the CNS, only supratentorial metastases allowed 
 No ongoing requirement for corticosteroids as therapy for CNS disease; 
anticonvulsants at a stable dose allowed 
 No stereotactic radiation or whole brain radiation within 14 days prior to 
randomization 


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 Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases. 
 Following treatment, these patients may then be eligible, provided all other 
criteria, including those for patients with a history of brain metastases, are met. 
12. Major surgical procedure requiring general anesthesia, or significant traumatic injury ≤ 
28 days prior to randomization, or anticipation of need for major surgical procedure 
during the course of the study. 
 Placement of vascular access device is not considered major surgery. 
13. Malignancy other than NSCLC. 
 Any active malignancy ≤ 2 years before randomization except for the specific cancer 
under investigation in this study with the exception of those with a negligible risk of 
metastasis or death, such as localized and adequately treated malignancies  (eg, 
resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in 
situ of the cervix or breast). 
14. Severe chronic or active infections (including tuberculosis infection) requiring systemic 
antibacterial, antifungal, antiviral therapy, or systemic oral/IV antibiotics within 14 days 
prior to randomization.   
 Severe infections within 4 weeks prior to randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia. 
15. A known history of human immunodeficiency virus (HIV) infection. 
16. Patients with active/symptomatic carrier or chronic hepatitis B virus (HBV) whose HBV 
DNA ≥ 500 IU/mL (or ≥ 2500 copies/mL) should be excluded. 
 Note: Patients with detectable hepatitis B surface antigen (HBsAg) or HBV DNA 
should be managed per treatment guidelines. Patients receiving antivirals at screening 
should have been treated for > 2 weeks prior to randomization and should continue 
treatment for 6 months after study drug treatment discontinues. 
 Note: Patients with active hepatitis C may enroll and those with detectable HCV 
RNA who are receiving antiviral therapy at time of screening should remain on 
continuous, effective antiviral therapy during the study 
17. Active autoimmune diseases or history of autoimmune diseases that may relapse should 
be excluded. Patients with the following autoimmune diseases are allowed: controlled 
Type 1 diabetes, hypothyroidism managed with hormone replacement therapy only, 
controlled celiac disease, skin diseases not requiring systemic treatment (such as vitiligo, 
psoriasis or alopecia), or diseases not expected to recur in the absence of external 
triggering factors (see Appendix 3). 
18. Requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or 
equivalent) or other immunosuppressive medications within 14 days of randomization. 


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a. A brief course (≤ 7 days) of corticosteroids for prophylaxis (eg, contrast dye allergy) 
or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by contact allergen) is permitted. 
b. Adrenal replacement steroid dose ≤ 10 mg daily prednisone equivalent are permitted 
in the absence of active autoimmune disease. 
c. Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with 
minimal systemic absorption) are permitted. 
19. With uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, 
sodium, or corrected calcium despite standard medical management or ≥ Grade 3 
hypoalbuminemia ≤ 14 days before randomization. 
20. Any of the following cardiovascular criteria: 
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. Acute myocardial infarction ≤ 6 months prior to randomization. 
d. Heart failure of New York Heart Association Classification III or IV (see 
Appendix 5) ≤ 6 months prior to randomization. 
e. Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to randomization. 
f. Cerebral vascular accident or transient ischemic attack ≤ 6 months prior to 
randomization. 
g. Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 100 
mmHg despite anti-hypertension medications ≤ 28 days before randomization. 
h. Any episode of syncope or seizure ≤ 28 days before randomization.  
21. Prior allogeneic stem cell transplantation or organ transplantation. 
22. Was administered a live vaccine ≤ 4 weeks before randomization.  
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed.  
Intranasal vaccines are live vaccines, and are not allowed ≤ 4 weeks before randomization. 
23. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that, will be unfavorable for the administration of study drug or 
affect the explanation of drug toxicity or AEs or result in insufficient or impaired 
compliance with study conduct. 
24. Concurrent participation in another therapeutic clinical study. 


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5. 
STUDY TREATMENT 
5.1. 
Packaging, Handling, and Storage 
5.1.1. 
Tislelizumab 
Tislelizumab is a monoclonal antibody formulated for IV injection in a single-use vial 
(20R glass, United States Pharmacopeia [USP] type I) containing a total of 100 mg antibody in 
10 mL of isotonic solution. Tislelizumab was aseptically filled in single-use vials with a 
Flurotec-coated butyl rubber stopper and an aluminum cap. One vial is packaged in a single 
carton box. 
The label will include at a minimum, drug name, dose strength, contents, Sponsor, protocol 
number, kit number, batch/lot number, directions for use, storage conditions, caution statements, 
retest or expiry date, and space to enter the patient number and name of investigator. The 
contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. Tislelizumab 
must be stored at temperatures between 2°C  and 8°C and protected from light. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal. 
5.1.2. 
Docetaxel 
Docetaxel will be provided in vials for infusion. The contents of the label will be in accordance 
with all applicable local regulatory requirements. 
Docetaxel must be kept at the temperature condition as specified on the label. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal. 
5.2. 
Dosage, Administration, and Compliance 
The first dose of study drug is to be administered within 2 business days of randomization. All 
patients will be monitored continuously for AEs. Treatment modifications (eg, dose delay, 
reduction, interruption or discontinuation) will be based on specific laboratory and AE criteria, 
as described in Section 5.5. 
Table 2: 
Selection and Timing of Dose for Each Patient 
Study Drug 
Dose 
Frequency of 
Administration 
Route of 
Administration 
Duration of Treatment 
Tislelizumab 
200 mg 
Every 3 weeks 
Intravenous  
 See Section 3.3 
Docetaxel 
75 mg/m2 
Every 3 weeks 
Intravenous  
See Section 3.3 


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5.2.1. 
Tislelizumab 
Tislelizumab 200 mg will be administered on Day 1 of each 21-day cycle (once every 3 weeks). 
Tislelizumab will be administered by IV infusion, using a volumetric pump (recommended to 
control infusion speed, but not required if infusion speed is controlled through alternative means 
consistent with approved institutional procedures) through an intravenous line containing a 
sterile, non-pyrogenic, 0.2 or 0.22 micron in-line or add-on filter. Specific instructions for 
product preparation and administration are provided in the Pharmacy Manual. 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 60 minutes afterwards in an area with resuscitation equipment and 
emergency agents. From Cycle 3 onward, at least a 30-minute monitoring period is required in 
an area with resuscitation equipment and emergency agents. 
The initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes. If this is well tolerated 
then the subsequent infusions may be administered over 30 minutes, which is the shortest time 
period permissible for infusion. Tislelizumab 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 irAEs and infusion-related reactions are provided in detail in Appendix 7 and 
Section 8.8.1. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.2.2. 
Docetaxel 
Docetaxel 75 mg/m2 will be administered as an IV infusion over 1 hour once every 3 weeks until 
disease progression, intolerable toxicity, or withdrawal of consent. Additional premedications 
should be administered as per standard practice. Please refer to the current docetaxel label for 
additional information. 
5.3. 
Overdose 
Any overdose (defined as ≥ 600 mg of tislelizumab in a 24-hour period) or incorrect 
administration of study drug should be noted on the study drug administration electronic case 
report form (eCRF). Adverse events associated with an overdose or incorrect administration of 
study drug will be recorded on the AEs eCRF. Any SAEs associated with an overdose or 
incorrect administration are required to be reported within 24 hours of awareness via SAE 
reporting process as described in Section 8.7. Supportive care measures should be administered 
as appropriate. 
5.4. 
Investigational Medicinal Product Accountability 
The investigational medicinal products required for completion of this study (tislelizumab and 
docetaxel) will be provided by the sponsor, as required by local or country-specific guidance. 
The investigational site will acknowledge receipt of investigational medicinal products. Any 
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Accurate records of all investigational medicinal products received, dispensed, returned, and 
disposed should be recorded on the site’s Drug Inventory Log. Refer to the Pharmacy Manual for 
details of investigational medicinal product management. 
Compliance will be assessed by the investigator and/or study personnel at each patient visit. 
The investigator and/or study personnel will keep accurate records of drug dispensed and used by 
each patient. This information must be captured in the source document at each patient visit. The 
investigator is responsible for tislelizumab and docetaxel reconciliation, and record maintenance. 
In accordance with all applicable regulatory requirements, the investigator or designated study 
center personnel must maintain tislelizumab and docetaxel accountability records throughout the 
course of the study. 
5.5. 
Dose Delay or Modification 
Every effort should be made to administer the study drug(s) according to the planned dose and 
schedule.  In the event of significant toxicities, dosing may be delayed and/or reduced based on 
the guidelines provided below. Reasons for dose modifications or delays, the supportive 
measures taken, and the outcome will be documented in the patient's chart and recorded in the 
eCRF.  
5.5.1. 
Dose Delay or Modification for Tislelizumab 
There will be no dose reduction of tislelizumab in this study. 
Patients may temporarily suspend study treatment if they experience a toxicity that is considered 
related to tislelizumab and requires that a dose be withheld. Patients should resume tislelizumab 
treatment as soon as possible after the AE recovers to baseline or Grade 1 severity (whichever is 
more severe) within 12 weeks after the last dose of tislelizumab. If the patient is unable to 
resume tislelizumab in that timeframe, study treatment should be discontinued. 
If a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with Sponsor medical 
monitor. 
Dose modification related to irAEs and infusion-related reactions are described in Appendix 7 
and Section 8.8.1 respectively . 
5.5.2. 
Dose Delay or Modifications of Docetaxel 
Guidelines for docetaxel dose modifications to manage general toxicities are shown in Table 3. 


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Table 3: 
Guidelines for Docetaxel Dose Modifications 
Adverse Event 
(Worst Grade in Previous Cycle) 
Action to Be Taken 
Febrile neutropenia/Grade 4 AGC ≥7 days 
Withhold docetaxel until symptoms resolve.a 
Reduce docetaxel to 75% of previous dose (eg, from 
75 mg/m2 to 55 mg/m2). 
Grade 3 skin/neuropathy/major organ/non-hematologic 
toxicity  
Withhold docetaxel until symptoms resolve. 
Reduce docetaxel to 75% of previous dose. 
Grade 4 skin/neuropathy/major organ/non-hematologic 
toxicity 
OR 
Recurrence of Grade 3 toxicity after prior dose 
reduction 
Discontinue docetaxel treatment. 
a Do not re-treat until AGC ≥1.5 × 109, platelets ≥100 × 109, and toxicity ≤Grade 2. 
Abbreviations: AGC = absolute granulocyte count. 
Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, 
neutrophils <500 cells/mm3 (Grade 4) for more than 1 week, severe or cumulative cutaneous 
reactions, or other Grade 3/4 non-hematological toxicities during docetaxel treatment should 
have treatment withheld until resolution of the toxicity and treatment then resumed at 55 mg/m2. 
Patients who develop Grade >3 peripheral neuropathy should have docetaxel treatment 
discontinued entirely. 
Guidelines for the management of hepatotoxicity for docetaxel-treated patients are shown in 
Table 4. 
Table 4: 
Guidelines for Management of Hepatotoxicity in Patients Receiving 
Docetaxel 
 
AST/ALT 
 
Alkaline 
Phosphatase 
 
Total Bilirubin 
Docetaxel Dose 
Mild to 
moderate 
>1.5 × ULN 
and 
>2.5 × ULN 
 
NA 
75% 
Severe 
>3.5 × ULN* 
and 
>6 × ULN 
OR 
>1.5 x ULN** 
Do not treat. 
Discontinue treatment 
if it is already started. 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; NA = not applicable; 
ULN = upper limit of normal.*>5 x ULN if liver metastasis exists; **>3 x ULN if Gilbert Syndrome or indirect 
bilirubin approved to be extrahepatic 
5.6. 
Disposal and Destruction 
After completion of the study, all unused tislelizumab and docetaxel will be inventoried by the 
hospital unit pharmacist or other designated study center personnel. The inventoried supplies can 
be destroyed on site or at the depot according to institutional policies, after receiving written 
Sponsor approval. 


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6. 
PRIOR AND CONCOMITANT THERAPY 
6.1. 
Prior Therapy 
The exclusion criteria (Section 4.2) specify that patients will not have received prior docetaxel 
treatment or therapies targeting PD-1, PD-L1, or CTLA-4. 
6.2. 
Concomitant Therapy 
6.2.1. 
Permitted Concomitant Medications/Procedures  
Most concomitant medications and therapies deemed necessary and in keeping with local 
standards of medical care at the discretion of the investigator for the supportive care (eg, anti-
emetics, anti-diarrheal) and in a patient’s interest are allowed.  
Systemic corticosteroids required for the control of irAEs must be tapered gradually (see 
Appendix 7) and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) 
before the next tislelizumab administration. The use of steroids > 10 mg/day as premedications 
of docetaxel for toxicity prophylaxis is permitted. The short-term use of steroids as prophylactic 
treatments (eg, patients with contrast allergies to diagnostic imaging contrast dyes) is also 
permitted. 
Patients may continue to receive hormone replacement therapy or supportive care if initiated 
prior to enrollment. Bisphosphonates and RANK-L inhibitors are allowed for bone metastases if 
initiated prior to enrollment and at a stable dose. Patients receiving bisphosphonates during the 
trial for a non-malignant indication are permitted for this study. 
Hematopoietic growth factors (ie, G-CSF or GM-CSF) are allowed according to institutional or 
other specific guidelines (eg, country, regional, or oncology organizations, such as American 
Society of Clinical Oncology [ASCO], etc.),while growth factors used as primary prophylaxis 
are not permitted. Growth factors must be discontinued for more than 48 hours prior to the next 
cycle of study drugs. The use of any growth factor support must be documented in the patient’s 
record and eCRF. 
Erythropoiesis stimulating agents are allowed for the treatment of cancer-related anemia in 
patients undergoing palliative treatment, 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 erythropoiesis stimulating agent use. 
Patients with active hepatitis B defined as either detectable HBsAg or HBV DNA at baseline 
must initiate treatment 2 weeks prior to randomization or first dose, and continue until 6 months 
after the last dose.  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 
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BeiGene does not require patients with active hepatitis C to receive treatment with antiviral 
therapy. Patients with detectable HCV RNA and who are receiving treatment at screening should 
remain on continuous, effective antiviral therapy during the study. Investigators can consider 
treatment with sofosbuvir alone or in combination with other antivirals following the AASLD 
guideline or the local guidelines as appropriate. However, interferon-based therapy for either 
HBV or HCV is not permitted on study. Patients who are given antiviral therapy must initiate 
treatment at least 2 weeks prior to randomization or first dose.   
Palliative (limited-field) radiation therapy is permitted, but only for pain control or prophylaxis 
of bone fracture to sites of bone disease present at baseline provided the following criteria are 
met: 
 Repeat imaging demonstrates no new sites of bone metastases. 
 The lesion being considered for palliative radiation is not a target lesion for 
RECIST v1.1. 
 The case is discussed with the medical monitor, and the medical monitor agrees 
that the conditions required to receive palliative radiation are met. 
Additionally, palliative radiation therapy or other focally ablative therapy for other non-target 
sites of the disease is permitted if clinically indicated per investigators’ discretion after 
consultation with the sponsor medical monitor. Whenever possible, these patients should have a 
tumor assessment of the lesion(s) before receiving the radiotherapy in order to rule out 
progression of disease. 
6.2.2. 
 Prohibited Concomitant Medications/Procedures 
The following medications are prohibited during the study:  
 Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including herbal medicine and 
Chinese patent medicines] for the treatment of cancer). 
 Live vaccines within 28 days prior to randomization, while on study, and 60 days 
following the last dose of tislelizumab. 
 Herbal remedies with immunostimulating properties (ie, mistletoe extract) or known 
to potentially interfere with major organ function (ie, hypericin). Patients must notify 
the investigator of all herbal remedies used during the study. 
For patients who receive docetaxel, any medications that have significant interactions with 
docetaxel (eg, substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and 
CYP3A4) should be avoided. Refer to the manufacturer’s prescribing information for complete 
information regarding drug-drug interactions. 
6.2.3. 
Restricted Concomitant Medications/Procedures 
The following medications are restricted during the study:  
 Immunosuppressive agents (except to treat a drug-related AE). 


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 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.  
 Radiation therapy is not allowed, except for palliative or focally ablative radiation 
therapy, as described in Section 6.2.1. 
 Systemic antibiotics are allowed to treat infection; however, tislelizumab should be 
held  until the infection is resolved for at least one week before redosing with 
tislelizumab.  
 Use of potentially hepatotoxic drugs in patients with impaired hepatic function should 
be carefully monitored.  
 Patients should be instructed to avoid alcohol completely and should avoid other 
addictive drugs during the study. 
 For use of live vaccines, refer to Section 6.2.2.  For use of antivirals with HBV or 
HCV, refer to Section 6.2.1. 
Opiates and other medication required for palliative management of patients are allowed.  
Patients must notify the investigator of all concurrent medications used during the study. 


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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 and eCRF for each patient. 
Dosing will occur only if the clinical assessment and local laboratory test values (that must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines. 
7.1. 
Screening 
Screening evaluations will be performed within 28 days prior to randomization or enrollment (in 
non-randomized studies). Patients who agree to participate will sign the informed consent form 
(ICF) prior to undergoing any screening procedure.  
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 7.8) sections. The PK sampling schedule is shown in Appendix 1. 
Rescreening under limited conditions may be allowed after consultation with BeiGene, eg, when 
a patient narrowly misses a laboratory criterion and it is correctable and not due to rapidly 
deteriorating condition or disease progression. Rescreening is allowed only once. 
7.1.1. 
Demographic Data and Medical History 
Medical history includes clinically significant diseases, surgeries, cancer history (including prior 
cancer therapies and procedures), 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 
randomization or the first dose. If appropriate, clinically significant disease should be graded 
according to NCI-CTCAE v 4.03 and reported in the Medical History eCRF. 
Demographic data will include age and date of birth (in accordance with local country 
requirements), gender, and self-reported race/ethnicity. 
Cancer history will include 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. 


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7.1.2. 
Females of Childbearing Potential and Contraception 
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer 
to Appendix 4 for contraception guidelines and definitions of “women of childbearing potential” 
and “no childbearing potential.” 
7.1.3. 
Informed Consent Forms and Screening Log 
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures. 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 by medical monitor to confirm that 
patients meet all eligibility criteria before randomization or first dose of study drug. 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 
Pulmonary function testing including spirometry and assessment of oxygenation, at a minimum 
pulse oximetry at rest and with exercise, or alternatively, assessment of diffusion capacity, are to 
be performed for all patients during the Screening Period to assist the determination of suitability 
on the study. Respective test results need to be submitted to the Sponsor.  
For test results indicative of significantly impaired pulmonary function, eg, resting pulse 
oximetry <90% on room air and further de-saturation upon exercise, FEV1 <60% or DLCO (if 
performed) <60% of age and sex adjusted predicted performance levels (Pellegrino et al, 2005), 
the medical monitor needs to be consulted to confirm eligibility.  
Tests may be repeated as clinically indicated while on study (refer to Appendix 1 for details). 
7.2. 
Enrollment 
7.2.1. 
Confirmation of Eligibility 
The investigator will assess and the Sponsor will 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’s confirmation has been received before randomization. 
7.2.2. 
Patient Numbering 
After obtaining informed consent, study site personnel will access the IWRT system to assign a 
unique patient number to a potential study participant. 


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7.2.3. 
Enrollment/Randomization 
After confirming the patient’s eligibility, site personnel will access the IWRT system to 
randomize the patients and to assign study drugs. Study treatment must commence within 
2 business days after randomization/treatment assignment. 
7.3. 
Tislelizumab and Docetaxel Dispensation 
Tislelizumab and docetaxel 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 study drugs, the patient’s vital signs should be determined within 
60 minutes before the infusion, and during and 30 minutes after the infusion. For subsequent 
infusions, vital signs will be collected within 60 minutes before infusion and if clinically 
indicated, during and 30 minutes after the infusion. Patients will be informed about the 
possibility of delayed post infusion symptoms and instructed to contact their study physician if 
they develop such symptoms. Refer to Section 5.2.1 regarding precautionary monitoring of 
patients post infusion of tislelizumab. 
7.4.2. 
Physical Examinations 
A complete physical examination including an evaluation of the head, eyes, ears, nose, throat, 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological 
systems should be performed at screening. Any abnormality identified at baseline will be graded 
according to NCI-CTCAE v 4.03 and should be recorded on the Medical History eCRF. Height 
(baseline only) and weight should be measured and recorded in the eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline should be recorded in patient notes. 
New or worsened clinically significant abnormalities should be recorded as AEs on the AE 
eCRF. Refer to Section 8.4 for AE definitions, reporting, and follow-up. 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG PS (Table 5) will be assessed at the Screening Visit, pretreatment on Day 1 of each 
treatment cycle, End of Treatment Visit, and Safety Follow-up Visit. 


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Table 5: 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Performance 
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 
7.4.4. 
Laboratory Safety Tests 
Laboratory assessments of serum chemistry, hematology, coagulation, and urinalysis will be 
conducted, of which certain elements will be collected as specified below. 
If hematology and serum chemistry laboratory tests at screening are not performed within 7 days 
prior to administration of study drug(s) on Cycle 1 Day 1, these tests should be repeated and 
reviewed before study drug administration. Hematology and serum chemistry (including liver 
function tests) as specified below should be performed weekly for the first 3 cycles and at the 
beginning of subsequent cycles. After Cycle 1, results are to be reviewed within 48 hours before 
study drug administration.  
Laboratory assessments will include the following: 
 Hematology (complete blood count, including red blood cell count, hemoglobin, 
hematocrit, WBC count with differential [neutrophils, eosinophils, lymphocytes, 
monocytes, and basophils], and platelet count) 
 Serum chemistry (glucose, BUN or urea, creatinine, sodium, potassium, magnesium, 
chloride, calcium, phosphorus, direct bilirubin, total bilirubin, ALT, AST, alkaline 
phosphatase, LDH, total protein, albumin).  
 All patients will have creatine kinase (CK), creatine kinase-cardiac muscle 
isoenzyme (CK-MB)1 testing at Screening and to be repeated at predose 
assessments in all treatment cycles, other scheduled visits during the first 3 
treatment cycles, and at the end of treatment and safety follow-up visits.  
1 In the event that CK-MB fractionation is not available, please assess troponin I 
and/or troponin T instead. 
 Coagulation tests (prothrombin time, partial thromboplastin time or activated partial 
thromboplastin time, international normalized ratio)  
 Urine or serum pregnancy test (for women of childbearing potential, including 
premenopausal women who have had a tubal ligation) and documented as negative 
within 7 days prior to Cycle 1 Day 1 (see Appendix 4) 
 Urinalysis (complete [including, but not limited to specific gravity, pH, glucose, 
protein, ketones] and/or microscopic at screening and if clinically indicated)  


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 Thyroid function testing (thyroid stimulating hormone [TSH], free T3, free T4) 
 HBV serology (antibodies against HBsAg, antibodies against hepatitis B core antigen 
[anti−HBcAb]) 
 Patients who are HBsAg positive at screening must not be enrolled until the HBV 
DNA titres has been confirmed to be less than 500 IU/mL  
(see Section 4.2) 
 Hepatitis C virus (HCV) serology (anti-HCV) 
 Patients positive for HCV antibody are eligible only if polymerase chain reaction 
is negative for HCV RNA 
Details about sample collection and shipment will be provided in a separate instruction manual. 
Laboratory values obtained prior to screening will be performed at a local laboratory. For sites in 
China, on study clinical safety laboratory evaluations will be performed at a local laboratory; on 
study PK and biomarker evaluations will be performed at a central laboratory.  For all other 
regions, baseline and on-study clinical laboratory evaluations (safety, PK, and biomarker testing) 
will be performed by a central laboratory. For all other regions, if Investigators believe that it is 
clinically indicated to obtain safety laboratory results from their own local laboratories on the 
day of the patient’s visit, and before the results are returned from the designated central 
laboratory, they may do so at their discretion. Investigators may use results from local 
laboratories for assessing eligibility, safety monitoring and dosing decision. However, per 
protocol samples for the central laboratory must still be collected, since these serve as the official 
laboratory results for this study.  Please refer to guidance document on use of central and local 
laboratories for study assessments. 
7.4.5. 
Electrocardiogram 
A 12-lead ECG is required at screening, Safety Follow-up, and as clinically indicated. When 
coinciding with blood draws at the same timepoint, ECG assessment should be performed prior 
to blood draws.  ECG recordings should be performed after the patient has been resting in a 
semi-recumbent supine position for at least 10 minutes. 
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. 
7.4.6. 
Adverse Events 
Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, 
v4.03 (NCI-CTCAE, June 2010). Characterization of toxicities will include severity, duration, 
and time to onset. 
All AEs, including SAEs, will be collected as described in Section 8.4. 
7.4.7. 
Ophthalmologic Examination 
Eye exam, visual acuity test, and optical coherence tomography (or equivalent diagnostic test for 
retinal examination) will be assessed by an appropriate specialist at screening.  Either diagnostic 


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test 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, preferably by utilizing the same test, by an appropriate specialist approximately 
every 15 weeks (± 7 days) during study treatment and a final assessment < 30 days after the last 
dose of study treatment. 
In addition, investigators should solicit patients regarding changes in vision, visual disturbance, 
or ocular inflammation at each scheduled study visit during study treatment. For any change in 
vision, referral to an appropriate specialist will be made for further management guidance (see 
Appendix 7). 
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 (see Appendix 1) 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, provided they meet the screening requirements. During the study, 
tumor imaging will be performed approximately every 9 weeks (±7 days) during Year 1 and 
every 12 weeks (±7 days) from Year 2 onwards based on RECIST v1.1. Investigators may 
perform additional scans or more frequent assessments if clinically indicated. 
Tumor assessments must include computed tomography (CT) scans (with oral/IV contrast, unless 
contraindicated) or magnetic resonance imaging (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. For subsequent tumor 
assessments, the same radiographic procedure used to assess disease sites at screening are 
required to be used throughout the study (eg, the same contrast protocol for CT scans).  
 An MRI (or CT scan if MRI is contraindicated or not readily available) scan of the 
brain is required for all patients during screening, ie, within 28 days of randomization, 
but ideally within 14 days of randomization, to confirm or refute the diagnosis of 
CNS metastases at baseline. Patients with brain metastases, including definitively 
treated stable CNS metastases may be eligible for the study (see Section 4.2). 
 If a patient is known to have a contraindication to CT contrast media, a contrast 
enhanced MRI (preferred) or non-contrast CT 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 sodium fluoride-positron emission 
tomography (NaF-PET) must be performed at screening. If bone scans have been 
performed within 3 months of randomization, the repeated scan is not required. If 
bone metastases are present at screening and cannot be seen on CT or MRI scans, or 
if clinically indicated, TC-99m or NaF-PET bone scans should be repeated when a 
CR is identified in target lesion or 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, only if there is evidence of metastatic disease in 


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these regions at screening. At the investigator’s discretion, other methods of 
assessment of measurable disease as per RECIST v1.1 may be used. 
Response will be assessed by the investigator using RECIST v1.1 (see Appendix 2). The same 
evaluator should perform assessments, if possible, to ensure internal consistency across visits.  
An objective response should be confirmed by repeat assessments ≥4 weeks after initial 
documentation. Tumor assessment will need to follow the original schedule after the 
confirmation scan. 
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune cell 
infiltration and other mechanisms leading to apparent increase of existing tumor masses or 
appearance of new tumor lesions.  Thus, if radiographic progressive disease is suspected by the 
investigator to reflect pseudoprogression, patients may continue treatment with tislelizumab until 
progressive disease is confirmed by repeated imaging ≥ 4 weeks later (but not exceeding 6 to 8 
weeks from the date of initial documentation of progressive disease). If at the investigator’s 
discretion a patient could continue to benefit from study treatment after progressive disease per 
RECIST v1.1 criteria, the patient may continue study treatment. The following criteria must be 
met in order to treat patients with suspected pseudoprogression or who may continue to benefit 
from study treatment after progressive disease:   
 Absence of clinical symptoms and signs of disease progression (including clinically 
significantly worsening of laboratory values)  
 Stable ECOG performance status ≤ 1 
 Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention 
 Investigators must obtain written informed consent for treatment beyond radiologic 
disease progression and inform patients that this practice is not considered standard in 
the treatment of cancer.  
The decision to continue study drug(s) beyond initial investigator-assessed progression must be 
agreed with the sponsor medical monitor and documented in the study records. 
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 closes, whichever occurs first. 
Tumor assessments should be performed on schedule regardless of whether study treatment has 
been administered or held. 
7.6. 
Pharmacokinetic Blood Sampling 
Pharmacokinetic samples will be collected only in patients randomized to receive tislelizumab 
and in sites that are able to adequately perform PK sampling and handling. For tislelizumab, 
predose (within 60 min before start infusion) samples should be collected at Day 1 of Cycle 1, 2, 
5, 9 and 17; postdose (within 30 min after the end of infusion) samples should be collected at 
Day 1 of Cycle 1 and Cycle 5. An additional PK sample should be collected at the mandatory 


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Safety Follow-up Visit. If a patient presents with any ≥ Grade 3 irAE, additional blood PK 
samples may be taken to determine the serum concentration of tislelizumab. 
Shipping, storage, and handling of samples for the assessment of tislelizumab PK assays will be 
managed through a central laboratory. Instruction manuals and supply kits will be provided for 
all central laboratory assessments. 
Serum samples will be assayed for tislelizumab concentration with use of a validated 
immunoassay. 
7.7. 
Anti-Drug Antibody Testing 
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. This 
tiered strategy will include an assessment of whether ADA responses correlate with relevant 
clinical endpoints. Implementation of ADA characterization assays will depend on the safety 
profile and clinical immunogenicity data. 
Serum samples will be tested for the presence of ADAs to tislelizumab using a validated 
immunoassay. 
7.8. 
Tumor Tissues Samples and Biomarkers Assessment Procedures 
Shipping, storage, and handling of archival tumor, fresh tumor, and leftover tumor tissue for the 
assessment biomarkers will be managed through a central laboratory. Refer to the Laboratory 
Manual for details of sample handling. 
Archival tumor tissues (formalin-fixed paraffin-embedded block with tumor tissue or 
approximately 11 [a minimum of 5] unstained slides) are required to be sent to central laboratory 
for central immunohistochemistry assay of PD-L1 status. In addition to PD-L1 expression, other 
exploratory predictive biomarkers, including but not limited to TMB, GEP, and tumor-
infiltrating immune cells, that are related to response or clinical benefit of tislelizumab may also 
be evaluated. 
Screening tests for patients with squamous NSCLC are summarized in Figure 2. Screening tests 
for patients with non-squamous NSCLC are summarized in Figure 3. For patients with non-
squamous NSCLC, documentation of wild type EGFR by tissue-based test is required before the 
patient enters the study. For undocumented cases, fresh or archival tumor tissues (FFPE block 
with tumor tissue or 6 additional freshly cut unstained FFPE slides) is required for the 
assessment of EGFR mutation at a designated central laboratory (slides should not be older than 
90 days at time of sample submission). If archival tissues are insufficient for biomarker analysis, 
a fresh biopsy of a tumor lesion at baseline (within 42 days before Cycle 1 Day 1) is mandatory 
(written informed consent is required prior to fresh tumor biopsies). Refer to Section 4.1 for the 
inclusion criteria for details. 


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Figure 2: 
Screening tests for Squamous Cell NSCLC 
 
 
Abbreviations: EGFR = epidermal growth factor receptor; WT = wild type 
Figure 3: 
Screening tests for Non-Squamous Cell NSCLC 
 
 
Known EGFR 
Mutation
EGFR status is 
NOT required
Excluded
Unknown EGFR 
Status/WT 
Eligible
Squamous
Non-
Squamous
Known EGFR 
Mutation
Unknown 
EGFR Status 
EGFR status is 
required
g
q
Excluded
Eligible
Known ALK 
Rearrangement
Unknown ALK 
Rearrangement/WT
Excluded
Known EGFR 
WT
Tissue-
Based WT
ctDNA-
Based WT
WT
Tissue-
Based Test
Mutation
Eligible
Excluded
Patient should have tissue-based EGFR WT report
ALK status is 
NOT required


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Abbreviations: ALK = anaplastic lymphoma kinase; ctDNA = circulating tumor DNA, EGFR = epidermal growth 
factor receptor; WT = wild type 
Tumor tissue should be of good quality based on total and viable tumor content. Fine needle 
aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. 
If no or insufficient archival samples are available, a fresh tumor biopsy at baseline is required. 
For fresh biopsy specimens, acceptable samples include core needle biopsies for deep tumor 
tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions. 
7.9. 
Health-Related Quality of Life Assessment 
Patients will be asked to complete the European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the European Organisation 
for Research and Treatment of Cancer Quality of Life Questionnaire – Lung Cancer-13 
Questions (EORTC QLQ-LC 13), and EQ-5D-5L before any clinical activities are performed, 
during on study clinic visits according to the schedule in Appendix 1. The questionnaires 
EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L will be completed in this sequence by 
the patients at the investigational site. The questionnaires will be provided in the patient’s 
preferred language. 
7.10. 
Visit Windows 
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see 
Appendix 1). All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed prior to study treatment infusion 
unless otherwise noted. Laboratory results should be reviewed prior to dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
event, the visit should be scheduled on the nearest feasible date (refer to the visit window in 
Appendix 1), with subsequent dosing continued on the 21-day intervals accordingly, with a 
minimum of 14 days between tislelizumab dosing. 
7.11. 
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; 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 detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in this protocol. 
8.1. 
Risks Associated with Tislelizumab 
Tislelizumab is an investigational agent that is currently in clinical development. Limited safety 
data are available in human patients and the full safety profile has not been characterized. The 
following information is based on results from nonclinical and clinical studies and published data 
on molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may 
increase the risk of irAEs, specifically the induction or enhancement of autoimmune conditions. 
AEs observed with tislelizumab treatment and which are potentially immune-mediated are 
presented in Section 8.8.3. 
Although most irAEs observed with immunomodulatory agents have been mild and self-limiting, 
such events should be recognized early and treated promptly to avoid potential major 
complications. Suggested workup procedures for suspected irAEs are provided in Appendix 7. 
8.2. 
Risks Associated with Docetaxel 
Please refer to the Table 6 for the reported toxicity for docetaxel. Because of the ethanol content 
in the docetaxel formulation, some patients may experience intoxication during and after 
treatment that should be monitored (and infusion rate decreased if appropriate). The investigator 
should refer to the package insert for a complete list of potential side effects. 
Table 6: 
A Summary of the Commonly Reported Toxicities of Docetaxel 
Most Common Side Effects 
Less Common Side Effects (but May Be Severe or 
Life Threatening 
 
Myelosuppression ± infection or bleeding (may be 
severe) 
 
Hypersensitivity (may be severe) 
 
Fluid retention (may be severe) 
 
Neuropathy (may be severe) 
 
Cutaneous effects (including nails, may be severe) 
 
Alopecia 
 
Gastrointestinal (anorexia, nausea, vomiting, 
stomatitis, diarrhea, constipation) 
 
Asthenia (may be severe) 
 
Secondary malignancy/leukemia 
 
Cardiotoxicity, arrhythmia 
 
Pneumonitis 
 
Gastrointestinal obstruction, perforation, 
hemorrhage 
 
Venous thromboembolism 
 
Arterial thromboembolism 
 
Disseminated intravascular coagulation 
 
Seizures 
 
Hepatotoxicity 
8.3. 
General Plan to Manage Safety Concerns 
8.3.1. 
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this trial. Results from the 
nonclinical toxicology studies with tislelizumab, as well as the nonclinical/clinical data from 


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other PD-L1/PD-1 inhibitors, were taken into account. Specifically, patients at risk for study-
emergent autoimmune conditions, with a prior autoimmune disease that may relapse, patients 
who have undergone allogenic stem cell or organ transplantation, patients with evidence of 
severe chronic or active  infections requiring treatment within 14 days, or hospitalization within 
4 weeks prior to randomization, and patients who have received a live viral vaccine within 
4 weeks before randomization are excluded from the study (see Section 4.2). 
8.3.2. 
Safety Monitoring Plan 
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v4.03. Patients will be assessed for safety (including laboratory 
values) according to the schedule in Appendix 1. Clinical laboratory results must be reviewed by 
investigator or appropriate delegate prior to the start of each cycle. 
In this study, all enrolled patients will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study. Safety evaluations will 
consist of medical interviews, recording of AEs, physical examinations, laboratory 
measurements (hematology and chemistry, etc.) and other assessments. In addition, patients will 
be closely monitored for the development of any signs or symptoms of autoimmune conditions 
and infection.  
Serum samples will be drawn for determination of ADAs to tislelizumab in patients randomized 
to the tislelizumab arm, if treatment assignment is known. Administration of tislelizumab will be 
performed in a setting where emergency medical equipment and staff who are trained to respond 
to medical emergencies are available (for additional information, see Section 5.2.1). 
All AEs will be recorded during the study (AE from the time of the first dose and SAEs from the 
time of signing of informed consent) and for up to 30 days after the last dose of either study drug 
or until the initiation of another anticancer therapy, whichever occurs first. At the end of 
treatment, ongoing AEs considered related to study treatment will be followed until the event has 
resolved to baseline or ≤ Grade 1, the event is assessed by the investigator as stable, the patient is 
lost to follow-up, the patient withdraws consent, or it has been determined that study treatment or 
participation is not the cause of the AEs. 
Immune-related AEs will be recorded up to 90 days after the last dose of tislelizumab, 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. 
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. 


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8.4. 
Adverse Events 
8.4.1. 
Definition 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 an AE 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 redacted on the 
copies of the medical records prior to submission to the Sponsor. 
8.4.2. 
Assessment of Severity 
The investigator will assess the severity for each AE and SAE reported during the study. AEs 
and SAEs should be assessed and graded based upon the NCI-CTCAE v4.03. 
Toxicities that are not specified in the NCI-CTCAE v4.03 will be defined as follows: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
 Grade 3: Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 
 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 


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regulatory definitions. Seriousness serves as the guide for defining regulatory reporting 
obligations from the Sponsor to applicable regulatory authorities as described in Section 8.7.2.3. 
8.4.3. 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE. The investigator will use clinical judgment to determine the relationship. 
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 will be considered 
and investigated. The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, 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 assessment of causality for every SAE prior to transmission of the 
SAE report/eCRF 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 considering follow-up information, amending the SAE report/eCRF 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: 
 There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
 There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. 
 There is some evidence to suggest a causal relationship (eg, the AE occurred within a 
reasonable time after administration of the study drug). However, the influence of 
other factors may have contributed to the AE (eg, the patient’s clinical condition or 
other concomitant AEs). 
8.4.4. 
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. 


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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. Once resolved, the appropriate AE or SAE eCRF page(s) will be updated. 
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, or consultation with other 
health care professionals. 
The Sponsor may request that the investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations to elucidate as fully as possible the nature and/or 
causality of the AE or SAE. The investigator is obligated to assist. If a patient dies during 
participation in the study or during a recognized follow-up period, the Sponsor will be provided 
with a copy of any post-mortem findings, including histopathology. 
New or updated information should be reported to the Sponsor according to the SAE instructions 
provided by the Sponsor within the time frames outlined in Section 8.7.2.1. 
8.4.5. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, complete blood count, coagulation, cardiac 
measures, or urinalysis) or other abnormal assessments (eg, ECGs, X-rays, or vital signs) that are 
judged by the investigator as clinically significant will be recorded as AEs or SAEs . This 
includes clinically significant abnormal laboratory findings or other abnormal assessments that 
are present at baseline and significantly worsen during the study. The definition of clinically 
significant is left to the judgment of the investigator. In general, these are the laboratory test 
abnormalities or other abnormal assessments that: 
 are associated with clinical signs or symptoms, or  
 require active medical intervention, or  
 lead to dose interruption or discontinuation, or 
 require close observation, more frequent follow-up assessments, or  
 further diagnostic investigation.   
8.5. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose: 
 Results in death. 
 Is life threatening. 
NOTE: The term “life threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE 
that hypothetically might have caused death if it was more severe. 
 Requires hospitalization or prolongation of existing hospitalization. 


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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 judgment 
(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 
8.6. 
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 serious adverse drug reaction (SADR), the specificity or severity of which is not 
consistent with those noted in the Investigator’s Brochure. 
8.7. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events 
8.7.1. 
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 either study drug or initiation of new anticancer 
therapy, whichever occurs first. In the tislelizumab arm, all irAEs (serious or non-serious) should 
be reported until 90 days after the last dose of tislelizumab, regardless of whether or not the 
patient starts a new anticancer therapy.  All drug-related SAEs should be recorded by the 
investigator after treatment discontinuation until patient death, withdrawal of consent, or loss to 
follow up, whichever occurs first. 


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8.7.2. 
Reporting Serious Adverse Events 
8.7.2.1. 
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 
Making Initial 
Report 
Documentation 
Method 
Timeframe 
for Making 
Follow-up 
Report 
Documentation 
Method 
Reporting 
Method 
All SAEs 
Within 24 h of first 
knowledge of the 
SAE 
SAE report 
As 
expeditiously 
as possible 
SAE report 
Email or fax 
SAE form or 
Pregnancy 
form 
Abbreviations: AE, adverse event; h, hours; SAE, serious adverse event. 
8.7.2.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she will report the 
information to the Sponsor within 24 hours as outlined in Section 8.7.2. The SAE report will 
always be completed as thoroughly as possible with all available details of the SAE, e-signed by 
the investigator, and forwarded to the Sponsor or designee within the designated time frames. 
If the investigator does not have all information regarding an SAE, he/she will 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 will always provide an assessment of causality for each SAE as described in 
Section 8.4.3. 
The Sponsor will provide contact information for SAE receipt. 
8.7.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the Sponsor in accordance with the procedures 
detailed in Section 8.7.2.1. 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 8.6) will be submitted to all applicable regulatory authorities 
and investigators for tislelizumab. 
When a study center receives an initial or follow-up report or other safety information (eg, 
revised Investigator’s Brochure) from the Sponsor, the responsible person according to local 


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requirements 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. 
8.7.3. 
Eliciting Adverse Events 
The investigator or designee will ask about AEs by asking the following standard questions: 
 How are you feeling? 
 Have you had any medical problems since your last visit? 
 Have you taken any new medicines since your last visit? 
8.7.4. 
Disease Progression 
Disease progression (including fatal disease progression), which is expected in this study 
population and measured as an efficacy endpoint, should not be reported as an AE term. Instead, 
the symptoms, signs or clinical sequelae that result from disease progression should be reported 
as the AE term(s).  
For instance, a patient presents with pleural effusion resulting from disease progression of 
metastasis to lungs.  The event term should be reported as “pleural effusion” instead of disease 
progression.  If a patient experienced a fatal multi-organ failure due to disease progression, the 
term “multi-organ failure” should be reported as the SAE with death as outcome instead of 
reporting “fatal disease progression” or “death due to disease progression.”  
8.7.5. 
Deaths 
Death is an outcome and not usually considered an event.  If the only information available is 
death and the cause of death is unknown, then the death is reported as an event, eg, “death,” 
“death of unknown cause,” or “death unexplained.” 
8.7.6. 
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 30 days after the 
last dose of docetaxel, a pregnancy report form should be completed and expeditiously submitted 
to the Sponsor to facilitate outcome follow-up. Information on the status of the mother and child 
will be forwarded to the Sponsor. Generally, follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any premature termination of the pregnancy will be 
reported. 
While pregnancy itself is not considered to be an adverse event, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
Any 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. 


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8.7.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards and 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 documents: 
 Tislelizumab Investigator’s Brochure 
 Local reference prescribing information for docetaxel (ie, EU SmPC, US label, China 
label, or other regional labels) 
8.7.8. 
Assessing and Recording Immune-Related Adverse Events 
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-related (see Section 8.8.3) should be classified as irAEs and identified 
as such in the eCRF AE page until day 90, after treatment discontinuation. 
Investigators should consult the guidance on diagnostic evaluation and management of irAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 7. 
An extensive list of potential irAEs appears in Section 8.8.3, Table 9. All conditions similar to 
those listed should be evaluated to determine whether they are irAEs, based on a similar 
diagnostic process to those reactions that are presented in more detail in Appendix 7. 
8.8. 
Management of AE of Special Interest 
As a routine precaution, after infusion of tislelizumab 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. From Cycle 3 onward, a minimum of a 30-minute monitoring period is 
required in an area with resuscitation equipment and emergency agents. 
The management of infusion-related reactions, severe hypersensitivity reactions and irAEs 
according to the NCI-CTCAE v4.03 criteria are outlined below. 
8.8.1. 
Infusion-Related Reactions 
The symptoms of infusion-related reactions include fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness 
or hypertension. Severe reactions may include acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation, and cardiogenic shock. Patients should be closely monitored 
for such reactions. Immediate access to an Intensive Care Unit or equivalent environment and 
appropriate medical therapy (including epinephrine, corticosteroids, IV antihistamines, 
bronchodilators, and oxygen) must be available to treat infusion-related reactions. 
Treatment modification for symptoms of infusion-related reactions due to study drug(s) is 
provided in Table 8. 


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Table 8: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) 
NCI-CTCAE Grade 
Treatment Modification for Tislelizumab 
Grade 1  mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Any worsening is 
closely monitored. Medical management as needed. 
Subsequent infusions should be given after 
premedication and at the reduced infusion rate.  
Grade 2 - moderate 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDS, narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 hrs 
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reactions have 
resolved or decreased to Grade 1 in severity. Any 
worsening is closely monitored. Proper medical 
management should be instituted as described below. 
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
Immediately stop the infusion. Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Grade 4 – life threatening 
Life threatening consequences; urgent intervention 
indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described below. 
The patient should be withdrawn from study drug(s) 
treatment. 
Hospitalization is recommended. 
Abbreviations: IV, intravenous; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse 
Event; NSAIDs, nonsteroidal anti-inflammatory drugs. 
Once the tislelizumab infusion rate has been decreased by 50% or suspended due to an infusion-
related reaction, it must remain decreased for all subsequent infusions with premedication. If the 
patient has a second infusion-related reaction (≥ Grade 2) on the slower infusion rate, infusion 
should be discontinued and the patient should be withdrawn from tislelizumab treatment. 
NCI-CTCAE Grade 1 or 2 infusion reaction: Proper medical management should be 
instituted, as indicated per the type of reaction. This includes but is not limited to an 
antihistamine (eg, diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), 
and if considered indicated oral or IV glucocorticoids, epinephrine, bronchodilators, and oxygen. 
In the next cycle, patients should receive oral premedication with an antihistamine (eg, 
diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or equivalent), and they 
should be closely monitored for clinical signs and symptoms of an infusion reaction. 
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to 
oral or IV antihistamine, antipyretic, glucocorticoids, epinephrine, bronchodilators, and oxygen. 


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8.8.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms 
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (UK) (Soar et al, 2008). 
Patients should be instructed to report any delayed reactions to the investigator immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction (typically manifested within 
minutes following administration of the drug/antigen, and characterized by: respiratory distress; 
laryngeal edema; and/or intense bronchospasm; and often followed by vascular collapse or shock 
without antecedent respiratory difficulty; cutaneous manifestations such as pruritus and urticaria 
with/without edema; and gastrointestinal manifestations such as nausea, vomiting, crampy 
abdominal pain, and diarrhea), the infusion must be immediately stopped and the patient 
discontinued from the study. 
The patients will be administered epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed and then the patient should be placed on monitor 
immediately and an Intensive Care Unit should be alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drugs(s) infusion. 
Alternative treatments for fever (ie, paracetamol) may be given to patients at the discretion of the 
investigator. 
8.8.3. 
Immune-Related Adverse Events 
Immune-related AEs are of special interest in this study. If the events listed below or similar 
events occur, the investigator should exclude alternative explanations (eg, combination drugs, 
infectious disease, metabolic, toxin, disease progression or other neoplastic causes) with 
appropriate diagnostic tests, which may include but are not limited to serologic, immunologic, 
and histologic (biopsy) data. If alternative causes have been ruled out; the AE required the use of 
systemic steroids, other immunosuppressants, or endocrine therapy and is consistent with an 
immune-mediated mechanism of action, the irAE indicator in the eCRF AE page should be 
checked. 
A list of potential irAEs is shown below in Table 9. All conditions similar to those listed should 
be evaluated in patients receiving tislelizumab to determine whether they are immune-related. 
Recommendation for diagnostic evaluation and management of irAEs is based on a recent 
European Society for Medical Oncology (ESMO) guideline and American Society of Clinical 
Oncology (ASCO) guidelines  (Haanen et al 2017, Brahmer et al 2018) and common immune-
related toxicities are detailed in Appendix 7. For any AEs not included in Appendix 7 please 
refer to the ASCO Clinical Practice Guideline (Brahmer et al 2018) for further guidance on 
diagnostic evaluation and management of immune-related toxicities. 


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Table 9: 
Immune-Related Adverse Events 
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet’s syndrome 
Skin (severe-rare) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or endoscopic/radiographic evidence 
of inflammation); pancreatitis; hepatitis; aminotransferase (ALT/AST) elevation; 
bowel perforation 
Endocrine 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with features of 
hypopituitarism, eg, fatigue, weakness, weight gain; insulin-dependent diabetes 
mellitus; diabetic ketoacidosis; adrenal insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Neuromuscular 
arthritis; arthralgia; myalgia; neuropathy; Guillain-barré syndrome; aseptic 
meningitis; myasthenic syndrome/myasthenia gravis, meningoencephalitis; 
myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase 
Recommendations for management for irAEs are detailed in Appendix 7. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the Sponsor. Patients who experience a recurrence of any event at the 
same or higher severity grade with rechallenge should permanently discontinue treatment. 
8.8.4. 
Renal Function Abnormalities 
Patients with moderate renal dysfunction (estimated glomerular filtration rate > 30 mL/min and < 
60 mL/min by Chronic Kidney Disease Epidemiology Collaboration equation) may be enrolled 
into the study. The following algorithm is proposed for the use of steroid treatment in the 
management of irAEs: 
 If the serum creatinine is normal at baseline, please see Section 8.8.3 and refer to 
Appendix 7 for diagnosis and management of patients with abnormal renal laboratory 
values. 
 If the serum creatinine is Grade 1 at baseline and increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 2 after starting treatment with 
tislelizumab, refer to Appendix 7 for diagnosis and management of patients with 
abnormal renal laboratory values. Check the estimated GFR using Appendix 6 and 
the eGFR calculator link. In the setting of a Grade 2 serum creatinine increase only, 
study treatment can continue unless the serum creatinine increases by at least 50% 
from the baseline value OR the eGFR falls below 20 mL/min. 


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 If the serum creatinine is Grade 2 at baseline and increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 3 after starting treatment with 
tislelizumab, refer to Appendix 7 for diagnosis and management of patients with 
abnormal renal laboratory values. In the setting of a Grade 3 serum creatinine 
increase only, study treatment will be held until serum creatinine improves to baseline 
and treatment may resume only after discussion with the Sponsor medical monitor. 


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9. 
STATISTICAL METHODS AND ANALYSIS PLAN 
The statistical analyses will be performed by the Sponsor or designee after the data collection for 
the primary efficacy and safety analyses are completed and the database is locked and released. 
Data will be listed and summarized using SAS® Version 9.3 or higher (SAS Institute, Inc., Cary, 
North Carolina) per Sponsor agreed reporting standards, where applicable. 
The trial was originally designed to enroll patients from China and Asia Pacific (CAP) region. 
After amendment 1, it has been expanded to enroll patients from the rest of the world (ROW) as 
well. The primary and secondary objectives of the trial have not been changed due to this 
expansion. As of amendment 3.0, the number of death events that triggers interim analysis has 
been changed to 426 (approximately 76% of total number of 560 deaths) in the ITT Analysis Set. 
All analyses and testing discussed in Section 9 pertaining to study Analysis Set include both 
CAP and ROW patients. Statistical strategy in the ROW is discussed in Section 9.9. Details of 
the statistical analyses will be included in a separate Statistical Analysis Plan. 
9.1. 
Statistical Analysis 
9.1.1. 
Randomization Methods 
As discussed in Section 7.2.3, patients will be randomized using the IWRT system for this study 
by permuted block stratified randomization. 
9.1.2. 
Analysis  Sets 
 The ITT Analysis Set includes all randomized patients. Patients will be analyzed 
according to their randomized treatment arms. This will be the primary Analysis Set 
for efficacy analysis. The ITT Analysis Sets will be summarized for both the China 
and Asia Pacific (ITT-CAP) Analysis Set and the rest of world (ITT-ROW) Analysis 
Set. 
 The PD-L1 positive Analysis Set includes all randomized patients whose tumors were 
PD-L1 positive. Patients will be analyzed according to their randomized treatment 
arms. This will be the dual primary analysis population for efficacy analysis. 
 Safety Analysis Set includes all patients who received at least one dose of study drug. 
It will be the population for the safety analyses. 
 The PK Analysis Set includes patients who contributed at least one quantifiable 
postdose PK sample. 
 The ADA Analysis Set includes all patients who have received at least 1 dose of 
tislelizumab for whom non-missing baseline ADA and at least 1 non-missing 
postbaseline ADA results are available. 
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 discontinuation will be summarized according to the categories in the eCRF. The end of 


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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 of the ITT Analysis Set will be summarized 
using descriptive statistics. Continuous variables include age, weight, vital signs, time since 
initial cancer diagnosis, and time since advanced/metastatic disease diagnosis; categorical 
variables include histology; prior line of therapy; PD-L1 expression in TC (≥25% TC versus 
<25% TC); gender; ECOG PS; race; smoking status; prior systemic therapies; and metastatic 
site. Demographic and disease characteristics will be summarized similarly in the PD-L1 positive 
Analysis Set. 
9.1.5. 
Prior and Concomitant Medication 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary drug codes. 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 for this protocol. Prior medications will be defined as medications that stopped 
before the first dose of study drug. Concomitant medications will be defined as medications that 
(1) started before the first dose of study drug and were continuing at the time of the first dose of 
study drug, or (2) started on or after the date of the first dose of study drug up to 30 days after the 
patient’s last dose (as of Safety Follow-up Visit).  In addition, telephone contacts with patients 
should be conducted to assess irAEs and associated concomitant medications at 60 and 90 days 
(± 14 days) after the last dose of tislelizumab regardless of whether or not the patient starts a new 
anticancer therapy. 
9.2. 
Efficacy Analysis 
The overall type I error will be strongly controlled at a one-sided α of 0.025 within the 2 dual 
primary hypotheses and 4 secondary efficacy hypotheses. Initially, α of 0.02 and 0.007 will be 
assigned to the primary hypothesis testing in the ITT and PD-L1 positive Analysis Sets, 
respectively. The α allocation accounts for the positive correlation between the test statistics in 
the 2 Analysis Sets (ie, PD-L1 positive is a subset of the ITT Analysis Set). The overall type I 
error is controlled at 0.025 when at least 30% of the deaths in the ITT Analysis Set are from the 
PD-L1 positive subset. The α of 0.007 in the PD-L1 testing will be adjusted downwards if the 
final observed percentage is lower. When the trial proceeds to the final analysis, the OS 
hypothesis in the ITT Analysis Set will be tested first. 
If the hypothesis in the ITT Analysis Set is rejected, the unused α will be passed on to the OS 
hypothesis test in PD-L1 positive Analysis Set; followed by the second efficacy hypothesis 
testing in the sequential order of ORR in the PD-L1 positive Analysis Set, DoR in the PD-L1 
positive Analysis Set, PFS in the PD-L1 positive Analysis Set, PFS in the ITT Analysis Set, 
ORR in the ITT Analysis Set, DoR in the ITT Analysis Set, lung cancer symptom scale 
measured by QLQ-LC13 and QLQ-C30 global health status/QoL in the ITT and PD-L1 Analysis 
Sets. Otherwise, if the OS hypothesis in the ITT Analysis Set cannot be rejected, hypothesis 


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testing will be carried out sequentially only in the PD-L1 positive Analysis Set for OS, ORR, 
DoR, PFS, lung cancer symptom scale measured by QLQ-LC13 and QLQ-C30 global health status/QoL 
scale  at α of 0.007. The testing will continue until the first non-significant outcome occurs, 
following the methodology of Glimm et al (2010).  
9.2.1. 
Primary Efficacy Analysis 
9.2.1.1. 
Overall Survival 
Overall Survival in the ITT Analysis Set: 
OS will be compared between tislelizumab (Arm A) and docetaxel (Arm B) in a stratified 
log-rank test using a significance level of 0.02 (one-sided). 
The null hypothesis to be tested is: 
 
H0: OS in Arm A = OS in Arm B 
against the alternative hypothesis: 
 
Ha: OS in Arm A ≠ OS in Arm B 
This will be the primary analysis once the targeted numbers of deaths are reached in ITT 
Analysis Set. 
 The p-value from stratified log-rank test will be presented using stratification factors (see 
Section 1.5.3). 
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 two-sided 95% CIs. Kaplan-Meier survival 
probabilities for each arm will be plotted over time. 
The hazard ratio between tislelizumab and docetaxel (HRA/B) and its 95% CI will be estimated 
using a Cox proportional hazard model with treatment arm as a factor and stratified by the actual 
value of the stratification factors. 
Overall Survival in the PD-L1 Positive Analysis Set: 
The hypothesis testing of OS in the PD-L1 positive Analysis Set will be carried out at a 
significance level of 0.007. If the OS hypothesis in the ITT Analysis Set is rejected, its 
corresponding α will be shifted to the testing in the PD-L1 positive Analysis Set (ie, a total α of 
0.025). Similar statistical methods as described above will be applied with histology and line of 
therapy as strata in the stratified analyses. 
Timing and Stopping Boundary in the Interim and Final Analyses of OS: 
There will be one interim analysis of OS performed in the ITT Analysis Set. The interim analysis 
will be performed when approximately 426 deaths (76% of the target number of 560 deaths) 
among the 2 treatment arms are observed in the ITT Analysis Set. It is estimated that it will take 
approximately 23.1 months to observe 426 events. The final analysis of OS will take place after 
560 deaths are observed in the ITT Analysis Set and 207 deaths are observed in its subgroup of 
patients with PD-L1 positive tumors. Thus, the predefined number of deaths in the ITT Analysis 
Set will trigger the interim and final analyses. The information fraction used in α spending 
function will be based on the observed number of deaths in the ITT Analysis Set at the 


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corresponding time points. A Hwang-Shih-DeCani spending function with γ parameter of -2 will 
be used in setting up the upper (efficacy) boundary. Stopping boundaries (p-value and Z score) 
of superiority test for OS at the interim and final analyses in the ITT Analysis Set, as well as OS 
at the final analysis in the PD-L1 positive Analysis Set are shown in Table 10. The boundaries 
for hypothesis testing in OS will be updated according to the actual numbers of death events in 
the interim and final analyses, using the pre-specified α spending function. 
Table 10: 
Stopping Boundaries (p-value and Z score) and Approximate HR Threshold 
of Interim and Final Analyses of OS 
 
Time 
(months) 
# Deaths 
p-value  
(Z score) for 
Efficacy 
Approximate HR 
Threshold for 
Efficacy 
Interim analysis in ITT 
23.1 
426 
<0.0112 (>2.28) 
<0.791 
Final analysis in ITT 
31.0 
560 
<0.0153 (>2.16) 
<0.824 
Final analysis in PD-L1 positive 
31.0 
207 
<0.007 (>2.46) 
<0.696 
Abbreviations: HR = hazard ratio; ITT = intent-to-treat (Analysis Set); PD-L1 – programmed cell death protein 
ligand 1 
Subgroup Analyses 
To determine if the treatment effect is consistent across various subgroups, the HR estimates of 
OS and its 95% CI will be estimated and plotted within each category of the following variables: 
PD-L1 expression in TC (≥25% TC versus <25% TC) in the ITT Analysis Set, histology 
(squamous versus non-squamous), line of therapy (2 versus 3), age (≤65 versus >65 years), 
gender (Female versus Male), ECOG PS (0 versus 1), smoking status and region (CAP versus 
ROW). 
9.2.2. 
Secondary Efficacy Analysis 
9.2.2.1. 
Objective Response Rate 
The statistical significance of the difference in ORR between arms in the ITT Analysis Set will 
be evaluated using the Cochran-Mantel-Haenszel chi-square test with the actual stratification 
factors as strata. The two-sided 95% CIs for the odds ratio and the difference in ORR will be 
calculated, as well as Clopper-Pearson 95% CIs for the ORR within each arm. 
9.2.2.2. 
Progression-Free Survival and Duration of Response 
Progression-free survival will be compared between 2 arms in the ITT Analysis Set using a 
stratified log-rank test using actual stratification factors as strata. 
The median PFS and the cumulative probability of PFS at every 3 months will be calculated for 
each treatment arm and presented with two-sided 95% CIs. PFS will be estimated using the 
Kaplan-Meier method. The PFS censoring rule will follow the (FDA Guidance for Industry 
2007). 
The actual tumor assessment visit date will be used to calculate PFS. Data for patients without 
disease progression or death at the time of analysis will be censored at the time of the last valid 
tumor assessment. Data for patients who start to receive new anticancer therapy or are lost to 


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follow-up will be censored at the last valid tumor assessment date prior to the introduction of 
new therapy or lost to follow-up. Patients who have a clinical determination of progression 
should undergo a CT/MRI, if possible, to correlate radiographic findings with the clinical 
findings. If a clinical determination of progression for a patient is confirmed, the date of the 
CT/MRI scan will be considered as the progression date for that patient. More details are 
provided in the Stastistical Analysis Plan. 
The DoR will be analyzed similarly as the PFS. It will be summarized within responders. 
Efficacy outcomes (ie, ORR, DoR, and PFS) in the PD-L1 positive Analysis Set will be 
summarized similarly. 
9.2.2.3. 
Health-Related Quality of Life 
European Organisation for Research and Treatment of Cancer Quality of Life Cancer 
Questionnaire (EORTC QLQ-LC13 and EORTC QLQ-C30) and EQ-5D-5L postbaseline scores 
will be compared between the 2 treatment arms, using a mixed model with baseline score and 
time since the randomization as covariates. Significant interaction between treatment and time 
since randomization or quadratic term of time since randomization (p-value<0.05) will also be 
included in the final model. 
In addition, changes from baseline in global health status/QoL of QLQ-C30 and the functional 
and symptom scales of QLQ-C30, QLQ-LC13 and EQ-5D-5L (descriptive scores and visual 
analog scales) will be summarized descriptively. 
9.2.3. 
Exploratory Efficacy Analysis 
Exploratory efficacy endpoints assessed by investigator per RECIST v1.1, including DCR, and 
CBR, will be analyzed in the exploratory analysis. 
The BOR will be defined as the best response recorded from start of study drug until data cut or 
start of new anticancer treatment. Patients with no post baseline response assessment (due to any 
reason) will be considered non-responders for BOR. 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. 
The DCR and CBR will be analyzed similarly as the ORR in the ITT and PD-L1 positive 
Analysis Sets. 
Analysis of the relationship of response to exploratory biomarker expression (eg, PD-L1 
expression) may be carried out. 
9.3. 
Safety Analysis 
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE v4.03. 
Laboratory values (eg, hematology, clinical chemistry, urinalysis), vital signs, ECGs, and 
physical examinations will also be used in determining safety. Descriptive statistics will be used 
to analyze all safety data in the Safety Analysis Set. 


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9.3.1. 
Extent of Exposure 
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity (in mg/3 weeks for tislelizumab and mg/m2/3 weeks for 
docetaxel), and relative dose intensity. 
The number (percentage) of patients requiring dose reduction for docetaxel, 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 classified into 
standardized medical terminology using MedDRA®. All AEs will be coded to MedDRA® 
(Version 18.1 or higher) by lower level term closest to the verbatim term. The linked MedDRA® 
Preferred Term (PT) and primary System Organ Class (SOC) are also captured in the database. 
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 either study drug up to 30 days following study drug 
discontinuation or initiation of new anticancer therapy, whichever occurs first. TEAE 
classification also applies to  irAEs and drug-related SAEs recorded up to 90 days after 
discontinuation from tislelizumab, 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 PT. A patient will be counted only once by the highest severity grade per NCI-CTCAE 
v.4.03 within an SOC and PT, even if the patient experienced more than one TEAE within a 
specific SOC and PT. The number (percentage) of patients with TEAEs will also be summarized 
by relationship to the study drug. 
Treatment related AEs include those events considered by the investigator to be related to study 
treatment or with missing assessment of the causal relationship (See Section 8.4.3). Serious 
adverse events; deaths; TEAEs of Grade 3 or above; irAEs; treatment related TEAEs; and 
TEAEs that led to treatment discontinuation, dose interruption, dose reduction, or dose delay will 
be summarized. 
9.3.3. 
Clinical 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 included in the Clinical Study Report for this trial. 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. 


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Laboratory parameters that are graded in NCI-CTCAE v.4.03 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, calcium, glucose, magnesium, 
potassium, sodium) will be summarized separately. 
9.3.4. 
Vital Signs Analyses 
Descriptive statistics for vital sign parameters and changes from baseline will be presented. Vital 
signs will be listed by patient and visit. 
9.3.5. 
Ophthalmologic Examination 
Ophthalmologic examination results will be listed by patient. 
9.4. 
Pharmacokinetic Analyses 
PK samples will be collected in this study as outlined in Appendix 1. PK samples 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. 
Tislelizumab serum concentration data, including but not limited to minimum observed plasma 
concentration (Ctrough), will be tabulated and summarized for each cycle at which 
pharmacokinetics are to be measured. Descriptive statistics will include means, medians, ranges, 
and standard deviations, as appropriate. 
Additional PK such as population PK analyses may be conducted as appropriate. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by 
data. The results of these additional analyses may be reported separately from the Clinical Study 
Report. 
9.5. 
Immunogenicity Analyses 
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. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable 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. 
9.6. 
Other Exploratory Analyses 
Distribution of PD-L1 expression will be examined in the ITT Analysis Set. Association between 
PD-L1 expression (not restricted to the pre-specified cut off level of 25%) and tislelizumab 
treatment effect over docetaxel (OS, ORR, PFS, DoR, DCR, CBR) will be explored. Other 
potential predictive markers including but not limited to GEP, TMB, and tumor-infiltrating 
immune cells will be assessed. 
Methodology for exploratory analyses is described in the Statistical Analysis Plan. 


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9.7. 
Sample Size Considerations 
The original sample size calculation (ie, approximately 640 patients in China and Asia Pacific 
region) is based on the number of events required to demonstrate the OS superiority of Arm A to 
Arm B in ITT-CAP and ITT-CAP patients with PD-L1 positive tumors. The sample size has 
been increased to include an additional 160 patients from ROW, hence a total of approximately 
800 patients will be recruited into the trial. 
Six hundred and forty patients in ITT-CAP will be enrolled over a 16-month period at a constant 
enrollment rate and randomized in a 2:1 ratio to Arms A and B. The enrollment of 160 patients 
in ITT-ROW is expected to start approximately 8 months after that for the ITT-CAP and to last 
about 12 months. The median OS is assumed as 10 months in Arm B. 
An interim analysis is planned when approximately 426 deaths in the ITT Analysis Set have 
been observed, which represents 76% of the planned number of events (ie 560) in the ITT 
Analysis Set for the final analysis. There is an approximately 87% power to detect an OS HR 
(Arm A/Arm B) of 0.75 with a one-sided type I error of 0.02 in the ITT.  
A Hwang-Shih-DeCani spending function with γ parameter of -2 based on the information 
fraction in the ITT Analysis Set is used in setting up the upper (efficacy) boundary. The stopping 
boundaries in Table 10 will be updated based on the actual death events observed in the ITT 
Analysis Set at the interim and final analyses. 
The superiority test of OS in the PD-L1 positive Analysis Set will be performed only in the final 
analysis. Two hundred and seven deaths in the ITT patients with PD-L1 positive tumors are 
required to have approximately 86% power to detect an OS HR of 0.60 with a one-sided type I 
error of 0.007. Assuming the prevalence of PD-L1 positivity is 40% in the ITT Analysis Set, it 
will take approximately 31.0 months to accumulate the required approximately 207 events in 
approximately 320 patients with PD-L1 positive tumors in the ITT Analysis Set. 
As described in Section 1.5.5, the PD-L1 expression status will be closely monitored and 
enrollment of patients whose tumors are PD-L1 negative will be stopped as necessary through 
IWRT upon reaching ~60%, that is to ensure that the percentage of PD-L1 positive patients is no 
less than 40% of the ITT Analysis Set. The capping of PD-L1 negative patients to ~60% will be 
implemented in both ITT-CAP and ITT-ROW independently.  
9.8. 
Interim Analyses 
An interim analysis for OS in the ITT Analysis Set will be performed by an independent 
statistician external to BeiGene. The timing and stopping boundary of the interim analysis are 
described in Section 9.2.1. The IDMC is advised to make the recommendation of stopping the 
trial early for efficacy only when the early stopping boundaries for efficacy are crossed in the 
ITT Analysis Set. More details will be given in the IDMC Charter. The independent statistician 
will generate statistical outputs as described in the IDMC Charter and perform any ad-hoc 
analyses requested by the IDMC. 


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9.9. 
Statistical Strategy for ITT-ROW 
Approximately 160 patients will be randomized in in the ITT-ROW in countries outside of China 
and Asia Pacific region, which consists of 20% of the ITT Analysis Set. With the additional 
region, the treatment effect of tislelizumab could be evaluated in a broader population, as well as 
its consistency between Asian and Caucasian populations. Subgroup analysis in the ITT-ROW is 
planned for descriptive purpose only due to the small sample size. 
Selected efficacy and safety variables will be summarized in the ITT-ROW as subgroup analysis 
using similar methodologies discussed earlier. 


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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 IDMC may recommend modifications to the study including termination of 
the study due to safety and/or efficacy concerns. In addition, the IDMC will monitor on study 
prevalence of PD-L1 negative subset, and send an alert to the Sponsor when the PD-L1 negative 
subset is close to reaching 60% of the planned ITT Analysis Set sample size. 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 Conference on Harmonisation (ICH) Good Clinical Practice 
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 in the course of these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by a regulatory authority the investigator agrees to notify the Sponsor or its designee 
immediately. The investigator agrees to provide to representatives of a regulatory agency or 
BeiGene access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 


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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 or 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 Good Clinical Practice 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 made 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 for inspection of 
study data, patients’ medical records, and eCRFs. The investigator will permit national and local 
health authorities; Sponsor study monitors, representatives, and collaborators; and the IRBs/ECs 
to inspect facilities and records relevant to this study. 
12.4. 
Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records, and returned or 
destroyed study product. Dispensation records will document quantities received from BeiGene’s 
designated depot or its designee and quantities dispensed to patients, including lot number, date 
dispensed, patient identifier number, patient initials, and the initials of the person dispensing the 
medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene’s requirements specified in the 
Pharmacy Manual. At appropriate times during the conduct of the study or at the end of the 
study, following drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, following drug inventory reconciliation by the 
monitor. These including empty containers, according to these procedures. If the site cannot meet 
BeiGene’s requirements specified in the Pharmacy Manual for disposal, arrangements will be 


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made between the site and BeiGene or its representative for destruction or return of unused study 
drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 


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13. 
ETHICAL CONSIDERATIONS 
13.1. 
Ethical Standard 
This study will be conducted by the principal investigator and the study center in full 
conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the 
Declaration of Helsinki or the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the individual. The study will comply 
with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting). 
13.2. 
Institutional Review Board/Independent Ethics Committee 
This protocol, the informed consent forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the principal investigator 
(or Sponsor) and reviewed and approved by the IRB/EC before the study is initiated. In addition, 
any patient recruitment materials must be approved by the IRB/EC. 
The principal investigator (or Sponsor) is responsible for providing written summaries of the 
status of the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators (or Sponsor) are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 13.2.1). 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 
IRB/EC. 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/EC and archived in the site’s study file. 
13.2.1. 
Protocol Amendments 
All 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 or 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 or 
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 Sponsor 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 willingness to remain in the study. 
13.3. 
Informed Consent 
The Sponsor’s sample informed consent form will be provided to each site. If applicable, it will 
be provided in a certified translation of the local language. The final IRB/EC-approved consent 


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forms must be provided to the Sponsor for health authority submission purposes according to 
local requirements. 
The consent forms must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study. 
The consent forms should 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/EC-approved consent forms must be provided to the Sponsor for health 
authority submission purposes. 
Patients must be re-consented to the most current version of the consent forms (or to a significant 
new information/findings addendum in accordance with applicable laws and IRB/EC policy) 
during their participation in the study. For any updated or revised consent forms, 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 consent forms for continued 
participation in the study. 
A copy of each signed consent form must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated consent forms 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 Sponsor maintains confidentiality and privacy standards by coding each patient enrolled in 
the study through assignment of a unique patient identification number. This means that patient 
names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed only to 
third parties as permitted by the informed consent form (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or required by 
law. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by representatives of 
the US Food and Drug Administration (FDA), the China National Medical Products 
Administration (NMPA), the European Medicines Agency (EMA), and all other national and 
local health authorities, Sponsor monitors, representatives, and collaborators, and the IRB/EC for 
each study site, as appropriate. 
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. The investigator agrees that all information 
received from Sponsor, including but not limited to the Investigator’s Brochure, this protocol, 
CRFs, the IND, and any other study information, remain the sole and exclusive property of 
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 Sponsor. The investigator further agrees to 


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take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain. 
13.5. 
Financial Disclosure 
Investigators are required to provide the Sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interest of the clinical investigators and/or disclose those 
financial interests, as required to the appropriate health authorities. This is intended to ensure 
financial interests and arrangements of the clinical investigators with BeiGene that could affect 
reliability of data submitted to health authorities are identified and disclosed by the sponsor.  
Investigators are responsible for providing information on financial interests during the course of 
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 Collections and Management Responsibilities 
14.1.1. 
Data Collection 
Data required by the protocol will be entered into an electronic data capture (EDC) system. 
Data collection in the eCRF must follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The investigator must provide e-signature in the EDC system 
to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available 
in any form to third parties without written permission from BeiGene, except for authorized 
representatives of BeiGene or appropriate regulatory authorities. 
14.1.2. 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol, will be stored at BeiGene at the end of the study. 
Standard procedures (including following data review guidelines, computerized validation to 
produce queries and maintenance of an audit file that includes all database modifications) will be 
followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. Checking the 
eCRFs for completeness, clarity and cross checking with source documents is required to 
monitor the progress of the study. Direct access to source data is also required for inspections 
and audits, and will be carried out with due consideration given to data protection and medical 
confidentiality. 
All AEs will be coded using the MedDRA® Dictionary Version 18.1 or higher. Concomitant 
medications will be coded using the World Health Organization Drug Dictionary. Concomitant 
diseases/medical history will be coded using the MedDRA® Dictionary 
14.2. 
Data Integrity and In-house Blinding 
Due to the open-label design of the study, access to the unblinded patient level clinical data in 
the EDC system will be assigned to predefined study personnel only. Functions/persons with 
access to the EDC system shall be prohibited from using the EDC system to generate 
unnecessary listings/summaries that may introduce unwanted bias, or share such outputs or the 
unblinded data from the EDC system with other functions/persons who do not have access to the 
EDC. Although the trial is open-label, analyses or summaries generated by randomized treatment 
assignment and actual treatment received will be limited and documented. PD-L1 status of each 


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individual patient will be blinded to the Sponsor, site and patient whenever feasible in order to 
avoid unwanted bias. A procedure of capping PD-L1 negative subset at 60% of the ITT Analysis 
Set (see Section 1.5.5) will be described in a Data Integrity Protection Plan. More details of in-
house blinding are provided in the Data Integrity Protection Plan. 
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 the following categories: (1) Investigator’s study file, and (2) patient 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, blank eCRF and query forms, 
IRB/IEC, and governmental approval with correspondence, informed consent, 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 (although not be limited to) 
the following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, 
original laboratory reports, ECG, X-ray, pathology and special assessment reports, consultant 
letters, screening and enrollment log, etc. 
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location. The records must be maintained to allow easy and timely retrieval, when needed 
(eg, audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel. Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must assure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including re-generating a hard copy, if required. Furthermore, the investigator must 
ensure there is an acceptable back up 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 or local laws or regulations, or the Sponsor’s standards/procedures; otherwise, the 
retention period will default to the 15 years. 
The investigator must notify the Sponsor of any changes in the archival arrangements, including, 
but not limited to, the following: archival at an off-site facility, transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all the 
documents, special arrangements must be made between the investigator and BeiGene to store 
these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 


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14.4. 
Protocol Deviations 
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert they will apply due 
diligence to avoid protocol deviations. 
The investigator should document and explain any deviations from the approved protocol. The 
investigator should promptly report any major deviations that might impact patient safety or data 
integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC policies and 
procedures. 
14.5. 
Publication and Data Sharing Policy 
A Clinical Study Report will be prepared and provided to the regulatory agency(ies). BeiGene 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulator guidance, and the need to protect the intellectual property of BeiGene (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. For multicenter studies, 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 2016. 
After conclusion of the study and without prior written approval from BeiGene, Investigators in 
this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
 The results of the study in their entirety have been publicly disclosed by or with the 
consent of BeiGene in an abstract, manuscript, or presentation form; or 
 The study has been completed at all study sites for at least 2 years. 
 No such communication, presentation, or publication will include BeiGene’s 
confidential information. 
 Each investigator agrees to submit all manuscripts or congress abstracts and 
posters/presentations to the Sponsor prior to submission. This allows the Sponsors to 
protect proprietary information, provide comments based on information from other 
studies that may not yet be available to the investigator, and ensure scientific and 
clinical accuracy. The details of the processes of producing and reviewing reports, 
manuscripts, and presentations based on the data from this trial will be presented in 
the investigator’s clinical study agreement. 


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14.6. 
Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
 Return of all study data to the Sponsor 
 Resolution and closure of all data queries 
 Accountability, reconciliation, and arrangements for unused study drug(s) 
 Review of study records for completeness 
 Return of treatment codes to the Sponsor 
 Shipment of PK samples to assay laboratories 
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 reasons including, 
but not limited to, safety or ethical issues or severe noncompliance. 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 prior to it taking effect. 
The Sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated, and will also inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action. If required by applicable 
regulations, the investigator must inform the IEC/IRB promptly and provide the reason for the 
suspension or termination. 
If the study is prematurely discontinued, all study data must be returned 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 
agreement established between the investigator and the Sponsor. 
14.7. 
Information Disclosure and Inventions 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial 
property rights which are conceived or reduced to practice by the study center personnel during 
the course of or as a result of the study are the sole property of the Sponsor, and are hereby 
assigned to the Sponsor. 
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between the Sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
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 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. 


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These restrictions do not apply to: 
 Information that becomes publicly available through no fault of the investigator or 
study center personnel 
 Information that is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
 Information that is necessary to disclose in order to provide appropriate medical care 
to a patient 
 Study results that may be published as described in Section 14.5 
If a written contract for the conduct of the study which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
 


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the Approval of Cancer Drugs and Biologics. 2007. 
Van Der Kraak L, Goel G, Ramanan K, Kaltenmeier C, Zhang L, Normolle DP, et al. 5-
Fluorouracil upregulates cell surface B7-H1 (PD-L1) expression in gastrointestinal cancers. J 
Immunother Cancer 2016;4:65. 
Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh D, et al. In vitro characterization 
of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human 
primates. Cancer Immunol Res 2014;2(9):846-56. 
Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with 
advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a 
randomised, controlled, open-label, phase 3 trial. The Lancet Oncology 2015;16:375-84. 
Worobec A, Rosenberg AS. A risk-based approach to immunogenicity concerns of therapeutic 
protein products, Part 1: considering consequences of the immune response to a protein. 
Available at: http://www.biopharminternational.com/risk-based-approach-immunogenicity-
concerns-therapeutic-protein-products-part-1-considering-conseque.. Accessed 01 February 
2017. 
Worobec AS and Rosenberg AS. A Risk-Based Approach to Immunogenicity Concerns of 
Therapeutic Protein Products, Part 2: Considering Host-Specific and Product-Specific Factors 
Impacting Immunogenicity. BioPharm Intl. 2004b;17(12). 
http://www.biopharminternational.com/risk-based-approach-immunogenicity-concerns-
therapeutic-protein-products-part-2-considering-host-spe. Accessed 01 August 2017. 
Zhou F, Zhou CC. Targeted therapies for patients with advanced NSCLC harboring wild-type 
EGFR: what's new and what's enough. Chin J Cancer 2015;34(7):310-9. 


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16. 
APPENDICES 
 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Assessment 
Screening1 
Treatment Cycles 
 
Safety Follow-up3 
Survival 
Follow-up4 
 
Cycles 1 to 3 
Cycle 4 and 
Subsequent 
cycles 
(Every 21 days) 
End of 
Treatment 
Visit2 
Days (window) 
-28 to -1 
1 (± 3) 
8 (± 2) 
15 (± 2) 
1 (± 3) 
0 to 7 days 
30 ± 7 days after last 
dose 
Every 3 
months 
Informed consent1,18 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
Randomization 
 
X23 
 
 
 
 
 
 
Demographic/Medical 
history5 
X 
 
 
 
 
 
 
 
Vital 
signs/Height/Weight6 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination25 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
X 
X 
 
 
X 
X 
X 
 
12-lead ECG7 
X 
as clinically indicated 
X 
 
Adverse events8 
X 
X 
X 
X 
X 
X 
X8 
X8 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
 
CBC with differential9 
X1 
X 
X 
X 
X 
X 
X 
 
Serum chemistry9 
X1 
X 
X 
X 
X 
X 
X 
 
CK and CK-MB24 
X  
X 
X 
X 
X 
X 
X 
 
Urinalysis9 
X 
As clinically indicated2,9 
 
 
Coagulation9 
X 
As clinically indicated 2,9 
 
 
Anti-tislelizumab 
antibodies10 
 
X 
 
 
X 
 
X 
 
Pregnancy test11 
X 
X 
 
 
X 
 
 
 


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Assessment 
Screening1 
Treatment Cycles 
 
Safety Follow-up3 
Survival 
Follow-up4 
 
Cycles 1 to 3 
Cycle 4 and 
Subsequent 
cycles 
(Every 21 days) 
End of 
Treatment 
Visit2 
Days (window) 
-28 to -1 
1 (± 3) 
8 (± 2) 
15 (± 2) 
1 (± 3) 
0 to 7 days 
30 ± 7 days after last 
dose 
Every 3 
months 
Thyroid function12 
X1 
 
 
 
X 
 
X 
 
Pharmacokinetics13 
 
X 
 
 
X 
 
X 
 
HBV/HCV tests14 
X 
as clinically indicated 
 
 
Tumor assessment15 
X 
tumor assessment starts 9 weeks after randomization 
 
 
Brain MRI/CT15 
X 
as clinically indicated 
 
 
Bone scan16 
X 
as clinically indicated 
 
 
Archival/Fresh tumor 
tissues collection17 
X1 
 
 
 
 
 
 
 
Study drug 
administration18 
 
X 
 
 
X 
 
 
 
EQ-5D-5L19 
 
X 
 
 
X 
X 
 
 
EORTC QLQ-C3019 
 
X 
 
 
X 
X 
 
 
EORTC QLQ-LC 1319 
 
X 
 
 
X 
X 
 
 
Survival status4 
 
 
 
 
 
 
 
X 
Pulmonary function 
tests20 
X 
 
 
 
 
 
 
 
Optical coherence 
tomography (or 
equivalent diagnostic 
test) and visual acuity 
tests21,22 
X 
 
 
 
X21 
X22 
X22 
 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; AESI = adverse event of special interest; ALK = anaplastic lymphoma kinase; CBC = complete 
blood count; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; EORTC QLQ-LC 13 = 
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Lung Cancer-13 Questions; EORTC QLQ-C30 = European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EQ-5D-5L = 5-level European Quality of Life 5-Dimensions (health 
questionnaire); EOT = End of Treatment; FFPE = formalin-fixed paraffin-embedded; HBcAB = hepatitis B core antigen; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; HCV = hepatitis C virus; irAE = immune-related adverse event; IV = intravenously; NCI-CTCAE = National Cancer Institute Common 


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Toxicity Criteria for Adverse Events; NSCLC = non-small cell lung cancer; PK = pharmacokinetic; PS = performance status; Q3W = once every 3 weeks; 
RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; SAE = serious adverse event; TSH = thyroid stimulating hormone; X = to be 
performed 
1. Written informed consent must be required for performing any study-specific tests or procedures. Results of standard of care tests or examinations performed 
prior to obtaining informed consent and within 28 days prior to randomization may be used for screening assessments rather than repeating such tests. Fresh 
tumor biopsy is permitted to be conducted up to 42 days prior to Cycle 1 Day 1, if no archival tumor tissue is available. 
2. The EOT Visit is defined as the day that the investigator determines that tislelizumab or docetaxel will no longer be administered to a patient. If routine 
laboratory tests (hematology, serum chemistry, etc.) are completed within 7 days before the EOT Visit, tests need not be repeated. The tumor assessment is not 
required at the EOT Visit provided that fewer than 6 weeks have passed since the last assessment 
3. The Safety Follow-up Visit should be conducted 30 days (±7 days) after the last dose of study treatment or before the initiation of a new anticancer treatment 
whichever comes first. Patients who are discontinued from the study due to an unacceptable drug-related AE will be followed until the resolution of the AE to 
Grade 0-1, baseline, or stabilization. In addition, telephone contacts with patients should be conducted to assess immune-related AEs and concomitant 
medications (if appropriate, ie, associated with an immune-related AE) at 60 days (±14 days), and 90 days (±14 days)  after the last dose of tislelizumab, 
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 and anticancer treatment will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 
3 months or at the Sponsor’s request, until death, loss to follow-up, withdrawal of consent, or study termination by Sponsor. All patients will be followed for 
survival unless the patient requests to be withdrawn from follow-up. 
5. Includes age or date of birth, gender, and self-reported race/ethnicity; history of treatment for the primary diagnosis, including prior systemic, radiation 
treatment and surgical treatment. Radiographic studies performed prior to study entry may be collected for review by the investigator. 
6. Vital signs include resting temperature (°C), pulse and blood pressure (systolic and diastolic) while the patient is in a seated position after resting for 
10 minutes. For the first infusion, the patient’s vital signs should be determined within 60 minutes before the infusion and 30 minutes after the infusion. For 
subsequent infusions, vital signs should be collected with 60 minutes before the infusion and if clinically indicated, during and 30 minutes after the infusion. 
Height should only be measured and recorded at baseline. Pulse oximetry should be obtained at rest and with exercise at baseline and to be repeated as 
clinically indicated while on study; see also footnote #20 regarding pulmonary function testing. 
7. ECG recordings will be obtained during screening, Safety Follow-up and as clinically indicated at other time points. Patients should be resting for at least 
10 minutes prior to ECG collection. 
8. The AEs and laboratory abnormalities will be graded per NCI-CTCAE Version 4.03. All AEs will also be evaluated for seriousness. 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 the last dose of either study treatment or initiation of a new anticancer therapy, whichever 
occurs first. Immune-related AEs (serious and non-serious) will be reported until 90 days after the last dose of tislelizumab, regardless of whether or not the 
patient starts a new anticancer therapy.  All drug-related SAEs should be recorded by the investigator after treatment discontinuation until patient death, 
withdrawal of consent, or loss to follow-up, whichever occurs first. 
9. Laboratory assessments on serum chemistry, hematology, coagulation, and urinalysis will be conducted, of which certain elements will be collected as 
specified in Section 7.4.4. If hematology and serum chemistry tests at screening are not performed within 7 days of Cycle 1 Day 1, these tests should be 
repeated and reviewed before Cycle 1 Day 1. Hematology and serum chemistry (including liver function tests) will be performed weekly for the first 3 cycles 
and then at the beginning of subsequent cycles (data collected as specified in Section 7.4.4). After Cycle 1, results are to be reviewed within 48 hours before 
study drug administration. Urinalysis and coagulation laboratory tests are to be conducted during the treatment period only if clinically warranted. Refer to 
Section 8.4.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities.  


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10. ADA samples will be collected only in patients randomized to receive tislelizumab and in sites that are able to adequately perform ADA sampling and 
handling. Blood for anti-tislelizumab antibodies should be collected within 60 minutes before start of infusion (predose) on Day 1 of Cycles 1, 2, 5, 9, 17, and 
at the mandatory Safety Follow-up Visit. All samples should be drawn at the same time as blood collection for PK predose sampling. 
11. Urine or serum pregnancy test (for women of childbearing potential, including premenopausal women who have had a tubal ligation) must be performed and 
documented as negative within 7 days prior to Cycle 1 Day 1. Urine pregnancy tests will be performed at each visit prior to dosing. A serum pregnancy test 
must be performed if the urine pregnancy test is positive or equivocal. 
12. Thyroid function tests will be performed at screening and every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc.), and at the Safety Follow-up Visit. Values within 28 
days of randomization are acceptable. 
13. PK samples will be collected only in patients randomized to receive tislelizumab and in sites that are able to adequately perform PK sampling and handling. 
For tislelizumab, predose (within 60 min before start infusion) samples should be collected at Day 1 of Cycle 1, 2, 5, 9 and 17; postdose (within 30 min after 
the end of infusion) samples should be collected at Day 1 of Cycle 1 and Cycle 5. An additional PK sample should be collected at the mandatory Safety 
Follow-up Visit. If a patient presents with any ≥ Grade 3 irAE, additional blood PK samples may be taken to determine the serum concentration of 
tislelizumab. 
14. Testing will be performed at screening and as clinically indicated, including HBsAg, HBcAb, and HCV antibody. Patients who are HBsAg positive or HCV 
antibody positive at screening must not be enrolled until further definitive testing results show HBV DNA titres <500 IU/mL (or 2500 copies/mL), or HCV 
RNA polymerase chain reaction test is negative, respectively. 
15. Examinations performed as standard of care prior to obtaining informed consent and within 28 days of randomization may be used rather than repeating tests, 
provided they meet screening requirements. Brain imaging should be obtained within 28 days of randomization, but ideally within 14 days of randomization. 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit and need to be reassessed at each subsequent tumor evaluation. 
The same radiographic procedure must be used throughout the study for each patient. The investigator must review results before dosing at the next cycle. 
Patients will undergo tumor assessments every 9 weeks (± 7 days) during Year 1, every 12 weeks (± 7 days) from Year 2 onwards based on RECIST v1.1. 
Patients who discontinue from treatment for reasons other than disease progression (eg, toxicity) will continue the tumor assessments as scheduled until disease 
progression, withdrawal of consent, lost to follow-up, death, or start of a new anticancer therapy. Investigators may perform additional scans or more frequent 
assessments if clinically indicated. Patients who continue tislelizumab beyond radiographic disease progression will be monitored with a follow-up scan at no 
more than 6 to 8 weeks beyond the initial diagnosis of PD before discontinuation of tislelizumab. See also Section 7.5 for further details. 
16. If performed within 3 months of randomization, it is not required to be repeated. 
17. Patients must be able to provide archival/fresh tumor tissues (FFPE blocks or approximately 11 [at least 5] freshly cut unstained FFPE slides) for biomarker 
analysis to assess PD-L1 expression and, provided sufficient tissue, including tumor mutational burden (TMB), gene expression profiling (GEP), and 
tumor-infiltrating immune cells. Documentation of wild type status of EGFR by tissue-based test must be provided for patients with non-squamous NSCLC 
prior to enrolment. For undocumented cases, archival/fresh tumor tissues (FFPE blocks or 6 freshly cut unstained FFPE slides) are required for central 
assessment of EGFR mutation. In the absence of archival tumor tissues, a fresh biopsy of a tumor lesion at baseline (within 42 days before Cycle 1 Day 1) is 
mandatory (written informed consent is required prior to fresh tumor biopsies). 
18. Tislelizumab will be given IV every three weeks  for patient in Arm A. Treatment could continue beyond progression at the investigator’s discretion if pseudo-
progression is suspected and/or if there is reasonable belief that the patient could continue to derive benefit, and as long as criteria defined in Section 7.5  are 
met. The patient should sign an informed consent form for continued treatment beyond RECIST v1.1. Docetaxel will be given IV every three weeks  for 
patients in Arm B until disease progression. Cross-over to tislelizumab is not allowed for docetaxel arm. 
19. To be completed prior to any clinical activities during on study site visits. 
20. Pulmonary function testing including spirometry and assessment of oxygenation, at a minimum pulse oximetry at rest and with exercise, or alternatively, 
assessment of diffusion capacity, are to be performed for all patients during the Screening Period to assist the determination of suitability on the study. 


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Respective test results need to be submitted to the Sponsor. Refer to Section 7.1.4 for further details. Tests may be repeated as clinically indicated while on 
study. 
21. For tislelizumab arm only: Eye exam, visual acuity test, and optical coherence tomography (OCT; 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 OCT (or equivalent diagnostic test) will be assessed by an appropriate specialist at the Screening Visit. Patients treated with 
tislelizumab will undergo repeat assessments approximately every 15 weeks (± 7 days). 
22. To be performed only once at either the EOT or during safety follow up, within 30 days of study treatment end in patients treated with tislelizumab. 
23. Patients will be randomized into either the tislelizumab or docetaxel via IRT.  All patients are required to receive study treatment within 2 business days of 
randomization. 
24. All patients will have creatine kinase (CK) and creatine kinase-cardiac muscle isoenzyme (CK-MB) testing at screening, and to be repeated at predose 
assessments in all treatment cycles, and other scheduled visits during the first 3 treatment cycles, and at the end of treatment and safety follow up visits. (In the 
event CK-MB fractionation is not available, please assess troponin I and/or troponin T instead.)  Refer to Section 8.4.5 for additional information regarding 
clinical assessment and management of clinical laboratory abnormalities. 
25. A complete physical examination is required at screening while subsequent visits entail limited, symptom-directed physical examinations (as detailed in 
Section 7.4.2).  Investigators should solicit patients regarding changes in vision, visual disturbance, or ocular inflammation at each scheduled study visit during 
tislelizumab treatment.  For any change in vision, referral to an appropriate specialist will be made for further management guidance.   
 


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APPENDIX 2. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1 
The text below was obtained from the following reference: 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
DEFINITIONS 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (v1.1). Changes in 
only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria. 
Note: Lesions are either measurable or non-measurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm) 
 10 mm caliper measurement by clinical exam (when superficial) 
 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter ≥ 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered nonmeasurable 
disease. Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable. 
Bone lesions: 
 Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 


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or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above 
 Blastic bone lesions are nonmeasurable 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts 
 Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Trial protocols should detail the conditions 
under which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image 
is obtained (for CT scan, this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered nontarget lesions. Nodes that have a short axis < 10 mm are considered 
nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 


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Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present”, “absent”, or in rare cases “unequivocal 
progression” (more details to follow). In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph node” or “multiple liver metastases”). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are accessible by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10 mm diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the trial. 
 Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions. However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
 CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. 
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (eg, for body scans). 
 Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead 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 


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pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response 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 complete response. Because tumor 
markers are disease specific, instructions for their measurement should be 
incorporated into protocols on a disease specific basis. Specific guidelines for both 
CA-125 response (in recurrent ovarian cancer) and prostate-specific antigen response 
(in recurrent prostate cancer), have been published. In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer. 
 Cytology, histology: These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain). When 
effusions are known to be a potential adverse effect of treatment (eg, with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in 
order to differentiate between response (or stable disease) and progressive disease. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
 Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
< 10 mm. 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters 
 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
one or more new lesions is also considered progression). 
 Stable Disease (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 
 Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study. This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if complete response criteria are met, since a normal lymph 
node is defined as having a short axis of < 10 mm. Case report recorded in a separate 


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


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


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While 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 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study drug treatment 
until the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of 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 trial and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in non-randomized trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one the “best overall 
response”. 
The best overall response is determined once all the data for the patient is known. Best response 
determination in trials where confirmation of complete or partial response IS NOT required: Best 
response in these trials is defined as the best response across all time points (for example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last assessment has 
a 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 time point response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same patient lost to 
follow-up after the first SD assessment would be considered inevaluable. 
 
 
 


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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 nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be  
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of “zero”. 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, 
in most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a 
confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. 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 at 


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the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, ie, in 
randomized trials (Phase 2 or 3) or trials where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in trials which 
are not blinded. 
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 complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between 2 measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity, and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made. 


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APPENDIX 3. 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 4. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL”, “NO 
CHILDBEARING POTENTIAL” 
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control. 
These methods include the following: 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal) 
 Progestogen-only hormonal contraception associated with the inhibition of ovulation 
(oral, injectable, or implantable) 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized male partner, provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success. 
 Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of exposure associated with the study treatment). 
 NOTE: Total sexual abstinence should only be used as a contraceptive method if 
it is in line with the patient’s usual and preferred lifestyle. Periodic abstinence (eg, 
calendar, ovulation, symptothermal, postovulation methods), declaration of 
abstinence for the duration of exposure to study drug, and withdrawal are not 
acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
combined with highly effective form of birth control listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant. 
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
 Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
 Postmenopausal, defined as: 
 ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 


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 < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle stimulating hormone concentration > 30 IU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, 
etc. 
If a follicle stimulating hormone 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 5. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION 
 
Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If 
any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria 
Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, MA: 
Lippincott Williams and Wilkins; March 1, 1994. 
 Original source: Criteria Committee, New York Heart Association, Inc.  Diseases of the Heart and Blood 
Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 


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APPENDIX 6. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation1 and the Modification of Diet in Renal Disease (MDRD) Study equation. The National 
Kidney Disease Education Program (NKDEP) calculators rely on creatinine determinations 
which are isotope dilution mass spectrometry (IDMS) traceable. All laboratories should be using 
creatinine methods calibrated to be IDMS traceable. 
This CKD-EPI equation calculator should be used when Scr is reported in mg/dL. This equation 
is recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area.  
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-
calculators 
 
1. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration 
rate. Ann Intern Med. 2009;150(9):604-12). 


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APPENDIX 7. IMMUNE-RELATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT 
The recommendations below for the diagnosis and management of any immune related AE are 
intended as a guidance. This document should be used in conjunction with expert clinical 
judgment (by specialist physicians experienced in the treatment of cancer using immunological 
agents), and individual institutional guidelines or policies. 
Criteria used to diagnose irAEs 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 irAE diagnosis: 
 What was the temporal relationship between initiation of tislelizumab and the adverse 
event? 
 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 irAE field 
associated with the AE in the eCRF should be checked. 
Recommended Diagnostic Tests in the Management of  
Possible Immune-related Adverse Events 
Immune-related Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeat thyroid function tests (TSH and T4).  
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such 
as an upper respiratory infection, new cough, shortness of breath or hypoxia should 
be assessed by high-resolution CT. Consider pulmonary function test including 
DLCO. 
Radiographic appearance is often nonspecific. Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered. Consult with a respiratory medicine physician for cases of uncertain 
cause.  


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Recommended Diagnostic Tests in the Management of  
Possible Immune-related Adverse Events 
Immune-related Toxicity 
Diagnostic Evaluation Guideline 
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications. Conduct a diabetic 
screen, and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology. Consider the need for brain/spine MRI/MRA and nerve conduction study 
for peripheral neuropathy. Consult with a neurologist if there are abnormal 
findings. 
Colitis 
Review dietary intake and exclude steatorrhea. Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, cryptosporidia (drug-resistant 
organism). 
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan. If a patient 
experiences bleeding, pain or distension, consider colonoscopy with biopsy and 
surgical intervention, as appropriate.  
Eye Disorders 
If a patient experiences acute, new onset, or worsening of eye inflammation, 
blurred vision, or other visual disturbances, refer the patient urgently to an 
ophthalmologist for evaluation and management.  
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend on 
severity of the AE (eg, daily if Grade 3-4; every 2-3 days if Grade 2, until 
recovering). Review medications (eg, statins, antibiotics) and alcohol history. 
Perform liver screen including hepatitis A/B/C serology, hepatitis E PCR and 
assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies. Consider imaging, eg, 
ultrasound scan for metastases or thromboembolism. Consult with a hepatologist 
and consider liver 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 nephrology 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. 


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Treatment of Immune-related Adverse Events 
 Immune-related AEs can escalate quickly; study treatment interruption, close 
monitoring, timely diagnostic workup and treatment intervention, as appropriate, with 
patients is required 
 Immune-related AEs should improve promptly after introduction of 
immunosuppressive therapy. If this does not occur, review the diagnosis, seek further 
specialist advice and contact the study medical monitor 
 For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after 
consultation with the study medical monitor 
 Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. 
Equivalent dosages of other corticosteroids can be substituted. For steroid-refractory 
irAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
 Consider prophylactic antibiotics for opportunistic infections if the patient is 
receiving long-term immunosuppressive therapy 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgment) 
Study Drug 
Management 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to normal 
range. 
Thyrotoxic patients should be 
referred to an endocrinologist. In 
cases with systemic symptoms: 
withhold study treatment, treat with a 
beta blocker and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain. Taper corticosteroids 
over 2-4 weeks. Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist. 
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for the 
elderly or those with co-morbidities, 
the suggested starting dose is 0.5 
µg/kg/day). Add oral prednisolone 
0.5 mg/kg/day for thyroid pain. 
Thyrotoxic patients require treatment 
with a beta blocker and may require 
carbimazole until thyroiditis 
resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgment) 
Study Drug 
Management 
Hypophysitis 
1-2 
Mild-moderate 
symptoms 
Refer patient to an endocrinologist 
for hormone replacement. Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation. 
Taper corticosteroids over at least 
1 month. If there is no improvement 
in 48 hours, treat as Grade 3-4. Taper 
corticosteroids over at least 1 month. 
Continue study 
treatment. 
3-4 
Severe or life-
threatening symptoms 
Refer patient to an endocrinologist 
for assessment and treatment. Initiate 
pulse IV methylprednisolone 1 
mg/kg for patients with 
headache/visual disturbance due to 
pituitary inflammation. Convert to 
oral prednisolone and taper over at 
least 1 month. Maintain hormone 
replacement according to 
endocrinology advice. Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less. 
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days. 
If appearance worsens, treat as Grade 
2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected. Add oral prednisolone 
1 mg/kg/day if symptoms/appearance 
persist for 48 hours or worsen. 
Consider Pneumocystis infection 
prophylaxis. Taper corticosteroids 
over at least 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment. 
Retreatment is 
acceptable if symptoms 
resolve completely or 
are controlled on 
prednisolone 
≤ 10 mg/day. 
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
3-4 
Severe or 
life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with IV 
methylprednisolone 2-4 mg/kg/day. 
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement). Convert to oral 
prednisolone and taper over at least 2 
months. Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 


BGB-A317-303 
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Protocol Amendment 3.0 
09 March 2020 
 
CONFIDENTIAL 
Page 136 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgment) 
Study Drug 
Management 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-1 
mg/kg/day. Taper over at least 4 
weeks. Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
3-4 
Severe/life-threatening 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms. Taper 
corticosteroids over at least 4 weeks. 
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: 
< 3 liquid stools per day 
over baseline and feeling 
well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-6 
liquid stools per day 
over baseline, or 
abdominal pain, or blood 
in stool, or nausea, or 
nocturnal episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment. Taper steroids over 
2-4 weeks, consider endoscopy if 
symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe 
symptoms: > 6 liquid 
stools per day over 
baseline, or if episodic 
within 1 hour of eating 
 
Initiate IV methylprednisolone 1-2 
mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks. Consider 
prophylaxis for adverse steroid 
effects, eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg if no perforation, 
sepsis, TB, hepatitis, NYHA Grade 
III/IV CHF or other 
immunosuppressive treatment: MMF 
or tacrolimus. 
Consult gastroenterologist to conduct 
colonoscopy/ sigmoidoscopy. 
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. 


BGB-A317-303 
BeiGene 
Protocol Amendment 3.0 
09 March 2020 
 
CONFIDENTIAL 
Page 137 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgment) 
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 judgment: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day for 3 
days then taper over 2-4 weeks. 
For severe symptoms: IV 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and 
taper over at least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
 
 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, 
erythema, purpura, 
epidermal detachment) 
Initiate IV methylprednisolone 1-2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 4 
weeks. 
Admit to a hospital and seek urgent 
dermatology consultation. 
Discontinue study 
treatment. 
 
Hepatitis 
1 
ALT or AST > ULN to 
3X ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 
2 
ALT or AST 3-5X ULN 
Recheck LFTs every 48-72 hours: 
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-1 
mg/kg/day for 3 days then taper over 
2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgment.  
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline Grade and 
prednisolone tapered to 
≤ 10 mg. 


BGB-A317-303 
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Protocol Amendment 3.0 
09 March 2020 
 
CONFIDENTIAL 
Page 138 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgment) 
Study Drug 
Management 
3 
ALT or AST 5-20X 
ULN 
ALT/AST < 400 IU/L and normal 
bilirubin/INR/albumin: Initiate oral 
prednisolone 1 mg/kg and taper over 
at least 4 weeks. 
ALT/AST > 400 IU/L or raised 
bilirubin/INR/low albumin: Initiate 
IV (methyl)prednisolone 
2 mg/kg/day. When LFTs improve to 
Grade 2 or lower, convert to oral 
prednisolone and taper over at least 4 
weeks.  
Hold study treatment 
until improved to 
baseline Grade; 
reintroduce only after 
discussion with the 
study medical monitor. 
4 
ALT or AST > 20X 
ULN 
Initiate IV methylprednisolone 2 
mg/kg/day. Convert to oral 
prednisolone and taper over at least 6 
weeks.  
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
 
If on oral prednisolone, change to pulsed IV methylprednisolone 
 
If on IV, add mycophenolate mofetil (MMF) 500-1000 mg twice a day 
 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
 
2 
Creatinine > 1.5X-3X 
baseline or > 1.5X-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection. Discuss with 
nephrologist the need for kidney 
biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-72 
hours. 
Hold study treatment. 
If not attributed to drug 
toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered to 
< 10 mg prednisolone. 
3 
Creatinine > 3X baseline 
or > 3X-6X ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
every 24 hours; refer to a 
nephrologist and discuss need for 
biopsy. If worsening, initiate IV 
(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 > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 


BGB-A317-303 
BeiGene 
Protocol Amendment 3.0 
09 March 2020 
 
CONFIDENTIAL 
Page 139 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgment) 
Study Drug 
Management 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; 
ULN to 8.9 mmol/L 
Monitor closely and treat according 
to local guideline. Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and islet 
cells are recommended. 
Continue study 
treatment. 
2 
Fasting glucose value 
160-250 mg/dL;  
8.9-13.9 mmol/L 
Obtain a repeat blood glucose level 
at least every week. Manage 
according to local guideline. 
Continue study 
treatment or hold 
treatment if 
hyperglycemia is 
worsening. Resume 
treatment when blood 
glucose is stabilized at 
baseline or Grade 0-1. 
3 
Fasting glucose value 
250-500 mg/dL; 13.9- 
27.8 mmol/L 
Admit patient to hospital and refer to 
a diabetologist for hyperglycemia 
management. Corticosteroids may 
exacerbate hyperglycemia and should 
be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline or 
Grade 0-1. 
4 
Fasting glucose 
value > 500 
mg/dL; > 27.8 mmol/L 
Admit patient to hospital and 
institute local emergency diabetes 
management. Refer the patient to a 
diabetologist for insulin maintenance 
and monitoring. 
Ocular Toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment. Consider a 
course of oral steroids. 
Continue study 
treatment or hold 
treatment if symptoms 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior uveitis/ 
panuveitis or significant 
symptoms 
Refer patient urgently to an 
ophthalmologist. Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1; reintroduce only 
after discussion with 
the study medical 
monitor. 
4 
Blindness (at least 
20/200) in the affected 
eyes 
Initiate IV (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 IV 
(methyl)prednisolone 1-2 mg/kg/day. 
Hold study treatment; 
reintroduce only after 
discussion with the 


BGB-A317-303 
BeiGene 
Protocol Amendment 3.0 
09 March 2020 
 
CONFIDENTIAL 
Page 140 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgment) 
Study Drug 
Management 
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks. 
study medical monitor. 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate referral.  
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.  
Continue study 
treatment. 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental 
(fine motor) activities 
Management as per local guideline. 
Consider referring patient to a 
rheumatologist. If symptoms worsen 
on treatment manage as a Grade 3 
event. 
Continue treatment or, 
if symptoms continue 
worsens, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with 
inflammation or 
permanent joint damage, 
daily living activity 
limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management. Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments and 
oral hygiene care. Ensure adequate 
hydration. If symptoms worsen or 
there is sepsis or bleeding, manage as 
a Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited 
food and fluid intake, 
daily living activity 
limited 
Admit to hospital for appropriate 
management. Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day. 
Convert to oral prednisolone when 
symptoms improved to Grade 2 and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to Grade 
0-1. 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency 
care. Consider IV 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 3X ULN or worse, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks 
Hold study treatment 
until improved to Grade 
0-1 


BGB-A317-303 
BeiGene 
Protocol Amendment 3.0 
09 March 2020 
 
CONFIDENTIAL 
Page 141 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgment) 
Study Drug 
Management 
3-4 
Severe weakness, 
limiting self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg.  Consider 
bolus IV (methyl)prednisolone and 
1-2 mg/kg/day maintenance for 
severe activity restriction or 
dysphagia.  If symptoms do not 
improve add immunosuppressant 
therapy.  Taper oral steroids over at 
least 4 weeks 
Hold study treatment 
until improved to Grade 
0-1. Discontinue if any 
evidence of myocardial 
involvement 
Myocarditis 
< 2  
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant 
intraventricular 
conduction delay 
Initiate cardiac evaluation under 
close monitoring with repeat serum 
cardiac testing; consider referral to a 
cardiologist. 
If diagnosis of myocarditis is 
confirmed, treat as Grade 2 
Hold study treatment. 
 
If a diagnosis of 
myocarditis is 
confirmed, permanently 
discontinue study 
treatment in patients 
with moderate or severe 
symptoms.  Patients 
with no symptoms or 
mild symptoms may 
not restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline and 
after discussion with 
the study medical 
monitor. 
2 
Symptoms on mild-
moderate exertion 
Admit to hospital and initiate oral 
prednisolone or IV 
(methyl)prednisolone at 1 2 
mg/kg/day.  Consult with a 
cardiologist and manage symptoms 
of cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of (methyl)prednisolone 
1g/day and add MMF, infliximab 
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; INR, 
international normalized ratio; IV, intravenous; LFT, liver function test; MMF, mycophenolate mofetil; NYHA, 
New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; TSH, thyroid-stimulating 
hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 


Approval
Approval
Approval
Approval
Approval
Approval
Approval
Approval


Approval
Approval

SAP_001.pdf: 
BeiGene, Ltd. 
 BGB-A317-303 
   (Statistical Analysis Plan) 
Version 1.0:  10/16/2020 
Page 1 of 37 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
Study Protocol 
Title: 
Date: 
Version: 
NCT ID:
BGB-A317-303 
A Phase 3, Open-Label, Multicenter, Randomized Study to 
Investigate the Efficacy and Safety of BGB-A317 
(Anti-PD1 Antibody) Compared with Docetaxel in 
Patients with Non-Small Cell Lung Cancer Who Have 
Progressed on a Prior Platinum-Containing Regimen 
October 16, 2020 
1.0 
NCT03358875
lmel BeiGene 
m 


 
BeiGene, Ltd.  
 BGB-A317-303 
                  (Statistical Analysis Plan) 
 
 
Version 1.0:  10/16/2020 
Page 2 of 37  
CONFIDENTIAL 
 
 
SIGNATURE PAGE 
Author: 
 
               Senior Principal Statistician,    
               Statistics and Data Science 
                
 
 
 
 
Approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vice President, 
Statistics and Data Science 
 
 
 
 
Executive Director, 
Clinical Development I/O 
 
 
 
 
 
 
Medical Director, 
Clinical Development 
 
 
 
 
 
 
 
 


 
BeiGene, Ltd.  
 BGB-A317-303 
                  (Statistical Analysis Plan) 
 
 
Version 1.0:  10/16/2020 
Page 3 of 37  
CONFIDENTIAL 
 
 
 
TABLE OF CONTENTS 
1 
INTRODUCTION 
7 
2 
STUDY OVERVIEW 
7 
3 
STUDY OBJECTIVES 
8 
3.1 
Primary Objectives 
8 
3.2 
Secondary Objectives 
9 
3.3 
Exploratory Objectives 
9 
4 
STUDY ENDPOINTS 
9 
4.1 
Primary Endpoints 
9 
4.2 
Secondary Endpoints 
9 
4.3 
Exploratory Endpoints 
10 
5 
SAMPLE SIZE CONSIDERATIONS 
10 
6 
STATISTICAL METHODS 
11 
6.1 
Analysis Sets 
11 
6.2 
Data Analysis General Considerations 
12 
6.2.1 
Definitions and Computations 
12 
6.2.2 
Conventions 
12 
6.2.3 
Handling of Missing Data 
13 
6.2.4 
Adjustment for Covariates 
13 
6.2.5 
Multiplicity Adjustment 
13 
6.3 
Patient Characteristics 
15 
6.3.1 
Patient Disposition 
15 
6.3.2 
Protocol Deviations 
15 
6.3.3 
Demographic and Other Baseline Characteristics 
15 
6.3.4 
Prior Anti-Cancer Systemic TherapiesRadiotherapy and 
Surgeries 
16 
6.3.5 
Prior and Concomitant Medications 
16 
6.3.6 
Medical History 
16 
6.4 
Efficacy Analysis 
16 
6.4.1 
Primary Efficacy Endpoints 
17 
6.4.2 
Secondary Efficacy Endpoints 
19 
6.4.3 
Exploratory Efficacy Endpoints 
21 
6.4.4 
Efficacy Endpoints in China patients 
22 
6.5 
Safety Analyses 
22 
6.5.1 
Extent of Exposure 
22 
6.5.2 
Adverse Events 
23 
6.5.3 
Laboratory Values 
25 
6.5.4 
Vital Signs 
26 
6.5.5 
Ophthalmologic Examination 
26 
6.5.6 
Electrocardiograms (ECG) 
26 


 
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Version 1.0:  10/16/2020 
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CONFIDENTIAL 
 
 
6.5.7 
ECOG 
26 
6.6 
Pharmacokinetic Analyses 
26 
6.7 
Immunogenic Analysis 
26 
6.8 
Other Exploratory Analyses 
27 
6.9 
Analyses To Evaluate Covid-19 Impact 
27 
7 
INTERIM ANALYSIS 
27 
8 
CHANGES IN THE PLANNED ANALYSIS 
29 
9 
REFERENCES 
29 
10 
APPENDIX 
31 
10.1 
PFS Censoring Rules 
31 
10.2 
Health Related Quality of Life 
31 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
BeiGene, Ltd.  
 BGB-A317-303 
                  (Statistical Analysis Plan) 
 
 
Version 1.0:  10/16/2020 
Page 5 of 37  
CONFIDENTIAL 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADA 
Antidrug antibody 
AE 
adverse event 
BOR 
best overall response 
BP 
blood pressure 
CAP 
China Asia Pacific 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CT 
computerized tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
Ctrough 
minimum observed plasma concentration 
DCR 
disease control rate 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
GEP 
gene expression profiling 
ITT 
Intent-to-treat 
irAE 
immune-related AE 
KM 
Kaplan-Meier 
MedDRA® 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PT 
preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 


 
BeiGene, Ltd.  
 BGB-A317-303 
                  (Statistical Analysis Plan) 
 
 
Version 1.0:  10/16/2020 
Page 6 of 37  
CONFIDENTIAL 
 
 
ROW 
rest of the world 
SAE 
serious adverse events 
SAF 
Safety Analysis Set 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
TC 
tumor cell 
TEAE 
treatment-emergent adverse event 
TLG 
table listing and graph 
TMB 
tumor mutational burden 


 
BeiGene, Ltd.  
 BGB-A317-303 
                  (Statistical Analysis Plan) 
 
 
Version 1.0:  10/16/2020 
Page 7 of 37  
CONFIDENTIAL 
 
 
1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for BGB-A317-303: A Phase 3, Open-
Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of BGB-A317 
(Anti-PD1 Antibody) Compared with Docetaxel in Patients with Non-Small Cell Lung Cancer 
Who Have Progressed on a Prior Platinum-Containing Regimen. The focus of this SAP is for the 
planned primary, secondary and exploratory analysis specified in the study protocol. 
The analysis details for exploratory biomarker analyses are not described within this SAP. Separate 
analysis plans may be completed for these analyses and may be attached to the clinical study report. 
Reference materials for this statistical plan include the protocol amendment BGB-A317-303 
(version 3.0, dated as 9 March 2020). If the protocol is amended or updated, then appropriate 
adjustments to the SAP may be made if they are related to the planned analyses. 
The SAP described hereafter is a priori plan. This is an open label study with a planned interim 
analysis, and the SAP will be finalized and approved before interim analysis. Statistical 
programming may occur as study data accumulate in order to have analysis programs ready prior 
to database lock. 
2 
STUDY OVERVIEW 
Study Design 
This is a randomized, open-label multicenter Phase 3 study designed to compare the efficacy and 
safety of tislelizumab versus docetaxel as treatment in the second- or third-line setting in patients 
with NSCLC. The primary endpoint of the study is OS in both the ITT and PD-L1 positive 
analysis sets. 
Patients must have histologically confirmed, locally advanced or metastatic NSCLC (squamous 
or non-squamous). Histology of NSCLC (squamous or non-squamous) will be confirmed at the 
investigator’s site. Patients with known epidermal growth factor receptor (EGFR) mutation or 
anaplastic lymphoma kinase (ALK) rearrangement are ineligible for the study. Documentation of 
wild type EGFR by tissue-based test is required for non-squamous patients to enter the study. 
Archival tumor tissues (not restricted to pretreatment) will be collected for biomarker analysis at 
a central laboratory. If archived formalin-fixed paraffin-embedded (FFPE) tissue is not 
sufficient, a fresh biopsy sample will be mandatory. 
Patients must have been treated with at least one platinum-containing regimen but not more than 
2 prior lines of systemic chemotherapy and have disease progression during or following 
chemotherapy treatment. Patients who progressed or have disease recurrence during or after 
neoadjuvant or adjuvant therapy with platinum-containing regimen (counted as one line of 
therapy) within 6 months are eligible to enroll into the study. 


 
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Version 1.0:  10/16/2020 
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CONFIDENTIAL 
 
 
After signing an informed consent form and screening for eligibility, patients will be randomized 
in a 2:1 ratio to receive tislelizumab or docetaxel in the following 2 arms: 
Arm A: Tislelizumab 200 mg intravenously (IV) once every 3 weeks 
Arm B: Docetaxel 75 mg/m2 IV once every 3 weeks 
Randomization will be stratified by histology (squamous versus nonsquamous), line of therapy 
(second versus third), and PD-L1 expression (≥25% TC versus <25% TC). 
Administration of docetaxel and tislelizumab will continue until disease progression, as assessed 
by investigator per RECIST v1.1, unacceptable toxicity, or withdrawal of informed consent, 
whichever occurs first. Patients receiving tislelizumab will be permitted to continue tislelizumab 
treatment beyond progression by RECIST v1.1 if clinical benefit is seen in the absence of 
symptomatic deterioration and unacceptable toxicity per investigator’s discretion. 
Tumor response will be evaluated by investigators every 9 weeks (± 7 days) during Year 1 and 
every 12 weeks (± 7 days) from Year 2 onwards based on RECIST v1.1. If a patient discontinues 
study treatment due to reasons other than disease progression, then tumor assessments should 
continue to be performed as scheduled until the start of new anticancer therapy, disease 
progression by RECIST v1.1, death, loss to follow-up,  withdrawn consent, or until the study 
closes, whichever occurs first. Any new anticancer therapy after discontinuation of study 
treatment from both arms will be documented. 
To determine the PK properties of tislelizumab and host immunogenic response to tislelizumab, 
blood samples will be collected at various time points. 
Patients will be evaluated for adverse events (AEs) and serious adverse events (SAEs) occurring 
up to 30 days after the last dose of either study drug or initiation of new anticancer therapy, 
whichever occurs first, (all severity grades according to NCI-CTCAE v4.03) and all immune-
related AEs (irAEs) (tislelizumab arm only) occurring up to 90 days after the last dose of 
tislelizumab, 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. 
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES  
• 
To compare the efficacy, as measured by overall survival (OS), of tislelizumab with 
docetaxel in the second- or third-line setting in patients with non-small cell lung 
cancer (NSCLC) who have progressed on a prior platinum-containing regimen. A 
comparison of the treatment arms will be performed in: 
          o The intent-to-treat (ITT) analysis set 


 
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          o The programmed cell death protein ligand-1 (PD-L1) positive analysis set,    
                             where PD-L1 positive is defined as ≥25% of tumor cells (TCs) with PD-L1    
                             membrane staining via the Ventana SP263 assay 
3.2 
SECONDARY OBJECTIVES  
• 
To compare the efficacy of tislelizumab and docetaxel as measured by objective 
response rate (ORR), duration of response (DoR), and progression-free survival (PFS) 
per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in: 
           o The ITT analysis set 
     o The PD-L1 positive analysis set 
• 
To compare health-related quality of life (HRQoL) between tislelizumab and 
docetaxel arms 
• 
To evaluate the safety and tolerability of tislelizumab versus docetaxel 
3.3 
EXPLORATORY OBJECTIVES 
• 
To compare tumor assessment outcomes (ie, disease control rate [DCR] and clinical 
benefit rate [CBR]) between tislelizumab and docetaxel assessed by investigator per 
RECIST v1.1 
• 
To explore potential predictive biomarkers for efficacy including but not limited to 
PD-L1 expression, tumor mutational burden (TMB), gene expression profile (GEP), 
and tumor-infiltrating immune cells 
• 
To characterize the pharmacokinetics (PK) of tislelizumab in patients with NSCLC 
• 
To determine host immunogenicity to tislelizumab in patients with NSCLC 
4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
• 
OS – defined as the time from the date of randomization to the date of death due to 
any cause in the ITT and PD-L1 positive analysis set 
4.2 
SECONDARY ENDPOINTS 
• 
ORR – defined as the proportion of patients in the ITT and PD-L1 positive analysis 
set who had a complete response (CR) or partial response (PR) as assessed by the 
investigator per RECIST v1.1 
• 
DoR – defined as the time from the first occurrence of a documented objective 
response to the time of relapse, as determined by the investigator per RECIST v1.1, 


 
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or death from any cause, whichever comes first in the ITT and PD-L1 positive 
analysis set 
• 
PFS – defined as the time from the date of randomization to the date of the first 
objectively documented tumor progression as assessed by the investigator per 
RECIST v1.1 or death from any cause, whichever occurs first, in the ITT and PD-L1 
positive analysis set 
• 
HRQoL – measured using European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire-Lung Cancer (EORTC QLQ-LC13), Core 30 
(EORTC QLQC30), and European Quality of Life 5-Dimensions, 5-level (EQ-5D-
5L) scale 
• 
Incidence and severity of treatment-emergent adverse events (TEAEs) graded 
according to National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE), v4.03 
4.3 
EXPLORATORY ENDPOINTS 
• 
DCR – defined as the proportion of patients whose best overall response (BOR) is 
CR, PR or stable disease (SD) per RECIST v1.1 
• 
CBR - defined as the proportion of patients who have CR, PR and SD that is ≥24 
weeks in duration per RECIST v1.1 
• 
PD-L1 expression, TMB, GEP, and tumor-infiltrating immune cells as predictive 
biomarkers for response 
• 
Summary of serum concentrations of tislelizumab in the pharmacokinetic analysis set 
• 
Assessments of immunogenicity of tislelizumab by determining the incidence of anti-
drug antibodies (ADAs) in the ADA analysis set 
5 
SAMPLE SIZE CONSIDERATIONS 
The original sample size calculation (ie, approximately 640 patients in China and Asia Pacific 
region (CAP) is based on the number of events required to demonstrate the OS superiority of 
Arm A to Arm B in ITT-CAP and ITT-CAP patients with PD-L1 positive tumors. At Protocol 
Amendment 1 of February 14, 2018, the sample size has been increased to include an additional 
160 patients from rest of world (ROW), hence a total of approximately 800 patients will be 
recruited into the trial. 
Six hundred and forty patients in ITT-CAP will be enrolled over a 16-month period at a constant 
enrollment rate and randomized in a 2:1 ratio to Arms A and B. The enrollment of 160 patients 
in ITT-ROW is expected to start approximately 8 months after that for the ITT-CAP and to last 
about 12 months. The median OS is assumed as 10 months in Arm B. 


 
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There is an approximately 87% power with planned 560 events to detect the difference between 
arms under the assumption of an OS HR (Arm A/Arm B) of 0.75 with a one-sided type I error of 
0.02 in the ITT. An interim analysis is planned when approximately 426 deaths in the ITT 
analysis set have been observed, which represents 76% of the planned number of events in the 
ITT analysis set for the final analysis. 
A Hwang-Shih-DeCani spending function with γ parameter of -2 based on the information 
fraction in the ITT analysis set is used in setting up the upper (efficacy) boundary. The stopping 
boundaries will be updated based on the actual death events observed in the ITT analysis set at 
the interim and final analyses. 
The superiority test of OS in the PD-L1 positive analysis set will be performed only in the final 
analysis. Two hundred and seven deaths in the ITT patients with PD-L1 positive tumors are 
required to have approximately 86% power to detect an OS HR of 0.60 with a one-sided type I 
error of 0.007. Assuming the prevalence of PD-L1 positivity is 40% in the ITT analysis set, 
approximately 207 events in approximately 320 patients with PD-L1 positive tumors in the ITT 
analysis set are required. 
The PD-L1 expression status will be closely monitored and enrollment of patients whose tumors 
are PD-L1 negative will be stopped as necessary through Interactive web response technology 
upon reaching ~60%, that is to ensure that the percentage of PD-L1 positive patients is no less 
than 40% of the ITT analysis set. The capping of PD-L1 negative patients to ~60% will be 
implemented in both ITT-CAP and ITT-ROW independently. 
6 
STATISTICAL METHODS 
6.1 
ANALYSIS SETS 
The Intent-to-Treat (ITT) analysis set includes all randomized patients. Patients will be analyzed 
according to their randomized treatment arms. This will be the primary analysis set for efficacy 
analysis. 
The PD-L1 positive analysis set (≥25% of TC with PD-L1 membrane staining) includes all 
randomized patients whose tumors were PD-L1 positive. Patients will be analyzed according to 
their randomized treatment arms. This will be the dual primary analysis population for efficacy 
analysis. 
The Per-Protocol (PP) analysis set includes patients in the ITT analysis set who had no critical 
protocol deviations. Critical protocol deviations are a subset of major protocol deviations 
impacting primary efficacy analysis. Criteria for exclusion from the PP will be determined and 
documented before the database lock for the primary analysis. 
The Safety (SAF) analysis set includes all randomized patients who received at least one dose of 
study drug. It will be the analysis set for the safety analyses. Patients who were randomized to 
tislelizumab arm but did not take any dose of tislelizumab will be included in the docetaxel arm 


 
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in the SAF. Patients who were randomized to docetaxel arm but took any dose of tislelizumab 
will be included in the tislelizumab arm in the SAF. 
The HRQoL analysis set includes all randomized patients who received at least one dose of study 
drug and completed at least one HRQoL assessment. This will be the analysis set for HRQoL 
analysis. 
The PD-L1 positive HRQoL analysis set includes all randomized patients whose tumors were 
PD-L1 positive and who received at least one dose of study drug and completed at least one 
HRQoL assessment. This will be the analysis set for PD-L1 positive HRQoL analysis. 
The PK analysis set includes all patients who received at least 1 dose of tislelizumab per the 
protocol, for whom any post-baseline PK data are available. 
The ADA analysis set includes all patients who received at least 1 dose of tislelizumab for whom 
both baseline ADA and at least 1 post-baseline ADA results are available. 
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
Statistical programming and analyses will be performed using SAS® (SAS Institute, Inc., Cary, 
NC, USA), version 9.4 or higher, and/or other validated statistical software as required. 
All descriptive statistics for continuous variables will be reported using mean, standard deviation 
(SD), median, 25 percentile (Q1), 75 percentile (Q3), minimum (Min), maximum (Max) and n.  
Categorical variables will be summarized as number (percentage) of patients.  
The study Table Listing Graph shells will be provided in a separate document, which will show 
the content and format of all tables, listings, and graphs in detail. 
6.2.1 Definitions and Computations 
Baseline: Unless otherwise specified, a baseline value for ITT analysis set is defined as the last 
non-missing value collected before or at the time of randomization date, if not available, defined 
as last non-missing value collected before or at the time of first dose date. A baseline value for 
safety analysis set is defined as the last non-missing value collected before or at the time of first 
dose date. If the above-mentioned non-missing values were collected at both central labs and local 
labs, the non-missing values at central labs will be prioritized. 
Unscheduled Visits: Unscheduled measurements will not be included in by-visit table summaries 
and graphs, but will contribute to best/worst case value where required (e.g. shift table). Listings 
will include scheduled and unscheduled data. 
6.2.2 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 


 
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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’.   
6.2.3 Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. Missing dates 
or partially missing dates will be imputed conservatively for adverse events and prior or 
concomitant medications/procedures. Missing data for the HRQoL data will be handled according 
to each PRO instrument manual (Fayer & Machin, 2000 in The EORTC QLQ-C30 (Third Edition), 
2001; https://euroqol.org/publications/user-guides/). Every effort should be made to ensure 
complete death dates. In the rare case, if day of death date is missing, death date will be imputed 
as the max of last available date showing patients alive + 1 and first day of year/month of death 
date. However, death date will not be imputed if year or month is missing.
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. 
6.2.4 Adjustment for Covariates 
If any baseline characteristics are unbalanced, certain analysis adjusted for covariates may be 
considered.  
6.2.5 Multiplicity Adjustment 
A sequential testing with alpha splitting approach will be implemented in the following orders to 
control overall type I error of 0.025 for the primary endpoints (OS in ITT and PD-L1 positive 
subset). The α allocation accounts for the positive correlation between the test statistics in the 2 
Analysis Sets (ie, PD-L1 positive is a subset of the ITT Analysis Set). The overall type I error is 
controlled at 0.025 when at least 30% of the deaths in the ITT Analysis Set are from the PD-L1 
positive subset. The α of 0.007 in the PD-L1 testing will be adjusted downwards if the final 
observed percentage is lower. 
x OS in ITT with α of 0.02 (0.0112 for interim analysis, 0.0153 for final analysis) 
x If the OS hypothesis in ITT is rejected,  
o OS in PD-L1 positive analysis set 


 
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o testing in the sequential order of ORR in the PD-L1 positive analysis set, DoR in 
the PD-L1 positive analysis set, PFS in the PD-L1 positive analysis set, PFS in the 
ITT analysis set, ORR in the ITT analysis set, DoR in the ITT analysis set, lung 
cancer symptom scale measured by QLQ-LC13 and QLQ-C30 global health 
status/Quality of Life (QoL)  in the ITT and PD-L1 positive analysis sets. 
x If the OS hypothesis in the ITT analysis set cannot be rejected, hypothesis testing will be 
carried out sequentially only in the PD-L1 positive Analysis Set for OS, ORR, DoR, PFS, 
lung cancer symptom scale measured by QLQ-LC13 and QLQ-C30 global health 
status/QoL scale at α of 0.007. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 sided α=0.025 
OS in ITT analysis set 
OS in PD-L1 positive 
analysis set 
α=0.02 
If positive, α=0.02 
α=0.007 
ORR in the PD-L1 positive analysis set, DoR in the 
PD-L1 positive analysis set, PFS in the PD-L1 positive 
analysis set, PFS in the ITT analysis set, ORR in the 
ITT analysis set, DoR in the ITT analysis set, lung 
cancer symptom scale measured by QLQ-LC13 and 
QLQ-C30 global health status/Quality of Life (QoL)  
in the ITT and PD-L1 positive analysis sets. 
If positive, α=0.025; 
testing in the sequential order, 
until the 
first non-significant outcome 
occurs 
1 sided α=0.025 
OS in ITT analysis set 
OS in PD-L1 positive 
analysis set 
α=0.02 
If negative, no pass 
α=0.007 
~, 


 
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6.3 
PATIENT CHARACTERISTICS 
6.3.1 Patient Disposition 
The number and percentage of patients randomized, treated, permanently discontinued from study 
treatment, remained on treatment, discontinued from study, and remained in study will be 
summarized in the ITT analysis set.  The primary reasons for study treatment discontinuation and 
study discontinuation will be summarized according to the categories in the CRF. Study follow-
up time and primary reason for screen failure will be summarized.   
6.3.2 Protocol Deviations 
Critical protocol deviations are a subset of major protocol deviations impacting primary efficacy 
analysis. Criteria for major protocol deviations and critical protocol deviations impacting primary 
efficacy will be established and patients with major and critical protocol deviations will be 
identified and documented before the database lock.  
Both major protocol deviations and critical protocol deviations, including relatedness to COVID-
19, will be summarized and listed by category in the ITT analysis set.  
6.3.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the ITT analysis set using 
descriptive statistics.   
Continuous demographic and baseline variables include age, BMI (in kg/m2), body weight (in kg), 
baseline target lesions sum of diameters by investigator (in mm), time from initial diagnosis to 
study entry; categorical variables include sex, age group (<65 years, ≥65 - <75 years, ≥75 - <85 years, 
≥85 years), race, ethnicity, country, region (China, ROW), ECOG performance status at baseline, 
smoking status, EGFR mutation, ALK rearrangement, disease stage, brain metastasis, liver 
metastasis and location of distant metastases. 
ORR in the PD-L1 positive analysis set, DoR in the 
PD-L1 positive analysis set, PFS in the PD-L1 positive 
analysis set, lung cancer symptom scale measured by 
QLQ-LC13 and QLQ-C30 global health status/QoL 
scale in the PD-L1 positive analysis set. 
If positive, α=0.007; 
testing in the sequential order, 
until the 
first non-significant outcome 
occurs 


 
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Stratification factors including histology, line of therapy, and PD-L1 expression will be summarized 
in the ITT analysis set. 
Cancer associated symptoms at baseline will also be summarized by SOC, preferred term and 
CTCAE grade. 
6.3.4 Prior Anti-Cancer Systemic TherapiesRadiotherapy and Surgeries 
The number and percentage of patients with any prior anti-cancer systemic therapies, time from 
end of last therapy to study entry, type of prior anti-cancer systemic therapy and setting of prior 
anti-cancer systemic therapy will be summarized in the ITT analysis set.  
The number and percentage of patients with any prior anti-cancer radiotherapy, and time from end 
of last radiotherapy to study entry will be summarized in the ITT analysis set.  
The number and percentage of patients with any prior anti-cancer surgeries, intention of surgery 
and time from last surgery to study entry will be summarized in the ITT analysis set. 
6.3.5 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the version of World Health Organization 
Drug Dictionary (WHO DD) drug codes currently in effect at BeiGene at the time of database 
lock, and will be further classified to the appropriate Anatomical Therapeutic Chemical (ATC) 
code. 
The number and percentage of patients reporting prior and concomitant medications will be 
summarized respectively by ATC medication class and WHO DD preferred term (PT) in the safety 
analysis set. Prior medications will be defined as medications that received within 30 days before 
randomization and stopped before the first dose of study drug. Concomitant medications will be 
defined as medications that (1) started before the first dose of study drug and were continuing at 
the time of the first dose of study drug, or (2) started on or after the date of the first dose of study 
drug up to 30 days after the patient’s last dose (as of Safety Follow-up Visit). In addition, telephone 
contacts with patients should be conducted to assess irAEs and associated concomitant 
medications at 60 and 90 days (± 14 days) after the last dose of tislelizumab regardless of whether 
or not the patient starts a new anticancer therapy. 
6.3.6 Medical History 
Medical history will be coded using MedDRA version currently in effect at BeiGene at the time 
of database lock. The number and percentage of patients reporting a history of any medical 
condition, as recorded on the eCRF, will be summarized by System Organ Class (SOC) and 
Preferred Term (PT) in the ITT analysis set. 
6.4 
EFFICACY ANALYSIS 
If not specified otherwise, efficacy analyses described in this section will be based on the ITT 
analysis set and the PD-L1 positive analysis set, respectively.  


 
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6.4.1 Primary Efficacy Endpoints 
Overall Survival 
Overall Survival in the ITT Analysis Set: 
OS is defined as the time from randomization to death from any cause. Data for patients who are 
not reported as having died at the time of analysis will be censored at the date last known to be 
alive. Data for patients who do not have post-baseline information will be censored at the date of 
randomization. 
OS will be compared between tislelizumab (Arm A) and docetaxel (Arm B) in a stratified log-rank 
test using a significance level of 0.02 (one-sided). 
The null hypothesis to be tested is: 
H0: OS in Arm A = OS in Arm B 
against the alternative hypothesis: 
Ha: OS in Arm A ≠ OS in Arm B 
This will be the primary analysis once the targeted numbers of deaths are reached in the ITT 
analysis set. 
The p-value will be calculated from a stratified log-rank test at one-sided significance level α=0.02 
based on the stratification factors defined in Section 2 using the actual values from EDC (histology 
and line of therapy) and from central lab (PD-L1 expression). 
Kaplan-Meier method will be used to estimate median and other quartiles of OS along with its 
95% confidence interval (constructed using Brookmeyer and Crowley method). Kaplan-Meier 
survival probabilities for each arm will be plotted over time. Event free rate at selected timepoints 
will be estimated with 95% confidence interval using Greenwood formula. Follow-up time will be 
estimated by the reverse Kaplan-Meier method. 
The hazard ratio for OS between tislelizumab and docetaxel (HRA/B) will be estimated using a 
stratified Cox proportional hazard model with Efron’s method of tie handling, with treatment arm 
as a factor and stratified by the same stratification variables used for the stratified log-rank test. 
The 95% CI for the HR will be provided. Unstratified log-rank test and Cox regression model will 
also be performed to provide p-value, HR and corresponding 95% CI. 
In order to evaluate the robustness of the OS, several sensitivity analyses are planned. 
The sensitivity analysis 1 is the same as the primary analysis except that it will be based on the 
stratification factors using the values from Interactive Response Technology, by which patients 
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The sensitivity analysis 2 is the same as the primary analysis except that it will use Rank Preserving 
Structural Failure Time Model (RPSFTM) to adjust survival estimates in the presence of arm B 
patients receiving any subsequent immunotherapy after discontinuation of docetaxel.   
The sensitivity analysis 3 is the same as the primary analysis except that a patient will be censored 
at the date last known to be alive before his/her COVID-19 related drug administration protocol 
deviation. 
When there are over 10% ITT patients who had critical protocol deviations, the sensitivity analysis 
4 in the PP analysis set will be implemented in the same way as the primary analysis. 
Overall Survival in the PD-L1 Positive Analysis Set: 
The hypothesis testing of OS in the PD-L1 positive analysis set will be carried out at a significance 
level of 0.007. If the OS hypothesis in the ITT analysis set is rejected, its corresponding α will be 
shifted to the testing in the PD-L1 positive analysis set (ie, a total α of 0.025). Similar statistical 
methods as described above will be applied with histology and line of therapy as strata in the 
stratified analyses. 
Subgroup Analyses 
To determine if the treatment effect is consistent across various subgroups, the HR estimates of 
OS from an unstratified Cox model and its 95% CI will be estimated and plotted within each 
category of the following variables (a subgroup may not be analyzed if it includes <10% of the 
ITT analysis set): 
x PD-L1 expression in TC (≥25% TC versus <25% TC) 
x histology (squamous versus non-squamous) 
x line of therapy (2 versus 3) 
x age (<65 versus ≥65 years) 
x sex (female versus male) 
x ECOG PS (0 versus 1) 
x smoking status (never versus former/current) 
x race (Asian, White, Other) 
x region (China, Europe, Other) 
x brain metastasis at baseline (yes versus no)  


 
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x liver metastasis at baseline (yes versus no) 
x disease stage (locally advanced versus metastatic) 
x EGFR mutation at baseline (wild type versus unknown) 
x ALK rearrangement at baseline (wild type versus unknown) 
Forest plot of subgroup analysis in OS will be provided. Additional subgroup analysis may also 
be conducted per additional prognosis factors as suggested. Subgroup analysis of secondary 
endpoints may also be conducted. 
6.4.2 Secondary Efficacy Endpoints 
Objective Response Rate 
ORR is the proportion of patients who had a CR or PR as assessed by the investigator per 
RECIST v1.1 in the ITT and PD-L1 positive analysis set. Patients without any postbaseline 
assessment will be considered non-responders. Patients without measurable disease at baseline 
will also be considered as non-responders. The difference in ORR between arms will be 
evaluated using the Cochran-Mantel-Haenszel (CMH) chi-square test with the actual 
stratification factors as strata. The two-sided 95% CIs for the odds ratio and the difference in 
ORR will be calculated, as well as Clopper-Pearson 95% CIs for the ORR within each arm.  
In addition, the number and percentage of patients for each of the BOR categories will be 
presented.  
A waterfall plot of best percent change in sum of target lesion diameters from baseline will be 
provided by treatment arm. The patients in each arm will be ordered by the percentage, patients 
with the largest percentage will be presented on the right. 
Progression-Free Survival 
PFS is defined as the time from randomization to the first objectively documented disease 
progression as assessed by the investigator per RECIST v1.1 or death from any cause, whichever 
occurs first, in the ITT and PD-L1 positive analysis sets. The actual tumor assessment visit date 
will be used to calculate PFS. The PFS censoring rules are specified in Appendix 10.1. Similar 
methodology except for sensitivity analyses used to evaluate OS will be applied to analysis of 
PFS. 
Duration of Response 
DoR is defined for patients with an objective response as the time from the first documented 
objective response to documented disease progression as assessed by the investigator using 
RECIST v1.1, or death from any cause, whichever occurs first, in the ITT and PD-L1 positive 
analysis sets. Only the subset of patients who show a complete response or partial response will 


 
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be included in the DoR analysis. Data for patients who are alive and who have not experienced 
disease progression at the time of analysis will be censored at the date of the last tumor 
assessment. If no tumor assessments were performed after the date of the first occurrence of the 
objective response (CR or PR), DoR will be censored at the date of the first occurrence of the 
objective response. Median DoR and corresponding 95% CIs will be estimated using Kaplan-
Meier methodology for each treatment arm. Comparisons of DoR between treatment arms will 
be made using the log-rank test. 
Health-Related Quality of Life 
Analysis Method 
 
Descriptive statistics will be used for all HRQoL analyses. All HRQoL analyses will be in the 
HRQoL analysis set and/or the PD-L1 positive HRQoL analysis set, unless otherwise specified. 
Both EORTC QLQ-C30 and EORTC QLQ-LC13 instruments have been extensively tested for 
reliability and validity (Bergman et al, 1994; Osoba et al, 1994; Groenvold et al, 1997). 
A linear mixed-effect model for repeated measures (MMRM) will be used to compare between 
the 2 treatment arms. The model includes the repeated measures (including baseline) of the index 
scores of QLQ-C30 and LC13 and dyspnoea, coughing and pain in chest of LC13 as the 
dependent variables, and treatment arm, randomization stratification factors, intercept and slope 
of time as fixed effects. The random subject effects include subject random intercept and subject 
random slope of time. Interaction between treatment and time since randomization or quadratic 
term of time since randomization may be considered to be included in the final model if it is 
significant when it needs to be formally tested at the final analysis. They will be performed in the 
ITT analysis set and the PD-L1 positive analysis set, respectively. Between-group comparisons 
will be reported as differences with the 95% CI and p-value. 
In addition, changes from baseline in global health status/QoL of QLQ-C30 and the functional 
and symptom scales of QLQ-C30, QLQ-LC13 scales and EQ-5D-5L (descriptive scores and 
visual analog scales) will be summarized descriptively.  
Compliance  
 
Compliance for the EORTC QLQ-C30, EORTC QLQ-LC13 and EQ-5D-5L modules, defined as 
the proportion of questionnaires actual received out of the expected number (i.e, number of 
patients on treatment), in the HRQoL analysis set will be summarized for each assessment time 
point and treatment arm. 
 
Change from Baseline by Visit 
 
For each scale or item of EORTC QLQ-C30, EORTC QLQ-LC13 and EQ-5D-5L, summary 
statistics at each assessment time point and change from baseline will be presented by treatment 


 
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arm in tables. Boxplot depicting the mean scores over time of global health status/quality of life 
will be provided for each treatment arm.   
 
Details of HRQoL scoring are specified in Appendix 10.2according to the algorithm described 
in the EORTC QLQ-C30 and EORTC QLQ-LC13 scoring manual (Fayers 2001) and EQ5D-5L 
(https://euroqol.org/publications/user-guides/).  
 
Time to Deterioration (TTD) of HRQoL  
 
Time to deterioration (TTD) is defined as the time from randomization to first occurrence of a 
worsening score confirmed at the subsequent visit or death from any cause. The minimum 
important clinically meaningful difference change (e.g. worsening) in symptoms of QLQ-C30 
and QLQ-LC13 is defined as ≥10 points increase from baseline (Osoba et al 1998; King, 1996; 
Maringwa et al 2011). The clinically meaningful deterioration in function and global health 
status/quality of life is defined as ≥10 points decrease from baseline. The median TTD of QLQ-
C30 global health status/quality of life and index score of the QLQ-LC13 will be calculated 
using Kaplan-Meier estimates, and presented with 2-sided 95% CIs. 
EQ-5D-5L 
 
Five level response to EQ-5D-5L will be summarized as a categorical variable by tabulating 
frequency of each response category by visit. The self-rated health state scale at each visit and its 
change from baseline will be summarized in descriptive statistics (n, mean, standard deviation, 
median, minimum, maximum). 
6.4.3 Exploratory Efficacy Endpoints 
Disease Control Rate per the Investigator 
DCR is defined as the proportion of patients with objective response (CR or PR), Non-CR/Non-
PD, or stable disease maintained for ≥ 9 weeks (with allowable visit window) using RECIST 
v1.1. DCR per the investigator will be analyzed. Similar methodologies for analysis of ORR will 
be applied. 
Clinical Benefit Rate per the Investigator 
CBR is defined as the proportion of patients who have CR, PR, Non-CR/Non-PD and SD that is 
≥24 weeks in duration per RECIST v1.1. CBR per the investigator will be analyzed. Similar 
methodologies for analysis of ORR will be applied. 
Time to Response per the Investigator 
TTR per the investigator is defined for patients with an objective response as determined by the 
investigator as the time from randomization to the first occurrence of a CR or PR as assessed by 
the investigator using RECIST v1.1. Only the subset of patients who show a CR or PR will be 


 
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included in the TTR analysis. TTR will be summarized for descriptive purposes. The mean, SD, 
median, and range of TTR will be provided. 
Time to First Subsequent Anti-cancer Systemic Therapy (TFST) 
TFST is defined for patients with the use of subsequent anti-cancer systemic therapy as the time 
from end of study treatment to first dose of subsequent anti-cancer systemic therapy. The mean, 
SD, median, and range of TFST will be provided. 
Subsequent Anti-cancer Therapy 
Subsequent anti-cancer therapy will be summarized by percentage, category and preferred term 
(PT) in the ITT and PD-L1 positive analysis sets for each treatment arm. 
PD-L1 Expression as a Predictive Biomarker for Response 
Distribution of PD-L1 expression will be examined in the ITT analysis set. Association between 
PD-L1 expression (not restricted to the pre-specified cut off level of 25%) and tislelizumab 
treatment effect over docetaxel (OS, ORR, PFS, DoR, DCR, CBR) will be explored. Exploratory 
analyses may not be included in the CSR for this study. 
6.4.4 Efficacy Endpoints in China patients 
According to the feedback from Center for Drug Evaluation (CDE) of National Medical Products 
Administration (NMPA) to Protocol Amendment 3 on July 28, 2020, it was required that China 
patients to be used as primary efficacy analysis population for China supplementary Biologics 
License Application (sBLA) using the O’Brien-Fleming boundary defined in the original protocol, 
and ITT population as supporting analysis results. Therefore, analyses of efficacy endpoints such 
as OS, PFS, ORR and DoR in China patients will be performed as well. 
6.5 
SAFETY ANALYSES 
All safety analyses will be performed by treatment arm based on the safety analysis set. The 
incidence of treatment-emergent adverse events (TEAEs) and SAEs will be summarized. 
Laboratory test results, vital signs, ECG, ECOG and their changes from baseline will be 
summarized using descriptive statistics (e.g., n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum for continuous variables; n [%] for categorical variables). Abnormal values 
will be flagged. 
6.5.1 Extent of Exposure 
Extent of exposure to each study drug will be summarized descriptively by the following 
variables: 
x Number of treatment cycles  
x Duration of exposure (weeks) is defined as: 


 
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(date of last dose of study drug + 21 days – date of first dose of study drug)/7, with 
censored by death date and cutoff date, without censoring when calculating actual dose 
intensity.   
x Cumulative dose (mg for tislelizumab and mg/m2 for docetaxel): the sum of all actual 
dose of study drug, given from first to last administration 
x Actual dose intensity (ADI) (mg/cycle for tislelizumab and mg/m2/cycle for docetaxel) is 
defined as  
Cumulative dose (mg for tislelizumab and mg/m2 for docetaxel) received by a patient / 
Duration of exposure (cycles) 
x Relative dose intensity (RDI) in % is defined as: 
100 ×
ADI (mg/cycle for tislelizumab and mg/mଶ/cycle for docetaxel)
Planned Dose Intensity (mg/cycle for tislelizumab and mg/mଶ/cycle for docetaxel) 
where planned dose intensity of tislelizumab equals to 200 mg/cycle and planned dose 
intensity of docetaxel equals to 75 mg/m2/cycle.  
6.5.2 Adverse Events  
AEs will be graded by the investigators using CTCAE v4.03. The AE verbatim descriptions 
(investigator terms from the CRF) will be classified into standardized medical terminology using 
the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events will be coded to the 
MedDRA (Version 23.0 or higher) lower level term closest to the verbatim term. The linked 
MedDRA preferred term (PT) and primary system organ class (SOC) are also captured in the 
database. 
A treatment-emergent AE (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 either study drug up to 30 days 
following study drug discontinuation or initiation of new anticancer therapy, whichever occurs 
first. TEAE classification also applies to irAEs and drug-related SAEs recorded up to 90 days 
after discontinuation from tislelizumab, 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. 
An overview table of patients with at least one TEAE will be presented with the incidence of: 
x patients with any TEAEs 
x patients with any TEAEs with grade ≥ 3  
x patients with any serious TEAEs 


 
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x patients with any TEAEs leading to death  
x patients with any TEAEs leading to permanent treatment discontinuation 
x patients with any TEAEs leading to treatment modification  
x patients with any treatment-related TEAEs 
x patients with any treatment-related TEAEs and grade ≥ 3 
x patients with any treatment-related serious TEAEs 
x patients with any treatment-related TEAEs leading to death  
x patients with any treatment-related TEAEs leading to permanent treatment 
discontinuation 
x patients with any irAEs 
Treatment-related TEAEs include those events considered by the investigator to be related or with 
missing assessment of the causal relationship. For patients with multiple occurrences of the same 
event will be counted only once in the summary tables if otherwise specified, and the maximum 
grade per CTCAE v4.03 will be used. 
If the grade is missing for one of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences with the same preferred term of the same patient 
will be used. If the patient has no other TEAEs with the same preferred term, then impute as the 
maximal severity on all TEAEs with the same preferred term; if the severity is missing for all the 
occurrences, do not impute, a “missing” category will be added in the summary table. 
The incidence of following TEAEs will be reported by SOC and PT, sorted by decreasing 
frequency of the SOC and PT: 
x TEAEs by maximum grade 
x TEAEs with grade ≥ 3  
x Serious TEAEs 
x TEAEs leading to death 
x TEAEs leading to permanent treatment discontinuation 
x Treatment-related TEAEs 


 
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x Treatment-related TEAEs and grade ≥ 3 
x Treatment-related serious TEAEs 
x Treatment-related TEAEs leading to death 
All deaths and causes of death will be summarized by treatment arm, including those occurred 
during the study treatment period and those reported during the survival follow-up period after 
treatment discontinuation.  
Additionally, if exposure to treatment is very different between the two arms, exposure-adjusted 
event rate (EAER) per 100 person-months may be reported by treatment arm. The EAER per 100 
person-months is defined as 100 times the number of events divided by the total exposure time (in 
months) among patients included in the analysis. Patients with multiple occurrences of the event 
will be counted multiple times in the numerator. The exposure time is the treatment duration for 
all patients with/without the event. The total exposure time in months is calculated by dividing the 
sum of exposure time in days over all the patients included in the analysis by 30.4375. The EAER 
per 100 person-months is interpreted as the expected number of events per 100 person-months of 
exposure to the investigational products. 
TEAEs will also be summarized and presented for certain subgroups.  
6.5.3 Laboratory Values 
Descriptive summary statistics (n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables) for selected laboratory parameters 
described in Table 1 and their changes from baseline will be summarized by visit.  
Selected laboratory parameters that are graded in NCI-CTCAE v4.03 will be summarized by 
shift from baseline CTCAE grades to maximum post-baseline grades. In the summary of 
laboratory parameters by CTCAE grade, parameters with CTCAE grading in both high and low 
directions will be summarized separately. 
The patients who met Hy's Law by lab value will be summarized. 
Patient data listings of selected laboratory parameters will be provided. 
Table 1. Clinical Laboratory Tests 
 
Serum Chemistry  
Hematology  
Thyroid Function  
ALP 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase 
(AST)  
Total bilirubin 
Creatinine 
Hemoglobin 
White blood cell (WBC) count 
Neutrophil (Absolute)  
Lymphocytes (Absolute) 
Platelet count 
Free Triiodothyronine (FT3)  
Free Thyroxine (FT4) 
Thyroid Stimulating Hormone 
(TSH) 
 


 
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Potassium 
Sodium  
Calcium (corrected) 
Creatine kinase (CK) 
Creatine kinase-cardiac muscle 
isoenzyme (CK-MB)  
Lactate dehydrogenase 
Glucose  
 
6.5.4 Vital Signs 
Descriptive statistics for vital sign parameters (i.e., systolic and diastolic blood pressure, pulse 
rate, body temperature, and weight) and changes from baseline will be summarized by visit.   
6.5.5 Ophthalmologic Examination 
Ophthalmologic examination results (optical coherence test and equivalent exams 
normal/abnormal) will be summarized. 
6.5.6 Electrocardiograms (ECG) 
12-Lead ECG will be performed during baseline and multiple time post-baseline points (refer the 
time points to the protocol study assessments and procedures schedule). Overall evaluation and 
clinical significance will be summarized.  
6.5.7 ECOG 
A shift table from baseline to worst post-baseline in ECOG performance score will be summarized.  
6.6 
PHARMACOKINETIC ANALYSES 
PK samples will be collected only in patients randomized to receive tislelizumab. Tislelizumab 
post-dose and Ctrough (pre-dose) will be tabulated and summarized for each cycle at which these 
concentrations are collected. Descriptive statistics will include means, medians, ranges, standard 
deviations, coefficient of variation (CV%), geometric mean and geometric CV%, as appropriate. 
Additional PK analyses, including population PK analyses and exposure-response (efficacy, safety 
endpoints) analyses may be conducted as appropriate and the results from these analyses will be 
reported separately from the CSR. 
6.7 
IMMUNOGENIC ANALYSIS 
Human anti-drug antibodies (ADA) to tislelizumab will be assessed during the study as defined 
in the protocol.  
ADA attributes:  


 
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x Treatment boosted ADA is defined as ADA positive at baseline that was boosted to a 4-
fold or higher level following drug administration.  
x Treatment-induced ADA is defined as ADA negative at baseline and ADA positive post-
baseline.  
x Persistent ADA response is defined as Treatment-induced ADA detected at 2 or more 
time points during treatment or follow-up, where the first and last ADA positive samples 
are separated by 16 weeks or longer; or detected in the last time point.  
x Transient ADA response is defined as treatment-induced response that is not considered 
persistent.  
x 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-emergent ADA, which include both 
treatment-induced and treatment-boosted ADA-positive patients, as a proportion of the 
ADA evaluable population.  
x ADA prevalence is defined as proportion of all patients that are ADA positive, including 
pre-existing ADA, at any time point.  
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADA. The incidence of positive ADA and 
neutralizing ADA will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy, and safety may be evaluated if data allow. 
6.8 
OTHER EXPLORATORY ANALYSES 
Other potential predictive markers including but not limited to GEP, TMB, and tumor-infiltrating 
immune cells will be assessed and presented in a separate report.  
6.9 
ANALYSES TO EVALUATE COVID-19 IMPACT 
Summary of COVID-19 impact will be presented as tables or listings for patient disposition, 
protocol deviations, sensitivity analysis of OS, tumor assessment, AEs and laboratory 
parameters. 
7 
INTERIM ANALYSIS 
There will be one interim analysis of OS performed in the ITT analysis set. The interim analysis 
will be performed when approximately 426 deaths (76% of the target number of 560 deaths) 
among the 2 treatment arms are observed in the ITT analysis set. It is estimated that it will take 


 
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approximately 23.1 months to observe 426 events. The final analysis of OS will take place after 
560 deaths are observed in the ITT analysis set and 207 deaths are observed in its subgroup of 
patients with PD-L1 positive tumors. Thus, the predefined number of deaths in the ITT analysis 
set will trigger the interim and final analyses. The information fraction used in α spending 
function will be based on the observed number of deaths in the ITT analysis set at the 
corresponding time points. A Hwang-Shih-DeCani spending function with γ parameter of -2 will 
be used in setting up the upper (efficacy) boundary. Stopping boundaries (p-value and Z score) 
of superiority test for OS at the interim and final analyses in the ITT analysis set, as well as OS 
at the final analysis in the PD-L1 positive analysis set are shown in Table 2. The boundaries for 
hypothesis testing in OS will be updated according to the actual numbers of death events in the 
interim and final analyses, using the pre-specified α spending function. 
Table 2. Stopping Boundaries (p-value and Z score) and Approximate HR Threshold of 
Interim and Final Analyses of OS 
 
Time 
(months) 
# 
Deaths 
p-value 
(Z score) for 
Efficacy 
Approximate 
HR Threshold 
for Efficacy 
Interim analysis in ITT 
23.1 
426 
<0.0112 (>2.28) 
<0.791 
Final analysis in ITT 
31.0 
560 
<0.0153 (>2.16) 
<0.824 
Final analysis in PD-L1 positive 31.0 
207 
<0.007 (>2.46) 
<0.696 
Abbreviations: HR = hazard ratio; ITT = intent-to-treat (analysis set); PD-L1 – programmed cell 
death protein ligand 1 
 
Additionally, as required by CDE, at the time of interim analysis in the ITT, the analysis of OS 
among China patients will be performed as well. The upper (efficacy) boundary is based on 
O’Brien-Fleming boundary approximated by Hwang-Shih-DeCani spending function with γ 
parameter set at -4. Stopping boundaries (p-value and Z score) of superiority test for OS at the 
interim and final analyses are shown in the table below as reference to facilitate the review of 
CDE. Meanwhile, the boundaries presented in the table below will be updated from the actual 
death events observed at the time of the interim analysis and final planned number of deaths in 
China patients, using the spending function. 
 
Time 
(months) 
# 
Deaths 
p-value 
(Z score) for 
Efficacy 
Approximate 
HR Threshold 
for Efficacy 
Interim analysis in China 
patients 
23.1 
372 
<0.0088 (>2.37) 
<0.770 
Final analysis in China 
patients 
31.0 
465 
<0.0176 (>2.11) 
<0.813 
Final analysis in PD-L1 
positive China patients 
31.0 
172 
<0.007 (>2.46) 
<0.672 
Abbreviations: HR = hazard ratio; PD-L1 – programmed cell death protein ligand 1 
 
 


 
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8 
CHANGES IN THE PLANNED ANALYSIS 
Not applicable.  
9 
REFERENCES 
Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M (1994) The EORTC QLQ-LC13: a 
modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung 
cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 30A: 635–642. 
Brookmeyer R, Crowley J. A Confidence interval for the median survival time. Biometrics. 1982; 
38: 29-41. 
Clopper, C. and Pearson, ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial, Biometrika 1934; 26: 404-413.  
Collett D. Modelling survival data in medical research. New York: Chapman & Hall; 1994.  
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, May 28, 2009. 
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. 
Fayers PM, Aaronson NK, Bjordal K,Groenvold M, Curran D, Bottomley A, on behalf of the 
EORTC Quality of Life Group. Brussels: EORTC, EORTC QLQ-C30 Scoring Manual (3rd 
edition). 2001. ISBN: 2-9300 64-22-6. 
Food and Drug Administration Center for Drug Evaluation Research CDER and Center for 
Biologics Evaluation and Research. FDA Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, 2007. 
Greenwood M. “The natural duration of cancer”. Reports on Public Health and Medical Patients 
(London: Her Majesty’s Stationery Office). 1926; 33:1-26. 
Groenvold M, Klee MC, Sprangers MA, Aaronson NK (1997) Validation of the EORTC QLQ-
C30 quality of life questionnaire through combined qualitative and quantitative assessment of 
patient-observer agreement. J Clin Epidemiol 50: 441–450. 
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.  
Washington, DC: United States Food and Drug Administration; 2007. 
Kaplan E, Meier P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc. 
1958; 53:457-81. 


 
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King MT. The interpretation of scores from the EORTC quality of life questionnaire QLQ-C30. 
Qual Life Res 1996; 5: 555–567. 
Maringwa J, Quinten C, King M, et al. Minimal clinically meaningful differences for the 
EORTC QLQ-C30 and EORTC QLQ-BN20 scales in brain cancer patients. Annals of Oncology 
2011; 22: 2107–2112. 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J (1998) Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 16: 139–144. 
Osoba D, Zee B, Pater J, Warr D, Kaizer L, Latreille J (1994) Psychometric properties and 
responsiveness of the EORTC quality of Life Questionnaire (QLQ-C30) in patients with breast, 
ovarian and lung cancer. Qual Life Res 3: 353–364. 
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Commun Stat-Theor M 1991;20(8):2609-31. 


 
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10  APPENDIX 
10.1 PFS CENSORING RULES 
Definition of Progression Date: Progression date is assigned to the first time when tumor 
progression was documented. 
The PFS derivation rules in this SAP follow the Table C1 and C2 described in Appendix C of Food 
and Drug Administration (FDA) “Guidance for Industry Clinical Trial Endpoints for the Approval 
of Non-Small Cell Lung Cancer Drugs and Biologics (2015)”, which includes documented 
progression only.  
Censoring rules for primary analysis of PFS are summarized in Table 3.  
Table 3.  Censoring Rules for Primary Analysis of PFS Per RECIST version 1.1 
No. 
Situation 
Primary Analysis 
1 
Incomplete or no baseline 
tumor assessments 
Censored at randomization date  
2 
No postbaseline tumor 
assessment and no death 
Censored at randomization date 
3 
No postbaseline tumor 
assessment and death 
Died at date of death  
4 
Progression documented 
between scheduled visits 
Progressed at date of documented progression  
5 
No progression    
Censored at date of last adequate tumor assessment with no documented 
progression 
6 
New anticancer treatment 
started 
Censored at date of last adequate tumor assessment before date of new 
anticancer treatment 
7 
Death between adequate 
assessment visits 
Died at date of death 
8 
Death or progression after  ≥2  
missed visit 
Censored at date of last adequate tumor assessment prior to the ≥2 missed 
tumor assessments 
 
10.2 HEALTH RELATED QUALITY OF LIFE 
EORTC QLQ-C30 measures HRQoL of general cancer and includes two items that measure 
Global health status and quality of life (Global health status/QoL). The instrument is also 
consisted of two Functional Scales and Symptom Scales/ Items. Functional scales are Physical (2 
items), Role (2 items), Emotional (4 items), Cognitive (2 items) and Social (2 items) functioning. 
Symptom scales are Fatigue (3 items), Nausea (2 items), Pain (2 items) symptoms. The single-
items measuring symptoms include Dyspnoea, Insomnia, Appetite loss, Constipation, Diarrhoea 
and Financial Difficulties. 


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


 
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The Index scores 
To calculate QlQ-C30 index-score, individual functioning scale are subtracted by 100 to 
convert them into having the same meaning as symptom/problem scales. These 6 
subtracted scores are subsequently summed with the 9 symptom/problem scales, and then 
divided by 15 (the total number of QLQ-C30 scales).  A higher C30 index-score reflects a 
worse overall HRQOL. This is the mathematical formula: 
 
QlQ- C30 index score =  ∑[(100 -  Physical functioning score), (100 -  Role functioning 
score ), (100 -  Emotional functioning score),  (100 -  Cognitive 
functioning score), (100 -  Social functioning score) , (100 -  global QOL 
score),  Fatigue score, Nausea/vomiting score , Pain score,  Dyspnoea 
score,  Insomnia score,  Appetite loss score,  Constipation score, Diarrhea 
score, Financial Difficulty score] ÷ 15 
LC13 index-score is defined as the sum of all 10 QLQ-LC13 symptom/problem scales 
divided by 10 (the total number of QLQ-LC13 scales). A higher LC13 index-score 
reflects a worse overall HRQOL. This is the mathematical formula: 
 
LC13 index score = Σ (scores of Dyspnoea, Coughing, Haemoptysis, Sore mouth, 
Dysphagia, Peripheral neuropathy, Alopecia, Pain in chest, Pain in arm or 
shoulder, Pain in other parts) ÷ 10   
Table 4 Scoring of QLQ-C30 
 
Scale 
Number 
of items 
Item 
range 
Item 
Numbers 
Global health status/ QoL 
 Global health status/QOL 
QL2 
2 
6 
29,30 
Functional Scales 
 
 
 
 
Physical functioning  
PF2 
5 
3 
1, 2, 3, 4, 5  
Linear transformation 
Apply the linear transfonnation to 0-100 to obtain the score S 
Functional scales: 
S = 1 1- (RS - l x 100 
range I 
Symptom sea.Jes / items: 
S =~RS -1 Vrange }x 100 
Global health status / QoL: S = { RS -1 Vnmge}x 100 


 
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Role functioning  
RF2 
2 
3 
6, 7  
Emotional functioning  
EF 
4 
3 
21, 22, 23, 24  
Cognitive functioning  
CF 
2 
3 
20, 25  
Social functioning  
SF 
2 
3 
26, 27  
Symptom Scales/ items 
 
 
 
 
Fatigue 
FA 
3 
3 
10, 12, 18 
Nausea and vomiting 
NV 
2 
3 
14, 15 
Pain 
PA 
2 
3 
9, 19 
Dyspnoea 
DY 
1 
3 
8 
Insomnia 
SL 
1 
3 
11 
Appetite loss 
AP 
1 
3 
13 
Constipation 
CO 
1 
3 
16 
Diarrhoea 
DI 
1 
3 
17 
Financial Difficulties 
FI 
1 
3 
28 
 
 
Table 5 Scoring of QLQ-LC13 
 
Scale 
Number 
of items 
Item 
range 
Item 
Numbers 
Symptom scales/items 
 
 
 
 
Dyspnoea 
LCDY 
3 
3 
3,4,5 
Coughing  
LCCO 
1 
3 
1 
Haemoptysis 
LCHA 
1 
3 
2 
Sore mouth 
LCSM 
1 
3 
6 
Dysphagia 
LCDS 
1 
3 
7 
Peripheral neuropathy 
LCPN 
1 
3 
8 


 
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Alopecia 
LCHR 
1 
3 
9 
Pain in chest 
LCPC 
1 
3 
10 
Pain in arm or shoulder 
LCPA 
1 
3 
11 
Pain in other parts 
LCPO 
1 
3 
12 
 
 
 


 
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EQ5d-5L: for the 5 level Dementions, scores on a 5-point likert scale of 1 to 5, with level 1 
indicating no problem and level 5 indicating extreme problems. 
VAS includes a scale of 0 to 100 with higher scores indicating better health status.   
 
Table 6 Scoring of Eq5D-5L 
MOBILITY 
I have no problems in walking about  
 
 
 
 
I have slight problems in walking about  
 
 
 
 
I have moderate problems in walking about   
 
 
 
I have severe problems in walking about  
 
 
 
 
I am unable to walk about  
 
 
 
 
 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
 
 
I have slight problems washing or dressing myself   
 
 
I have moderate problems washing or dressing myself  
 
 
I have severe problems washing or dressing myself   
 
 
I am unable to wash or dress myself  
 
 
 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities  
 
 
 
I have slight problems doing my usual activities  
 
 
 
I have moderate problems doing my usual activities  
 
 
I have severe problems doing my usual activities  
 
 
 
I am unable to do my usual activities  
 
 
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
 
I have slight pain or discomfort  
 
 
 
 
 
I have moderate pain or discomfort   
 
 
 
 
I have severe pain or discomfort  
 
 
 
 
 
I have extreme pain or discomfort  
 
 
 
 
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
 
I am slightly anxious or depressed  
 
 
 
 
 
I am moderately anxious or depressed  
 
 
 
 
I am severely anxious or depressed   
 
 
 
 
I am extremely anxious or depressed  
 
 
 
 
• • • • • 
• • • • • 
• • • • • 
• • • • • 
• • • • • 


 
BeiGene, Ltd.  
 BGB-A317-303 
                  (Statistical Analysis Plan) 
 
 
Version 1.0:  10/16/2020 
Page 37 of 37  
CONFIDENTIAL 
 
 
 
 
• We wm.1ld like to kJnow how good or bad your health is TODAY_ 
• 
Tu i,s scale is numbered from o to 1 oo_ 
• 
1100 means the Dest health you can imagine_ 
o means th.e worst healltlh you can imagine_ 
• 
Mm1k. an X on the scal'e to indlicate lhowyour health iiS TODAY_ 
• 
Now, pl'ease wriitethe number you ,marked on the scal'e in the box 
below_ 
YOURHEALTlHTODAY = D 
The bes lheallfl 
you can imagine 
T 
+ 
+ 
+ i T 
-+-i 
T t 
mo 
95 
90 
85 
80 
75 
70 
65 
60 
55 
80 
45 
40 
35 
30 
25 
20 
ts 
5 
0 
Th e worot Ilea ti 
you earn umagirne