A Randomized Phase 3 Study of Tislelizumab in Combination With Sitravatinib in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer That Progressed on or After Platinum-Based Chemotherapy and Anti-PD-(L)1 Antibody
Phase: PHASE3
Conditions: Non-Small Cell Lung Cancer (NSCLC)
Sponsor: BeiGene

BGB-A317-Sitravatinib-301 
BeiGene 
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CLINICAL STUDY PROTOCOL 
TITLE PAGE  
Protocol Title:  
A Randomized Phase 3 Study of Tislelizumab in 
Combination With Sitravatinib in Patients With 
Locally Advanced or Metastatic Non-Small Cell Lung 
Cancer That Progressed on or After Platinum-Based 
Chemotherapy and Anti-PD-(L)1 Antibody 
Protocol Identifier: 
BGB-A317-Sitravatinib-301 
Phase: 
3 
Investigational Product(s): 
Tislelizumab (BGB-A317) and Sitravatinib 
(BGB-9468) 
Indication: 
Locally Advanced or Metastatic Non-Small Cell Lung 
Cancer 
EudraCT Number: 
2022-001779-15 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
1840 Gateway Drive 
3rd Floor 
San Mateo, CA 94404, USA 
 
Sponsor Medical Monitor: 
 
 
 
 
Original Protocol Version 0.0: 
04 February 2021 
Protocol Amendment Version 1.0: 
03 November 2021 
Protocol Amendment Version 2.0: 
20 May 2022 
Protocol Amendment Version 3.0: 
09 August 2022 
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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INVESTIGATOR SIGNATURE PAGE  
Protocol Title: 
A Randomized Phase 3 Study of Tislelizumab in Combination With 
Sitravatinib in Patients With Locally Advanced or Metastatic Non-Small 
Cell Lung Cancer That Progressed on or After Platinum-Based 
Chemotherapy and Anti-PD-(L)1 Antibody 
Protocol Identifier: BGB-A317-Sitravatinib-301 
This protocol is a confidential communication of BeiGene, Ltd., and its subsidiaries. I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol and the 
terms of the clinical study agreement governing the study. I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd., or one of its subsidiaries. 
Instructions for Investigator: Please SIGN and DATE this signature page before implementation 
of this sponsor-approved protocol. PRINT your name, title, and the name of the center in which the 
study will be conducted.  
I have read this protocol in its entirety and agree to conduct the study accordingly: 
Signature of Investigator: _______________________________ 
Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: _______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
 FINAL PROTOCOL APPROVAL SHEET ...................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................12 
SYNOPSIS ....................................................................................................................................13 
LIST OF ABBREVIATIONS AND TERMS ................................................................................21 
1. 
INTRODUCTION ......................................................................................................23 
1.1. 
Background Information on Non-Small Cell Lung Cancer ........................................23 
1.2. 
Current Treatment of Non-Small Cell Lung Cancer and Unmet Clinical 
Needs ..........................................................................................................................26 
1.3. 
Antibody Therapy for Non-Small Cell Lung Cancer .................................................27 
1.4. 
Background Information on Tislelizumab ..................................................................27 
1.4.1. 
Pharmacology .............................................................................................................27 
1.4.2. 
Toxicology ..................................................................................................................27 
1.4.3. 
Clinical Pharmacology ................................................................................................28 
1.4.4. 
Prior Clinical Experience of Tislelizumab .................................................................28 
1.4.4.1. 
Safety Assessment of Monotherapy Studies ...............................................................28 
1.4.4.2. 
Efficacy Assessment of Tislelizumab .........................................................................31 
1.5. 
Background Information on Sitravatinib ....................................................................33 
1.5.1. 
Pharmacology .............................................................................................................33 
1.5.2. 
Toxicology ..................................................................................................................34 
1.5.3. 
Clinical Pharmacology ................................................................................................35 
1.5.4. 
Clinical Experience With Sitravatinib ........................................................................36 
1.5.4.1. 
Safety Assessment of Monotherapy Study .................................................................36 
1.5.4.2. 
Safety Assessment of Combination Study ..................................................................37 
1.5.4.3. 
Efficacy Assessment of Sitravatinib Monotherapy ....................................................40 
1.5.4.4. 
Efficacy Assessment of Sitravatinib Combination with PD-1 Blocking Agent .........41 
1.6. 
Study Rationales .........................................................................................................42 
1.6.1. 
Rationale for Tislelizumab in the Treatment of Non-Small Cell Lung Cancer ..........42 
1.6.2. 
Rationale for Selection of Tislelizumab Dose ............................................................42 
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1.6.3. 
Rationale for Selection of Sitravatinib Dose ..............................................................43 
1.6.4. 
Rationale for Dose Selection of Sitravatinib and Tislelizumab in 
Combination Treatment ..............................................................................................44 
1.6.5. 
Rationale for Docetaxel as the Comparator ................................................................45 
1.6.6. 
Rationale for Combination of Tislelizumab and Sitravatinib in the Treatment 
of Non-Small Cell Lung Cancer .................................................................................45 
1.7. 
Benefit-Risk Assessment ............................................................................................46 
1.8. 
Study Conduct ............................................................................................................47 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................48 
2.1. 
Study Objectives .........................................................................................................48 
2.1.1. 
Primary Objective .......................................................................................................48 
2.1.2. 
Secondary Objectives .................................................................................................48 
2.1.3. 
Exploratory Objectives ...............................................................................................48 
2.2. 
Study Endpoints ..........................................................................................................49 
2.2.1. 
Primary Endpoint ........................................................................................................49 
2.2.2. 
Secondary Endpoints ..................................................................................................49 
2.2.3. 
Exploratory Endpoints ................................................................................................49 
3. 
STUDY DESIGN .......................................................................................................51 
3.1. 
Summary of Study Design ..........................................................................................51 
3.2. 
Screening Period .........................................................................................................53 
3.3. 
Treatment Period ........................................................................................................53 
3.4. 
End of Treatment/Safety Follow-up ...........................................................................55 
3.5. 
Survival Follow-up .....................................................................................................56 
3.6. 
Discontinuation From the Study Treatment or From the Study .................................56 
3.6.1. 
Patient Discontinuation From Study Treatment .........................................................56 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........56 
3.7. 
End of Study ...............................................................................................................57 
4. 
STUDY POPULATION .............................................................................................58 
4.1. 
Inclusion Criteria ........................................................................................................58 
4.2. 
Exclusion Criteria .......................................................................................................60 
5. 
STUDY TREATMENT ..............................................................................................65 
5.1. 
Formulation, Packaging, and Handling ......................................................................65 
5.1.1. 
Tislelizumab ...............................................................................................................65 
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5.1.2. 
Sitravatinib ..................................................................................................................65 
5.1.3. 
Docetaxel ....................................................................................................................65 
5.2. 
Dosage, Administration, and Compliance ..................................................................65 
5.2.1. 
Tislelizumab ...............................................................................................................66 
5.2.2. 
Sitravatinib ..................................................................................................................67 
5.2.3. 
Docetaxel ....................................................................................................................67 
5.3. 
Overdose .....................................................................................................................67 
5.3.1. 
Tislelizumab ...............................................................................................................67 
5.3.2. 
Sitravatinib ..................................................................................................................67 
5.3.3. 
Docetaxel ....................................................................................................................68 
5.4. 
Study Drug Accountability .........................................................................................68 
5.5. 
Dose Delay or Modification .......................................................................................68 
5.5.1. 
Dose Delay or Modification for Tislelizumab and/or Sitravatinib .............................69 
5.5.2. 
Dose Delay, Interruption or Modifications for Docetaxel ..........................................70 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................72 
6.1. 
Prior Therapy ..............................................................................................................72 
6.2. 
Concomitant Therapy .................................................................................................72 
6.2.1. 
Permitted Concomitant Medications/Procedures .......................................................72 
6.2.1.1. 
Systemic Corticosteroids ............................................................................................72 
6.2.1.2. 
Hepatitis B Treatment .................................................................................................72 
6.2.1.3. 
Radiation Therapy ......................................................................................................73 
6.2.2. 
Prohibited Concomitant Medications/Procedures ......................................................73 
6.2.3. 
Restricted Concomitant Medications/Procedures .......................................................73 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................74 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................76 
7.1. 
Screening ....................................................................................................................76 
7.1.1. 
Informed Consent and Screening Log ........................................................................76 
7.1.2. 
Patient Numbering ......................................................................................................76 
7.2. 
Enrollment ..................................................................................................................77 
7.2.1. 
Confirmation of Eligibility .........................................................................................77 
7.2.2. 
Randomization ............................................................................................................77 
7.3. 
Tislelizumab, Sitravatinib, and Docetaxel Dispensation ............................................77 
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7.4. 
Safety Assessments .....................................................................................................77 
7.4.1. 
Vital Signs ..................................................................................................................77 
7.4.2. 
Physical Examinations ................................................................................................77 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status ........................................78 
7.4.4. 
Laboratory Safety Tests ..............................................................................................78 
7.4.4.1. 
Cardiac Enzyme Monitoring .......................................................................................78 
7.4.5. 
Electrocardiograms .....................................................................................................79 
7.4.6. 
Multigated Acquisition Scans or Echocardiograms ...................................................79 
7.4.7. 
Adverse Events ...........................................................................................................79 
7.4.8. 
Hepatitis B, Hepatitis C, and HIV Testing .................................................................79 
7.5. 
Tumor and Response Evaluations ..............................................................................79 
7.6. 
Pharmacokinetic and Antidrug Antibody Testing ......................................................82 
7.7. 
Biomarkers ..................................................................................................................82 
7.7.1. 
Tissue Biomarkers ......................................................................................................82 
7.7.2. 
Blood Biomarkers .......................................................................................................83 
7.8. 
Patient-Reported Outcomes ........................................................................................83 
7.9. 
Visit Windows ............................................................................................................84 
7.10. 
Unscheduled Visits .....................................................................................................84 
8. 
SAFETY MONITORING AND REPORTING .........................................................85 
8.1. 
Risks Associated With Study Drug ............................................................................85 
8.1.1. 
Risks Associated With Tislelizumab and Sitravatinib ................................................85 
8.1.2. 
Risks Associated with Docetaxel ................................................................................85 
8.2. 
General Plan to Manage Safety Concerns ..................................................................86 
8.2.1. 
Eligibility Criteria .......................................................................................................86 
8.2.2. 
Safety Monitoring Plan ...............................................................................................86 
8.3. 
Adverse Events ...........................................................................................................87 
8.3.1. 
Definitions and Reporting ...........................................................................................87 
8.3.2. 
Assessment of Severity ...............................................................................................87 
8.3.3. 
Assessment of Causality .............................................................................................88 
8.3.4. 
Follow-up of Adverse Events .....................................................................................89 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................89 
8.4. 
Definition of a Serious Adverse Event .......................................................................90 
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8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................90 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................91 
8.6.1. 
Adverse Event Recording Period ................................................................................91 
8.6.2. 
Reporting Serious Adverse Events .............................................................................91 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................91 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................92 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................92 
8.6.3. 
Eliciting Adverse Events ............................................................................................93 
8.6.4. 
Disease Progression ....................................................................................................93 
8.6.5. 
Deaths .........................................................................................................................93 
8.6.6. 
Pregnancies .................................................................................................................93 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................94 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................94 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................94 
8.7. 
Management of Adverse Events Potentially Associated With Either or Both 
of Sitravatinib and Tislelizumab .................................................................................94 
8.8. 
Management of Adverse Events of Special Interest of Tislelizumab .........................95 
8.8.1. 
Managing Infusion-Related Reactions .......................................................................95 
8.8.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................97 
8.8.3. 
Immune-Mediated Adverse Events ............................................................................97 
8.9. 
Management of Sitravatinib-specific Adverse Events ...............................................98 
8.9.1. 
Management of Non-Hematological Toxicities of Sitravatinib .................................98 
8.9.2. 
Management of Hematological Toxicities of Sitravatinib ..........................................99 
8.9.3. 
Dose Modification Guidelines for Sitravatinib-Specific AEs ....................................99 
8.9.3.1. 
Management of Hy’s Law Cases ..............................................................................101 
8.9.4. 
Hypertension .............................................................................................................101 
8.9.5. 
Palmar-Plantar Erythrodysesthesia ...........................................................................101 
8.9.6. 
Diarrhea ....................................................................................................................101 
8.9.7. 
Hemorrhagic Events .................................................................................................102 
8.9.8. 
Thrombotic Events ....................................................................................................102 
8.9.9. 
Thyroid Dysfunction Other Than Immune-Mediated ...............................................102 
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8.9.10. 
Decreased Left Ventricular Ejection Fraction ..........................................................102 
8.9.11. 
Proteinuria .................................................................................................................102 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ...............103 
9.1. 
Statistical Analysis ....................................................................................................103 
9.1.1. 
Randomization Methods ...........................................................................................103 
9.1.2. 
Analysis Sets .............................................................................................................103 
9.1.3. 
Multiplicity ...............................................................................................................103 
9.1.4. 
Patient Disposition ....................................................................................................104 
9.1.5. 
Demographic and Other Baseline Characteristics ....................................................104 
9.1.6. 
Prior and Concomitant Medications .........................................................................104 
9.2. 
Efficacy Analyses .....................................................................................................104 
9.2.1. 
Primary Efficacy Analysis ........................................................................................105 
9.2.1.1. 
Overall Survival ........................................................................................................105 
9.2.1.2. 
Progression-free Survival by Independent Review Committee ................................105 
9.2.1.3. 
Sensitivity Analyses for the Primary Endpoints .......................................................106 
9.2.2. 
Secondary Efficacy Analysis ....................................................................................106 
9.2.3. 
Exploratory Efficacy Analysis ..................................................................................107 
9.3. 
Safety Analyses ........................................................................................................107 
9.3.1. 
Extent of Exposure ...................................................................................................107 
9.3.2. 
Adverse Events .........................................................................................................107 
9.3.3. 
Laboratory Analyses .................................................................................................108 
9.3.4. 
Vital Signs ................................................................................................................108 
9.4. 
Pharmacokinetic Analysis ........................................................................................108 
9.5. 
Immunogenicity Analyses ........................................................................................109 
9.6. 
Other Exploratory Analyses .....................................................................................109 
9.6.1. 
Exploratory biomarker analyses ...............................................................................109 
9.7. 
Sample Size Consideration .......................................................................................109 
9.8. 
Interim Analyses .......................................................................................................110 
10. 
STUDY COMMITTEES AND COMMUNICATION ............................................111 
10.1. 
Independent Review Committee ...............................................................................111 
10.2. 
Independent Data Monitoring Committee ................................................................111 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .............................................................................................112 
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11.1. 
Access to Information for Monitoring ......................................................................112 
11.2. 
Access to Information for Auditing or Inspections ..................................................112 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................113 
12.1. 
Regulatory Authority Approval ................................................................................113 
12.2. 
Quality Assurance .....................................................................................................113 
12.3. 
Study Center Inspections ..........................................................................................113 
12.4. 
Drug Accountability .................................................................................................113 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ................................................115 
13.1. 
Ethical Standard ........................................................................................................115 
13.2. 
Institutional Review Board/Independent Ethics Committee ....................................115 
13.2.1. 
Protocol Amendments ..............................................................................................115 
13.3. 
Informed Consent .....................................................................................................116 
13.4. 
Patient and Data Confidentiality ...............................................................................116 
13.5. 
Financial Disclosure .................................................................................................118 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................119 
14.1. 
Data Collection and Management Responsibilities ..................................................119 
14.1.1. 
Data Entry in the Electronic Case Report Form .......................................................119 
14.1.2. 
Data Collection .........................................................................................................119 
14.1.3. 
Data Management/Coding ........................................................................................119 
14.2. 
Data Integrity and In-house Blinding .......................................................................120 
14.3. 
Study Records Retention ..........................................................................................120 
14.4. 
Protocol Deviations ..................................................................................................121 
14.5. 
Study Report and Publications..................................................................................121 
14.6. 
Study and Study Center Closure ...............................................................................122 
14.7. 
Information Disclosure and Inventions ....................................................................122 
15. 
REFERENCES .........................................................................................................124 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................130 
APPENDIX 2. SCHEDULE OF PHARMACOKINETICS/ ANTIDRUG ANTIBODY 
ASSESSMENTS.......................................................................................................135 
APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS ..............................................137 
APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .....................................................................................138 
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APPENDIX 5. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................139 
APPENDIX 6. PREEXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................149 
APPENDIX 7. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................150 
APPENDIX 8. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................151 
APPENDIX 9. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................166 
APPENDIX 10. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................167 
APPENDIX 11. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR USED 
WITH CAUTION DURING TREATMENT WITH STUDY DRUGS ...................169 
APPENDIX 12. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE QLQ-C30 .................................................................................172 
APPENDIX 13. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE QUESTIONNAIRE 
LUNG CANCER QLQ-LC13 ..................................................................................174 
APPENDIX 14. THE 5-LEVEL VERSION OF EUROPEAN QUALITY OF LIFE 
5DIMENSIONAL QUESTIONNAIRE ...................................................................175 
LIST OF TABLES  
Table 1: 
Summary of Treatment-Emergent, Treatment-Related Adverse Events 
(≥ 10%) by Preferred Term for Study 516-001 ........................................................36 
Table 2: 
Summary of Treatment-Emergent, Treatment-Related Adverse Events 
(≥ 10%) by Preferred Term for Study MRTX-500 ...................................................38 
Table 3: 
Summary of Treatment-Emergent, Treatment-Related AEs (≥ 10%) by 
Preferred Term for Study BGB-900-103 ....................................................................40 
Table 4: 
Selection and Timing of Dose for Each Patient ..........................................................66 
Table 5: 
Sitravatinib Dose Reductions .....................................................................................69 
Table 6: 
Guidelines for Docetaxel Dose Modifications ...........................................................70 
Table 7: 
Guidelines for Management of Hepatotoxicity in Patients Receiving 
Docetaxel ....................................................................................................................71 
Table 8: 
A Summary of the Commonly Reported Toxicities of Docetaxel .............................85 
Table 9: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Arms ....................................................................................................91 
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Table 10: Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................92 
Table 11: Treatment Modifications for Symptoms of Infusion-Related Reactions Due 
to Tislelizumab ...........................................................................................................96 
Table 12: Examples of Immune-Mediated Adverse Events .......................................................98 
Table 13: Sitravatinib Dose Modifications – Non-Hematological Drug-Related 
Toxicities ....................................................................................................................99 
Table 14: Sitravatinib Dose Modification for Increased Blood Pressure .................................100 
Table 15: Sitravatinib Dose Modification for Increased Hepatic Transaminase ......................100 
Table 16: Sitravatinib Dose Modification for Palmar-Plantar Erythrodysesthesia ..................100 
Table 17: Stopping Boundaries (in p-value and z-score) of Primary Analysis of  
Progression-Free Survival and Overall Survival ......................................................110 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................52 
Figure 2: 
Type 1 Error Reallocation Strategy Following Graphical Approach .......................104 
 
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SYNOPSIS  
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Product: Tislelizumab (BGB-A317) and Sitravatinib (BGB-9468) 
Title of Study: A Randomized Phase 3 Study of Tislelizumab in Combination With Sitravatinib in 
Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer That Progressed on or 
After Platinum-Based Chemotherapy and Anti-PD-(L)1 Antibody 
Protocol Identifier: BGB-A317-Sitravatinib-301 
Phase of Development: 3 
Number of Patients: Approximately 420 
Study Centers: Approximately 100 centers globally 
Study Objectives: 
Primary: 
• 
To compare the overall survival (OS) of tislelizumab and sitravatinib combination therapy with 
that of docetaxel monotherapy  
• 
To compare the progression-free survival (PFS) of tislelizumab and sitravatinib combination 
therapy with that of docetaxel monotherapy, as assessed by the Independent Review 
Committee (IRC)  
Secondary: 
• 
To compare the PFS of tislelizumab and sitravatinib combination therapy with that of 
docetaxel monotherapy, as assessed by the investigator  
• 
To compare the overall response rate (ORR), duration of response (DOR), and disease control 
rate (DCR) of tislelizumab and sitravatinib combination therapy with that of docetaxel 
monotherapy, as assessed by the IRC  
• 
To evaluate the safety and tolerability of tislelizumab and sitravatinib combination therapy 
compared with that of docetaxel monotherapy 
• 
To evaluate and compare health-related quality of life (HRQoL) between the tislelizumab and 
sitravatinib combination therapy with that of docetaxel monotherapy via patient reported 
outcomes using EORTC-QLQ-C30 (measuring general cancer) and its lung cancer module, 
QLQ-LC13, and the European Quality of Life 5-Dimension 5-Level (EQ-5D-5L)  
• 
To characterize the pharmacokinetics (PK) of sitravatinib when given in combination with 
tislelizumab, if data permit 
Exploratory: 
• 
To compare the combination of tislelizumab with sitravatinib versus docetaxel monotherapy, as 
measured by ORR, DOR, and DCR assessed by the investigator  
• 
To explore the predictive and prognostic effect of programmed cell death protein ligand-1 
(PD-L1) expression level 
• 
To characterize the PK of the active metabolite M10 of sitravatinib when given in combination 
with tislelizumab, if deemed necessary 
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• 
To characterize the PK and immunogenicity of tislelizumab when given in combination with 
sitravatinib 
• 
To explore potential biomarkers that may correlate with clinical responses or resistance to 
sitravatinib in combination with tislelizumab 
Study Endpoints: 
Primary: 
• 
OS, defined as the time from randomization to death from any cause 
• 
PFS, defined as the time from randomization to the first occurrence of disease progression as 
determined by the IRC based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, 
or death from any cause, whichever occurs first 
Secondary: 
• 
PFS, defined as the time from randomization to the first occurrence of disease progression as 
determined by the investigator based on RECIST v1.1, or death from any cause, whichever 
occurs first 
• 
ORR, defined as the proportion of patients with partial response or complete response as 
determined by the IRC based on RECIST v1.1 
• 
DOR, defined as the time from the first occurrence of a documented objective response to the 
time of the first occurrence of disease progression, as determined by the IRC based on RECIST 
v1.1, or death from any cause, whichever comes first 
• 
DCR, defined as the proportion of patients whose best overall response (BOR) is complete 
response, partial response or stable disease as determined by the IRC based on RECIST v1.1 
• 
HRQoL, defined as changes in patient-reported outcomes (PRO), according to the European 
Organisation for Research and Treatment of Cancer (EORTC) core cancer (QLQ-C30) and its 
lung cancer module, QLQ-LC13, and the European Quality of Life 5-Dimension 5-Level 
(EQ-5D-5L) from time of randomization to End of Treatment Visit, death or drop out, 
whichever comes first.  
• 
Incidence and severity of treatment-emergent adverse events (TEAEs) graded according to 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
v5.0 
• 
Plasma concentrations and the derived PK parameters of sitravatinib if data permit 
Exploratory: 
• 
ORR, defined as the proportion of patients with partial response or complete response as 
determined by the investigator based on RECIST v1.1 
• 
DOR, defined as the time from the first occurrence of a documented objective response to the 
time of the first occurrence of disease progression, as determined by the investigator based on 
RECIST v1.1, or death from any cause, whichever comes first 
• 
DCR, defined as the proportion of patients whose BOR is complete response, partial response, 
or stable disease based on RECIST v1.1 by investigator 
• 
To explore the predictive and prognostic effect of PD-L1 expression level on OS 
• 
To evaluate the predictive and prognostic effect of PD-L1 expression level using PFS, ORR, 
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and DCR by IRC and investigator 
• 
Plasma concentrations and the derived PK parameters of M10 if data permit 
• 
Serum concentrations of tislelizumab and the incidence of antidrug antibodies (ADAs) 
• 
Potential biomarkers such as PD‑L1 expression, gene expression profiling, tissue and blood 
tumor mutation burden and microsatellite instability, and alterations in tissue and circulating 
tumor DNA, and the association of biomarkers with disease status, and response/resistance to 
sitravatinib in combination with tislelizumab. 
Study Design: 
This is an open-label, randomized, multicenter, Phase 3 clinical study evaluating the efficacy and safety 
of tislelizumab in combination with sitravatinib compared with docetaxel in patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) who have disease progression following 
platinum-based chemotherapy and anti-programmed cell death protein-1 (PD-1)/programmed cell death 
ligand-1 (PD-L1) antibody, with the anti-PD-(L)1 antibody administered in combination with, or 
sequentially before or after the platinum-based chemotherapy. 
Patients must have received no more than 2 lines of prior systemic therapy for locally advanced and 
unresectable or metastatic disease. In addition, patients must have had radiographic progression per 
RECIST v1.1 on or after anti-PD-(L)1-containing therapy for locally advanced and unresectable or 
metastatic NSCLC. If anti-PD-(L)1-containing therapy is not the most recent systemic treatment, 
patients should also have radiographic progression per RECIST v1.1 on or after the most recent 
systemic treatment. Adjuvant or neo-adjuvant chemotherapy will be counted as 1 prior line of 
chemotherapy if the disease progressed on or within 6 months after the completion of the last dose. In 
locally advanced and unresectable NSCLC, disease progression on or within 6 months after the end of 
systemic therapy as part of prior curatively intended multimodal therapy will be counted as 1 prior line 
of systemic therapy. If chemoradiation is followed by planned systemic therapy without documented 
progression between chemoradiation and systemic therapy, the entire treatment course counts as 1 line 
of therapy (Patients who received anti-PD-[L]1 antibody as consolidation treatment following 
definitive chemoradiation for unresectable Stage III NSCLC can be enrolled immediately after disease 
progression, if the disease progression occurred within 6 months after the end of platinum-based 
chemotherapy component of the definitive chemoradiation). Maintenance therapy following 
platinum-based chemotherapy is not considered as a separate line of therapy. No other prior 
immunotherapies with antibody or drug specifically targeting T-cell costimulation or checkpoint 
pathways, including but not limited to anti-TIGIT, anti-OX40, and anti-CD137, will be allowed (prior 
anti-cytotoxic T-lymphocyte protein 4 [CTLA-4] used in combination with anti-PD-[L]1 is permitted); 
no prior anticancer therapy having the same mechanism of action as sitravatinib (eg, tyrosine kinase 
inhibitor with a similar target profile or VEGF- or VEGFR inhibitor) will be allowed either. 
The study will be conducted at approximately 100 centers globally. The study will consist of a 
screening period, a treatment period, and a long-term follow-up period. Approximately 420 patients 
with locally advanced or metastatic NSCLC will be enrolled and randomized in a 1:1 ratio to receive 
either tislelizumab in combination with sitravatinib or docetaxel monotherapy.  
Patients with histologically or cytologically confirmed locally advanced or metastatic (Stage IIIB/IIIC 
or Stage IV) NSCLC who have disease progression following platinum-based chemotherapy and 
anti-PD-(L)1 antibody, with the anti-PD-(L)1 antibody administered in combination with, or 
sequentially before or after platinum-based chemotherapy, are eligible. Histology of NSCLC will be 
confirmed at the investigator’s site. Patients with known EGFR or BRAF sensitizing mutation, or ALK 
or ROS1 rearrangement are ineligible for the study; for patients with nonsquamous NSCLC without 
tissue-based EGFR status, fresh or archival tumor tissues are required for EGFR mutation assessment. 
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Archival tumor specimens will be prospectively tested for PD-L1 expression by a central laboratory. If 
archived formalin-fixed paraffin-embedded tissue is not sufficient for PD-L1 analysis, a fresh biopsy 
sample will need to be obtained. PD-L1 status will be determined by the percentage of tumor cells with 
any membrane staining (tumor cells [TC]+) above background. Patients will be stratified by 
histological subtype (nonsquamous versus squamous), PD-L1 expression (< 1% TC versus ≥ 1% TC by 
the Ventana SP263 assay; patients whose tissues are unevaluable for PD-L1 expression will be 
included in the < 1% TC group), and race (Asian versus non-Asian) to receive one of the following 
treatment regimens: 
• 
Arm A: tislelizumab 200 mg intravenously once every 3 weeks in combination with 
sitravatinib 100 mg orally once a day 
• 
Arm B: docetaxel 75 mg/m2 intravenously once every 3 weeks  
Cycle 1 Day 1 will be defined as the first day the patient receives the study drug. A cycle is 21 days in 
length ± 3 days, unless a delay is medically necessary . A ± 3 -day window is allowed for 
protocol-required assessments, unless otherwise specified. Tumor assessment will be conducted (by 
magnetic resonance imaging and/or computed tomography [with oral and/or intravenous contrast, 
unless contraindicated]) during screening (within 28 days of Day 1); every 6 weeks from Cycle 1 Day 1 
(± 7 days) (at Weeks 7, 13, 19, 25, 31, 37, 43, and 49), and then at 9-week intervals (± 7 days) 
thereafter, until disease progression, withdrawal of consent, lost to follow-up, start of a new anticancer 
therapy, or death, whichever occurs earlier. 
Patients in both arms will receive study treatment until disease progression, intolerable toxicity, death, 
or withdrawal of consent, whichever occurs earlier. 
Patients will not be allowed to cross over to the other treatment arm. Tumor assessment and response 
will be determined by the IRC, who will evaluate disease progression and responses without the 
knowledge of randomization assignments, in accordance with RECIST v1.1. 
Response and disease progression will be assessed using RECIST v1.1. When disease progression is 
assessed by the investigator, the IRC is required to complete central image review and convey the 
results to the investigator as soon as possible. If disease progression is not confirmed by the IRC, it is 
recommended to continue the study treatment until disease progression is confirmed by the IRC, if this 
is in the best interest of the patient as discussed with the medical monitor. In the situation where the 
investigator believes the patient must urgently discontinue study treatment without waiting for the 
IRC’s confirmation, the investigator should contact the medical monitor to inform him/her of the 
decision of treatment discontinuation.  
A patient who discontinues study drugs early for reasons other than disease progression as assessed by 
IRC (eg, toxicity, disease progression assessed by the investigator) will continue to undergo tumor 
assessments following the original plan until the patient experiences disease progression per 
RECISTv1.1 as assessed by the IRC, withdraws consent, is lost to follow-up, starts a new anticancer 
treatment, until death, or until the study terminates, whichever occurs first.  
In selected cases, patients in Arm A may continue treatment beyond radiologic progression if they 
continue to demonstrate clinical benefit, at the discretion of the investigator and with the sponsor’s 
agreement. The following criteria must be met in order to treat patients beyond progression:  
• 
Absence of clinical symptoms and signs of disease progression (including clinically 
significantly worsening of laboratory values) 
• 
Stable ECOG performance status ≤ 1 
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• 
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.  
Patients who could benefit from study treatment in Arm A after disease progression as assessed by the 
investigator or IRC per RECIST v1.1 criteria may continue treatment until loss of clinical benefit as 
assessed by the investigator, withdrawal of consent, unacceptable toxicity, study completion by the 
sponsor, start of a new anticancer therapy, or death, whichever occurs first. Tumor assessment should 
continue as planned in patients receiving study treatment beyond initial investigator-assessed 
progression. Tumor assessment in such patients should continue until study treatment discontinuation. 
At the end of treatment or after treatment discontinuation, the date of progression, type and duration of 
subsequent therapies, response to subsequent therapy, date of progression on subsequent therapy, and 
survival data will be collected. 
Study Schema: 
 
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Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; EGFR, epidermal growth factor receptor; 
imAE, immune mediated adverse event; IV, intravenously; NSCLC, non-small cell lung cancer; PD-(L)1, programmed cell 
death protein-1/programmed cell death protein ligand-1; PO, orally; ROS1, ROS proto oncogene 1; QD, once a day; Q3W: 
every 3 weeks; TC, tumor cells 
Study Assessments: 
Study assessments will be described in the schedule of assessments. Patients will be closely monitored 
for safety and tolerability throughout the study. 
Duration of Patient Participation: 
The duration of the study from the first enrolled patient to the final analysis for the primary endpoint of 
OS is estimated to be approximately 32 months. 
Study Population: 
Approximately 420 patients with locally advanced or metastatic NSCLC who have experienced disease 
progression following platinum-based chemotherapy and anti-PD-(L)1 antibody, with the anti-PD-(L)1 
antibody administered in combination with, or sequentially before or after the platinum-based 
chemotherapy. 
Key Eligibility Criteria: 
Adult patients (≥ 18 years of age or the legal age of consent if > 18) with metastatic or unresectable 
locally advanced histologically or cytologically confirmed NSCLC, who were previously treated with 
no more than 2 lines of prior systemic chemotherapy and anti-PD-(L)1 antibody therapy are eligible. 
Patients with known EGFR or BRAF sensitizing mutation, or ALK or ROS1 rearrangement are 
ineligible for the study; for patients with nonsquamous NSCLC without tissue-based EGFR status, 
fresh or archival tumor tissues are required for EGFR mutation assessment. In addition, archival tumor 
specimens will be prospectively tested for PD-L1 expression by a central laboratory. If archived 
formalin-fixed paraffin-embedded tissue is not sufficient for PD-L1 analysis, a fresh biopsy sample will 
need to be obtained. All patients are also required to have an Eastern Cooperative Oncology Group 
(ECOG) Performance Status score of ≤ 1 and adequate organ function. 
Investigational Product, Dose, and Mode of Administration: 
Sitravatinib: Sitravatinib will be administered orally at a dose of 100 mg, once daily continuously. 
Dosing of sitravatinib can be withheld for up to approximately 28 days consecutively. Generally, A 
maximum of 2 dose reductions are allowed before the patient must be permanently withdrawn from the 
study drug. Dose reduction below 50 mg once daily may be undertaken after discussion with the 
sponsor. If the study drug is planned to be held for > 28 days, the medical monitor should be contacted 
before the patient is permanently discontinued from the study drug.  
The following guidelines should be followed for sitravatinib administration: 
• 
Dosing in the morning is preferred. 
• 
Capsules should be taken on an empty stomach (≥ 2-hour fast before each dose and no food for 
a minimum of 1 hour after each dose).  
• 
Capsules should be taken with at least 200 mL (approximately 1 cup) of water. 
• 
Patients should swallow the capsules whole and not chew them. 
• 
If vomiting occurs after dosing, sitravatinib doses should not be replaced.  
• 
If a patient forgets to take sitravatinib for more than 12 hours, he/she should skip the dose and 
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resume taking the drug the next day. 
Tislelizumab: Tislelizumab will be administered at a dose of 200 mg intravenously once every 
3 weeks. 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 if no symptoms are observed after the prior 
2 drug administrations. 
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 if no symptoms are observed during the 
first treatment administration. Thirty minutes is the shortest time period permissible for infusion of 
tislelizumab. Tislelizumab must not be concurrently administered with any other drug.  
There will be no dose reduction for tislelizumab in this study. Dose delays of ≤ 12 weeks will be 
permitted. The tumor assessment schedule will not be altered even if the administration of study 
drug(s) is delayed.  
On days when sitravatinib and tislelizumab dosing are both scheduled, the daily dose of sitravatinib 
should precede tislelizumab infusion for logistical reasons. This order of dosing is important on days 
when blood sampling is scheduled for sitravatinib and M10 PK analysis. 
In the event of unacceptable AEs potentially attributed to anti-PD-1 therapy and clearly not attributed 
to RTK inhibitor, sitravatinib can be continued as monotherapy at the discretion of the investigator. 
However, due to limited anticancer effect of rechallenging PD-(L)1 monotherapy after progression on 
PD-(L)1 inhibitor or PD-(L)1-inhibitor-based therapy, tislelizumab should not be used as monotherapy 
after permanent discontinuation of sitravatinib. When attribution to an unacceptable adverse event by 
either drug cannot be ruled out, both sitravatinib and tislelizumab should be held or the dose of 
sitravatinib should be reduced according to dose modification guidelines.  
Reference Therapy, Dose, and Mode of Administration: 
Docetaxel: Docetaxel will be administered every 3 weeks by intravenous infusion at 75 mg/m2 over 
1 hour, or according to institutional practices. Premedication with corticosteroids will be required in 
accordance with regional standards.  
Statistical Methods: 
OS and PFS by IRC are dual primary endpoints in this study. The type I error is strongly controlled by 
initially assigning a 1-sided alpha of 0.001 to the PFS hypothesis and 0.024 to the OS hypothesis. By 
using the graphic approach of Bretz (2009), if the PFS by IRC or the OS hypotheses are both rejected, 
the corresponding alpha will be shifted to the hypothesis test of the secondary efficacy endpoints, ORR 
per RECIST v1.1 assessed by the IRC. 
Analysis Sets: 
• 
The Intent-to-Treat Analysis Set includes all randomized patients. It will be the primary 
analysis set for the efficacy analysis.  
• 
The Safety Analysis Set includes all patients who received ≥ 1 dose of any of the study drugs. 
It will be the primary analysis set for the safety analysis. 
• 
The Sitravatinib PK Analysis Set includes all patients in the Safety Analysis Set who 
contributed ≥ 1 quantifiable postbaseline PK sample for sitravatinib. 
• 
The M10 PK Analysis Set includes all patients in the Safety Analysis Set who contributed 
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≥ 1 quantifiable postbaseline PK sample for M10. 
• 
The Tislelizumab PK Analysis Set includes all patients in the Safety Analysis Set who 
contributed ≥ 1 quantifiable postbaseline PK sample for tislelizumab. 
• 
The ADA Analysis Set includes all patients who received ≥ 1 dose of tislelizumab and for 
whom both baseline ADA and ≥ 1 postbaseline ADA result are available. 
The final analysis of OS will take place after approximately 289 OS events have been observed.  
On the basis of emerging external data, the testing strategy may be modified to improve the efficiency 
of the design. Should this occur, modifications to the testing strategy will be documented in the 
statistical analysis plan (SAP) before the unblinding of the study. 
Sample Size Considerations: 
The sample size calculation is based on the primary efficacy analysis of OS in the Intent-to-Treat 
Analysis Set. The hazard ratio of OS is assumed to be 0.70, with a median OS of 14.3 months in the 
treatment arm and 10.0 months in the comparator arm. The dropout rate for OS is assumed to be 5% 
per year. A total of 420 patients will be enrolled in a 1:1 randomization over an 18-month period, at a 
maximum enrollment rate of 28 patients/month and a ramp-up period of 6 months. Approximately 
289 OS events are planned for the final analysis, to have a power of 85% with an alpha of 0.024. A 
group sequential testing of OS will be performed. The hazard ratio assumption of PFS is 0.63 with a 
median PFS of 5.4 months in the treatment arm and 3.4 months in the control arm. Approximately 
332 PFS events are expected to occur at the final analysis of PFS, to have a power of 87% with an 
alpha of 0.001.  
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma or serum concentration-time curve 
BGB-A317 
tislelizumab 
BGB-9468 
sitravatinib 
CR 
complete response 
CT 
computed tomography 
DCR 
disease control rate 
CYP3A4 
cytochrome P450 3A4 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture (system) 
EOT 
End-of-Treatment (Visit) 
Fc 
fragment crystallizable region (typically, of immunoglobulin G) 
FDG 
fluorodeoxyglucose 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
imAE 
immune-mediated adverse event 
IB 
Investigator’s Brochure 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
Intent-to-Treat 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NSCLC 
non-small cell lung cancer 
OS 
overall survival 
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Abbreviation 
Definition 
ORR 
objective response rate 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein ligand-1 
PD-(L)1 
programmed cell death protein-1/programmed cell death protein ligand-1 
PFS 
progression-free survival 
PET 
positron emission tomography 
PK 
pharmacokinetic(s) 
PPE 
palmar-planta erythrodysesthesia 
PR 
partial response 
PRO 
patient -reported outcome 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
TEAE 
treatment-emergent adverse event 
TC 
tumor cells 
TME 
tumor microenvironment  
ULN 
upper limit of normal 
 
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1. 
INTRODUCTION  
1.1. 
Background Information on Non-Small Cell Lung Cancer  
Lung cancer is the most common type of cancer occurring in both men and women in the past 
decades and is the leading cause of cancer deaths worldwide. In 2020, an estimated 228,820 new 
cases of lung cancer will be diagnosed, and 135,720 deaths are estimated to occur because of the 
disease in the United Sates (NCCN Guideline Version 1, 2020). Lung cancer is also the most 
commonly diagnosed lung malignancy and it remains one of the deadliest diseases in China; 
about 782,000 new cases of lung cancer were diagnosed in 2014 (Chen et al 2015). According to 
statistics from the National Office on Tumor Cure and Prevention, about 626,000 people die of 
lung cancer each year in China (Chen et al 2018). 
Characterized by uncontrolled growth of abnormal cells in the lung, lung cancer includes 2 major 
pathological types: non-small cell lung cancer (NSCLC) and small cell lung cancer. NSCLC 
accounts for 80% to 85% of all lung cancers (American Cancer Society 2020). There are 2 main 
types of NSCLC: nonsquamous carcinoma (including adenocarcinoma, large-cell carcinoma, and 
other subtypes) and squamous cell (epidermoid) carcinoma (NCCN Guideline Version 1, 2020). 
For several decades, the conventional anticancer strategies have been surgery, chemotherapy, 
and radiotherapy. The success of immune checkpoint therapy in recent years has revolutionized 
traditional cancer treatment. Inhibitors of programmed cell death protein-1 (PD-1) and 
programmed cell death protein ligand-1 (PD-L1) are a group of checkpoint inhibitors being 
developed for the treatment of cancer. The United States Food and Drug Administration (FDA) 
has approved 6 different monoclonal antibodies targeting the PD-1/PD-L1 pathway: 
pembrolizumab (PD-1 inhibitor) (KEYTRUDA® prescribing information), nivolumab (PD-1 
inhibitor) (OPDIVO® prescribing information), atezolizumab (PD-L1 inhibitor) 
(TECENTRIQ® prescribing information), durvalumab (PD-L1 inhibitor) (IMFINZI™ 
prescribing information), avelumab (PD-L1 inhibitor) (BAVENCIO® prescribing information), 
and cemiplimab-rwlc (PD-1 inhibitor) (LIBTAYO® prescribing information). 
In the first-line setting, KEYNOTE-042 (Lopes et al 2018) demonstrated that single-agent 
pembrolizumab significantly improved overall survival (OS) compared with platinum-based 
chemotherapy in patients with advanced NSCLC, with ≥ 1% PD-L1 expression, but without 
EGFR mutation or ALK rearrangement. Treatment-related adverse events of Grade 3 or higher 
occurred in 113 (18%) of 636 patients treated in the pembrolizumab group and in 252 (41%) of 
615 patients treated in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, 
respectively (Mok et al 2019). Based on these results, the FDA approved pembrolizumab as a 
single agent for the first-line treatment of patients with Stage III NSCLC not amenable to 
surgical resection or definitive chemoradiation or metastatic NSCLC whose tumors express 
PD-L1 (tumor proportion score ≥ 1%) with no EGFR or ALK genomic tumor aberrations 
(KEYTRUDA® prescribing information). 
Furthermore, pembrolizumab in combination with chemotherapy was also approved by the FDA 
in 2018, for patients with metastatic nonsquamous or squamous NSCLC. 
In the KEYNOTE-189 study of patients with metastatic nonsquamous NSCLC without 
sensitizing EGFR or ALK mutations, the addition of pembrolizumab to chemotherapy resulted in 
significantly longer OS (estimated rate of OS at 12 months was 69.2% versus 49.4%, hazard 
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ratio of 0.49), longer progression-free survival (PFS) (median 8.8 months versus 4.9 months, 
hazard ratio of 0.52), and a higher response rate (47.6% versus 18.9%) than chemotherapy alone 
(Gandhi et al 2018). 
In the KEYNOTE-407 study of patients with previously untreated metastatic squamous NSCLC, 
the addition of pembrolizumab to standard chemotherapy resulted in significantly longer OS 
(median 15.9 months versus 11.3 months, hazard ratio of 0.64), longer PFS (median 6.4 months 
versus 4.8 months, hazard ratio of 0.56), and a higher response rate (57.9% versus 38.4%) than 
chemotherapy alone, regardless of the level of PD-L1 expression (Paz Ares et al 2018). 
RATIONALE-307 (NCT03594747, known as BGB-A317-307) is a Phase 3, randomized, 
open-label, multicenter study investigating tislelizumab combined with either paclitaxel and 
carboplatin (Arm A) or nab-paclitaxel and carboplatin (Arm B) compared with paclitaxel and 
carboplatin alone (Arm C) in patients with untreated Stage IIIB or Stage IV squamous NSCLC 
from mainland China (Wang et al 2020). An assessment by an independent review committee 
(IRC) showed that PFS was significantly longer in both Arm A and Arm B (7.6 months), than in 
Arm C (5.5 months). The benefits were seen regardless of the level of PD-L1 expression. 
Response rates were better with tislelizumab, reaching 73% in Arm A and 75% in Arm B, 
compared with 50% in Arm C, as was the duration of response (DOR), which nearly doubled in 
Arm A (8.2 months) and Arm B (8.6 months), compared with that in Arm C (4.2 months). 
RATIONALE-304 (NCT 03663205, known as BGB-A317-304) is a Phase 3, randomized, 
open-label, multicenter study conducted in mainland China, investigating tislelizumab in 
combination with platinum (carboplatin or cisplatin) and pemetrexed (Arm A) compared with 
platinum and pemetrexed alone (Arm B) in patients with histologically confirmed stage IIIB or 
IV nonsquamous NSCLC (Lu et al 2021). Addition of tislelizumab to chemotherapy led to 
significantly longer IRC-assessed PFS compared with chemotherapy alone (HR = 0.645 [95% 
CI: 0.462 to 0.902], p = 0.0044); the median PFS by IRC assessment was 9.7 months (95% CI: 
7.7 to 11.5 months) and 7.6 months (95% CI: 5.6 to 8.0 months) in Arm A and Arm B, 
respectively. A higher ORR assessed by the IRC was observed with tislelizumab plus 
chemotherapy (57.4%; 95% CI: 50.6% to 64.0%) compared with chemotherapy alone (36.9%; 
95% CI: 28.0% to 46.6%). The median DOR assessed by the IRC was longer in Arm A than that 
in Arm B, at 8.5 months (95% CI: 6.80 to 10.58 months) versus 6.0 months (95% CI: 
4.99 months to not estimable), respectively. Higher ORR was observed across all TC PD-L1 
expression cutoff subgroups in Arm A than in Arm B.  
The addition of pembrolizumab or tislelizumab did not appear to increase the frequency of 
adverse events (AEs) that are commonly associated with chemotherapy regimens involving 
pemetrexed and platinum-based drugs. AEs of Grade 3 or higher in the 
pembrolizumab-combination group versus the placebo-combination group occurred in 67.2% 
versus 65.8% of the patients, respectively, in the KEYNOTE-189 study and in 69.8% versus 
68.2% of the patients, respectively, in the KEYNOTE-407 study. In the RATIONALE-307 
study, AEs leading to discontinuation of any treatment were reported in 12.5%, 29.7%, and 
15.4% of patients in Arms A, B, and C, respectively. The most commonly reported 
≥ Grade 3 AEs were hematologic in nature (eg, neutropenia) and were consistent with known 
chemotherapy-related AEs. Serious treatment-related AEs (TRAEs) were reported in 72 patients 
(37.5% [Arm A]; 38.9% [Arm B]; 23.6% [Arm C]); TRAEs leading to death were reported in 
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6 patients (n = 1 [Arm A]; n = 2 [Arm B]; n = 3 [Arm C]), none of which were solely attributed 
to tislelizumab. 
Three studies evaluated the efficacy and safety of atezolizumab in combination with 
chemotherapy (IMpower130 [Cappuzzo et al 2018], IMpower131 [Jotte et al 2018], and 
IMpower132 [Papadimitrakopoulou et al 2018]) as first-line treatment for advanced NSCLC. 
The use of the PD-L1 inhibitor atezolizumab in combination with chemotherapy demonstrated 
improved PFS in patients with Stage IV nonsquamous or squamous NSCLC. 
The addition of atezolizumab to bevacizumab in combination with chemotherapy significantly 
improved PFS and OS among patients with metastatic nonsquamous NSCLC, regardless of 
PD-L1 expression and EGFR or ALK genetic alteration status (Socinski et al 2018; Reck et al 
2019). TRAEs of ≥ Grade 3 occurred in 58.5% and 50.0% of patients in the 
atezolizumab/bevacizumab/chemotherapy group versus the bevacizumab/chemotherapy group, 
respectively. 
CHECKMATE-227 included patients with recurrent or Stage IV NSCLC without previous 
treatment. Patients with a PD-L1 expression level of 1% or more were randomized in a 1:1:1 
ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The 
chemotherapy used was cisplatin or carboplatin, combined with either gemcitabine for patient 
with squamous cell NSCLC or pemetrexed for patients with nonsquamous disease. The median 
duration of OS was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab 
plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (p = 0.007), with 
2-year OS rate of 40.0% and 32.8%, respectively. The median duration of response was 23.2 
months with nivolumab plus ipilimumab and 6.2 months with chemotherapy (Hellmann et al 
2019). CHECKMATE-9LA study randomized patients with Stage IV or recurrent NSCLC, to 
nivolumab + ipilimumab + 2 cycles of chemotherapy or 4 cycles of chemotherapy alone. 
Immunotherapy plus chemotherapy led to a significantly longer median OS than chemotherapy 
alone at the preplanned interim analysis (hazard ratio [HR] = 0.69, 96.71% CI: 0.55 – 0.87; 
p = 0.0006) and after a longer follow-up (a minimum of 12.7 months), a median OS of 
15.6 months versus 10.9 months (HR = 0.66) , regardless of the levels of PD-L1 expression. 
Statistically significant improvements in PFS and ORR were also seen (Martin et al 2020). Based 
on these results, the FDA approved the combination of nivolumab plus ipilimumab as the 
first-line treatment for patients with metastatic NSCLC whose tumors express PD-L1(≥ 1%) and 
the combination of nivolumab with ipilimumab plus 2 cycles of platinum-doublet chemotherapy 
as the first-line treatment for patients with metastatic or recurrent NSCLC. 
Two immune checkpoint inhibitors targeting PD-1, nivolumab and pembrolizumab, were 
approved in 2015 for second-line therapy in patients with metastatic NSCLC whose disease 
progressed on or after platinum-containing chemotherapy. Among these, nivolumab 
demonstrated a survival benefit versus docetaxel in advanced nonsquamous NSCLC, resulting in 
27% lower risk of death at a minimum follow-up of 13.2 months (median OS of 12.2 versus 
9.4 months; ORR of 19% versus 12%), and a better safety profile than standard-of-care 
chemotherapy (Grade 3 and Grade 4 AEs: 10% versus 54%) (Borghaei et al 2015). Nivolumab 
was also evaluated in a Phase 3 clinical study in patients with squamous NSCLC whose disease 
had progressed during or after 1 prior platinum-based doublet chemotherapy regimen. Median 
survival was 9.2 months for nivolumab compared with 6.0 months for docetaxel (a HR of 0.59, 
p < 0.001). The response rate was 20% with nivolumab versus 9% with docetaxel (p = 0.008). 
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The median PFS was 3.5 months with nivolumab versus 2.8 months with docetaxel (a HR of 
0.62, p < 0.001) (Brahmer et al 2015). In 2016, another checkpoint inhibitor targeting PD-L1, 
atezolizumab, was approved for the same indication.  
Despite this stream of new life-extending treatments involving anti-PD-(L)1 therapy, advanced 
or metastatic NSCLC remains an incurable disease for most patients. The interactions between 
the human immune system and tumor cells are continuous, dynamic, and evolving. Acquired 
resistance is described as the lack of response to immunotherapy after the patient initially 
responds to anti-PD-(L)1 then relapses or progresses (Sharma et al 2017). The frequencies of 
primary resistance in advanced NSCLC patients whose best responses were progressive disease 
in first-line immune checkpoint inhibitors with or without chemotherapy varied from 7% to 27%; 
whilst in a pretreated setting with immune checkpoint monotherapy, the reported rates ranged 
from 20% to 44% (Walsh and Soo 2020). For patients who experienced complete response, 
partial response, or stable disease from immunotherapy but tumor eventually relapsed or 
progressed, more effective treatment options with combating resistance and expanding the 
duration of response are needed.  
1.2. 
Current Treatment of Non-Small Cell Lung Cancer and Unmet 
Clinical Needs  
Docetaxel, pemetrexed, and erlotinib were 3 single agents approved by the US FDA and the 
European Medicines Agency (EMA) for use in the second- and subsequent-line setting for 
NSCLC after the first-line treatment of platinum-based doublet chemotherapy. In the US, 
erlotinib is limited to patients whose tumors have EGFR sensitizing mutation. 
Docetaxel was the first agent demonstrating a survival benefit, compared with best supportive 
care (BSC) in patients with NSCLC that relapsed following first-line therapy, and was associated 
with an ORR in the range of 6% to 11% (Taxotere EPAR 2020). 
Pemetrexed appeared to be noninferior to docetaxel in terms of efficacy outcomes in the 
second-line treatment of patients with advanced NSCLC (all histologies), with a median OS 
(mOS) of 8.3 months compared with an mOS of 7.9 months in the docetaxel arm (Hanna et al 
2004); subsequent subgroup analysis revealed improved survival in patients with nonsquamous 
histologies, thus limiting its approval to patients with nonsquamous NSCLC (Alimta EPAR 
2020). 
Improved OS (median OS of 6.7 versus 4.7 months) was observed with erlotinib when compared 
with BSC in a randomized study that included patients with poor Eastern Cooperative Oncology 
Group Performance Status (ECOG PS) scores (Tarceva EPAR 2020). Erlotinib has therefore 
often been used for patients who cannot receive cytotoxic chemotherapy due to poor ECOG PS. 
Overall, the therapeutic index of these second-line NSCLC therapies has been restricted both by 
limited survival benefit and significant toxicities such as myelosuppression and neuropathy 
(docetaxel), diarrhea (pemetrexed, erlotinib), and rash (erlotinib) (Stinchcombe and Socinski 
2008). Outcomes are poor for patients with previously treated, advanced or metastatic NSCLC; 
systemic chemotherapy (eg, docetaxel) or erlotinib provide only modest benefit (Al-Farsi and 
Ellis 2014; Stinchcombe and Socinski 2008). 
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1.3. 
Antibody Therapy for Non-Small Cell Lung Cancer  
Tislelizumab binds with high affinity to PD-1. It was engineered to minimize binding of 
fragment crystallizable region receptors (FcR) on macrophages in order to abrogate 
antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to 
anti-PD-1 therapy. 
Tislelizumab is being developed, as monotherapy or in combination with other drugs, for 
patients with locally advanced or metastatic NSCLC, esophageal squamous cell carcinoma, and 
other types of cancers (eg, hepatocellular carcinoma, gastric cancer, Hodgkin lymphoma, 
urothelial bladder cancer, B-cell lymphoid malignancies, nasopharyngeal cancer, and 
extensive-stage small-cell lung cancer). 
1.4. 
Background Information on Tislelizumab  
1.4.1. 
Pharmacology  
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against PD-1. 
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as 
well as high affinity (dissociation constant [KD] = 0.15 nM). It competitively blocks binding 
efforts by both PD-L1 and programmed cell death protein ligand-2 (PD-L2), thus inhibiting 
PD-1-mediated negative signaling in T cells. In addition, tislelizumab has no effector functions 
mediated through Fc gamma receptors (Zhang et al 2018). Tislelizumab has demonstrated in 
vivo antitumor activity in several allogeneic xenograft models. 
Please refer to the tislelizumab IB 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 cynomolgus monkeys and in a 13-week, repeat-dose toxicology study in 
cynomolgus monkeys. 
No apparent toxicity was noted in single dose or 13-week repeat-dose monkey toxicity studies. 
No tissue cross-reactivity was found in either human or monkey tissues, nor was any effect on 
cytokine release observed in the 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 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, 
BGB-A317-Sitravatinib-301. 
Please refer to the tislelizumab IB for more detailed information on the toxicology of 
tislelizumab. 
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1.4.3. 
Clinical Pharmacology  
Tislelizumab exhibited dose-proportional increase in exposure over the entire dose range (0.5 to 
10 mg/kg). The population pharmacokinetic (popPK) analysis was performed based on pooled 
data (PK, dosing information, demographics, and patient or disease characteristics) from 2596 
patients across 12 clinical studies. The PK of tislelizumab was best characterized using a 
3-compartmental model with linear clearance mechanism. No time-varying clearance was 
observed in tislelizumab PK. The typical estimates of clearance (CL), central volume of 
distribution (Vc), and peripheral volumes 2 and 3 (V2 and V3, respectively), were 0.153 L/day, 
3.05 L, 1.27 L, and 2.10 L, respectively, with interindividual variability in CL (26.3%), Vc 
(16.7%), V2 (74.7%), and V3 (99.9%). The terminal half-life (t½) was estimated to be 
approximately 23.8 days. The accumulation ratios were estimated to be 2.14 and 2.49 for area 
under the serum concentration-time curve at steady state (AUCss) and minimum concentration at 
steady-state (Cmin,ss), respectively. Steady state is expected to be reached in approximately 12 
weeks. 
The popPK analyses demonstrated that race, baseline alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), bilirubin, lactate dehydrogenase (LDH), estimated glomerular filtration 
rate (eGFR), Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, and 
sum of products of perpendicular diameters (SUMPPD) of classical Hodgkin lymphoma (cHL) 
did not have statistically significant influences on tislelizumab PK. Baseline body weight, tumor 
size of solid tumors, albumin level, age, sex, immunogenicity, and tumor type were found to be 
statistically significant covariates on the PK of tislelizumab; however, the exposure changes by 
these covariates were relatively small compared to overall estimated PK exposures range, and 
hence are not considered clinically meaningful. 
Tislelizumab exposure-efficacy relationships were also evaluated in a range of solid tumor 
indications. No consistent and clinically relevant E-R relationship was observed for either the 
efficacy endpoint of objective response rate (ORR) or the safety endpoints of imAEs, IRRs, 
AEs ≥ Grade 3, AEs leading to dose modification, and AEs leading to drug discontinuation 
based on tislelizumab-treated patients. 
1.4.4. 
Prior Clinical Experience of Tislelizumab  
As of 20 May 2021, there are 9 completed studies and 33 ongoing studies with tislelizumab, with 
over 3498 patients treated with tislelizumab as monotherapy or in combination with other 
therapies. Of these, 15 studies have preliminary data available and are presented in the 
tislelizumab IB edition 9.0, dated 20 October 2021. These include 6 monotherapy studies, 
2 chemotherapy combination therapy studies; and 7 targeted therapy combination studies. 
Refer to the tislelizumab IB for more detailed information on tislelizumab safety and efficacy 
data when given as monotherapy or in combination with chemotherapy. 
1.4.4.1. 
Safety Assessment of Monotherapy Studies  
A pooled analysis of monotherapy studies was conducted to provide a comprehensive safety 
assessment separately from combination therapy.  
A total of 2150 patients were treated in the monotherapy studies included in the pooled safety 
analysis. Within the 7 solid tumor monotherapy studies, 1992 patients were treated. Refer to the 
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tislelizumab IB for more detailed information on tislelizumab safety data when given as 
monotherapy or in combination with chemotherapy. 
1.4.4.1.1. Treatment-Emergent Adverse Events  
For the solid tumor monotherapy studies, a TEAE is defined as an AE that began or worsened in 
severity from baseline (pretreatment) after the first dose of study drug and before starting a new 
anticancer therapy or ≤ 30 days after the last dose of study drug, whichever occurred first. 
TEAEs also include immune-mediated adverse events (imAEs) and treatment-related SAEs that 
began or worsened from baseline ≤ 90 days after the last dose of study drug, regardless of 
whether a new anticancer therapy was started. 
Of the 1992 patients in the solid tumor group of monotherapy studies, 1922 (96.5%) experienced 
≥ 1 TEAE and 1391 patients (69.8%) experienced ≥ 1 TEAE considered treatment related. 
TEAEs ≥ Grade 3 in severity were experienced by 847 of 1992 patients (42.5%), and 
269 patients (13.5%) experienced a ≥ Grade 3 TEAE considered treatment related. Serious 
TEAEs were reported in 706 patients (35.4%) and 209 patients (10.5%) experienced ≥ 1 serious 
TEAE considered treatment related. A total of 141 patients (7.1%) experienced a TEAE leading 
to death. The most commonly occurring TEAEs were anaemia (502 of 1992 patients, 25.2%), 
AST increased (18.0%), ALT increased (16.7%), decreased appetite (16.5%), and cough 
(15.1%). 
Treatment-Emergent Adverse Events by Severity 
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 847 (42.5%) 
experienced ≥ 1 TEAE of ≥ Grade 3 severity. The most commonly occurring ≥ Grade 3 TEAEs 
were anaemia (87 of 1992 patients, 4.4%), pneumonia (4.3%), AST increased (2.3%), 
hyponatraemia (2.1%), gamma-glutamyltransferase increased (1.7%), and hypertension (1.7%). 
1.4.4.1.2. Treatment-Emergent Serious Adverse Events  
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 706 (35.4%) 
experienced ≥ 1 treatment-emergent SAE. The most commonly occurring SAEs were pneumonia 
(95 of 1992 patients, 4.8%), pneumonitis (1.7%), dysphagia (1.2%), pleural effusion (1.0%), and 
pyrexia (1.0%). 
Tislelizumab-Related Treatment-emergent Serious Adverse Events 
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 209 (10.5%) 
experienced ≥ 1 tislelizumab-related treatment-emergent SAE. The most commonly occurring 
treatment-related SAE was pneumonitis (31 of 1992 patients, 1.6%). All other events occurred in 
less than 1% of patients. 
1.4.4.1.3. Immune-Mediated Adverse Events  
Anti-PD-1 therapies are known to cause imAEs in some patients and therefore have been defined 
as AEs of special interest (AESIs) in tislelizumab clinical studies. 
Immune-mediated AEs are consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. Immune-mediated AEs can include events with an alternate 
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etiology that were exacerbated by the induction of autoimmunity. There is a potential temporal 
relationship between the initiation of treatment with tislelizumab and onset of an imAE that 
spans a window of days to several months. 
All imAEs presented here are assessed as related to study drug by the investigator and 
categorized by the BeiGene Safety/Pharmacovigilance team. Certain imAEs have multiple 
Medical Dictionary for Regulatory Activities (MedDRA) terms associated with the same 
category. Special categories have been created to group patients experiencing these events.  
Of the 1912 patients in the adjudicated solid tumor group of pooled monotherapy studies, 
286 (15.0%) experienced ≥ 1 imAE of any grade. The most commonly occurring imAEs of any 
grade were hypothyroidism (115 of 1912 patients, 6.0%), pneumonitis (2.1%), immune-mediated 
lung disease (0.7%), rash (0.7%), alanine aminotransferase increased (0.6%), and 
hyperthyroidism (0.6%). The categories of imAEs experienced by ≥ 1% of patients were 
immune-mediated hypothyroidism (118 of 1912 patients, 6.2%), immune-mediated pneumonitis 
(3.7%), immune-mediated hepatitis (1.8%), and immune-mediated skin adverse reaction (1.3%). 
Adjudicated Immune-Mediated Adverse Events by Severity 
Of the 1912 patients in the adjudicated solid tumor group of pooled monotherapy studies, 
73 (3.8%) experienced ≥ 1 imAE that was ≥ Grade 3 in severity. The most commonly occurring 
≥ Grade 3 imAEs were pneumonitis (15 of 1912 patients, 0.8%), interstitial lung disease (0.4%), 
ALT increased (0.3%), AST increased (0.3%), and hepatitis (0.3%). 
Immune-mediated AEs of hepatitis, pneumonitis, colitis, endocrinopathies, myocarditis, and 
serious skin adverse reactions have been identified as risks of tislelizumab. Refer to the 
tislelizumab IB for more detailed information. 
1.4.4.1.4. Infusion-Related Reactions  
Infusion-related reactions (IRRs), including high-grade hypersensitivity reactions, following 
administration of tislelizumab are uncommon. Of the 1992 patients in the solid tumor group of 
pooled monotherapy studies, 58 (2.9%) experienced ≥ 1 IRR of any grade. The most commonly 
occurring IRRs were “infusion-related reaction” (28 of 1992 patients, 1.4%), pyrexia (0.9%), 
rash (0.3%), hypotension (0.2%), nausea (0.2%), and pruritus (0.2%). 
Infusion-Related Reactions by Severity 
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 5 (0.3%) 
experienced ≥ Grade 3 IRRs. The most common ≥ Grade 3 IRR was “infusion-related reaction” 
(2 of 1992 patients, 0.1%). All other ≥ Grade 3 IRRs occurred in single patients. 
1.4.4.1.5. Fatal Adverse Events  
Deaths 
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 163 (8.2%) died 
≤ 30 days after their last dose of tislelizumab. The causes of death for these patients were adverse 
events (54 of 1992 patients, 2.7%), disease under study (2.6%), disease progression (2.5%), and 
“other” (0.4%). A total of 1230 patients (61.7%) died > 30 days after their last dose of 
tislelizumab. The causes of death for these patients were disease under study 
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(664 of 1992 patients, 33.3%), disease progression (22.7%), “other” (4.5%), adverse events 
(1.1%), and “missing” (0.1%). 
Treatment-Emergent Adverse Events Leading to Death 
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 141 (7.1%) 
experienced ≥ 1 TEAE leading to death. The most commonly occurring TEAEs leading to death 
were “death” (16 of 1992 patients, 0.8%), pneumonia (0.7%), multiple organ dysfunction 
syndrome (0.6%), general physical health deterioration (0.5%), hepatic failure (0.5%), and 
respiratory failure (0.5%). 
Tislelizumab-Related Treatment-Emergent Adverse Events Leading to Death 
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 20 (1.0%) 
experienced ≥ 1 tislelizumab-related TEAE leading to death. The most commonly occurring 
tislelizumab-related TEAEs leading to death were pneumonia (3 of 1992 patients, 0.2%), “death” 
(0.1%), hepatic failure (0.1%), multiple organ dysfunction syndrome (0.1%), and pneumonitis 
(0.1%). All other events occurred in single patients. 
1.4.4.2. 
Efficacy Assessment of Tislelizumab  
Efficacy data are available from 3 studies in solid tumors, BGB-A317_Study_001, 
BGB-A317-102, and BGB-A317-303, which are summarized below. 
1.4.4.2.1. Study BGB-A317_Study_001  
Study BGB-A317 Study_001 is a 2-stage study consisting of a Phase 1a dose-escalation (0.5 to 
10 mg/kg) and a dose-finding component with 3 parts (2 and 5 mg/kg given either once every 
2 or 3 weeks, and a fixed dose of 200 mg given once every 3 weeks) to establish the maximum 
tolerated dose (MTD), if any, a recommended Phase 2 dose (RP2D), and followed by a Phase 1b 
component to investigate efficacy in select tumor types at the RP2D to further evaluate safety 
and tolerability of tislelizumab. Indication-specific cohorts included esophageal cancer, gastric 
cancer, hepatocellular carcinoma, and NSCLC. 
Responses were assessed by the investigator per RECIST v1.1 criteria.  
Of the 451 patients treated with tislelizumab in the study across all disease cohorts (Safety 
Analysis Set), best overall responses of CR were reported in 6 patients (1.3%) and of PR in 
54 patients (12.0%). The resulting overall clinical response rate (CR + PR) was 13.3%. 
Additionally, there were 141 patients (31.3%) with a best overall response of stable disease. 
Of the 49 patients in the NSCLC cohort (Safety Analysis Set), 12.2% (95% CI: 4.63% to 
24.77%) of patients had a best overall response of CR or PR (tislelizumab IB). 
1.4.4.2.2. Study BGB-A317-102  
Study BGB-A317-102 is a nonrandomized, Phase 1/2 study of tislelizumab monotherapy in 
Chinese patients with advanced solid tumors. Phase 1 included a dose verification substudy and a 
substudy of PK evaluation of the products derived from 2 manufacturing processes and scales. 
Phase 2 evaluated the activity and safety of tislelizumab at its RP2D of 200 mg given once every 
3 weeks in indication specific expansion cohorts. 
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Responses were assessed by the investigator per the RECIST v1.1 criteria.  
Of the 300 patients treated in Study BGB-A317-102, efficacy data were presented for 
238 patients (79.3%) treated with ≥ 1 dose of tislelizumab in the study (Safety Analysis Set) 
(data cutoff date: 01 December 2018). Of the presented indications, ORR was ≥ 15% in 
nasopharyngeal carcinoma (43%), microsatellite instability-high/mismatch repair deficient solid 
tumors (19%), NSCLC (18%), gastric cancer (17%), HCC (17%), and melanoma (15%). The 
median duration of response was only mature for the nasopharyngeal carcinoma cohort, which 
had a duration of response of 8.3 months (range 3.9 months to not estimable) with a median 
follow-up of 4.8 months. 
The tumor responses in the patients of the NSCLC cohort (56 patients) in BGB-A317-102 
showed no CR in any patient (0%) and PR in 10 patients (18%). Additionally, there were 
21 patients (38%) with a best overall response of stable disease. Twenty-one patients (38%) had 
a best overall response of PD in this cohort (tislelizumab IB). 
1.4.4.2.3. Study BGB-A317-303  
Study BGB-A317-303 (RATIONALE 303) is a Phase 3, open-label, multicenter, randomized 
study to evaluate the efficacy and safety of tislelizumab monotherapy compared with docetaxel 
as second- or third-line treatment for patients with locally advanced or metastatic NSCLC of 
squamous- or nonsquamous histology. A total of 805 patients were randomly assigned in a 2:1 
ratio to receive tislelizumab 200 mg intravenously once every 3 weeks (535 patients) or 
docetaxel 75 mg/m2 intravenously once every 3 weeks treatment (270 patients). 
OS, as the primary endpoint, was compared between tislelizumab and docetaxel treatment arms, 
both in the Intent-to-Treat (ITT) Analysis Set and the PD-L1-Positive Analysis Set, where 
PD-L1 positive was defined as ≥ 25% of TC with PD-L1 membrane staining via the Ventana 
SP263 assay.  
Results from the interim analysis (data cutoff date: 10 August 2020), showed statistically 
significant and clinically meaningful improvement in OS with tislelizumab treatment in the ITT 
Analysis Set. The median OS was 17.2 months (95% CI: 15.28 to 20.04 months) for patients 
who received tislelizumab and 11.9 months (95% CI: 10.18 to 13.93 months) for patients who 
received docetaxel; the hazard ratio was 0.64 (95% CI: 0.527 to 0.778), with a 1-sided log-rank 
p < 0.0001. The improvement in OS with tislelizumab treatment was more prominent in the 
PD-L1-Positive Analysis Set, with a median OS of 19.1 months (95% CI: 16.82 to 
25.79 months) for tislelizumab and 11.9 months (95% CI: 8.90 to 14.03 months) for docetaxel 
treatment; the hazard ratio was 0.52 (95% CI: 0.384 to 0.713), with a 1-sided log-rank 
p < 0.0001. 
Longer median PFS was also observed with tislelizumab treatment compared with docetaxel 
treatment in the ITT Analysis Set, 4.1 months (95% CI: 3.75 to 5.03 months) versus 2.6 months 
(95% CI: 2.17 to 3.78 months), respectively.  
Tumor response in the ITT Analysis Set showed a higher ORR rate (21.9% versus 7.0%) and 
longer DOR with tislelizumab treatment: the median DOR was 13.5 months (95% CI: 5.58 to 
21.78 months) with tislelizumab treatment and 6.2 months (95% CI: 2.10 to 7.16 months) with 
docetaxel. The DCR rate was 55.7% and 42.2% for tislelizumab and docetaxel treatment, 
respectively (Zhou et al 2021). 
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1.5. 
Background Information on Sitravatinib  
Receptor tyrosine kinases (RTKs) are essential components of signal transduction pathways that 
mediate cell-to-cell communication (Hubbard and Miller 2007). They are a subclass of 
cell-surface growth-factor receptors with an intrinsic, ligand-controlled tyrosine-kinase activity. 
These single-pass transmembrane receptors that bind polypeptide ligands (mainly growth 
factors) play key roles in processes such as cell growth, differentiation, metabolism, and motility. 
In cancer, constitutive and aberrant activations of components of those pathways result in 
increased proliferation, survival, and metastasis. Therefore, these signaling pathways became 
prime targets for cancer therapy. 
Sitravatinib (BGB-9468) is an orally bioavailable RTK inhibitor with potential antineoplastic 
activity. It is a potent inhibitor of multiple RTKs, including AXL, MER, MET, KIT, FLT3, RET, 
VEGFR1, VEGFR2, VEGFR3, PDGFRα, DDR2, TRKA, and TRKB. Sitravatinib targets are 
genetically altered in a variety of cancers and act as oncogenic drivers, promoting cancer 
development and progression. In addition to targeting genetically altered oncogenic drivers, 
sitravatinib targets are expressed in a number of immune cell types and promote an 
immunosuppressive tumor microenvironment (TME), thus providing a rationale for combining 
with PD-1 checkpoint inhibitor therapy. Along with the immunostimulatory effects, the 
immunomodulatory effects of sitravatinib mediated through VEGFR and KIT inhibition may 
further condition the TME in favor of antitumor activity. Preclinical data for sitravatinib indicate 
that it can increase PD-L1 expression in tumor cells, in vitro and in vivo. Pilot studies in 
syngeneic mouse tumor models also suggest that sitravatinib increases the proliferation and 
fraction of systemic/spleen CD4+ and CD8+ T lymphocytes and reduces the number of systemic 
myeloid-derived suppressor cells (MDSCs). 
1.5.1. 
Pharmacology  
Sitravatinib was demonstrated to be a potent inhibitor of the catalytic activity of a subset of 
closely related recombinant human RTKs with IC50 values ranging from 0.5 to 76 nmol/L. 
Sitravatinib showed potent activity in RTK-target dependent cell-based assays with IC50 values 
ranging from < 10 to 181 nmol/L. Consistent with this antitumor and antiangiogenic mechanism 
of action, sitravatinib demonstrated antitumor efficacy over a broad spectrum of human tumor 
xenograft models. In addition, concurrent treatment with sitravatinib greatly enhanced the 
activity of anti-PD-1 therapy in the CT26 syngeneic mouse tumor model.  
In vitro, sitravatinib is a substrate of P-glycoprotein (P-gp) but is not a substrate of Breast Cancer 
Resistance Protein (BCRP), Organic Anion Transporter (OAT) 1 or 3, Organic Cation 
Transporter (OCT) 2, Organic Transporting Polypeptide (OATP) 1B1 or 1B3, or 
Multi-Antimicrobial Extrusion Protein (MATE) 1 or 2K. Sitravatinib inhibited the efflux 
transporters P-gp and BCRP, and Bile Salt Export Pump (BSEP) mediated transport with IC50 
values of 0.838 μM, 1.51 μM, and 5.06 μM, respectively. Sitravatinib demonstrated direct 
inhibition of CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, with IC50 values of 
2.9 μM, 11 μM, 10 μM, 1.9 μM, 11 μM, and 0.81 μM, respectively.  
Sitravatinib was more extensively metabolized in dogs than in mice, rats, and humans in vitro. In 
vitro results from the hERG assay demonstrate an IC50 of 0.6 μM (0.38 μg/mL) on the potassium 
current, which is approximately 227-fold higher than the mean free Cmax at stead-state 
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(0.00265 μM) in patients, suggesting a low risk for QTc prolongation. At the dose of 150 mg, the 
mean steady state plasma concentrations (adjusted for free fraction) observed in patients are 
approximately 290-fold lower than the hERG IC50 concentration. In vivo results demonstrated 
that there were no adverse effects on the cardiovascular system in telemetered dogs, including no 
effect on the QTc interval, when sitravatinib was administered as a single-dose to dogs at doses 
up to 4 mg/kg (mean 6-hour concentration of 0.072 μg/mL). Minor increases in vascular 
pressures were observed during the dog cardiovascular study. 
Assessment of the neurological functional observation battery and respiratory evaluations (tidal 
volume, respiration rate, and minute volume) did not reveal any sitravatinib-related effects at 
doses up to 25 mg/kg in rats (Day 1 mean Cmax = 4.9 μg/mL). 
Please refer to the sitravatinib IB for additional details regarding nonclinical studies of 
sitravatinib. 
1.5.2. 
Toxicology  
In the 4-week repeated-dose toxicology study in Beagle dogs, sitravatinib was tolerated at doses 
up to 3 mg/kg/day, the highest dose tested (TX-MGCD516-006). No unscheduled deaths 
occurred in the study; however, 1 dog in the 3 mg/kg/day group was taken off dosing on Day 8 
due to decreased body weight, emesis, loose feces, and dehydration. The remaining dogs in this 
dose group also exhibited decreased body weight and food consumption throughout the 
remainder of the dosing period. Upon necropsy, there were no treatment-related gross findings, 
clinical pathology changes, or microscopic findings attributed to sitravatinib at any dose level. 
Given the marked loss of body weight and decreased food consumption at 3 mg/kg/day, the 
NOAEL was considered 1 mg/kg/day. 
In the 13-week repeat-dose study in dogs (TX-MGCD516-014), sitravatinib was tolerated at 
doses up to 2 mg/kg/day, the highest dose tested. There were no test article-related unscheduled 
deaths and no adverse sitravatinib-related ophthalmic or clinical pathology parameter changes. 
Target organ effects were limited to necrotizing vascular/perivascular inflammation in the serosa 
of the oviduct and uterus of 2 mg/kg/day group females. These reproductive organ effects in 
females were not present after the 4-week recovery period, demonstrating complete reversal of 
these effects. Based on the adverse effects in the reproductive organs of female dogs given 
2 mg/kg/day of sitravatinib, the NOAEL was considered to be 2 mg/kg/day in males and 
0.6 mg/kg/day in females. 
In rats, VEGF-related target organs were identified, including the adrenal gland, Brunner’s 
glands in the duodenum, lymphoid tissues, ovary, kidney (increased basophilic tubules), liver, 
pancreas, and tongue, bone, and teeth. All effects, except those in the kidney, bile duct, and 
pancreas, either recovered or showed partial recovery. Daily oral administration of sitravatinib to 
Crl:CD (Sprague Dawley) rats at a dose level of 25 mg/kg/day was not tolerated and resulted in 
adverse clinical observations, changes in body weight and food consumption, mortality, and 
early termination. Based on the severity of the sitravatinib-related toxicity at 25 mg/kg/day and 
mortality (though reduced) in animals given ≥ 10 mg/kg/day, the NOAEL was determined as 
2.5 mg/kg/day.  
Administration of sitravatinib in the 4-week repeat-dose rat study (TX-MGCD516-007) led to 
early deaths at 10 and 25 mg/kg/day. The cause of death and morbidity at these dose levels 
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consisted of adrenal hemorrhage and necrosis. Based on the severity of the sitravatinib-related 
toxicity at ≥10 mg/kg/day, the NOAEL is 2.5 mg/kg/day. 
Sitravatinib was evaluated in a standard battery of Good Laboratory Practice genotoxicity studies 
(Ames, chromosome aberrations and in vivo rat micronucleus assays) and was considered 
negative for mutagenicity and clastogenicity. 
Refer to the sitravatinib IB for more detailed information on the toxicology of sitravatinib. 
1.5.3. 
Clinical Pharmacology  
The PK profile of single-agent treatment with the sitravatinib freebase capsule has been 
evaluated in Studies 516-001 and MRTX-500 after single- and repeated-dose administration in 
patients with advanced solid tumor malignancies, and in Study 516-006 in healthy volunteers. 
Exposure parameters (maximum concentration [Cmax] and area under the concentration-time 
curve [AUC]) were approximately dose proportional with single doses from 10 mg to 200 mg. 
After a 120 mg sitravatinib freebase single-dose administration under fasting condition, 
sitravatinib reached peak concentration in a median time (tmax) of approximately 6 to 8 hours. 
The arithmetic mean elimination half-life in patients is approximately 35.5 hours. After multiple 
oral administration, steady-state appeared to have been reached within 8 days and sitravatinib 
accumulated approximately 1.75- and 2-fold for Cmax and AUC0-24 to that of a single dose, 
respectively. The food effect on sitravatinib PK is being evaluated. 
Sitravatinib underwent multiple biotransformation reactions following single oral administration 
to healthy male volunteers, with metabolism mediated via oxidation, and oxidative O- and 
N-dealkylation, as well as secondary sulfation, demethylation, dehydrogenation, deamination, 
and reduction. Sitravatinib was the most abundant circulating component in human plasma, 
accounting for > 56% of the total drug-related exposure. M10 was the only major metabolite, 
accounting for approximately 19% of the total drug-related exposure. M10 was evaluated in 
nonclinical studies, and the data suggested M10 was pharmacologically active against 
sitravatinib RTK targets. 
Following a single oral dose of radio-labelled sitravatinib, the majority of the administered 
radioactivity (98.9%) was recovered from feces, indicating fecal excretion as the major route of 
elimination for sitravatinib. Only 0.05% of the administered dose was excreted in urine as 
unchanged sitravatinib, indicating negligible renal clearance for sitravatinib. 
Sitravatinib exhibits a pH-dependent solubility. The effect of acid-reducing agents on the PK of a 
single oral dose of sitravatinib in healthy adult subjects is being evaluated in Study 516-011. The 
emerging PK results showed that repeated oral doses of pantoprazole, a proton pump inhibitor 
(PPI), 40 mg once daily had no effect on the PK of sitravatinib. Given a PPI has no effect on the 
PK of sitravatinib, other acid-reducing agents (ie, H2 blockers, antacid) are also not expected to 
have any effect on the PK of sitravatinib. 
Pharmacodynamic (PD) effects of sitravatinib treatment were examined by analyzing biomarkers 
VEGFA, soluble VEGF-R2 and soluble MET ectodomain (sMET) levels in patients’ plasma 
samples collected before and/or after sitravatinib administration (at PK lead-in, Cycle 1 Day 1, 
Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1, and Cycle 3 Day 1) in Study 516-001. The EC50 
for VEGF-R2 was determined to be 36.8 ng/mL which is similar to the IC50 (30.9 ng/mL) 
determined from a nonclinical tumor growth inhibition (TGI) model (Source: 
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PK-MGCD516-011). At the clinical dose of 120 mg sitravatinib freebase QD, a geometric mean 
Ctrough of 70.6 ng/mL was observed, which is almost 2-fold higher than the EC50. The clinical 
dose of 120 mg sitravatinib freebase QD is expected to achieve an approximately near maximal 
effect on the drug target for sitravatinib.  
Refer to the sitravatinib IB for more detailed information on clinical pharmacology of 
sitravatinib. 
1.5.4. 
Clinical Experience With Sitravatinib  
Sitravatinib monotherapy and sitravatinib in combination with nivolumab are being evaluated in 
ongoing studies. Refer to the sitravatinib IB for more detailed information on sitravatinib and the 
currently ongoing studies. 
1.5.4.1. 
Safety Assessment of Monotherapy Study  
Study 516-001 is a multicenter Phase 1/1b first-in-human clinical study evaluating the safety, 
PK, metabolism, pharmacodynamics (PD), and clinical activity of single-agent sitravatinib in 
patients with advanced solid tumor malignancies. The study determined that the 200-mg dose 
exceeded the MTD and 150 mg QD was initially considered the viable Phase 1b starting dose, 
which was subsequently decreased to 120 mg QD based on ongoing assessment of tolerability. 
The Phase 1b expansion included patients having tumors with selected histological diagnoses 
(renal cell carcinoma, castrate-resistant prostate cancer) or with histological diagnosis and/or 
tumor molecular markers (genetic alterations in sitravatinib RTK targets, or loss of function 
mutations in CBL, the negative regulators of AXL, MET, and PDGFR/KIT signaling). As of 
26 June 2021, among the 193 patients with available safety data, 190 patients (98.4%) had 
experienced ≥ 1 AE regardless of causality, and 174 patients (90.2%) had experienced 
≥ 1 treatment-related AE. Treatment-related AEs reported in ≥ 10% of patients are provided in 
Table 1. 
Treatment-related Grade 3 to 5 AEs reported in ≥ 5% of patients were hypertension (21%), 
diarrhoea (10%), fatigue (7%), and palmar-plantar erythrodysaesthesia (PPE) syndrome (6%). 
Treatment-related Grade 4 AEs were reported in 3 patients and included lipase increased in 
2 patients and febrile neutropenia in 1 patient. A treatment-related Grade 5 AE of cardiac arrest 
was reported in 1 patient. 
Table 1: 
Summary of Treatment-Emergent, Treatment-Related Adverse Events 
(≥ 10%) by Preferred Term for Study 516-001 
Adverse Event 
 Preferred Term, n (%) 
Patients (N = 193) 
Any Related AE 
174 (90.2) 
 Diarrhoea 
99 (51.3) 
 Fatigue 
83 (43.0) 
 Hypertension 
78 (40.4) 
 Nausea 
58 (30.1) 
 Decreased appetite 
51 (26.4) 
 Vomiting 
46 (23.8) 
 Palmar-Plantar Erythrodysaesthesia Syndrome 
39 (20.2) 
 Aspartate aminotransferase increased 
36 (18.7) 
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Adverse Event 
 Preferred Term, n (%) 
Patients (N = 193) 
 Alanine aminotransferase increased 
35 (18.1) 
 Hypothyroidism 
33 (17.1) 
 Stomatitis 
28 (14.5) 
 Weight decreased 
28 (14.5) 
 Dysphonia 
27 (14.0) 
 Abdominal pain 
22 (11.4) 
 Constipation 
22 (11.4) 
 Proteinuria 
22 (11.4) 
 Dry mouth 
21 (10.9) 
 Rash 
21 (10.9) 
 Dizziness 
20 (10.4) 
Abbreviation: AE, adverse event.  
Serious Adverse Events: Overall, 79 patients (40.9%) have experienced ≥ 1 SAE regardless of 
causality, and treatment-related SAEs were reported in 30 patients (15.5%). Treatment-related 
SAEs reported in 2 or more patients (≥ 1%) included diarrhoea in 6 patients (3.1%), nausea and 
vomiting in 5 patients each (2.6%), fatigue in 4 patients (2.1%), hypertension in 3 patients 
(1.6%), and headache, left ventricular dysfunction, pancreatitis, and pulmonary embolism in 
2 patients each (1.0%). 
Treatment Discontinuation and Deaths: Of the 193 treated patients, 191 (99.0%) have 
discontinued receiving study treatment, in most cases due to objective disease progression 
(92 patients [47.7%]), AE (31 [16.1%]), or subject withdrawal (31 [16.1%]). A total of 
120 patients (62.2%) have discontinued the study due to death, with the most common cause of 
death being the primary disease under study. 
1.5.4.2. 
Safety Assessment of Combination Study  
Study MRTX-500 is an open-label, parallel group Phase 2 evaluation of sitravatinib in the 
combination with nivolumab in patients with locally advanced, unresectable or metastatic 
nonsquamous NSCLC. Patients who have experienced PD on or after treatment with a 
checkpoint inhibitor (CIT-experienced) as well as those who have experienced PD after 
treatment with platinum-based doublet chemotherapy (CIT-naïve) are enrolled. The sitravatinib 
treatment arm began with a lead-in evaluation of sitravatinib 120 mg once daily in combination 
with nivolumab administered by intravenous infusion, 240 mg once every 2 weeks or 480 mg 
once every 4 weeks. No protocol-defined dose-limiting toxicities (DLTs) were reported in the 
first 6 evaluable patients treated with the sitravatinib freebase at the starting dose of 120 mg once 
daily in combination with nivolumab. Based on the preliminary long-term tolerability 
assessments from Study 516-001 (Mirati 2018) and data from Study MRTX-500, Mirati decided 
to evaluate only the 120-mg dose of sitravatinib as this dose level should be adequate to achieve 
plasma exposure required for the inhibition of VEGF and TAM receptors necessary to achieve 
antitumor efficacy in the combination setting. The 120-mg dose level was selected as the RP2D. 
Based on the experience of patients enrolled into this study and in Study 516-001, 120 mg once 
daily was selected as the Phase 2 dose of sitravatinib in combination with nivolumab at 240 mg 
once every 2 weeks or 480 mg once every 4 weeks. 
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As of 26 June 2021, patient data were entered in the clinical study database for 207 patients 
(median age: 66 years; range: 30 to 89 years) with advanced or metastatic NSCLC. A total of 
156 patients were treated in the main study, 47 patients in the PK formulation substudy, and 
3 patients in the PK food effect substudy. Enrollment is complete. 
As of 26 June 2021, among the 206 patients with available safety data, 204 patients (99%) had 
experienced ≤1 AE regardless of causality; 193 patients (94%) had experienced treatment-related 
AEs; 191 patients (93%) had experienced sitravatinib-related AEs; and 149 patients (72%) had 
experienced nivolumab-related AEs. Treatment-related AEs reported in ≥ 10% of patients are 
provided in Table 2. 
Treatment-related Grade ≥ 3 AEs were reported for 115 patients (56%) and included 
hypertension (15%), diarrhoea (12%), and weight decreased (5%) as the most common events. 
Sitravatinib-related Grade 3 AEs were reported for 97 patients (47%), and the most common 
events (in > 5% of patients) by PT were hypertension (15%), diarrhoea (11%), and weight 
decreased (5%). Nivolumab-related Grade 3 AEs were reported for 45 patients (23%), and no 
events occurred in > 5% of patients by PT. 
Treatment-related Grade 4 AEs were reported for 8 patients (4%) overall, including 8 patients 
(4%) with sitravatinib-related Grade 4 AEs and 5 (2%) with nivolumab-related Grade 4 AEs. 
Grade 4 AEs related to sitravatinib only included acute kidney injury, cardiac failure, gastric 
ulcer perforation, hypertensive crisis, hyperuricemia, and lactobacillus test positive (in 1 patient 
each). Grade 4 AEs related to both sitravatinib and nivolumab included hemorrhagic shock, 
duodenal ulcer, lipase increased, lymphocyte count decreased, and pneumonitis (in 1 patient 
each), and Grade 4 AEs related to nivolumab only included cerebrovascular accident (1 patient). 
The Grade 4 events of hemorrhagic shock, duodenal ulcer, and lactobacillus test positive 
occurred in the same patient. Treatment-related Grade 5 AEs were reported for 2 patients (1%) 
overall and included cardiac arrest (related to sitravatinib) and cerebrovascular accident (related 
to sitravatinib) in 1 patient each. 
Table 2: 
Summary of Treatment-Emergent, Treatment-Related Adverse Events 
(≥ 10%) by Preferred Term for Study MRTX-500 
Adverse Event  
 Preferred Term, n (%) 
Patients (N = 206) 
Sitravatinib 
Related 
Nivolumab 
Related 
Any Treatment 
Related 
Any Treatment-Related AE 
191 (92.7) 
149 (72.3) 
193 (93.7) 
 Diarrhoea 
103 (50.0) 
49 (23.8) 
107 (51.9) 
 Fatigue 
80 (38.8) 
54 (26.2) 
86 (41.7) 
 Nausea 
80 (38.8) 
29 (14.1) 
80 (38.8) 
 Decreased appetite 
68 (33.0) 
21 (10.2) 
68 (33.0) 
 Weight decreased 
57 (27.7) 
15 (7.3) 
57 (27.7) 
 Hypertension 
56 (27.2) 
2 (1.0) 
56 (27.2) 
 Vomiting 
51 (24.8) 
23 (11.2) 
53 (25.7) 
 Hypothyroidism 
20 (9.7) 
42 (20.4) 
46 (22.3) 
 Dysphonia 
37 (18.0) 
7 (3.4) 
38 (18.4) 
 Palmar-plantar erythrodysaesthesia 
syndrome 
35 (17.0) 
2 (1.0) 
35 (17.0) 
 Aspartate aminotransferase increased 
31 (15.0) 
23 (11.2) 
34 (16.5) 
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Adverse Event  
 Preferred Term, n (%) 
Patients (N = 206) 
Sitravatinib 
Related 
Nivolumab 
Related 
Any Treatment 
Related 
 Alanine aminotransferase increased 
32 (15.5) 
24 (11.7) 
33 (16.0) 
 Stomatitis 
27 (13.1) 
6 (2.9) 
29 (14.1) 
 Dysgeusia 
24 (11.7) 
4 (1.9) 
24 (11.7) 
 Dry mouth 
21 (10.2) 
7 (3.4) 
23 (11.2) 
 Proteinuria 
21 (10.2) 
5 (2.4) 
22 (10.7) 
 Dehydration 
20 (9.7) 
8 (3.9) 
21 (10.2) 
Abbreviation: AE, adverse event.  
Note: AEs are ordered by decreasing frequency within the overall “any treatment related” column. 
Serious Adverse Events: Among the 206 patients receiving study treatment, 102 (50%) 
experienced ≥ 1 SAE regardless of causality. Treatment-related SAEs were reported in 
51 patients (25%) overall, including sitravatinib-related SAEs in 42 patients (20%) and 
nivolumab-related SAEs in 24 patients (12%). Sitravatinib-related SAEs occurring 
in > 2 patients (> 1%) included diarrhoea (8 patients [4%]), pulmonary embolism (4 [2%]), deep 
vein thrombosis, nausea and vomiting (3 [1.5%] each). Nivolumab-related SAEs occurring 
in > 2 patients (> 1%) included diarrhoea and pneumonitis (4 patients [1.9%] each), and 
vomiting (3 [1.5%]). 
Treatment Discontinuation and Deaths: Of the 206 treated patients, 200 (97%) have 
discontinued sitravatinib, in most cases due to disease progression (47%), or AE (25%), and 
200 patients (97%) have discontinued nivolumab, in most cases due to disease progression 
(49%), or AE (24%). A total of 141 patients have died, with the primary cause of death being the 
primary disease under study (118/141 patients). One death was attributed to study treatment 
toxicity (Grade 5 event of cerebrovascular accident [verbatim term: stroke] related to 
sitravatinib).  
Study BGB-900-103 is an open-label, multicenter, nonrandomized, multicohort, Phase 1b study 
to evaluate the safety, tolerability, PK, and preliminary antitumor activity of sitravatinib in 
combination with tislelizumab in patients with advanced solid tumors (NCT03666143). As of 
26 June 2021, safety data were available for 216 patients with advanced solid tumors who were 
treated with sitravatinib in combination with tislelizumab in this study (sitravatinib IB).  
Among the 216 patients who received study treatment, 215 patients (99.5%) experienced ≥ 1 AE 
regardless of causality. A total of 210 (97%) experienced treatment-related AEs overall, 
including 203 (94%) experiencing sitravatinib-related AEs and 164 (76%) experiencing 
tislelizumab-related AEs. Treatment-related AEs reported in ≥10% of patients overall are 
presented in Table 3.  
Treatment-related ≥ Grade 3 AEs were reported in 105 patients (49%), and those reported in 5 or 
more patients (≥ 3%) were hypertension (35 patients [16%]), ALT increased (12 [6%]), diarrhea 
(8 [4%]), and PPE syndrome (7 [3%]). 
Treatment-related Grade 4 events were reported for 6 patients (2.8%) and treatment-related 
Grade 5 events were reported for 4 patients (death [2 patients, 0.9%], and cardiac failure and 
ischaemic stroke [1 patient each, 0.5%]). 
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Table 3: 
Summary of Treatment-Emergent, Treatment-Related AEs (≥ 10%) by 
Preferred Term for Study BGB-900-103 
Adverse Event 
 Preferred Term, n (%) 
Patients (N = 216) 
Sitravatinib 
Related 
Tislelizumab 
Related 
Any Treatment 
Related 
Any Related AE 
203 (94.0) 
164 (75.9) 
210 (97.2) 
 Diarrhoea 
92 (42.6) 
31 (14.4) 
96 (44.4) 
 Alanine aminotransferase increased 
81 (37.5) 
63 (29.2) 
93 (43.1) 
 Aspartate aminotransferase increased 
81 (37.5) 
64 (29.6) 
90 (41.7) 
 Hypertension 
75 (34.7) 
7 (3.2) 
76 (35.2) 
 Hypothyroidism 
14 (6.5) 
60 (27.8) 
62 (28.7) 
 Palmar-plantar erythrodysaesthesia syndrome 
62 (28.7) 
4 (1.9) 
62 (28.7) 
 Decreased appetite 
54 (25.0) 
14 (6.5) 
55 (25.5) 
 Nausea 
52 (24.1) 
14 (6.5) 
54 (25.0) 
 Vomiting 
40 (18.5) 
5 (2.3) 
41 (19.0) 
 Weight decreased 
39 (18.1) 
9 (4.2) 
39 (18.1) 
 Blood creatine phosphokinase increased 
19 (8.8) 
28 (13.0) 
35 (16.2) 
 Fatigue 
32 (14.8) 
12 (5.6) 
35 (16.2) 
 Proteinuria 
35 (16.2) 
6 (2.8) 
35 (16.2) 
 Rash 
24 (11.1) 
21 (9.7) 
34 (15.7) 
 Dysphonia 
27 (12.5) 
4 (1.9) 
29 (13.4) 
 Blood creatine phosphokinase MB increased 
22 (10.2) 
14 (6.5) 
25 (11.6) 
 Blood lactate dehydrogenase increased 
21 (9.7) 
17 (7.9) 
25 (11.6) 
 Blood bilirubin increased 
24 (11.1) 
11 (5.1) 
24 (11.1) 
 Stomatitis 
23 (10.6) 
1 (0.5) 
24 (11.1) 
 Platelet count decreased 
19 (8.8) 
17 (7.9) 
22 (10.2) 
Abbreviation: AE, adverse event. 
Note: AEs are ordered by decreasing frequency within the overall “any treatment related” column. 
Serious Adverse Events: Among the 216 patients with available safety data, 118 patients (55%) 
experienced at least one SAE regardless of causality. Treatment-related SAEs were reported in 
70 patients (32%), and included diarrhea in 8 patients (4%), hepatic function abnormal in 
5 patients (2%), and pneumonia and transaminases increased in 4 patients each (2%). All other 
treatment-related SAEs occurred in 2 or fewer patients (<1 %) overall.  
Treatment Discontinuation and Deaths: Of the 216 patients receiving study treatment, 
179 patients (83%) have discontinued sitravatinib and 176 (82%) have discontinued tislelizumab 
treatment. The most common reasons for discontinuation from sitravatinib were progressive 
disease (116 patients [54%]), AE (42 [19%]), and withdrawal by patient (15 [7%]). The most 
common reasons for discontinuation from tislelizumab were progressive disease (128 patients 
[59%]), AE (26 [12%]), and withdrawal by patient (18 [8%]). A total of 103 deaths have been 
reported, and the primary cause of death was progressive disease (83 of 103 patients [81%]). 
1.5.4.3. 
Efficacy Assessment of Sitravatinib Monotherapy  
Efficacy results are available from the Phase 1b study 516-001(Werner et al 2017). In this 
Phase 1b dose expansion study, sitravatinib was evaluated in different patient populations: 
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• Tumors harboring genetic alterations resulting in dysregulation of sitravatinib’s RTK 
targets: 
− NSCLC with activating genetic alteration in RET, KDR, PDGFRA, KIT, NTRK, 
DDR2, MET, AXL or with loss of function mutation with CBL 
− Any solid tumor malignancy with genetic alteration of sitravatinib RTK targets or 
CBL 
• Metastatic renal cell carcinoma (mRCC) refractory to VEGF pathway inhibitors 
(simultaneously targeting MET and VEGFR) 
• Castration resistant prostate cancer (CRPC) with bone metastases 
As of 18 April 2018, 29 patients were enrolled in the Phase 1b mRCC study, after failure of prior 
anti-angiogenic therapy. Sitravatinib monotherapy showed 20% confirmed ORR among 
20 evaluable patients. Prolonged stable disease for ≤ 24 weeks was observed in 6 additional 
patients.  
As of 4 September 2018, 16 patients were enrolled in the Phase1b CBL loss of function cohort. 
Among 8 clinical activity evaluable patients (received ≤ 1 cycle of sitravatinib for more than 
80% of assigned total dose and ≤ 1 on-study disease assessment), sitravatinib monotherapy 
demonstrated anti-tumor activity in 2 patients (one with NSCLC and one with melanoma, 
respectively).  
1.5.4.4. 
Efficacy Assessment of Sitravatinib Combination with PD-1 Blocking Agent  
Early signs of clinical activity from the Phase 2 MRTX-500 study have been observed in patients 
with nonsquamous NSCLC, who have experienced disease progression following prior 
anti-PD-(L)1 therapy. As of the cutoff date of 01 June 2021, the median OS was 14.9 months 
(95% CI: 9.3 to 21.1 months) in patients with nonsquamous NSCLC who had clinical benefit 
from prior CPI therapy and received the sitravatinib plus nivolumab treatment in the study 
(N = 68) (Leal et al 2021). Among the 68 patients, the ORR was 18% (12 responders of 
68 patients) including 2 CRs (3%) and 10 PRs (15%), with a median DOR of 12.8 months; the 
median PFS was 5.7 months (95% CI: 4.9 to 7.6 months) (Leal et al 2021). The combination of 
sitravatinib with nivolumab is a rational approach to restore or enhance the clinical activity of 
CIT in patients with immunotherapy resistant NSCLC.  
Study 516-003 is a Phase 2 study of sitravatinib in combination with nivolumab in patients 
diagnosed with advanced or metastatic urothelial carcinoma. In a cohort of patients (N = 22, data 
cutoff date of 17 October 2019) who have progressed on or after CIT as the most recent 
treatment before the study, and were previously treated with platinum-based chemotherapy, 
confirmed ORR was 27% whilst 86% of patients had CR/PR/stable disease longer than 12 weeks 
(Msaouel et al 2019). In cohort of CIT naïve and platinum treated patients, sitravatinib plus 
nivolumab demonstrated consistent clinical activity (confirmed ORR 37%, clinical benefit rate 
73%, median PFS 4.0 months, median DOR 5.6 months, and median OS 9.2 months) as of the 
data cutoff on 30 July 2020 (Msaouel et al 2020).  
In Study BGB-900-103, Cohort A and Cohort F enrolled patients with nonsquamous and 
squamous metastatic NSCLC, respectively, with the disease refractory/resistant to anti-PD-(L)1 
therapy. From December 2018 to June 2020, a total of 47 patients with NSCLC, nonsquamous 
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(n = 24) and squamous (n = 23), were enrolled. As of the data cutoff date of 13 October 2020, 
the confirmed ORR was 13.6% and the DCR rate was 86.4%. The median DOR was 6.90 months 
(95% CI: 3.06 to not evaluable). The median PFS was 5.2 months (95% CI: 4.1 to 5.9 months). 
As of the data cutoff date, the median OS was 10.1 months (95% CI: 6.1 to 18.1 months), with a 
median follow-up duration of 12.4 months. The OS data were not mature (ESMO Poster 2021). 
1.6. 
Study Rationales  
1.6.1. 
Rationale for Tislelizumab in the Treatment of Non-Small Cell Lung Cancer  
High levels of FcγR-expressing MDSCs (eg, M2 macrophage, MDSC) in tumor tissues predict a 
poor survival of tumor-bearing animals after anti-PD-1 monoclonal antibody treatment; this is 
possibly due to Fc-FcγR-mediated antibody-dependent cellular cytotoxicity (ADCC) or 
antibody-dependent cellular phagocytosis (ADCP) depletion of effector T cells (Gül et al 2015 ; 
Prieto et al 2015; Makarova-Rusher et al 2015; Beers et al 2016; Dahan et al 2015). As a no- to 
low-FcγR-binding agent (thus causing minimal ADCC/ADCP effect), tislelizumab may show 
improved efficacy and reduced toxicity in NSCLC. 
Latest data collected from the Phase 1 BGB-A317_Study_001, tislelizumab monotherapy has 
established a manageable safety profile, with the most common side effects consistent with 
known class effects of other anti-PD-1 antibodies. Finally, data from Study BGB-A317-303 
showed superiority with tislelizumab monotherapy as compared with docetaxel for the treatment 
of patients with squamous- or nonsquamous NSCLC in the second- or third-line settings 
(Section 1.4.4.2.3).  
1.6.2. 
Rationale for Selection of Tislelizumab Dose  
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 and the 
fixed dosage of 200 mg once every 3 weeks was determined to be the clinical recommended dose 
for tislelizumab. 
In the Study BGB-A317_Study_001, the dose of tislelizumab was escalated from 0.5 mg/kg to 
10 mg/kg once every 2 weeks and no maximum tolerated dose was reached. For dose schedule 
and dose exploration, a dosage of 2 mg/kg or 5 mg/kg scheduled for either once every 2 weeks or 
once every 3 weeks and a fixed dose of 200 mg once every 3 weeks were evaluated. All dosages 
tested were tolerated. Comparable safety and efficacy profiles were observed between the 2 and 
5 mg/kg dose levels with an administration frequency of either once every 2 weeks or once every 
3 weeks, suggesting no clear dose-dependence across these regimens. Also, exposure-response 
analysis indicated a lack of clinically significant exposure-response relationships for ORR and 
safety endpoints across a variety of tumor types based on the combined data including dose 
ranges up to 10 mg/kg. The less frequent regimen of once every 3 weeks regimen was selected 
based on the similarity in efficacy and safety events observed between the once every 2 weeks 
and once every 3 weeks regimens tested in the study. Combined with the forementioned 
observations, the fixed dose of 200 mg once every 3 weeks was selected to be the recommended 
dose as tislelizumab concentrations with this dose largely overlapped with those observed with 
the 2 mg/kg and 5 mg/kg once every 3 weeks.  
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The efficacy and safety of tislelizumab at the recommended dosage of 200 mg once every 
3 weeks have been subsequently studied in multiple clinical studies across different tumor types, 
including NSCLC. With this dose regimen, marketing approvals have been granted in China for 
tislelizumab in combination with chemotherapy as the first-line treatment and for tislelizumab 
monotherapy as the second- or third-line treatment for patients with locally advanced or 
metastatic NSCLC. In this study, the dose regimen of 200 mg once every 3 weeks will be used 
for tislelizumab to evaluate its combination with sitravatinib in patients with NSCLC. 
1.6.3. 
Rationale for Selection of Sitravatinib Dose  
The 120 mg QD freebase dose level was selected as the optimized dose for clinical evaluation in 
the planned Phase 2 and Phase 3 studies based on the totality of evidence available for clinical 
activity, safety, and supportive pre-clinical and clinical pharmacology data including E-R 
analysis. 
In Study 516-001, the safety, PK, and clinical activities of sitravatinib following oral 
administration of doses ranging from 10 mg to 200 mg were evaluated in patients with advanced 
solid tumor malignancies. Based on the Phase 1 dose escalation, 150 mg QD freebase 
formulation was established as the MTD and the starting dose for the Phase 1b components. 
During the conduct of the study, the dose was decreased from 150 mg QD to 120 mg QD 
because of early suggestion that treatment discontinuations may be higher than expected and that 
tolerability over a longer treatment period favors a lower dose (preliminary data from 
Study 516-001). As a result, 120 mg sitravatinib freebase was selected for further assessment in 
the Phase 2 Study MRTX-500.  
Pharmacokinetic results demonstrated that sitravatinib exposure increased approximately dose 
proportionally when orally administered at doses between 10 and 200 mg sitravatinib freebase 
QD in patients. At the 120 mg QD dose level, between-patient variability was approximately 
50% to 60%. The following preclinical and clinical pharmacology findings support 120 mg QD 
as the appropriate dose to achieve efficacy:  
• 
Sitravatinib targets several receptor tyrosine kinases that have been shown in preclinical 
models to mediate an immunosuppressive TME. As determined in enzyme and cellular 
assays, the key target kinases it showed potency against include AXL, MERT, VEGFR2, 
KIT, and MET. The observed mean steady-state trough level with sitravatinib 120 mg 
QD in patients was 73.4 ng/mL (Study MRTX-500). The free fraction adjusted trough 
plasma concentration of sitravatinib (1.64 nM based on 98.6% plasma protein binding) 
compared with the biochemical and cellular IC50 values (ranging from 1.5 to 70 nM) for 
the key target kinases suggests several targets are only partially inhibited at the end of 
the dosing interval using the 120 QD dose level. Lower dose levels result in even lower 
predicted target kinase inhibition at the end of the dosing interval. These data suggest the 
120 mg QD freebase dose is required to more fully inhibit key kinases for the entire 
dosing interval. 
• 
PK/PD analysis using PK and biomarkers data from Study 516-001 showed a 
concentration- and dose-dependent modulation of s-VEGF-R2. The EC50 was 
determined to be 36.8 ng/mL. The clinical dose of 120 mg sitravatinib freebase QD 
achieved the mean Ctrough,ss (73.4 ng/mL; Study MRTX-500) approximately 2-fold higher 
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than the EC50 and is expected to achieve an a near-maximal effect on the drug target for 
sitravatinib.  
Exposure-response analyses were performed for efficacy endpoints (ie, clinical benefit [CB] and 
ORR) and safety endpoints (ie, fatigue, diarrhea, system blood pressure, PPE, any TEAEs 
≥ Grade 3, and any AEs ≥ Grade 3 and 4) in patients with NSCLC receiving nivolumab and 
sitravatinib combination regimens. Overall, statistically significant E-R relationship was 
observed for CB, ORR, and PPE or oral dysaesthesia (ie, increasing the probabilities of ORR and 
CB, as well as AE PPE or oral dysaesthesia with increasing sitravatinib exposure). Sitravatinib 
steady-state exposure associated with 120 mg QD is predicted to achieve approximately 85.4% 
probability for CB, which is near the maximal effect and 22.2% probability for ORR. In contrast, 
doses lower than 120 mg QD (eg, 80 mg QD) is expected to be suboptimal for efficacy based on 
the predicted probability for CB and ORR of 80% and 13.6%, respectively. From the 
safety/tolerability perspective, sitravatinib 120 mg QD is predicted to have approximately 24% 
probability for the AE palmar-plantar incidence. Increasing sitravatinib exposure or doses might 
result in a higher probability of any grade PPE or oral dysaesthesia incidence. 
Sitravatinib 150 mg QD freebase showed treatment discontinuations at a higher-than expected 
rate (Study 516-001) and is predicted to result in a higher probability for the AE PPE incidence 
based on E-R analysis. In contrast, sitravatinib freebase 80 mg QD is expected to be sub-optimal 
for efficacy based on pre-clinical and clinical pharmacology properties and E-R analysis. Thus, 
sitravatinib 120 mg QD freebase was the optimal dose selected for further clinical evaluation in 
combination regimens based on the totality of clinical data, preclinical and clinical 
pharmacology properties, and E-R results. 
To introduce malate capsule formulation into the development of sitravatinib, Studies 516-006 
and BGB-Sitravatinib-101 have been conducted to compare the systemic exposure of sitravatinib 
between the malate and the freebase capsule formulation. The results showed that the PK 
exposures of 100 mg malate capsule formulations and 120 mg freebase capsule formulations 
were comparable (sitravatinib IB). Therefore, the 100 mg QD dose of sitravatinib malate capsule 
is recommended for further evaluation in NSCLC patients.  
1.6.4. 
Rationale for Dose Selection of Sitravatinib and Tislelizumab in Combination 
Treatment  
Given the low potential of pharmacokinetic and pharmacodynamic drug-drug interaction 
between tislelizumab and sitravatinib, the dose regimens recommended for sitravatinib and 
tislelizumab monotherapy have been adopted for combination assessment and have been 
evaluated in patients with advanced or metastatic malignancies (including NSCLC) in 
Studies BGB-900-103 and BGB-900-104. As of June 2021, a total of 327 patients were enrolled 
and the tolerability data further supported the combination of tislelizumab 200 mg once every 
3 weeks and sitravatinib freebase capsule formulation 120 mg QD (Section 1.5.4). The dose 
regimen of 200 mg tislelizumab once every 3 weeks in combination with 120 mg sitravatinib 
freebase capsule QD are tolerable. The PK exposures of a single dose of 100 mg sitravatinib 
malate capsule and 120 mg freebase capsule in healthy subjects are considered comparable 
(Section 1.6.3). Therefore, tislelizumab 200 mg once every 3 weeks in combination with 
sitravatinib 100 mg QD malate capsule will be used in this study.  
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1.6.5. 
Rationale for Docetaxel as the Comparator  
Docetaxel 75 mg/m² administered intravenously once every 3 weeks was chosen as the active 
control. This dosing regimen is recommended as the standard of care in the second- and 
third-line treatment setting for NSCLC based on international guidelines used consistently and 
globally, including within the European Union, the United States of America, and China, and it 
is also a commonly used standard treatment option in all regions participating in the studies. 
Furthermore, despite the potential differences between Asian and Western patients with lung 
cancer in terms of epidemiology (eg, risk factors, demographics, and genetic susceptibility), the 
treatment outcome with docetaxel is similar between patients in China and Europe with 
advanced non-oncogene driven NSCLC. A median OS of 7 to 10 months was observed in the 
docetaxel arms across pivotal studies with other anti-PD-1/PD-L1 agents, including 
CHECKMATE 017, CHECKMATE057, KEYNOTE-010, and OAK studies (Brahmer et al 
2015; Borghaei et al 2015; Herbst et al 2016; Rittmeyer et al 2017). Consistent median OS was 
reported for docetaxel in a Phase 3 study comparing docetaxel with pemetrexed as second-line 
treatment in Chinese patients with NSCLC (Sun et al 2013). 
1.6.6. 
Rationale for Combination of Tislelizumab and Sitravatinib in the Treatment of 
Non-Small Cell Lung Cancer  
Cancer cells face selective pressures while being treated, and mutations occurring in individual 
cancer cells represent continuous evolution of the original cancer. Almost all malignancies 
develop resistance to anticancer therapies eventually. This is also the case for treatment with 
checkpoint blockade agents where acquired resistance occurs in a large portion of treated 
patients who achieved an initial meaningful response. This phenomenon of acquired resistance 
helps cancer cells adapt to the environment and survive immune attacks and is a reminder of the 
therapeutic challenges that need to be overcome (Syn et al 2017). One of the mechanisms is an 
immunosuppressive TME. It includes a collection of various cell types that have switched sides 
and protect the cancer cells from immune system attacks. Various RTKs have been implicated in 
creating and maintaining an immunosuppressive TME.  
Combining an immunotherapeutic PD-1 checkpoint inhibitor with an RTK inhibitor that has both 
immunomodulatory and antitumor properties could enhance the antitumor efficacy observed with 
either agent alone. By targeting the specific RTK receptors, an immunosuppressive TME is 
converted to an immune-supportive TME, which makes the cancers more likely to respond to 
checkpoint inhibitor treatment. The use of RTK blocking agents to treat cancer is well 
established based on robust clinical efficacy achieved with well tolerated inhibitors directed 
toward oncogenic tyrosine kinases. In addition, selected targeted therapies have been shown to 
modulate the immunogenic status of tumors, improve tumor perfusion by reducing intratumoral 
pressure and modulate subsets of immune cells, thereby increasing the frequency and function of 
effector immune elements while decreasing the number and function of immune suppressor cells.  
Sitravatinib is a potent, spectrum-selective RTK inhibitor. It inhibits several closely related 
RTKs, including members of the TAM family (TYRO3, AXL and MER), as well as VEGFR2 
and KIT. This inhibition weakens the cancer’s defenses in the TME. First, the antitumor activity 
of sitravatinib may promote the release of tumor antigens. Second, inhibition of the split kinase 
receptors VEGFR-2 and KIT may decrease the number of regulatory T cells (Tregs) and 
myeloid-derived suppressor cells (MDSCs), thus promoting the expansion and migration of 
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antitumor cytotoxic T cells and their infiltration into tumor tissue. Third, sitravatinib may reverse 
the immunosuppressive effects within the TME that are mediated by the TAM receptors through 
inhibition of MERTK, resulting in an increased number of M1 versus M2-polarized 
macrophages and release of interleukin (IL)-12, IL-6, and tumor necrosis factor. These 
downstream effects enhance CD8+ T cell activation, and through the inhibition of AXL, promote 
increased antigen presentation through termination of the Toll-like receptor-dependent 
inflammatory response in dendritic cells. 
Treatment options after prior immunotherapy in lung cancer remain a significant unmet medical 
need. Combination therapy with agents that target the molecular and cellular mechanisms of 
resistance to checkpoint inhibitor therapy is a rational approach to improving outcomes in 
patients. Targeting RTKs has been shown to stimulate the immune system and cause synergistic 
effects that stimulate tumor shrinkage. 
Early clinical studies demonstrated encouraging data that support this hypothesis. In a Phase 1b/2 
study of lenvatinib (a multikinase inhibitor of vascular endothelial growth factor receptor 
[VEGFR] 1 to 3, fibroblast growth factor receptor 1 to 4, platelet-derived growth factor receptor 
α, RET and KIT) plus pembrolizumab in patients with histologically and/or cytologically 
confirmed metastatic NSCLC, the combination therapy showed promising clinical activity in 
NSCLC (Taylor et al 2020). With 52% of patients experienced anti-PD-(L)1 as prior therapy, the 
ORR at 24 weeks was 33.3% per immune-related Response Evaluation Criteria in Solid Tumors 
(irRECIST) in previously treated patients while the median DOR was 10.9 months and median 
PFS was 5.9 months. 
Another Phase 2 study MRTX-500 demonstrated encouraging preliminary OS data with 
sitravatinib in combination with nivolumab in patients with NSCLC that progressed on or after 
checkpoint inhibitor. The median OS was 14.9 months for the subset of patients with prior 
clinical benefit who received the combination in the second- or third-line of treatment (Leal et al 
2021). Study BGB-900-103 showed additional promising efficacy data with the combination 
treatment of sitravatinib and tislelizumab for patients with nonsquamous (Cohort A) or squamous 
(Cohort F) metastatic NSCLC that are refractory/resistant to anti-PD-(L)1 therapy (see details in 
Section 1.5.4.4). In both of these studies, anti-PD-(L)1 therapy was required to be the most 
recent prior treatment. As patients who have disease progression on or after the upfront 
anti-PD-(L)1 therapy that was followed by chemotherapy are also refractory/resistant to 
anti-PD-(L)1 therapy, based on the mechanism of sitravatinib, it is speculated that sitravatinib in 
combination with a checkpoint inhibitor is beneficial to those patients, just as to the subset of 
patients who received anti-PD-(L)1 therapy as the most recent prior treatment. 
In summary, selective RTKs inhibit key molecular and cellular pathways strongly implicated in 
checkpoint inhibitor resistance and therefore represent reasonable strategies to enhance or restore 
antitumor immunity when combined with anti-PD-(L)1 monoclonal antibodies. Therefore, 
tislelizumab, which belongs to the same class of PD-1 blocking antibodies, may elicit 
comparable antitumor activity when combined with sitravatinib.  
1.7. 
Benefit-Risk Assessment  
Patients with locally advanced or metastatic NSCLC represent a population with a great unmet 
medical need. Docetaxel, pemetrexed, and erlotinib are currently the 3 approved systemic 
therapy available to patients with NCSLC worldwide with manageable safety profiles 
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(characterized by a relatively moderate incidence of dose reductions or drug discontinuations; 
see Section 1.2). 
Immunotherapy with checkpoint inhibitors has demonstrated responses in patients with NSCLC. 
Combination therapy with a small-molecule inhibitor of the VEGFR pathway may improve the 
clinical efficacy of immunotherapies and overcome resistance to checkpoint inhibitor therapy. 
Access to new treatment options and/or treatment options after prior immunotherapy remains a 
significant unmet medical need. Based on the available data for tislelizumab and sitravatinib and 
publications for other PD-(L)1 inhibitors and other small-molecule inhibitors targeting the 
VEGFR pathway, the combination of sitravatinib and tislelizumab may elicit greater antitumor 
activity and have a manageable safety profile.  
More than 1000 patients have been treated with sitravatinib either as monotherapy or in 
combination with other drugs. Nonclinical toxicology studies, as well as clinical safety data from 
the Phase 1/1b and Phase 2 studies, suggest that AEs associated with sitravatinib are similar to 
those observed with other small-molecule inhibitors of the VEGFR pathway. For further 
discussion on the safety profile of sitravatinib, please refer to the sitravatinib IB. 
More than 3000 patients have been treated with tislelizumab as monotherapy at clinically 
relevant doses (≥ 2 mg/kg) or in combination with other drugs. The safety profile is consistent 
with known class effects of anti-PD-1 antibodies and includes mostly mild and moderate AEs. 
Very few Grade 3 or Grade 4 imAEs have been observed, which are generally reversible and 
manageable with study treatment interruption and/or steroid treatment. For further discussion on 
the safety profile of tislelizumab, please refer to the tislelizumab IB. 
1.8. 
Study Conduct  
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and in accordance with Good 
Clinical Practice (GCP) standards. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives  
2.1.1. 
Primary Objective  
• To compare the overall survival (OS) of tislelizumab and sitravatinib combination 
therapy with that of docetaxel monotherapy  
• To compare the progressive-free survival (PFS) of tislelizumab and sitravatinib 
combination therapy with that of docetaxel monotherapy, as assessed by the Independent 
Review Committee (IRC)  
2.1.2. 
Secondary Objectives  
• To compare the PFS of tislelizumab and sitravatinib combination therapy with that of 
docetaxel monotherapy, as assessed by the investigator  
• To compare the overall response rate (ORR), duration of response (DOR), and disease 
control rate (DCR) of tislelizumab and sitravatinib combination therapy with that of 
docetaxel monotherapy as assessed by the IRC  
• To evaluate the safety and tolerability of tislelizumab and sitravatinib combination 
therapy compared with that of docetaxel monotherapy 
• To evaluate and compare health-related quality of life (HRQoL) between the tislelizumab 
and sitravatinib combination therapy with that of docetaxel monotherapy via patient 
reported outcomes (PROs) using EORTC-QLQ-C30 (measuring general cancer) and its 
lung cancer module, QLQ-LC13, and the European Quality of Life 5-Dimension 5-Level 
(EQ-5D-5L)  
• To characterize the pharmacokinetics (PK) of sitravatinib when given in combination 
with tislelizumab, if data permit 
2.1.3. 
Exploratory Objectives  
• To compare the combination of tislelizumab with sitravatinib versus docetaxel 
monotherapy, as measured by ORR, DOR, and DCR assessed by the investigator  
• To explore the predictive and prognostic effect of PD-L1 expression level  
• To characterize the PK of the active metabolite M10 of sitravatinib when given in 
combination with tislelizumab, if deemed necessary 
• To characterize the PK and immunogenicity of tislelizumab when given in combination 
with sitravatinib 
• To explore potential biomarkers that may correlate with clinical responses or resistance to 
sitravatinib in combination with tislelizumab 
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2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoint  
• OS, defined as the time from randomization to death from any cause 
• PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by the IRC based on Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1, or death from any cause, whichever occurs first 
2.2.2. 
Secondary Endpoints  
• PFS, defined as the time from randomization to the first occurrence of disease 
progression as determined by the investigator based on RECIST v1.1, or death from any 
cause, whichever occurs first 
• ORR, defined as the proportion of patients with PR or CR as determined by the IRC 
based on RECIST v1.1 
• DOR, defined as the time from the first occurrence of a documented objective response to 
the time of the first occurrence of disease progression, as determined by the IRC based on 
RECIST v1.1, or death from any cause, whichever occurs first 
• DCR, defined as the proportion of patients whose best overall response (BOR) is CR, PR 
or stable disease as determined by the IRC based on RECIST v1.1 
• HRQoL, defined as changes in patient-reported outcomes (PROs), according to the 
European Organisation for Research and Treatment of Cancer (EORTC) core cancer 
(QLQ-C30) and its lung cancer module, QLQ-LC13, as well as the European Quality of 
Life 5-Dimension 5-Level (EQ-5D-5L) from time of randomization to End of Treatment 
Visit (EOT), death or study discontinuation whichever comes first.  
• Incidence and severity of TEAEs graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 
• Plasma concentrations and the derived PK parameters of sitravatinib if data permit 
2.2.3. 
Exploratory Endpoints  
• ORR, defined as the proportion of patients with PR or CR as determined by the 
investigator based on RECIST v1.1 
• DOR, defined as the time from the first occurrence of a documented objective response to 
the time of the first occurrence of disease progression, as determined by the investigator 
based on RECIST v1.1, or death from any cause, whichever occurs first 
• DCR, defined as the proportion of patients whose BOR is CR, PR, or stable disease based 
on RECIST v1.1 by the investigator 
• To explore the predictive and prognostic effect of PD-L1 expression level on OS 
• To evaluate the predictive and prognostic effect of PD-L1 expression level using PFS, 
ORR, and DCR by the IRC and investigator 
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• Plasma concentrations and the derived PK parameters of M10 if data permit 
• Serum concentrations of tislelizumab and the incidence of antidrug antibodies (ADAs) 
• Potential biomarkers such as PD‑L1 expression, gene expression profiling (GEP), tissue 
and blood tumor mutation burden (tTMB/bTMB) and microsatellite instability (MSI), 
and alterations in tissue and circulating tumor DNA (ctDNA), and the association of 
biomarkers with disease status, and response/resistance to sitravatinib in combination 
with tislelizumab 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is an open-label, randomized, multicenter, Phase 3 clinical study evaluating the efficacy and 
safety of tislelizumab in combination with sitravatinib compared with docetaxel in patients with 
locally advanced or metastatic NSCLC who have disease progression following platinum-based 
chemotherapy and anti-PD-(L)1 antibody, with the anti-PD-(L)1 antibody administered in 
combination with, or sequentially before or after the platinum-based chemotherapy. 
The study will be conducted at approximately 100 centers globally. The study will consist of a 
screening period, a treatment period, and a long-term follow-up period. Approximately 
420 patients with locally advanced or metastatic NSCLC, who received no more than 2 lines of 
prior systemic therapy, will be enrolled and randomized in a 1:1 ratio to receive either 
tislelizumab in combination with sitravatinib, or docetaxel monotherapy.  
Patients must have had radiographic progression per RECIST v1.1 on or after anti-PD-(L)1 
containing therapy for locally advanced and unresectable or metastatic NSCLC. If 
anti-PD-(L)1-containing therapy is not the most recent systemic treatment, patients should also 
have radiographic progression per RECIST v1.1 on or after the most recent systemic treatment. 
Adjuvant or neo-adjuvant chemotherapy will be counted as 1 prior line of chemotherapy if the 
disease progressed on or within 6 months after the completion of the last dose. In locally 
advanced and unresectable NSCLC, disease progression on or within 6 months after the end of 
systemic therapy as part of prior curatively intended multimodal therapy will count as 1 prior 
line of systemic therapy. If chemoradiation is followed by planned systemic therapy without 
documented progression between chemoradiation and systemic therapy, the entire treatment 
course counts as 1 line of therapy (patients who received anti-PD-[L]1 antibody as consolidation 
treatment following definitive chemoradiation for unresectable Stage III NSCLC can be enrolled 
immediately after disease progression, if the disease progression occurred within 6 months after 
the end of platinum-based chemotherapy component of the definitive chemoradiation). 
Maintenance therapy following platinum-based chemotherapy is not considered as a separate line 
of therapy. No other prior immunotherapies, including but not limited to anti-TIGIT, anti-OX40, 
and anti-CD137, will be allowed (prior anti-CTLA4 used in combination with anti-PD-[L]1 is 
permitted); no prior anticancer therapy having the same mechanism of action as sitravatinib (eg, 
tyrosine kinase inhibitor with a similar target profile or anti-VEGF or anti-VEGFR antibody) 
will be allowed either. 
Patients with histologically or cytologically confirmed locally advanced or metastatic 
(Stage IIIB/IIIC or Stage IV) NSCLC who have disease progression following platinum-based 
chemotherapy and anti-PD-(L)1 antibody, with the anti-PD-(L)1 antibody administered in 
combination with, or sequentially before or after the platinum-based chemotherapy, are eligible. 
Histology of NSCLC will be confirmed at the investigator’s site. Patients with known EGFR or 
BRAF sensitizing mutations, or ALK or ROS1 rearrangement are ineligible for the study; for 
patients with nonsquamous NSCLC without tissue-based EGFR status, fresh or archival tumor 
tissues are required for EGFR mutation assessment. Archival tumor specimens will be 
prospectively tested for PD-L1 expression by a central laboratory. If archived formalin-fixed 
paraffin-embedded (FFPE) tissue is not sufficient for PD-L1 analysis, a fresh biopsy sample will 
need to be obtained. PD-L1 status will be determined by the percentage of TC with any 
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membrane staining (TC+) above background via the Ventana SP263 assay. Patients will be 
stratified by histological subtype (nonsquamous versus squamous), PD-L1 expression (< 1% TC 
versus ≥ 1% TC; patients whose tissues are unevaluable for PD-L1 expression will be included 
in the < 1% TC group), and race (Asian versus non-Asian) to receive 1 of the following 
treatment regimens: 
• Arm A: tislelizumab 200 mg intravenously once every 3 weeks in combination with 
sitravatinib 100 mg orally once a day; 
• Arm B: docetaxel 75 mg/m2 intravenously once every 3 weeks. 
The study design schematic is presented in Figure 1. 
Figure 1: 
Study Schema 
 
Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; EGFR, epidermal growth factor 
receptor; imAE, immune-mediated adverse event; IV, intravenously; NSCLC, non-small cell lung cancer; PD-(L)1, 
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programmed cell death protein-1/programmed cell death protein ligand-1; PO, orally; ROS1, ROS 
proto-oncogene 1; QD, once a day; Q3W: every 3 weeks; TC, tumor cells 
For all study procedures, see Section 7 and Appendix 1 and Appendix 2. 
3.2. 
Screening Period  
Screening evaluations will be performed within 28 days of randomization. Patients who agree to 
participate in this study will sign the informed consent form (ICF) before undergoing any 
screening procedure (see Appendix 1 for details). Screening evaluations may be repeated as 
needed within the screening period; the investigator is to assess preliminary patient eligibility 
according to the latest Screening assessment results.  
Archival tumor tissue must be collected for the purpose of PD-L1 analysis. If no archival 
samples are available, a fresh tumor biopsy at Screening is required. Refer to Section 7.7.1 for 
details. 
3.3. 
Treatment Period  
After completing all screening activities, eligible patients will be randomized in a 1:1 ratio to 
receive either tislelizumab in combination with sitravatinib or docetaxel monotherapy. 
Randomization will be stratified according to histological subtype (nonsquamous versus 
squamous), PD-L1 expression (< 1% TC versus ≥ 1% TC; patients whose tissues are unevaluable 
for PD-L1 expression will be included in the < 1% TC group), and race (Asian versus 
non-Asian), for 1 of the following treatment regimens: 
• Arm A: tislelizumab 200 mg intravenously once every 3 weeks in combination with 
sitravatinib 100 mg orally once a day 
• Arm B: docetaxel 75 mg/m2 intravenously once every 3 weeks  
Cycle 1 Day 1 will be defined as the first day the patient receives the study drug. A cycle is 
21 days in length ± 3 days, unless a delay is medically necessa ry. A ± 3 -day window is allowed 
for protocol-required assessments, unless otherwise specified. Tumor assessment will be 
conducted (by magnetic resonance imaging [MRI] and/or computed tomography [CT], with oral 
and/or intravenous contrast, unless contraindicated) during screening (within 28 days of 
randomization); every 6 weeks from Cycle 1 Day 1 (± 7 days) (at Weeks 7, 13, 19, 25, 31, 37, 
43, and 49), and then at 9-week intervals (± 7 days) thereafter, until disease progression, 
withdrawal of consent, lost to follow-up, start of a new anticancer therapy, or death, whichever 
occurs earlier. 
Patients in both arms will receive study treatment until disease progression, intolerable toxicity, 
death, or withdrawal of consent, whichever occurs earlier.  
Patients will not be allowed to cross over to the other treatment arm. Tumor assessment and 
response will be determined by the IRC, who will evaluate disease progression and responses 
without the knowledge of randomization assignments, in accordance with RECIST v1.1. Details 
are provided in Section 7.5. 
Safety will be assessed throughout the study by monitoring AEs/SAEs (toxicity grades assigned 
per NCI-CTCAE v5.0) and laboratory results. Vital signs, physical examinations, ECOG PS 
changes, electrocardiogram (ECG) results, and other examinations will also be used for safety 
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assessment. Safety assessments are further detailed in Section 7.4 and the Schedule of 
Assessments (Appendix 1). 
In the event of unacceptable AEs potentially attributed to anti-PD-1 therapy and clearly not 
attributed to RTK inhibitor, sitravatinib can be continued as monotherapy at the discretion of the 
investigator. However, due to limited anticancer effect of rechallenging PD-(L)1 monotherapy 
after progression on PD-(L)1 inhibitor or PD-(L)1-inhibitor-based therapy, tislelizumab should 
not be used as monotherapy after permanent discontinuation of sitravatinib.  
Response and disease progression will be assessed using RECIST v1.1. When disease 
progression is assessed by the investigator, the IRC is required to complete central image review 
and convey the results to the investigator as soon as possible. If disease progression is not 
confirmed by the IRC, it is recommended to continue the study treatment until disease 
progression is confirmed by the IRC if this is in the best interest of the patient as discussed with 
the medical monitor. In the situation where the investigator believes the patient must urgently 
discontinue study treatment without waiting for the IRC confirmation, the investigator should 
contact the medical monitor to inform him/her of the decision of treatment discontinuation.  
A patient who discontinues study drugs early for reasons other than disease progression as 
assessed by the IRC (eg, toxicity, disease progression assessed by the investigator) will continue 
to undergo tumor assessments following the original plan until the patient experiences disease 
progression per RECIST v 1.1 as assessed by the IRC, withdraws consent, is lost to follow-up, 
starts a new anticancer treatment, or until death, or until the study terminates, whichever occurs 
first.  
In selected cases, patients in Arm A may continue treatment beyond radiologic progression if 
they continue to demonstrate clinical benefit; this decision will be at the discretion of the 
investigator and with the sponsor’s agreement. The following criteria must be met in order to 
treat patients beyond progression:  
• 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.  
Patients who could benefit from study treatment in Arm A after disease progression as assessed 
by the investigator or IRC per RECIST v1.1 criteria may continue treatment until loss of clinical 
benefit as assessed by the investigator, withdrawal of consent, unacceptable toxicity, study 
completion by the sponsor, start of a new anticancer therapy, or death, whichever occurs first. 
Tumor assessment should continue as planned in patients receiving study treatment beyond 
initial investigator-assessed progression. Tumor assessment in such patients should continue 
until study treatment discontinuation. 
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At the end of treatment or after treatment discontinuation, the date of progression, type and 
duration of subsequent therapies, response to subsequent therapy, date of progression on 
subsequent therapy, and survival data will be collected. 
The duration of the study from the first enrolled patient to the final analysis for the primary 
endpoint OS is estimated to be approximately 32 months. 
When a patient in Arm A reaches 2 years of treatment (as measured from Cycle 1 Day 1): 
• Patients may continue on study therapy beyond 2 years if the investigator considers this 
to be in the best interest of the patient based on an assessment of clinical benefit and 
potential risks. Continuation of study therapy beyond 2 years must be explicitly approved 
by the sponsor and will be contingent on the continued availability of tislelizumab and/or 
sitravatinib. The study assessment and procedure schedule will remain the same. 
• Patients with confirmed CR, PR, or stable disease may stop treatment after 2 years if the 
patient wishes. The decision should be based on the investigator’s evaluation, with the 
patient’s clinical benefit and risk taken into consideration. The investigator should notify 
the sponsor that treatment will be stopped before stopping the treatment. In these cases, 
the study assessments and procedures will be performed every 12 weeks (in conjunction 
with repeat radiographic imaging, as described in Section 7.5) rather than every cycle. If 
new information becomes available indicating the patient should restart treatment, the 
patient must sign a new ICF and meet (continued) treatment eligibility, and the 
investigator must receive approval before the patient can restart treatment. 
− 
If a patient has evidence of PD within 1 year of treatment interruption, the investigator 
can consider restarting tislelizumab and sitravatinib therapy (or sitravatinib alone) 
after discussion with the sponsor, contingent on the continued availability of the study 
drug(s). 
3.4. 
End of Treatment/Safety Follow-up  
The EOT Visit/Safety Follow-up is conducted when the investigator determines that the 
tislelizumab and sitravatinib combination or docetaxel monotherapy will no longer be used. If 
routine laboratory tests (eg, hematology, serum chemistry) are completed ≤ 7 days before the 
EOT, these tests need not be repeated. Tumor assessment is not required at the EOT if ≤ 6 weeks 
have passed since the last assessment and should follow the regular schedule of assessment in 
Section 7.5. If the study drug(s) were initially interrupted due to AEs and then permanently 
discontinued, the EOT Visit may occur later, but no later than the permitted time of dose delay 
plus 7 days.  
Patients who discontinue treatment for any reason will be asked to return to the clinic for the 
EOT Visit (to occur 30 days [± 7 days] after the last dose of study drug(s), or before the initiation 
of a new anticancer treatment, whichever occurs first). In addition, telephone contacts (safety 
follow-up phone call) with patients should be conducted to assess imAEs and concomitant 
medications (if appropriate, ie, associated with an imAE or is a new anticancer therapy) at 
60 days (± 14 days) and 90 days (± 14 days) after the last dose of tislelizumab, regardless of 
whether or not the patient starts a new anticancer therapy. If patients report a suspected imAE at 
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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 8.6. 
Patients who discontinue study treatment before disease progression will need to undergo tumor 
assessments as outlined in Section 7.5. 
See Appendix 1 for assessments to be performed at the EOT Visit/Safety Follow-up phone calls. 
3.5. 
Survival Follow-up  
Patients will be followed for survival and to obtain information on subsequent anticancer therapy 
after discontinuation of study treatment via telephone calls, patient medical records, and/or clinic 
visits approximately every 3 months (± 14 days) after the EOT Visit or as directed by the 
sponsor until death, withdrawal of consent, lost to follow-up, or end of study.  
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 study treatment at any time for any reason. In addition, the 
investigator has the right to discontinue a patient from the study treatment at any time. Patients 
who discontinue study treatment for reasons other than disease progression should be followed 
for assessments of antitumor activity (Section 7.5), safety (Section 7.4) and survival 
(Section 3.5), if possible. 
The primary reason for discontinuation from the study treatment should be documented on the 
appropriate electronic case report form (eCRF). Patients may discontinue study treatment for 
reasons which include, but are not limited to, the following: 
• Disease Progression 
• Adverse event 
• Patient Decision 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety, if he or she were to continue the study treatment 
• Use of any concurrent anticancer therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese herbal medicine 
and Chinese patent medicines] for the treatment of cancer) 
• Patient noncompliance 
Investigative site staff should first counsel patients who are significantly noncompliant 
(eg, missing 2 treatment cycles) on the importance of study drug compliance and drug 
accountability. The investigator may, in consultation with the medical monitor, 
discontinue patients from treatment who are consistently noncompliant. 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient)  
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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  
The end of study is defined as the timepoint when the final data point is collected from the last 
patient in the study. This is when the last patient dies, withdraws consent, completes all study 
assessments, or is lost to follow-up. Alternatively, the end of study is when the sponsor decides 
to terminate the study. 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
early 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 
• A rollover study becomes available 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients should be seen as soon as possible for an EOT 
Visit, and Safety Follow-up phone calls. 
The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) of the early termination of the study. 
At the end of study, any patients who, in the opinion of the investigator, continue to benefit from 
tislelizumab and/or sitravatinib at study termination will be offered the option to continue 
treatment in a company-sponsored clinical study until the loss of benefit, termination of the study 
by sponsor or the study drug(s) is commercially available in the country of the patient’s 
residence. 
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4. 
STUDY POPULATION  
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all the following criteria: 
1. Able to provide written informed consent and can understand and agree to 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 if > 18 in the jurisdiction in which the study is taking place) 
3. Metastatic or unresectable locally advanced histologically or cytologically confirmed 
NCSLC, not amenable to treatment with curative intent 
4. Able to provide archival/fresh tumor tissues for biomarker analysis to assess PD-L1 
expression and other biomarkers. Tumor tissues should be of good quality and acceptable 
sample type (see Section 7.7.1 for details). Written informed consent is required before 
performance of fresh tumor biopsies.  
5. No known EGFR or BRAF sensitizing mutation, or ALK rearrangement or ROS1 
rearrangement 
a. Documentation of EGFR status with no sensitizing mutation by tissue-based test must 
be provided for patients with nonsquamous NSCLC before enrollment. For EGFR 
undocumented cases, archival or fresh tumor tissues are required for central 
assessment of EGFR mutation status. In the absence of archival tumor tissues, a fresh 
biopsy of a tumor lesion at screening is mandatory. Written informed consent is 
required before performance of fresh tumor biopsies. 
b. Given that testing for EGFR mutation is not considered standard due to its low 
frequency in the squamous patient population (Chiu et al 2014), patients with 
squamous NSCLC and an unknown EGFR mutational status will not be required to 
be tested at screening. 
c. Patients with unknown ALK fusion oncogene or ROS1 rearrangement status will not 
be required to be tested at screening given the low frequency in squamous and 
nonsquamous NSCLC.  
6. Radiographic progression per RECIST v1.1 on or after anti-PD-(L)1-containing therapy 
for locally advanced and unresectable or metastatic NSCLC. If the 
anti-PD-(L)1-containing therapy is not the most recent systemic treatment, patients 
should also have radiographic progression per RECIST v1.1 on or after the most recent 
systemic treatment. Prior line(s) of treatment must include a platinum-based 
chemotherapy and an anti-PD-(L)1 antibody, with the anti-PD-(L)1 antibody 
administered in combination with, or sequentially before or after the platinum-based 
chemotherapy. Patients must have received no more than 2 lines of prior systemic therapy 
for locally advanced and unresectable or metastatic disease. 
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a. Adjuvant and neo-adjuvant chemotherapy will count as 1 prior line of chemotherapy 
if the disease progressed on or within 6 months after the completion of the last dose.  
b. In locally advanced and unresectable NSCLC, disease progression on or within 
6 months after the end of systemic therapy as part of prior curatively intended 
multimodal therapy will count as 1 prior line of systemic therapy. If chemoradiation 
is followed by planned systemic therapy without documented progression between 
the chemoradiation and systemic therapy, the entire treatment course counts as 1 line 
of therapy. 
Note: Patients who received anti-PD-(L)1 antibody as consolidation treatment 
following definitive chemoradiation for unresectable Stage III NSCLC can be 
enrolled immediately after disease progression, if the disease progression occurred 
within 6 months after the end of platinum-based chemotherapy component of the 
definitive chemoradiation. 
c. Maintenance therapy following platinum-based doublet chemotherapy is not 
considered as a separate line of therapy. 
d. No other prior immunotherapies with antibody or drug specifically targeting T-cell 
costimulation or checkpoint pathways, including but not limited to anti-TIGIT, 
anti-OX40, and anti-CD137; prior anti-CTLA-4 used in combination with 
anti-PD-(L)1 is permitted. 
e.  No prior anticancer therapy having the same mechanism of action as sitravatinib (eg, 
tyrosine kinase inhibitor with a similar target profile or VEGF- or VEGFR inhibitor). 
7. Criterion deleted 
8. At least 1 measurable lesion as defined based on RECIST v1.1 by investigator 
Note: The target lesion(s) selected have not been previously treated with local therapy or 
the target lesion(s) selected that are within the field of prior local therapy have 
subsequently progressed as defined by RECIST v1.1. 
9. Eastern Cooperative Oncology Group Performance Status ≤ 1 
10. Adequate organ function as indicated by the following laboratory values (obtained 
≤ 7 days before randomization): 
a. Patients must not have required blood transfusion or growth factor support ≤ 14 days 
before sample collection at screening for the following: 
i. 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
ii. 
Platelets ≥ 100 x 109/L 
iii. 
Hemoglobin ≥ 90 g/L 
b. Estimated glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m2 by Chronic Kidney 
Disease Epidemiology Collaboration equation (Appendix 9) 
c. Urinary protein < 2+ by urine dipstick. If dipstick is ≥ 2+, then 24-hour urinary 
protein < 2 g per 24 hours. 
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d. Aspartate aminotransaminase (AST) and alanine aminotransferase (ALT) 
≤ 2.5 x ULN, or AST and ALT ≤ 5.0 x ULN for patients with documented liver 
metastases. If AST and/or ALT > 1.5 x ULN, alkaline phosphatase should be 
≤ 2.5 x ULN. 
e. Serum total bilirubin ≤ 1 x ULN. 
f. International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 x ULN. 
g. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. 
11. Females of childbearing potential must be willing to use a highly effective method of 
birth control while on study treatment, and within 180 days after the last dose of study 
drug(s) and have a negative serum pregnancy test ≤ 7 days before randomization. See 
Appendix 10. 
12. Nonsterile males must be willing to use a highly effective method of birth control for the 
duration of the study and for ≥ 180 days after the last dose of study drug(s). 
• A sterile male is defined as one for whom azoospermia has been previously 
demonstrated in a semen sample examination as definitive evidence of infertility. 
• Males with known “low sperm counts” (consistent with “subfertility”) are not to be 
considered sterile for purposes of this study. 
• A nonsterile male that has a partner of non-childbearing potential may not be required 
to use highly effective method of birth control. 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria are not eligible to enroll: 
1. Has received docetaxel as monotherapy or in combination with other therapies. 
2. Squamous NSCLC with central cavitation, or NSCLC with hemoptysis (> 50 mL/day) 
3. Patients with tumor shown by imaging to be located around important vascular structures 
or if the investigator determines that the tumor is likely to invade important blood vessels 
and may cause fatal bleeding (ie, radiologic evidence of tumors invading or abutting 
major blood vessels). 
4. Active leptomeningeal disease for metastatic NSCLC, or uncontrolled or untreated brain 
metastasis. 
Note: Patients with a history of treated and, at the time of screening, stable central 
nervous system (CNS) metastases are eligible, provided they meet all the following 
criteria: 
a. Brain imaging at screening shows no evidence of interim progression, clinically 
stable for at least 2 weeks and have no evidence of new brain metastases 
b. Measurable disease outside the CNS 
c. No ongoing requirement for corticosteroids as therapy for CNS disease; off steroids 
for 3 days before randomization; anticonvulsants at a stable dose are allowed  
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d. No stereotactic radiation or whole-brain radiation within 14 days before 
randomization 
5. Active autoimmune diseases or history of autoimmune diseases that may relapse. 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening: 
a. Controlled Type I diabetes 
b. Hypothyroidism (provided it is managed with hormone replacement therapy only) 
c. Celiac disease controlled by diet alone 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
6. Any active malignancy ≤ 2 years before randomization except for the specific cancer 
under investigation in this study and any locally recurring cancer that has been treated 
curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, 
carcinoma in situ of the cervix or breast) 
7. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
randomization 
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) is 
permitted in the absence of active autoimmune disease 
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption is permitted  
c. A brief course of corticosteroid prescribed prophylactically (eg, for contrast dye 
allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen) is permitted 
8. History of 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  
9. History of interstitial lung disease, noninfectious pneumonitis or uncontrolled lung 
diseases, including pulmonary fibrosis and acute lung diseases. 
10. Severe chronic or active infection (including tuberculosis infection, etc) requiring 
systemic antibacterial, antifungal, or antiviral therapy (not including antiviral therapy for 
hepatitis or HIV) within 14 days before randomization 
11. Untreated HIV infection, if known. Patients with a known HIV infection are eligible if 
the following criteria are met: 
a. Stable on antiretroviral therapy for ≥ 4 weeks before randomization 
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b. Patient agrees to adhere to antiretroviral therapy per World Health Organization 
(WHO) guidelines 
c. No documented multidrug resistance that would prevent effective antiretroviral 
therapy 
d. Viral load of < 400 copies per mL at screening 
e. CD4+ T-cell count ≥ 350 cells/μL at screening 
f. No history of an AIDS-defining opportunistic infection ≤ 12 months before 
randomization unless eligibility is agreed to by the medical monitor after consultation 
g. If prophylactic antimicrobial drugs are indicated, patients may still be eligible upon 
agreement with the medical monitor 
For sites in Germany, patients with a known history of HIV infection or if HIV status is 
unknown, a positive HIV test at screening are excluded 
12. Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV DNA 
≥ 500 IU/mL or 2500 copies/mL, or active hepatitis C virus (HCV) carriers 
Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B 
(HBV DNA < 500 IU/mL or 2500 copies/mL) patients, and cured hepatitis C patients can 
be enrolled. Patients with detectable HBsAg or detectable HBV DNA should be managed 
per treatment guidelines. Patients receiving antivirals at screening should have been 
treated for > 2 weeks before randomization. 
13. Any major surgical procedure ≤ 28 days before randomization. Patients must have 
recovered adequately from the toxicity and/or complications from the intervention before 
randomization. 
14. Prior allogeneic stem cell transplantation or organ transplantation 
15. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days before randomization 
b. Any history of acute myocardial infarction ≤ 6 months before randomization 
c. Any history of heart failure meeting New York Heart Association (NYHA) 
Classification III or IV ≤ 6 months before randomization (Appendix 7) 
d. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
randomization 
e. Any history of cerebrovascular accident ≤ 6 months before randomization 
f. QT interval corrected by Fridericia’s method (QTcF) > 470 msec  
Note: If a patient has QTcF interval > 470 msec on an initial ECG, a follow-up ECG 
will be performed to confirm the result. 
g. Cardiac left ventricular ejection fraction < 50% or lower limit of normal as assessed 
by echocardiography or multigated acquisition (MUGA). The same modality used at 
baseline must be applied for subsequent evaluations. 
16. Patients with inadequately controlled hypertension (defined as systolic blood 
pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) 
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17. Patients with hypersensitivity to tislelizumab, sitravatinib, docetaxel, to any ingredient in 
the formulation, or to any component of the container. 
18. Patients who use anticoagulants such as warfarin or similar agents requiring therapeutic 
INR monitoring.  
19. Within 4 weeks before randomization, patients with active bleeding disorder or any 
bleeding events ≥ CTCAE level 3, unhealed wounds, ulcers, or fractures 
20. Patients with a history of artery/deep vein thrombosis within 6 months before 
randomization, such as cerebrovascular incident (including temporary ischemic attack), 
deep vein thrombosis, and pulmonary embolism 
21. Received any Chinese herbal medicine or Chinese patent medicine for the treatment of 
NSCLC within 14 days before randomization, or received palliative radiation within 
28 days before randomization for the lung or within 14 days before randomization for 
other organs. 
22. Unacceptable toxicity on prior anti-PD-(L)1 treatment, defined as follows: 
a. ≥ Grade 3 AE related to anti-PD-1/PD-L1 treatment that did not respond to standard 
therapy and warranted treatment discontinuation. 
b. ≥ Grade 2 imAE associated with anti-PD-(L)1 unless the AE resolved or was well 
controlled by withholding the anti-PD-(L)1 treatment and/or treatment with steroids, 
with the exception of prior colitis, myocarditis, hepatitis, and pneumonitis, which are 
exclusionary. 
c. CNS or ocular AE of any grade related to anti-PD-(L)1. 
Note: Patients with a prior endocrine AE are permitted to enroll if they are stably 
maintained on appropriate replacement therapy and are asymptomatic. 
23. Patient was administered a live vaccine ≤ 28 days before randomization. 
Note: Vaccines for COVID-19 are allowed except for any live vaccine that may be 
developed. Seasonal vaccines for influenza are generally inactivated vaccines and are 
allowed. Intranasal vaccines are live vaccines and are not allowed. 
24. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study drug, affect 
the explanation of drug toxicity or AEs, or result in insufficient or impaired compliance 
with study conduct according to the investigator’s judgement. 
25. Concurrent participation in another therapeutic clinical study. 
Note: Concurrent participation in observational or non-interventional studies is allowed. 
In addition, patients who have completed active treatment in a clinical study and are in 
the follow-up period can be enrolled in this study. 
26. Unable to swallow capsules or with disease significantly affecting gastrointestinal 
function such as malabsorption syndrome, resection of the stomach or small bowel, 
bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or 
complete bowel obstruction. 
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27. Patients with spinal cord compression due to metastatic disease not definitively treated 
with surgery and/or radiation or previously diagnosed and treated spinal cord 
compression without evidence that the disease has been clinically stable for > 2 weeks 
before randomization. 
28. Criterion deleted 
29. Prior randomization in a tislelizumab study regardless of the treatment arm, until the 
primary and key secondary endpoints of the study have read out. 
30. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered 
to baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, 
neuropathy and specific laboratory abnormalities). 
31. Women who are pregnant or are breastfeeding. 
32. Known COVID-19 antigen positive by a licensed test during the screening period. 
33. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence ≤ 14 days after intervention) 
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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Tislelizumab  
Tislelizumab is a monoclonal antibody formulated for intravenous injection in a single-use vial 
(20R glass, United States Pharmacopeia [USP] type I), containing a total of 100 mg of antibody 
in 10 mL of isotonic solution. Tislelizumab has been aseptically filled in a single-use glass vial 
with a rubber stopper and capped by an aluminum flip-off seal cap. Each vial is packaged into a 
single carton box. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. 
Refer to the pharmacy manual for details regarding intravenous administration, accountability, 
and disposal. Please also refer to the tislelizumab IB for other details regarding tislelizumab. 
5.1.2. 
Sitravatinib  
Sitravatinib malate formulation will be provided as 50 mg and 35 mg capsules.  
Sitravatinib drug product is packaged in 30-count, high-density polyethylene (HDPE), opaque 
white, round 75 cc bottles. A tamper-proof heat induction seal and a child-resistant closure are 
used. 
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. Refer to the 
pharmacy manual for details regarding administration, accountability, and disposal. Please also 
refer to the sitravatinib IB for other details regarding sitravatinib. 
5.1.3. 
Docetaxel  
Docetaxel will be provided in vials for infusion.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
Management (ie, handling, storage, and disposal) of docetaxel will be in accordance with the 
relevant local guidelines and/or prescribing information. 
Refer to the pharmacy manual for details regarding administration, accountability, and disposal.  
5.2. 
Dosage, Administration, and Compliance  
On days when sitravatinib and tislelizumab dosing are both scheduled, the daily dose of 
sitravatinib should precede tislelizumab infusion. This order of dosing is important on days when 
blood sampling is scheduled for sitravatinib and M10 PK analysis. 
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Table 4: 
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 
Sitravatinib 
100 mg 
Once a day 
Oral 
See Section 3.3 
Docetaxel  
75 mg/m2 
Every 3 weeks  
Intravenous 
See Section 3.3 
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 intravenous infusion through an intravenous line 
containing a sterile, nonpyrogenic, low-protein-binding 0.2 or 0.22 micron in-line or add-on 
filter. Specific instructions for product preparation 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 afterward in an area with resuscitation equipment and 
emergency agents. From Cycle 3 onward, a ≥ 30-minute monitoring period is required in an area 
with resuscitation equipment and emergency agents if no symptoms are observed after the prior 
2 treatment administrations. 
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 if no symptoms are 
observed during the first treatment administration. Thirty minutes 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 imAEs and infusion-related reactions are provided in detail in Section 8.7 and 
Appendix 8. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
Section 5.5. 
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5.2.2. 
Sitravatinib  
Sitravatinib will be administered orally at a dose of 100 mg, once a day, continuously.  
The following guidelines should be followed for sitravatinib administration: 
• Dosing in the morning is preferred. 
• Capsules should be taken on an empty stomach (≥ 2-hour fast before each dose and no 
food for a minimum of 1 hour after each dose).  
• Capsules should be taken with at least 200 mL (approximately 1 cup) of water. 
• Patients should swallow the capsules whole and not chew them. 
• If vomiting occurs after dosing, sitravatinib doses should not be replaced. 
• If a patient forgets to take sitravatinib for more than 12 hours, he/she should skip the dose 
and resume taking the drug the next day. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
Section 5.5. 
5.2.3. 
Docetaxel  
Docetaxel will be administered by intravenous infusion at 75 mg/m2 over 1 hour or according to 
institutional practices, every 3 weeks. Premedication with corticosteroids will be required in 
accordance with regional standards. 
Before each cycle of docetaxel, 
• Liver function tests (LFTs) should be reviewed, and docetaxel should not be given if 
bilirubin > 1 x ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline 
phosphatase > 2.5 × ULN.  
• Blood counts should be reviewed, and docetaxel should not be given if neutrophil counts 
are < 1500 cells/mm3. 
5.3. 
Overdose  
5.3.1. 
Tislelizumab  
Any overdose (defined as ≥ 600 mg of tislelizumab in a 24-hour period) or incorrect 
administration of study drug should be noted in the patient’s chart and on the appropriate eCRF. 
AEs associated with an overdose or incorrect administration of study drug will be recorded on 
the AE eCRF. Any SAEs associated with an overdose or incorrect administration must be 
reported within 24 hours of awareness via the SAE reporting process described in Section 8.6.2. 
Supportive care measures should be administered as appropriate. 
5.3.2. 
Sitravatinib  
Any overdose or incorrect administration of sitravatinib should be noted in the patient’s chart 
and on the appropriate eCRF. AEs associated with an overdose or incorrect administration of 
study drug will be recorded on the AE eCRF. Any SAEs associated with an overdose or incorrect 
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administration are required to be reported within 24 hours of awareness via SAE reporting 
process as described in Section 8.6.2. Supportive care measures should be administered as 
appropriate. 
5.3.3. 
Docetaxel  
There is no known antidote for docetaxel injection overdosage. In case of overdose, the patient 
should be kept in a specialized unit where vital functions can be closely monitored. Anticipated 
complications of overdose include bone marrow suppression, peripheral neurotoxicity, and 
mucositis. Patients should receive therapeutic granulocyte colony-stimulating factor as soon as 
possible after discovery of overdose. Other appropriate symptomatic measures should be taken 
as needed. 
5.4. 
Study Drug Accountability  
The study drugs required for completion of this study (tislelizumab, sitravatinib, and docetaxel) 
will be provided by the sponsor, as required by local or country-specific guidance. The 
investigational site will acknowledge receipt of study drugs. Any damaged shipments will be 
replaced. 
Accurate records of all study drugs received, dispensed, returned, and disposed of should be 
recorded on the site’s Drug Inventory Log. Refer to the pharmacy manual for details of study 
drug management. 
Compliance will be assessed by the investigator and/or appropriately delegated study personnel 
at each patient visit and through information provided by the patient. Patients enrolled in Arm A 
will be provided with patient diaries. The patient is responsible for maintaining the patient diary 
and will record the number of capsules of sitravatinib taken and if any were missed. The site 
personnel responsible for drug accountability will record the quantity of drug dispensed and 
quantity of drug received after the cycle visit. The patient diaries and the pharmacist record of 
the drugs will be assessed by the investigator/study personnel at each 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  
A dose delay is a deviation from the prescribed dosing schedule (ie, the drug is withheld beyond 
the visit window). A dose interruption is an interruption of an infusion of tislelizumab, or 
docetaxel. 
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 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. 
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5.5.1. 
Dose Delay or Modification for Tislelizumab and/or Sitravatinib  
Patients may temporarily suspend 1 component of the study treatment or both, if they experience 
toxicity that is considered related to the study drug(s) and requires a dose to be withheld. Patients 
should resume study drug(s) as soon as possible after the AE(s) recover to baseline or Grade 1 
(whichever is more severe) and within 4 weeks after the last dose of sitravatinib or within 
12 weeks after the last dose of tislelizumab. Sitravatinib should be resumed at a reduced dose 
level as outlined in Table 5. If the administration of sitravatinib is interrupted for reasons other 
than sitravatinib-related toxicity, then treatment with the study drug(s) may be resumed at the 
same dose. 
Table 5: 
Sitravatinib Dose Reductions 
Dose Level 1 
100 mg once daily 
Dose Level -1 
70 mg once daily 
Dose Level -2 
50 mg once daily a 
a Dose reduction below 50 mg once daily may be undertaken after discussion with the sponsor. 
The following dose delays or interruptions will be permitted: 
• 
Sitravatinib can be interrupted for up to 28 consecutive days. If the treatment with 
sitravatinib is delayed for ≥ 14 days, then resumption at a reduced dose should be 
considered. If the drug is planned to be interrupted for > 28 days, the medical monitor 
should be contacted before permanent patient discontinuation from the study drug. 
• 
Tislelizumab can be delayed or interrupted for up to 12 weeks. 
Treatment intervals may be increased due to toxicity according to the dose modification 
guidelines. Cycle numbers will be counted based on the dosing of tislelizumab. For example, if 
the dosing of tislelizumab is delayed for 14 days, the next cycle can resume after an additional 
21 days (ie, Day 35). Sitravatinib will be given continuously, unless interruption or 
discontinuation criteria are met.  
If treatment intervals are increased, all procedures except imaging will be completed according 
to the cycle number, and not weeks on treatment. The tumor assessment schedule will not be 
altered even if the administration of study drug(s) is delayed. 
If the patient is unable to resume sitravatinib and/or tislelizumab within the permitted timeframe 
after the last dose of study drug(s), then the patient should be discontinued from the study 
drug(s). Continuation/resumption of study drug(s) after an interruption of more than the 
permitted timeframe must be discussed with the medical monitor. 
There will be no dose reductions for tislelizumab in this study. Dose reductions for sitravatinib 
are presented in Table 5. Once the dose has been reduced, re-escalation is not recommended.  
In the event of unacceptable AEs potentially attributed to anti-PD-1 therapy and clearly not 
attributed to RTK inhibitor, sitravatinib can be continued as monotherapy at the discretion of the 
investigator. However, due to limited anticancer effect of rechallenging PD-(L)1 monotherapy 
after progression on PD-(L)1 inhibitor or PD-(L)1-inhibitor-based therapy, tislelizumab should 
not be used as monotherapy after permanent discontinuation of sitravatinib. When attribution to 
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an unacceptable AE by either drug cannot be ruled out, both sitravatinib and tislelizumab should 
be held or the dose of sitravatinib should be reduced according to dose modification guidelines.  
Based on the known toxicity profiles of sitravatinib and tislelizumab, certain AEs are likely to be 
associated with one drug versus the other. For example, treatment-emergent hypertension or 
palmar plantar erythrodysesthesia are likely to be associated with sitravatinib rather than 
tislelizumab; similarly, imAEs are likely to be associated with tislelizumab rather than 
sitravatinib. However, some drug-related AEs such as diarrhea and elevated liver function tests 
are overlapping. Therefore, it is crucial to fully evaluate each AE to confirm the etiology or 
exclude other causes in order to determine proper management of the adverse reaction and 
potential action regarding study treatment. The management guidelines for AEs of special 
interest for tislelizumab and sitravatinib-specific AEs are provided in detail in Section 8.8 and 
Section 8.9, respectively. 
AEs (both nonserious and serious) associated with tislelizumab exposure may represent an 
immunologic etiology. These AEs may occur shortly after the first dose or several months after 
the last dose of treatment. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Tislelizumab must be withheld for drug-related severe or life-threatening 
AEs. See Appendix 8 for supportive care guidelines, including use of corticosteroids. 
5.5.2. 
Dose Delay, Interruption or Modifications for Docetaxel  
Guidelines for docetaxel dose modifications to manage general toxicities are shown in Table 6. 
Table 6: 
Guidelines for Docetaxel Dose Modifications 
Adverse event 
(Worst grade in previous cycle) 
Action to be taken 
Febrile neutropenia/Grade 4 AGC ≥ 7 days 
Grade 3/4 skin/ major organ/non hematologic 
toxicity 
Withhold docetaxel until symptoms resolve a 
Reduce docetaxel to 75% of previous dose (eg, 
from 75 mg/m2 to 55 mg/m2) in the first episode; 
Discontinue treatment or reduce docetaxel to 
75% of previous dose in the second episode; 
Discontinue treatment in the third episode. 
Abbreviations: AGC, absolute granulocyte count. 
a Do not re-treat until AGC ≥ 1.5 x 109, platelets ≥100 x 109, and docetaxel related toxicity ≤ Grade 1 except for 
alopecia or Grade 2 fatigue or laboratory abnormalities (For AST, ALT, or total bilirubin, please refer to 
Section 5.2.3 and Table 7). 
Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, 
neutrophils < 500 cells/mm3 (Grade 4) > 1 week, severe or cumulative cutaneous reactions, or 
other Grade 3/4 non-hematologic toxicities during docetaxel treatment should have treatment 
withheld until resolution of the toxicity and treatment then resumed at 55 mg/m2. Should these 
AEs occur after the first dose reduction, then a second dose reduction is permitted. During this 
study, local standard practice for docetaxel administration may be used. Patients requiring more 
than 2 dose reductions of docetaxel due to adverse events should discontinue treatment with 
docetaxel. Patients who develop ≥ Grade 3 peripheral neuropathy should have docetaxel 
treatment discontinued entirely. 
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Guidelines for the management of hepatotoxicity for docetaxel-treated patients are shown in 
Table 7. 
Table 7: 
Guidelines for Management of Hepatotoxicity in Patients Receiving 
Docetaxel 
 
AST/ALT 
 
Alkaline 
phosphatase 
 
Total 
bilirubin 
Docetaxel dose 
Mild to 
moderate 
> 1.5x ULN 
and 
> 2.5 x ULN 
 
NA 
75% 
Severe 
> 3.5 x ULNa 
and 
> 6 x ULN 
OR 
> 1.5x ULNb 
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. 
a > 5 x ULN if liver metastasis exists;  
b > 3 x ULN if Gilbert Syndrome or indirect bilirubin proven to be extrahepatic 
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6. 
PRIOR AND CONCOMITANT THERAPY  
6.1. 
Prior Therapy  
All prior therapies, their dates of administration, best responses, and dates of progression for 
NSCLC will be collected at study entry. 
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 supportive care (eg, antiemetics, 
antidiarrheals) and in a patient’s interest are allowed.  
All concomitant medications, including all prescription and over-the-counter drugs, supplements, 
and intravenous medications and fluids, taken by or administered to the patient within 30 days 
before randomization will be recorded. 
Opiates and other medications required for palliative management of patients are allowed. 
Patients must notify the investigator of all concurrent medications used during the study. 
6.2.1.1. 
Systemic Corticosteroids  
Systemic corticosteroids given to control imAEs must be tapered gradually (see Appendix 8) and 
be administered at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) 
before the next tislelizumab administration. The short-term use of steroids as prophylactic 
treatments (eg, patients with contrast allergies to diagnostic imaging contrast dyes) is permitted. 
6.2.1.2. 
Hepatitis B Treatment  
Patients with active hepatitis B, defined as HBV DNA ≥ 500 IU/mL or 2500 copies/mL at 
Screening, must initiate treatment 2 weeks before randomization and continue until 6 months 
after the last dose of study drug(s). Patients should continue effective antiviral treatment during 
the study to decrease potential viral reactivation 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 may use other antiviral agents, if appropriate, following local guidelines. 
However, interferon-based therapy for hepatitis B is not permitted on study. 
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 500 IU/mL or 2500 copies/mL) is at the discretion of the investigator, 
as aligned with local guidance. Such medications must be documented in the patient’s chart and 
recorded in the eCRF. Patients receiving antivirals at screening should be treated for > 2 weeks 
before randomization and continue treatment during the study, and for 6 months after the last 
dose of study drug(s). 
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6.2.1.3. 
Radiation Therapy  
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: 
• Repeated 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 or other focally ablative therapy for other nontarget sites of the 
disease is permitted if clinically indicated per investigators’ discretion. The medical monitor 
should be informed of the on-study radiotherapy. These patients should have a tumor assessment 
of the lesion(s) before receiving the radiotherapy in order to rule out progression of disease. 
Withhold of study treatment is required during palliative radiotherapy. 
6.2.2. 
Prohibited Concomitant Medications/Procedures  
Live vaccines ≤ 28 days before randomization for patients in both arms, during tislelizumab 
treatment and ≤ 60 days after the last dose of tislelizumab for patients in Arm A are prohibited. 
The following medications are prohibited during Screening and through the EOT/Safety 
Follow-up Visit: 
• Any concurrent anticancer therapy, including chemotherapy, hormonal therapy, 
immunotherapy, standard anticancer agents, or investigational anticancer agents 
• Herbal remedies for the treatment of cancer or Chinese patent medicines with approval 
from the China National Medical Products Administration (NMPA) for use as anticancer 
treatment (regardless of cancer type) 
• Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or that are 
known to potentially interfere with liver or other major organ functions (eg, hypericin) 
Patients must notify the investigator of all herbal remedies used during the study. 
6.2.3. 
Restricted Concomitant Medications/Procedures  
The following medications are restricted during the study: 
Arm A: 
• Immunosuppressive agents (except to treat a drug-related AE) 
• 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 
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Arm A and Arm B:  
• Patients should not abuse alcohol or other drugs during the study. 
• Use of potentially hepatotoxic drugs in patients with impaired hepatic function should be 
carefully monitored. 
• Radiation therapy is not allowed, except for palliative radiation therapy described in 
Section 6.2.1.3. 
• Surgeries, except: 
− To treat an AE (eg, appendectomy) 
In the event that major surgery is needed during study treatment, the patient should, if 
possible, interrupt dosing with study treatment 2 weeks in advance of the surgery and 
may resume dosing 2 weeks after the surgery. 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
Potential Interaction of Docetaxel With CYP3A4 inhibitors 
Docetaxel is a cytochrome P450 3A4 (CYP3A4) substrate. In vitro studies have shown that the 
metabolism of docetaxel may be modified by the concomitant administration of compounds that 
induce, inhibit, or are metabolized by CYP3A4.  
In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was 
coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, 
particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of docetaxel and 
drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In 
patients receiving treatment with docetaxel, close monitoring for toxicity and a docetaxel dose 
reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be 
avoided (examples listed in Appendix 11). 
Potential Interaction of Sitravatinib With CYP Enzyme Inhibitors/Substrates 
Sitravatinib is not considered a high-risk compound as a victim of drug-drug interaction (DDI) 
because multiple enzymes, including CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, and 3A4 are 
involved in its metabolism.  
In vitro, sitravatinib showed direct inhibition of CYP2C8, CYP2C9, CYP2C19, CYP2D6, and 
CYP3A4/5 (Section 1.5.1). Concomitant medications that are sensitive substrates or substrates 
with a narrow therapeutic index for these CYP enzymes (examples listed in Appendix 11) should 
be avoided during sitravatinib treatment. 
Potential Interaction of Sitravatinib With Transporter Inhibitors/Substrates 
Sitravatinib was identified to be a substrate of P-gp and inhibitor of both P-gp and BCRP 
(Section 1.5.1). Inhibitors of P-gp (eg, clarithromycin, itraconazole, propafenone, quinidine, 
ranolazine, ritonavir, verapamil) may increase sitravatinib exposure while inducers of P-gp (eg, 
rifampin) may decrease sitravatinib exposure. Concomitant medications that inhibit or induce 
P-gp should be avoided when administering sitravatinib to patients. Concomitant medications 
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that are sensitive substrates or substrates with narrow therapeutic indices for P-gp and/or BCRP 
transporters (examples listed in Appendix 11) should be avoided during sitravatinib treatment. 
Sitravatinib With Medications That Prolong QT/QTc 
Per the International Council for Harmonisation (ICH) E14 guidance, it is recommended to avoid 
medications with the potential to prolong QT/QTc intervals or cause Torsades. Please refer to 
Appendix 11 for a list of medications or substances to be avoided or used with caution during 
treatment with sitravatinib. 
Potential Interaction of Sitravatinib With Tislelizumab 
Sitravatinib administered in combination with tislelizumab is unlikely to result in clinically 
relevant DDI based on the characteristics of absorption, metabolism, elimination, or protein 
binding. Tislelizumab is a monoclonal antibody and is administered intravenously, whereas 
sitravatinib is a small molecule therapeutic administered orally. No absorption interactions are 
expected. No studies on the metabolism of tislelizumab have been reported in vitro or in humans. 
Like most therapeutic proteins, tislelizumab is not expected to be metabolized by liver 
cytochrome P450 (CYP) or other drug-metabolizing enzymes and is unlikely to have an effect on 
CYPs or other metabolizing enzymes in terms of inhibition or induction. 
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7. 
STUDY ASSESSMENTS AND PROCEDURES  
A table of scheduled study assessments is provided in Appendix 1 and Appendix 2. Patients will 
be closely monitored for safety and tolerability throughout the study. All assessments must be 
performed and documented in the medical record for each patient. 
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 before randomization. Patients who 
agree to participate will sign the ICF before undergoing any screening procedure. The screening 
period begins on the first day a screening procedure is conducted. Screening evaluations may be 
repeated as needed within the screening period; the investigator is to assess patient eligibility 
according to the latest screening assessment results. 
Results of standard-of-care tests or examinations performed before obtaining informed consent 
and ≤ 28 days before the first dose of study drug(s) may be used for the purposes of screening 
rather than repeating the standard-of-care tests, unless otherwise indicated. If laboratory tests at 
Screening are performed within 7 days before randomization, these tests (hematology, clinical 
chemistry, urinalysis, coagulation and pregnancy test) do not have to be repeated and must be 
reviewed before randomization. 
Procedures conducted during the Screening Visit only are described in this section. For the 
description of other assessments that are conducted during screening, as well as throughout the 
study, refer to Safety Assessments (Section 7.4), Tumor and Response Evaluations (Section 7.5) 
and Biomarkers (Section 7.7) sections. The PK sampling schedule is shown in Appendix 2.  
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. 
Informed Consent 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 center.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization. The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable. 
7.1.2. 
Patient Numbering  
After obtaining informed consent, study personnel will access the Interactive Response 
Technology (IRT) system to assign a unique patient number to a potential study participant. 
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7.2. 
Enrollment  
7.2.1. 
Confirmation of Eligibility  
Prior to enrollment, the investigator is responsible for assessing and confirming that each patient 
meets all inclusion eligibility criteria for this study and that none of the exclusion criteria apply. 
All results from the screening procedures and relevant medical history must be available and 
reviewed by the investigator before eligibility can be determined. No eligibility waivers will be 
granted. 
Sponsor verification of patient eligibility will be managed by way of source data verification in 
accordance with the International Council for Harmonisation (ICH) E6. 
The sponsor’s medical monitor will support the investigator and/or site staff by answering any 
queries or questions relating to protocol eligibility criteria. 
7.2.2. 
Randomization  
Site personnel will access the IRT system to randomize treatment assignment and to assign the 
study drug. Study treatment must commence within 2 business days after 
randomization/treatment assignment. 
7.3. 
Tislelizumab, Sitravatinib, and Docetaxel Dispensation  
Tislelizumab, sitravatinib, and docetaxel will be dispensed and administered as described in 
Section 5.2. On days when sitravatinib and tislelizumab dosing are both scheduled, the daily 
dose of sitravatinib should precede tislelizumab infusion. 
7.4. 
Safety Assessments  
7.4.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate, and blood pressure 
(systolic and diastolic). Pulse rate and blood pressure will be collected while the patient is in a 
seated or supine position after resting for 10 minutes. 
The patient’s vital signs are required to be recorded within 60 minutes before, during, and within 
30 minutes after the first infusion of tislelizumab. For subsequent infusions, vital signs will be 
collected within 60 minutes before infusion and if clinically indicated, during and within 
30 minutes after the infusion. Vital signs should also be recorded before administration of 
sitravatinib; recorded values may be used for pre-tislelizumab assessment if vital signs are 
collected within 60 minutes before tislelizumab infusion. 
7.4.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted including 
evaluations of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 4) 
musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) neurological systems. Any 
abnormality identified during screening will be graded according to NCI-CTCAE v5.0 and 
recorded on the eCRF with appropriate disease/condition terms. 
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At subsequent visits (and as clinically indicated), limited, symptom-directed physical 
examinations will be performed. New or worsened clinically significant abnormalities are to be 
recorded as AEs on the eCRF. Refer to Section 8.3 regarding AE definitions and reporting and 
follow-up requirements. 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (Appendix 4) will be assessed during the study. 
7.4.4. 
Laboratory Safety Tests  
Local and/or central laboratory assessments of serum chemistry, hematology, coagulation, and 
urinalysis will be conducted, of which certain elements will be collected as specified in 
Appendix 3. 
If laboratory tests at screening are performed within 7 days before randomization, these tests 
(hematology, clinical chemistry, coagulation, urinalysis, and pregnancy test, if applicable) do not 
have to be repeated and the test results must be reviewed before the first dose of study drug(s). 
Hematology and serum chemistry (including liver function tests) as specified in Appendix 3 
should be performed at each cycle for both arms. Additional laboratory tests are required weekly 
for patients in Arm A in Cycle 1 and Cycle 2.  
After Cycle 1, laboratory tests can be performed up to 2 days before Day 1 of subsequent cycles 
and results are to be reviewed within 48 hours before study drug administration. Coagulation 
tests as specified in Appendix 3 are required at Screening and subsequently as clinically 
indicated. Refer to Section 8.3.5 for additional information regarding clinical assessment and 
management of clinical laboratory abnormalities. Urinalysis will be performed on Cycle 1 Day 1 
(if not done within 7 days before randomization) and subsequently as clinically indicated. 
Serum pregnancy test (for women of childbearing potential, including women who have had a 
tubal ligation) must be performed and documented as negative within 7 days before 
randomization. Urine or serum pregnancy tests will be performed once every 3 weeks during 
treatment before administration of study drug(s) at each cycle and at the EOT Visit. A negative 
pregnancy test must be completed and recorded before administration of study drug(s) at each 
cycle. A serum pregnancy test must be performed if the urine pregnancy test is positive or 
equivocal. 
Thyroid assessments will be performed at screening, every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, 
etc), and at the EOT Visit, as specified in Appendix 1. 
Details about sample collection and shipment will be provided in a separate instruction manual. 
Investigators may use results from local laboratories for assessing eligibility, safety monitoring, 
and dosing decisions. 
7.4.4.1. 
Cardiac Enzyme Monitoring  
Although immune-mediated myocarditis is a rare complication of immune checkpoint inhibitors, 
serum creatine kinase (CK) and CK cardiac isoenzyme (CK-MB) is monitored in all tislelizumab 
studies to protect study participants and to quantify the risk of muscle inflammation (see 
Appendix 1 for the blood collection schedule and Appendix 8 for guidelines for management of 
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suspected immune-mediated myocarditis). Serum troponins may be substituted per local 
guidelines if used consistently throughout the study. 
7.4.5. 
Electrocardiograms  
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. 
For patients in Arm A, ECG assessments will be performed at pre-dose (within 30 minutes 
before pre-dose PK sample collection of sitravatinib) and approximately 6 hours post dose 
(within 30 minutes before post-dose PK sample collection of sitravatinib) on Cycle 1 Day 1 and 
Cycle 2 Day 1. For other ECG assessments, when coinciding with blood draws at the same 
timepoint, ECG assessment should be performed either before blood draws, or at least 30 
minutes after blood draws. Patients should rest in semirecumbent supine position for at least 
10 minutes before ECG collection. If an ECG has been performed within 7 days before 
randomization (for patients in Arm B) or before the EOT visit (for all patients), the test does not 
need to be repeated on Cycle 1 Day 1, and the EOT visit, respectively. ECG collection may be 
done at other timepoints as clinically indicated.  
7.4.6. 
Multigated Acquisition Scans or Echocardiograms  
Evaluations of cardiac function will be performed at screening and every 12 weeks (± 7 days). 
Evaluation by echocardiogram is preferred. Evaluation by MUGA scan is an acceptable 
alternative if necessary. The method used for individual patients should be consistent throughout 
the study. 
7.4.7. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0. 
Characterization of toxicities will include severity, duration, and time to onset. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
7.4.8. 
Hepatitis B, Hepatitis C, and HIV Testing  
Testing will be performed by the local laboratory at Screening and will include HBV/HCV 
serology (HBsAg, hepatitis B surface antibody [HBsAb], hepatitis B core antibody [HBcAb], 
and HCV antibody). Viral load assessment (HBV DNA and HCV RNA) will be performed if the 
HBsAg and/or HCV antibody test is positive. HIV serology is required at screening for patients 
in Germany with an unknown HIV status and will include antigen and/or antibodies. Viral load 
assessment (HIV RNA) and CD4+ T-cell count tests will be conducted at screening for patients 
outside Germany with a known HIV infection. 
7.5. 
Tumor and Response Evaluations  
Tumor imaging will be performed within 28 days before randomization and while on study, 
approximately every 6 weeks (± 7 days ) from Day 1 of Cycle 1 in the first 12 months and 
approximately every 9 weeks (± 7 days ) thereafter, based on RECIST v1.1. Results of 
standard-of-care tests or examinations performed before obtaining informed consent and 
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≤ 28 days before randomization may be used for the purposes of screening rather than repeating 
the standard-of-care tests. If a tumor assessment is missed or conducted outside of the specified 
assessment window, all subsequent scans should be conducted on the planned schedule. 
Screening assessments and each subsequent assessment of the tumor must include CT scans 
(with oral and/or intravenous contrast, unless contraindicated) or MRI of the chest, abdomen, and 
pelvis. Other known or suspected sites of disease must be included in the imaging assessments. 
All measurable and nonmeasurable lesions should be assessed and documented at the Screening 
Visit and reassessed at each subsequent tumor evaluation. The same radiographic procedure used 
to assess disease sites at screening is required to be used throughout the study (eg, the same 
contrast protocol for CT scans). 
• Imaging of the brain (preferably MRI) at baseline is required for all screened patients. 
Screening evaluations will be performed within 28 days before randomization. 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a non-contrast CT of the chest plus a contrast-enhanced 
MRI (if possible) of the abdomen and pelvis should be performed. 
• If a CT scan for tumor assessment is performed on a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards of a 
diagnostic CT scan. 
• Bone scans (Technetium-99m [Tc-99m]) or PET should be performed at Screening if 
clinically indicated. If bone metastases are present at Screening and cannot be seen on CT 
or MRI scans, Tc-99m or PET bone scans should be repeated when a complete response 
(CR) is suspected in target lesion or when progression in bone is suspected. 
− If bone metastases are visualized on the bone scan or PET scan at screening, a 
confirmatory CT/MRI scan should be performed. If the metastases are confirmed by 
CT/MRI, then evaluation by CT/MRI should be given preference for subsequent 
assessments. If the metastases are not confirmed by CT/MRI, then the use of bone 
scan or CT/MRI for subsequent assessments is at the investigator’s discretion. 
− If an increase in the uptake of existing lesions is seen on a bone scan, or the 
appearance of new osteoblastic bone lesions is seen on an x-ray, CT, or MRI, this 
should not automatically be considered evidence of progression in an otherwise stable 
or responding subject. It may in fact be indicative of response to therapy. 
− New areas of uptake seen on a bone scan should not automatically result in diagnosis 
of progressive disease but should be correlated with other available imaging (eg, CT, 
MRI, or x-ray). 
• CT scans of the neck or extremities should be performed at Screening only if clinically 
indicated and should be repeated throughout the study if there is evidence of metastatic 
disease in these regions at Screening. 
• At the investigator’s discretion, other methods of assessing target lesions and nontarget 
lesions per RECIST v1.1 may be used. However, CT or MRI should be given preference 
for assessment of target lesions. 
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Response will be assessed by the IRC and the investigator using RECIST v1.1 (see Appendix 5). 
The same evaluator should perform assessments, if possible, to ensure internal consistency 
across visits. 
After first documentation of response (CR or PR), confirmation of tumor response should occur 
4 weeks or later after the first response or at the next scheduled assessment timepoint.  
After disease progression is assessed by the investigator or IRC per RECIST v 1.1, and at the 
investigator’s discretion, a patient that would continue to benefit from the study treatment in 
Arm A may continue their assigned treatment.  
The following criteria must be met in order to treat patients who may continue to benefit from 
the study treatment in Arm A after disease progression: 
• 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. Patients must be informed that they may be forgoing treatment that 
has shown benefit by continuing treatment beyond progression.  
• 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. 
Tumor assessment should continue as planned in patients receiving study drug(s) beyond initial 
investigator-assessed progression. Tumor assessment in such patients should continue until study 
treatment discontinuation. 
Response and PD will be assessed using RECIST v1.1. When PD is assessed by the investigator, 
the IRC is required to complete central image review and convey the results to the investigator as 
soon as possible. If PD is not confirmed by IRC, it is recommended to continue study treatment 
until PD is confirmed by IRC, if this is in the best interest of the patient as discussed with the 
medical monitor. In the situation where the investigator believes the patient must urgently 
discontinue study treatment without waiting for IRC confirmation, the investigator should 
contact the medical monitor to inform him/her of the decision of treatment discontinuation.  
Patients who discontinue study treatment early for reasons other than disease progression (eg, 
toxicity, PD by the investigator) will continue to undergo tumor assessments following the 
original plan until the patient, experiences disease progression per RECISTv1.1 assessed by the 
IRC, withdraws consent, is lost to follow-up, starts a new anticancer treatment, until death, or 
until study termination, whichever occurs first. 
Tumor assessments are required to be performed on schedule regardless of whether study 
treatment has been administered or held. That is, they should not be adjusted for delays in cycles. 
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7.6. 
Pharmacokinetic and Antidrug Antibody Testing  
The PK concentrations will be determined using plasma (sitravatinib and its active metabolite 
M10) or serum (tislelizumab) samples collected at specified timepoints within a reasonable 
variation window (refer to Appendix 2). As sitravatinib malate capsule is an alternative 
formulation previously not evaluated in patients, intensive PK samples for sitravatinib and M10 
will be collected in 12 patients (6 from China and 6 from ex-China) according to the 
chronological order during enrollment in Arm A if patients agree, while sparse samples will be 
collected from the remaining patients in Arm A. For tislelizumab, sparse samples will be 
collected from patients who received tislelizumab treatment (Arm A). The actual time of each 
sample collection will be recorded on the source document and CRF. An additional sitravatinib 
PK blood sample may be drawn before a daily sitravatinib dose at a clinic visit at least one week 
following a dose modification of sitravatinib, or as soon as possible after a serious AE. 
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 timepoints throughout the study (refer to 
Appendix 2). The immunogenicity evaluation will utilize a risk-based immunogenicity strategy 
(Koren et al 2008; Worobec and Rosenberg 2004a; Worobec and Rosenberg 2004b) to 
characterize ADA responses to tislelizumab in support of the clinical development program.  
The following assessments will be performed at a bioanalysis laboratory: 
• ADA assays: serum samples will be tested for the presence of ADAs to tislelizumab 
using a validated immunoassay 
• Tislelizumab PK assay: serum samples will be assayed for tislelizumab concentrations 
using a validated immunoassay 
• Sitravatinib PK assay: plasma samples will be assayed for sitravatinib concentrations 
using a validated LC-MS/MS method. 
• M10 PK assay: plasma samples will be assayed for M10 concentrations using a validated 
method. 
Shipping, storage, and handling of samples for the PK and ADA assessment will be managed 
through a central laboratory. Instruction manuals and supply kits will be provided for all central 
laboratory assessments. 
7.7. 
Biomarkers  
Shipping, storage, and handling of blood, archival tumor, fresh tumor, and leftover tumor tissue 
for the assessment of biomarkers will be managed through a central laboratory. Refer to the 
laboratory manual for details of sample handling. 
7.7.1. 
Tissue Biomarkers  
See Appendix 1 for the tissue biomarker sample collection schedule. 
Archival tumor tissues (FFPE blocks or approximately 15 [at least 5 slides for PD-L1 
assessment] freshly cut unstained FFPE slides from each block) must be collected (if available) 
for biomarker analysis to assess PD-L1 expression (mandatory) and, if tissue samples are 
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sufficient, to assess biomarkers such as GEP, DNA alteration, tTMB and MSI (optional). Tissues 
for optional biomarker analysis can be retrospectively provided after relative regulation approval, 
eg, regulations on the management of Human Genetic Resource Administration of the People's 
Republic of China (HGRAC). Submission of < 15 unstained slides is not a protocol deviation. If 
no archival tumor tissues can be provided, a fresh biopsy is mandatory during screening for 
PD-L1 assessment. For nonsquamous NSCLC, documentation of EGFR status with no 
sensitizing mutation by tissue-based test must be provided before enrollment. For undocumented 
cases, additional archival or fresh biopsy tumor tissues (FFPE blocks or approximately 3 freshly 
cut unstained FFPE slides from each block) will be required for central assessment of EGFR 
mutation status during screening.  
Tumor tissue should be of good quality based on total and viable tumor content. Acceptable 
samples include core needle biopsies for nonsuperficial tumor tissue or excisional, incisional, 
punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Fine-needle 
aspiration, brushing, cell pellets from pleural effusion, lavage samples, and bone/bone marrow 
aspirates are not acceptable. Written patient consent is required for fresh tumor biopsies. 
In addition to archival tumor tissues, fresh biopsies from an accessible tumor site(s) at screening 
(within 28 days before randomization) and/or at the time of confirmed PD are recommended to 
explore response or resistance mechanisms. If feasible, any follow-up biopsy should ideally be 
taken from the same tumor lesion as the baseline biopsy. 
7.7.2. 
Blood Biomarkers  
See Appendix 1 for the blood biomarker sample collection schedule. 
Peripheral blood samples will be collected for biomarker analysis, such as DNA alteration, 
bTMB, MSI and ctDNA. Approximately 10 mL of peripheral blood samples will be collected at 
baseline (pre-dose on Cycle 1 Day1) and pre-dose on Cycle 3 Day 1. For patients who have 
confirmed CR/PR (± 14 days) or confirmed PD, additional blood samples (approximately 
10 mL) will be collected upon each confirmation. Written patient consent is required for blood 
sample collections. 
7.8. 
Patient-Reported Outcomes  
Patients will be asked to complete PRO questionnaires before any clinical activities (including 
blood draws or imaging scans) are performed during on-study clinic visits according to the 
schedule in Appendix 1.  
The PRO questionnaires include the European Organisation for Research and Treatment of 
Cancer (EORTC) core cancer (QLQ-C30) and its lung cancer module QLQ-LC13, as well as the 
European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) (Appendix 12, Appendix 13, and 
Appendix 14).  
The PROs are to be completed on Cycle 1 Day 1 before any assessments, then coincide with 
disease evaluations and continue at the same intervals until the start of subsequent therapy; if the 
disease evaluation does not coincide with a clinic visit, the PRO assessments should be 
completed at the clinic visit closest to the disease evaluation. 
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7.9. 
Visit Windows  
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see 
Appendix 1). In Cycle 1 and Cycle 2, all the patients in Arm A will return for assessments on 
Day 8 (± 1 day) and Day 15 (± 2 days). Sitravatinib will be given in the clinic. 
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 before study treatment infusion/dose unless otherwise 
noted. Laboratory results are required to be reviewed before 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 (the visit window is provided in 
Appendix 1), with subsequent visits conducted according to the planned schedule every 3 weeks 
from Day 1 of the previous cycle. 
7.10. 
Unscheduled Visits  
Unscheduled visits may be performed at any time at the patient’s or the 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 the investigator assessment as appropriate, and the 
results of these tests should be entered on the unscheduled visit eCRF. 
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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol. 
8.1. 
Risks Associated With Study Drug  
8.1.1. 
Risks Associated With Tislelizumab and Sitravatinib  
Tislelizumab and sitravatinib are investigational agents that are currently in clinical 
development. Across studies, the safety profile of tislelizumab is consistent with the therapeutic 
class of the drug. When combined with another investigational agent, the safety profile of the 
combination is generally consistent with the safety profiles of each drug given as monotherapy. 
Limited safety data for sitravatinib in combination with tislelizumab in patients are available, and 
the full safety profiles have not been characterized. The following recommendations are based on 
results from nonclinical and clinical studies with tislelizumab or sitravatinib and published data 
on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions. AEs observed with anti-PD-1 therapy are presented in Section 8.8.3. 
The guidelines for management of potential AEs more specific to treatment with sitravatinib or 
agents in the same class of cancer treatment are presented in Section 8.9. 
Although most imAEs 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 evaluation and management guidelines for suspected imAEs are 
provided in Appendix 8. 
8.1.2. 
Risks Associated with Docetaxel  
Please refer to Table 8 for the reported toxicities of 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 prescribing information for a complete list of potential side effects. 
Table 8: 
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 
• 
Secondary malignancy/leukemia 
• 
Cardiotoxicity, arrhythmia 
• 
Pneumonitis 
• 
Gastrointestinal obstruction, perforation, 
hemorrhage 
• 
Venous thromboembolism 
• 
Arterial thromboembolism 
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• 
Gastrointestinal (anorexia, nausea, vomiting, 
stomatitis, diarrhea, constipation) 
• 
Asthenia (may be severe) 
• 
Disseminated intravascular coagulation 
• 
Seizures 
• 
Hepatotoxicity 
8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria  
Eligibility criteria were selected to guard the safety of patients in this study. Results from the 
nonclinical toxicology studies of sitravatinib and tislelizumab and clinical data with sitravatinib 
and tislelizumab, as well as the nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were 
considered. Specifically, patients at risk for study-emergent active autoimmune diseases or with 
a history of autoimmune diseases that may relapse, patients who have undergone allogeneic stem 
cell or organ transplantation, and patients who have received a live vaccine ≤ 28 days before 
randomization are excluded from the study. Patients with contraindications for docetaxel 
treatment are also excluded from the study (see Section 4.2 for the full list of exclusion criteria). 
8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v5.0. All enrolled patients will be evaluated clinically and with 
standard laboratory tests at regular intervals during their participation in this study. Safety 
evaluations will consist of medical interviews, recording of AEs (see Table 9), physical 
examinations, laboratory measurements (hematology, chemistry, etc) and other assessments 
including those listed in Appendix 1. In addition, patients will be closely monitored for the 
development of any signs or symptoms of infections or autoimmune conditions. 
At the start of each cycle, study drug(s) will only be administered after clinical laboratory results 
have been reviewed. Administration of study drug(s) will be performed in a setting where 
emergency medical equipment and staff who are trained to respond to medical emergencies are 
available (see Section 5.2.1). 
Serum samples will be drawn for determination of ADAs to tislelizumab in patients randomized 
to the tislelizumab arm, if treatment assignment is known. Otherwise, samples will be drawn 
from all randomized patients but will only be analyzed in patients treated with tislelizumab. 
All AEs will be recorded during the study (AE from the time of the first dose of study drug(s) 
and SAEs from the time of signing of informed consent) and for up to 30 days after the last dose 
of study treatment 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 AE. 
Immune-mediated AEs will be recorded until up to 90 days after the last dose of tislelizumab, 
regardless of whether the patient starts a new anticancer therapy. All drug-related SAEs will be 
recorded by investigator after treatment discontinuation until patient death, withdrawal of 
consent, or loss to follow up, whichever occurs first. 
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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 Section 8.7. 
8.3. 
Adverse Events  
8.3.1. 
Definitions and Reporting  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not. 
Examples of AEs include: 
• Worsening of a chronic or intermittent preexisting condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome 
• Detection or diagnosis of a new condition after study drug administration, even though 
the condition may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or 
a concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor. In this instance, all patient identifiers will be blinded on the 
copies of the medical records before submission to the sponsor. 
8.3.2. 
Assessment of Severity  
The investigator will assess the severity of each AE and SAE reported during the study. AEs and 
SAEs should be assessed and graded based upon the NCI-CTCAE v5.0. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
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Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(eg, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the 
regulatory definitions. Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.6.2. 
8.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE, using best clinical judgment. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
the AE or SAE to the study drug should be considered and investigated. The investigator should 
consult the tislelizumab IB, sitravatinib IB, and prescribing information for docetaxel 
(TAXOTERE prescribing information) in the determination of his/her assessment. 
There may be situations when an SAE has occurred, and the investigator has only limited 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always assesses causality for every SAE before transmission of the SAE report to 
the sponsor, because the causality assessment is 1 of the criteria used when determining 
regulatory reporting requirements. The investigator may subsequently change his/her opinion of 
causality considering follow-up information and may amend the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related” based on all information available at the time of reporting. 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 criteria are 
met, otherwise the event should be assessed as “not related”: 
− There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out 
− 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). 
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8.3.4. 
Follow-up of Adverse Events  
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts.  
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient 
withdraws consent. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, clinical chemistry, complete blood count [CBC], coagulation, 
or urinalysis) or other abnormal assessments (eg, ECGs, X-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen during the study. The definition of clinically significant is left 
to the judgment of the investigator. In general, these are the laboratory test abnormalities or other 
abnormal assessments that: 
• are associated with clinical signs or symptoms, or 
• require active medical intervention, or 
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or further diagnostic 
investigation. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 x ULN associated with cholestasis), only the diagnosis (ie, 
cholestasis) should be recorded on the AE eCRF. 
If the laboratory abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE. For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
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Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the AE eCRF, unless the etiology changes. The initial severity of 
the event should be recorded, and the severity or seriousness should be updated any time the 
event worsens. 
8.4. 
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 were more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually involving 
at least an overnight stay) to the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. 
• Results in disability/incapacity 
Note: The term “disability” means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), which may interfere with or 
prevent everyday life functions, but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
• Is considered a significant medical AE by the investigator based on medical judgement 
(eg, may jeopardize the patient or may require medical/surgical intervention to prevent 1 
of the outcomes listed above) 
The following are NOT considered to be SAEs: 
• Hospitalization for elective treatment of a preexisting 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 
8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets 
the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is 
not consistent with those noted in the IB. 
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8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
8.6.1. 
Adverse Event Recording Period  
After informed consent has been signed but before the administration of the study drug, only 
SAEs should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until either 30 days after last dose of study drug(s) or initiation of new anticancer 
therapy, whichever occurs first. Immune-mediated AEs (serious or nonserious) 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 SAEs considered related to the study drug(s) that are brought 
to the attention of the investigator should be reported regardless of time since the last dose of 
treatment. 
AEs and SAEs should be recorded according to the details in Table 9. For the follow-up period 
for AEs, see Section 8.3.4. For the definition of TEAEs, see Section 9.3.1. 
Table 9: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Arms 
Event type 
Record new or worsening events that occur during this period 
Begin 
End  
SAEs a 
Signing of informed 
consent 
Up to 30 days after last dose, initiation of 
new anticancer therapy, death, withdrawal 
of consent, or loss to follow-up, whichever 
occurs first 
Nonserious AEs due to PD 
Do not record (see Section 8.6.4) 
All nonserious AEs, except 
those due to PD 
First dose of study drug 
Up to 30 days after last dose, initiation of 
new anticancer therapy, death, withdrawal 
of consent, or loss to follow-up, whichever 
occurs first 
Immune-mediated AEs 
(serious or nonserious) 
First dose of study drug 
Up to 90 days after last dose (regardless of 
initiation of new anticancer therapy), death, 
withdrawal of consent, or loss to follow-up, 
whichever occurs first 
Abbreviations: AE, adverse event; PD, progressive disease; SAE, serious adverse event. 
a All SAEs considered related to the study drug(s) that are brought to the attention of the Investigator should be 
reported regardless of time since the last dose of treatment. 
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 10. 
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Table 10: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Timeframe for sending 
initial/follow-up a report 
Documentation method 
Reporting method 
All 
SAEs  
Within 24 hours of first 
knowledge of the SAE 
SAE report 
Electronic submission of 
SAE form to safety portal b 
Abbreviations: EDC, electronic data capture; SAE, serious adverse event. 
a Report follow-up information that is clinically relevant and pertaining to the SAE which includes but is not limited 
to the following: Update to the SAE, new additional SAE, outcome, seriousness criteria, investigator causality, event 
start date/date of onset, date of death, relationship to each study drug. Follow-up information will also be reported at 
the discretion of the investigator if the new or updated information changes the medical assessment of the case. 
b SAE reports should be submitted to the sponsor safety database electronically from within the EDC. If the 
electronic submission is not available for any reason, a paper SAE form should be submitted by email or fax. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 8.6.2.1. The SAE report 
will always be completed as thoroughly as possible with all available details of the event and 
forwarded to the sponsor or designee within the designated time frames. 
If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will report all SAEs to the sponsor in accordance with the procedures detailed in 
Section 8.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation. 
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
All SUSARs (as defined in Section 8.5), will be submitted to all applicable regulatory authorities 
and investigators for tislelizumab, sitravatinib, and docetaxel studies. 
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised IB) from the sponsor, the investigator or designated responsible person is required to 
promptly notify his/her IRB or IEC. The investigator should place copies of Safety Reports from 
the sponsor in the Investigator Site File. 
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8.6.3. 
Eliciting Adverse Events  
The investigator or designee will ask patients about AEs by asking the following standard 
questions: 
• How are you feeling? 
• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
8.6.4. 
Disease Progression  
Disease progression, which is expected in this study population and measured as an efficacy 
endpoint, should not be recorded as an AE term. Similarly, nonserious AEs that are clearly 
consistent with the pattern of progression of the underlying disease and are considered 
unequivocally due to disease progression should not be recorded. However, if there is any 
uncertainty as to whether a nonserious AE is due to disease progression, it should be recorded as 
an AE. All SAEs and deaths regardless of relatedness to disease progression should be recorded 
and reported (see Section 8.6.2). 
8.6.5. 
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 AE (eg, “death,” “death 
of unknown cause,” or “death unexplained”). 
8.6.6. 
Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy or within 180 days after the last dose of study drug(s), a pregnancy report 
form is required to 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 AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should be always reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as an SAE. 
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8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees  
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information (RSI) documents: 
• Tislelizumab IB 
• Sitravatinib IB 
• Prescribing information for docetaxel 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events  
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune-mediated (see Section 8.8.3) should be classified as imAEs and 
identified as such in the eCRF AE page.  
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 8. 
An extensive list of potential imAEs appears in Table 12. All conditions similar to those listed 
should be evaluated to determine whether they are imAEs, based on a similar diagnostic process 
to those reactions that are presented in more detail in Appendix 8. 
8.6.9. 
Recording Infusion-Related Reactions  
The symptoms of infusion-related reactions may include, but are not limited to, fever, 
chills/rigor, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness, or hypertension. Severe reactions may include acute respiratory 
distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Sign and 
symptoms should be reported as the AE term(s).  
8.7. 
Management of Adverse Events Potentially Associated With Either 
or Both of Sitravatinib and Tislelizumab  
Based on the known toxicity profiles of sitravatinib and tislelizumab, certain treatment-related 
AEs are uniquely associated with one drug versus the other. For example, hypertension, arterial 
thrombotic events, palmar plantar erythrodysesthesia, and hemorrhagic events are known risks 
for sitravatinib treatment, while imAEs are risks for tislelizumab treatment. However, certain 
AEs may be initially considered attributed to either study drugs, such as diarrhea, 
hypothyroidism, and liver enzyme elevation. Therefore, evaluation of attribution is important for 
determining the study drug most likely related to the AE, or an alternative etiology, and 
subsequently proper clinical management. 
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If an AE is suspected to be treatment related and is severe/life threatening at the time of onset or 
is rapidly worsened, action including interrupting or holding both drugs, initiating treatment with 
a corticosteroid (with exception of hypothyroidism, type I diabetes mellitus) to treat an imAE, 
and other supportive care should be taken promptly. 
8.8. 
Management of Adverse Events of Special Interest of Tislelizumab  
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for ≥ 60 minutes afterward 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 imAEs 
according to the NCI-CTCAE criteria are outlined below. 
8.8.1. 
Managing Infusion-Related Reactions  
Patients should be closely monitored for infusion-related reactions. Immediate access to an 
Intensive Care Unit (ICU) or equivalent environment and appropriate medical therapy (including 
epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen) must be 
available to treat infusion-related reactions. 
Treatment modifications for symptoms of infusion-related reactions due to study drug(s) is 
provided in Table 11. 
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Table 11: 
Treatment Modifications for Symptoms of Infusion-Related Reactions Due to 
Tislelizumab 
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, intravenous 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reaction has 
resolved or decreased to Grade 1 in severity. 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: 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 and be 
administered with premedication. If the patient has a second infusion-related reaction 
(≥ Grade 2) on the slower infusion rate, infusion should be discontinued, and the patient should 
be withdrawn from tislelizumab treatment. 
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 intravenous 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. 
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NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes, but is not limited 
to, oral or intravenous antihistamines, antipyretics, glucocorticoids, epinephrine, bronchodilators, 
and oxygen. 
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 the infusion must be immediately 
stopped and the patient discontinued from the study. Systemic anaphylactic/anaphylactoid 
reactions typically manifest within minutes following administration of the drug/antigen and are 
characterized by respiratory distress, laryngeal edema, and/or intense bronchospasm; and often 
followed by vascular collapse or shock without antecedent respiratory difficulty; cutaneous 
manifestations such as pruritus and urticaria with/without edema; and gastrointestinal 
manifestations such as nausea, vomiting, crampy abdominal pain, and diarrhea. 
The patient will be administered epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed. The patient should then be placed on a monitor 
immediately, and an ICU 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 infusion. 
Alternative treatments for fever (ie, paracetamol) may be given to patients at the discretion of the 
investigator. 
8.8.3. 
Immune-Mediated Adverse Events  
Immune-mediated 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 that 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 imAE indicator in the eCRF AE page should be 
checked. 
A list of potential imAEs is shown below in Table 12. All conditions similar to those listed 
should be evaluated in patients receiving tislelizumab to determine whether they are 
immune-mediated. 
Recommendations for diagnostic evaluation and management of imAEs is based on European 
Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) 
guidelines (Haanen et al 2017, Brahmer et al 2018), and common immune-mediated toxicities 
are detailed in Appendix 8. For any AEs not included in Appendix 8, please refer to the ASCO 
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Clinical Practice Guideline (Brahmer et al 2018) for further guidance on diagnostic evaluation 
and management of immune-mediated toxicities. 
Table 12: 
Examples of Immune-Mediated Adverse Events 
Body system affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet 
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 managing imAEs are detailed in Appendix 8. 
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 after restart of study drug should permanently discontinue 
treatment. 
8.9. 
Management of Sitravatinib-specific Adverse Events  
8.9.1. 
Management of Non-Hematological Toxicities of Sitravatinib  
Patients experiencing symptomatic Grade 2 non-hematological sitravatinib-related AEs should 
have a dose reduction to the next lower dose level at the discretion of the investigator, per the 
reduction schedule (Table 13). Dose reductions are expected to improve treatment tolerability. 
Non-hematological toxicities ≥ Grade 3 considered to be related to sitravatinib treatment are to 
be managed with sitravatinib interruption, until resolution of toxicity to ≤ Grade 1 or to baseline 
value. In the case of Grade 3 or 4 electrolyte abnormalities that are not clinically complicated and 
that resolve spontaneously or with conventional medical treatment within 72 hours, or Grade 3 
asymptomatic amylase or lipase elevation, treatment can be resumed at the same dose; if not, 
treatment should be resumed at a reduced dose as outlined in Table 13. Recurrence of the 
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toxicity is managed similarly. If treatment is interrupted for ≥ 28 days, permanent 
discontinuation from study treatment should be considered. 
Table 13: 
Sitravatinib Dose Modifications – Non-Hematological Drug-Related 
Toxicities 
Toxicity 
Treatment delay 
Dose modification 
Grade 1 
Not required  
Grade 2 - Asymptomatic 
Implemented based on investigator and patient discretion 
Grade 2 - Symptomatic 
Implemented based on 
investigator and patient 
discretion 
Dose reduction to next lower 
dose level 
Grade 3 or 4 
Hold until ≤ Grade 1 or return to 
baseline 
Resume at dose one or more 
levels below that inducing the 
toxicity. Exceptions are 
presented in footnotes 
Notes:  
1. Management of specific adverse events (eg, hypertension) for sitravatinib are presented in sections below. 
2. Patients may resume at the same dose in the following cases:  
• 
Grade 3 or 4 electrolyte abnormality that is not clinically complicated and resolves spontaneously or with 
conventional medical treatment within 72 hours 
• 
Grade 3 amylase or lipase elevation that is not associated with the symptoms or the clinical manifestations 
of pancreatitis 
8.9.2. 
Management of Hematological Toxicities of Sitravatinib  
Hematological toxicities are not a frequent cause of treatment interruption or discontinuation of 
sitravatinib treatment. Observed ≥ Grade 3 hematological events that are considered to be 
causally related to sitravatinib should initially be managed using treatment interruption. In 
addition, dose reduction of sitravatinib will be implemented at the discretion of the investigator in 
the following cases:  
• Grade 3 or 4 febrile neutropenia 
• Grade 4 neutropenia persisting for ≥ 8 days  
• Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with bleeding 
8.9.3. 
Dose Modification Guidelines for Sitravatinib-Specific AEs  
Dose modification guidelines for increased blood pressure, increased hepatic transaminase not 
likely to be immune-mediated, and palmar-plantar erythrodysesthesia (PPE) are presented in 
Table 14, Table 15, and Table 16, respectively. Guidance for management of Hy’s Law cases is 
also provided below. Additional management guidelines for sitravatinib-specific AEs are also 
described below. 
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Table 14: 
Sitravatinib Dose Modification for Increased Blood Pressure 
Toxicity  
Drug interruption 
Dose modification  
Grade 1 or 2 hypertension  
Not required 
Grade 3 hypertension without clinically 
significant increases in BP as defined below  
Implemented based on investigator discretion 
Consider antihypertensives per Section 8.9.4  
Grade 3 hypertension with clinically 
significant increases in BP defined as either 
an increase of ≥ 30 mm Hg in systolic BP to 
≥ 180 mm Hg or increase of ≥ 20 mm Hg in 
diastolic BP to ≥ 110 mm Hg, confirmed 
with repeated testing after ≥ 5 minutes  
Hold until ≤ Grade 2 or 
return to baseline  
Dose reduction to next lower 
dose level 
Grade 4 hypertension  
Discontinue sitravatinib  
Discontinue sitravatinib  
Abbreviation: BP, blood pressure. 
For cases where transaminase increases are not likely to be immune-mediated, treatment 
management decisions are to be made per investigator’s discretion in consideration of clinical 
factors. Recommended treatment modifications for sitravatinib are provided in Table 15. 
Table 15: 
Sitravatinib Dose Modification for Increased Hepatic Transaminase 
Toxicity  
Drug interruption 
Dose modification  
Grade 1 (> ULN to 3.0 x ULN)  
Not required 
Grade 2 (> 3.0 to 5.0 x ULN) 
Hold until ≤ Grade 1 or return 
to baseline 
Decrease by 1 dose level 
Grade 3 or 4 (> 5.0 x ULN) 
Hold until ≤ Grade 1 or return 
to baseline 
If resolution occurs within 
22 days, decrease by 1 dose 
level. 
If no resolution within 22 days, 
discontinue sitravatinib. 
Abbreviation: ULN, upper limit of normal. 
Table 16: 
Sitravatinib Dose Modification for Palmar-Plantar Erythrodysesthesia  
Toxicity* 
Treatment Delay 
Dose Modification 
Grade 1 
Not required 
Not required 
Grade 2 
Based on investigator discretion 
Dose reduction to the next lower 
level 
Grade 3 
Hold until ≤ Grade 1 or return to 
baseline 
Resume at dose one or more 
levels below that inducing the 
toxicity 
Abbreviation: PPE, palmar-plantar erythrodysesthesia. 
*For any event of PPE, regardless of severity, patients are to be counseled on measures to mitigate the effects of 
PPE, including avoidance of exposure of hands and feet to hot water, other sources of heat, activities that cause 
unnecessary force or friction (rubbing), chemicals (eg, cleaning products), and wearing well-ventilated shoes or 
clothing. Treatment may include topical moisturizing agents, topical anesthetics, or topical anti-inflammatory 
medications such as corticosteroid creams. 
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8.9.3.1. 
Management of Hy’s Law Cases  
In the event a patient develops concurrent increase in AST and/or ALT ≥ 3 x ULN, and  
bilirubin ≥ 2 x ULN but without concurrent increases in alkaline phosphatase (ie, alkaline 
phosphatase < 2 x ULN) that is not attributable to liver metastases or biliary obstruction, 
sitravatinib and tislelizumab should be permanently discontinued and steroids administered. 
8.9.4. 
Hypertension  
Hypertension, including Grade 4 events, has been reported with sitravatinib. Dihydropyridine 
calcium channel blockers such as nifedipine, amlodipine, and nicardipine should be considered if 
antihypertensive therapy is required and should be considered for patients with Grade 3 
hypertension without clinically significant increases in blood pressure (BP) (see Table 14). In 
cases of Grade 3 hypertension with clinically significant increases in blood pressure, sitravatinib 
dosing should be hold until resolution of hypertension to ≤ Grade 2 or to baseline. Treatment 
with sitravatinib should resume at a lower dose at the discretion of the investigator. If significant 
hypertension recurs, options include a change in medical management of the patient, reduction of 
sitravatinib dose, or discontinuation of study treatment, at the discretion of the investigator. In 
the event of Grade 4 hypertension, sitravatinib will be permanently discontinued (see Table 14). 
8.9.5. 
Palmar-Plantar Erythrodysesthesia  
PPE syndrome has been reported as a DLT in the Phase 1 study of sitravatinib. Measures that can 
be taken to manage the syndrome include avoidance of exposure of hands and feet to hot water 
when washing dishes or bathing, or to other sources of heat; avoidance of activities that cause 
unnecessary force or friction (rubbing) on the hands or feet; avoiding contact with harsh 
chemicals such as cleaning products; use of tools or household items that result in pressure on 
the hands, such as garden tools, knives, and screwdrivers, and wearing of loose fitting, well-
ventilated shoes and clothes. Treatment may include use of topical moisturizing agents, topical 
anesthetics, or topical anti-inflammatory medications such as corticosteroid creams. In more 
severe cases, dose interruption and reduction may be warranted (See Table 16). 
8.9.6. 
Diarrhea  
Diarrhea has been reported with sitravatinib treatment, though the mechanism remains unclear, 
as with other small molecule RTK inhibitors. Patients should be counseled that diarrhea is a 
possible side effect and advised to take loperamide or a similar medication as needed if diarrhea 
develops. Any patients developing dehydration or clinically significant electrolyte abnormalities 
should interrupt treatment, but treatment may be restarted once diarrhea is controlled. 
Investigators should also evaluate whether diarrhea may be attributable to the imAE of colitis. 
The presence of abdominal pain, mucus or blood in the stool, or peritoneal signs should raise the 
index of suspicion for immune-mediated colitis, as these features are generally not observed with 
sitravatinib treatment-associated diarrhea. The diarrhea observed with sitravatinib generally 
improves within several days of interrupting study medication, and close observation may help 
establish the most likely causality. 
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8.9.7. 
Hemorrhagic Events  
The risk of hemorrhagic events with sitravatinib is unknown; however, such events have been 
reported with inhibitors of VEGFR. Patients with active hemoptysis or gastrointestinal bleeding 
should not take sitravatinib, and suspension of treatment is to be implemented for patients 
developing clinically significant bleeding.  
8.9.8. 
Thrombotic Events  
Though thrombotic events (eg, pulmonary embolism) have been reported with sitravatinib and 
with inhibitors of VEGFR, the risk of such events with sitravatinib is unknown. Precautions 
should be taken in patients with recent, clinically significant thrombotic events, and treatment is 
to be discontinued in patients who develop clinically significant thromboembolic complications 
such as acute myocardial infarction or severe pulmonary embolism. 
8.9.9. 
Thyroid Dysfunction Other Than Immune-Mediated  
Hypothyroidism and increases in thyroid-stimulating hormones have been reported in patients 
taking sitravatinib. Patients diagnosed with hypothyroidism should be treated with hormone 
replacement therapy and may continue treatment with sitravatinib at the investigator’s discretion. 
8.9.10. 
Decreased Left Ventricular Ejection Fraction  
Decreased left ventricular ejection fraction has been reported with sitravatinib. In addition, 
decreases of left ventricular ejection fraction to < 50% on-study were observed in patients 
undergoing scheduled MUGA scans or echocardiograms. The dose of sitravatinib should be 
interrupted and/or reduced in patients with an ejection fraction < 50% and > 20% below baseline. 
Discontinuation should be considered for patients requiring acute hospitalization for treatment of 
congestive heart failure.  
8.9.11. 
Proteinuria  
Although the risk with sitravatinib is unknown, proteinuria has been described with other 
inhibitors of the VEGFR pathway. Patients who develop ≥ 2+ proteinuria should undergo 
24-hour urine collection for assessment of urine protein; treatment with sitravatinib should be 
discontinued in the presence of ≥ 2 grams of urine protein/24 hours and may restart when protein 
levels decrease to less than 2 grams/24 hours. Patients who develop nephrotic syndrome should 
be withdrawn from treatment with sitravatinib. 
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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
The statistical analyses will be performed by the sponsor or designee after the data collection is 
completed and the database is locked and released. Details of the statistical analyses will be 
included in a separate SAP. 
9.1. 
Statistical Analysis  
9.1.1. 
Randomization Methods  
As discussed in Section 7.2.2, patients will be randomized using the IRT system for this study by 
permuted block stratified randomization with stratification factors of histological subtype 
(nonsquamous versus squamous), PD-L1 expression (< 1% TC versus ≥ 1% TC; patients whose 
tissues are unevaluable for PD-L1 expression will be included in the < 1% TC group), and race 
(Asian versus non-Asian). There are 2 treatment arms. Patients will be randomized 1:1 to receive 
tislelizumab in combination with sitravatinib or docetaxel monotherapy.  
9.1.2. 
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 
all efficacy analyses. 
The Safety Analysis Set includes all patients who received ≥ 1 dose of any of the study drugs; it 
will be the analysis set for the safety analyses.  
The Sitravatinib PK Analysis Set includes all patients in the Safety Analysis Set who contributed 
≥ 1 quantifiable postbaseline PK sample for sitravatinib. 
The M10 PK Analysis Set includes all patients in the Safety Analysis Set who contributed 
≥ 1 quantifiable postbaseline PK sample for M10. 
The Tislelizumab PK Analysis Set includes all patients in the Safety Analysis Set who 
contributed ≥ 1 quantifiable postbaseline PK sample for tislelizumab. 
The ADA Analysis Set includes all patients who received ≥ 1 dose of tislelizumab and for whom 
both baseline ADA and ≥ 1 postbaseline ADA result are available.  
9.1.3. 
Multiplicity  
OS and PFS are the dual primary endpoints in this study. The type I error is strongly controlled 
by initially assigning a 1-sided alpha of 0.001 to the PFS hypothesis and 0.024 to the OS 
hypothesis. By using the graphic approach of Bretz et al 2009, if the PFS or OS hypotheses are 
both rejected, the corresponding alpha will be shifted to the hypothesis test of the secondary 
efficacy endpoint ORR per RECIST v1.1 assessed by the IRC. 
Figure 2 shows the initial 1-sided alpha allocation for each hypothesis in the ellipses. The 
weights for reallocation to other hypothesis tests are represented in boxes on the edges. 
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9.2.1. 
Primary Efficacy Analysis  
9.2.1.1. 
Overall Survival  
OS is defined as the time from randomization to death from any cause. The null hypothesis to be 
tested is:  
H0: OS in Arm A ≤ OS in Arm B  
against the alternative:  
H1: OS in Arm A > OS in Arm B  
The OS curve will be estimated using the Kaplan-Meier method in the ITT Analysis Set. The 
difference in the OS curve between the 2 arms is tested using a stratified log-rank test. The 
1- sided alpha of 0.024 will be used initially for the testing. The significance level at interim and 
final analyses will be determined by Lan-DeMets’ approximation of the O’Brien Fleming alpha 
spending function. The hazard ratio of OS will be estimated by a Cox regression model including 
treatment arm as a factor and prespecified stratification factors as strata. 
The median OS and the cumulative probability of OS at every 3 months, if estimable, will be 
calculated for each treatment arm and presented with 2-sided 95% CIs. Landmark OS will be 
compared between 2 treatment arms for landmark analysis.  
If the proportional hazard assumption for OS curves is not valid, the restricted mean survival rate 
(RMST) analysis for OS may be conducted as the supplementary analysis. In addition, the max 
combo test may also be applied. 
The treatment effect for OS in the absence of subsequent anticancer therapy may be estimated 
using models, such as the rank preserving structural failure time and the inverse probability 
of censoring weighting. The choice of model will depend on an examination of the 
appropriateness of the data to the assumption required by the method. 
The primary analysis of OS will treat death due to COVID-19 as an OS event and will be 
performed regardless of any other COVID-19-related intercurrent events. COVID-19-related 
sensitivity/supplementary analyses will be specified in the SAP. 
Other analyses for emerging intercurrent events for OS may be considered and will 
be specified in SAP.  
9.2.1.2. 
Progression-free Survival by Independent Review Committee  
PFS by IRC is defined as the time from randomization to the first documented disease 
progression, as assessed by the IRC based on RECIST v1.1, or death from any cause, whichever 
comes first. The null hypothesis to be tested is:  
H0: PFS by IRC in Arm A ≤ PFS by IRC in Arm B  
against the alternative:  
H1: PFS by IRC in Arm A > PFS by IRC in Arm B  
The PFS by IRC curve will be estimated using the Kaplan-Meier method in the ITT Analysis 
Set. The difference in the PFS by IRC curve will be tested using a stratified log-rank test. A 
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significance level of 1-sided 0.001 will be used for the testing. The HR of PFS by IRC will be 
estimated and presented with a 2-sided 95% CI using the same method as that for OS.  
The primary and sensitivity censoring rules will follow United States (US) Food and Drug 
Administration (FDA) Guidance for Industry, Clinical Trial Endpoints for Approval of Cancer 
Drugs and Biologics (FDA 2018). The detailed censoring rules will be described in detail in the 
SAP. 
The median PFS and the cumulative probability of PFS at every 3 months, if estimable, will be 
calculated for each treatment arm and presented with 2-sided 95% CIs. The landmark PFS rates 
by IRC will be compared between 2 treatment arms for the landmark analysis.  
The analyses accounting for nonproportional hazard of PFS by IRC may be carried out 
as the supplementary analyses when necessary using the same method as of that for OS.  
The COVID-19 related sensitivity/supplementary analyses of PFS may be considered and will be 
specified in the SAP. 
9.2.1.3. 
Sensitivity Analyses for the Primary Endpoints  
Sensitivity analyses for OS and PFS by IRC will be conducted to examine the robustness of the 
statistical methods. In addition to the above specified analyses, post-hoc sensitivity analyses 
may also be used to address the censoring and missing data problem caused 
by unanticipated reasons. The details of the sensitivity analyses will be described in the SAP.  
9.2.2. 
Secondary Efficacy Analysis  
The PFS by investigators is defined as the time from randomization to the first documented 
disease progression, as assessed by the investigators based on RECIST v1.1; or death from any 
cause, whichever comes first. Similar methods as those for the analysis of PFS by IRC will be 
applied.  
DCR by IRC is defined as the proportion of patients whose best overall response (BOR) is CR, 
PR, or stable disease as determined by the IRC based on RECIST v1.1 in the ITT Analysis Set. 
ORR by IRC is defined as the proportion of patients with confirmed objective response (CR or 
PR), as assessed by IRC based on RECIST v1.1 in the ITT Analysis Set. Patients with no 
postbaseline response assessment (for any reason) will be considered non-responders. 
The null hypotheses of no difference in DCR and ORR by IRC will be tested by a stratified 
Cochran-Mantel-Haenszel test. The odds ratio and the 2-sided 95% CIs for DCR and ORR will 
be calculated.  
DOR by IRC is defined as the time from the first occurrence of a documented objective response 
to the time of the first occurrence of disease progression, as determined by assessment of the IRC 
based on RECIST v1.1, or death from any cause, whichever comes first. DOR by IRC will be 
analyzed similarly to PFS in the patients with objective responses. An unstratified model will be 
used for the DOR endpoint.  
HRQoL is assessed via changes in EORTC QLQ-C30's Global Health Status/Quality of Life, 
functional and symptom scales and the single item scores, QLQ-LC13’s symptoms scales’ scores 
and scores of the EQ-5D-5L dimensions scales and Visual Analogue Scale (VAS). Observed 
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values and changes from baseline will be summarized using descriptive statistics. Clinically 
meaningful changes postbaseline (percentage of patients with a 10-point improvement or 
worsening, or to be defined in the SAP) for global health scores and physical function of the 
QLQ-C30 and dyspnoea, coughing, haemoptysis, peripheral neuropathy, pain in the arms and 
shoulders, and pain in the chest of LC13 will be calculated by timepoint and compared between 
the treatment arms using the mixed models which include baseline score, prespecified 
stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects 
with visit as a repeated measure with an unstructured covariance structure.  
Time to deterioration, defined as worsening scores (10-point change, or to be defined in the SAP 
if otherwise) of the global health score of QLQ-C30 for 2 consecutive assessments or 
1 assessment followed by death from any cause before the next scheduled data collection. Time 
to deterioration between treatment arms will be compared using a log-rank test, and its 
Kaplan-Meier probabilities for each arm will be plotted over time.  
9.2.3. 
Exploratory Efficacy Analysis  
• ORR by investigators, defined as the proportion of patients with PR or CR as determined 
by the investigator based on RECIST v1.1 
• DOR by investigators, defined as the time from the first occurrence of a documented 
objective response to the time of the first occurrence of disease progression, as 
determined by the investigator based on RECIST v1.1, or death from any cause, 
whichever comes first 
• DCR by investigators, defined as the proportion of patients whose BOR is CR, PR, or 
stable disease based on RECIST v1.1 by investigator 
The analytic methods for ORR, DOR and DCR by investigators are the same as those for the 
analyses of ORR, DOR and DCR by IRC. 
9.3. 
Safety Analyses  
Safety will be assessed by the monitoring and recording of all AEs graded by NCI-CTCAE v5.0. 
Laboratory values, 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. 
9.3.1. 
Extent of Exposure  
Extent of exposure to each study drug will be summarized descriptively in terms of the number 
of cycles received (number and percentage of patients), duration of exposure (days), cumulative 
total dose received per patient (mg), dose delays and reductions, dose intensity, and relative dose 
intensity. 
9.3.2. 
Adverse Events  
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 and up to 30 days following study drug 
discontinuation or initiation of new anticancer therapy, whichever occurs first. Only those AEs 
that were treatment-emergent will be included in summary tables of TEAEs. 
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Immune-mediated AEs will be identified from all AEs that had an onset date or a worsening in 
severity from baseline (pretreatment) on or after the first dose of tislelizumab and up to 90 days 
from the last dose of tislelizumab, regardless of whether the patient starts a new anticancer 
therapy. 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 
System Organ Class (SOC) and preferred term. A patient will be counted only once by the 
highest severity grade per NCI-CTCAE v5.0 within an SOC and preferred term, even if the 
patient experienced more than 1 TEAE within a specific SOC and preferred term. The number 
(percentage) of patients with TEAEs will also be summarized by relationship to the study drug. 
Treatment-related AEs include those events considered by the investigator to be related to a 
study drug or with missing assessment of the causal relationship. SAEs, deaths, TEAEs with 
≥ Grade 3 severity, imAEs, treatment-related TEAEs, and TEAEs that led to treatment 
discontinuation, dose interruption, dose reduction, or dose delay will be summarized. 
9.3.3. 
Laboratory Analyses  
Clinical laboratory values will be evaluated for each laboratory parameter as appropriate. 
Abnormal laboratory values will be flagged and identified as those outside (above or below) the 
normal range. Reference (normal) ranges for laboratory parameters will be provided. Descriptive 
summary for laboratory parameters and their changes from baseline will be calculated. 
9.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters and changes from baseline will be presented.  
9.4. 
Pharmacokinetic Analysis  
Blood samples for PK analysis of sitravatinib, M10, and tislelizumab will be collected at 
specified timepoints (Appendix 2). The actual collection date and time of each blood sample will 
be recorded. The timing of PK samples may be altered and/or PK samples may be obtained at 
additional timepoints upon sponsor approval to ensure thorough PK monitoring. 
For the PK analysis sets that contribute serial plasma samples for sitravatinib and M10 on 
Cycle 1 Day 1 and Cycle 2 Day 1, plasma concentration-time data of each patient will be 
tabulated and graphically presented on linear and semilogarithmic scales. Plots of sitravatinib 
concentration-time data will be presented for Cycle 1 Day 1 (after single dose) and Cycle 2 
Day 1 (at steady state). Pharmacokinetic parameters will be determined using a standard 
noncompartmental method. A listing of patients excluded from the analysis sets and individual 
data points excluded from the analysis will be provided. The final analysis of PK parameters will 
be calculated based on actual sample collection times rather than scheduled times. The 
parameters will be summarized with descriptive statistics (eg, N, arithmetic mean, standard 
deviation, minimum, median, maximum, geometric mean, and coefficient of variation [CV] % 
associated with the geometric mean). 
PK parameters will include, but are not limited to, the following as allowed by data: 
Cmax (ng/mL) 
Observed maximum plasma concentration during a sample interval. 
Cτ (ng/mL) 
Observed trough concentration at steady state. 
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Tmax (hr) 
Observed time to maximum plasma concentration during a sampling 
interval. 
AUC(0-t) (ng•h/mL) 
Area under the plasma concentration-time curve from time zero to the 
last measurable timepoint calculated by log-linear trapezoidal 
summation. 
The sitravatinib, M10, and tislelizumab concentration data collected sparsely at pre-dose and 
around Tmax will be tabulated and summarized by visit/cycle. Descriptive statistics will include 
means, standard deviations, medians, and ranges as appropriate. 
Additional PK assessments, including population PK analyses, may be conducted as appropriate, 
and the results of such analyses may be reported separately from the clinical study report. 
9.5. 
Immunogenicity Analyses  
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADAs. The incidence of positive ADAs and 
neutralizing ADAs will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy, and safety may be evaluated if data allow and reported separately from the main study 
report. 
9.6. 
Other Exploratory Analyses  
9.6.1. 
Exploratory biomarker analyses  
Distribution of PD-L1 expression in TC will be examined. Association between the PD-L1 
expression level and efficacy endpoints (OS, PFS, ORR, DOR, and DCR) will be explored. The 
association between PD-L1 expression and treatment effect will also be examined. The detailed 
analysis method will be discussed in the SAP. 
Analysis of the relationship of response to other exploratory biomarkers (eg, GEP, DNA 
alteration, tTMB/bTMB, MSI, and ctDNA) may be carried out, depending on the adequacy of 
available data. 
9.7. 
Sample Size Consideration  
The sample size calculation is based on the primary efficacy analysis of OS in the ITT Analysis 
Set. The hazard ratio of OS is assumed to be 0.70, with a median OS of 14.3 months in the 
treatment arm and 10.0 months in the comparator arm. The dropout rate for OS is assumed to be 
5% per year. A total of 420 patients will be enrolled in a 1:1 randomization over an 18-month 
period, at a maximum enrollment rate of 28 patients/month and a ramp-up period of 6 months. 
Approximately 289 OS events are planned for the final analysis, to have a power of 85% with an 
alpha of 0.024. A group sequential testing of OS will be performed. The hazard ratio assumption 
of PFS is 0.63 with a median PFS of 5.4 months in the treatment arm and 3.4 months in the 
control arm. Approximately 332 PFS events are expected to occur at the final analysis of PFS, to 
have a power of 87% with an alpha of 0.001. 
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9.8. 
Interim Analyses  
One interim analysis is planned to occur when approximately 197 of the targeted 289 OS events 
(68.0%) are documented in the ITT Analysis Set (expected around 22.1 months from the date of 
first patient randomization if alternative hypothesis is true). Final analysis of PFS will be 
performed at the time of the interim analysis of OS. No interim analysis of PFS for efficacy is 
planned. 
Stopping boundaries in p-value and z-score for primary analyses of PFS and OS are shown in the 
Table 17. The boundaries will be updated according to the actual numbers of events in the 
interim and final analyses, and the revised alpha level due to alpha recycling as described above, 
using the above prespecified alpha spending function. 
Table 17: 
Stopping Boundaries (in p-value and z-score) of Primary Analysis of  
Progression-Free Survival and Overall Survival 
Endpoint 
Analysis 
Time 
(month) 
Events 
(n) 
p-value a  
(z-score) for 
efficacy 
Approximate HR 
threshold 
PFS 
Final 
analysis 
22.1 
332 
0.0010 
0.712 
OS 
Interim 
analysis 
22.1 
197 
< 0.0062 (> 2.50) 
0.700 
OS 
Final 
analysis 
32.5 
289 
< 0.0221 (> 2.01) 
0.789 
Abbreviations: HR, hazard ratio; OS, overall survival; PFS, progression-free survival.  
a. 
One-sided 
On the basis of emerging external data, the testing strategy may be modified to improve the 
efficiency of the design. Should this occur, modifications to the testing strategy will be 
documented in the SAP before the unblinding of the study. 
An early futility analysis based on PFS will be performed, when approximately 48 PFS events 
were documented in the ITT Analysis Set. The analysis is expected to occur around 8 months 
from the date of first patient randomization. The non-binding futility boundary is specified at 
HR = 1.076, as is determined by a Hwang-Shih-DeCani (HSD) beta spending function with 
parameter 1.  
The aim of the interim analysis of efficacy is to determine if there is convincing evidence of 
outstanding OS and/or PFS benefit. An Independent Data Monitoring Committee (IDMC) will 
be responsible for making the recommendation regarding stopping the study early based on 
predefined criteria for OS and/or PFS. More details will be provided in the IDMC charter. 
Patients will continue to be randomized if enrollment has not been completed and treated per 
protocol at the time of interim analysis and until a final decision is made by the sponsor after 
considering the recommendation provided by the IDMC. 
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10. 
STUDY COMMITTEES AND COMMUNICATION  
10.1. 
Independent Review Committee  
An IRC will be established to perform an independent review of all radiologic images for the 
efficacy analysis and to determine all instances of response and disease progression on the basis 
of the RECIST v1.1 criteria, in addition to the local investigator review of radiographs. The 
results from the investigator’s review of radiographic images will be used to determine whether 
patients should be enrolled at Screening and whether patients on study should continue to receive 
the study drug. The tumor assessments by the IRC will be used for the reporting of the study 
results. 
All decisions made during the performance of the study will be based on the local investigator’s 
assessment of radiographic images, clinical status, and relevant examination of the patients. Sites 
will submit specific radiographic image files to the centralized data review facility during the 
study on an ongoing basis or at the sponsor’s request. Detailed rules and guidelines for 
radiographic imaging and tumor assessments by the IRC are outlined separately in the imaging 
manual and IRC charter. 
10.2. 
Independent Data Monitoring Committee  
Regular safety monitoring (at least every 6 months) and efficacy monitoring will be performed 
by an IDMC. The first IDMC safety review will occur after ≥ 20 patients have been randomized 
to study treatment (ie, approximately 10 patients per treatment arm) and have been on treatment 
for ≥ 1 month in order to determine if the proposed dosing schedule of tislelizumab and 
sitravatinib combination therapy is safe and tolerable. The IDMC may recommend study 
modification, including termination of the study, due to safety and/or efficacy concerns. 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 be performed based on new 
information. 
Following IDMC review and discussion, the sponsor will make all final decisions regarding any 
changes in study conduct. Please see the details in the IDMC charter. 
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study may be fully documented. Such records include, but are not limited to, the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals. In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data. 
11.1. 
Access to Information for Monitoring  
In accordance with International Council for Harmonisation (ICH) GCP guidelines, the study 
monitor must have direct access to the investigator’s source documentation in order to verify the 
data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during 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 GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Center Inspections  
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study.  
12.4. 
Drug Accountability  
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes 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 batch/lot number, 
date dispensed, patient identifier number, and the initials of the person dispensing the 
medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene requirements specified in the 
pharmacy manual. At appropriate times during the conduct of the study or at the end of the study 
following final drug inventory reconciliation by the monitor, the study center will dispose of 
and/or destroy all unused study drug supplies, 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 made between the site and BeiGene or its representative for 
destruction or return of unused study drug supplies. 
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All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. A patient diary will be provided to each patient in 
Arm A to record the sitravatinib dose taken each day. Any missed doses with explanations 
should be recorded in the diary. The diary should be returned to the site personnel for review and 
will be reviewed by the investigator/study personnel on a regular basis. 
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13. 
ETHICS/PROTECTION OF HUMAN PATIENTS  
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 patient. The study will also 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 ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted, reviewed, and approved by the IRB/IEC before the study is 
initiated. In addition, any patient recruitment materials must be approved by the IRB/IEC. Copies 
of the IEC/IRB correspondence and approval of the amended ICF/other information and the 
approved amended ICF/other information must be forwarded to the sponsor promptly. 
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments. In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and IRB/IEC. Investigators may receive written 
investigational new drug (IND) safety reports or other safety-related communications from the 
sponsor. Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file. 
13.2.1. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements. Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming their willingness to remain in the study. 
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13.3. 
Informed Consent  
The sponsor’s sample ICF will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. The final IRB/IEC-approved ICFs must be provided to 
the sponsor for health authority submission purposes according to local requirements. 
The ICFs must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained before participation in the study. 
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate. The 
final revised IRB/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes. 
Patients must be reconsented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study. For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
13.4. 
Patient and Data Confidentiality  
The principal investigator, institution, sponsor, and site will maintain confidentiality and privacy 
standards for the collection, storage, transmission, and processing of patients’ personal and 
medical information by following applicable laws and regulations related to the confidentiality, 
use, and protection of such information, including the ICH Good Clinical Practice Guideline, as 
implemented locally. Such laws may be more stringent than the requirements in this protocol. 
The principal investigator and site shall code the personal and medical information obtained 
during the study with a unique patient identification number assigned to each patient enrolled in 
the study. The investigator must ensure that patients’ anonymity will be strictly maintained and 
that their identities are protected from unauthorized parties. Unless required to be provided by 
laws or regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the principal investigator and site must ensure that any personal and medical 
information transmitted to the sponsor or its service providers is: 1) required by the protocol, and 
2) appropriately de-identified (eg, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients are NOT shared: 
o names or initials (full or partial); 
o full dates of birth; 
o contact information (such as phone numbers or home or email addresses);  
o numerical identifiers (eg, hospital or medical record, government, health insurance, 
or financial account numbers) other than patient identification numbers assigned as 
part of this study; 
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o geographic identifiers smaller than a state, province, or local equivalent (such as 
city, county, zip code, or other equivalent geographic identifiers); or  
o information about marital status, family, or household members; employment, sex life, 
sexual preference, or other sensitive data that is not relevant to the study. 
Patient personal and medical information obtained during this study is confidential and may only 
be disclosed to third parties as permitted by the signed ICF (or a separate authorization for the 
use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law. In limited circumstances, such as in connection with insurance 
purposes or patient support services ancillary to certain study sites (eg, for patient travel or 
reimbursement), the principal investigator and site may provide certain of this personal or 
medical information to the sponsor or its representatives. Such personal or medical information 
may not be provided as part of the protocol (eg, as part of the eCRF, or on samples or reports 
submitted to the central lab). 
Investigator and site personnel must use only the specific forms and clinical trial systems, (eg, 
the electronic data capture [EDC] system and any secure file transfer platforms [SFTPs]) 
designated by the sponsor for sharing and transferal of personal and medical information.  
In the event of a breach of the confidentiality of a patient’s personal or medical information, the 
principal investigator, site personnel, and sponsor, as appropriate, shall fulfill all mediation steps 
and reporting obligations under applicable laws. If the sponsor identifies personal or medical 
information that was not properly de-identified, it may be required to report the disclosure under 
local applicable laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes where allowed by local 
law or the patient’s signed ICF. 
Data generated during this study must be available for inspection upon request by representatives 
of the United States Food and Drug Administration (US FDA), the China National Medical 
Products Administration (China NMPA), the European Medicines Agency (EMA), and all other 
national and local health authorities; by sponsor monitors, representatives, and collaborators; and 
by the IRBs/IECs for each study site, as appropriate. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator’s Brochure, this protocol, eCRFs, the investigational drugs, and any other 
study information, are confidential and remain the sole and exclusive property of the sponsor 
during the conduct of the study and thereafter. This information is not to be disclosed to any third 
party (except employees or agents directly involved in the conduct of the study or as required by 
law) without prior written consent from the sponsor. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
Ethnic factors could influence the effects (safety and efficacy) of medicines and the risk/benefit 
assessment in different populations. Race and Ethnicity data are collected in the Clinical Data 
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Interchange Standards Consortium (CDISC) Study Data Tabulation Model (SDTM, 
Implementation Guide v3.2), in accordance with ICH guidance (ICH E5 1998) adopted by the 
EMA and FDA, to support population PK analysis, which is a well-established, quantitative 
method that can quantify and explain the variability in drug concentrations among patients. 
Variability can be attributed to intrinsic factors (eg, body weight, age, gender, race/ethnicity), or 
to extrinsic factors (eg, concomitant medications). In some cases, intrinsic or extrinsic factors 
lead to clinically relevant changes in drug concentrations that require a change in the dose or 
dosing regimen. Results from population PK analyses will be incorporated into drug product 
labeling to provide guidance on the dose or dosing regimen including any potential dose 
adjustment in some subpopulations (eg, race or ethnic group). Therefore, collecting 
race/ethnicity data in the study is essential to understand whether race/ethnicity could influence 
the PK, safety, and/or efficacy. 
13.5. 
Financial Disclosure  
Investigators 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 about their financial interests before 
participation in the study and to update this information if any relevant changes occur during the 
study and for 1 year after completion of the study (ie, last patient, last visit). 
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14. 
DATA HANDLING AND RECORD KEEPING  
14.1. 
Data Collection and Management Responsibilities  
14.1.1. 
Data Entry in the Electronic Case Report Form  
All study-related data collected or received by the investigator or study team shall be promptly 
entered into the eCRFs. In no event should the entry of the study data into the eCRF be later than 
what is stipulated in the site contract after the data is collected or received by the investigator or 
study team without prior communication with and approval by the sponsor. 
14.1.2. 
Data Collection  
Data required by the protocol will be entered into an electronic data capture (EDC) system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The e-signature of the investigator or designee must be 
provided in the EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of 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. 
14.1.3. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol will be stored by 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. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA by the lowest level term, preferred term, and primary 
SOC. Concomitant medications will be coded using the World Health Organization Drug 
Dictionary. Concomitant diseases/medical history will be coded using MedDRA. 
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14.2. 
Data Integrity and In-house Blinding  
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 to share such 
outputs from the EDC system with other functions/persons who do not have access to the EDC. 
In addition, the central imaging vendor will perform the central imaging review without 
knowledge of treatment arm assignment. Although the study is open-label, analyses or 
summaries generated by randomized treatment assignment and actual treatment received will be 
limited and documented. 
14.3. 
Study Records Retention  
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least 1 of the following 2 categories: 1) investigator’s study file, and/or 2) 
patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent forms, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include documents such as 
(although not be limited to) the following: patient hospital/clinic records, physician’s and nurse’s 
notes, appointment book, original laboratory reports, ECG, electroencephalogram, X-ray, 
pathology and special assessment reports, consultant letters, screening and enrollment logs, etc. 
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 ensure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating a hard copy if required. Furthermore, the investigator must 
ensure there is an acceptable backup of these reproductions and that an acceptable quality control 
process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements, local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
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, or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
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If the investigator cannot guarantee this archiving requirement at the study center for any or all 
of 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. 
Biological samples at the conclusion of this study may be retained as outlined in the agreement 
with the Clinical Research Organization managing the biological samples, for the shorter of: a 
period of up to 10 years or as allowed by your IRB/IEC. 
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 and shall report all protocol deviations to sponsor. 
The investigator is to document and explain any deviations from the approved protocol. The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures. 
14.5. 
Study Report and Publications  
A clinical study report will be prepared and provided to the regulatory agency(ies). 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 
regulatory guidance and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study. The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential. As this is a multicenter study, the first publication or disclosure 
of study results shall be a complete, joint multicenter publication or disclosure coordinated by 
the sponsor. Thereafter, any secondary publications will reference the original publication(s). 
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of Medical 
Journal Editors 2018). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this study will be presented in the investigator’s clinical study agreement. Each investigator 
agrees that, in accordance with the terms of the clinical study agreement, a further delay of the 
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publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 
14.6. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Collection of all study documents for the trial master file filing according to GCP and 
local regulation 
• Shipment of samples (including, but not limited to, those for PK, ADA, and biomarkers) 
to the assay lab for central lab analysis according to protocol and lab manual 
requirements  
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for any reason. 
Potential reasons for suspension or discontinuation include but are not limited to: safety or 
ethical issues or noncompliance with this protocol, GCP, the sponsor’s written instructions, the 
clinical study agreement, or applicable laws and regulations. If the sponsor determines such 
action is needed, the sponsor will discuss this with the investigator (including the reasons for 
taking such action) at that time. When feasible, the sponsor will provide advance notification to 
the investigator of the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons. The sponsor will also inform the 
regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action. If required by applicable regulations, the investigator must inform the IEC/IRB promptly 
and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor. In 
addition, arrangements will be made for the return of all unused study drug(s) in accordance with 
the applicable sponsor procedures for the study.  
Financial compensation to the investigators and/or institutions will be in accordance with the 
clinical study agreement established between the investigator and/or institutions and the sponsor. 
14.7. 
Information Disclosure and Inventions  
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial 
property rights that are conceived or reduced to practice by the study center personnel during the 
course of or as a result of the study are the sole property of the sponsor and are hereby assigned 
to the sponsor. 
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If a written contract for the conduct of the study, which includes ownership provisions 
inconsistent with this statement, is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel. 
This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor. 
These restrictions do not apply to: 
• 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 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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Core Cancer Questionnaire; QLQ-LC13, European Organisation for Research and Treatment of Cancer lung cancer module questionnaire; TT3, serum total 
triiodothyronine, TT4, serum total thyroxine; TSH, thyroid stimulating hormone; X, to be performed;  
Note: On days when sitravatinib and tislelizumab dosing are both scheduled, the daily dose of sitravatinib should precede tislelizumab infusion.  
1. During screening, written informed consent must be signed before performing any study-specific tests or procedures. Results of standard-of-care tests or 
examinations performed before obtaining informed consent and within 28 days before randomization may be used for screening assessments, rather than 
repeating such tests. If laboratory tests at screening are performed within 7 days before randomization, these tests (hematology, clinical chemistry, 
coagulation, urinalysis, and pregnancy test) do not have to be repeated and must be reviewed before the first dose of study drug(s). 
2. Includes age or year of birth, gender, self-reported race/ethnicity, smoking history, and drinking history; history of treatment for the primary diagnosis, 
including prior medication, loco-regional treatment(s), and surgical treatment(s). Information on radiographic studies performed before study entry may be 
collected for review by the investigator. Pre-existing AEs at baseline should be recorded as medical history. 
3. All assessments on Cycle 2 Day 1 may be performed within a time window of ± 3 days.  
4. In Cycle 1 and Cycle 2, all the patients in Arm A will return for assessments on Day 8 and Day 15. Sitravatinib will be given in the clinic. 
5. Unscheduled visits may occur any time necessary as per investigator decision or patient’s request, for reasons such as assessment or follow-up of AEs. Study 
activities, as indicated by “X” should be performed based on the reason for the unscheduled visit. If PD is suspected, imaging studies should be performed. 
The date and reason for an unscheduled visit should be recorded in the eCRF. 
6. Patients who discontinue treatment for any reason will be asked to return to the clinic for the EOT Visit 30 days (± 7 days) after the last dose of study drug, 
or before the initiation of a new anticancer treatment, whichever occurs first. If routine laboratory tests (eg, hematology, clinical chemistry) were completed 
≤ 7 days before the EOT Visit, these tests do not need to be repeated. A tumor assessment is not required at the EOT Visit if ≤ 6 weeks have passed since the 
last assessment. If the study drug(s) were initially interrupted due to AEs and then permanently discontinued, the EOT Visit may occur later, but no later 
than the permitted time of dose delay + 7 days. 
7. Telephone contacts (Safety Follow-up phone call) with patients should be conducted to assess imAEs and concomitant medications (if appropriate, eg, 
associated with an AE or a new anticancer therapy) 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 imAE at a telephone follow-up contact, the investigator should arrange an 
unscheduled visit if further assessment is indicated. 
8. Vital signs collected on study include temperature (°C), pulse, and blood pressure (systolic and diastolic). Pulse rate and blood pressure will be collected 
while the patient is in a seated or supine position after resting for 10 minutes. The patient’s vital signs are required to be recorded within 60 minutes before; 
during; and within 30 minutes after the first infusion of tislelizumab. For subsequent infusions, vital signs will be collected within 60 minutes before infusion 
and if clinically indicated, during and within 30 minutes after the infusion. Vital signs should also be recorded before administration of sitravatinib; recorded 
values may be used for pre-tislelizumab assessment if vital signs are collected within 60 minutes before tislelizumab infusion. Docetaxel will follow the 
same procedure as tislelizumab/sitravatinib. 
9. For patients in Arm A, ECG assessments will be performed at pre-dose (within 30 minutes before pre-dose PK sample collection of sitravatinib) and 
approximately 6 hours post dose (within 30 minutes before post-dose PK sample collection of sitravatinib) on C1D1 and C2D1. For other ECG assessments, 
when coinciding with blood draws at the same timepoint, ECG assessment should be performed either before blood draws, or at least 30 minutes after blood 
draws. Patients should rest in semi-recumbent supine position for ≥ 10 minutes before each ECG collection. If an ECG has been performed within 7 days 
before randomization (for patients in Arm B) or before the EOT visit (for all patients), the test does not need to be repeated on Cycle 1 Day 1, and the EOT 
visit, respectively. ECG collection may be done at other timepoints as clinically indicated.  
10. AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0. 
11. All concomitant medications received within 30 days before the first dose of study drug should be recorded.  
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12. Hematology and clinical chemistry will be performed at each cycle for both arms. Additional laboratory tests are required weekly for patients in Arm A in 
Cycle 1 and Cycle 2. After Cycle 1, laboratory tests can be performed up to 2 days before Day 1 of subsequent cycles, and results are to be reviewed within 
48 hours before study drug administration. Coagulation tests as specified in Appendix 3 are required at screening and subsequently as clinically indicated. 
Refer to Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory abnormalities. Urinalysis will be 
performed on Cycle 1 Day 1 (if not done within 7 days before the randomization) and subsequently as clinically indicated. 
13. Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative 
within 7 days before randomization. Urine or serum pregnancy tests will be performed during treatment, and at the EOT Visit. A negative pregnancy test 
must be completed and recorded before administration of study drug(s) at each cycle. A serum pregnancy test must be performed if the urine pregnancy test 
is positive or equivocal.  
14. Thyroid function tests for FT3, FT4, and TSH will be performed at Screening and every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc), and at the EOT Visit. If 
test for FT3 or FT4 is not available, TT3 or TT4 should be tested instead. 
15. Testing will be performed by the local laboratory at Screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody). Viral 
load assessment (HBV DNA and HCV RNA) will be performed if the HBsAg and/or HCV antibody test is positive. HIV serology is required at screening 
for patients in Germany with an unknown HIV status and will include antigen and/or antibodies. Viral load assessment (HIV RNA) and CD4+ T-cell count 
tests will be conducted at screening for patients outside Germany with a known HIV infection. 
16. Tumor imaging will be performed within 28 days before randomization and while on study, approximately every 6 weeks ± 7  days from Cycle 1 Day 1 in 
the first 12 months and approximately every 9 weeks ± 7  days thereafter. All measurable and nonmeasurable lesions should be assessed and documented; 
Screening assessments and each subsequent assessment of the tumor must include CT scans (with oral/intravenous contrast, unless contraindicated) or MRI 
of the chest, abdomen, and pelvis. Other known or suspected sites of disease must be included in the imaging assessments. Imaging of the brain (preferably 
MRI) at baseline is required for all screened patients. Bone scans (Technetium-99m [Tc-99m]) or PET should be performed at Screening if clinically 
indicated. If bone metastases are present at Screening and cannot be seen on CT or MRI scans, Tc-99m or PET bone scans should be repeated when a 
complete response (CR) is suspected in target lesion or when progression in bone is suspected. Tumor assessments are required to be performed on schedule 
regardless of whether study treatment has been administered or held. The same imaging technique should be used throughout the study for each patient. 
After the first documentation of response (CR or PR), confirmation of tumor response should occur ≥ 4 weeks after the first response or at the next 
scheduled assessment timepoint (see Section 7.5 for details). 
17. Archival tumor tissues (FFPE blocks or approximately 15 [at least 5 slides for PD-L1 assessment] freshly cut unstained FFPE slides from each block) must 
be collected (if available) for biomarker analysis to assess PD-L1 expression (mandatory) and, if tissue samples are sufficient, to assess biomarkers such as 
GEP, DNA alteration, tTMB and MSI (optional). Tissues for optional biomarker analysis can be retrospectively provided after relative regulation approval, 
eg HGRAC (Regulations on Management of Human Genetic Resources of the People's Republic of China). Submission of < 15 unstained slides is not a 
protocol deviation. If no archival tumor tissues can be provided, a fresh biopsy is mandatory during Screening for PD-L1 assessment. For nonsquamous 
NSCLC, documentation of EGFR status with no sensitizing mutation by tissue-based test must be provided prior enrollment. For undocumented cases, 
additional archival or fresh biopsy tumor tissues (FFPE blocks or approximately 3 freshly cut unstained FFPE slides from each block) will be required for 
central assessment of EGFR mutation status during the screening period. Tumor tissue should be of good quality based on total and viable tumor content. 
Acceptable samples include core needle biopsies for non-superficial tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions. Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples, and bone/bone marrow aspirates 
are not acceptable. Written patient consent is required for fresh tumor biopsies.  
18. In addition to archival tumor tissues, fresh biopsies from an accessible tumor site(s) at screening (within 28 days before randomization) and/or at the time of 
confirmed PD are recommended to explore response or resistance mechanisms. If feasible, any follow-up biopsy should ideally be taken from the same 
tumor lesion as the baseline biopsy.  
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19. Information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months after the EOT, or as directed by 
the sponsor until death, lost to follow-up, withdrawal of consent, or study termination by sponsor. All patients will be followed up for survival and 
subsequent anticancer therapy information unless a patient requests to be withdrawn from follow-up. 
20. Evaluations of cardiac function will be performed at screening and every 12 weeks (± 7 days). Evaluation by echocardiogram is preferred. Evaluation by 
MUGA scan is an acceptable alternative, if necessary. The method used for individual patients should be consistent throughout study participation.  
21. EORTC-QLQ-C30, QLQ-LC13 and EQ-5D-5L should always be completed before other assessments performed during a visit and drug administration. 
PROs are to be completed at baseline (Cycle 1 Day 1), then every 6 weeks from Cycle 1 Day 1 (± 7 days) (at weeks 7, 13, 19, 25, 31, 37, 43, and 49), and then at 
9-week intervals (± 7 days) thereafter to EOT . If the disease evaluation does not coincide with a clinic visit, the assessment of PRO should be completed at the 
clinic visit closest to the disease evaluation. 
22. See Appendix 2 for schedule of PK sampling for sitravatinib and M10, PK sampling for tislelizumab, and ADA sampling for tislelizumab.  
23. Peripheral blood samples will be collected for biomarker assessments, such as DNA alteration, bTMB, MSI and ctDNA. Approximately 10 mL of peripheral 
blood samples will be collected at baseline (pre-dose on Cycle 1 Day 1) and pre-dose on Cycle 3 Day 1. For patients who have confirmed CR/PR (± 14 days) 
or confirmed PD, additional blood samples (approximately 10 mL) will be collected upon each confirmation. Instructions for the processing, storage, and 
shipping of samples will be provided in the laboratory manual. Written patient consent is required for blood sample collections. 
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APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS  
Serum chemistry 
Hematology 
Coagulation 
Urinalysis 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Albumin 
Total bilirubin 
Direct bilirubin 
Blood urea nitrogen or urea 
Potassium 
Sodium 
Total calcium a  
Creatinine 
Glucose 
Lactate dehydrogenase 
Total protein 
Creatine kinase b  
CK-MB  b 
Hematocrit 
Hemoglobin 
Platelet counts 
WBC count 
Lymphocyte count 
Neutrophil count 
Prothrombin time 
Partial thromboplastin 
time or activated 
partial thromboplastin 
time 
International 
normalized ratio 
Glucose 
Protein c 
Blood 
 
Abbreviations: CK-MB, creatine kinase cardiac isoenzyme; WBC, white blood cell. 
 a Total calcium values will be corrected for patients with hypoproteinemia. 
 b All patients will undergo a creatine kinase and CK-MB testing at screening, and the tests are to be repeated at all 
scheduled visits during the first 3 treatment cycles, all pre-dose assessments from Cycle 4 onwards, and at the 
End-of-Treatment. If CK-MB fractionation is not available, assess troponin I and/or troponin T instead. Refer to 
Section 8.3.5 for additional information regarding clinical assessment and management of clinical laboratory 
abnormalities. 
c  If urinary protein by dipstick is ≥ 2+, then 24-hour urinary protein. 
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APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Source: Oken et al 1982. Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair. 
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APPENDIX 5. THE RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS (RECIST) GUIDELINES, VERSION 1.1  
Source: Eisenhauer et al 2009. 
Definitions  
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (v1.1). Changes in 
only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria. 
Note: Lesions are either measurable or nonmeasurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) and magnetic resonance imaging (MRI) (no less 
than double the slice thickness and a minimum of 10 mm). Assumes a scan slice 
thickness no greater than 5 mm. 
• 10 mm caliper measurement by clinical exam (when superficial) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered nonmeasurable 
disease. Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all nonmeasurable. 
Bone lesions: 
• Bone scan, positron-emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are nonmeasurable. 
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Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) 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. 
• The concept of cystic metastases also applies to metastatic lesions with a necrotic 
component. Hence, measurable lesions with a necrotic component may be selected as 
target lesions. However, if non-necrotic lesions are present, these are preferred for 
selection as target lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. A maximum of 2 measurable 
lymph nodes, inclusive of all lymphatic chains involved, may be chosen as target lesions (ie, the 
lymphatic system is considered one organ). Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), how representative they are of all involved organs, and 
whether they lend themselves to reproducible repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 perpendicular dimensions in the plane in 
which the image is obtained (for CT scan, this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, sagittal, or coronal, but the axial plane is recommended for 
measurements). The smaller of these measures is the short axis. For example, an abdominal node 
which is reported as being 20 mm by 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should 
be considered nontarget lesions. Nodes that have a short axis < 10 mm are considered 
nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
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progression” (more details to follow). In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”). If a nontarget lymph node normalizes 
(< 10 mm in short axis) after baseline, the respective evaluation should be “absent.” 
Guidelines for Evaluation of Measurable Disease  
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is suggested. As noted above, when lesions can be evaluated by both 
clinical examination and imaging, imaging evaluation should be undertaken since it is 
more objective and may also be reviewed at the end of the 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: Target lesion measurements should be performed in the axial plane. CT is the 
best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (eg, for body scans). If there is a 
change from CT to MRI or the reverse, target lesions should continue to be measured 
provided the imaging parameters do not render measurements incomparable. 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date, and because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in studies where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
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• Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
If markers are initially above the upper normal limit, however, they must normalize for a 
patient to be considered in CR. Because tumor markers are disease specific, instructions 
for their measurement should be incorporated into protocols on a disease specific basis. 
Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and prostate-
specific antigen response (in recurrent prostate cancer), have been published. In addition, 
the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are 
to be integrated with objective tumor assessment for use in first-line studies in ovarian 
cancer. 
• Cytology, histology: These techniques can be used to differentiate between partial 
response (PR) and CR in rare cases if required by protocol (for example, residual lesions 
in tumor types such as germ cell tumors, where known residual benign tumors can 
remain). When effusions are known to be a potential adverse effect of treatment (eg, with 
certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in order 
to differentiate between response (or stable disease) and progressive disease. 
Response Criteria  
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes must have reduction in short axis to < 10 mm. 
• Partial Response (PR): ≥ a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters 
• Progressive Disease (PD): ≥ 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 ≥ 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 
• Both PR and PD: If the change in sum of diameters is consistent with both PR and PD at 
a tumor assessment visit, PD should take precedence. 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the “sum” of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
< 10 mm. Case report form may be designed to have target nodal lesions recorded in a 
separate section where, to qualify for CR, each node must achieve a short axis <10 mm. 
For PR, SD and PD, the actual short axis measurement of the nodes is to be included in 
the sum of target lesions. 
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• Target lesions that become “too small to measure.” While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan 
that the radiologist may not feel comfortable assigning an exact measure and may report 
them as being “too small to measure.” 
When this occurs, it is important that a value be recorded on the electronic case report 
form (eCRF). If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. If the lesion is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned. 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a 
definable size when normal and are frequently surrounded by fat, such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this circumstance 
as well). This default value is derived from the 5 mm CT slice thickness (but should not 
be changed with varying CT slice thickness). The measurement of these lesions is 
potentially nonreproducible; therefore, providing this default value will prevent false 
responses or progressions based upon measurement error. To reiterate, however, if the 
radiologist is able to provide an actual measure, that measurement should be recorded, 
even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion.” 
Evaluation of Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the timepoints specified in the protocol. 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker level. All 
lymph nodes must be nonpathological in size (< 10 mm short axis). 
• Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance of 
tumor marker level above the normal limits 
• PD: Unequivocal progression (as detailed below) of existing nontarget lesions. (Note: 
The appearance of 1 or more new lesions is also considered progression.) 
• When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the nontarget disease, there must be an overall level of 
substantial worsening in nontarget disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in the size of 1 or more nontarget lesions 
is usually not sufficient to qualify for unequivocal progression status. The designation of 
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overall progression solely on the basis of change in nontarget disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
• When the patient has only nonmeasurable disease: This circumstance arises in some 
phase 3 studies when it is not a criterion of trial entry to have measurable disease. The 
same general concept applies here as noted above; however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in 
nonmeasurable disease burden. Because worsening in nontarget disease cannot be easily 
quantified (by definition: if all lesions are truly nonmeasurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in nonmeasurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease: 
ie, an increase in tumor burden representing an additional 73% increase in “volume” 
(which is equivalent to a 20% increase diameter in a measurable lesion). 
• Examples include an increase in a pleural effusion from “trace” to “large,” an increase in 
lymphangitic disease from localized to widespread, or it may be described in protocols as 
“sufficient to require a change in therapy.” If “unequivocal progression” is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal 
to have objective criteria to apply to nonmeasurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of preexisting lesions). This is particularly important 
when the patient’s baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up 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 study has a CT or MRI brain scan ordered that 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if he 
or 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. 
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible “new” disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of PD 
based on a new lesion. 
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• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a preexisting site 
of disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
• Timepoint Response 
• It is assumed that at each protocol specified timepoint, a response assessment occurs. The 
following table provides a summary of the overall response status calculation at each 
timepoint for patients who have measurable disease at baseline: 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease. 
When patients have nonmeasurable (therefore nontarget) disease only, the following table is to 
be used: 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
SD (Non-CR/non-PD) 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; SD, stable disease. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study drug treatment 
until the end of treatment considering any requirement for confirmation. On occasion a response 
may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
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response designation. The patient’s best overall response assignment will depend on the findings 
of both target and nontarget disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in nonrandomized studies where response 
is the primary endpoint, confirmation of PR or CR is needed to deem either one the “best overall 
response.” 
The best overall response is determined once all the data for the patient is known. 
Best response determination in studies where confirmation of complete or partial response IS 
NOT required: Best response in these studies is defined as the best response across all timepoints 
(for example, a patient who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best response, it must 
also meet the protocol specified minimum time from baseline. If the minimum time is not met 
when SD is otherwise the best timepoint response, the patient’s best response depends on the 
subsequent assessments. For example, a patient who has SD at first assessment, PD at second 
and does not meet minimum duration for SD, will have a best response of PD. The same patient 
lost to follow-up after the first SD assessment would be considered non-evaluable. 
Best response determination in studies where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent timepoint as specified in the protocol (generally 4 weeks later). 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of “zero.” 
In studies where confirmation of response is required, repeated "NE" (not evaluable) timepoint 
assessments may complicate best response determination. The analysis plan for the study must 
address how missing data/assessments will be addressed in determination of response and 
progression. For example, in most studies it is reasonable to consider a patient with timepoint 
responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. 
Conditions that define “early progression, early death, and inevaluability” are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR. FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of 
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FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication. However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
progression is confirmed at the next scheduled assessment, the date of progression should be the 
earlier date when progression was suspected. 
Confirmation of Measurement/Duration of Response  
Confirmation 
In nonrandomized studies where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such studies. However, in all other circumstances, ie, in 
randomized studies (phase 2 or 3) or studies where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in studies 
which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks). 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular 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. 
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However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between studies are to be made. 
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APPENDIX 6. PREEXISTING 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 medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions. 
Acute disseminated encephalomyelitis 
Addison 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 disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating polyneuropathy 
Chung-Strauss syndrome 
Crohn disease 
Dermatomyositis 
Dysautonomia 
Epidermolysis bullosa acquisita 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture syndrome 
Granulomatosis with polyangiitis 
Graves disease 
Guillain-Barré syndrome  
Hashimoto disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki disease 
Lambert-Eaton myasthenic syndrome 
Lupus erythematosus 
Lyme disease (chronic) 
Mooren ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus syndrome 
Optic neuritis 
Ord thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodosa 
Polyarthritis 
Polyglandular autoimmune syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter syndrome 
Rheumatoid arthritis 
Sarcoidosis  
Sjögren syndrome  
Stiff person syndrome 
Takayasu arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
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APPENDIX 7. NEW YORK HEART ASSOCIATION 
FUNCTIONAL CLASSIFICATION  
Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest. If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin et al 1994. 
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. 
Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 
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APPENDIX 8. IMMUNE-MEDIATED ADVERSE EVENT 
EVALUATION AND MANAGEMENT  
The recommendations below for the diagnosis and management of any immune-mediated 
adverse event (imAE) are intended as a guidance. This document should be used in conjunction 
with expert clinical judgement (by specialist physicians experienced in the treatment of cancer 
using immunological agents), and individual institutional guidelines or policies. 
Criteria used to diagnose imAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, disease progression, 
and adverse effects of concomitant drugs. In addition to the results of these tests, the following 
factors should be considered when making an imAE diagnosis: 
• What was the temporal relationship between initiation of tislelizumab and the AE? 
• How did the patient respond to withdrawal of tislelizumab? 
• Did the event recur when tislelizumab was reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is disease progression or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the imAE field 
associated with the AE in the eCRF should be checked. If further diagnostic evaluations change 
the assessment, the eCRF should be updated accordingly. 
Recommended Diagnostic Tests in the Management of 
Possible Immune-mediated Adverse Events 
Immune-mediated 
Toxicity 
Diagnostic Evaluation Guideline 
Thyroid Disorders 
Scheduled and repeated thyroid function tests (TSH and T4). 
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss, and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, such 
as an upper respiratory infection, new cough, shortness of breath, or hypoxia 
should be assessed by high-resolution CT. Consider pulmonary function test 
including DLCO. 
Radiographic appearance is often nonspecific. Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered. Consult with a respiratory medicine physician for cases of uncertain 
cause.  
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Recommended Diagnostic Tests in the Management of 
Possible Immune-mediated Adverse Events 
Immune-mediated 
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, and 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 to 4; every 2 to 3 days if Grade 2, until 
recovering). Review medications (eg, statins, antibiotics) and alcohol history. 
Perform liver screen including Hepatitis A/B/C serology, Hepatitis E PCR and 
assess anti-ANA/SMA/LKM/SLA/LP/LCI, iron studies. Consider imaging (eg, 
ultrasound scan for metastases or thromboembolism). Consult with a hepatologist 
and consider liver biopsy. 
Renal toxicity 
Review hydration status and medication history. Test and culture urine. Consider 
renal ultrasound scan, protein assessment (dipstick/24-hour urine collection), or 
phase-contrast microscopy. Refer to a nephrologist for further management 
assistance. 
Dermatology 
Consider other causes by conducting a physical examination. Consider 
dermatology referral for skin biopsy. 
Joint or muscle 
inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination. Consider joint X-ray and other imaging as required to exclude 
metastatic disease. Perform autoimmune serology and refer to rheumatology for 
further management assistance. 
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin, and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and refer to a 
cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; CNS, central nervous system; 
CRP, C-reactive protein; CT, computed tomography; DLCO, diffusing capacity for carbon monoxide; ECG, 
electrocardiogram; ESR, erythrocyte sedimentation rate; FBC, full blood count; HIV, human immunodeficiency 
virus; INR, international normalized ratio; LCI, liver cytosolic antigen; LFT, liver function test; LKM, liver kidney 
microsomal antibody; LP, liver pancreas antigen; MRA, magnetic resonance angiogram; MRI, magnetic resonance 
imaging; PCR, polymerase chain reaction; SLA, soluble liver antigen; SMA, smooth muscle antibody; T4, 
thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating hormone; UEC, urea electrolytes and creatinine. 
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Treatment of Immune-mediated Adverse Events  
• Immune-mediated AEs can escalate quickly. Study treatment interruption, close 
monitoring, timely diagnostic work-up, and treatment intervention as appropriate is 
required. 
• Immune-mediated AEs should improve promptly after introduction of 
immunosuppressive therapy. If this does not occur, review the diagnosis, seek further 
specialist advice, and contact the study medical monitor. 
• For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after consultation 
with the study medical monitor. 
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. 
Equivalent dosages of other corticosteroids can be substituted. For steroid-refractory 
imAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]). 
• Consider prophylactic antibiotics for opportunistic infections if the patient is receiving 
long-term immunosuppressive therapy. 
 
Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT abnormality or 
mild symptoms 
Replace thyroxine if 
hypothyroid, until 
TSH/T4 levels return 
to normal range. 
Thyrotoxic patients 
should be referred to 
an endocrinologist. In 
cases with systemic 
symptoms: withhold 
study treatment, treat 
with a beta blocker, 
and consider oral 
prednisolone 
0.5 mg/kg/day for 
thyroid pain. 
Taper corticosteroids 
over 2-4 weeks. 
Monitor thyroid 
function regarding the 
need for hormone 
replacement. 
Continue study treatment or 
withhold treatment in cases 
with systemic symptoms. 
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Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
3-4 
Severe symptoms, hospitalization 
required 
Refer patient to an 
endocrinologist. 
If hypothyroid, replace 
with thyroxine 
0.5-1.6 µg/kg/day (for 
the elderly or those 
with comorbidities, the 
suggested starting dose 
is 0.5 µg/kg/day).  Add 
oral prednisolone 
0.5 mg/kg/day for 
thyroid pain. 
Thyrotoxic patients 
require treatment with 
a beta blocker and may 
require carbimazole 
until thyroiditis 
resolves. 
Hold study treatment; 
resume when 
resolved/improved to Grade 
0-1.  
 
Hypophysitis 
1-2 
Mild-moderate symptoms 
Refer patient to an 
endocrinologist for 
hormone replacement. 
Add oral prednisolone 
0.5-1 mg/kg/day for 
patients with pituitary 
inflammation. Taper 
corticosteroids over at 
least 1 month. 
If there is no 
improvement in 
48 hours, treat as 
Grade 3-4. 
Continue study treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
3-4 
Severe or life-threatening 
symptoms 
Refer patient to an 
endocrinologist for 
assessment and 
treatment. 
Initiate pulse 
intravenous 
methylprednisolone 
1 mg/kg for patients 
with headache/visual 
disturbance due to 
pituitary inflammation. 
Convert to oral 
prednisolone and taper 
over at least 1 month. 
Maintain hormone 
replacement according 
to endocrinologist’s 
advice. 
Hold study treatment for 
patients with 
headache/visual disturbance 
due to pituitary 
inflammation until 
resolved/improved to 
≤ Grade 2. 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. 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
3-4 
Severe or life-threatening 
symptoms: breathless at rest 
Admit to a hospital 
and initiate treatment 
with intravenous 
methylprednisolone 
2-4 mg/kg/day. If there 
is no improvement, or 
worsening after 
48 hours, add 
infliximab 5 mg/kg (if 
no hepatic 
involvement). 
Convert to oral 
prednisolone and taper 
over at least 2 months. 
Cover with empiric 
antibiotics and 
consider prophylaxis 
for Pneumocystis 
infection and other 
adverse steroid effects, 
eg, blood glucose 
monitoring, vitamin 
D/calcium supplement. 
Discontinue study treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study treatment. 
2 
Moderate symptoms 
Treat with oral 
prednisolone 
0.5-1 mg/kg/day. 
Taper over at least 
4 weeks. 
Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to Grade 
0-1. 
3-4 
Severe/life-threatening symptoms 
Initiate treatment with 
oral prednisolone or 
intravenous 
methylprednisolone 
1-2 mg/kg/day, 
depending on 
symptoms. Taper 
corticosteroids over at 
least 4 weeks. 
Consider azathioprine, 
MMF, cyclosporine if 
no response within 
72-96 hours. 
Discontinue study treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
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 
(nonenteric 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 intravenous 
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 
Class III/IV CHF or 
other 
immunosuppressive 
treatment: MMF or 
tacrolimus. 
Consult 
gastroenterologist to 
conduct colonoscopy/ 
sigmoidoscopy. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the study 
medical monitor. 
 
4 
Life-threatening symptoms 
Discontinue study treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
Skin reactions 
1 
Skin rash, with or without 
symptoms, < 10% BSA 
Avoid skin irritants 
and sun exposure; 
topical emollients 
recommended. 
Continue study treatment. 
2 
Rash covers 10%-30% of BSA 
Avoid skin irritants 
and sun exposure; 
topical emollients 
recommended. 
Topical steroids 
(moderate strength 
cream once a day or 
potent cream twice a 
day) ± oral or topical 
antihistamines for itch. 
Consider a short 
course of oral steroids. 
Continue study treatment. 
3 
Rash covers > 30% BSA or Grade 
2 with substantial symptoms 
Avoid skin irritants 
and sun exposure; 
topical emollients 
recommended. 
Initiate steroids as 
follows based on 
clinical judgement: 
For moderate 
symptoms: oral 
prednisolone 
0.5-1 mg/kg/day for 
3 days then taper 
over 2-4 weeks. 
For severe 
symptoms: 
intravenous 
methylprednisolone 
0.5-1 mg/kg/day; 
convert to oral 
prednisolone and 
taper over at least 
4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to mild 
rash (Grade 1-2) after 
discussion with the study 
medical monitor. 
 
4 
Skin sloughing > 30% BSA with 
associated symptoms (eg, 
erythema, purpura, epidermal 
detachment) 
Initiate intravenous 
methylprednisolone 
1-2 mg/kg/day. 
Convert to oral 
prednisolone and taper 
over at least 4 weeks. 
Admit to a hospital 
and seek urgent 
dermatology 
consultation. 
Discontinue study treatment. 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
Hepatitis 
1 
ALT or AST > ULN to 3 x ULN 
Check LFTs within 
1 week and before the 
next dose; check LFTs 
to verify that there has 
been no worsening. 
If LFTs are worsening, 
recheck every 
48-72 hours until 
improvement is seen. 
Continue study treatment if 
LFTs are unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening until 
improvement is seen. 
2 
ALT or AST 3-5 x ULN 
Recheck LFTs every 
48-72 hours. 
For persistent 
ALT/AST elevation: 
consider oral 
prednisolone 
0.5-1 mg/kg/day for 
3 days, then taper over 
2-4 weeks. 
For rising ALT/AST: 
start oral prednisolone 
1 mg/kg/day and taper 
over 2-4 weeks; 
re-escalate dose if 
LFTs worsen, 
depending on clinical 
judgement.  
Hold study treatment; 
treatment may be resumed 
when resolved/improved to 
baseline Grade and 
prednisolone tapered to 
≤ 10 mg. 
3 
ALT or AST 5-20 x ULN 
ALT/AST < 400 IU/L 
and normal 
bilirubin/INR/albumin: 
Initiate oral 
prednisolone 1 mg/kg 
and taper over at least 
4 weeks. 
ALT/AST > 400 IU/L 
or raised 
bilirubin/INR/low 
albumin: Initiate 
intravenous 
(methyl)prednisolone 
2 mg/kg/day. 
When LFTs improve 
to Grade 2 or lower, 
convert to oral 
prednisolone and taper 
over at least 4 weeks.  
Hold study treatment until 
improved to baseline grade; 
reintroduce only after 
discussion with the study 
medical monitor.  
 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
4 
ALT or AST > 20 x ULN 
Initiate intravenous 
methylprednisolone 
2 mg/kg/day. Convert 
to oral prednisolone 
and taper over at least 
6 weeks.  
Discontinue study treatment. 
Worsening LFTs despite steroids: 
• 
If on oral prednisolone, change to pulsed intravenous methylprednisolone. 
• 
If on intravenous methylprednisolone, add mycophenolate mofetil (MMF) 
500 to 1000 mg twice a day. 
• 
If worsens on MMF, consider addition of tacrolimus. 
Duration and dose of steroid required will depend on severity of event. 
Nephritis 
1 
Creatinine 1.5 x baseline 
or > ULN to 1.5 x ULN 
Repeat creatinine 
weekly. 
If symptoms worsen, 
manage as per criteria 
below. 
Continue study treatment. 
2 
Creatinine > 1.5-3 x baseline 
or > 1.5-3 x ULN 
Ensure hydration and 
review creatinine in 
48-72 hours; if not 
improving, consider 
creatinine clearance 
measurement by 
24-hour urine 
collection. 
Discuss with 
nephrologist the need 
for kidney biopsy. 
If attributed to study 
drug, initiate oral 
prednisolone 
0.5-1 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. 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
3 
Creatinine > 3 x baseline 
or > 3-6 x ULN 
Hospitalize patient for 
monitoring and fluid 
balance; repeat 
creatinine every 
24 hours; refer to a 
nephrologist and 
discuss need for 
biopsy. 
If worsening, initiate 
intravenous 
(methyl)prednisolone 
1-2 mg/kg. Taper 
corticosteroids over at 
least 4 weeks. 
Hold study treatment until 
the cause is investigated.  
If study drug suspected: 
Discontinue study treatment. 
 
4 
Creatinine > 6 x ULN 
As per Grade 3, 
patient should be 
managed in a hospital 
where renal 
replacement therapy is 
available. 
Discontinue study treatment. 
Diabetes/ 
Hyperglycemia 
1 
Fasting glucose value ULN to 
160 mg/dL; ULN to 8.9 mmol/L 
Monitor closely and 
treat according to local 
guideline. Check for 
C-peptide and 
antibodies against 
glutamic acid 
decarboxylase and 
islet cells are 
recommended. 
Continue study treatment. 
2 
Fasting glucose value 
160-250 mg/dL; 8.9-13.9 mmol/L 
Obtain a repeat blood 
glucose level at least 
every week. Manage 
according to local 
guideline. 
Continue study treatment or 
hold treatment if 
hyperglycemia is worsening. 
Resume treatment when 
blood glucose is stabilized at 
baseline or Grade 0-1. 
3 
Fasting glucose value 
250-500 mg/dL; 13.9-27.8 mmol/L 
Admit patient to 
hospital and refer to a 
diabetologist for 
hyperglycemia 
management. 
Corticosteroids may 
exacerbate 
hyperglycemia and 
should be avoided. 
Hold study treatment until 
patient is hyperglycemia 
symptom-free, and blood 
glucose has been stabilized 
at baseline or Grade 0-1. 
 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
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. 
Hold study treatment until 
patient is hyperglycemia 
symptom-free, and blood 
glucose has been stabilized 
at baseline or Grade 0-1. 
 
Ocular Toxicity 
1 
Asymptomatic eye examination/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 intravenous 
(methyl)prednisolone 
2 mg/kg/day. Convert 
to oral prednisolone 
and taper over at least 
4 weeks. 
Discontinue study treatment. 
Pancreatitis 
2 
Asymptomatic, blood test 
abnormalities 
Monitor pancreatic 
enzymes. 
Continue study treatment. 
3 
Abdominal pain, nausea and 
vomiting 
Admit to hospital for 
urgent management. 
Initiate intravenous 
(methyl)prednisolone 
1-2 mg/kg/day. 
Convert to oral 
prednisolone when 
amylase/lipase 
improved to Grade 2 
and taper over at least 
4 weeks. 
Hold study treatment; 
reintroduce only after 
discussion with the study 
medical monitor. 
 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
4 
Acute abdominal pain, surgical 
emergency 
Admit to hospital for 
emergency 
management and 
appropriate referral.  
Discontinue study treatment. 
Arthritis 
1 
Mild pain with inflammation, 
swelling 
Management per local 
guideline.  
Continue study treatment. 
2 
Moderate pain with inflammation, 
swelling, limited instrumental (fine 
motor) activities 
Management as per 
local guideline. 
Consider referring 
patient to a 
rheumatologist. 
If symptoms worsen 
on treatment, manage 
as a Grade 3 event. 
Continue treatment or, if 
symptoms continue to 
worsen, hold study treatment 
until symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with inflammation or 
permanent joint damage, daily 
living activity 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. 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
3 
Severe pain, limited food and fluid 
intake, daily living activity limited 
Admit to hospital for 
appropriate 
management. 
Initiate intravenous 
(methyl)prednisolone 
1-2 mg/kg/day. 
Convert to oral 
prednisolone when 
symptoms improve to 
Grade 2 and taper over 
at least 4 weeks. 
Hold study treatment until 
improved to Grade 0-1. 
 
4 
Life-threatening complications or 
dehydration 
Admit to hospital for 
emergency care. 
Consider intravenous 
corticosteroids if not 
contraindicated by 
infection. 
Discontinue study treatment. 
Myositis/ 
Rhabdomyolysis 
1 
Mild weakness with/without pain 
Prescribe analgesics. 
If CK is significantly 
elevated and patient 
has symptoms, 
consider oral steroids 
and treat as Grade 2. 
Continue study treatment. 
2 
Moderate weakness with/without 
pain 
If CK is 3 x ULN or 
worse, initiate oral 
prednisolone 
0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment until 
improved to Grade 0-1. 
3-4 
Severe weakness, limiting self-care 
Admit to hospital and 
initiate oral 
prednisolone 1 mg/kg. 
Consider bolus 
intravenous 
(methyl)prednisolone 
and 1-2 mg/kg/day 
maintenance for severe 
activity restriction or 
dysphagia. 
If symptoms do not 
improve, add 
immunosuppressant 
therapy. 
Taper oral steroids 
over at least 4 weeks. 
For Grade 3: Hold study 
treatment until improved to 
Grade 0-1. Discontinue upon 
any evidence of myocardial 
involvement. 
 
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Autoimmune 
Toxicity 
Grade 
Treatment 
Guidelines (Subject 
to Clinical 
Judgement) 
Study Drug Management 
Myocarditis a 
< 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 testing and 
including ECG, 
cardiac echo/MUGA, 
and/or other 
interventions per 
institutional 
guidelines; consider 
referral to a 
cardiologist. 
If diagnosis of 
myocarditis is 
confirmed, treat as 
Grade 2. 
Hold study treatment. 
If a diagnosis of myocarditis 
is confirmed and considered 
immune-mediated, 
permanently discontinue 
study treatment in patients 
with moderate or severe 
symptoms. 
Patients with no symptoms 
or mild symptoms may not 
restart tislelizumab unless 
cardiac parameters have 
returned to baseline and after 
discussion with the study 
medical monitor. 
2 
Symptoms on mild-moderate 
exertion 
Admit to hospital and 
initiate oral 
prednisolone or 
intravenous 
(methyl)prednisolone 
at 1-2 mg/kg/day. 
Consult with a 
cardiologist and 
manage symptoms of 
cardiac failure 
according to local 
guidelines. 
If no immediate 
response, change to 
pulsed doses of 
(methyl)prednisolone 
1 g/day and add MMF, 
infliximab, or anti-
thymocyte globulin. 
3 
Severe symptoms with mild 
exertion 
Hold study treatment. 
If a diagnosis of myocarditis 
is confirmed and considered 
immune related, 
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. 
 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; ECG, 
electrocardiogram; INR, international normalized ratio; LFT, liver function test; MMF, mycophenolate mofetil; 
MUGA, multigated acquisition scan; NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, 
thyroid function test; TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 
a If clinically significant cardiac enzyme abnormalities are detected during laboratory assessment and serial cardiac 
enzyme assessments pose logistical hardship for the patient, then patient hospitalization should strongly be 
considered until immune-mediated myocarditis has been ruled out. 
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APPENDIX 9. 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) 
equation (Levey et al 2009) 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 serum creatinine (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 (S cr /κ, 1)α × max(S cr /κ, 1)-1.209 × 0.993 Age × 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 
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APPENDIX 10. CONTRACEPTION GUIDELINES AND 
DEFINITIONS OF “WOMEN OF CHILDBEARING 
POTENTIAL,” “NO CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group recommendations related to contraception and pregnancy 
testing in clinical studies include the use of highly effective forms of birth control (Clinical 
Trials Facilitation Group 2014). 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, implantable 
Note: Oral birth control pills are not considered a highly effective form of birth 
control, and if they are selected, they must be used with a second, barrier method of 
contraception such as condoms with or without spermicide. 
• An intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
Note: This is only considered a highly effective form of birth control when the 
vasectomized partner is the sole partner of the study participant and there has been a 
medical assessment confirming surgical success. 
− A sterile male is one for whom azoospermia, in a semen sample, has been 
demonstrated as definitive evidence of infertility. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatment) 
Note: Total sexual abstinence should only be used as a contraceptive method if it is in 
line with the patients’ usual and preferred lifestyle. Periodic abstinence (eg, calendar, 
ovulation, sympto-thermal, post-ovulation methods), declaration of abstinence for the 
duration of exposure to study drug, and withdrawal are not acceptable methods of 
contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception, and if used, this method must be 
used in combination with one of the highly effective forms of birth control listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant. 
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Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
− < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone (FSH) concentration > 30 mIU/mL and 
all alternative medical causes for the lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
Adapted from Clinical Trials Facilitation Group (CTFG) 2014. 
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Appendix 11. Medications Or Substances to Be Avoided or Used 
With Caution During Treatment With Study Drugs  
Examples of Drugs with a Known Risk of Torsades de Pointes 
Aclarubicin (Only on 
Non-US Market) 
Cocaine 
Hydroxychloroquine 
Probucol (Removed from 
US Market) 
Amiodarone 
Disopyramide 
Ibogaine (Only on 
Non-US Market) 
Procainamide 
Anagrelide 
Dofetilide 
Ibutilide 
Propofol 
Arsenic trioxide 
Domperidone (Only on 
Non-US Market) 
Levofloxacin 
Quinidine 
Astemizole (Removed 
from US Market) 
Donepezil 
Levomepromazine 
(Methotrimeprazine) 
(Only on Non-US 
Market) 
Roxithromycin (Only on 
Non-US Market) 
Azithromycin 
Dronedarone 
Levomethadyl acetate 
(Removed from US 
Market) 
Sevoflurane 
Bepridil 
Droperidol 
Levosulpiride (Only on 
Non-US Market) 
Sotalol 
Cesium Chloride 
Erythromycin 
Mesoridazine (Removed 
from US Market) 
Sparfloxacin (Removed 
from US Market) 
Chloroquine 
Escitalopram 
Methadone 
Sulpiride (Only on 
Non-US Market) 
Chlorpromazine 
Flecainide 
Moxifloxacin 
Sultopride (Only on 
Non-US Market) 
Chlorprothixene (Only on 
Non-US Market) 
Fluconazole 
Nifekalant (Only on 
Non-US Market) 
Terfenadine (Removed 
from US Market) 
Cilostazol 
Gatifloxacin (Removed 
from US Market) 
Ondansetron 
Terlipressin (Only on 
Non-US Market) 
Ciprofloxacin 
Grepafloxacin (Removed 
from US Market) 
Oxaliplatin 
Terodiline (Only on 
Non-US Market) 
Cisapride (Removed from 
US Market) 
Halofantrine (Only on 
Non-US Market) 
Papaverine HCl (Intra- 
coronary) 
Thioridazine 
Citalopram 
Haloperidol 
Pentamidine 
Vandetanib 
Clarithromycin 
Hydroquinidine 
(Dihydroquinidine) (Only 
on Non-US Market) 
Pimozide 
* 
Woosley RL, Heise CW, Gallo T, Tate J, Woosley D and Romero KA, www.CredibleMeds.org, QTdrugs List, 
[Accession Date: 10 April 2020], AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755; for the most 
current information, access the website: www.CredibleMeds.org. 
Examples of Drugs with Conditional Risk of Torsades de Pointes  
Abiraterone 
Eperisone (Only on 
Non-US Market) 
Ketoconazole 
Propafenone 
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Amantadine 
Esomeprazole 
Lansoprazole 
Quetiapine 
Amisulpride 
Famotidine 
Loperamide 
Quinine sulfate 
Amitriptyline 
Fluoxetine 
Metoclopramide 
Ranolazine 
Amphotericin B 
Fluvoxamine 
Metolazone 
Risperidone 
Amsacrine (Acridinyl 
anisidide) (Only on 
Non-US Market) 
Furosemide (frusemide) 
Metronidazole 
Sertraline 
Atazanavir 
Galantamine 
Nelfinavir 
Solifenacin 
Bendroflumethiazide 
(Bendrofluazide) 
Garenoxacin (Only on 
Non-US Market) 
Olanzapine 
Telaprevir 
Chloral hydrate 
Hydrochlorothiazide 
Omeprazole 
Torsemide (Torasemide) 
Cimetidine 
Hydroxyzine 
Pantoprazole 
Trazodone 
Clomipramine 
Indapamide 
Paroxetine 
Voriconazole 
Diphenhydramine 
Itraconazole 
Piperacillin/Tazobactam 
Ziprasidone 
Doxepin 
Ivabradine 
Posaconazole 
* 
Woosley RL, Heise CW, Gallo T, Tate J, Woosley D and Romero KA, www.CredibleMeds.org, QTdrugs List, 
[Accession Date: 10 April 2020], AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755; for the most 
current information, access the website: www.CredibleMeds.org. 
Examples of Sensitive Substrates and Substrates with Narrow Therapeutic Index for P-gp 
and BCRP transporters 
Transporter 
Substrates 
P-gp 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, 
imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, 
sitagliptin, talinolol, tolvaptan, topotecan. 
BCRP 
Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, 
topotecan. 
Abbreviations: BCRP, breast cancer resistance protein; P-gp, P-glycoprotein  
Exmples of Sensitive Substrates and Substrates with Narrow Therapeutic Index for the 
indicated CYP Enzymes 
Enzyme 
Substrates 
CYP2C8 
Repaglinide.  
CYP2C9 
Celecoxib 
CYP2C19 
S-mephenytoin, omeprazole 
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CYP2D6 
Atomoxetine, desipramine, dextromethorphan, eliglustat, nebivolol, nortriptyline, perphenazine, 
tolterodine, venlafaxine.  
CYP3A 
Alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, ebastine, eletriptan, eplerenone, everolimus, felodipine, ibrutinib, indinavir, 
lomitapide, lovastatin, lurasidone, maraviroc, midazolam, naloxegol, nisoldipine, quetiapine, 
saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, ticagrelor, tipranavir, tolvaptan, 
triazolam, vardenafil.  
 
Examples of Inhibitors of CYP3A4 or P-gp. 
Strong 
CYP3A4 
Inhibitors 
Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, diltiazem, 
elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, nefazodone, nelfinavir, paritaprevir/ritonavir/ombitasvir plus dasabuvir, 
posaconazole, ritonavir, saquinavir/ritonavir, telaprevir, tipranavir/ritonavir, troleandomycin, 
voriconazole. 
Moderate 
CYP3A4 
Inhibitors 
Aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, 
erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, verapamil. 
P-gp Inhibitors 
Amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and 
ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, verapamil 
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Appendix 12. 
European Organisation For Research And Treatment Of 
Cancer Quality Of Life Cancer Questionnaire QLQ-C30  
 
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APPENDIX 13. European Organisation For Research And Treatment 
Of Cancer Quality Of Life Questionnaire Lung Cancer 
QLQ-LC13  
 
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Appendix 14. The 5-Level Version Of European Quality Of Life 
5-Dimensional Questionnaire  
 
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