Clinical trial NCT04716634
Conditions: Advanced Solid Tumors
Keywords: Solid tumors
Sponsor: BeiGene
Start date: 2021-04-19; Completion date: 2024-02-22
Enrollment: 84 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was an open label, multicenter, Phase 2 study designed to assess the efficacy and safety of tislelizumab in combination with fruquintinib in participants with advanced or metastatic, unresectable gastric cancer (GC), or colorectal cancer (CRC) or non-small cell lung cancer (NSCLC). The study was conducted in 2 parts. Part 1 was the safety run-in stage to determine dose-limiting toxicity (DLT) and recommended Phase 2 dose (RP2D). Part 2 assessed the preliminary efficacy of tislelizumab in combination with fruquintinib in participants as measured by the overall response rate (ORR) and other efficacy and safety profiles.

Detailed description:
This was an open label, multicenter, Phase 2 study designed to assess the efficacy and safety of tislelizumab in combination with fruquintinib in patients with advanced or metastatic, unresectable GC, and CRC or NSCLC. The study was conducted in 2 parts.

Part 1 of the study was the safety run-in stage which assessed dose-limiting toxicities (DLTs) and RP2D. Part 2 began at RP2D. Participants enrolled in Part 1 at RP2D were counted towards Part 2; up to approximately 30 patients per cohort were enrolled at RP2D.

The primary outcome measure of the study was ORR as assessed by the investigator as per response evaluation criteria in solid tumors (RECIST) version (v) 1.1. Tislelizumab and fruquintinib were administered until disease progression, intolerable toxicity, death, withdrawal of consent or until the study terminates.

Arms: arm 1: Participants with advanced or metastatic, unresectable GC received fruquintinib 5 milligrams (mg) daily (3 weeks receiving fruquintinib followed by 1 week off) in combination with tislelizumab 300 mg intravenously on Day 1 of every 4-week cycle (each cycle of 28-days) until disease progression, unacceptable toxicity, or withdrawal for other reasons, whichever occurred first. arm 2: Participants with advanced or metastatic, unresectable CRC received fruquintinib 5 mg daily (3 weeks receiving fruquintinib followed by 1 week off) in combination with tislelizumab 300 mg intravenously on Day 1 of every 4-week cycle (each cycle of 28-days) until disease progression, unacceptable toxicity, or withdrawal for other reasons, whichever occurred first. arm 3: Participants with programmed cell death protein ligand-1 (PD-L1) expression, and advanced or metastatic, unresectable non-small cell lung cancer (NSCLC) received fruquintinib 5 mg daily (3 weeks receiving fruquintinib followed by 1 week off) in combination with tislelizumab 300 mg intravenously on Day 1 of every 4-week cycle (each cycle of 28-days) until disease progression, unacceptable toxicity, or withdrawal for other reasons, whichever occurred first.
Interventions: intervention 1: Tislelizumab intervention 2: Fruquintinib
Intervention descriptions: intervention 1: Tislelizumab is a humanized, immunoglobulin G4 (IgG4)-variant monoclonal antibody against PD 1. intervention 2: Fruquintinib is a potent, oral VEGFR tyrosine kinase inhibitor (TKI)

Protocol documents:
Prot_000.pdf: 
BGB-A317-fruquintinib-201 
BeiGene 
Protocol Amendment 1.0 
 16 December 2020 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Protocol Title: 
A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
TISLELIZUMAB IN COMBINATION WITH FRUQUINTINIB 
IN PATIENTS WITH SELECTED SOLID TUMORS 
Protocol Number: 
BGB-A317-fruquintinib-201 
Phase: 
2 
Investigational Product(s): 
Tislelizumab (BGB-A317), fruquintinib 
Proposed Indication(s): 
Advanced Solid Tumors 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, California 94403 
USA 
Sponsor Medical Monitor: 
, MD 
Telephone: 
 
Email: 
  
Original Protocol 
Version 0.0: 
Protocol Amendment 
Version 1.0: 
18 August 2020 
16 December 2020 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd., and its 
subsidiaries. This document is for use by individuals and their designated representatives for their 
confidential review, consideration, and/or participation in investigational trial(s). This document may not 
be copied or distributed for review by any unauthorized individuals without the prior written authorization 
of BeiGene, Ltd., or one of its subsidiaries. Your acceptance of this document constitutes agreement that 
you will not disclose the information contained herein to others without prior written authorization from 
BeiGene, Ltd., or one of its subsidiaries. 
NCT Number:
NCT04716634


BGB-A317-fruquintinib-201 
BeiGene 
Protocol Amendment 1.0 
 16 December 2020 
 
CONFIDENTIAL 
Page 2 
 FINAL PROTOCOL APPROVAL SHEET 
 
A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF TISLELIZUMAB IN COMBINATION WITH FRUQUINTINIB IN 
PATIENTS WITH SELECTED SOLID TUMORS  
BeiGene, Ltd., Approval: 
 
 
____
____________________________ 
Jian
D 
Sponsor Medical Monitor 
 
 
___________________ 
Date 
 


BGB-A317-fruquintinib-201 
BeiGene 
Protocol Amendment 1.0 
 16 December 2020 
 
CONFIDENTIAL 
Page 3 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: 
A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF TISLELIZUMAB 
IN COMBINATION WITH FRUQUINTINIB IN PATIENTS WITH 
SELECTED SOLID TUMORS 
 
Protocol Identifier: 
BGB-A317-fruquintinib-201 
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 prior to 
implementation of this sponsor-approved protocol. PRINT your name, title, and the name 
and address of the center in which the study will be conducted. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
_______________________________ Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 


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 16 December 2020 
 
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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 .......................................................................................................................11 
SYNOPSIS 12 
LIST OF ABBREVIATIONS AND TERMS ................................................................................20 
1. 
INTRODUCTION AND RATIONALES ..................................................................22 
1.1. 
Introduction .................................................................................................................22 
1.2. 
Fruquintinib ................................................................................................................22 
1.2.1. 
Pharmacology .............................................................................................................22 
1.2.2. 
Toxicology ..................................................................................................................23 
1.2.3. 
Clinical Pharmacology ................................................................................................23 
1.2.4. 
Prior Clinical Experience of Fruquintinib ..................................................................24 
1.2.4.1. 
Pooled Safety Assessment of Monotherapy Studies ..................................................24 
1.2.4.2. 
Efficacy Assessment of Fruquintinib ..........................................................................25 
1.3. 
Tislelizumab ...............................................................................................................25 
1.3.1. 
Pharmacology .............................................................................................................25 
1.3.2. 
Toxicology ..................................................................................................................26 
1.3.3. 
Clinical Pharmacology ................................................................................................26 
1.3.4. 
Prior Clinical Experience of Tislelizumab .................................................................27 
1.3.4.1. 
Pooled Safety Assessment of Monotherapy Studies ..................................................27 
1.3.4.2. 
Efficacy Assessment of Tislelizumab .........................................................................28 
1.4. 
Study Rationale ...........................................................................................................30 
1.4.1. 
Rationale for the Starting Dose...................................................................................30 
1.4.1.1. 
Tislelizumab ...............................................................................................................31 
1.4.1.2. 
Fruquintinib ................................................................................................................32 
1.4.2. 
Rationale for Combination of Tislelizumab and Fruquintinib in the 
Treatment of Advanced Solid Tumors .......................................................................32 
1.4.3. 
Rationale for Tumor Type(s) ......................................................................................33 
1.4.3.1. 
Gastric Cancer ............................................................................................................33 


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1.4.3.2. 
Colorectal Cancer .......................................................................................................34 
1.4.3.3. 
Non-Small Cell Lung Cancer .....................................................................................34 
1.4.4. 
Rationale for Biomarker Strategy ...............................................................................36 
1.5. 
Benefit-Risk Assessment ............................................................................................37 
1.6. 
Study Conduct ............................................................................................................38 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................39 
2.1. 
Study Objectives for Part 1 .........................................................................................39 
2.1.1. 
Primary Objective(s) ...................................................................................................39 
2.2. 
Study Objectives for Part 2 .........................................................................................39 
2.2.1. 
Primary Objective(s) ...................................................................................................39 
2.2.2. 
Secondary Objectives .................................................................................................39 
2.2.3. 
Exploratory Objectives ...............................................................................................39 
2.3. 
Study Endpoints for Part 1 ..........................................................................................40 
2.3.1. 
Primary Endpoint ........................................................................................................40 
2.4. 
Study Endpoints for Part 2 ..........................................................................................40 
2.4.1. 
Primary Endpoint ........................................................................................................40 
2.4.2. 
Secondary Endpoints ..................................................................................................40 
2.4.3. 
Exploratory Endpoint ..................................................................................................41 
3. 
STUDY DESIGN .......................................................................................................42 
3.1. 
Assessment of Dose-Limiting Toxicity ......................................................................44 
3.2. 
Dose-Limiting Toxicity Definition .............................................................................44 
4. 
STUDY POPULATION .............................................................................................46 
4.1. 
Inclusion Criteria ........................................................................................................46 
4.2. 
Exclusion Criteria .......................................................................................................49 
5. 
STUDY TREATMENT ..............................................................................................53 
5.1. 
Formulation, Packaging, and Handling ......................................................................53 
5.1.1. 
Tislelizumab ...............................................................................................................53 
5.1.2. 
Fruquintinib ................................................................................................................53 
5.2. 
Dosage, Administration, and Compliance ..................................................................53 
5.2.1. 
Tislelizumab ...............................................................................................................54 
5.2.2. 
Fruquintinib ................................................................................................................54 
5.3. 
Overdose .....................................................................................................................55 


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5.4. 
Dose Delay or Modification .......................................................................................55 
5.4.1. 
Dose Delay or Modification for Tislelizumab ............................................................56 
5.4.2. 
Dose Delay or Modification for Fruquintinib .............................................................56 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................58 
6.1. 
Prior Therapy ..............................................................................................................58 
6.2. 
Permitted Concomitant Medications/Procedures .......................................................58 
6.3. 
Prohibited Concomitant Medications/Procedures ......................................................59 
6.4. 
Medications to Be Used With Caution .......................................................................60 
6.5. 
Potential Interactions Between Tislelizumab and Fruquintinib ..................................60 
7. 
STUDY PERIODS, VISITS, OR PROCEDURES ....................................................61 
7.1. 
Screening Period .........................................................................................................61 
7.1.1. 
Informed Consent and Screening Log ........................................................................61 
7.2. 
Enrollment ..................................................................................................................61 
7.3. 
Treatment Period ........................................................................................................61 
7.4. 
End-of-Treatment Visit ...............................................................................................61 
7.5. 
Follow-up Periods .......................................................................................................62 
7.5.1. 
Safety Follow-up Period .............................................................................................62 
7.5.2. 
Efficacy Follow-up Period ..........................................................................................62 
7.5.3. 
Survival Follow-up Period ..........................................................................................62 
7.5.4. 
Lost to Follow-up .......................................................................................................62 
7.6. 
Discontinuation From Study Treatment or From the Study .......................................63 
7.6.1. 
Patient Discontinuation From Study Treatment (End of Treatment for an 
Individual Patient) ......................................................................................................63 
7.6.2. 
Patient Discontinuation From the Study (End of Study for an Individual 
Patient) ........................................................................................................................64 
7.7. 
End of Study ...............................................................................................................64 
8. 
STUDY ASSESSMENTS ..........................................................................................65 
8.1. 
Screening Assessments ...............................................................................................65 
8.1.1. 
Pulmonary Function Tests ..........................................................................................65 
8.2. 
Safety Assessments .....................................................................................................66 
8.2.1. 
Vital Signs ..................................................................................................................66 
8.2.2. 
Physical Examinations ................................................................................................66 
8.2.3. 
Eastern Cooperative Oncology Group Performance Status ........................................66 


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8.2.4. 
Laboratory Safety Tests ..............................................................................................66 
8.2.4.1. 
Cardiac Enzyme Monitoring .......................................................................................67 
8.2.5. 
Electrocardiograms .....................................................................................................67 
8.2.6. 
Adverse Events ...........................................................................................................67 
8.2.7. 
Hepatitis B and C Testing ...........................................................................................67 
8.3. 
Tumor and Response Evaluations ..............................................................................68 
8.4. 
Pharmacokinetic Assessment and Antidrug Antibody Testing ..................................69 
8.5. 
Biomarkers ..................................................................................................................70 
8.6. 
Visit Windows ............................................................................................................71 
8.7. 
Unscheduled Visits .....................................................................................................71 
9. 
SAFETY MONITORING AND REPORTING .........................................................72 
9.1. 
General Plan to Manage Safety Concerns ..................................................................72 
9.1.1. 
Eligibility Criteria .......................................................................................................72 
9.1.2. 
Abnormal Liver Function Tests ..................................................................................72 
9.1.3. 
Safety Monitoring Plan ...............................................................................................72 
9.2. 
Adverse Events ...........................................................................................................73 
9.2.1. 
Definitions and Reporting ...........................................................................................73 
9.2.2. 
Assessment of Severity ...............................................................................................73 
9.2.3. 
Assessment of Causality .............................................................................................74 
9.2.4. 
Follow-up of Adverse Events .....................................................................................75 
9.2.5. 
Laboratory Test Abnormalities ...................................................................................76 
9.3. 
Definition of a Serious Adverse Event .......................................................................76 
9.4. 
Suspected Unexpected Serious Adverse Reaction .....................................................77 
9.5. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................77 
9.5.1. 
Adverse Event Recording Period ................................................................................77 
9.5.2. 
Reporting Serious Adverse Events .............................................................................78 
9.5.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................78 
9.5.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................79 
9.5.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................79 
9.5.3. 
Eliciting Adverse Events ............................................................................................79 
9.5.4. 
Progressive Disease ....................................................................................................80 
9.5.5. 
Deaths .........................................................................................................................80 


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9.5.6. 
Recording Pregnancies ...............................................................................................80 
9.5.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................80 
9.5.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................80 
9.5.9. 
Recording Infusion-Related Reactions .......................................................................81 
9.6. 
Management of Adverse Events of Special Interest for Tislelizumab .......................81 
9.6.1. 
Managing Infusion-Related Reactions .......................................................................81 
9.6.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................82 
9.6.3. 
Immune-Mediated Adverse Events ............................................................................83 
9.7. 
Management of Adverse Events of Special Interest for Fruquintinib ........................84 
10. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................88 
10.1. 
Statistical Analysis ......................................................................................................88 
10.1.1. 
General Consideration ................................................................................................88 
10.1.2. 
Analysis Sets ...............................................................................................................88 
10.1.3. 
Patient Disposition ......................................................................................................89 
10.1.4. 
Demographic and Other Baseline Characteristics ......................................................89 
10.1.5. 
Prior and Concomitant Medications ...........................................................................89 
10.2. 
Efficacy Analyses .......................................................................................................89 
10.2.1. 
Primary Efficacy Analysis ..........................................................................................90 
10.2.1.1. 
Overall Response Rate ................................................................................................90 
10.2.2. 
Secondary Efficacy Analysis ......................................................................................90 
10.2.2.1. 
Progression-free survival ............................................................................................90 
10.2.2.2. 
Disease control rate .....................................................................................................90 
10.2.2.3. 
Clinical benefit rate .....................................................................................................90 
10.2.2.4. 
Duration of response ...................................................................................................90 
10.2.2.5. 
Overall Survival ..........................................................................................................91 
10.3. 
Safety Analyses ..........................................................................................................91 
10.3.1. 
Dose-Limiting Toxicity Analysis ...............................................................................91 
10.3.2. 
Extent of Exposure .....................................................................................................91 
10.3.3. 
Adverse Events ...........................................................................................................91 
10.3.4. 
Laboratory Analyses ...................................................................................................92 
10.3.5. 
Vital Signs ..................................................................................................................92 
10.3.6. 
Pulmonary Function Test ............................................................................................92 


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10.4. 
Pharmacokinetic Analyses ..........................................................................................92 
10.5. 
Immunogenicity Analyses ..........................................................................................93 
10.6. 
Other Exploratory Analyses .......................................................................................93 
10.7. 
Sample Size Consideration .........................................................................................93 
10.8. 
Interim Analyses .........................................................................................................93 
11. 
STUDY COMMITTEES ............................................................................................94 
11.1. 
Safety Monitoring Committee ....................................................................................94 
12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................95 
12.1. 
Access to Information for Monitoring ........................................................................95 
12.2. 
Access to Information for Auditing or Inspections ....................................................95 
13. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................96 
13.1. 
Regulatory Authority Approval ..................................................................................96 
13.2. 
Quality Assurance .......................................................................................................96 
13.3. 
Study Site Inspections.................................................................................................96 
13.4. 
Drug Accountability ...................................................................................................96 
14. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................97 
14.1. 
Ethical Standard ..........................................................................................................97 
14.2. 
Institutional Review Board/Independent Ethics Committee ......................................97 
14.2.1. 
Protocol Amendments ................................................................................................97 
14.3. 
Informed Consent .......................................................................................................98 
14.4. 
Patient and Data Confidentiality .................................................................................98 
14.5. 
Financial Disclosure ...................................................................................................99 
15. 
DATA HANDLING AND RECORD KEEPING ....................................................100 
15.1. 
Data Collection and Management Responsibilities ..................................................100 
15.1.1. 
Data Entry in the Electronic Case Report Form .......................................................100 
15.1.2. 
Data Collection .........................................................................................................100 
15.1.3. 
Data Management/Coding ........................................................................................100 
15.2. 
Study Records Retention ..........................................................................................101 
15.3. 
Protocol Deviations ..................................................................................................102 
15.4. 
Study Report and Publications..................................................................................102 
15.5. 
Study and Study Center Closure ...............................................................................103 
15.6. 
Information Disclosure and Inventions ....................................................................103 


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16. 
REFERENCES .........................................................................................................105 
17. 
APPENDICES ..........................................................................................................111 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................112 
APPENDIX 2. SCHEDULE OF PK AND ADA ASSESSMENTS .........................................117 
APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS ..............................................119 
APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .....................................................................................120 
APPENDIX 5. CHRONIC KIDNEY DISEASE-EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................121 
APPENDIX 6. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................122 
APPENDIX 7. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................124 
APPENDIX 8. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................125 
APPENDIX 9. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................126 
APPENDIX 10. MEDICATIONS TO BE USED WITH CAUTION DURING 
TREATMENT WITH FRUQUINTINIB .................................................................141 
APPENDIX 11. MEDICATIONS THAT HAVE A KNOWN RISK OF CAUSING QT 
PROLONGATION AND/OR TORSADES DE POINTES .....................................142 
APPENDIX 12. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................143 
APPENDIX 13. CLINICAL EVALUATION OF POSSIBLE DRUG-INDUCED 
LIVER INJURY (DILI) ............................................................................................153 
APPENDIX 14. CLINICAL MANAGEMENT OF SEVERE OR SERIOUS 
HEMORRHAGIC EVENTS ....................................................................................155 
APPENDIX 15. MANAGEMENT OF HYPERTENSION IN PATIENTS 
RECEIVING FRUQUINTINIB ...............................................................................158 
 


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LIST OF TABLES 
Table 1: 
Selection and Timing of Dose for Each Patient ..........................................................54 
Table 2: 
Fruquintinib Dose Reductions ....................................................................................57 
Table 3: 
Dose Modification Recommendations for Hematologic and Non-
Hematologic Toxicity .................................................................................................57 
Table 4: 
Guidance for Duration of Recording New or Worsening Adverse Events ................78 
Table 5: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................78 
Table 6: 
Treatment Modifications for Symptoms of Infusion-Related Reactions Due 
to Tislelizumab ...........................................................................................................81 
Table 7: 
Examples of Immune-Mediated Adverse Events .......................................................83 
Table 8: 
Management of Adverse Events Related to Fruquintinib ...........................................84 
Table 9: 
95% CI (%) When Observing Different Number of Responders in 30 
Patients ........................................................................................................................93 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................44 
Figure 2: 
Severe or Serious Hemorrhagic Events Management Flow Chart ...........................157 
Figure 3: 
Schema from American Heart Association/ American College of Cardiology 
for Controlling Hypertension in Adults ....................................................................159 
 


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SYNOPSIS 
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Products: tislelizumab (BGB-A317); fruquintinib 
Title of Study: A multicenter, open-label Phase 2 study to evaluate the efficacy and safety of 
tislelizumab in combination with fruquintinib in patients with selected solid tumors 
Protocol Identifier: BGB-A317-fruquintinib-201 
Phase of Development: 2 
Number of Patients: Approximately 90 patients 
Study Centers: Approximately 8 centers  
Study Objectives: 
Part 1  
Primary: 
• 
To assess the safety and tolerability of tislelizumab in combination with fruquintinib 
• 
To confirm the recommended Phase 2 dose (RP2D) of fruquintinib in combination with 
tislelizumab   
Part 2 
Primary: 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by the 
investigator in patients with selected solid tumors as measured by the overall response rate 
(ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 
Secondary: 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by the 
investigator in patients with selected solid tumors as measured by the progression-free 
survival (PFS) per RECIST v1.1 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by the 
investigator in patients with selected solid tumors as measured by the disease control rate 
(DCR) per RECIST v1.1 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by the 
investigator in patients with selected solid tumors as measured by the clinical benefit rate 
(CBR) per RECIST v1.1 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by the 
investigator in patients with selected solid tumors as measured by the duration of response 
(DOR) per RECIST v1.1 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib in patients with 
selected solid tumors as measured by overall survival (OS) 
• 
To assess the safety of tislelizumab in combination with fruquintinib 


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Exploratory: 
• 
To characterize the immunogenicity of tislelizumab and its time-pairing pharmacokinetic 
(PK) when given in combination with fruquintinib  
• 
To assess the PK of fruquintinib when given in combination with tislelizumab 
• 
To explore potential biomarkers that may correlate with clinical responses/resistance to 
tislelizumab in combination with fruquintinib  
Study Endpoints: 
Part 1  
Primary: 
• 
Safety and tolerability will be assessed throughout the study by monitoring adverse events 
(AEs) characterized by type, frequency, severity per National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, timing, seriousness, and 
relationship to study drug(s); and other safety assessments 
• 
The RP2D of fruquintinib in combination with tislelizumab     
Part 2 
Primary: 
• 
ORR – defined as the proportion of patients whose best overall response is complete 
response (CR) or partial response (PR) as assessed by investigator per RECIST v1.1  
Secondary: 
• 
PFS – defined as the time from the date of first dose to the date of the first determination of 
an objectively documented tumor progression as assessed by investigator per RECIST 
v1.1, or death, whichever occurs first 
• 
DCR – defined as the proportion of patients whose best overall response is CR, PR, or 
stable disease (SD) as assessed by investigator per RECIST v1.1 
• 
CBR – defined as the proportion of patients whose best overall response is CR, PR, or 
durable SD as assessed by investigator per RECIST v1.1 
• 
DOR – defined as the time from the first occurrence of documented objective response to 
the time of progression as assessed by investigator per RECIST v1.1 or death from any 
cause, whichever occurs first 
• 
OS – defined as the time from the date of first dose to the date of death due to any cause 
• 
AEs characterized by type, frequency, severity per NCI‑CTCAE v5.0, timing, seriousness, 
and relationship to study drug(s); and other safety assessments 
Exploratory: 
• 
Incidence of anti-tislelizumab antibodies (ADA) and its time-paring serum concentrations 
of tislelizumab  
• 
Plasma concentrations and derived PK parameters of fruquintinib as data permit 


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• 
Potential biomarkers including but not limited to programmed cell death protein ligand-1 
(PD‑L1) expression, tumor mutational burden (TMB) and DNA mutation/blood tumor 
mutational burden (bTMB) and DNA mutation, gene expression profile (GEP) in the 
gastric cancer (GC), microsatellite stable (MSS) colorectal cancer (CRC) and non-small 
cell lung cancer (NSCLC) cohorts, Epstein-Barr virus (EBV) in the GC cohort, 
MSS/microsatellite instable (MSI) status in the GC cohort, and the association of 
biomarkers with disease status, response/resistance to tislelizumab in combination with 
fruquintinib 
Study Design: 
This is an open label, multicenter, Phase 2 study designed to assess the efficacy and safety of 
tislelizumab in combination with fruquintinib in patients with advanced or metastatic, unresectable GC, 
MSS CRC and PD-L1 positive (defined as TC≥1% by SP263 IHC) NSCLC. The study will be 
conducted in 2 parts. 
Part 1 of the study will be the safety run-in stage during which the first 6 patients will be enrolled and 
assessed for dose-limiting toxicities (DLTs) during the 28-day DLT observation period. Study drug 
administration will begin at the full dose of fruquintinib (5 mg daily, 3 weeks on followed by 1 week 
off every 4-week cycle) in combination with tislelizumab (300 mg once every 4 weeks). A lower dose 
level of fruquintinib (4 mg daily, 3 weeks on followed by 1 week off every 4-week cycle) will be 
explored as necessary depending on observed toxicity. The determination of DLTs will be made by the 
investigator and sponsor after safety data has been reviewed. Only DLTs during the first 28 days of 
treatment will be assessed. The Safety Monitoring Committee (SMC) will evaluate the safety and 
tolerability of the combination therapy and will review the safety information including, but not limited 
to DLTs, all treatment-emergent adverse events (TEAEs), and laboratory abnormalities when the first 6 
DLT-evaluable patients have completed their first 28 days of treatment or when ≥ 2 DLTs at the tested 
dose level occur. The SMC will make recommendations on safety management, including resumption 
of enrollment, de-escalation of fruquintinib to one lower dose level, or termination of enrollment. The 
final decision will be made by sponsor. Once sponsor has determined that the combination therapy 
could proceed, the current dose will be confirmed as the RP2D and enrollment for Part 2 will begin at 
RP2D. Patients enrolled in Part 1 at RP2D will be counted towards Part 2 by the diagnosis of the tumor 
types; up to approximately 30 patients per cohort will be enrolled at RP2D.   
Tislelizumab and fruquintinib will be administered until disease progression, intolerable toxicity, death, 
withdrawal of consent or until the study terminates. 
The study design schema is as follows: 
 
 
Study Assessments: 


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In Part 1, DLT will be assessed per the DLT criteria below during the 28-day DLT assessment window, 
which begins on the first day of the administration of study drugs. 
A DLT is defined as 1 of the following toxicities occurring during the DLT assessment window (first 
28 study days of treatment) and considered by the investigator to be related to 1 or more study drugs.  
Hematologic: 
• 
Grade 4 neutropenia lasting > 7 days 
• 
≥ Grade 3 febrile neutropenia 
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Grade 4 thrombocytopenia lasting > 7 days 
• 
≥ Grade 4 anemia 
Nonhematologic: 
• 
Any ≥ Grade 4 toxicity 
• 
Any Grade 3 toxicity that does not resolve to baseline or ≤ Grade 1 within 7 days after 
optimal supportive care is initiated 
Note: The following nonhematologic AEs will not be considered DLTs: 
• 
Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
• 
Grade 3 rash 
• 
Grade 3 infusion-related AE that is transient (resolving within 6 hours of onset) 
• 
Grade 3 amylase or lipase elevation without clinical symptoms indicative of acute 
pancreatitis 
• 
Grade 3 hypertension that returns to baseline or ≤ Grade 1 with appropriate supportive 
treatment 
Tumor assessments will be performed by the investigator using RECIST v1.1 criteria (Eisenhauer et al 
2009). Tumor imaging (computed tomography [CT] with oral/intravenous [IV] contrast, unless 
contraindicated, or magnetic resonance imaging [MRI]) must be performed within 28 days prior to 
enrollment. On-study tumor assessments will occur every 8 weeks (±7 days) during the first 56 weeks 
and every 12 weeks (±7 days) thereafter until disease progression. If a patient discontinues study 
treatment due to any reasons other than disease progression, tumor assessments will continue to be 
performed as scheduled until disease progression, loss to follow up, initiation of subsequent therapy, 
withdrawal of consent, death, or until the study terminates, whichever occurs first. 
Patients will be evaluated for any AEs and serious adverse events (SAEs) during the study (AEs will be 
collected from the time of the first dose and SAEs from the time of signing the informed consent) and 
occurring up to 30 days after the last dose of study drugs (all severity grades, per NCI-CTCAE v5.0) or 
until initiation of new anticancer therapy, whichever occurs first, and for immune-mediated adverse 
events (imAEs) occurring from the time of the first dose of tislelizumab and up to 90 days after the last 
dose of tislelizumab regardless of whether or not the patient starts a new anticancer therapy. All drug-
related SAEs will be recorded by the investigator after treatment discontinuation until patient death or 
loss to follow-up, whichever occurs first. All study drug-related SAEs will be followed until they 
resolve , 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, whichever occurs first. 


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Duration of Patient Participation:  
Duration of study participation will vary by patient, depending on the duration of treatment and 
treatment outcomes. Each patient treatment course will include: 
• 
Screening up to 28 days 
• 
Treatment until disease progression (or other reason for discontinuation before 
progression) 
− 
In select cases, patients may continue treatment beyond disease progression.  
• 
End of Treatment (EOT) Visit: ≤ 7 days after the investigator determines that the patient 
must permanently discontinue all study drugs. 
• 
Safety Follow-up Visit: up to 30 days after the last dose of study drug 
• 
Survival Follow-up Visits: every 3 months until death (or other reason before death) 
Study Population: Patients with histologically or cytologically confirmed advanced or metastatic, 
unresectable GC, MSS CRC and PD-L1 positive (defined as TC≥1% by SP263 IHC) NSCLC. 
Key Eligibility Criteria: 
Eligible patients in both part 1 and part 2 must have at least 1 measurable lesion as defined per 
RECIST v1.1; have an Eastern Cooperative Oncology Group performance status of 0 or 1; adequate 
organ function; and available archival tissue (or baseline tumor biopsy is required). Patients should 
have no prior therapies targeting CTLA-4, PD-1, PD-L1 or PD-L2, or any antibody or drug targeting 
T-cell costimulation or checkpoint pathway, and no prior treatment with a vascular endothelial growth 
factor receptor (VEGFR) tyrosine kinase inhibitor or anti-VEGFR antibody (eg, ramucirumab). The 
indication-specific inclusion criteria are as follows: 
GC 
• 
Histological or cytological documentation of adenocarcinoma of gastric or esophagogastric 
junction. All other histological types are excluded. 
• 
Progression during or after prior first-line therapy containing any platinum/ 
fluoropyrimidine doublet (combination with anti-HER2 antibody is mandatory if tumor 
HER2 is documented positive). If relapse or metastasis occur during the 
adjuvant/neoadjuvant treatment containing platinum/fluoropyrimidine or within 6 months 
after the completion of the above treatment, that adjuvant/neoadjuvant therapy is 
considered as the failure of first line systemic chemotherapy for progressive disease (PD). 
MSS CRC  
• 
Histological or cytological documentation of adenocarcinoma of the colon or rectum. All 
other histological types are excluded.  
• 
Patients must have failed 2 lines of standard chemotherapies, including fluoropyrimidine, 
oxaliplatin, or irinotecan. Failed chemotherapies are defined as the occurrence of PD or 
intolerable toxicities during the treatment or after the last dose. 
• 
Notes: a) Each line of treatment for advanced disease until PD includes one or more 
chemotherapy drugs used for ≥ 1 cycles; b) Previous adjuvant/neoadjuvant therapy is 
allowed. If relapse or metastasis occur during the adjuvant/neoadjuvant treatment period 
for patients with nonmetastatic or metastatic disease who have received curative surgery or 


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within 6 months after the completion of the above treatment, that adjuvant/neoadjuvant 
therapy is considered as the failure of first line systemic chemotherapy for PD; c) Patients 
could be enrolled once they have failed fluoropyrimidine, oxaliplatin and irinotecan based 
regimen as first line treatment. 
• 
For RAS wild type tumor, must have received anti-VEGF and/or EGFR antibody 
treatment. For RAS mutation or RAS status unknown, must have received anti-VEGF 
antibody treatment. 
• 
Tumor tissues were identified as MSS by polymerase chain reaction (PCR) by a central 
laboratory. 
NSCLC 
• 
Histologically or cytologically confirmed, locally advanced (Stage IIIB) not amenable to 
curative surgery or radiotherapy, or metastatic (Stage IV) NSCLC.  
• 
Have had no prior systemic therapy for advanced or metastatic NSCLC. Patients who have 
received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or chemoradiotherapy 
with curative intent for non-metastatic disease must have experienced a disease-free 
interval of at least 6 months from the last dose of chemotherapy and/or radiotherapy prior 
to first dose. 
• 
Patients with documented EGFR mutation or known ALK gene translocation (both must 
be tissue-based test) will be excluded. For non-squamous patients with unknown EGFR 
status, archival or fresh tumor tissues are required for EGFR mutation assessment in 
central/local laboratory prior to enrollment and only those with wild type EGFR will be 
enrolled. 
• 
Tumor tissues were identified as PD-L1 positive defined as TC≥1% by SP263 IHC by a 
central laboratory. 
Investigational Product, Dose, and Mode of Administration: 
Tislelizumab will be administered at a dose of 300 mg intravenously on Day 1 of every 4-week cycle.  
In part 1, fruquintinib administration will begin at a dose of 5 mg once daily orally for 3 weeks on 
followed by 1 week off for every 4-week cycle in safety run-in stage.  A lower dose level of 
fruquintinib (4 mg daily, 3 weeks on followed by 1 week off every 4-week cycle) will be explored as 
necessary depending on observed toxicity. In part 2, fruquinitinib will be administrated at RP2D. 
Reference Therapy, Dose, and Mode of Administration: 
Not applicable 
Statistical Methods: 
Analysis Set 
• 
The Safety Analysis Set (SAS) includes all patients who received ≥ 1 dose of study 
drug(s). This will be the analysis set for the safety and efficacy analyses. 
• 
The Evaluable Analysis Set (EAS) includes all patients who received ≥ 1 dose of study 
drug(s), have evaluable disease at baseline, and have ≥ 1 evaluable postbaseline tumor 
response assessment unless any clinical PD or death occurred before the first postbaseline 
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• 
The DLT Evaluable Analysis Set includes all patients who received at least 85% of the 
assigned total dose of fruquintinib and at least 67% (approximately two-thirds) of the 
assigned total dose of tislelizumab for the DLT assessment period. Additionally, patients 
who had a DLT event will also be considered evaluable. Only patients from Part 1 are 
eligible for inclusion in the DLT Evaluable Analysis Set. This will be the analysis set for 
the DLT analyses. 
• 
The PK Analysis Set includes all patients who received ≥ 1 dose of study drug(s) and have 
≥ 1 quantifiable postbaseline PK data. 
• 
The Antidrug Antibody (ADA) Analysis Set includes all patients who received ≥ 1 dose of 
study drug(s) and have a baseline and at least 1 postbaseline ADA result. 
Primary Efficacy Analysis 
The ORR is defined as the proportion of patients who had confirmed CR or PR as determined by the 
investigator using RECIST v1.1 in the Safety Analysis Set. ORR will be summarized for descriptive 
purposes in SAS. A two-sided Clopper-Pearson 95% CI of ORR will be constructed. ORR will be 
summarized based on patients from the RP2D dose level in overall and by tumor types. Additional 
summaries will be based on all dose levels in overall and by tumor types if necessary.  
Best overall response (BOR) is defined as the best response recorded from the start of study drug(s) 
until data cut or start of new anticancer therapy. Patients with no postbaseline response assessment (due 
to any reason) will be considered non-responders for BOR. The proportion and its corresponding 
Clopper-Pearson 95% CI for each of the response categories (CR, PR, SD, and PD) will be presented. 
BOR will be summarized based on patients from the RP2D dose level in overall and by tumor types. 
Additional summaries will be based on all dose levels in overall and by tumor types if necessary. 
Outcomes in the Evaluable Analysis Set will be evaluated as a sensitivity analysis. 
Secondary Efficacy Analysis 
PFS assessed by the investigators per RECIST v1.1 will be estimated using the Kaplan-Meier method 
in the Safety Analysis Set. The Kaplan-Meier estimates of PFS will be plotted over time. PFS at 
selected time points will be estimated with its 95% CI using Greenwood’s formula. The corresponding 
quantiles (including the median), if estimable, will also be estimated using Kaplan-Meier method. A 
two-sided 95% CIs of median, if estimable, will be constructed using the generalized Brookmeyer and 
Crowley method (Brookmeyer and Crowley 1982). PFS censoring rule will follow the United States 
Food and Drug Administration Guidance for Industry Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics (FDA 2018). PFS will be summarized based on patients from RP2D dose 
level in overall and by tumor types. Additional summaries will be based on dose levels in overall and 
by tumor types if necessary. 
DCR and CBR, assessed by the investigator per RECIST v1.1, will be summarized in a similar way as 
ORR. 
DOR and OS will be analyzed similarly as PFS. Only patients who have achieved an objective 
response will be included in the analysis of DOR. 
DLT analysis 
DLTs during the DLT assessment period will be used to determine safety and tolerability of 
tislelizumab in combination of fruquintinib. The DLT events will be summarized descriptively in the 
DLT Evaluable Analysis Set. 
Safety Analysis 
Safety will be determined by the reporting of AEs and by laboratory values (hematology, clinical 
chemistry, coagulation, and urinalysis). Vital signs, physical examinations, and electrocardiogram 
findings will also be used in determining the safety profile. The severity of AEs will be graded 


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according to NCI-CTCAE v5.0. Descriptive summary statistics will be used to analyze all safety data 
in the Safety Analysis Set. Safety analysis will be based on the summary of overall and by dose level. 
Additional safety analyses will also be summarized based on tumor types if necessary. 
Pharmacokinetics Analysis 
Blood samples will be collected for tislelizumab PK evaluation at postdose and trough (Ctrough). The 
serum concentration data of tislelizumab will be tabulated and summarized by visit/cycle at which 
these samples are collected. For fruquintinib, serial PK blood samples will be collected for part 1 and 
sparse samples will be collected for part 2. Plasma fruquintinib concentration data will be summarized 
using descriptive statistics, C-T profiles, and other plots as appropriate. The corresponding PK 
parameters of fruquintinib will be calculated as data permit.  
Immunogenicity Analysis 
The immunogenicity results for tislelizumab 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.  
Sample Size 
Approximately 30 patients are expected to be enrolled in each tumor type cohort at RP2D. There will 
be 3 cohorts based on selected solid tumors. Approximately 6 to 12 DLT evaluable patients will be 
enrolled in Part 1. Patients enrolled in Part 1 at RP2D will be counted towards Part 2 by the diagnosis 
of tumor types. Approximately 96 patients will be enrolled at maximum.  


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BGB-A317 
tislelizumab 
bTMB 
blood tumor mutational burden 
CRC 
colorectal cancer 
CR 
complete response 
CT 
computed tomography 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
End-of-Treatment (Visit) 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEP 
gene expression profile 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MSS 
microsatellite stable 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NSCLC 
non-small cell lung cancer 


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Abbreviation 
Definition 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death ligand-1 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
RP2D 
recommended Phase 2 dose 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
SMC 
Safety Monitoring Committee 
TKI 
tyrosine kinase inhibitor 
TMB 
tumor mutational burden 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VEGFR 
vascular endothelial growth factor receptor 


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1. 
INTRODUCTION AND RATIONALES 
1.1. 
Introduction 
Combination therapy with a small molecule inhibitor of the vascular endothelial cell growth 
factor receptor (VEGFR) pathway may improve the clinical efficacy of immunotherapies and 
promote effective inhibition of angiogenesis in the tumor region which can suppress the growth 
of tumor cells and reduce the incidence of metastasis. The combination of immunotherapies and 
anti-angiogenic agents has been shown nonclinically to generate more potent antitumor effects 
(Khan and Kerbel 2018) and has shown benefit in various therapeutic settings (Georganaki et al 
2018). For patients with advanced or metastatic, unresectable gastric cancer (GC), microsatellite 
stable (MSS) colorectal cancer (CRC) or non-small cell lung cancer (NSCLC), combination 
therapy may improve the clinical efficacy of single-agent immunotherapies. Based on this, 
tislelizumab in combination with fruquintinib will be evaluated in patients with advanced or 
metastatic GC, MSS CRC or NSCLC. 
Fruquintinib is a potent, oral VEGFR tyrosine kinase inhibitor (TKI) with good kinase selectivity 
approved for the treatment of metastatic colorectal cancer in patients who have failed at least 
2 prior systemic antineoplastic therapies in China. Tislelizumab (also known as BGB-A317) is a 
humanized, immunoglobulin G4-variant monoclonal antibody against programmed cell death 
protein-1 (PD-1). Tislelizumab is approved for the treatment of patients for the following 
indications in China: 
• with relapsed or refractory classical Hodgkin lymphoma who have received at least 
2 lines of systemic chemotherapy regimens  
• with locally advanced or metastatic urothelial carcinoma with programmed cell death 
ligand-1 (PD-L1) high expression whose disease has progressed during, following, or 
within 12 months of platinum-containing chemotherapy  
1.2. 
Fruquintinib 
1.2.1. 
Pharmacology 
Fruquintinib primarily targets the VEGFR family, VEGFR 1, 2 and 3 with 50% inhibitory 
concentration (IC50) of 33 nM, 35 nM, and 0.5 nM, respectively. In multiple human tumor 
xenograft models in Nu/Nu mice, fruquintinib demonstrated a dose dependent anti-tumor activity 
accompanied by strong anti-angiogenesis effect in tumor tissues. In all tested tumor models 
fruquintinib showed statistically significant tumor growth inhibition at doses as low as 
2 mg/kg/day.  
Refer to the fruquintinib Investigator’s Brochure for detailed information regarding 
pharmacology studies 


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1.2.2. 
Toxicology 
No deaths occurred at single doses of 2000 mg/kg and 1000 mg/kg for rats and dogs, 
respectively. In repeated dose toxicity studies up to 9 months, there was a general trend for 
increased toxicity associated with increased duration of treatment. The main target organs were 
liver, kidney, adrenal gland, immune system (thymus, spleen, and lymph nodes), gastrointestinal 
system, bone marrow (sternum) and femur. The toxic responses were reversible after 
discontinuation of drug treatment.  
• Safety Pharmacology: No adverse effects were observed in dog cardiovascular and 
respiratory systems at 0.34 mg/kg and in central nervous system at10 mg/kg.  
• Reproductive and development toxicology: In the fertility and early embryonic 
development/implantation study, the no observed adverse effect level (NOAEL) for 
fertility in both male and female rats was 3 mg/kg and 0.5 mg/kg, respectively. The 
NOAEL for early embryonic development was 0.15 mg/kg. In the embryo-fetal 
development study, the NOAEL for both maternal effects and embryo-fetal 
development was 0.1 and 0.025 mg/kg in rats. 
• Genetic toxicology: No genetic toxicity was found in either the bacterial reverse 
mutation test or the micronucleus test in mice. In the chromosome aberration test, 
fruquintinib, at 36.0 µg/mL, induced a significant increase in aberrant cells with 
structural chromosome aberrations in Chinese Hamster Lung cells, but this is not 
observed in other treated groups.  
Refer to the fruquintinib Investigator’s Brochure for detailed information regarding toxicology 
studies. 
1.2.3. 
Clinical Pharmacology 
The pharmacokinetics of fruquintinib were evaluated in patients with advanced malignant solid 
tumors (2009-013-00CH1). Following a single oral dose of 1, 2, 4, 5 or 6 mg of fruquintinib, 
clearance was found to be low. The half-life (t1/2) was > 35 hours, therefore, a once daily dose 
regimen is suitable. Both the area under the plasma concentration-time curve (AUC) and the 
maximum plasma concentration (Cmax) increased proportionally within dose levels of 1 to 6 mg. 
The steady state was reached following 14 days of consecutive once daily dosing and the AUC 
on Day 14 was 3-fold higher than on Day 1. The 4-week continuous dosing regimen was 
compared with 3 weeks of continuous dosing (once daily) with either 5 mg or 6 mg of 
fruquintinib, followed by a 1-week break (3 weeks on/1 week off). The pharmacokinetic (PK) 
results showed that fruquintinib profiles were similar between the two dosing regimens on the 
same dosing days (Days 1 and 14). Tumor types had little effect on the pharmacokinetic 
characteristics of fruquintinib. 
In the food effect study conducted in healthy male volunteers, Cmax from the fed condition group 
reduced 17% (geometric mean ratio 82.9%, 90% CI: 76.7% to 89.5%) compared to fasted 
condition group, and the AUC is comparable (geometric mean ratio 97.2%, 90% CI: 94.0% to 
100.4%).  


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1.2.4. 
Prior Clinical Experience of Fruquintinib 
As of 03 September 2019, there were 5 ongoing studies with fruquintinib. An additional 
11 clinical studies have been completed, 7 in patients with cancer and 4 in healthy volunteers.  
Refer to the fruquintinib Investigator’s Brochure for more detailed information on fruquintinib 
safety and efficacy data when given as monotherapy or in combination with chemotherapy or 
other agents.  
1.2.4.1. 
Pooled Safety Assessment of Monotherapy Studies 
A pooled analysis of 4 completed, double-blind, placebo-controlled monotherapy studies was 
conducted to provide a comprehensive safety assessment separately from combination therapy. 
In each study, patients randomized to fruquintinib treatment received 5 mg once daily, 3 weeks 
on/1 week off in a 4-week cycle. A total of 739 patients received at least 1 dose of fruquintinib in 
the pooled analysis of monotherapy studies.  
1.2.4.1.1. Treatment-Emergent Adverse Events 
Of the 739 patients in the pooled analysis of monotherapy studies, 729 (98.6%) patients reported 
treatment-emergent adverse events (TEAEs) and 711 (96.2%) patients reported treatment-related 
TEAEs. TEAEs ≥ Grade 3 were reported by 443 (59.9%) patients. The most commonly reported 
TEAEs ≥ Grade 3 (≥ 5.0% patients) were hypertension (19.9%) and palmar-plantar 
erythrodysesthesia (PPE) syndrome (10.7%). TEAEs ≥ Grade 3 reported by 363 (49.1%) patients 
were considered to be treatment-related by the investigator.  
1.2.4.1.2. Treatment-Emergent Serious Adverse Events 
Of the 739 patients in the pooled analysis of monotherapy studies, 169 (22.9%) patients reported 
serious adverse events (SAEs). The most common SAEs (≥ 1.0% patients) by Preferred Term 
included infectious pneumonia (24 [3.2 %] patients), intestinal obstruction (17 [2.3%] patients), 
pleural effusion (9 [1.2%] patients), death (10 [1.4%] patients), hepatic function abnormal 
(8 [1.1%] patients), and gastrointestinal haemorrhage (8 [1.1%] patients). One hundred twelve 
(15.2%) patients reported treatment-related SAEs; 41 (5.5%) patients had a fatal SAE.  
1.2.4.1.3. Adverse Events of Special Interest 
In the pooled analysis of monotherapy studies, the most frequently reported adverse events of 
special interest (AESIs) (> 10% of patients) were dermatological toxicity (59.7%), hypertension 
(49.7%), thyroid dysfunction (46.3%), proteinuria (40.6%), hepatic function abnormal (38.4%), 
hemorrhages (36.1%), and infections (31.9%). AESIs ≥ Grade 3 (> 5% of patients) included 
hypertension (22.1%), dermatological toxicity (11.1%), infections (7.3%), and hepatic function 
abnormal (6.5%). 
1.2.4.1.4. Fatal Adverse Events  
A total of 44 (6.0%) patients had TEAEs leading to death. Refer to the fruquintinib Investigator’s 
Brochure for more detailed information on fruquintinib safety.  


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1.2.4.2. 
Efficacy Assessment of Fruquintinib 
As of 03 September 2019, the available efficacy data from the Phase 1 study in solid tumors 
(2009-013-00CH1) and Phase 1b study in patients with CRC (2012-013-00CH3) showed 
promising clinical activity of fruquintinib including durable partial response (PR) and stable 
disease (SD) observed in the majority of the heavily pretreated patients with advanced cancer, 
particularly in patients with CRC, GC, and NSCLC. The results from the Phase 3 study in 
patients with CRC (FRESCO, 2013-013-00CH1) met its primary efficacy endpoint of OS and 
showed fruquintinib significantly improved the overall survival (OS), progression-free 
survival (PFS), overall response rate (ORR), and disease control rate (DCR) as compared to 
placebo. A total of 416 patients were randomized to receive fruquintinib (5 mg once daily) or 
placebo in a 2:1 ratio, 3 weeks on/1 week off in a 4-week cycle. As the primary endpoint, the 
OS was significantly improved in the fruquintinib group compared with the placebo group (9.3 
months versus 6.6 months; HR = 0.65; p < 0.001). The secondary endpoints of PFS (3.7 
months versus 1.8 months; HR = 0.26; p < 0.001), ORR (4.7% versus 0.0%; p = 0.01) and 
DCR (62.2% versus 12.3%; p < 0.001), were also significantly increased in the fruquintinib 
group compared with placebo. Fruquintinib was granted approval by the China National 
Medical Product Administration (NMPA) based on results of the FRESCO study. 
Promising efficacy results were also observed in the Phase 1b/2 study of fruquintinib in 
combination with paclitaxel as second-line therapy in patients with GC (2014-013-00CH3), 34 
patients were enrolled and treated: 3, 3 and 28 patients in the fruquintinib 2 mg, 3 mg and 
4 mg plus paclitaxel groups, respectively. The overall ORR and DCR were 27.3% 
(9/33 patients) and 63.6% (21/33 patients), respectively. The median PFS and median OS at 
the recommended Phase 2 dose (RP2D) (fruquintinib 4 mg + paclitaxel) were 4.0 and 
7.8 months, respectively.  
Another Phase 3 study of fruquintinib was completed in patients with non-squamous NSCLC 
who had failed second-line standard chemotherapy (2015-013-00CH1): there was no 
significant difference between the fruquintinib group and the placebo group in the primary 
efficacy endpoint (OS). However, fruquintinib significantly prolonged the PFS compared to 
placebo with a HR of 0.34 (95% CI: 0.279, 0.425) with p < 0.001 (stratified log-rank test). 
Statistically significant benefits were also obtained with fruquintinib in ORR and DCR. 
1.3. 
Tislelizumab 
1.3.1. 
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 (BGB-A317) Investigator’s Brochure for additional details 
regarding nonclinical studies of tislelizumab. 


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1.3.2. 
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 and human peripheral blood 
mononuclear cell 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 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-fruquintinib-201. 
Please refer to the tislelizumab (BGB-A317) Investigator’s Brochure for more detailed 
information on the toxicology of tislelizumab. 
1.3.3. 
Clinical Pharmacology 
Population PK analysis was conducted using data from 798 patients with solid tumors or 
classical Hodgkin lymphoma who received doses ranging from 0.5 to 10 mg/kg once every 2 or 
3 weeks. The PK of tislelizumab was best characterized using a 3-compartmental linear 
population PK model with linear clearance mechanisms. No time-varying clearance was 
observed in tislelizumab PK. The typical estimates of clearance (CL), central volume (Vc), and 
peripheral volumes (V2, V3), were 0.164 L/day, 2.92 L, 0.928 L, and 1.39 L, respectively, with 
moderate inter-individual variability in CL (32.2%), Vc (16.7%), V2 (56.6%), and V3 (94.2%). 
Consistent with other therapeutic IgG monoclonal antibodies, the volume of distribution at 
steady state (Vss) was 5.238 L and the terminal half-life is approximately 25.5 days. (Deng et al 
2012; Dirks and Meibohm 2010; Keizer et al 2010; Ryman and Meibohm 2017).  
Population PK analysis demonstrated that baseline age, race, alanine aminotransferase, aspartate 
aminotransferase, bilirubin, lactate dehydrogenase, estimated glomerular filtration rate, Eastern 
Cooperative Oncology Group (ECOG) Performance Status, immunogenicity, and sum of 
products of perpendicular diameters in classical Hodgkin lymphoma patients did not show 
statistically significant impact on the PK of tislelizumab. Although tumor size, albumin, and 
tumor type were significant covariates on CL, while body weight, sex, and tumor type were 
significant covariates on Vc, these covariates are not expected to have a clinically relevant impact 
on tislelizumab exposure. Exposure-response analysis indicated that there was a lack of clinically 
significant exposure-response relationships for ORR and safety endpoints across a variety of 
advanced solid tumors and classical Hodgkin lymphoma for tislelizumab. Population PK analysis 
supports flat-dosing across different ethnic groups. 


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1.3.4. 
Prior Clinical Experience of Tislelizumab 
As of 20 May 2019, there were 22 ongoing studies with tislelizumab with over 1705 patients 
treated. Of these, 13 studies have preliminary data available in the Investigator’s Brochure (IB) 
version 7, 13 September 2019: 7 monotherapy studies, 2 chemotherapy combination therapy 
studies; and 4 investigational agent combination therapy studies. 
Refer to the tislelizumab (BGB-A317) Investigator’s Brochure for more detailed information on 
tislelizumab safety and efficacy data when given as monotherapy or in combination with 
chemotherapy. 
1.3.4.1. 
Pooled Safety Assessment of Monotherapy Studies 
A pooled analysis of 7 monotherapy studies was conducted to provide a comprehensive safety 
assessment separately from combination therapy. There were 1273 patients in the Pooled 
Monotherapy studies: 1137 patients treated in 5 solid tumor studies and 136 patients treated in 
2 hematologic malignancies studies. Of the 1273 enrolled, 544 patients (42.7%) remained on 
study as of 20 May 2019; and 272 patients (21.4%) were still receiving tislelizumab treatment. 
Refer to the tislelizumab (BGB-A317) Investigator’s Brochure for more detailed information on 
tislelizumab safety data when given as monotherapy or in combination with chemotherapy. 
1.3.4.1.1. Treatment-Emergent Adverse Events  
Of the 1273 total patients treated in the Pooled Monotherapy studies, 1210 (95.1%) experienced 
at least 1 TEAE and 846 (66.5%) experienced at least one treatment-related TEAE. TEAEs 
≥ Grade 3 were reported by 548 (43.0%) patients. The most commonly occurring ≥ Grade 3 
TEAEs were anaemia (64 patients, 5.0%), aspartate transaminase (AST) increased, pneumonia 
(35 patients each, 2.7%), and ascites (25 patients, 2.0%). All other events occurred in under 2.0% 
of the total Pooled Monotherapy population. A total of 163 (12.8%) patients experienced at least 
1 ≥ Grade 3 TEAE assessed as related to tislelizumab.  
1.3.4.1.2. Treatment-Emergent Serious Adverse Events 
Of the 1273 total patients treated in the Pooled Monotherapy studies, 424 (33.3%) experienced at 
least 1 treatment-emergent serious adverse event (SAE). The most commonly occurring 
treatment-emergent SAEs were pneumonia (35 patients, 2.7%), pyrexia (22 patients, 1.7%), and 
ascites (17 patients, 1.3%). 
1.3.4.1.3. Immune-Mediated Adverse Events 
Anti-PD1 therapies are known to cause immune-mediated adverse events (imAEs) in some 
patients and therefore have been defined as adverse events of special interest (AESI) 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 etiology which 
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. 


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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. 
Immune-mediated AEs of hepatitis, pneumonitis, colitis, endocrinopathies, myocarditis, and 
serious skin adverse reactions have been identified as risks for tislelizumab. Refer to the 
tislelizumab (BGB-A317) Investigator’s Brochure for more detailed information. 
1.3.4.1.4. Infusion-Related Reactions 
Infusion-related reactions, including high-grade hypersensitivity reactions, following 
administration of tislelizumab are uncommon. Of the 1273 total patients in the Pooled 
Monotherapy studies, 97 (7.6%) experienced at least one infusion-related reaction of any grade. 
The most commonly occurring infusion-related reactions of any grade that occurred in the total 
pooled analysis were pyrexia (50 patients, 3.9%), infusion-related reactions (28 patients, 2.2%), 
and pruritus (11 patients, 0.9%). There were 6 patients who reported a total of 7 ≥ Grade 3 
infusion-related reactions in the Pooled Monotherapy studies (reported events included back 
pain, hypotension, infusion-related reaction, musculoskeletal chest pain, pyrexia, and rash). 
1.3.4.1.5. Fatal Adverse Events 
A total of 68 patients (5.3%) had TEAEs leading to death. Refer to tislelizumab (BGB-A317) 
Investigator’s Brochure Edition 7, Section 5.2.1.9) for a summary of the treatment-emergent fatal 
AEs that occurred in the Pooled Monotherapy studies. 
1.3.4.2. 
Efficacy Assessment of Tislelizumab 
Efficacy data are available from 2 of the ongoing monotherapy studies in solid tumors, 
BGB-A317_Study_001 and BGB-A317-102, which are summarized below (data cut-off 
20 May 2019). 
1.3.4.2.1. Study BGB-A317_Study_001 
Study BGB-A317 Study_001 is a 2-stage study consisting of a Phase 1a dose-escalation (0.5 to 
10 mg/kg) and dose-finding component with 3 parts (2 and 5 mg/kg given either once every 2 or 
3 weeks, and a fixed dose of 200 mg given once every 3 weeks) to establish the maximum 
tolerated dose, if any, a 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, GC, CRC, and NSCLC. 
Responses were assessed by the Investigator per the Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 criteria. 
There were 451 patients treated in the study and 441 patients were included in the Efficacy 
Evaluable Analysis Set. The analysis set included all treated patients who had at least 
1 measurable baseline target lesion and had at least 1 evaluable post-baseline tumor assessment. 
This set included 52 patients in the gastric cancer cohort, 21 patients in the colorectal cohort and 
46 patients in the NSCLC cohort. 


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Across all disease cohorts, there were 5 patients (1.1%) with a complete response (CR). A total 
of 55 patients (12.5%) had a confirmed PR. The resulting overall clinical response rate was 
13.65%. Additionally, there were 142 patients (32.2%) with a best overall response of SD. A 
total of 199 patients (45.1%) had a best response of progressive disease (PD) in this study. 
Of the 52 patients in the GC cohort, 7 patients (13.5%) had a confirmed PR. Additionally, there 
were 9 patients (17.3%) with a best overall response of SD. A total of 31 patients (59.6%) had a 
best response of PD in this cohort, and the assessment for 5 patients (9.6%) was missing. Of the 
21 patients in the CRC cohort, 3 (14.3%) had a confirmed PR and 7 patients (33.3%) had a best 
overall response of PD. Two patients (9.5%) had missing assessments. Of the 46 patients in the 
NSCLC cohort, 6 patients (13%) had a confirmed PR. Additionally, there were 23 patients (50%) 
with a best overall response of SD. A total of 13 patients (28.3%) had a best response of PD in 
this cohort, and the assessment for 4 patients (8.7%) was missing. 
1.3.4.2.2. Study BGB-A317-102 
Study BGB-A317-102 is a non-randomized, Phase 1/2 study of tislelizumab monotherapy in 
Chinese patients with advanced solid tumors. Phase 1 includes a dose verification substudy and a 
substudy of PK evaluation of the products derived from 2 manufacturing processes and scales.  
Phase 2 evaluates the activity and safety of tislelizumab at its recommended Phase 2 dose of 
200 mg given once every 3 weeks in indication specific expansion cohorts. 
Responses were assessed by the Investigator per the RECIST v1.1 criteria. 
Overall, of the 300 patients treated in Study BGB-A317-102, 249 patients were included in the 
Efficacy Evaluable Analysis Set. The Efficacy Evaluable Analysis Set includes all treated 
patients who had at least 1 measurable baseline target lesion and had at least 1 evaluable post-
baseline tumor assessment. In Phase 2, this set included 12 patients in the GC cohort, 16 patients 
in the CRC cohort, 18 patients in the PD-L1 positive NSCLC cohort and 24 patients in the PD-
L1 negative NSCLC cohort. 
The tumor responses in the efficacy evaluable analysis set of Study BGB-A317-102 across all 
disease cohorts and study phases was 1 patient (0.4%) with a CR and 44 patients (17.7%) with 
confirmed PR. The resulting overall clinical response rate was 18.1%. Additionally, there were 
91 patients (36.5%) with a best overall response of SD. A total of 113 patients (45.4%) had a 
best response of PD in this study. 
The tumor responses in the efficacy evaluable analysis set of Study BGB-A317-102 in the GC 
cohort (12 patients) was 3 patients (25.0%) had a confirmed PR. Additionally, there were 
2 patients (16.7%) with a best overall response of SD. A total of 7 patients (58.3%) had a best 
response of PD in this cohort. In the CRC cohort (16 patients), 3 patients (18.8%) had a 
confirmed PR; 5 patients (31.3%) had a best overall response of SD, and 8 patients (50.0%) had 
a best response of PD. In the PD-L1 positive NSCLC cohort (18 patients), 2 patients (11.1%) had 
a confirmed PR; 7 patients (38.9%) had a best overall response of SD, and 9 patients (50.0%) 
had a best response of PD. In the PD-L1 negative NSCLC cohort (24 patients), 5 patients 
(20.8%) had a confirmed PR; 11 patients (45.8%) had a best overall response of SD, and 8 
patients (33.3%) had a best response of PD. 


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1.4. 
Study Rationale 
Numerous clinical studies are underway in a variety of indications (eg, renal cell carcinoma, 
NSCLC, CRC, gastrointestinal malignancies, melanoma, breast cancer, and urothelial 
carcinoma) to evaluate the combination of immunotherapies and anti-angiogenics.  
Promising antitumor results have been reported in GC, MSS CRC and NSCLC (e.g. EPOC1603, 
EPOC1706, E7080-A001-111) with this combination therapies demonstrating a manageable 
safety profile consistent with individual monotherapy profiles (Fukuoka et al 2020). Refer to 
Section 1.4.3 for tumor type rationales. Additionally, since 2019, a number of similar 
combinations have been approved for a variety of indications demonstrating the therapeutic 
potential of immunotherapy and anti-angiogenic combinations. These include pembrolizumab 
plus axitinib for patients with advanced renal cell carcinoma (KEYNOTE‑426, NCT02853331); 
pembrolizumab and lenvatinib for patients with advanced endometrial cancer (KEYNOTE-146, 
NCT02501096); and atezolizumab and bevacizumab for patients with unresectable or metastatic 
hepatocellular carcinoma (IMbrave150, NCT03434379).  
Based on the available clinical data from the combination of immunotherapy and anti-
angiogenics, demonstrating promising antitumor effect compared with the therapeutic effect of a 
single agent alone, the combination of tislelizumab and fruquintinib may provide a tolerable, 
effective treatment option for the patients with GC, MSS CRC or NSCLC.  
1.4.1. 
Rationale for the Starting Dose 
The full dose of fruquintinib (5 mg daily, 3 weeks on followed by 1 week off every 4-week 
cycle) in combination with tislelizumab (300 mg once every 4 weeks) were selected as the 
starting doses for this study due to the well-established safety profiles of fruquintinib and 
tislelizumab, the non-overlapping mechanisms of action, and the desire to treat patients at doses 
shown to be effective in previous studies. Starting treatment with the full dose of each agent in 
an immunotherapy plus a TKI combination therapy is consistent with other trials. Axitinib, like 
fruquintinib, targets VEGFR 1, 2, 3 in addition to other pathways and has been evaluated in 
combination with an immunotherapy (pembrolizumab) for advanced renal cell carcinoma (RCC). 
The Phase 1b enrolled 52 patients (11 in dose-finding phase, 41 in dose-expansion phase) and 
treatment was initiated with the full dose of both agents (Atkins et al 2018). No unexpected 
toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated 
during the dose-finding phase: 1 patient had a transient ischemic attack and 2 patients were only 
able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. 
The maximum tolerated dose of this regimen was estimated to be the full doses of each agent; 
overall, patients received almost the full protocol-planned doses of both drugs. 32 (62%) patients 
had their axitinib dose reduced (ie, to <5 mg twice per day for two consecutive doses) because of 
axitinib-related toxicities. Overall, 25 (48%) patients discontinued axitinib because of adverse 
events (n = 16) and disease progression (n = 9); 24 (46%) patients discontinued pembrolizumab 
early because of adverse events (n = 12) and disease progression (n = 12). Unprecedented 
antitumor activity and tolerability of this combination treatment led to breakthrough status 
designation from the U.S. Food and Drug Administration (FDA); subsequent FDA approval of 
this combination at full dosages for each agent for RCC was based on data from the Phase 3 
KEYNOTE-426 study. 


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1.4.1.1. 
Tislelizumab 
The PK, safety, and efficacy data obtained from the first-in-human study 
BGB-A317_Study_001, as well as other clinical study data, were analyzed in aggregate to 
determine the recommended dose for pivotal studies of tislelizumab. Tislelizumab has a wide 
safety margin (the dose ranged from 0.5 mg/kg to 10 mg/kg every 2 weeks in 
Study BGBA317_Study_001) with no maximum tolerated dose identified in 
Study BGB-A317_Study_001. The flat dose of 200 mg intravenously once every 3 weeks was 
selected for further evaluation. 
Rates of treatment-related AEs and SAEs observed in patients receiving 2 mg/kg and 5 mg/kg 
once every 2 weeks and once every 3 weeks were comparable, suggesting no clear dose-
dependence across these regimens. Additionally, PK data also shows no relationship between 
exposure and treatment-emergent imAEs. Similarly, confirmed ORRs in patients treated with 
tislelizumab 2 mg/kg and 5 mg/kg once every 2 weeks ranged between 10% and 15%, compared 
with a range of 15% to 38% for patients treated at 2 mg/kg and 5 mg/kg once every 3 weeks. 
According to PK data from BGB-A317_Study_001, Phase 1a, the CL of tislelizumab was found 
to be independent of body weight, ethnicity, and gender, and the observed serum exposure of a 
200mg dose fell between serum exposure observed after 2 mg/kg and 5 mg/kg doses (dose range 
with comparable safety and efficacy rates). 
In addition, no unexpected treatment-related AEs occurred in the 200-mg fixed dose cohort 
(BGB-A317_Study_001, Phase 1a, Part 3) when compared to body-weight-based cohorts. Of the 
evaluable patients treated (n = 13), 3 patients (23%) had a BOR of partial response (PR), 
4 patients (31%) had a BOR of stable disease (SD), and 6 patients (46%) had a BOR of 
progressive disease. Therefore, clinical activity with a manageable and tolerable safety profile is 
expected to be maintained in patients receiving tislelizumab 200 mg once every 3 weeks. 
The observed clinical activity in patients with advanced tumors, coupled with a manageable 
safety profile and supportive data, support the proposed tislelizumab dose of 200 mg 
intravenously once every 3 weeks as the recommended dose for pivotal studies. This dose 
regimen has been approved for treating patients with classical Hodgkin lymphoma and urothelial 
bladder cancer. The dosage of 200 mg Q3W was also used in other pivotal studies under the 
development, for more information please refer to the tislelizumab (BGB-A317) Investigator’s 
Brochure. 
The alternate regimen of 300 mg once every 4 weeks is selected by matching dosing and 
exposure (AUC) with the exposure of 200 mg once every 3 weeks regimen. Exposure-response 
(E-R) assessment of available clinical data from studies including BGB-A317_Study_001, BGB-
A317-102, and BGB-A317-203 suggest no clinically significant relationships observed between 
tislelizumab exposure and efficacy (ORR) or safety across tumor types. Thus, 300 mg once every 
4 weeks regimen is not expected to be clinically different from the 200 mg once every 3 weeks in 
terms of safety or efficacy outcomes. The higher maximum concentrations (Cmax) of 300 mg 
once every 4 weeks regimen compared with the 200 mg once every 3 weeks is well covered by 
the available safety data at higher doses (up to 10 mg/kg once every 2 weeks were used in Study 
BGB-A317_Study_001). Moreover, the alternative 4-weekly dose administration is expected to 
increase patient compliance when in combination with fruquintinib and offer additional 
convenience for care providers. 


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1.4.1.2. 
Fruquintinib 
The dose and mode of administration of fruquintinib (5mg, once daily, 3 weeks on /1 week off) 
determined for this study were based on the safety and efficacy results of the Phase 1 study 
(2009-013-00CH1) and Phase 1b study for the treatment of advanced colorectal cancer (2012-
013-00CH3). As described in Section 1.2.3, PK data from Study 2009-013-00CH1 demonstrated 
that fruquintinib profiles were similar for the 2 dosing regimens (4-week continuous dosing and 
3 weeks on/1 week off) on the same dosing days. 
Study 2012-013-00CH3, a Phase 1b, randomized, open-label study, compared 2 different dosing 
regimens of fruquintinib as third-line or above therapy for advanced colorectal cancer. Patients 
were randomized to fruquintinib “4 mg once daily continuous regimen” (Group A) or “5 mg 
once daily 3 weeks on /1 week off regimen” (Group B). The efficacy under Group B was similar 
to the regimen of Group A even though the total amount of drug administration was slightly 
lower in Group B. The analysis of duration of treatment showed the average duration of 
treatment in Group B was longer than that in Group A, indicating better tolerance to the “5 mg 
once daily 3 weeks on/1 week off” regimen and the potential to prolong the treatment and 
impede disease progression. Therefore, “5 mg once daily 3 weeks on/1 week off” was confirmed 
as the recommended dosage for Phase 2/3 studies. The drug-drug interaction potential between 
tislelizumab and fruquintinib is considered to be low (refer to Section 6.5 for details), so no 
starting dose adjustment is needed for either drugs.  
1.4.2. 
Rationale for Combination of Tislelizumab and Fruquintinib in the Treatment 
of Advanced Solid Tumors 
Immunotherapy has recently emerged as a novel strategy for treating different types of solid 
tumors, with promising results. However, a large proportion of patients do not respond to such 
approaches, and initial responders sooner or later develop resistance. One of the possible reasons 
for treatment failure with PD-1 blockade for advanced cancers is immune suppression through 
the immune checkpoints other than the PD-1/PD-L1 axis that regulate lymphocyte activation or 
through the immunosuppressive cells, including forkhead box P3 (Foxp3)+CD25+ regulatory 
T cells (T regs) and tumor-associated macrophages (TAMs) (Fukuoka et al 2020).VEGF-A, 
well-characterized for its major role in tumor vessel growth (neoangiogenesis), was recently 
identified as a key factor in tumor-induced immunosuppression. In particular, VEGF-A fosters 
the proliferation of immunosuppressive cells, limits T-cell recruitment into tumors, and promotes 
T-cell exhaustion (Lapeyre-Prost et al 2017). 
As abnormal and augmented tumor vessels often occur in cancerogenesis, anti-angiogenic drugs 
have already demonstrated their eﬀectiveness both in preclinical and in clinical settings. 
Although these VEGF pathway inhibitors can improve survival in many cancer types, some 
tumors have little or no beneficial effect from such therapies. Mechanisms related to the 
resistance to anti-VEGF/VEGFR therapy are not completely known. However, it is known that 
in anti-angiogenic therapy resistance often involves the activation of signaling pathways other 
than the VEGF pathway. Intra-tumor hypoxia and the related inﬁltration of immunosuppressive 
cells may also play a significant role in angiogenic relapse and drug resistance (Itatani et al 2018; 
Zarrin et al 2017).  


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Combining immunotherapy of anti-PD-L1 with anti-angiogenic therapy had reciprocal beneﬁcial 
eﬀects: anti-angiogenic drugs blocked the negative immune signals by increasing the ratio of 
anti-/pro-tumor immune cells and decreasing immune checkpoints expression, while 
immunotherapy restored immune-supportive microenvironment and promotes vascular 
normalization increasing lymphocyte inﬁltration and activation (Huang et al 2013). 
1.4.3. 
Rationale for Tumor Type(s) 
1.4.3.1. 
Gastric Cancer 
Gastric cancer is the fifth most common malignancy and the third leading cause of cancer 
mortality worldwide (Globocan 2018d). Almost 1 million new cases of stomach cancer were 
estimated to have occurred in 2012 (952,000 cases, 6.8% of the total) according to the World 
Health Organization’s Globocan 2012 database (Ferlay et al 2015). There were 456,124 new 
diagnosed cases of stomach cancer and 390,182 deaths in China in 2018 (Globocan 2018a). 
Stomach cancer is the second highest incidences and mortality in China. In Korea, stomach 
cancer had the 4th highest incidences (5127 new diagnosed cases) and 3rd highest mortality 
(3660 deaths) of cancers in 2018 (Globocan 2018c).   
Patients with newly diagnosed inoperable locally advanced or metastatic disease generally 
receive chemotherapy regimens containing platinum and fluoropyrimidine (Smyth et al 2016; 
NCCN 2017). The duration of first-line chemotherapy typically does not exceed 6 months 
because of PD or due to the toxicities of chemotherapy (Cunningham et al 2008; Van Cutsem et 
al 2006; Hess et al 2016). 
In the second-line setting, the anti-VEGFR-2 antibody, ramucirumab, is an option since it has 
shown a survival benefit when added to chemotherapy compared with chemotherapy alone or as 
monotherapy compared with placebo (Fuchs et al 2014; Wilke et al 2014). In the third-line or 
above setting, apatinib, as monotherapy, is the only approved VEGFR-TKI in China. More 
recently, immunotherapy with anti-PD-1 antibodies pembrolizumab and nivolumab has resulted 
in durable remissions for a subset of patients (Le et al 2016; Muro et al 2016). Pembrolizumab 
has been approved by the FDA for the treatment of patients with PD-L1–positive recurrent or 
advanced gastric or gastroesophageal junction adenocarcinoma who have received 2 or more 
lines of chemotherapy (pembrolizumab label 2014). Nivolumab has been approved by NMPA 
for the treatment of patients with recurrent or advanced gastric or gastroesophageal junction 
adenocarcinoma who have received 2 or more lines of systemic treatment. 
In preclinical models, the simultaneous blockade of PD-1 and VEGFR-2 enhanced T-cell 
recruitment, activated local immune status, and induced synergistic antitumor effects (Yasuda et 
al 2013). Recent preliminary efficacy results in patients with GC treated with lenvatinib plus 
pembrolizumab from a Phase 2 study (NCT03609359) were promising. In 29 patients, enrolled 
in the first-line or second-line setting, the ORR was 69% (1 CR, 19 PR) (Kawazoe et al 2020). 
The DCR was 100%. The median PFS was 7.1 months. The median OS had not been reached 
when the data was reported. In a Phase 1b trial, 25 patients with advanced GC received treatment 
with regorafenib plus nivolumab. Objective tumor response was observed in 11 patients (44%). 
Median progression-free survival was 5.6 months. Median OS was 12.3 months (Fukuoka et al 
2020). 


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Specific application strategies for the combination of anti-PD-1/PD-L1 and VEGFR need further 
exploration.  
1.4.3.2. 
Colorectal Cancer 
Colorectal cancer is the third most diagnosed cancer and the second leading cause of cancer 
death worldwide, in both males and females(Globacan 2018b). It is the sixth most diagnosed 
cancer and the fifth leading cause of cancer death in China and Korea (Globocan 2018a; 
Globocan 2018c). In China, the age-standardized incidence and mortality rate of CRC has 
increased by about 1.9% per year for incidence and about 0.9% per year for mortality rate from 
2000 to 2014 (Zheng et al 2018). In 2017, CRC was responsible for 1.79% of the total deaths in 
China (Yin et al 2019).  
Although surgery is currently the primary course of treatment, it is ineffective in cases where the 
cancer has metastasized. The mainstay of first‐line therapy for advanced CRC is combination 
chemotherapy plus an anti‐vascular endothelial growth factor (VEGF) or anti‐epidermal growth 
factor receptor (EGFR) antibody, depending on the tumor characteristics (NCCN 2020). 
However, most patients progress within 1 year (Chau and Cunningham 2009). Patients with CRC 
who do not benefit from first line therapy are often treated with second line chemotherapy. 
Beyond second line, targeted therapy such as regorafenib or fruquintinib have been shown to 
prolong survival in Chinese patient with mCRC compared with placebo in Phase 3 studies 
(Grothey et al 2013; Li et al 2018). Recently, immune checkpoint inhibitors have demonstrated 
impressive activity in patients with CRC and other solid tumors that are microsatellite instability‐
high (MSI‐H)/mismatch repair deficient (dMMR). Nivolumab and pembrolizumab are currently 
approved by the FDA for patients with MSI‐H/dMMR metastatic CRC (Morse et al 2020). 
However, the PD-1 blockade is particularly ineffective in patients with microsatellite stable 
(MSS) or mismatch repair (MMR)–proficient colorectal cancer which makes up the majority 
(95%) of mCRC patients (Ali et al 2018). This can be explained by the lower antigenicity due to 
the presence of fewer neoantigens, regardless of tumor mutation burden, resulting in fewer 
infiltrating CD8+ T cells in general and fewer strongly positive for PD‐1 (Morse et al 2020). 
Recently, several strategies to turn a “cold” CRC tumor into an immunoreactive “hot” tumor 
were being tested in clinical trials. In a Phase 1b trial, 25 patients with advanced CRC received 
treatment with regorafenib plus nivolumab. Objective tumor response was observed in 9 patients 
(36%). After the exclusion of 1 patient with MSI-high CRC, the ORR was 33.3% in patients with 
MSS CRC. Median progression-free survival was 7.9 months (Fukuoka et al 2020). 
The combination of anti-PD-1/PD-L1 and VEGFR warrants further evaluation as a treatment 
paradigm for patients with MSS colorectal cancer. 
1.4.3.3. 
Non-Small Cell Lung Cancer 
Lung cancer remains the most commonly diagnosed cancer and the leading cause of cancer 
deaths worldwide (Bray et al 2018). NSCLC represents 80-85% of lung primary malignancies 
(PDQ Adult Treatment Editorial Board 2017). NSCLC is most often diagnosed at a metastatic 
stage, where 5-year survival rate ranges between 0 and 5% using traditional chemotherapy-based 
strategies (Goldstraw et al 2016). The success in immune checkpoint therapy in recent years has 
revolutionized traditional cancer treatment in NSCLC. In the first-line setting, KEYNOTE-042 
demonstrated that single-agent pembrolizumab significantly improved overall survival (OS) 


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compared with platinum-based chemotherapy with advanced NSCLC, PD-L1 expression of 1% 
or more, but without EGFR mutation or ALK rearrangement (Mok et al 2019). Based on these 
results, the FDA approved pembrolizumab as a single agent for the first-line treatment of patients 
with advanced NSCLC whose tumors express PD-L1 (tumor proportion score, TPS ≥ 1%) with 
no EGFR or ALK genomic tumor aberrations. However, the use of pembrolizumab monotherapy 
in the less than <50% TPS score subset remains controversial as a specific look at the TPS score 
1–49% versus 50% + subsets suggests that greatest benefit is noted in the group of high PD-L1 
expressors and best might be preserved for patients who are not good candidates for 
chemotherapy (Mok et al 2019). The benefit of pembrolizumab used in the frontline setting in 
combination with chemotherapy versus chemotherapy alone has also been demonstrated in Phase 
3 studies. Based on the positive results of KEYNOTE-189 (Gandhi et al 2018) and KEYNOTE-
407 (Paz-Ares et al 2018), FDA has approved pembrolizumab combined with platinum-doublet 
chemotherapy in first-line NSCLC with squamous and non-squamous histology regardless of 
PD-L1 expression. Recently, two Phase 3 studies of tislelizumab plus platinum-doublet 
chemotherapy as first-line treatment in locally advanced and metastatic non-squamous and 
squamous NSCLC are ongoing (BGB-A317-304 and BGB-A317-307). Both studies have 
already announced positive result of PFS as primary endpoint. In Study BGB-A317-304, the 
addition of tislelizumab resulted in significantly improved PFS (9.7 months vs 7.6 months; 
P=0.0044, HR=0.645 [95% CI: 0.462, 0.902]) as well as higher ORR and longer DoR than 
observed with chemotherapy alone in patients with advanced non-squamous NSCLC. In Study 
BGB-A317-307, median PFS was 7.6 months (95% CI: 6.0, 9.8) and 7.6 months (95% CI: 5.8, 
11.0) with tislelizumab combined with either paclitaxel and carboplatin or nab‑paclitaxel and 
carboplatin, respectively, both of which were significantly longer than the median PFS (5.5 
months [95% CI:4.2, 5.7]) with paclitaxel and carboplatin alone in patients with advanced 
squamous NSCLC. 
PD1 blockade treatment is a new standard of first line treatment for PD-L1 positive NSCLC. 
However, a large proportion of patients do not respond to such treatment with an ORR of about 
27% (Mok et al 2019). For patients with low tumor PD-L1 expression who can tolerate 
chemotherapy, PD-1 blockade plus chemotherapy was considered as the optimal approach, but at 
the cost of chemotherapy related toxicities. Despite the recent advances with anti-PD-1 therapy, 
most patients with advanced NSCLC have incurable diseases; more effective treatment options 
with better tolerability profile are needed, as first-line treatment for PD-L1 positive advanced 
NSCLC. Immunotherapy plus antiangiogenesis agents have been evaluated in some Phase 1and 
2 studies. In a Phase 1b/2 study (E7080-A001-111), Lenvatinib plus pembrolizumab 
demonstrated a manageable safety profile and promising antitumor activity in patients with 
selected solid tumor types, including NSCLC. 21 NSCLC patients were enrolled. Most patients 
(86%) received at least 1 prior systemic therapy, 52% of the patients received prior an-PD(L)1 
treatment before enrollment. ORR for patients with NSCLC were 33% (95% CI, 14.6% to 
57.0%). The median DOR was 10.9 months (95% CI, 2.4 months to NE), and the median PFS 
was 5.9 months (95% CI, 2.3 to 13.8 months) (Taylor et al 2020). 


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1.4.4. 
Rationale for Biomarker Strategy 
A number of biomarkers have been identified that correspond with a response to immunotherapy 
for patients with GC, MSS CRC or NSCLC.  
PD-L1 expression has been demonstrated to be positively correlated with response to anti-PD-1 
therapy across tumor types (Cristescu et al 2018). For GC, the expression of PD-L1 is positively 
correlated with response to anti-PD-1 monotherapy (Keynote-061, Keynote-062). Additionally, 2 
pilot studies have demonstrated the trend of patients who express PD-L1 benefiting from anti-
PD(L)-1 plus VEGFR-TKI, compared to those negative for PD-L1 expression (Jianming et al 
2019; Fukuoka et al 2020). This indicates that PD-L1 may be a potential biomarker predicting 
response to anti-PD(L)-1 in combination with VEGFR-TKI in GC. For MSS CRC, clear 
correlation between PD-L1 expression and response to anti-PD(L)-1 has not been reported. One 
pilot study has demonstrated the negative correlation between PD-L1 expression and response to 
anti-PD(L)-1 in combination with VEGFR-TKI (Fukuoka et al 2020). Due to the limited number 
of patients, the role of PD-L1 expression in predicting response to anti-PD(L)-1 in combination 
with VEGFR-TKI warrants further exploration. For NSCLC, the expression of PD-L1 is 
positively correlated with response to anti-PD(L)-1 monotherapy (KEYNOTE-042, IMpower-
110). The correlation between PD-L1 and response to anti-PD(L)-1 in combination with 
VEGFR-TKI therapies has not been conclusive from limited data reported (MRTX-500, 
Keynote-146, COSMIC021). Thus, the correlation of PD-L1 with response needs further 
exploration. 
Tumor mutational burden (TMB) works as the surrogate marker for neo-antigen prediction and 
has been reported to positively correlate with the response to anti-PD(L)-1, and serves as an 
independent biomarker from PD-L1, indicating that its combination with PD-L1 may lead to 
predictive synergy (Fumet et al 2020; Cristescu et al 2018). For GC, the positive correlation 
between TMB and anti-PD(L)-1 monotherapy has been reported; however, pilot studies 
investigating the role of TMB in predicting response to anti-PD(L)-1 in combination with 
VEGFR-TKI have shown conflicting results in a limited number of patients. Thus, the 
correlation of TMB with response needs to be explored in larger cohorts (Jianming et al 2019; 
Fukuoka et al 2020). For CRC, 1 pilot study has shown the trend of patients with high TMB 
benefiting from anti-PD(L)-1 in combination with VEGFR-TKI, compared to those with low 
TMB. Due to the limited number of patients evaluated, this trend requires further verification 
(Fukuoka et al 2020). For NSCLC, one pilot study demonstrates that there is a trend of patients 
with higher TMB benefiting from anti-PD(L)-1 in combination with VEGFR-TKI, and this also 
requires further exploration in larger cohorts (WCLC 2019, NCT02954991). Blood TMB 
(bTMB), demonstrated good correlation with TMB if assessed with large panels, which has been 
explored due to its non-invasiveness feature, and has been reported to predict clinical benefit 
with anti-PD(L)-1 therapy in several clinical trials (POPLAR, OAK, MYSTIC trials, etc.) 
(Gandara et al 2018). Apart from tumor mutational burden, DNA mutation can also be explored 
from the TMB detection panel, thus its role in predicting response/resistance can also be 
investigated. 
Gene expression profile (GEP) panels have been designed to investigate immune features (tumor 
immunogenicity, interferon gamma signature, immune cell population abundance, etc.), and 
tumor features (epithelial-mesenchymal transition, angiogenesis, hypoxia, cell adhesion, etc.). 
Interferon gamma signature has been shown to be positively correlated with response to anti-


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PD(L)-1 monotherapy across tumor types (Cristescu et al 2018). Results related to GEP have not 
been reported in anti-PD(L)-1 plus VEGFR-TKI studies in patients with GC, MSS CRC or 
NSCLC yet, however, publications or presentations in hepatocellular carcinoma (GO30140 trial, 
ASCO 2020), melanoma (NCT03086174, ASCO 2020), and RCC have reported the association 
of GEP panels (selected genes) with response to anti-PD(L)-1 in combination with anti-
VEGF/VEGFR-TKI (McDermott et al 2018; Wallin et al 2016), implying GEP panels may play 
a potential role in predicting response to anti-PD(L)-1 plus VEGFR-TKI in patients with GC, 
MSS CRC and NSCLC. Apart from its potential predictive value, GEP panels can be designed to 
explore underlying resistance mechanism like immunosuppressive cytokines and cells to guide 
potential combination strategies (Fumet et al 2020; Cristescu et al 2018).   
Consequently, in the GC, MSS CRC and NSCLC cohorts, PD-L1, TMB and DNA 
mutation/bTMB and DNA mutation, and GEP can be explored in tumor or blood samples to 
identify their potential predictive value, as well as resistance mechanisms in patients who receive 
tislelizumab in combination with fruquintinib. Epstein-Barr virus (EBV) and MSS/MSI 
status(TMB panel can report the MSS/MSI status) in the GC cohort will be explored since 
EBV+/MSI-H GC patients were reported sensitive to anti-PD(L)-1 monotherapy (Figueroa-Protti 
et al 2019).  
1.5. 
Benefit-Risk Assessment 
Patients with advanced or metastatic, unresectable GC, MSS CRC who failed standard 
chemotherapies represent a population with a great unmet medical need. More effective 
treatment options with better tolerability profile are needed, as first-line treatment for PD-L1 
positive advanced NSCLC. The combination of immunotherapies with VEGFR inhibitors may 
improve response rates and duration of response with immunotherapies. Recent clinical studies 
have demonstrated the synergistic effect of anti-angiogenics and immune checkpoint inhibitors 
in solid tumors, including MSS CRC, GC and NSCLC.   
Data from the Phase 1b EPOC1603 trial of regorafenib plus nivolumab demonstrated objective 
tumor response in patients with advanced GC (44%) and in patients with MSS CRC (33.3%) 
(Fukuoka et al 2020). Similarly, promising antitumor activity was observed in the Phase 2 
EPOC1706 trial of pembrolizumab plus lenvatinib in patients with advanced GC with 20 (69%) 
of 29 patients having an objective response (Kawazoe et al 2020). In Phase 1b/2 E7080-A001-
111 study, lenvatinib plus pembrolizumab demonstrated promising antitumor activity in 
advanced NSCLC, although around half of the patients received prior anti-PD(L)1 treatment. 


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More than 1273 patients have been treated with tislelizumab monotherapy at clinically relevant 
doses (≥ 2 mg/kg) with additional patients treated in combination studies. The safety profile is 
largely consistent with that of other anti-PD-1 antibodies and included mostly mild/moderate 
AEs. Grade 3 and Grade 4 imAEs have been observed and have been generally reversible and 
manageable with study drug interruption and/or steroid treatment. The programmed cell death 
protein ligand-1 (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 9.6.3. 
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 9. For further information on the safety profile of tislelizumab, please refer 
to the tislelizumab (BGB-A317) Investigator’s Brochure. 
For fruquintinib, as of 03 September 2019, 7 clinical trials in patients with cancer had been 
completed and 5 clinical studies were ongoing. Important identified risks for fruquintinib 
included hemorrhage, hepatic function abnormal (including blood bilirubin increased, 
transaminase increased), infection, and hypertension. The AESIs included hemorrhages, hepatic 
function abnormal, infections, hypertension, dermatological toxicity, proteinuria, thyroid 
dysfunction, embolic and thrombotic events, arterial and venous, and gastrointestinal 
perforation/fistula. AE management guidelines are presented in Section 9.7. For further 
information on the safety profile of fruquintinib, please refer the fruquintinib Investigator’s 
Brochure. 
The potential drug-drug interaction between tislelizumab, a monoclonal antibody, and 
fruquintinib, a small molecule drug product, is expected to be very low. The tolerability of anti-
PD-1 therapy and TKI combination has been demonstrated in other combination trials (eg, 
lenvatinib plus pembrolizumab in patients with advanced endometrial cancer [Makker et al 2019] 
and avelumab plus axitinib in patients with advanced hepatocellular carcinoma [Kudo et al 
2019]). The toxicity profile of each therapy appeared consistent with their monotherapy profiles; 
thus, no severe overlapping toxicity is expected with fruquintinib in combination with 
tislelizumab.   
To mitigate risk, the study will include a safety run-in (Part 1) during which the recommended 
Phase 2 dose (RP2D) of fruquintinib in combination with tislelizumab will be assessed by the 
Safety Monitoring Committee (SMC) before enrollment into Part 2 can proceed. Given the 
unmet medical need, the expected tolerability of the combination, the antitumor activity of 
tislelizumab and fruquintinib in GC, CRC and NSCLC, and potential for synergy with the 
combination as seen with other similar combination trials, the benefit-risk profile based on 
available tislelizumab and fruquintinib data, is considered favorable. In order to assess the 
potential benefit and safety of tislelizumab in combination with fruquintinib, an open-label study 
will be conducted. 
1.6. 
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 for Part 1 
2.1.1. 
Primary Objective(s) 
• To assess the safety and tolerability of tislelizumab in combination with fruquintinib 
• To confirm the RP2D of fruquintinib in combination with tislelizumab  
2.2. 
Study Objectives for Part 2 
2.2.1. 
Primary Objective(s) 
• To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by 
investigator in patients with selected solid tumors as measured by the overall response 
rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 
(v)1.1 
2.2.2. 
Secondary Objectives 
• To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by 
the investigator in patients with selected solid tumors as measured by the progression 
free survival (PFS) per RECIST v1.1 
• To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by 
the investigator in patients with selected solid tumors as measured by the disease 
control rate (DCR) per RECIST v1.1 
• To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by 
the investigator in patients with selected solid tumors as measured by the clinical 
benefit rate (CBR) per RECIST v1.1 
• To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by 
the investigator in patients with selected solid tumors as measured by the duration of 
response (DOR) per RECIST v1.1 
• To assess the efficacy of tislelizumab in combination with fruquintinib as in patients 
with selected solid tumors as measured by overall survival (OS) 
• To assess the safety of tislelizumab in combination with fruquintinib 
2.2.3. 
Exploratory Objectives 
• To characterize the immunogenicity of tislelizumab and its time-pairing PK when 
given in combination with fruquintinib 
• To assess the PK of fruquintinib when given in combination with tislelizumab 
• To explore potential biomarkers that may correlate with clinical response/resistance 
to tislelizumab in combination with fruquintinib 


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2.3. 
Study Endpoints for Part 1 
2.3.1. 
Primary Endpoint 
• Safety and tolerability will be assessed throughout the study by monitoring adverse 
events (AEs) characterized by type, frequency, severity per National Cancer Institute-
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, timing, 
seriousness, and relationship to study drug(s); and other safety assessments 
• RP2D of fruquintinib in combination with tislelizumab  
2.4. 
Study Endpoints for Part 2 
2.4.1. 
Primary Endpoint 
• ORR – defined as the proportion of patients whose best overall response is complete 
response (CR) or partial response (PR) as assessed by investigator per RECIST v1.1  
2.4.2. 
Secondary Endpoints 
• PFS – defined as the time from the date of first dose to the date of the first 
determination of an objectively documented tumor progression as assessed by 
investigator per RECIST v1.1, or death, whichever occurs first 
• DCR – defined as the as the proportion of patients whose best overall response is CR, 
PR, or stable disease (SD) as assessed by investigator per RECIST v1.1 
• CBR – defined as the as the proportion of patients whose best overall response is CR, 
PR, or durable SD as assessed by investigator per RECIST v1.1 
• DOR – defined as the time from the first occurrence of documented objective 
response to the time of progression as assessed by investigator per RECIST v1.1 or 
death from any cause, whichever occurs first 
• OS - defined as the time from the date of first dose to the date of death due to any 
cause  
• AEs characterized by type, frequency, severity (as graded by the NCI‑CTCAE v5.0), 
timing, seriousness, and relationship to study drug(s); and other safety assessments 


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2.4.3. 
Exploratory Endpoint 
• Incidence of anti-tislelizumab antibodies (ADA), and its time-pairing serum 
concentration of tislelizumab 
• Plasma concentrations and derived PK parameters of fruquintinib as data permit 
• Potential biomarkers including but not limited to programmed cell death protein 
ligand-1 (PD‑L1) expression, tumor mutational burden (TMB) and DNA 
mutation/blood tumor mutational burden (bTMB) and DNA mutation, gene 
expression profile (GEP) in the GC, MSS CRC and NSCLC cohorts, Epstein-Barr 
virus (EBV) in the GC cohort, microsatellite stable (MSS)/microsatellite instable 
(MSI) status in the GC cohort, and the association of biomarkers with disease status, 
response/resistance to tislelizumab in combination with fruquintinib 


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3. 
STUDY DESIGN 
This is an open label, multicenter, Phase 2 study designed to assess the efficacy and safety of 
tislelizumab in combination with fruquintinib in patients with advanced or metastatic, 
unresectable GC, MSS CRC and PD-L1 positive (defined as TC≥1% by SP263 IHC) NSCLC. 
The study will be conducted in 2 parts. 
After providing written informed consent, completing all screening assessments, and being 
confirmed as eligible for study participation, approximately 90 patients (approximately 30 
patients per each indication) will be enrolled and receive tislelizumab plus fruquintinib treatment 
at RP2D.  
Part 1 of the study will be the safety run-in stage during which the first 6 patients will be enrolled 
and assessed for DLTs during the 28-day DLT observation period. Study drug administration 
will begin at the full dose of fruquintinib (5 mg daily, 3 weeks on followed by 1 week off every 
4-week cycle) in combination with tislelizumab (300 mg once every 4 weeks) based on the well-
established safety profiles of tislelizumab and fruquintinib, the non-overlapping mechanisms of 
action, and the desire to treat patients at doses shown to be effective in previous studies. A lower 
dose level of fruquintinib (4 mg daily, 3 weeks on followed by 1 week off every 4-week cycle) 
will be explored as necessary depending on observed toxicity. Refer to Section 3.1 and 
Section 3.2 for assessment of DLT guidance and DLT definitions, respectively. The 
determination of the DLT will be made jointly by the investigator and sponsor after safety data 
has been reviewed. Only DLTs during the first 28 days of treatment will be assessed. Once they 
complete the DLT assessment, each subject still receiving study treatment will continue with the 
same dosage. 
• If 0-1 of 6 patients experience a DLT, the study may proceed at the current dose of 
both drugs. 
• If 2 or more patients experience a DLT, then, following consultation with the SMC, 
the study will proceed with enrollment in the next defined lower dose (Dose Level -
1), an additional 6 patients will be enrolled, and the 28-day DLT observation period 
will be repeated.    
• If 2 or more patients experience a DLT in Dose Level -1, enrollment in the study will 
cease.  
The SMC will evaluate the safety and tolerability of the combination therapy when the first 
6 DLT-evaluable patients have completed the first 28 days of treatment or when ≥ 2 DLTs at the 
tested dose level occur. Safety information including but not limited to the DLTs, all TEAEs, and 
laboratory abnormalities will be reviewed by the SMC. The SMC will make recommendations 
on safety management, including resumption of enrollment, de-escalation of fruquintinib to one 
lower dose level, or termination of enrollment. The final decision will be made by sponsor. Once 
the sponsor has determined that the combination therapy could proceed, the current dose will be 
confirmed as the RP2D, and enrollment for Part 2 will begin at RP2D. Patients enrolled in Part 1 
at RP2D will be counted towards Part 2 by the diagnosis of the tumor types; up to approximately 
30 patients per cohort will be enrolled at RP2D.  


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Tumor assessments will be performed by the investigator using RECIST v1.1 criteria 
(Eisenhauer et al 2009). Tumor imaging (computed tomography [CT] with oral/IV contrast, 
unless contraindicated, or magnetic resonance imaging [MRI]) must be performed within 
28 days prior to enrollment. On-study tumor assessments will occur every 8 weeks (±7 days) 
during the first 56 weeks and every 12 weeks (±7 days) thereafter until PD. If a patient 
discontinues study treatment due to any reasons other than PD, tumor assessments will continue 
to be performed as scheduled until disease progression, loss to follow up, initiation of subsequent 
therapy, withdrawal of consent, death, or until the study terminates, whichever occurs first. 
All patients will be closely monitored for AEs throughout the study and for up to 30 days after 
the last dose of study drug(s). AEs will be graded according to the NCI-CTCAE v5.0. Refer to 
Section 9 for additional and specific information regarding AE monitoring and reporting. 
PK analysis will be performed for fruquintinib and tislelizumab. Biomarker analysis will include, 
but is not limited to tumor mutation burden, cytokine analysis, tumor-infiltrating lymphocytes 
assessment, and gene expression profiling (Section 8.5). 
Tislelizumab and fruquintinib will be administered until PD, intolerable toxicity, death, 
withdrawal of consent, or until the study terminates. Patients may continue to receive 
tislelizumab and fruquintinib or either of the study drugs beyond the initial investigator-assessed 
PD, as defined by RECIST v1.1, provided that the patient has investigator-assessed clinical 
benefit and is tolerating study drug(s). For patients in the CRC cohort, tislelizumab monotherapy 
will not be permitted. Refer to Section 7.6 and Section 8.3 for additional considerations 
regarding treatment continuation and withdrawal. Patients who, at time of progression, have an 
ongoing AE that leads to treatment discontinuation and has completed the scheduled Safety 
Follow-up Visit will be followed until the event resolves, the investigator assesses the event as 
stable, the patient is lost to follow-up, or the patient starts a new anticancer therapy. If a patient 
discontinues study drug(s) due to reasons other than PD or death, tumor assessments should 
continue to be performed following the scheduled assessment plan until the start of new 
anticancer therapy, PD, death, lost to follow-up, or withdrawal of consent for efficacy follow-up 
(Section 7.5.2). 
Patients who have discontinued study drug(s) should return to the site for an End-of-Treatment 
(EOT) Visit within ≤ 7 days as detailed in Section 7.4. After the EOT Visit, patients will have 
scheduled follow-up visits for safety and, if applicable, for efficacy per the Schedule of 
Assessments (Appendix 1). 
Study procedures and assessments are further detailed in Section 7 and Section 8, respectively, 
and the Schedule of Assessments can be found in Appendix 1.  


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Figure 1: 
Study Schema 
 
Abbreviations: DLT, dose limiting toxicity; RP2D, recommended Phase 2 dose; SMC, Safety Monitoring Committee. 
Notes: The first 6 patients will be enrolled and assessed for DLTs during the 28-day DLT observation period. Dosing will begin 
at Dose Level 0. Dose Level -1 will be explored as necessary depending on observed toxicity. The SMC will evaluate the safety 
and tolerability of the combination therapy when the first 6 DLT-evaluable patients have completed the DLT observation period 
or when ≥ 2 DLTs at the tested level occur. Enrollment for Part 2 will begin once the sponsor has determined that the 
combination could proceed and confirmed the RP2D of fruquintinib in combination with tislelizumab. 
• 
Tislelizumab will be administered intravenously on Day 1 of every 4-week cycle.  
• 
Fruquintinib will be administered daily, orally with 3 weeks on followed by 1 week off for every 4-week cycle. 
3.1. 
Assessment of Dose-Limiting Toxicity 
DLTs will be assessed per the DLT criteria below (Section 3.2) during the 28-day DLT 
assessment window, which begins on the first day of the administration of the study drugs. 
Patients will be considered evaluable for DLTs if they 1) received ≥ 85% of scheduled 
fruquintinib and ≥ 67% (approximately two-thirds) of scheduled tislelizumab administration 
during the DLT assessment window and/or 2) experienced a DLT. 
Patients will be considered not evaluable for DLTs if during the DLT assessment window they 
1) were withdrawn from the study, 2) did not receive ≥ 85% of scheduled fruquintinib and ≥ 67% 
(approximately two-thirds) of scheduled tislelizumab drug administration, 3) received 
prophylactic supportive care that confounds the evaluation of DLTs (not including supportive 
care described as part of the DLT definition), OR 4) have taken a strong inhibitor or inducer of 
enzyme CYP3A4 (Appendix 10) as the exposure to fruquintinib may be impacted. Patients who 
are not DLT-evaluable must be replaced, if needed.  
Any patient who experiences a DLT may be withdrawn from treatment or may continue at a 
lower dose level following discussion with and approval by the medical monitor. 
3.2. 
Dose-Limiting Toxicity Definition 
All toxicities or AEs will be graded according to the NCI-CTCAE Version 5.0. A DLT is defined 
as 1 of the following toxicities occurring during the DLT assessment window (first 28 study days 
of treatment) and considered by the investigator to be related to 1 or more study drugs.  


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Hematologic: 
• Grade 4 neutropenia lasting > 7 days 
• ≥ Grade 3 febrile neutropenia 
• Grade 3 thrombocytopenia with clinically significant bleeding 
• Grade 4 thrombocytopenia lasting > 7 days 
• ≥ Grade 4 anemia 
Nonhematologic: 
• Any ≥ Grade 4 toxicity 
• Any Grade 3 toxicity that does not resolve to baseline or ≤ Grade 1 within 7 days 
after optimal supportive care is initiated  
Note: The following nonhematologic AEs will not be considered DLTs: 
• Grade 3 endocrinopathy that is adequately controlled by hormonal replacement 
• Grade 3 rash 
• Grade 3 infusion-related AE that is transient (resolving within 6 hours of onset) 
• Grade 3 amylase or lipase elevation without clinical symptoms indicative of acute 
pancreatitis 
• Grade 3 hypertension that returns to baseline or ≤ Grade 1 with appropriate 
supportive treatment 


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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 must meet all of the following inclusion criteria to be considered eligible for 
participation in this study: 
1. Signed informed consent form (ICF) and able to comply with study requirements. 
2. Age ≥ 18 years (or the legal age of consent). 
3. At least 1 measurable lesion as defined by RECIST v1.1. 
Note: Selected target lesion(s) must meet one of these criteria: 1) not previously treated 
with local therapy or 2) within the field of prior local therapy but with subsequent 
progression as per RECIST v1.1. 
4. Tumor tissue (archival tumor tissues as formalin-fixed paraffin-embedded blocks or 
approximately 15 unstained slides) for central laboratory assessment of MSS status (MSI 
test) for the CRC patients, PD-L1 status for the NSCLC patients, for central/local 
laboratory assessment of EGFR status for the non-squamous NSCLC patients with no 
EGFR documentation during the screening period, and for retrospective analysis of other 
exploratory biomarkers related to response and resistance for the CRC, GC and NSCLC 
patients in a BeiGene designated central or test laboratory. 
• A fresh biopsy is mandatory in the absence of archival tumor tissues.  
• For the CRC patients, approximately 2 mL peripheral whole blood will be collected 
for MSI test control during the screening period. 
• Submission of < 15 unstained slides is not a protocol deviation. If patients cannot 
provide 15 unstained slides, patients may be enrolled after confirmation with the 
sponsor. 
Note:  
Written informed consent is required prior to obtaining fresh tumor biopsies and blood 
samples. Biopsy tumor tissue must be obtained from a core or punch biopsy. Tumor 
tissue from a fine-needle aspiration is not acceptable. 
5. In case of submitting unstained cut slides, freshly cut slides should be submitted to the 
testing laboratory within 14 days from when the slides are cut. Eastern Cooperative 
Oncology Group (ECOG) Performance Status ≤ 1 (Appendix 4). 


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6. Adequate organ function as indicated by the following laboratory values ≤ 7 days before 
the first dose of study drug(s). 
a. Absolute neutrophil count ≥ 1.5 x 109/L 
b. Platelet count ≥ 100 x 109/L  
c. Hemoglobin ≥ 90 g/L, without blood transfusion or growth factor support ≥ 14 days 
before sample collection 
d. AST and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN), or 
AST and ALT ≤ 5 x ULN for patients with liver metastases 
e. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients 
with Gilberts syndrome) 
f. Urine protein is ≤1+ by dipstick or 24-hour urine protein is < 1.0g/24-h 
• Patients with > 1+ proteinuria on urinalysis must undergo a 24-hour urine 
collection.   
g. Serum creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate 
(GFR) ≥ 60 mL/min/1.73 m2 by Chronic Kidney Disease-Epidemiology 
Collaboration (CKD-EPI) equation (Appendix 5) 
h. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless 
patient is receiving anticoagulant therapy and PT values are within the intended 
therapeutic range of the anticoagulant 
7. Females of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study, and ≥ 120 days after the last dose of study 
drug(s), and have a negative urine or serum pregnancy test ≤ 7 days of the first dose of 
study drug(s) (Appendix 6). 
8.  Nonsterile males must be willing to use highly effective method of birth control for the 
duration of the study and for ≥ 120 days after the last dose of study drug(s) (Appendix 6). 
• 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. 
9. Patients enrolled in part 1 and part 2 should be histologically or cytologically diagnosed 
with one of the following indications and meet the indication specific inclusion criteria. 
a. Gastric Cancer 
i. 
Histologically or cytologically confirmed, advanced or metastatic, 
unresectable adenocarcinoma of gastric or esophagogastric junction. All other 
histological types are excluded.  
ii. 
Progression during or after prior first-line therapy containing any 
platinum/fluoropyrimidine doublet (combination with anti-HER2 antibody is 
mandatory if tumor HER2 is documented positive). If relapse or metastasis 
occur during the adjuvant/neoadjuvant treatment containing 
platinum/fluoropyrimidine or within 6 months after the completion of the 


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above treatment, that adjuvant/neoadjuvant therapy is considered as the failure 
of first line systemic chemotherapy for PD.  
b. MSS CRC  
i. 
Histologically or cytologically confirmed, advanced or metastatic, 
unresectable adenocarcinoma of the colon or rectum. All other histological 
types are excluded.  
ii. 
Patients must have failed 2 lines of standard chemotherapies, including 
fluoropyrimidine, oxaliplatin, or irinotecan. Failed chemotherapies are defined 
as the occurrence of PD or intolerable toxicities during the treatment or after 
the last dose. 
• 
Notes: a) Each line of treatment for advanced disease until PD includes 
one or more chemo drugs used for ≥ 1 cycle; b) Previous 
adjuvant/neoadjuvant therapy is allowed. If relapse or metastasis occur 
during the adjuvant/neoadjuvant treatment period for patients with 
nonmetastatic or metastatic disease who have received curative surgery or 
within 6 months after the completion of the above treatment, that 
adjuvant/neoadjuvant therapy is considered as the failure of first line 
systemic chemotherapy for PD; c) Patients could be enrolled once they 
have failed fluoropyrimidine, oxaliplatin and irinotecan based regimen as 
first line treatment. 
iii. 
Patients with RAS wild type tumor must have received anti-VEGF and/or 
EGFR antibody treatment. Patients with RAS mutation or RAS status 
unknown must have received anti-VEGF antibody treatment. 
iv. 
Tumor tissues were identified as microsatellite stable (MSS) by polymerase 
chain reaction (PCR) by a central laboratory. 
c. NSCLC 
i. 
Histologically or cytologically confirmed, locally advanced (Stage IIIB) not 
amenable to curative surgery or radiotherapy, or metastatic (Stage IV) 
NSCLC.  
ii. 
Have had no prior systemic therapy for advanced or metastatic NSCLC. 
Patients who have received prior neo-adjuvant, adjuvant chemotherapy, 
radiotherapy, or chemoradiotherapy with curative intent for non-metastatic 
disease must have experienced a disease-free interval of at least 6 months 
from the last dose of chemotherapy and/or radiotherapy prior to first dose. 
iii. 
Patients with documented EGFR mutation or known ALK gene translocation 
(both must be tissue-based test) will be excluded. For non-squamous patients 
with unknown EGFR status, archival or fresh tumor tissues are required for 
EGFR mutation assessment in central/local laboratory prior to enrollment and 
only those with wild type EGFR will be enrolled. 
iv. 
Tumor tissues were identified as PD-L1 positive defined as TC≥1% by SP263 
IHC by a central laboratory. 


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4.2. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from this study: 
1. Has at screening any central nervous system metastasis and/or leptomeningeal disease. 
2. Prior therapy targeting CTLA-4, PD-1, PD-L1 or programmed cell death protein ligand-2 
(PD-L2) or any other antibody or drug specifically targeting T-cell costimulation or 
checkpoint pathways. 
3. Prior treatment with VEGFR-TKI or anti-VEGFR antibody (eg, ramucirumab). 
4. Received more than 1 line of systemic treatment for advanced or metastatic, unresectable 
adenocarcinoma of gastric or esophagogastric junction, or more than 2 lines of systemic 
treatment for advanced or metastatic, unresectable adenocarcinoma of the colon or 
rectum. 
5. Active autoimmune diseases or history of autoimmune diseases that may relapse 
(Appendix 7), with the following exceptions: 
a. Controlled Type 1 diabetes 
b. Hypothyroidism (provided it is managed with hormone-replacement therapy only) 
c. Controlled celiac disease 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, or 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 the first dose of study drug(s) except for the 
specific cancer under investigation in this study and any locally recurring cancer that has 
been treated with curative intent (eg, resected basal or squamous cell skin cancer, 
superficial bladder cancer, or 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 
the first dose of study drug(s), with the following exceptions: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 
b. Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid with 
minimal systemic absorption 
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for 
contrast dye allergy) or for the treatment of a non-autoimmune condition 
(eg, delayed-type hypersensitivity reaction caused by contact allergen) 
8. History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung 
diseases including but not limited to pulmonary fibrosis, acute lung diseases, etc. 
9. Clinically significant pericardial effusion. 
10. Clinically uncontrolled pleural effusion or ascites that requires pleurocentesis or 
abdominal tapping for drainage within 2 weeks prior to the first dose of study drug(s). 
11. 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 the first dose of study drug(s). 


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12. Infection (including tuberculosis infection, etc) requiring systemic antibacterial, 
antifungal, or antiviral therapy (not including antiviral therapy for hepatitis) ≤ 14 days 
prior to the first dose of study drug(s). 
13. 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 at screening. 
• Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B 
(HBV DNA < 500 IU/mL or < 2500 copies/mL) 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 the first dose of study drug(s). 
• Patients with a negative hepatitis C virus (HCV) antibody test at Screening or positive 
HCV antibody test followed by a negative HCV RNA test at Screening are eligible. 
The HCV RNA test will be performed only for patients testing positive for HCV 
antibody. 
14. Known history of HIV infection 
15. Any major surgical procedure ≤ 28 days before the first dose of study drug(s). Patients 
must have recovered adequately from the toxicity and/or complications from the 
intervention prior to the first dose of study drug(s). 
16. Prior allogeneic stem cell transplantation or organ transplantation. 
17. 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 the first dose of study drug(s) 
b. Pulmonary embolism ≤ 6 months before the first dose of study drug(s) 
c. Acute myocardial infarction ≤ 6 months before the first dose of study drug(s) 
d. Heart failure meeting New York Heart Association Classification III or IV 
(Appendix 8) ≤ 6 months before the first dose of study drug(s) 
e. Ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before the first dose of 
study drug(s) 
f. Cerebrovascular accident ≤ 6 months before the first dose of study drug(s) 
g. Uncontrolled hypertension that cannot be managed by standard antihypertension 
medications, defined as: systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 
90 mmHg ≤ 28 days before the first dose of study drug(s) 
h. Syncope or seizure ≤ 28 days before the first dose of study drug(s) 
18. Patients with active gastrointestinal and duodenal ulcers, ulcerative colitis, and other 
gastrointestinal disease or unresectable tumors with active bleeding, or other conditions 
that the investigator determines to possibly cause gastrointestinal bleeding, perforation 
and other conditions; or prior gastrointestinal perforation or gastrointestinal fistula that 
has not recovered after surgical treatment. 
19. Evidence of tendency or medical history of bleeding (such as melena, hematemesis, 
hemoptysis, fresh in stool, etc.) within 2 months before first dose of study drug(s). 


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20. High risk of bleeding at screening due to tumor invasion into major vessels, such as 
pulmonary artery, the superior vena cava, or the inferior vena cava, as determined by 
investigators. 
21. Have a medical history arterial thrombus or deep vein thrombosis within 6 months prior 
to the first drug administration; or experienced a stroke event and/or transient ischemic 
attack within 12 months; patients with implanted intravenous infusion pump or catheter 
related thrombosis or superficial vein thrombosis, except for patients with stable 
thrombus after routine anticoagulant therapy. 
22. Known allergy to any of the components of tislelizumab or fruquintinib preparations 
including tartrazine (E102) and sunset yellow (E110) or have any previous history of 
severe hypersensitivity reactions to other monoclonal antibodies. 
23. Chemotherapy, immunotherapy (eg, interleukin, interferon, thymosin), or investigational 
therapy ≤ 28 days or 5 half-lives (whichever is shorter, but ≥ 14 days) before the first 
dose of study drug(s). Also, palliative radiation treatment or other locoregional therapies 
within 14 days prior to the first dose of study drug. 
24. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks or 5 times half-lives 
whichever is longer before the first dose of study drugs(Appendix 10) 
25. Concomitant medications with a known risk of causing QT prolongation and/or Torsades 
de Pointes (Appendix 11) 
26. Any Chinese herbal or Chinese patent medicine with anticancer activity approved by the 
NMPA (regardless of the type of cancer) used ≤ 14 days before the first dose of study 
drug(s). 
27. Toxicities (as a result of prior anticancer therapy) that have not recovered to baseline or 
stabilized, except for AEs not considered a likely safety risk (eg, alopecia, neuropathy). 
28. Live vaccine ≤ 28 days before the first dose of study drug(s). 
• Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines and are not allowed. 
29. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study drug(s), or 
will affect the explanation of drug toxicity or AEs, or result in insufficient or impaired 
compliance with study conduct. 
30. Inability to swallow capsules or disease significantly affecting gastrointestinal function 
such as malabsorption syndrome, resection of the complete small bowel, symptomatic 
inflammatory bowel disease, or partial or complete bowel obstruction. 
31. Prior randomization in a tislelizumab study regardless of the treatment arm, until the 
primary and key secondary endpoints of the study have read out. 


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32. Concurrent participation in another therapeutic clinical study. 
• 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. 
33. Women who are pregnant or are breastfeeding. 


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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 sterile glass vial 
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 Investigator’s Brochure for other details regarding 
tislelizumab. 
5.1.2. 
Fruquintinib 
Fruquintinib is presented as 2 capsule strengths (1 mg and 5 mg). The 1 mg capsule is presented 
as a No. 3 hard gelatin capsule containing 52 mg of a blended white to off-white powder that is 
composed of fruquintinib drug substance, microcrystalline cellulose, starch, and talc. The 5 mg 
capsule is presented as a No. 1 hard gelatin capsule containing 260 mg of the same blended 
powder as the 1 mg capsule. 
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. 
For further details, see the manufacturer’s prescribing information for fruquintinib. 
5.2. 
Dosage, Administration, and Compliance 
Treatment with study drug(s) on Day 1 of Cycle 1 must begin within 2 business days after a 
patient’s enrollment (Section 7.2). Treatment modifications (eg, dose delay/holds) will be based 
on specific laboratory and AE criteria, as described in Section 5.4. Guidelines for study treatment 
modification, delay, or discontinuation as well as management of imAEs or infusion-related 
reactions are provided in Section 9.6, Section 9.7, and Appendix 9. 
Accurate records of all study drug(s) received, dispensed, returned, and disposed of should be 
maintained in the site’s Pharmacy Folder. Refer to the Pharmacy Manual for details of study 
drug management, drug preparation, storage, and administration. 


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Table 1: 
Selection and Timing of Dose for Each Patient 
Study Drug 
Dose 
Frequency of Administration 
Route of Administration 
Tislelizumab 
300 mg 
Every 4 weeks 
Intravenous  
Fruquintinib  
5 mg or 4 mg 
3 weeks on/1 week off  
Oral  
Note: Fruquintinib starting dose will depend on which part of the study the patient is enrolled and if the 
RP2D has been determined. 
5.2.1. 
Tislelizumab 
Tislelizumab 300 mg will be administered on Day 1 of each 28-day cycle (once every 4 weeks). 
Tislelizumab will be administered by intravenous infusion through an intravenous line 
containing a sterile, non-pyrogenic, 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. 
The initial infusion (Cycle 1, Day 1) will be delivered over 60 minutes; if this is well tolerated, 
then the subsequent infusions may be administered over 30 minutes, which is the shortest time 
period permissible for infusion. Tislelizumab must not be concurrently administered with any 
other drug. 
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of imAEs and infusion-related reactions are provided in detail in Section 9.5.8 and 
Appendix 9. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.2.2. 
Fruquintinib 
Fruquintinib will be self-administered orally once daily for 21 days, followed by 7 days off in 
28-day cycles with or without food. The capsules should be swallowed with a glass of water. On 
days when fruquintinib and tislelizumab dosing are both scheduled, the daily dose of fruquintinib 
should precede tislelizumab infusion.  
In Part 1, the staring dose is 5 mg once daily. Depending on safety observations, the fruquintinib 
dose may be de-escalated to 4 mg once daily. The sponsor will confirm the RP2D of the 
combination treatment. In Part 2, fruquintinib will be administered at the RP2D. 
An adequate supply of fruquintinib will be dispensed to patients on Day 1 of each new cycle 
(once every 4 weeks). Patients should record the date and time of drug administration and 
amount in the patient diary. Each time study drug is dispensed, compliance will be evaluated and 
reinforced. Treatment compliance will also be monitored by drug accountability and recorded in 


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the patient’s medical record and electronic case report form (eCRF). If the number of capsules 
returned does not agree with the expected number, the patient should be counseled, and proper 
dosing reinforced. 
The following guidelines should be followed for fruquintinib administration: 
• Fruquintinib may be taken either in the fasting state or after meals. 
• Capsules should be taken with 100 to 200 mL (1 cup) of water at approximately the 
same time each day. 
• Patients should swallow the capsules whole and not chew them. 
• If vomiting occurs after dosing, fruquintinib doses should not be replaced.  
• If a dose is missed, the missed dose can be taken within a 12-hour window of the time 
the patient typically takes the dose. A double dose should not be administered to 
make up for missed individual doses. 
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any and all AEs. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of fruquintinib therapy. Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 5.4.2 and 
Section 9.7.  
5.3. 
Overdose 
Any incorrect administration of study drug(s) or overdose of tislelizumab (defined as ≥ 600 mg 
in a 24-hour period) or fruquintinib (defined as any dose greater than 5 mg daily dose) should be 
noted in the patient’s chart and on the appropriate eCRF. AEs associated with an incorrect 
administration or overdose of study drug(s) will be recorded on the AE eCRF. Any SAEs 
associated with an incorrect administration or overdose must be reported within 24 hours of 
awareness via the SAE reporting process as described in Section 9.5.2. In the event of overdose, 
further study drug administration should be held, and the patient should be observed closely for 
signs of toxicities. Appropriate supportive care measures should be provided if clinically 
indicated. Sites must contact the medical monitor prior to the patient resuming fruquintinib 
treatment.  
5.4. 
Dose Delay or Modification 
A dose delay is a deviation from the prescribed dosing schedule (ie, the drug is withheld beyond 
visit window). A dose interruption is an interruption of an infusion. Treatment cycles will be 
counted continuously regardless of dose delays. 
Every effort should be made to administer the study drug(s) according to the planned dosage 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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5.4.1. 
Dose Delay or Modification for Tislelizumab  
There will be no dose reduction for tislelizumab in this study. 
Tislelizumab treatment may be temporarily suspended if the patient experiences a toxicity that is 
considered related to tislelizumab or fruquintinib and requires a dose to be withheld. 
Tislelizumab treatment should resume as soon as possible after the AEs recover to baseline or 
Grade 1 (whichever is more severe) and within 12 weeks after the last dose of tislelizumab. If the 
administration of study drug can resume within ≤ 14 days, it should be administered in the 
current cycle. If tislelizumab needs to be withheld for > 14 days, it should be omitted from the 
current cycle and administration should continue at the start of the next cycle. If the patient is 
unable to resume tislelizumab within 12 weeks after the last dose of tislelizumab, then the patient 
should be discontinued from tislelizumab treatment. If the patient is unable to resume 
tislelizumab ≤ 12 weeks after the last dose for unforeseen non-drug-related reasons, continued 
treatment may be allowed if approved by the medical monitor. 
5.4.2. 
Dose Delay or Modification for Fruquintinib 
Should drug-related AEs occur, the severity of AEs will be graded according to the NCI CTCAE 
v5.0. Reasons for dose modifications or delays, the supportive measures taken, and the outcome 
should be documented in the patient’s chart and recorded in the eCRF.  
• For any concomitant conditions already apparent at baseline, the dose modifications 
will apply according to the corresponding shift in toxicity grade, if the investigator 
feels it is appropriate. For example, if a patient has Grade 1 asthenia at baseline that 
increases to Grade 2 during treatment, this will be considered a shift of one grade and 
treated as Grade 1 toxicity for dose-modification purposes.  
• For toxicities that are considered by the investigator to be unlikely to develop into 
serious or life-threatening events, treatment can be continued at the same dose.  
• To recover from acute toxicity, unless otherwise indicated, the treatment can be 
delayed for up to 14 days. If a treatment delay longer than 14 days is required, 
treatment should be discontinued. Continuation/resumption of fruquintinib treatment 
after an interruption of more than 14 days must be discussed with the medical 
monitor.  
• Where several toxicities with different grades or severity occur at the same time, the 
dose modifications should be according to the highest grade observed.  
Treatment cycles will be counted continuously, regardless of dose delay. 
The dose can be adjusted at any time due to the intolerable toxicity (Error! Reference source 
not found.). Once reduced, the dose cannot be re-escalated to the previous level.  
• If the patient’s original dose is 5 mg once daily, up to 2 dose reductions are permitted: 
one reduction from 5 mg once daily to 4 mg once daily, and if not tolerated, then a 
second reduction from 4mg once daily to 3 mg once daily.  
• If the patient’s original dose is 4 mg once daily, only 1 dose reduction is permitted: a 
reduction from 4mg once daily to 3 mg once daily.  


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Table 2: 
Fruquintinib Dose Reductions 
Dose Level 
Dose 
Dose 
Dose Level 0 (original dose) 
5 mg once daily 
4 mg once daily 
Dose Level -1 (1st dose reduction) 
4 mg once daily 
3 mg once daily 
Dose Level -2 (2nd dose reduction) 
3 mg once daily 
Not available 
Dose reduction guidelines for haematologic and non-haematologic toxicities, other than guidance 
for important identified risks (palmar-plantar erythrodysesthesia [PPE], proteinuria, 
hypertension, decreased platelet count, hemorrhage, and liver function impairment in Table 8), 
are provided below (Table 3). Treatment should be held until AE/toxicity resolves or improves to 
≤ Grade 1. If a patient has a Grade 3 toxicity that is expected to be manageable and reversible 
with a dose reduction, treatment should be held until toxicity resolves to ≤ Grade 1. Patients with 
Grade 3 non-haematologic toxicity not described below that does not resolve to ≤ Grade 1 within 
14 days should permanently discontinue fruquintinib unless approval to continue is obtained in 
writing from the sponsor. 
Table 3: 
Dose Modification Recommendations for Hematologic and Non-Hematologic 
Toxicity  
AE Grade 
Action 
Grade 1 or 2a  
None  
Grade 3b  
Interrupt the dose until the toxicity resolved to ≤ Grade 1 or baseline level 
within 14 days, then reduce the dose to a lower dose level  
Grade 4  
Discontinue treatment permanently  
a. 
Should any arterial thrombosis occur, fruquintinib should be terminated.  
b. 
Including Grade 3 diarrhea and stomatitis, etc. that are ineffectively treated by drug therapies, but excluding 
Grade 3 menstrual cycle extension.  


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6. 
PRIOR AND CONCOMITANT THERAPY 
6.1. 
Prior Therapy 
All prior therapy, dates of administration, best response, and date of progression for patient’s 
cancer type will be collected at study entry and entered into the eCRF. 
6.2. 
Permitted Concomitant Medications/Procedures 
Unless noted otherwise, 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, hematopoietic growth factors, red blood cell/platelet 
transfusions) 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 28 days 
before the first dose of study drug(s) and 30 days after the last dose of study drug(s) will be 
recorded. 
Bisphosphonates and RANKL inhibitors are allowed for bone metastases if initiated before 
enrollment and at a stable dose. Bisphosphonates are permitted during the study for a 
nonmalignant indication. 
Patients who use oral contraceptives, hormone-replacement therapy, or other allowed 
maintenance therapy may continue their use if indicated. 
Prophylactic use of anticoagulation for the maintenance of patency of permanent indwelling 
central venous access devices or for patients at high risk of venous thromboembolism is 
permitted during study treatment. If patients are receiving anti-coagulation, they should be very 
closely monitored for potential hemorrhage. 
The investigator should closely monitor patients receiving anti-platelet and/or anti-thrombotic 
drugs during study drug treatment and make a timely decision on whether to continue or stop 
such drugs in patients that report ≥ Grade 2 hemorrhagic events at any site, based on an 
individual assessment of the risk-benefit balance. 
Prophylactic antiemetic, granulocyte colony stimulating factors, granulocyte macrophage colony 
stimulating factors, platelet simulating factors or erythropoietin are permitted as clinically 
indicated. 
Systemic Corticosteroids 
Systemic corticosteroids administered for the control of imAEs must be tapered gradually (see 
Appendix 9 and must be administered at nonimmunosuppressive doses (≤ 10 mg/day of 
prednisone or equivalent) before the next tislelizumab administration. The short-term use of 
steroids as prophylactic treatment (eg, patients with contrast allergies to diagnostic imaging 
contrast dyes) is permitted.  


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Hepatitis B Treatment 
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 500 IU/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 
enrollment and continue treatment during the study and for 6 months after study drug 
discontinuation. 
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 if the following criteria are met: 
• Repeat imaging demonstrates no new sites of bone metastases 
• The lesion being considered for palliative radiation is not a target lesion for  
• The case is discussed with the medical monitor and he/she agrees that the conditions 
required to receive palliative radiation are met 
In addition, palliative radiation or other focally ablative therapy for other nontarget sites of the 
disease is permitted if clinically indicated per the investigator’s 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 radiation therapy to rule out progression of disease. 
6.3. 
Prohibited Concomitant Medications/Procedures 
The following medications are prohibited during the study or as otherwise noted: 
• Any concurrent anticancer therapy, including chemotherapy, hormonal therapy, 
immunotherapy, standard or investigational agents (including Chinese [or other 
Country] herbal medicine and Chinese [or other Country] patent medicines for the 
treatment of cancer is not allowed. Chinese [or other Country] herbal and Chinese [or 
other Country] patent medicines with anticancer activity are defined as medication 
with approval by the NMPA (or other Country) for use as anticancer treatment 
(regardless of the type of cancer). 
• Live vaccines  28 days before the first dose of study drug(s) and  60 days following 
the last dose of tislelizumab. 
• 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. 
• Patients should not abuse alcohol or other drugs. 


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• 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) ≤ 28 days (or ≤ 5 half-lives, if applicable, whichever is shorter) before 
the first dose of study drug(s) and during the study. Patients must notify the 
investigator of all herbal remedies used during the study.  
• Radiation therapy, except for palliative radiation therapy described in Section 6.2. 
• Concomitant use of medications that have a known risk of causing QT prolongation 
and/or torsades de pointes (see Appendix 11 or refer to http://www.crediblemeds.org) 
6.4. 
Medications to Be Used With Caution 
The use of potentially hepatotoxic drugs in patients with impaired hepatic function is allowed but 
should be carefully monitored. 
Medications that are strong inhibitor or strong inducer of CYP3A should not be administered 
concomitantly with fruquintinib (See Appendix 10 for detailed information) unless investigator 
consider it necessary. Fruquintinib is metabolized through CYP3A so strong inhibitor or strong 
inducer of enzyme CYP 3A4 may significantly influence the metabolism of fruquintinib.  
Fruquintinib showed inhibition of P-glycoprotein (P-gp) and breast cancer resistance protein 
(BCRP) transporter in the in vitro studies, so drugs which are sensitive substrates, and substrates 
with narrow therapeutic index for P-gp and BCRP transporters should be  avoided if possible 
(see Appendix 10). If used together, monitor patients more frequently for adverse reactions, and 
consider dose reduction of the P-gp or BCRP substrate medication. 
Fruquintinib shows pH-dependent solubility (ie, solubility at pH 6.0–6.5 < solubility at pH 1–2) 
and is less well absorbed as gastrointestinal pH increases. Patients should avoid using proton 
pump inhibitors (eg, esomeprazole, lansoprazole, pantoprazole) during the study. If concomitant 
use of an acid-reducing agent is unavoidable, H2-antagonist (eg, famotidine, ranitidine, 
nizatidine) may be used but should be administered approximately 10 hours before or 2 hours 
after fruquintinib dosing. Antacid may be used, but the antacid dose should be administered at 
least 2 hours before or 2 hours after fruquintinib dosing.  
6.5. 
Potential Interactions Between Tislelizumab and Fruquintinib 
The potential for drug-drug interaction between tislelizumab and fruquintinib is expected to be 
low based on the metabolism of the drugs and their respective AE profiles. Tislelizumab is a 
therapeutic monoclonal antibody and 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. Even though 
fruquintinib was mainly metabolized via CYP enzymes, the possibility of tislelizumab interfering 
with this metabolism pathway is low.    


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7. 
STUDY PERIODS, VISITS, OR PROCEDURES 
7.1. 
Screening Period 
Screening evaluations will be performed ≤ 28 days before the first dose of study drug(s). A 
patient who agrees to participate in this study will sign the ICF before undergoing any study-
specific screening assessment. Refer to Section 8.1 for instructions regarding screening 
assessments. 
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. ICFs for enrolled patients and for patients who are 
screened but not enrolled will be maintained at the study site.  
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. 
7.2. 
Enrollment 
All screening results and relevant medical history must be available before eligibility can be 
determined. The investigator must confirm that all eligibility criteria are met. The study site 
personnel will complete the Eligibility Authorization Packet, which must be signed by the 
investigator or a subinvestigator. The medical monitor or designee will review and approve if 
appropriate. No eligibility waivers will be granted. The study site personnel must ensure that 
confirmation of eligibility by the medical monitor has been received before the patient receives 
the first dose of study drug(s). 
7.3. 
Treatment Period 
Patients will be treated as described in Section 5.2. 
Patients may continue to receive study drug(s) beyond the initial investigator-assessed PD, as 
defined by RECIST v1.1, provided that the patient has investigator-assessed clinical benefit and 
is tolerating study drug(s). Refer to Section 7.6 and Section 8.3 for additional considerations 
regarding treatment continuation and withdrawal. 
7.4. 
End-of-Treatment Visit 
The EOT Visit is conducted ≤ 7 days after the investigator determines that the patient must 
permanently discontinue all study drugs. 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 EOT Visit did not occur until 30 days (± 7 days) or later after the last dose of 
study drugs, the EOT Visit may also be used as the Safety Follow-up Visit. 
See Appendix 1 for assessments to be performed for the EOT Visit. 


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7.5. 
Follow-up Periods 
7.5.1. 
Safety Follow-up Period  
Patients who permanently discontinue all study drugs will be asked to return to the clinic for the 
Safety Follow-up Visit, which is required to be conducted within 30 days [± 7 days] after the last 
dose of study drugs or before the initiation of new anticancer therapy, whichever occurs first. In 
addition, telephone contacts with patients should be conducted to assess imAEs and concomitant 
medications (if appropriate, ie, associated with an imAE or is a new anticancer therapy) at 60 and 
90 days (± 14 days) after the last dose of tislelizumab, regardless of whether or not patients have 
started a new anticancer therapy. If patients report a suspected imAE at a telephone follow-up 
contact, the investigator should arrange an unscheduled visit if further assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 9.5. 
See Appendix 1 for assessments to be performed at the Safety Follow-up Visit. 
7.5.2. 
Efficacy Follow-up Period 
Patients who discontinue study drug(s) for reasons other than PD (eg, toxicity) will continue to 
undergo tumor assessments following the original plan until the patient experiences PD, starts 
new anticancer therapy, or for any other reason listed in Section 7.6.2, whichever occurs first. 
If patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact the patients by telephone to determine their disease status. 
7.5.3. 
Survival Follow-up Period 
After discontinuation of study treatment, patients will be followed for survival and further 
anticancer therapy information via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months (± 14 days) after the EOT or Safety Follow-up Visit or as directed 
by the sponsor until death, loss to follow-up, withdrawal of consent, or study completion by the 
sponsor.   
7.5.4. 
Lost to Follow-up 
If attempts to contact the patient by telephone are unsuccessful, additional attempts should be 
made to obtain protocol-required follow-up information. It may be possible to obtain the 
information from other contacts, such as referring physicians or relatives. Attempts to contact 
should be documented in the patient’s source documents. If a patient cannot be contacted despite 
all attempts, the patient will be considered lost to follow-up, and death information should be 
obtained through a public record search if local agencies permit. 


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7.6. 
Discontinuation From Study Treatment or From the Study 
7.6.1. 
Patient Discontinuation From Study Treatment (End of Treatment for an 
Individual Patient) 
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 study treatment at any time. Patients who 
discontinue study treatment for reasons other than PD should be followed for assessments of 
preliminary anticancer activity (Section 8.3) and safety (Section 8.2), if possible. 
The primary reason for discontinuation from study treatment should be documented on the 
appropriate eCRF. Patients may discontinue study treatment for reasons including but not limited 
to the following: 
• PD 
• AE 
• 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, including chemotherapy, hormonal therapy, 
immunotherapy, standard or investigational agents (including Chinese [or other 
Country] herbal medicine and Chinese [or other Country] patent medicines) for the 
treatment of cancer [regardless of cancer type]) 
• Patient noncompliance 
Study 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. 
If tislelizumab or fruquintinib is discontinued permanently for reasons other than disease 
progression, the other drug could be continued per the study protocol.  
If the decision is made to continue fruquintinib monotherapy treatment beyond initial 
progression, the patient will remain on the trial and will continue to be treated and monitored 
according to the schedule in Appendix 1. Fruquintinib monotherapy treatment must be 
discontinued permanently upon documentation of further progression, either symptomatic or 
radiographic.  
For patients with CRC, if fruquintinib is permanently discontinued, tislelizumab must be 
discontinued. Tislelizumab monotherapy is not allowed in the CRC cohort.  


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7.6.2. 
Patient Discontinuation From the Study (End of Study for an Individual Patient) 
Patients may discontinue from the study for reasons that include but are not limited to the 
following: 
• Patient withdrawal of consent 
• Death 
• Lost to follow-up  
7.7. 
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 include but are not limited to the following:  
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
• Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients must be seen for an EOT Visit and Safety 
Follow-up Visit as described in Section 7.4 and Section 7.5.1, respectively. 
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 IRBs/IECs of the early termination of the study. 
In the opinion of the investigator, any patient who continues to derive clinical benefit at the end 
of study and remains eligible for continued treatment with tislelizumab or tislelizumab plus 
fruquintinib or fruquintinib alone will be offered the option to continue treatment either by 
enrolling into a long-term extension study after signing the respective informed consent form or 
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8. 
STUDY ASSESSMENTS 
A table of scheduled study assessments is provided in Appendix 1. Patients will be closely 
monitored for safety and tolerability throughout the study. All assessments must be performed 
and documented in the medical record for each patient. 
Where applicable, 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. 
8.1. 
Screening Assessments 
Screening evaluations will be performed ≤ 28 days before the first dose of study drug(s) (refer to 
Appendix 1 for details). Patients who agree to participate will sign the ICF before undergoing 
any study-specific screening assessment. The screening period begins on the first day that a 
screening assessment 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 informed consent has been 
obtained 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. 
Procedures conducted only during the Screening Visit are described in this section. For the 
description of assessments that are conducted during screening as well as throughout the study, 
refer to Safety Assessments (Section 8.2), Tumor and Response Evaluations (Section 8.3), PK 
and ADA Assessments (Section 8.4) and Biomarkers (Section 8.5) sections. 
Rescreening under limited conditions may be allowed after consultation with BeiGene (eg, when 
a patient’s laboratory result narrowly misses a laboratory criterion and it is correctable and not 
due to rapidly deteriorating condition or PD). Rescreening is allowed only once. 
8.1.1. 
Pulmonary Function Tests 
Pulmonary function testing including spirometry and assessment of oxygenation, at a minimum, 
pulse oximetry at rest and with exercise, or alternatively, assessment of diffusion capacity, are to 
be performed for all NSCLC patients during the screening period to assist the determination of 
suitability on the study. Respective test results need to be submitted to the sponsor. 
For test results indicative of significantly impaired pulmonary function, eg, resting pulse 
oximetry < 90% on room air and further desaturation upon exercise, forced expiratory volume 
(FEV1) < 60% or diffusing capacity of the lungs for carbon monoxide (DLCO) (if performed) 
< 60% of age- and sex-adjusted predicted performance levels (Pellegrino et al 2005), the medical 
monitor needs to be consulted to confirm eligibility. 
Tests may be repeated as clinically indicated while on study. 


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GC or MSS CRC patients who are suspected of having or known to have serious/severe 
respiratory conditions, or exhibit significant respiratory symptoms unrelated to the underlying 
cancer, or with a history of thoracic radiotherapy will undergo pulmonary function testing that 
may include but is not limited to spirometry and assessment of diffusion capacity done during 
the screening period to assist the determination of suitability on the study. 
8.2. 
Safety Assessments 
8.2.1. 
Vital Signs 
Vital signs will include measurements of body temperature (˚C), pulse rate, respiration rate and 
blood pressure (systolic and diastolic). Pulse rate and blood pressure will be measured while the 
patient is in a seated position after resting for 10 minutes. 
8.2.2. 
Physical Examinations 
During the Screening Visit, a complete physical examination will be conducted, including 
evaluations of 1) head, eyes, ears, nose, and 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 in the eCRF with appropriate disease/condition terms. 
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 in the eCRF. Refer to Section 9.2 regarding AE definitions, reporting, and 
follow-up requirements. 
8.2.3. 
Eastern Cooperative Oncology Group Performance Status 
ECOG Performance Status (Appendix 4) will be assessed during the study. 
8.2.4. 
Laboratory Safety Tests 
Local and/or central laboratory assessments of clinical chemistry, hematology, coagulation, and 
urinalysis will be conducted as outlined in Appendix 3 per the timepoints shown in Appendix 1. 
If clinical chemistry, hematology, coagulation , and urinalysis at screening are not performed 
≤ 7 days before study drug administration on Day 1 of Cycle 1, these tests should be repeated 
and reviewed before study drug administration. After Day 1 of Cycle 1, results are to be 
reviewed within 72 hours before study drug administration.  
For central laboratory assessments, details regarding sample collection and shipment will be 
provided in a separate laboratory manual. 


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The following tests will also be conducted in this study at timepoints shown in Appendix 1. 
• Serum pregnancy test (for women of childbearing potential, including women who 
have had a tubal ligation) must be performed and documented as negative ≤ 7 days 
before the first dose of study drug(s). Furthermore, a negative urine pregnancy test 
must be completed and recorded before administration of study drug(s) at each cycle 
and in safety follow up visit. A serum pregnancy test must be performed if the urine 
pregnancy test is positive or equivocal. 
• Thyroid function testing (ie, thyroid stimulating hormone, free triiodothyronine [T3], 
and free thyroxine [T4]) 
• Hepatitis serology and viral load (refer to Section 8.2.7) 
8.2.4.1. 
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) are monitored in all 
tislelizumab studies to protect study patients and to quantify the risk of muscle inflammation (see 
Appendix 1 for the blood collection schedule and Appendix 9 for guidelines for management of 
suspected immune-mediated myocarditis, respectively). Serum troponins may be substituted per 
local guidelines if used consistently throughout the study. If tislelizumab has been permanently 
discontinued, CK and CK-MB testing is no longer required. Patients who continue to receive 
fruquintinib monotherapy may receive CK and CK-MB testing if clinically indicated. 
8.2.5. 
Electrocardiograms 
For safety monitoring purposes, the investigator must review, sign, and date all 
electrocardiogram (ECG) tracings. Paper or electronic copies of ECG tracings will be kept as 
part of the patient’s permanent study file at the site. 
All ECGs are to be obtained before other assessments scheduled at that same time (eg, vital sign 
measurements, blood draws). The patient should rest in a semirecumbent supine position for 
≥ 10 minutes in the absence of environmental distractions that may induce changes in heart rate 
(eg, television, radio, conversation) before each ECG collection. 
8.2.6. 
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 9.5. 
8.2.7. 
Hepatitis B and C Testing 
Testing will be performed by a central laboratory and/or the local laboratory at screening (and as 
clinically indicated) and will include HBV/HCV serology (HBsAg, hepatitis B surface antibody 
[HBsAb], hepatitis B core antibody [HBcAb], and HCV antibody). In the case of active HBV or 
HCV infection, these tests will be followed by viral load assessment (HBV DNA and HCV 
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Patients who have detectable HBV DNA at screening will perform the viral load test every 4 
cycles starting at Cycle 5. 
8.3. 
Tumor and Response Evaluations 
Tumor imaging will be performed ≤ 28 days before the first dose of study drug(s). Results of 
standard-of-care tests or examinations performed before informed consent has been obtained 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. During the study, tumor imaging will be performed 
every 8 weeks (± 7 days), from Day 1 of Cycle 1, for the first 56 weeks, then every 12 weeks 
(± 7 days) thereafter based on RECIST v1.1 (Appendix 12). If a tumor assessment is missed or 
conducted outside of the specified assessment window, all subsequent scans should be conducted 
according to the planned schedule. 
Screening assessments and each subsequent tumor assessment must include computed 
tomography (CT) scans (with oral/intravenous contrast, unless contraindicated) or magnetic 
resonance imaging (MRI) of the chest, abdomen, and pelvis. Other known or suspected sites of 
disease must be included in the imaging assessments (neck, brain, etc). 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit 
and reassessed at each subsequent tumor evaluation. The same radiographic procedure used to 
assess disease sites at screening must be used throughout the study (eg, the same contrast 
protocol for CT scans).  
• Imaging of the brain (MRI or CT) at baseline is required for all screened NSCLC 
patients. 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a noncontrast CT of the chest plus a contrast-
enhanced MRI (if possible) of abdomen and pelvis should be performed. 
• If a CT scan for tumor assessment is performed 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. 
• CT scans of the neck or extremities should be performed at screening, only if 
clinically indicated, and should be followed throughout the study if there is evidence 
of metastatic disease in these regions at screening.  
• At the investigator’s discretion, other methods of assessment of target lesion and 
nontarget lesions per RECIST Version 1.1 may be used. 
Response will be assessed by the investigator using RECIST v1.1 (see Appendix 12). The same 
evaluator should perform assessments, if possible, to ensure internal consistency across visits.  


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After first documentation of response (CR or partial response [PR]), confirmation of tumor 
response should occur at 4 weeks or later after the first response or at the next scheduled 
assessment timepoint. 
For immune therapies such as tislelizumab, pseudoprogression may occur due to immune-cell 
infiltration and other mechanisms leading to an apparent increase of existing tumor masses or 
appearance of new tumor lesions. Also, some patients may benefit from additional immune 
therapies or anti-angiogenic therapies despite evidence of PD. The following criteria must be met 
to treat patients with suspected pseudoprogression or confirmed evidence of PD:  
• Absence of clinical symptoms and signs of PD (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 
PD and inform patients that this practice is not considered standard in the treatment of 
cancer.  
• The decision to continue study drug(s) beyond initial investigator-assessed 
progression must be agreed to with the 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. 
A patient who discontinues study drug(s) early for reasons other than PD (eg, toxicity) will 
continue to undergo tumor assessments following the original plan until the patient begins a new 
anticancer therapy, experiences PD, withdraws consent, is lost to follow-up, dies, or until the 
study terminates, whichever occurs first. 
Tumor assessments must be performed on schedule regardless of whether study treatment has 
been administered or withheld. That is, they should not be adjusted for delays in cycles. 
8.4. 
Pharmacokinetic Assessment and Antidrug Antibody Testing 
Blood sampling for the PK of tislelizumab and fruquintinib will be collected at the timepoints 
specified in the Schedule of PK Assessments (Appendix 2).   
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 (see 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. This tiered strategy 
will include an assessment of whether ADA responses correlate with relevant clinical endpoints.  
Implementation of ADA characterization assays will depend on the safety profile and clinical 
immunogenicity data. 


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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 
• PK assays: serum samples will be assayed for tislelizumab concentration with use of 
a validated immunoassay and the plasma concentration of fruquintinib will be 
assayed using the validated LC-MS/MS method by request from the sponsor.  
Shipping, storage, and handling of samples for the assessment of PK and ADA assays will be 
managed through a central laboratory. Instruction manuals and supply kits will be provided for 
all central laboratory assessments. 
Refer to the laboratory manual for instructions regarding sample collection, handling, labeling, 
storage, and shipping of laboratory samples to the central laboratory. 
8.5. 
Biomarkers 
Instructions for the processing, storage, and shipping of samples will be provided in the study 
laboratory manual. Refer to the Schedule of Assessments (Appendix 1) for sample collection 
timepoints. 
Archival tumor tissues (formalin-fixed paraffin-embedded [FFPE] blocks or approximately 
15 freshly cut unstained FFPE slides) need to be sent for central laboratory assessment of MSS 
status (MSI test) for the CRC patients, PD-L1 status for the NSCLC patients, for central/local 
laboratory assessment of EGFR status for the non-squamous NSCLC patients with no EGFR 
documentation during the screening period, and for retrospective analysis of other exploratory 
biomarkers related to response and resistance for all patients in a BeiGene-designated central or 
test laboratory. These exploratory biomarkers include but are not limited to PD-L1, TMB/DNA 
mutation, and GEP for all enrolled patients, and EBV, MSS/MSI status (TMB panel can report 
the MSS/MSI status) for the GC patients. Submission of < 15 unstained slides is not a protocol 
deviation. 
A fresh tumor biopsy at a tumor lesion is mandatory if there are no available archival tumor 
samples during the screening period. Optional fresh biopsies in patients who have confirmed PD 
will also be collected in the three cohorts during the study from accessible tumor sites. If 
feasible, any follow-up biopsy should ideally be taken from the same tumor lesion as the baseline 
biopsy. Written patient consent is required for fresh tumor biopsies. 
For fresh biopsies, acceptable samples include core needle biopsies for nonsuperficial tumor 
tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions. Tumor tissue should be of good quality based on total and viable tumor content. 
Fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable. 
Approximately 2 mL of peripheral whole blood will be required for collection to work as the 
MSI test control during the screening period for CRC patients. Blood samples will be obtained 
for the evaluation of exploratory biomarkers including, but not limited to bTMB/DNA mutation 
for all enrolled patients, which will be collected at baseline (Predose on Cycle 1 Day 1, 
required), at the time of first tumor response (Predose on Day 1 of the following cycle, optional), 


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and at the time of progressive disease (optional) (approximately 10 mL for each timepoint). 
Written patient consent is required for blood sample collections. 
8.6. 
Visit Windows 
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see 
Appendix 1). All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed before study treatment administration, 
unless otherwise noted. Laboratory results must 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 for the nearest feasible date (the visit window is provided in 
Appendix 1), with subsequent visits conducted according to the planned schedule every 4 weeks 
from Day 1 of Cycle 1. 
8.7. 
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 clinical 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 PD, 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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9. 
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. 
9.1. 
General Plan to Manage Safety Concerns 
9.1.1. 
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this study. Results from the 
nonclinical toxicology studies and clinical data with tislelizumab and fruquintinib, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors and anti-VEGFR TKIs, 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 the 
first dose of study drug(s) are excluded from the study. Patients with contraindications for 
fruquintinib treatment are also excluded from the study (see Section 4.2 for the full list of 
exclusion criteria). 
9.1.2. 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 x baseline value) in combination with either an 
elevated total bilirubin (> 2 x ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. Therefore, 
investigators must report as an AE the occurrence of either of the following: 
• Treatment-emergent ALT or AST > 3 x baseline value in combination with total 
bilirubin > 2 x ULN (of which 35% is direct bilirubin) 
• Treatment-emergent ALT or AST > 3 x baseline value in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory 
values should be recorded on the AE eCRF and reported to the sponsor immediately (ie, no more 
than 24 hours after learning of the event). 
9.1.3. 
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 4), physical examinations, laboratory measurements 
(hematology, clinical 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. 


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At the start of each cycle, study drug(s) will be administered only 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 (for additional information, see Section 5.1.1). 
Serum samples will be drawn for determination of ADAs to tislelizumab in patients.  
Investigators are instructed to report all AEs (includes 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 9.6. 
9.2. 
Adverse Events 
9.2.1. 
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 study 
drug(s), whether considered related to study drug(s) or not. 
Examples of AEs include:  
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome 
• Detection or diagnosis of a new condition after study drug(s) administration even 
though the condition might 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(s) 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. 
9.2.2. 
Assessment of Severity 
The investigator will assess the severity for each AE and SAE reported during the study. AEs 
and SAEs should be assessed and graded based upon NCI-CTCAE Version 5.0. 
Toxicities that are not specified in 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 


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• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(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 9.5.2. 
9.2.3. 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug(s) 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(s) should be considered and investigated. The 
investigator should consult the tislelizumab (BGB-A317) and the fruquintinib Investigator’s 
Brochure 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(s) (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(s) 
• Biological plausibility 


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• An AE should be considered “related” to study drug(s) 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[s]). However, the 
influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs). 
9.2.4. 
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 timeframes outlined in Section 9.5.2. 


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9.2.5. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, clinical chemistry, complete blood count, 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 treatment 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.” 
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. 
9.3. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE 
that hypothetically might have caused death if it was more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
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. 


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• 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 one of the outcomes listed above) 
The following are NOT considered to be SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
9.4. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction is a serious adverse reaction that is both 
unexpected (ie, not present in the study drug’s reference safety information) and meets the 
definition of a serious adverse drug reaction, the specificity or severity of which is not consistent 
with those noted in the tislelizumab (BGB-A317) and the fruquintinib Investigator’s Brochure. 
9.5. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events 
9.5.1. 
Adverse Event Recording Period 
After informed consent has been signed but before the administration of the study drug(s), only 
SAEs should be reported. 
After the first dose of study drug(s), all AEs and SAEs, regardless of relationship to study drugs, 
will be reported until either 30 days after last dose of study drug(s) (including fruquintinib) 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 4. For the follow-up period 
for AEs, see Section 9.2.4. For the definition of treatment-emergent adverse events (TEAEs), see 
Section 10.3.3. 


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Table 4: 
Guidance for Duration of Recording New or Worsening Adverse Events  
Event Type 
Record new or worsening events that occur during this period 
Begin 
End 
SAEsa 
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 9.5.4) 
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. 
9.5.2. 
Reporting Serious Adverse Events 
9.5.2.1. 
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 5. 
Table 5: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Timeframe for sending 
initial/Follow-up*1 
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*2 
Abbreviations: IMP, investigational medical product, SAE, serious adverse event.  
*1. Report follow-up information clinically relevant and pertaining to the SAE which includes but 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 IMP. Follow-up information will also be reported as per the 
discretion of the investigator if the new or updated information changes the medical assessment of the case. 
 


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*2. 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. 
9.5.2.2. 
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 9.5.2.1. The SAE report 
will always be completed as thoroughly as possible, including all available details of the event 
and forwarded to the sponsor or designee within the designated timeframes. 
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 9.2.3. 
The sponsor will provide contact information for SAE receipt. 
9.5.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will report all SAEs to the sponsor in accordance with the procedures detailed in 
Section 9.5.2.1. The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a drug 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 suspected unexpected serious adverse reactions (as defined in Section 9.4) will be submitted 
to all applicable regulatory authorities and investigators for tislelizumab and fruquintinib studies. 
When a study center receives an initial or follow-up safety report or other safety information 
(eg, revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC. The investigator should place copies of 
safety reports from the sponsor in the investigator site file. 
9.5.3. 
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? 


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9.5.4. 
Progressive Disease 
PD, 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 PD should not 
be recorded. However, if there is any uncertainty as to whether a nonserious AE is due to PD, it 
should be recorded as an AE. All SAEs and deaths regardless of relatedness to PD should be 
recorded and reported. 
9.5.5. 
Deaths 
Death is an outcome and not usually considered an event. If the only information available is 
death and the cause of death is unknown, then the death is reported as an event (eg, “death,” 
“death of unknown cause,” or “death unexplained”). 
9.5.6. 
Recording Pregnancies 
If a female patient or the partner of a male patient becomes pregnant while receiving study 
drug(s) or within 120 days after the last dose of study drug(s), a pregnancy report form must 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 always be reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug(s) should be recorded and reported as an SAE. 
9.5.7. 
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 documents: 
• tislelizumab (BGB-A317) Investigator’s Brochure  
• fruquintinib Investigator’s Brochure  
9.5.8. 
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 related (see Section 9.6.3) should be classified as imAEs and 
identified as such in the eCRF AE page.  


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Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 9. 
An extensive list of potential imAEs appears in Table 7. 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 9. 
9.5.9. 
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. Individual signs 
and symptoms of an infusion reaction should be recorded each as a separate AE in the eCRF and 
identified as an infusion-related reaction. Refer to the eCRF completion guidelines for details. 
9.6. 
Management of Adverse Events of Special Interest for Tislelizumab 
As a routine precaution, following completion of tislelizumab administration, patients must be 
monitored for a period afterward in a setting where emergency medical equipment and staff who 
are trained to respond to medical emergencies are available. 
The management for infusion-related reactions, severe hypersensitivity reactions, and imAEs 
according to the NCI-CTCAE criteria are outlined in the following subsections. 
9.6.1. 
Managing Infusion-Related Reactions 
Patients should be closely monitored for infusion-related reactions. Immediate access to an 
Intensive Care Unit 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 tislelizumab are 
provided in Table 6. 
Table 6: 
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, 
nonsteroidal anti-inflammatory drugs, 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 in the 
text following this table.  
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 


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NCI-CTCAE grade 
Treatment modification for tislelizumab  
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 in the 
text following this table. 
The patient should be withdrawn from study drug 
treatment. 
Grade 4 – life-threatening 
Life-threatening consequences; urgent intervention 
indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described in the 
text following this table. 
The patient should be withdrawn from study drug 
treatment. 
Hospitalization is recommended. 
Abbreviations: NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events. 
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 premedication must be 
administered. If the patient has a second infusion-related reaction (≥ Grade 2) on the slower 
infusion rate, the 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, the patient should receive oral premedication with an 
antihistamine (eg, diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or 
equivalent), and the patient should be closely monitored for clinical signs and symptoms of an 
infusion reaction. 
NCI-CTCAE Grade 3 or 4 infusion reaction: Proper medical management should be instituted 
immediately, as indicated per type and severity of the reaction. This includes but is not limited to 
oral or intravenous antihistamines, antipyretics, glucocorticoids, epinephrine, bronchodilators, 
and oxygen. 
9.6.2. 
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 (United Kingdom) 
(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 stopped 
immediately 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 are 
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. 


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The patient will be administered epinephrine injection and dexamethasone infusion if 
hypersensitivity reaction is observed. The patient should then be placed on monitor immediately 
and an Intensive Care Unit should be alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drug infusion. 
Alternative treatments for fever (ie, paracetamol) may be administered to the patient at the 
discretion of the investigator. 
9.6.3. 
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, PD, 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 7. All conditions similar to those listed should 
be evaluated in patients receiving tislelizumab to determine whether they are immune related. 
Recommendation for diagnostic evaluation and management of imAEs is based on European 
Society for Medical Oncology and American Society of Clinical Oncology guidelines 
(Haanen et al 2017; Brahmer et al 2018) and common immune-mediated toxicities are detailed in 
Appendix 9. For any AEs not included in Appendix 9, please refer to the American Society of 
Clinical Oncology Clinical Practice Guideline (Brahmer et al 2018) for further guidance on 
diagnostic evaluation and management of immune-mediated toxicities. 
Table 7: 
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-Barre syndrome; aseptic meningitis; 
myasthenic syndrome/myasthenia gravis; meningoencephalitis; myositis 
Blood 
anemia; leukopenia; thrombocytopenia 


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Body system affected 
Events 
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 9. 
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. 
9.7. 
Management of Adverse Events of Special Interest for Fruquintinib 
The AE management guidance for important identified risks for fruquintinib are provided below. 
(Table 8). 
Table 8: 
Management of Adverse Events Related to Fruquintinib  
AE Grading Standard  
Dose Adjustment  
Treatment Suggestions  
Palmar-Plantar Erythrodysethesia  
Grade 1: numb, paresthesia, 
dysesthesia, erythema, painless 
edema, desquamation, thicken 
skin and hand and foot 
discomfort which does not 
affect the normal activities; 
without any pain  
None.  
Active supportive treatment can be 
adopted to relieve the symptoms; for 
example, moisturizing skin cream, 
lotion, or hydrophilic urea ointment 
can be used.  
Grade 2: erythema with pain 
accompanied by hand and foot 
swelling and /or discomfort, 
which affects normal activities  
• Hold treatment.  
• If the AE recovers to Grade 1 or 
baseline level within 14 days, 
resume treatment at the same 
dose level.  
Active supportive treatment can be 
adopted to relieve the symptoms; for 
example, moisturizing skin cream, 
lotion, or hydrophilic urea ointment 
can be used.  
Grade 3: wet desquamation, 
ulcer, blister or severe hand and 
foot pain or severe discomfort, 
which affects work or normal 
activities.  
• Hold treatment.  
• If the AE recovers to Grade 1 or 
baseline level within 14 days, 
resume treatment with a dose 
reduction to the next lower dose 
level.  
Active supportive treatment can be 
adopted to relieve the symptoms; 
Should the same AE occur for 
3 times or still occurs after 2 times of 
dose reduction, the drug should be 
terminated. 
Proteinuriaa  
Grade 1: Proteinuria 1+ by 
urinalysis;  
24-hour urine protein 
quantitation < 1.0 g  
None  
Follow up at scheduled study visits.  
Grade 2: Proteinuria 2+ by the 
urinalysis;  
None  
Provide supportive treatment and 
increase the frequency of urine 
monitor to once a week; consult 
nephrologist if necessary.  


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AE Grading Standard  
Dose Adjustment  
Treatment Suggestions  
24-hour urine protein 
quantitation is between 1.0 to 
< 2.0 g  
Grade 2: Proteinuria 2+ or 
above by urinalysis;  
24-hour urine protein 
quantitation is between 2.0 to 
< 3.5 g (excluding 3.5 g)  
• Hold treatment.  
If the AE recovers to Grade 1 or 
baseline level within 14 days, 
resume treatment with a dose 
reduction to the next lower dose 
level.  
Provide supportive treatment and 
increase the frequency of urine 
monitor to once a week; consult 
nephrologist if necessary.  
Grade 3: 24-hour urine protein 
quantitation ≥ 3.5 g  
• Hold treatment.  
• If the AE recovers to Grade 1 or 
baseline level within 14 days, 
resume treatment with a dose 
reduction to the next lower dose 
level.  
Provide supportive treatment and 
increase the frequency of urine 
monitor to once or twice a week; 
consult nephrologist if necessary. 
Should the same AE occur for 3 
times or still occurs after 2 times of 
dose reduction, the drug should be 
terminated.  
Hypertension  
Grade 1: prehypertension  
(systolic BP 120-139 mmHg or 
diastolic BP 80-89 mmHg)  
None.  
Follow up as planned schedule  
Grade 2: SBP 140-159 mmHg 
or DBP of 90-99 mmHg; or 
DBP symptomatic increase 
> 20 mmHg  
None.  
Treatment objective: lower the blood 
pressure to < 140/90 mm Hg (or 
< 130/80 mm Hg in patients with 
chronic renal disease and/or 
diabetes).  
Refer to Appendix 15.  
Grade 3: SBP ≥ 160 mmHg or 
DBP ≥ 100mmHg; or more 
than one drug or more intensive 
therapy are used  
• If BP > 160/100 mmHg lasts for 
> 7 days after initiation of anti-
hypertensive treatment or 
modification of current anti-
hypertensive treatment, 
treatment should be held.  
• If hypertension resolves to 
Grade 1 or baseline level within 
14 days, resume treatment with 
a dose reduction to the next 
lower dose level.  
Treatment objective: lower the blood 
pressure to < 140/90 mmHg (or 
< 130/80 mm Hg in patients with 
chronic renal disease and/or 
diabetes).  
Refer to Appendix 15.  
Grade 4: Life threatening (eg, 
malignant hypertension, 
temporary or permanent 
neurological deficits and 
hypertensive crisis)  
Permanently discontinue study 
treatment.  
Emergent medical treatment.  
Decreased Platelet Count  
Grade1:  Platelet count 
< LLN - 75,000/ mm3;  
None 
Perform follow up visit as scheduled.  
 


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AE Grading Standard  
Dose Adjustment  
Treatment Suggestions  
< LLN - 75.0 ×109/L 
Grade 2:  
Platelet count < 75,000-
50,000/mm3;  
< 75.0 - 50.0 ×109/L  
• Hold treatment.  
• If the AE recovers to Grade 1 or 
baseline level within 7 days, 
resume treatment at the same 
dose level.  
Hematology test should be monitored 
every 2-3 days; active treatment for 
platelet elevation is recommended.  
 
 
• Hold treatment.  
• If the AE recovers to Grade 1 or 
baseline level within 14 days, 
resume treatment with a dose 
reduction to the next lower dose 
level.  
Hematology test should be monitored 
every 2-3 days; active treatment for 
platelet elevation is recommended.  
Grade 3:  
Platelet count < 50,000 - 
25,000/mm3;  
< 50.0 - 25.0 × 109/L  
• Hold treatment.  
• If the AE recovers to Grade 1 or 
baseline level within 14 days, 
resume treatment with a dose 
reduction to the next lower dose 
level.  
 
Hematology test should be monitored 
every 2-3 days; active treatment 
(platelet transfusion) to elevate the 
platelet count is recommended.  
Hematology examination should be 
performed once every week in the 
follow up visit.  
Grade 4:  
Platelet count < 25,000/mm3;  
< 25.0 × 109/L  
Permanently discontinue study 
treatment.  
Hematology test should be performed 
once daily until the AE recovers to 
Grade 2 or a lower grade; platelet 
transfusion or other active treatment 
should be provided  
Hemorrhage at Any Site  
Grade 1  
None  
Perform follow up visit as scheduled.  
Grade 2  
• Hold treatment.  
• If the AE recovers to Grade 1 or 
baseline level within 14 days, 
resume treatment with a dose 
reduction to the next lower dose 
level.  
Provide active treatmentc  
Grade 3 or aboveb  
Permanently discontinue study 
treatment.  
Emergent medical interventionc  
Abnormal Liver Functiond  
Grade 1  
None.  
Follow up per planned schedule.  
Grade 2 or 3 (Liver function is 
abnormal but the biochemical 
criteria for Hy’s Lawe are not 
met)  
• Hold treatment.  
• If the AE recovers to Grade 1 or 
baseline level within 14 days, 
resume treatment with a dose 
reduction to the next lower dose 
level.  
Provide supportive care and increase 
the frequency of liver function 
monitoring to 1-2 times a week.  


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AE Grading Standard  
Dose Adjustment  
Treatment Suggestions  
Grade 2 or 3 (Liver function is 
abnormal and the biochemical 
criteria for Hy’s Lawe are met)  
The study drug should be 
terminated immediately.  
Provide supportive care and increase 
the frequency of liver function 
monitoring to 2-3 times a week. 
Urgent medical intervention 
indicated.  
Grade 4  
The study drug should be 
terminated.  
Urgent medical intervention 
indicated.  
a. 
If protein ≥ 2+ on urinalysis during the study, a 24-hour urine test should be conducted within 1 week, and 
dose modification will be done by the result of 24-hour urine protein quantitation.  
b. Refer to Appendix 14 for clinical management of severe or serious hemorrhage. 
c. 
The investigator should closely monitor patients receiving anti-platelet and/or anti-thrombotic drugs 
during study drug treatment and make a timely decision on whether to continue or stop such drugs in 
patients that report ≥ Grade 2 hemorrhagic events at any site, based on an individual assessment of the 
risk-benefit balance (See Section 6.2). 
d. Including increasing of ALT, AST, and total bilirubin, whether or not the biochemical criteria for Hy’s 
Law have been met. 
e. 
Hy’s Law is an increase in serum AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN, and no 
other reason can be found to explain the biochemical changes, for example, new or worsening 
hepatobiliary metastases, elevated serum alkaline phosphatase indicating cholestasis, viral hepatitis, 
another suspect drug, or any other specific cause of severe hepatocellular injury. The elevation in 
transaminases must precede or be coincident with (ie, on the same day as) the elevation in total bilirubin, 
but there is no specified timeframe within which the elevations in transaminases and total bilirubin must 
occur. See Appendix 13 for additional information regarding Hy’s Law. 


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10. 
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 Statistical Analysis Plan (SAP). 
10.1. 
Statistical Analysis 
10.1.1. 
General Consideration 
For qualitative variables, the population size (N for sample size and n for available data) and the 
percentage (of available data) for each class of the variable will be presented. Quantitative 
variables will be summarized using descriptive statistics, including N, mean, standard deviation, 
median, minimum, and maximum values. Geometric mean and geometric coefficient of variation 
(CV) % will be included for PK parameters, where applicable. Coefficient of variation will not 
be presented for change-from-baseline results. 
All derivations, statistical analyses, summaries, and listings will be generated using SAS 
Version 9.2 or higher. Graphics may be prepared using the same versions of SAS, or with 
SigmaPlot 12.5, or higher. 
10.1.2. 
Analysis Sets 
The Safety Analysis Set (SAS) includes all patients who received ≥ 1 dose of study drug(s). This 
will be the analysis set for the safety and efficacy analyses. 
The Evaluable Analysis Set (EAS) includes all patients who received ≥ 1 dose of study drug(s), 
have evaluable disease at baseline, and have ≥ 1 evaluable postbaseline tumor response 
assessment unless any clinical PD or death occurred before the first postbaseline tumor 
assessment. 
The DLT Evaluable Analysis Set includes all patients who received at least 85% of the assigned 
total dose of fruquintinib and at least 67% (approximately two-thirds) of the assigned total dose 
of tislelizumab for the DLT assessment period. Additionally, patients who had a DLT event will 
also be considered evaluable. Only patients from Part 1 are eligible for inclusion in the DLT 
Evaluable Analysis Set. This will be the analysis set for the DLT analyses. 
The PK Analysis Set includes all patients who received ≥ 1 dose of study drug(s) and have 
≥ 1 quantifiable postbaseline PK data.  
The ADA Analysis Set includes all patients who received ≥ 1 dose of study drug(s) and have a 
baseline and at least 1 postbaseline ADA result. 


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10.1.3. 
Patient Disposition 
The number of patients that were treated, were discontinued from study drug(s) and/or the study, 
and were recorded with important protocol deviations will be counted in SAS. The primary 
reason for study drug(s) and/or study discontinuation will be summarized according to the 
categories in the eCRF. The end-of-study status (alive, dead, withdrew consent, or lost to follow-
up) at the data cutoff date will be summarized using the data from the eCRF. Patient disposition 
will be summarized overall and by tumor types. 
Important protocol deviations will be summarized and listed by category. 
10.1.4. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the Safety Analysis Set 
using descriptive statistics. 
Baseline patient characteristics will include a summary of the following: 
• Patient demographic 
• Baseline disease characteristics  
• Prior anticancer therapies  
Continuous variables include age, weight, height, time since initial cancer diagnosis, and time 
since advanced/metastatic disease diagnosis. Categorical variables include gender, ECOG, 
Performance Status, race, TNM staging, number of prior system therapies received, and tumor 
type. Demographic and baseline characteristics will be summarized overall and by tumor types. 
Other patient characteristics will be summarized as deemed appropriate. 
10.1.5. 
Prior and Concomitant Medications 
Prior medications will be defined as medications that stopped before the day of first dose of 
study drug(s). Concomitant medications will be defined as medications that 1) started before the 
first dose of study drug(s) and were continuing at the time of the first dose of study drug(s), or 
2) started on or after the date of the first dose of study drug(s) up to 30 days after the patient’s 
last dose (as of the Safety Follow-up Visit). In addition, concomitant medication associated with 
an imAE or that is a new anticancer therapy at 60 and 90 days after the last dose of study drug(s) 
regardless of whether or not the patient starts a new anticancer therapy, may also be included as 
part of the analysis where applicable. Any steroid use will be also included in the analysis where 
applicable. Concomitant medications will be coded using the World Health Organization Drug 
Dictionary drug codes and will be further coded to the appropriate Anatomical Therapeutic 
Chemical code indicating therapeutic classification. Prior and concomitant medications will be 
summarized and listed by drug and drug class. Prior and concomitant medication will be 
summarized overall and by tumor types. A listing of prior and concomitant medications will be 
provided. 
10.2. 
Efficacy Analyses 
No formal hypothesis testing is planned in this trial. 


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10.2.1. 
Primary Efficacy Analysis 
10.2.1.1. Overall Response Rate 
The ORR is defined as the proportion of patients who had confirmed CR or PR as determined by 
the investigator using RECIST v1.1 in the Safety Analysis Set. ORR will be summarized for 
descriptive purposes in SAS. A two-sided Clopper-Pearson 95% CI of ORR will be constructed. 
ORR will be summarized based on patients from the RP2D dose level in overall and by tumor 
types. Additional summaries will be based on all dose levels in overall and by tumor types if 
necessary. 
Best overall response (BOR) is defined as the best response recorded from the start of study 
drug(s) until data cut or start of new anti-cancer therapy. Patients with no postbaseline response 
assessment (due to any reason) will be considered non-responders for BOR. The proportion and 
its corresponding Clopper-Pearson 95% CI for each of the response categories (CR, PR, SD, and 
PD) will be presented. BOR will be summarized based on patients from the RP2D dose levels in 
overall and by tumor types. Additional summaries will be based on all dose level in overall and 
by tumor types if necessary. 
Outcomes in the Evaluable Analysis Set will be evaluated as a sensitivity analysis. 
10.2.2. 
Secondary Efficacy Analysis 
10.2.2.1. Progression-free survival 
PFS assessed by the investigators per RECIST v1.1 will be estimated using the Kaplan-Meier 
method in the Safety analysis set. The Kaplan-Meier estimates of PFS will be plotted over time. 
PFS at selected time points will be estimated with its 95% CI using Greenwood’s formula. The 
corresponding quantiles (including the median), if estimable, will also be estimated using 
Kaplan-Meier method. Two-sided 95% CIs of median, if estimable, will be constructed with 
generalized Brookmeyer and Crowley method (Brookmeyer and Crowley 1982). PFS censoring 
rule will follow the US FDA Guidance for Industry Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics (2018). PFS will be summarized based on patients from the RP2D 
dose level in overall and by tumor types. Additional summaries will be based on all dose levels 
in overall and by tumor types if necessary. 
10.2.2.2. Disease control rate 
DCR assessed by the investigator per RECIST v1.1 will be summarized in a similar way as 
ORR.  
10.2.2.3. Clinical benefit rate 
CBR assessed by the investigator per RECIST v1.1 will be summarized in a similar way as ORR.  
10.2.2.4. Duration of response 
DOR by the investigator per RECIST v1.1 will be similarly analyzed only in responders in 
Safety Analysis Set using the Kaplan-Meier method as described above. The statistical method 
applied to DOR is similar to the analysis described in Section 10.2.2.1.  


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10.2.2.5. Overall Survival 
The OS is defined as the time from the date of first dose of study treatment until the date of death 
due to any cause. The statistical methods applied to OS is similar to the analysis described in 
Section 10.2.2.1. 
10.3. 
Safety Analyses 
Safety will be determined by the reporting of AEs and by laboratory values (hematology, clinical 
chemistry, coagulation, and urinalysis). Vital signs, physical examinations, and ECG findings 
will also be used in determining the safety profile. The severity of AEs will be graded according 
to NCI-CTCAE v5.0. Descriptive summary statistics will be used to analyze all safety data in the 
Safety Analysis Set. Safety analysis will be based on the summary of overall and by dose level. 
Additional safety analyses will also be summarized based on tumor types if necessary.  
10.3.1. 
Dose-Limiting Toxicity Analysis 
DLTs during the DLT assessment period will be used to determine safety and tolerability of 
tislelizumab in combination with fruquintinib. The DLT events will be summarized descriptively 
in the DLT Evaluable Analysis Set. 
10.3.2. 
Extent of Exposure 
Extent of exposure to tislelizumab and fruquintinib will be summarized descriptively as the 
number of cycles received (number and percentage of patients), duration of exposure (days), 
cumulative total dose received per patient (mg), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring treatment interruption, dose delay, dose reduction, 
or drug discontinuation because of AEs will be summarized for each study drug. Reasons for 
dose modifications will be summarized as well. 
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
10.3.3. 
Adverse Events 
The AE verbatim descriptions (investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA lowest level term, preferred term, and primary system 
organ class. 
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(s) and up to 30 days following study 
drug(s) discontinuation or initiation of new anticancer therapy, whichever occurs first. The 
TEAE classification also applies to imAEs that are recorded up to 90 days after discontinuation 
from tislelizumab, regardless of whether or not the patient starts a new anticancer therapy. Only 
those AEs that were treatment emergent will be included in summary tables. All AEs, treatment 
emergent or otherwise, will be presented in patient data listings. 


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The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
system organ class and preferred term. A patient will be counted only once by the highest 
severity grade per NCI-CTCAE v5.0 within a system organ class and preferred term, even if the 
patient experienced ≥ 1 TEAE within a specific system organ class and preferred term. The 
number (percentage) of patients with TEAEs will also be summarized by relationship to the 
study drug(s).  
Treatment-related AEs include those events considered by the investigator to be related to study 
treatment or with missing assessment of causal relationship. SAEs, deaths, ≥ Grade 3 TEAEs, 
imAEs, treatment-related TEAEs, and TEAEs that led to treatment discontinuation, treatment 
interruption, dose reduction, or dose delay will be summarized. 
10.3.4. 
Laboratory Analyses 
Clinical laboratory (eg, hematology, clinical chemistry, coagulation, and urinalysis) values will 
be evaluated for each laboratory parameter as appropriate. Abnormal laboratory values will be 
flagged and identified as those outside (above or below) the normal range. Reference (normal) 
ranges for laboratory parameters will be provided. Descriptive summary statistics (eg, n, mean, 
standard deviation, median, minimum, and maximum for continuous variables; n [%] for 
categorical variables) for laboratory parameters and their changes from baseline will be 
calculated. Laboratory values will be summarized by visit and by visit with the maximum 
postbaseline change. 
Laboratory parameters that are graded by NCI-CTCAE v5.0 or higher will be summarized by 
NCI-CTCAE grade. In the summary of laboratory parameters by NCI-CTCAE grade, parameters 
with NCI-CTCAE grading in both high and low directions (eg, calcium, glucose, magnesium, 
potassium, and sodium) will be summarized separately. 
10.3.5. 
Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse rate, 
respiration rate and body temperature) and changes from baseline will be presented by visit for 
all visits. Vital signs will be listed by patient and visit. 
10.3.6. 
Pulmonary Function Test 
Descriptive statistics for pulmonary function test result will be presented overall and by visit.  
10.4. 
Pharmacokinetic Analyses 
Blood samples will be collected for tislelizumab PK evaluation at postdose and trough (Ctrough). 
The serum concentration data will be tabulated and summarized by the visit/cycle at which these 
samples are collected. For fruquintinib, serial PK samples will be collected for part 1 and sparse 
samples will be collected for part 2. Plasma fruquintinib concentration data will be summarized 
using descriptive statistics, C-T profiles, and other plots as appropriate. The corresponding PK 
parameters of fruquintinib will be calculated as data permit.  


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10.5. 
Immunogenicity Analyses 
The immunogenicity results for tislelizumab 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.  
10.6. 
Other Exploratory Analyses 
Potential biomarkers including but not limited to PD-L1 expression, TMB and DNA 
mutation/bTMB and DNA mutation, GEP in the GC, MSS-CRC and NSCLC cohorts, EBV in 
the GC cohort, MSS/MSI status in the GC cohort, and the association of biomarkers with disease 
status or response/resistance to tislelizumab in combination with fruquintinib may be explored.  
Exploratory biomarker analyses will be performed in an effort to understand the association of 
these markers with study drug(s) response, such as efficacy and resistance.  
10.7. 
Sample Size Consideration 
Approximately 6 to 12 DLT evaluable patients will be enrolled at Part 1. Patients enrolled in 
Part 1 at RP2D will be counted towards Part 2 by the diagnosis of tumor types. Approximately 
96 patients will be enrolled at maximum, and about 30 patients will be enrolled at RP2D per 
cohort to evaluate the preliminary efficacy, safety, and clinical pharmacokinetics.  
The study plans to enroll approximately 90 patients at RP2D according to the business 
agreement: 
• Cohort A:  Gastric cancer (n = 30) 
• Cohort B:  Colorectal cancer (n = 30) 
• Cohort C:  Non-small cell lung cancer (n = 30) 
No formal hypothesis testing is planned in this trial.  
The 95% CIs when observing different numbers of responders among 30 patients in each cohort 
are presented in Table 9. 
Table 9: 95% CI (%) When Observing Different Number of Responders in 30 Patients 
Number of responders 
(ORR observed) 
2 (6.7%) 
3 (10.0%) 
5 (16.7%) 
6 (20.0%) 
8 (26.7%) 
9 (30.0%) 
(95% CI) (%) 
(0.82, 
22.07) 
(2.11, 
26.53) 
(5.64, 
34.72) 
(7.71, 
38.57) 
(12.28, 
45.89) 
(14.73, 
49.40) 
Abbreviations: CRC, colorectal cancer; GC, gastric cancer; MSS, microsatellite stable; NSCLC, non-small cell lung 
cancer; ORR, overall response rate. 
Notes: The historical response rate for the standard of care (SOC) in each cohort are the following: 
ORR data of the SOC for 3rd line MSS CRC: fruquintinib (4.7%, Li et al 2018) / regorafenib (4%, Li et al 2015)  
ORR data of the SOC for 2nd line GC: paclitaxel (16%) (Wilke et al 2014). 
ORR data of the SOC for 1st line PD-L1+ NSCLC: pembrolizumab (27%) (Mok et al 2019)  
10.8. 
Interim Analyses 
Not applicable. 


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11. 
STUDY COMMITTEES 
11.1. 
Safety Monitoring Committee 
An SMC will be established and include both the sponsor (including the medical monitor and 
study team members from Pharmacovigilance/Drug Safety, Clinical Pharmacology, and 
Biostatistics with other members as appropriate) and investigators. The SMC will evaluate the 
safety and tolerability of the combination therapy and will review the safety information 
including but not limited to DLTs, all TEAEs, and laboratory abnormalities when the first 6 
patients have completed the first 28 days of treatment or when ≥ 2 DLTs occur. The SMC will 
make recommendations on safety management (including resumption of enrollment, or de-
escalation of fruquintinib dose to the next level, or termination of enrollment) and will assess the 
RP2D of the combination treatment. The SMC may also be called upon by the sponsor on an ad 
hoc basis where applicable to the conduct of the study. 


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12. 
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. 
12.1. 
Access to Information for Monitoring 
In accordance with International Council for Harmonisation GCP guidelines, the study monitor 
must have direct access to the investigator’s source documentation 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 in the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
12.2. 
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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13. 
QUALITY ASSURANCE AND QUALITY CONTROL 
13.1. 
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. 
13.2. 
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. 
13.3. 
Study Site Inspections 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study. 
13.4. 
Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug(s). This includes acknowledgment of receipt of each shipment 
of study drug(s) (quantity and condition), patient drug dispensation records, and returned or 
destroyed study drug(s). 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 site 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 for disposal specified in the 
Pharmacy Manual, arrangements will be made between the site and BeiGene or its representative 
for destruction or return of unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 


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14. 
ETHICS/PROTECTION OF HUMAN PATIENTS 
14.1. 
Ethical Standard 
This study will be conducted by the principal investigator and the study center in full 
conformance with the International Council for Harmonisation E6 guideline for GCP 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 International Council for Harmonisation E2A guideline 
(Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 
14.2. 
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 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. 
14.2.1. 
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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14.3. 
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. 
14.4. 
Patient and Data Confidentiality 
The principal investigator and sponsor will maintain confidentiality and privacy standards by 
following applicable data privacy laws covering the collection, storage, transmission, and 
processing of patients’ personal and medical information. 
The principal investigator shall code the medical information obtained during the study with a 
unique patient identification number assigned to each patient enrolled in the study. This approach 
ensures that patients’ names are not included in any data set transmitted to any sponsor location. 
Patient 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 the event of a breach of the confidentiality of a patient’s personal and medical information, the 
principal investigator and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable data privacy 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. 
Data generated during this study must be available for inspection upon request by representatives 
of the US FDA and China NMPA and all other national and local health authorities; by sponsor 
monitors, representatives, and collaborators; and by the IRBs/IECs for each study site, as 
appropriate. 


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The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. The investigator agrees that all information 
received from the sponsor, including but not limited to the tislelizumab (BGB-A317) and 
fruquintinib Investigator’s Brochures, this protocol, eCRFs, the Investigational New Drug, and 
any other study information, 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 includes confidentiality provisions inconsistent 
with this section is executed, that contract’s provisions shall apply to the extent they are 
inconsistent with this section. 
14.5. 
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 interests 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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15. 
DATA HANDLING AND RECORD KEEPING 
15.1. 
Data Collection and Management Responsibilities 
15.1.1. 
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. 
15.1.2. 
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. 
15.1.3. 
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 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 and 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 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 lowest level term, preferred term, and primary 
system organ class. 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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15.2. 
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, ICFs, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include but not be limited to 
documents such as 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. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and 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. 
At the conclusion of this study, biological samples may be retained as outlined in the agreement 
with the CRO managing the biological samples, for the shorter of a period of up to 10 years or as 
allowed by your IRB/IEC. 


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15.3. 
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 the 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. 
15.4. 
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 International Council for Harmonisation 
Guideline for Structure and Content of Clinical Study Reports (ICH E3). 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 2016). 
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 
publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 


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15.5. 
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/provide 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 regulations 
• Shipment of samples (including but not limited to those for PK, ADA, and 
biomarkers) to the assay laboratory for central laboratory analysis according to 
protocol and laboratory manual requirements 
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for any reason. 
Potential reasons for suspension or discontinuation include but are not limited to: safety or 
ethical issues or noncompliance with this protocol, GCP, the sponsor’s written instructions, the 
clinical study agreement, or applicable laws and regulations. If the sponsor determines such 
action is needed, the sponsor will discuss this with the investigator (including the reasons for 
taking such action) at that time. When feasible, the sponsor will provide advance notification to 
the investigator of the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons. The sponsor will also inform the 
regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action. If required by applicable regulations, the investigator must inform the 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. 
15.6. 
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. 
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. 


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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 15.4 
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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16. 
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JAMA. 2018;319(24):2486-2496.  


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Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients with 
advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 
2 trial. Lancet Oncol. 2019;20(5):711-18. 
McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of 
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Mok TSK, Wu YL, Kudaba I et al. Pembrolizumab versus chemotherapy for previously 
untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer 
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Morse MA, Hochster H, Benson A. Perspectives on Treatment of Metastatic Colorectal Cancer 
with Immune Checkpoint Inhibitor Therapy. Oncologist. 2020;25(1):33-45.  
Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive 
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National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in 
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17. 
APPENDICES 
 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
 
Screeninga 
Treatment cycles 
Safety 
follow-upc 
Survival 
follow-upd 
 
 
Cycle 1-2 
(28 days) 
≥ Cycle 3 
(every 28 days) 
EOT Visitb 
Visit day 
-28 to -1 
1 
15 
1 
0 to 7 days 
+ 30 days 
(visit) 
Every 3 
months 
Visit window 
 
± 3 
± 3 
± 3 
 
± 7 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Demographics/medical history/disease 
history 
X 
 
 
 
 
 
 
Vital signs/height and weighte 
X 
Xe 
X 
Xe 
X 
X 
 
Physical examinationf 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
 
12-lead ECGg 
X 
As clinically indicated 
X 
 
Adverse eventsh 
X 
X 
X 
X 
X 
X 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
 
Prior and concomitant procedures 
X 
X 
X 
X 
X 
X 
 
Hematologyi 
Xi 
X 
X 
Xi 
Xb 
X 
 
Clinical chemistryi 
Xi 
X 
X 
Xi 
Xb 
X 
 
CK and CK-MBj 
X 
X 
X 
X 
Xb 
X 
 
Coagulation parametersi 
Xi 
X 
X 
Xi 
Xb 
X 
 
Urinalysisi 
Xi 
X 
X 
X 
 
X 
 
Pregnancy testk 
X 
X 
 
X 
  
X 
 


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Screeninga 
Treatment cycles 
Safety 
follow-upc 
Survival 
follow-upd 
 
 
Cycle 1-2 
(28 days) 
≥ Cycle 3 
(every 28 days) 
EOT Visitb 
Visit day 
-28 to -1 
1 
15 
1 
0 to 7 days 
+ 30 days 
(visit) 
Every 3 
months 
Visit window 
 
± 3 
± 3 
± 3 
 
± 7 
Thyroid functionl 
X 
 
 
Cycles 4, 7, and 
every 3 cycles 
 
X 
 
HBV/HCV testsm 
Xm 
As clinically indicatedm 
 
 
Pulmonary function testsn 
Xn 
As clinically indicated 
 
Pharmacokinetics 
 
See Appendix 2 
 
Anti-tislelizumab antibodies 
 
See Appendix 2 
 
Blood biomarkerso 
X 
At baseline, time of response, and time of confirmed PDo 
 
 
 
Tumor assessmentp 
X 
Every 8 weeks (± 7 days) from Cycle 1 Day 1 for the first 
56 weeks, then every 12 weeks (± 7 days) thereafter 
Xb 
 
X 
Archival or fresh tumor tissueq 
X 
At time of confirmed PD 
 
 
 
Tislelizumab administrationr 
 
X 
 
X 
 
 
 
Fruquintinib administrations 
 
3 weeks on/1 week off 
 
 
 
Survival status 
 
 
 
 
 
X 
Abbreviations: AE, adverse event; CK, creatine kinase; CK-MB, creatine kinase-muscle/brain; CRC, colorectal cancer; CT, computed tomography; 
ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, End-of-Treatment (Visit); GC, gastric cancer; HBcAb, hepatitis B core antibody; 
HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; ICF, informed consent form; 
imAE, immune-mediated AE; MRI, magnetic resonance imaging; MSI, microsatellite instability; MSS, microsatellite stable; NCI-CTCAE, National Cancer 
Institute-Common Terminology Criteria for Adverse Events; NSCLC, non-small cell lung cancer; PD, progressive disease; RECIST, Response Evaluation 
Criteria in Solid Tumors; SAE, serious adverse event; TFTs, thyroid function tests; TSH, thyroid stimulating hormone; T3, triiodothyronine; T4, thyroxine. 
Note: Timepoints containing numbers represent timepoints with special considerations for that respective assessment. 
a. Written informed consent is required before performing any study-specific procedure. Results of standard-of-care tests or examinations performed before 
informed consent has been obtained and ≤ 28 days before the first dose of study drug(s) may be used for screening assessments rather than repeating such 
tests unless otherwise indicated. The ICF signature alone does not define the start of the screening period, but the first study-related assessment date is to be 
used for the date of the Screening Visit. 


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b. The EOT Visit is conducted ≤ 7 days after the investigator determines that the patient must permanently discontinue tislelizumab and fruquintinib. 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 EOT Visit did not occur until 30 days (± 7 days) or later 
after the last dose of study drugs, the EOT Visit may also be used as the Safety Follow-up Visit. 
c. Patients who permanently discontinue all study drugs will be asked to return to the clinic for the Safety Follow-Up Visit, which is required to be conducted 
within 30 days [± 7 days] after the last dose of study drugs or before the initiation of new anticancer therapy, whichever occurs first. The Safety Follow-up 
Visit may coincide with the EOT Visit (see Section 7.4) but cannot occur before the EOT Visit. In addition, telephone contacts with patients should be 
conducted to assess imAEs and concomitant medications (if appropriate, ie, is associated with an imAE or is a new anticancer therapy) at 60 and 90 days 
(± 14 days) after the last dose of tislelizumab, regardless of whether or not patients started 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.  
d. Survival Follow-Up Period: information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months after 
the EOT/Safety Follow-up Visit until death, loss to follow-up, withdrawal of consent, or study termination by sponsor. All patients will be followed for 
survival and subsequent anticancer therapy information unless a patient requests to be withdrawn from follow-up. 
e. Height assessment is required only at screening. Vital signs will include measurements of body temperature (˚C), pulse rate, respiration rate and blood 
pressure (systolic and diastolic). Pulse rate and blood pressure will be measured while the patient is in a seated position after resting for 10 minutes. The 
patient’s vital signs are required to be recorded within 60 minutes before, during, and 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 30 minutes after the infusion. Vital signs 
should also be recorded prior to administration of fruquintinib; recorded values may be used for pre-tislelizumab assessment if vital signs are collected within 
60 minutes before tislelizumab infusion.  
f. A complete physical examination should include an evaluation of the head, eyes, ears, nose, throat, cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems at screening. At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  
g. All ECGs are to be obtained before other assessments scheduled at that same time (eg, vital sign measurements, blood draws). The patient should rest in 
semirecumbent supine position for ≥ 10 minutes in the absence of environmental distractions that may induce changes in heart rate (eg, television, radio, 
conversation, etc) before each ECG collection. 
h. The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0. All AEs will also be evaluated for seriousness. After the ICF has been signed but 
before the administration of study drug(s), only SAEs should be reported. After the first dose of study drug(s), all AEs and SAEs, regardless of relationship to 
study drug, will be reported until either 30 days after the last dose of study drug(s) (including tislelizumab and fruquintinib) or initiation of new anticancer 
therapy, whichever occurs first. Immune-mediated AEs (serious and nonserious) should be reported for tislelizumab treatment until 90 days after the last dose 
of tislelizumab regardless of whether 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. 
i. Local laboratory assessments of clinical chemistry, hematology, coagulation, and urinalysis will be conducted as outlined in Appendix 3. If clinical chemistry, 
hematology, coagulation, and urinalysis at screening are not performed ≤ 7 days before study drug administration on Day 1 of Cycle 1, these tests should be 
repeated and reviewed before study drug administration. After Day 1 of Cycle 1, results are to be reviewed within 72 hours before study drug administration. 
Hematology, clinical chemistry, coagulation, and urinalysis(data collected as specified in Appendix 3) will be performed biweekly for the first two cycles and 
then at the beginning of each subsequent cycle. Refer to Section 9.2.5 for additional information regarding clinical assessment and management of clinical 
laboratory abnormalities.  
j. CK and CK-MB levels will be evaluated at the timepoints specified within the table and when clinically indicated. If CK-MB fractionation is not available, 
troponin I and/or troponin T should be tested instead. If tislelizumab has been permanently discontinued, CK and CK-MB testing is no longer required. 
Patients who continue to receive fruquintinib monotherapy may receive CK and CK-MB testing if clinically indicated. 


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k. Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative 
≤ 7 days before the first dose of study drug(s). A negative urine pregnancy test must be completed and recorded ≤ 72 hours before the administration of study 
drug(s) at subsequent cycles and in safety follow up visit. A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
l. TFTs by analysis of FT3, FT4, and TSH will be performed at screening, every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc) and Safety Follow Up Visit. If FT3 
or FT4 is not available, TT3 or TT4 should be tested instead. 
m. Testing will be performed by the local or central laboratory at screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody) 
and viral load assessment (HBV DNA and HCV RNA), which will be assessed only when HBsAg or HCV antibody is positive, respectively. Additionally, for 
patients who have detectable HBV DNA at screening, the respective viral load test will be performed every 4 cycles starting at Cycle 5 (ie, Day 1 of Cycles 5, 
9, 13, etc) and the EOT Visit. 
n. Pulmonary function testing including spirometry and assessment of oxygenation, at a minimum, pulse oximetry at rest and with exercise, or alternatively, 
assessment of diffusion capacity, are to be performed for all NSCLC patients during the screening period to assist the determination of suitability on the 
study. Respective test results need to be submitted to the sponsor. For test results indicative of significantly impaired pulmonary function, eg, resting pulse 
oximetry < 90% on room air and further desaturation upon exercise, forced expiratory volume (FEV1) < 60% or diffusing capacity of the lungs for carbon 
monoxide (DLCO) (if performed) < 60% of age- and sex-adjusted predicted performance levels (Pellegrino et al 2005), the medical monitor needs to be 
consulted to confirm eligibility. Tests may be repeated as clinically indicated while on study. GC or CRC patients who are suspected of having or known to 
have serious/severe respiratory conditions, or exhibit significant respiratory symptoms unrelated to the underlying cancer, or with a history of thoracic 
radiotherapy will undergo pulmonary function testing that may include but is not limited to spirometry and assessment of diffusion capacity done during the 
screening period to assist the determination of suitability on the study. 
o. Approximately 2 mL peripheral whole blood must be sent to the central laboratory for MSI test control during the screening period in the CRC patients. 
Additionally, blood samples will be collected for all patients at baseline (Predose on Cycle 1 Day 1, required), at the time of first tumor response (Predose on 
Day 1 of the following cycle, optional), and at the time of PD (optional). Approximately 10 mL for each timepoint. Written patient consent is required for 
blood sample collections. 
p. Tumor imaging will be performed ≤ 28 days before the first dose of study drug(s). Results of standard-of-care tests or examinations performed before 
informed consent has been obtained 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. During the study, tumor imaging will be performed every 8 weeks (± 7 days), from Day 1 of Cycle 1, for the first 56 weeks, then every 
12 weeks (± 7 days) thereafter, based on RECIST v1.1. Tumor assessments are required to be performed on schedule regardless of whether study treatment 
has been administered or held. Tumor assessments must include CT scans (with oral/intravenous contrast, unless contraindicated) or MRI, with preference for 
CT, of the chest, abdomen, and pelvis. Imaging of the brain (MRI or CT) at baseline is required for all screened NSCLC patients. 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit and reassessed at each subsequent tumor evaluation. The 
same radiographic procedure used to assess disease sites at screening must be used throughout the study (eg, the same contrast protocol for CT scans). 
Patients who discontinue study treatment early for reasons other than disease progression (eg, toxicity) will continue to undergo tumor assessments following 
the original plan until the patient begins a subsequent anticancer treatment, experiences disease progression, withdraws consent, is lost to follow-up, death, or 
until the study terminates, whichever occurs first. See Section 8.3 for more information. 
q. Archival tumor tissues (if available) must be sent to the central laboratory for MSS status detection (MSI test) for the CRC patients, PD-L1 status for the 
NSCLC patients and EGFR status (central/local laboratory) for the non-squamous NSCLC patients with no EGFR documentation during the screening period 
and for retrospective analysis of exploratory biomarkers for all enrolled patients. If archival tumor tissues are not available during the screening period, a fresh 
tumor biopsy is mandatory. Optional fresh biopsies in patients who have confirmed PD in both cohorts will be collected during the study from accessible 
tumor sites. If feasible, any follow-up biopsy should ideally be taken from the same tumor lesion as the baseline biopsy. Written patient consent is required 
for fresh tumor biopsies. 
For fresh biopsy, acceptable samples include core needle biopsies for nonsuperficial tumor tissue or excisional, incisional, punch, or forceps biopsies for 


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cutaneous, subcutaneous, or mucosal lesions. Tumor tissue should be of good quality based on total and viable tumor content. Fine-needle aspiration, 
brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. 
r. Tislelizumab will be given intravenously on Day 1 of each 28-day cycle (once every 4 weeks) (see Section 5.2.1 for details).  
s. Fruquintinib will be self-administered orally once daily with 3 weeks on/1 week off (see Section 5.2.2 for details).


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APPENDIX 2. SCHEDULE OF PK AND ADA ASSESSMENTS 
 
Collection Time and 
Allowable Window 
Part 1:  
PK-Fruquintiniba 
Part 2: 
PK-Fruquintinibb 
Part 1+Part 2:  
PK-Tislelizumabc 
Part 1+Part 2 
ADA-
Tislelizumabd 
C1D1 
Predose - 60 min 
x 
x 
x 
(Pre-tisle-dose [-60 min]) 
x 
(Pre-tisle-dose [-
60 min]) 
Postdose + 30 min  
 
 
x 
(Post-tisle infusion + 30 
min) 
 
1 h ± 10 min 
x 
 
 
 
2 h ± 15 min 
x 
x 
 
 
4 h ±30 min 
x 
 
 
 
6 h ±30 min 
x 
 
 
 
8 h ± 60 min 
x 
 
 
 
C1D15 
(optiona
l)  
Predose - 60 min 
x 
x 
 
 
C2D1 
Predose - 60 min 
x 
x 
x 
(Pre-tisle-dose [-60 min]) 
x 
(Pre-tisle-dose [-
60 min]) 
C2D15 
(optiona
l) 
Predose - 60 min 
x 
x 
 
 
C4D1 
Predose - 60 min 
x 
x 
x 
(Pre-tisle-dose [-60 min]) 
x 
(Pre-tisle-dose [-
60 min]) 
Postdose + 30 min 
 
 
x 
(Post-tisle infusion + 
30min) 
 
C7D1 
Predose - 60 min 
x 
x 
x 
(Pre-tisle-dose [-60 min]) 
x 
(Pre-tisle-dose [-
60 min]) 
C13D1 
Predose - 60 min 
x 
x 
x 
(Pre-tisle-dose [-60 min]) 
x 
(Pre-tisle-dose [-
60 min]) 
SFU 
Within 30 days after last 
dose of study drug(s) 
 
 
x 
x 
Abbreviations: ADA, antidrug antibody; C, cycle; D, day; DLT, dose limiting toxicity; EC, ethics committee; IRB, 
institutional review board; min, minutes; PK, pharmacokinetics; SFU, safety follow-up; tisle, tislelizumab. 
a. Procedures for collection of PK samples are described in the Laboratory Manual. PK samples for fruquintinib 
will be collected from all patients in Part 1 at predose (within 60 minutes before dosing), 1 (± 10 min), 2 (± 15 
min), 4 (±30 min), 6 (± 30 min), and 8 hours (± 60 min) after dosing on Cycle 1 Day 1; predose (within 60 


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minutes before dosing) on Day 1 of Cycle 2, 4, 7, 13, and on Day 15 of Cycle 1 and 2 (optional) per site 
feasibility. If a patient is present with DLT event or any SAE, an additional blood PK sample may be taken to 
determine the plasma concentration of fruquintinib. These PK samples will be measured only if any safety 
issues occur and is requested from sponsor. If fruquintinib is permanently discontinued, the scheduled PK 
sampling of fruquintinib is no longer required.  
b. Procedures for collection of PK samples are described in the Laboratory Manual. PK samples for fruquintinib 
will be collected from all patients in Part 2 at predose (within 60 minutes before dosing) on Day 1 of Cycle 1, 2, 
4, 7, 13, and on Day 15 of Cycle 1 and 2 (optional); and 2 h (± 15 min) after dosing on Cycle 1 Day 1 per site 
feasibility. If a patient is present with DLT event or any SAE, an additional blood PK sample may be taken to 
determine the plasma concentration of fruquintinib. If fruquintinib is permanently discontinued, the scheduled 
PK sampling of fruquintinib is no longer required. 
c. Procedures for collection of PK samples are described in the Laboratory Manual. For tislelizumab, predose 
(within 60 minutes before starting infusion) samples are required to be collected on Day 1 of Cycles 1, 2, 4, 7, 
and 13. A postdose (within 30 minutes after completing tislelizumab infusion) sample is required to be collected 
on Day 1 of Cycles 1 and 4. An additional PK sample is required to be collected at the Safety Follow-up. If 
tislelizumab is permanently discontinued, scheduled PK sampling is no longer required except for Safety 
Follow-up Visit. Should a patient present with DLT event or any ≥ Grade 3 imAE, an additional blood PK 
sample may be taken to determine the serum concentration of tislelizumab. These tests are required when it is 
allowed by local regulations/IRBs/ECs. 
d. Blood used to test for anti-tislelizumab antibodies should be collected within 60 minutes before beginning the 
Day 1 infusion of Cycles 1, 2, 4, 7, and 13 and at the mandatory Safety Follow-up Visit. If tislelizumab is 
permanently discontinued, ADA sampling is no longer required except for Safety Follow-up Visit. All samples 
should be drawn at the same time as blood collection for predose PK analysis. These tests are required when it 
is allowed by local regulations/IRBs/ECs. 


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APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS 
Clinical chemistry 
Hematology 
Coagulation 
Urinalysis 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Albumin 
Total bilirubin 
Direct bilirubin 
Blood urea nitrogen or urea 
Potassium 
Sodium 
Total calciuma 
Creatinine 
Glucose 
Lactate dehydrogenase 
Total protein 
Creatine kinaseb 
CK-MBb 
Red blood cell count 
Hematocrit 
Hemoglobin 
Platelet count 
White blood cell count 
Lymphocyte count 
Neutrophil count 
Prothrombin time 
Partial thromboplastin 
time or activated 
partial thromboplastin 
time 
International 
normalized ratio 
Glucose 
Protein 
Blood 
Ketones 
24-hour proteinc 
Random urine protein 
to creatinine ratio 
Abbreviations: CK-MB, creatine kinase-muscle/brain. 
a Total calcium values will be corrected for patients with hypoproteinemia. 
b All patients will have creatine kinase and CK-MB testing at screening, and to be repeated at all scheduled visits 
during the first 2 treatment cycles, all predose assessments from Cycle 3 onwards, and at the End-of-
Treatment/Safety Follow-up visit. If CK-MB fractionation is not available, assess troponin I and/or troponin T 
instead. Refer to Section 8.2.4 for additional information regarding clinical assessment and management of clinical 
laboratory abnormalities. 
c On routine urinalysis, if urine protein is ≥ 2+ by dipstick, then obtain a 24-hour urine sample for total protein and a 
random urine sample for total protein and creatinine to determine a protein to creatinine ratio. 


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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. 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 Study (MDRD) study 
equation. The National Kidney Disease Education Program calculators rely on creatinine 
determinations that are isotope dilution mass spectrometry traceable. All laboratories should be 
using creatinine methods calibrated to be isotope dilution mass spectrometry traceable. 
The CKD-EPI equation calculator should be used when serum creatinine (Scr) reported in mg/dL. 
This equation is recommended when estimated GFR values above 60 mL/min/1.73 m2 are 
desired. 
GFR = 141 × min (Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr/κ or 1, and 
max indicates the maximum of Scr/κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-
calculators 


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APPENDIX 6. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL” 
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control 
(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, or implantable 
Note: Oral birth control pills are not considered a highly effective form of birth 
control, and if they are selected, they must be used with a second, barrier method 
of contraception such as condoms with or without spermicide. 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized male 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 azoospermia has been demonstrated in a semen sample 
examination as definitive evidence of infertility. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of exposure associated with the study treatment).  
NOTE: Total sexual abstinence should only be used as a contraceptive method if it is in 
line with the patient’s usual and preferred lifestyle. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, or postovulation methods), declaration of abstinence for the 
duration of exposure to study drug(s), and withdrawal are not acceptable methods of 
contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
combined with another acceptable method 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 a 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, 
etc. 
If 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 2014. 


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APPENDIX 7. PRE-EXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES 
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease. Please contact the 
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 myasthenia 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-Koyanagi-Harada disease 


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APPENDIX 8. 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 9. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT 
The recommendations below for the diagnosis and management of any immune-mediated AE 
(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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Autoimmune 
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 
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 10. MEDICATIONS TO BE USED WITH CAUTION DURING 
TREATMENT WITH FRUQUINTINIB 
Restricted drugs during the study are as follows:  
Strong inhibitors and strong inducers of CYP3A4. Note, the list of drugs in this table is not 
exhaustive.  Please refer to the prescribing information and Summary of Product Characteristics 
to check for CYP3A inhibition or induction risks or contact the medical monitor of the protocol. 
Strong CYP3A Inhibitors 
Antibiotics:  clarithromycin, telithromycin, troleandomycin, erythromycin 
Antifungals:  itraconazole, ketoconazole, posaconazole, voriconazole, fluconazole 
Antivirals:  boceprevir, telaprevir 
Other:  cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone, idelalisib 
Protease inhibitors:  indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, 
Grapefruit juicea,b 
Strong/Moderate CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), 
St. John’s wort (hypericum perforatum), apalutamide, enzalutamide, mitotane, bosentan, efavirenz, 
etravirine, modafinil 
Abbreviations: CYP3A, cytochrome P450, family 3, subfamily A. 
Source: Food and Drug Administration Drug Development and Drug Interactions: Table of Substrates, Drug 
Development and Drug Interactions and Inducers: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers 
For a more complete list, please refer to the Flockhart Table: http://medicine.iupui.edu/clinpharm/ddis/main-table 
a. 
Super-concentrated grapefruit juice  
b. During the study, patients should not consume large amounts of grapefruit or lime (or products that include 
these fruits, such as grapefruit juice, Seville oranges, and orange jam). No more than one cup (120 mL) of 
grapefruit juice, half a grapefruit, or a spoon full (15 g) of orange jam should be consumed each day. 
Medications to be used with caution during the study are as follows: 
Sensitive Substrates and Substrates with Narrow Therapeutic Index for P-gp and BCRP 
Transporters 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. 


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APPENDIX 11. MEDICATIONS THAT HAVE A KNOWN RISK OF 
CAUSING QT PROLONGATION AND/OR TORSADES 
DE POINTES  
 
amiodarone 
droperidol 
oxaliplatin 
anagrelide 
erythromycin 
pentamidine 
arsenic trioxide 
escitalopram 
pimozide 
astemizole 
flecainide 
probucol   
azithromycin 
fluconazole 
procainamide 
bepridil   
gatifloxacin   
propofol 
chloroquine 
grepafloxacin   
quinidine 
chlorpromazine 
halofantrine   
roxithromycin   
cilostazol 
haloperidol 
sevoflurane 
ciprofloxacin 
ibogaine   
sotalol 
cisapride   
ibutilide 
sparfloxacin   
citalopram 
levofloxacin 
sulpiride   
clarithromycin 
levomepromazine/methotrimeprazine 
sultopride  
cocaine 
levomethadyl   
terfenadine   
disopyramide 
levosulpiride   
terlipressin   
dofetilide 
mesoridazine   
terodiline   
domperidone   
methadone 
thioridazine 
donepezil 
moxifloxacin 
vandetanib 
dronedarone 
ondansetron 
 
Source:  www.crediblemeds.org 


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APPENDIX 12. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1 
Source: Eisenhauer et al 2009. 
Definitions 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Version 1.1). 
Changes in only the largest diameter (unidimensional 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 ≥ 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 > 5 mm. 
• 10 mm caliper measurement by clinical examination (when superficial). 
• 20 mm by chest x-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no > 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 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Trial protocols should detail the conditions 
under which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT. Only the short axis of these nodes will contribute to the baseline sum. The short 
axis of the node is the diameter normally used by radiologists to judge if a node is involved by 
solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image is 
obtained (for CT scan, this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm by 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) 
should be considered nontarget lesions. Nodes that have a short axis < 10 mm are considered 
nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 


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Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at baseline. Measurements are not required, and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression” (more details to follow). In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”). 
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, because CT is more sensitive than x-ray, particularly in 
identifying new lesions. However, lesions on chest x-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
• CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. 
When CT scans have slice thickness > 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness. MRI is also acceptable in certain situations 
(eg, for body scans). 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date, and because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 


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• 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 trials 
where recurrence following complete response (CR) or surgical resection is an 
endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in CR. Because tumor markers are disease 
specific, instructions for their measurement should be incorporated into protocols on a 
disease specific basis. Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and prostate-specific antigen response (in recurrent prostate cancer), 
have been published. In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials 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 (PD). 
Response Criteria 
Evaluation of Target Lesions 
• Complete response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or nontarget) 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 1 or more new 
lesions is also considered progression). 
• Stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 


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


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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 1 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 stable 
disease or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. A modest “increase” in the size of 1 or more 
nontarget lesions is usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the basis of change in 
nontarget disease in the face of stable disease or PR of target disease will therefore be 
extremely rare. 
• When the patient has only nonmeasurable disease: This circumstance arises in some 
Phase 3 trials when it is not a criterion of trial entry to have measurable disease. The 
same general concept 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 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. 


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New Lesions 
The appearance of new malignant lesions denotes PD; therefore, some comments on detection of 
new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some “new” bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be 
reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate PD. 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/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 fluorine-18 [F-18]fluorodeoxyglucose (FDG)-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression (particularly possible “new” disease). New lesions on 
the basis of FDG-PET imaging can be identified according to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of 
PD based on a new lesion.  
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
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 


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Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
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 taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the findings 
of both target and nontarget disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the trial and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in nonrandomized trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one the “best overall 
response.” 
The best overall response is determined once all the data for the patient is known. Best response 
determination in trials where confirmation of complete or partial response IS NOT required: Best 
response in these trials is defined as the best response across all timepoints (for example, a 
patient who has stable disease at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When stable disease 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 stable disease is otherwise the best timepoint response, the patient’s best 
response depends on the subsequent assessments. For example, a patient who has stable disease 
at first assessment, PD at second and does not meet minimum duration for stable disease, will 
have a best response of PD. The same patient lost to follow-up after the first stable disease 
assessment would be considered inevaluable. 


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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 trials where confirmation of response is required, repeated ‘NE’ timepoint assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, 
in most trials it is reasonable to consider a patient with 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 PD at that time should be reported as “symptomatic deterioration.” 
Every effort should be made to document objective progression even after discontinuation of 
treatment. Symptomatic deterioration is not a descriptor of an objective response: it is a reason 
for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial-specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR. FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-
PET in this circumstance should be prospectively described in the protocol and supported by 
disease specific medical literature for the indication. However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
progression is confirmed at the next scheduled assessment, the date of progression should be the 
earlier date when progression was suspected. 
Confirmation of Measurement/Duration of Response 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, ie, in 
randomized trials (Phase 2 or 3) or trials where stable disease or progression are the primary 


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endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in trials which 
are not blinded. 
In the case of stable disease, measurements must have met the stable disease 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 PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized 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 PFS are influenced by the 
frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define 
a standard follow-up frequency. The frequency should take into account many parameters 
including disease types and stages, treatment periodicity, and standard practice. However, these 
limitations of the precision of the measured endpoint should be taken into account if comparisons 
between trials are to be made. 


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APPENDIX 13. CLINICAL EVALUATION OF POSSIBLE DRUG-
INDUCED LIVER INJURY (DILI) 
If ALT or AST is elevated to higher than 3 x ULN and bilirubin is elevated to higher than 
2 x ULN, fruquintinib treatment should be discontinued immediately, and supportive treatment 
should be given. This combination of lab abnormalities meets the biochemical criteria for Hy’s 
law, which is associated with a markedly increased possibility of severe drug-induced liver 
injury (DILI), and may progress to liver transplantation or death (FDA Guidance for Industry - 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation. FDA, 2009).  
If the biochemical criteria for Hy’s law are met, fruquintinib should be immediately 
discontinued, and patients need to be very closely monitored (bilirubin, ALP, AST, and ALT 
measured 2 to 3 times weekly until the results return to baseline or normal), and other causes of 
liver injury evaluated (eg, new or worsening hepatobiliary metastases; non-malignant biliary 
obstruction; viral hepatitis A, B, or C; alcoholic or autoimmune hepatitis; preexisting or acute 
liver disease; ischemic liver injury; right-sided congestive heart failure; new or worsening liver 
metastases; or concomitant medication that could cause the observed injury). Consultation with a 
gastroenterologist or hepatologist should be considered.  
Recommended Data Collection for Suspected DILI  
The investigator is recommended to obtain the following information, so as to further evaluate 
and follow up and complete the clinical data. Data should be recorded on eCRFs where possible, 
and supplemented by investigator reporting as text in the clinical database:  
• Medical history of the patient  
− Detailed history of current symptoms, diagnosis of complications and medical 
history  
− Previous medical history (viral hepatitis, alcoholic hepatitis, autoimmune disease, 
biliary tract disease and cardiovascular disease, etc.)  
− History of concomitant medication (including over-the-counter and prescription 
drugs, herbal medicine and dietary supplements), alcohol consumption, 
recreational drugs and special diet  
− History of exposure to potentially hepatotoxic chemicals  
• Complete the following laboratory tests:  
− Hematology  
− Clinical biochemistry: ALT, AST, bilirubin (including total bilirubin and direct 
bilirubin), ALP, albumin, PTT or INR, amylase, fasting blood glucose, cholesterol 
and triglycerides  
− Other Serum Tests: Hepatitis A (Anti-IgM and Anti-IgG), hepatitis B (HbsAg, 
Anti-HBs and HBV DNA), hepatitis C (Anti-HCV, and HCV RNA test is 
required for any patient with positive test result), hepatitis D (Anti-IgM and Anti -
IgG), hepatitis E (Anti-HEV and Anti-HEV IgM).  


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• Complete appropriate auxiliary examination:  
− Patients with confirmed elevation of ALT/AST combined with TBili are required 
to receive abdominal ultrasonography or other clinically applicable imaging 
examination within 48 hours (to exclude biliary tract, pancreatic, or intrahepatic 
causes, such as new or worsening hepatobiliary metastases or biliary calculi) and 
obtain the liver imaging result as soon as possible. If an alternative cause (such as 
biliary tract, pancreatic, or intrahepatic causes) of abnormal hepatic results cannot 
be confirmed by imaging, paracentesis is recommended for pathological 
examination after obtaining consent of the patient;  
− If suspected cardiovascular causes exist, cardiac ultrasonography is recommended 
to exclude cardiovascular dysfunction (ie, right heart failure);  
Long-term follow-up: Perform close monitoring on the patient through repetitive tests of ALT, 
AST and bilirubin (including total bilirubin and direct bilirubin) two to three times weekly until 
the laboratory ALT and/or AST abnormality becomes stable or recovers, and then proceed 
according to the protocol. 


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APPENDIX 14. CLINICAL MANAGEMENT OF SEVERE OR SERIOUS 
HEMORRHAGIC EVENTS  
If hemorrhagic events are evaluated as severe (CTCAE ≥ Grade 3) or SAEs, fruquintinib 
treatment should be discontinued or interrupted immediately, and appropriate treatment measures 
initiated to control bleeding (eg transfusion, radiologic, endoscopic, or elective operative 
intervention as indicated). When the patient is not well enough to tolerate an invasive procedure 
or operation, best supportive care is given (see Section 9.7). Patients need to be very closely 
monitored, both clinically (continuously), and by relevant laboratory testing (INR, aPTT, platelet 
count, hemoglobin) every 2 to 3 days until the results return to baseline or normal). During the 
initial assessment, a focused history and physical examination, with collection of vital signs and 
laboratory evaluation and imaging evaluation should be obtained, aimed at determining the time 
of onset, location, severity of bleeding, and whether bleeding is ongoing. Clinicians should be 
mindful of comorbidities and concomitant treatments (eg, anti-platelet therapy and/or 
thrombocytopenia, or liver disease) that could also contribute to bleeding and manage them as 
appropriate. Consultation with other department clinicians should be considered when necessary.  
The investigator should closely monitor patients receiving anti-platelet and/or anti-thrombotic 
drugs during study drug treatment and make a timely decision on whether to continue or stop 
such drugs in patients that report ≥ Grade 2 hemorrhagic events at any site, based on an 
individual assessment of the risk-benefit balance.  
See Figure 2 below for guidance on the management of severe or serious hemorrhage at any site.  
Recommended Data Collection for Severe or Serious Hemorrhagic Events:  
The investigator is recommended to obtain the following information, so as to further evaluate 
and follow up and complete the clinical data. Data should be recorded on SAE/AESI report form 
where possible, and supplemented by Bleeding Event Follow-Up Questionnaire:  
• Medical history of the patient  
− Detailed history of current symptoms, diagnosis of complications and medical 
history  
− Previous medical history  
− History of concomitant medication  
o Vitamin K antagonists (eg, warfarin)  
o NSAIDs (eg, aspirin)  
o Anti-platelet drugs (eg, clopidogrel/glycoprotein GPIIb/IIIa 
inhibitors/dipyridamole)  
o Other anticoagulants (eg, heparin/thrombolytics/SSRIs)  
o Food and herbal supplements with anticoagulant property  
o Immunosuppressants  
o Alcohol consumption  
o Recreational drugs and special diet  


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− Family history of bleeding events  
• Complete the following laboratory tests:  
− Hematology: hemoglobin, platelet, hematocrit, reticulocyte count  
− Clinical biochemistry: bleeding time, PTT, aPTT, INR  
• Complete appropriate auxiliary examination:  
− Patients with confirmed bleeding are required to receive upper or lower GI 
endoscopy, bronchoscopy or other clinically applicable procedure or radiologic 
imaging within 48 hours, to confirm the site of bleeding.  
− If suspected cardiovascular causes exist, cardiac ultrasonography is recommended 
to exclude cardiovascular dysfunction (ie, right heart failure).  
 


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Figure 2: 
Severe or Serious Hemorrhagic Events Management Flow Chart 
 
•
Closely monitor 
•
Interrupt study drug 
•
Initiate appropriate measures to 
control bleeding if necessary 
•
Closely monitor patients 
receiving anti-platelet and/or anti-
thrombotic drugs during study 
drug treatment, and make a 
timely decision on whether to 
continue or stop such drugs in 
patients that report ≥ Grade 2 
hemorrhagic events at any site 
•
If the hemorrhagic event meets SAE criteria, fill in SAE form and expedited reporting of this 
hemorrhagic event to sponsor 
•
Continue monitoring 
•
Expedited reporting to 
sponsor if upgraded to 
serious hemorrhagic event 
Hemorrhagic event meeting any of the criteria below: 
•
CTCAE ≥ Grade 3 (severe AE) 
•
Serious adverse event 
•
CTCAE ≥ Grade 2 and receiving anti-platelet and/or anti-thrombotic drugs during study drug treatment 
Hemorrhage is severe (CTCAE ≥ Grade 3) (regardless of 
whether or not it meets “serious” criteria) 
Hemorrhage is non-severe (CTCAE ≤ Grade 2)  
Does the hemorrhagic event meet SAE criteria? 
•
Discontinue study drug immediately 
•
Initiate appropriate measures to control bleeding 
•
Closely monitor laboratory tests (INR, aPTT, 
platelet count, hemoglobin and blood pressure) 
every 2-3 days 
•
A focused history and physical examination, 
with collection of vital signs, and laboratory 
evaluation as appropriate 
•
Closely monitor patients receiving anti-platelet 
and/or anti-thrombotic drugs during study drug 
treatment, and make a timely decision on 
whether to continue or stop such drugs in 
patients that report ≥ Grade 2 hemorrhagic 
events at any site 
Grade = 2 
Grade = 1 
Yes 
No 
•
Closely monitor 
•
Initiate appropriate measures to control 
bleeding if necessary 


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APPENDIX 15. MANAGEMENT OF HYPERTENSION IN PATIENTS 
RECEIVING FRUQUINTINIB  
Hypertension is a common AE that has been reported in patients taking angiogenesis inhibitors 
(Izzedine 2009), including fruquintinib. Grade 3 AEs have been reported in 16% of patients 
treated with fruquintinib; no Grade 4 events have been reported to date. It appears that 
hypertension is a class-effect of VEGFR inhibitors (either antibodies or small molecules).  
There is no standard therapy for angiogenesis inhibitor-induced hypertension because there have 
not been any published controlled clinical trials with specific agents. Therefore, one can take an 
approach based on the clinical characteristics of particular patients. Calcium channel blockers 
and angiotensin converting enzyme inhibitors (ACEI) are a reasonable first choice in most cases. 
For patients with proteinuria, chronic renal disease or metabolic disease, an ACE inhibitor or 
angiotensin II receptor blockers (ARB) may be preferred; for elderly patients, dihydropyridine 
calcium channel blockers may be preferred. In this appendix is a summary of the most recent 
American Heart Association (AHA)/American College of Cardiology (ACC) hypertension 
treatment guidelines. A cardiologist may be consulted if appropriate.  
The objective of antihypertensive therapy in general is to control the blood pressure to a target 
level <140/90 mmHg. For high-risk populations, such as patients with chronic renal disease 
and/or diabetes, it may be appropriate to aim for a target blood pressure < 130/80 mmHg. Please 
see a summary of the most recent AHA/ACC hypertension treatment guidelines (Figure 3). 


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Figure 3: 
Schema from American Heart Association/ American College of Cardiology 
for Controlling Hypertension in Adults 
Source: Go et al 2014. 
 


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Signature Page 
Approval
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SAP_001.pdf: 
BGB-A317-fruquintinib-201 
BeiGene 
Statistical Analysis Plan 1.0 
27 February 2024 
CONFIDENTIAL 
Page 1 
STATISTICAL ANALYSIS PLAN 
Study Protocol Number: 
BGB-A317-fruquintinib-201 
Study Protocol Title: 
A MULTICENTER, OPEN-LABEL PHASE 2 STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
TISLELIZUMAB IN COMBINATION WITH FRUQUINTINIB IN 
PATIENTS WITH SELECTED SOLID TUMORS  
Date: 
27 February 2024 
Version: 
1.0 
~
BeiGene 
NCT Number
NCT04716634


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7 
1. ................ INTRODUCTION ........................................................................................................9 
2. ................ STUDY OVERVIEW ...................................................................................................9 
2.1. ............. Study Design .................................................................................................................9 
2.1.1. .......... Part 1 (Safety Run-in) ...................................................................................................9 
2.1.2. .......... Part 2 (Expansion) ......................................................................................................10 
2.2. ............. Study Assessments......................................................................................................10 
3. ................ STUDY OBJECTIVES ..............................................................................................11 
3.1. ............. Primary Objective .......................................................................................................11 
3.2. ............. Secondary Objective ...................................................................................................11 
3.3. ............. Exploratory Objective .................................................................................................12 
4. ................ STUDY ENDPOINTS ................................................................................................12 
4.1. ............. Primary Endpoint(s) ....................................................................................................12 
4.2. ............. Secondary Endpoints ..................................................................................................12 
4.3. ............. Exploratory Endpoints ................................................................................................12 
5. ................ SAMPLE SIZE CONSIDERATIONS .......................................................................13 
6. ................ STATISTICAL METHODS .......................................................................................13 
6.1. ............. Analysis Sets ...............................................................................................................13 
6.2. ............. Multiplicity Adjustment..............................................................................................14 
6.3. ............. Data Analysis General Considerations .......................................................................14 
6.3.1. .......... Definitions and Computations ....................................................................................14 
6.3.2. .......... Conventions ................................................................................................................14 
6.3.3. .......... Handling of Missing Data ...........................................................................................15 
6.4. ............. Patient Characteristics ................................................................................................15 
6.4.1. .......... Patient Disposition ......................................................................................................15 
6.4.2. .......... Protocol Deviations ....................................................................................................15 
6.4.3. .......... Demographic and Other Baseline Characteristics ......................................................16 
6.4.4. .......... Disease History ...........................................................................................................16 
6.4.5. .......... Prior Anticancer Drug Therapies and Surgeries .........................................................16 
6.4.6. .......... Prior and Concomitant Medications ...........................................................................16 


 
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6.4.7. .......... Medical History ..........................................................................................................17 
6.5. ............. Efficacy Analysis ........................................................................................................17 
6.5.1. .......... Primary Efficacy Endpoint(s) .....................................................................................17 
6.5.2. .......... Secondary Efficacy Endpoints ....................................................................................17 
6.5.3. .......... Post-Treatment Subsequent Anti-Cancer Therapy .....................................................19 
6.6. ............. Safety Analyses ..........................................................................................................20 
6.6.1. .......... Extent of Exposure .....................................................................................................20 
6.6.2. .......... Adverse Events ...........................................................................................................21 
6.6.2.1        Treatment Emergent Adverse Event ...........................................................................21 
6.6.2.2        Immune- Mediated Adverse Event .............................................................................22 
6.6.2.3        Infusion-related Adverse Event ..................................................................................23 
6.6.2.4        Death ...........................................................................................................................23 
6.6.3. .......... Laboratory Values ......................................................................................................23 
6.6.4. .......... Vital Signs ..................................................................................................................24 
6.6.5. .......... Electrocardiograms (ECG) .........................................................................................24 
6.6.6. .......... Eastern Cooperative Oncology Group (ECOG) Performance Status .........................24 
6.7. ............. Pharmacokinetic Analyses ..........................................................................................25 
6.7.1. .......... Pharmacokinetic Analysis of Fruquintinib .................................................................25 
6.7.2. .......... Pharmacokinetic Analysis of Tislelizumab ................................................................27 
6.8. ............. Immunogenicity Analyses ..........................................................................................27 
7. ................ INTERIM ANALYSES ..............................................................................................28 
8. ................ CHANGES IN THE PLANNED ANALYSIS ...........................................................28 
9. ................ REFERENCES ...........................................................................................................29 
APPENDIX 1. IMPUTATION OF MISSING OR PARTIALLY MISSING DATES...............30 
1.1 .............. Prior/concomitant medications/procedures ................................................................30 
1.2 .............. Adverse events ............................................................................................................30 
1.3 .............. Disease history and prior therapy (drug, surgery/procedure, radiotherapy) ...............31 
1.4 .............. Subsequent anti-cancer therapy ..................................................................................32 
1.5 .............. Fruquintinib administration date and actual dose .......................................................32 
APPENDIX 2. RULES FOR IDENTIFYING MISSING TUMOR ASSESSMENTS ..............34 
 


 
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LIST OF TABLES 
Table 1: ..... Estimate of 95% CI (%) Using Clopper-Pearson When Observing Different 
Number of Responders in 30 Patients ........................................................................13 
Table 2: ..... Censoring Rules for Progression-free Survival Per RECIST Version 1.1 .................18 
Table 3:      Clinical Laboratory Assessment .................................................................................23 
Table 4: ..... Statistical Analysis Plan Changes ...............................................................................28 
Table 5:      Example of scheduled tumor assessments with time window ....................................34 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Antidrug Antibody 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical  
BGB-A317 
Tislelizumab 
CI 
Confidence Interval 
CR 
Complete Response 
CRC 
Colorectal cancer 
CT 
Computed Tomography 
DCR 
Disease Control Rate 
DLT 
Dose-Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
imAE 
immune-mediated Adverse Event 
GC 
Gastric Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MSS 
Microsatellite stable 
NCI-CTCAE 
National Cancer Institute-Common Terminology 
Criteria for Adverse Events 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-1 
Programmed cell Death protein-1 
PD-L1 
Programmed cell Death Ligand-1 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 


 
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Abbreviation 
Definition 
PR 
Partial Response 
PT 
Preferred Term 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
TA 
Tumor Assessment 
TEAE 
Treatment-Emergent Adverse Event 
WHO DD 
World Health Organization Drug Dictionary  


 
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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for BGB-A317-fruquintinib-201: a 
multicenter, open-label phase 2 study to evaluate the efficacy and safety of tislelizumab in 
combination with fruquintinib in patients with selected solid tumors. This SAP is based on BGB-
A317-fruquintinib-201 Protocol Amendment 1.0, dated on 16 December 2020. The focus of this 
SAP is for the final analysis specified in the study protocol.  
2. 
STUDY OVERVIEW 
2.1. 
Study Design 
This is an open label, multicenter, phase 2 study designed to assess the efficacy and safety of 
tislelizumab in combination with fruquintinib in patients with advanced or metastatic, 
unresectable GC, MSS CRC and PD-L1 positive (defined as TC ≥1% by SP263 IHC) NSCLC. 
The study will be conducted in 2 parts (Figure 1). 
2.1.1. 
Part 1 (Safety Run-in)  
Part 1 of the study will be the safety run-in stage during which the first 6 patients will be enrolled 
and assessed for DLTs during the 28-day DLT observation period. Study drug administration 
will begin at the full dose of fruquintinib (5 mg daily, 3 weeks on followed by 1 week off every 
4-week cycle) in combination with tislelizumab (300 mg once every 4 weeks). A lower dose 
level of fruquintinib (4 mg daily, 3 weeks on followed by 1 week off every 4-week cycle) will be 
explored as necessary depending on observed toxicity. Only DLTs during the first 28 days of 
treatment will be assessed. Once they complete the DLT assessment, each patient who still 
receive study treatment will continue with the same dosage. 
 If 0-1 of 6 patients experience a DLT, the study may proceed at the current dose of 
both drugs. 
 If 2 or more patients experience a DLT, then, following consultation with the SMC, 
the study will proceed with enrollment in the next defined lower dose (Dose Level -
1), an additional 6 patients will be enrolled, and the 28-day DLT observation period 
will be repeated.    
 If 2 or more patients experience a DLT in Dose Level -1, enrollment in the study will 
cease.  
The SMC will evaluate the safety and tolerability of the combination therapy when the first 
6 DLT-evaluable patients have completed the first 28 days of treatment or when ≥ 2 DLTs at the 
tested dose level occur. Safety information including but not limited to the DLTs, all TEAEs, and 
laboratory abnormalities will be reviewed by the SMC. The SMC will make recommendations 
on safety management, including resumption of enrollment, de-escalation of fruquintinib to one 
lower dose level, or termination of enrollment. The final decision will be made by sponsor. Once 


 
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the sponsor has determined that the combination therapy could proceed, the current dose will be 
confirmed as the RP2D, and enrollment for Part 2 will begin at RP2D.  
2.1.2. 
Part 2 (Expansion) 
Patients enrolled in Part 1 at RP2D will be counted towards Part 2 by the diagnosis of the tumor 
types; up to approximately 30 patients per cohort will be enrolled at RP2D.  
There will be a total of 3 cohorts in part 2.  
 Cohort A:  second line gastric cancer  
 Cohort B: third line MSS colorectal cancer 
 Cohort C: first line PD-L1 positive non-small cell lung cancer 
The study schema is in Figure 1. 
Figure 1: 
Study Schema 
 
Abbreviations: DLT, dose limiting toxicity; RP2D, recommended Phase 2 dose; SMC, Safety Monitoring Committee. 
Notes: The first 6 patients will be enrolled and assessed for DLTs during the 28-day DLT observation period. Dosing will begin 
at Dose Level 0. Dose Level -1 will be explored as necessary depending on observed toxicity. The SMC will evaluate the safety 
and tolerability of the combination therapy when the first 6 DLT-evaluable patients have completed the DLT observation period 
or when ≥ 2 DLTs at the tested level occur. Enrollment for Part 2 will begin once the sponsor has determined that the 
combination could proceed and confirmed the RP2D of fruquintinib in combination with tislelizumab. 
 
Tislelizumab will be administered intravenously on Day 1 of every 4-week cycle.  
 
Fruquintinib will be administered daily, orally with 3 weeks on followed by 1 week off for every 4-week cycle. 
2.2. 
Study Assessments 
Tumor Assessments: 
Tumor assessments will be performed by the investigator using RECIST v1.1 criteria 
(Eisenhauer et al 2009). Tumor imaging (computed tomography [CT] with oral/IV contrast, 
unless contraindicated, or magnetic resonance imaging [MRI]) must be performed within 
28 days prior to enrollment. On-study tumor assessments will occur every 8 weeks (±7 days) 
during the first 56 weeks and every 12 weeks (±7 days) thereafter until PD. If a patient 
discontinues study treatment due to any reasons other than PD, tumor assessments will continue 
to be performed as scheduled until disease progression, loss to follow up, initiation of subsequent 
therapy, withdrawal of consent, death, or until the study terminates, whichever occurs first. 
Safety Assessment: 
Unresectable 
Locally advanced 
or metastatic 
gastric cancer or 
MSS colorectal 
cancer or PD-
L l + non-small 
cell lung cancer 
Pm11: Safety run-in stage 
(n=6-l2) 
Dose Level 0 
Tislelizumab 300mg 
+ 
Fruquinlinib 5mg/day 
--, 
Dose Level I 
Tislelizumab 300mg 
+ 
Fruquintinib 4mg/day 
I 
I 
I 
: RP2D 
L.-----
1 
I 
I 
I 
I 
__ ! 
Pa112 
Cohort A: 2nd line Gastric Cancer 
_ 
Treatment until 
(n:,:30) 
~:;;:::.::.:, __________ ___, 
unacceptable 
Cohort B: 3'" line MSS Colorectal 
Cancer (~30) 
Cohort C: I" line PD-LI+ on-
small Cell Lung Cancer (n:::::30) 
toxicity or 
-
disease 
progression or 
withdrawal of 
_ 
consent. 


 
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All patients will be closely monitored for AEs throughout the study and for up to 30 days after 
the last dose of study drug(s). AEs will be graded according to the NCI-CTCAE v5.0. Refer to 
protocol for additional and specific information regarding AE monitoring and reporting. After 
informed consent has been signed but before the administration of the study drug(s), only SAEs 
should be reported. After the first dose of study drug(s), all AEs and SAEs, regardless of 
relationship to study drugs, will be reported until either 30 days after last dose of study drug(s) 
(including fruquintinib) 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. 
3. 
STUDY OBJECTIVES 
3.1. 
Primary Objective 
• 
To assess the safety and tolerability of tislelizumab in combination with fruquintinib. 
• 
To confirm the RP2D of fruquintinib in combination with tislelizumab.  
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by 
investigator in patients with selected solid tumors as measured by the overall response rate 
(ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 
3.2. 
Secondary Objective 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by the 
investigator in patients with selected solid tumors as measured by the progression free 
survival (PFS) per RECIST v1.1. 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by the 
investigator in patients with selected solid tumors as measured by the disease control rate 
(DCR) per RECIST v1.1. 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by the 
investigator in patients with selected solid tumors as measured by the clinical benefit rate 
(CBR) per RECIST v1.1. 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as assessed by the 
investigator in patients with selected solid tumors as measured by the duration of response 
(DOR) per RECIST v1.1. 
• 
To assess the efficacy of tislelizumab in combination with fruquintinib as in patients with 
selected solid tumors as measured by overall survival (OS). 
• 
To assess the safety of tislelizumab in combination with fruquintinib. 


 
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3.3. 
Exploratory Objective 
• 
To characterize the immunogenicity of tislelizumab and its time-pairing pharmacokinetic  
(PK) when given in combination with fruquintinib 
• 
To assess the PK of fruquintinib when given in combination with tislelizumab  
4. 
STUDY ENDPOINTS 
4.1. 
Primary Endpoint(s) 
• 
Safety and tolerability will be assessed throughout the study by monitoring adverse events 
(AEs) characterized by type, frequency, severity per National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, timing, seriousness, and 
relationship to study drug(s); and other safety assessments.  
• 
RP2D of fruquintinib in combination with tislelizumab. 
• 
ORR – defined as the proportion of patients whose best overall response is confirmed 
complete response (CR) or partial response (PR) as assessed by investigator per RECIST 
v1.1. 
4.2. 
Secondary Endpoints 
• 
PFS – defined as the time from the date of first dose to the date of the first determination of 
an objectively documented tumor progression as assessed by investigator per RECIST v1.1, 
or death, whichever occurs first.  
• 
DCR – defined as the as the proportion of patients whose best overall response is CR, PR, or 
stable disease (SD) as assessed by investigator per RECIST v1.1. 
• 
CBR – defined as the as the proportion of patients whose best overall response is CR, PR, or 
durable SD (Durable SD is defined as a SD with at least 24 weeks in duration) as assessed 
by investigator per RECIST v1.1. 
• 
DOR – defined as the time from the first occurrence of documented objective response to the 
time of progression as assessed by investigator per RECIST v1.1 or death from any cause, 
whichever occurs first.  
• 
OS - defined as the time from the date of first dose to the date of death due to any cause.  
• 
AEs characterized by type, frequency, severity (as graded by the NCI-CTCAE v5.0), timing, 
seriousness, and relationship to study drug(s); and other safety assessments. 
4.3. 
Exploratory Endpoints 
• 
Incidence of anti-tislelizumab antibodies (ADA), and its time-pairing serum concentration of 
tislelizumab. 
• 
Plasma concentrations and derived PK parameters of fruquintinib as data permit. 


 
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5. 
SAMPLE SIZE CONSIDERATIONS 
Approximately 6 to 12 DLT evaluable patients will be enrolled at Part 1. Patients enrolled in 
Part 1 at RP2D will be counted towards Part 2 by tumor types. Approximately 96 patients will be 
enrolled at maximum, and about 30 patients will be enrolled at RP2D per cohort to evaluate the 
preliminary efficacy, safety, and clinical pharmacokinetics.  
The study plans to enroll approximately 90 patients at RP2D : 
 Cohort A: Gastric cancer (n = 30) 
 Cohort B: Colorectal cancer (n = 30) 
 Cohort C: Non-small cell lung cancer (n=30) 
No formal hypothesis testing is planned in this trial.  
The 95% CIs when observing different numbers of responders among 30 patients in each cohort 
are presented in Table 1. 
Table 1: 
Estimate of 95% CI (%) Using Clopper-Pearson When Observing Different 
Number of Responders in 30 Patients 
Number of responders 
(ORR observed) 
2 (6.7%) 
3 (10.0%) 
5 (16.7%) 
6 (20.0%) 
8 (26.7%) 
9 (30.0%) 
(95% CI) (%) 
(0.82, 
22.07) 
(2.11, 
26.53) 
(5.64, 
34.72) 
(7.71, 
38.57) 
(12.28, 
45.89) 
(14.73, 
49.40) 
Abbreviations: CRC, colorectal cancer; GC, gastric cancer; MSS, microsatellite stable; NSCLC, non-small cell lung 
cancer; ORR, overall response rate. 
Notes: The historical response rate for the standard of care (SOC) in each cohort are the following: 
ORR data of the SOC for 3rd line MSS CRC: Fruquintinib (4.7%, Li et al 2018) / regorafenib (4%, Li et al 2015)  
ORR data of the SOC for 2nd line GC: Paclitaxel (16%) (Wilke et al 2014).  
ORR data of the SOC for 1st line PD-L1+ NSCLC: pembrolizumab (27%) (Mok et al 2019) 
6. 
STATISTICAL METHODS 
6.1. 
Analysis Sets 
The Safety Analysis Set (SAS) includes all patients who received ≥ 1 dose of study drug(s). This 
will be the primary analysis set for the safety and efficacy analyses. 
The Evaluable Analysis Set (EAS) includes all patients who received ≥ 1 dose of study drug(s), 
have evaluable disease at baseline, and have ≥ 1 evaluable postbaseline tumor response 
assessment unless any clinical PD or early death (within 17 weeks of first dose date). Outcomes 
in the Evaluable Analysis Set will be evaluated as a sensitivity analysis. 
The DLT Evaluable Analysis Set includes all patients who received at least 85% of the assigned 
total dose of fruquintinib and at least 67% (approximately two-thirds) of the assigned total dose 
of tislelizumab for the DLT assessment period. Additionally, patients who had a DLT event will 


 
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also be considered evaluable. Only patients from Part 1 are eligible for inclusion in the DLT 
Evaluable Analysis Set. This will be the analysis set for the DLT analyses. 
The PK Analysis Set includes all patients who received ≥ 1 dose of study drug(s) and have ≥ 1 
quantifiable postbaseline PK data.  
The ADA Analysis Set includes all patients who received ≥ 1 dose of study drug(s) and have a 
baseline and at least 1 postbaseline ADA result. 
6.2. 
Multiplicity Adjustment 
Not applicable. 
6.3. 
Data Analysis General Considerations 
6.3.1. 
Definitions and Computations 
Study drugs: Study drugs include tislelizumab and fruquintinib. 
Reference date: Reference date is defined as the date of the first dose of any study drugs. 
Study Day: Study Day will be calculated in reference to the date of the first dose of any study 
drug. For assessments conducted on or after the date of the first dose, the study day will be 
calculated as (assessment date – the first dose date + 1). For assessments conducted before the 
date of the first dose, study day is calculated as (assessment date – the first dose date). There is 
no study day 0. In the situation where the event date is partial or missing, the date will appear 
partial or missing in the listings. Study day and any corresponding durations will be presented 
based on the imputations specified in Appendix 1. 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before the first dose of study drug(s). 
Study Follow-up Duration (SFD): Study follow-up duration is defined as the duration from the 
reference date to death date if the patient died prior to data cutoff, or the study discontinuation 
date if the patient discontinued from study prior to data cutoff, otherwise to the data cutoff date. 
All calculations and analyses will be conducted using SAS® Version 9.4 or higher. 
6.3.2. 
Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
significant digit. 
 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded 
up to 1 significant digit. 
 Age will be calculated as the integer part of (date of informed consent – date of birth 
+ 1)/365.25. 


 
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 P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as 
‘> 0.9999’.  
 Duration of image-based event endpoints (such as PFS) will be based on the actual 
date the radiograph was obtained rather than the associated visit date. 
 For lab results collected as < or >, a numeric value, 0.0000000001 will be subtracted 
or added, respectively, to the value. 
 For by-visit observed data analyses, percentages will be calculated based on the 
number of patients with non-missing data as the denominator, unless otherwise 
specified. 
 For continuous endpoints, summary statistics will include n, mean, standard 
deviation, median, Q1, Q3 and range (minimum and maximum). 
 For discrete endpoints, summary statistics will include frequencies and percentages. 
 The unit of time duration is month unless otherwise specified. 
6.3.3. 
Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in this SAP. Missing 
dates or partially missing dates will be imputed conservatively for adverse events, disease history 
and prior therapy, prior/concomitant medications/procedures and subsequent anticancer therapy. 
Specific rules for the handling of missing or partially missing dates are provided in Appendix 1. 
By-visit endpoints will be analyzed using observed data unless otherwise specified. For observed 
data analyses, missing data will not be imputed, and only the observed records will be included. 
6.4. 
Patient Characteristics 
6.4.1. 
Patient Disposition 
The number (percentage) of patients enrolled, treated, discontinued from the study, reasons for 
discontinued from the study, and the study follow-up duration will be summarized in the safety 
analysis set. The patients who discontinued treatment and the primary reason for the end of 
treatment will be summarized among patients who were treated. 
6.4.2. 
Protocol Deviations 
Important protocol deviation criteria will be established, and patients with important protocol 
deviations will be identified and documented. Important protocol deviations will be summarized 
for all patients in the safety analysis set. They will also be listed by each category. Deviation 
categories are not mutually exclusive. Multiple deviations within the same category are counted 
once per patient. 


 
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6.4.3. 
Demographic and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized using descriptive statistics 
in the safety analysis set, including but not limited to the following variables: 
 Age (continuously and by categories [<65 or ≥65 years]) 
 Sex 
 Race 
 Country 
 Weight 
 BMI 
 ECOG performance status at baseline 
6.4.4. 
Disease History 
The number (percentage) of patients reporting a history of disease characteristics, as recorded on 
the eCRF, will be summarized in the safety analysis set. Disease characteristics include disease 
stage at initial diagnosis, metastatic disease at study entry, time from initial diagnosis to first 
dose date, time from initial diagnosis of metastatic disease to first dose date, histology/cytology, 
histologic grade.  
6.4.5. 
Prior Anticancer Drug Therapies and Surgeries 
Prior anti-cancer drug therapies, prior anti-cancer radiotherapy, and prior anti-cancer surgeries 
will be summarized in the safety analysis set. The variables include number of patients with any 
prior anti-cancer drug therapy, number of prior lines, reason(s) for discontinuation of last prior 
anticancer drug therapy, best overall response to the last prior anticancer drug therapy, time from 
end of last prior anticancer drug therapy to first dose date, treatment setting for prior anti-cancer 
drug therapies, number of patients with any prior anticancer surgery, time from last prior 
anticancer surgery to first dose date and number of patients with any prior anticancer 
radiotherapy, time from last prior anticancer radiotherapy to first dose date. The last prior 
anticancer drug therapy/surgery/radiotherapy is defined as the anticancer drug 
therapy/surgery/radiotherapy with the last end date. Prior anti-cancer drug therapies with the 
same sequence/regimen number are counted as one prior therapy. 
6.4.6. 
Prior and Concomitant Medications 
Prior medications are defined as medications that started before the first dose of study drug. 
Concomitant medications will be defined as medications that (1) started before the first dose of 
study drug and were continuing at the time of the first dose of study drug, or (2) started on or 
after the date of the first dose of study drug up to 30 days after the patient’s last dose or the 
initiation of a new anti-cancer therapy. 


 
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Prior and concomitant medications will be coded using the version of World Health Organization 
Drug Dictionary (WHO DD) drug codes version for the study at the time of database lock. They 
will be further classified to the appropriate Anatomical Therapeutic Chemical (ATC) code.  
The number (percentage) of patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred name in the safety analysis set.  
6.4.7. 
Medical History 
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version for the study at the time of database lock. The number (percentage) of patients reporting 
a history of any medical condition, as recorded on the CRF, will be summarized by system organ 
class and preferred term in the safety analysis set.  
Patient data listings of medical history will be provided. 
6.5. 
Efficacy Analysis 
No formal hypothesis testing is planned for efficacy analysis. All efficacy analyses will be 
performed descriptively by tumor types. 
6.5.1. 
Primary Efficacy Endpoint(s) 
ORR by Investigators 
Best Overall Response (BOR) which is defined as the best response recorded from the start of 
the study drug until progressive disease (PD), death, data cut or start of new anticancer therapy, 
whichever comes first.  
The ORR is defined as the percentage of patients whose BOR is confirmed CR or confirmed PR 
assessed by investigators per RECIST v1.1. Patients with no post-baseline response assessment (for 
any reason) will be considered as non-responders. The ORR will be summarized with descriptive 
statistics by tumor types and the corresponding two-sided 95% CIs calculated from Clopper-Pearson 
exact method will be also presented. The primary analysis of ORR is based on Safety Analysis Set 
and the sensitivity analysis of ORR is based on the Evaluable Analysis Set.  
A swimmer plot of time on treatment (i.e., duration of exposure), with indicators for the start and 
end of each response episode, will also be provided for selected tumor types with sufficient 
sample size. The patients will be ordered by the duration of exposure. Patients with the longest 
duration will be presented at the top of the plot. 
6.5.2. 
Secondary Efficacy Endpoints 
Progression Free Survival (PFS)  
Kaplan Meier methodology will be used to estimate median PFS, Q1 and Q3 of PFS, and the 
event-free rates at selected timepoints, e.g., 3, 6, 9, and 12 months based on Safety Analysis Set. 
95% Cis for median and other quantiles of PFS will be estimated using the method of 
Brookmeyer and Crowley (Brookmeyer and Crowley, 1982). And 95% Cis for event-free rates 
will be estimated using Greenwood’s formula (Greenwood, 1926). Kaplan Meier curves will be 


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constructed to provide a visual description of the PFS change with time for each tumor type. The 
censoring rules for the primary analysis of PFS are presented in Table 2. 
Table 2: 
Censoring Rules for Progression-free Survival Per RECIST Version 1.1 
Derivation rules 
Outcome 
No progression at the time of data 
cut-off or withdrawal from study or 
lost to follow up 
Date of last adequate radiologic assessment prior to 
or on date of data cut-off or withdrawal from study 
Censored 
New anticancer therapy started prior 
to disease progression or death 
Last adequate disease assessment before the new 
anticancer therapy  
Censored 
No baseline or post-baseline tumor 
assessments without death within 17 
weeks after date of the first dose 
Date of the first dose 
Censored 
No baseline or post-baseline tumor 
assessments and died within 17 
weeks after the first dose 
Date of death 
Event 
Death or progression after more than 
one missed tumor assessment * 
Date of last adequate radiologic assessment before 
missed tumor assessments 
Censored 
Progression documented at or 
between scheduled visits  
Date of first radiologic PD assessment 
Event 
With baseline and post -baseline 
tumor assessment and death before 
the first disease progression 
Date of death 
Event 
* More than one missed tumor assessment is identified in Appendix 2.
Disease control rate (DCR) 
DCR is defined as the proportion of patients whose best overall response is CR, PR, or stable 
disease (SD) as assessed by investigator per RECIST v1.1. DCR will be analyzed using methods 
similar to those described for ORR based on the Safety Analysis Set. 
Clinical benefit rate (CBR) 
CBR is defined as the proportion of patients whose best overall response is CR, PR, or durable 
SD (Durable SD is defined as a SD with at least 24 weeks in duration) as assessed by 
investigator per RECIST v1.1. CBR will be analyzed using methods similar to those described 
for ORR based on the Safety Analysis Set. 
Duration of Response (DOR) 


 
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DOR is defined as the time from the first determination of an objective response until the first 
documentation of PD as assessed by the investigator per RECIST v1.1, or death, whichever 
comes first. Duration of response analysis will only include patients with confirmed CR/PR. The 
censoring rule for DOR will follow the PFS censoring rule. Kaplan Meier methodology will be 
used to estimate the median duration, and the 95% confidence interval for the duration of 
response will be provided based on Safety Analysis Set. 
Waterfall plots will be provided for the maximum tumor shrinkage based on target lesion(s). The 
maximum tumor shrinkage based on target lesion(s) used in the plots will be listed for selected 
tumor types with sufficient sample size.  
Overall survival (OS)  
OS is defined as the time from first dose date to the documented death date for patients who died 
prior to or on the clinical cutoff date. For patients who are alive by the clinical cutoff date, OS 
will be censored at the last known alive date. The last known alive date will be defined as either 
the clinical data cutoff date for patients who are still on treatment, or last available date showing 
patients alive or cut-off date whichever comes first for other alive patients.  
Every effort should be made to ensure complete death dates. In the rare case, if day of death date 
is missing, death date is imputed as the max (last available date showing patients alive + 1, first 
day of month of death date). The patient with imputed death date will be considered as an event 
for OS analysis. 
The distribution of OS, including median, Q1, and Q3, and event-free rates at 3, 6, 9 and 12 
months, will be estimated using the Kaplan-Meier method by tumor types. 95% CIs for median, 
Q1, and Q3 of OS will be estimated using the method of Brookmeyer and Crowley (Brookmeyer 
and Crowley, 1982). The 95% CIs for event-free rates will be estimated using Greenwood's 
formula (Greenwood, 1926). Kaplan-Meier survival probabilities over time will be plotted. 
OS will be analyzed in the Safety Analysis Set. 
6.5.3. 
Post-Treatment Subsequent Anti-Cancer Therapy 
Post treatment anti-cancer therapy is defined as the anti-cancer therapy started after the last dose 
of study drug(s).  
A summary of number and percentage of patients who received any subsequent systemic 
anticancer therapy, radiotherapy, immunotherapy will be provided by tumor types based on 
safety analysis set.  
Separate flags of start date of new anti-cancer therapy for efficacy and safety analyses are 
derived individually. 
- As for efficacy analysis, start date of new anti-cancer therapy will be the earliest date of 
prohibited anti-cancer therapy taken during treatment. 
- The start date of new anti-cancer therapy in defining TEAE for safety analysis is always the 
first date of new systemic anti-cancer therapy taken after the last study treatment. 


 
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Tumor response per RECIST or event driven endpoints have not been commonly used for the 
efficacy evaluation of TCM. ORR, PFS or OS benefit of Chinese herbal medicines or Chinese 
patent medicines has not yet been established. Therefore, TCM will not be considered as new 
anti-cancer therapy in the efficacy and safety analysis. 
Patient data listings of post-treatment anti-cancer therapy, procedure, radiotherapy will be 
provided. 
 
6.6. 
Safety Analyses 
All safety analyses will be performed by tumor types based on safety analysis set except for 
analysis of DLT which is only applicable to patients in DLT Evaluable Set. Safety and 
tolerability will be assessed, where applicable, by incidence, severity, and change from baseline 
values for all relevant parameters including AEs, laboratory values (hematology, clinical 
chemistry and coagulation), vital signs, ECG findings and physical examination.  
6.6.1. 
Extent of Exposure 
The following measures of the extent of exposure will be summarized ： 
Duration of exposure (months): 
 
For tislelizumab, duration of exposure (months) is defined as (last date of exposure - 
first dose date + 1) / 30.4375. For treatment ongoing patients, use cutoff date as the 
'last date of exposure'; for patients discontinued from treatment, 'last date of exposure' 
is defined as the earliest date of cutoff date, death date, or last dose date + 27. 
 
For fruquintinib, duration of exposure (months) is defined as (last date of exposure – 
first dose date + 1) / 30.4375. For treatment ongoing patients, use cutoff date as the 
'last date of exposure'; for patients discontinued from treatment, 'last date of exposure' 
is defined as the earliest date of cutoff date, death date, or last dose date + 7.  
Number of treatment cycles received: defined as the total number of treatment cycles in which at 
least one dose of the study drug is administered. 
Total dose received per patient (mg): defined as the cumulative dose of the study drug during the 
treatment period of the study. 
Actual dose intensity (mg/cycle): defined as the total dose received by a patient divided by the 
duration of exposure. For tislelizumab, it will be calculated as 
 cumulative dose ∗28
date of last dose +  28 days –  date of first dose 
For fruquintinib, it will be calculated as 
cumulative dose ∗28
date of last dose +  8 day –  date of first dose 


 
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Relative dose intensity (%): defined as the ratio of the actual dose intensity and the planned dose 
intensity. Planned dose intensity is defined as the planned one cycle dose (mg). Planned dose 
intensity for tislelizumab and fruquintinib is 300mg/cycle and 5mg*21/cycle, respectively.  
Number (%) of patients with dose delay. 
Number (%) of patients with dose interruptions. 
Number (%) of patients with dose modifications. 
For tislelizumab, dose modifications include dose delay, administration interruption and infusion 
rate decrease.  
Reasons for dose delay, interruptions and modification of tislelizumab. 
Patient data listings will be provided for all dosing records, and for the above calculated 
summary statistics. 
6.6.2. 
Adverse Events  
AEs will be graded by the investigators using CTCAE version 5.0. The AE verbatim descriptions 
(investigator terms from the eCRF) will be classified into standardized medical terminology 
using MedDRA. Adverse events will be coded to the MedDRA (Version for the study at the time 
of database lock) lowest level term closest to the verbatim term, along with the linked MedDRA 
preferred term (PT) and primary system organ class (SOC). 
6.6.2.1        Treatment Emergent Adverse Event 
A treatment-emergent adverse event (TEAE) is defined as an AE that had onset or increase in 
severity level date on or after the date of the first dose of study drug through 30 days after the 
last dose (any component of combination treatment whichever is last) or the initiation of new 
anti-cancer therapy, whichever is earlier. Treatment-related TEAEs include those events 
considered by the investigator to be related to study drug or with a missing assessment of the 
causal relationship. Summary tables will generally focus on TEAEs and treatment-related 
TEAEs. An AE overview table, including the number and percentage of patients with TEAEs, 
treatment-emergent serious adverse events (SAEs), TEAEs with Grade 3 or above, TEAEs that 
led to death, TEAEs that led to treatment discontinuation, TEAEs that led to dose modification, 
treatment-related TEAEs, treatment-related version of any of the above categories will be provided 
by tumor types. The incidence of TEAEs will be reported as the number (percentage) of patients with 
TEAEs by SOC and PT. A patient will be counted only once by the highest severity grade within an 
SOC and PT, even if the patient experienced more than 1 TEAE within a specific SOC and PT. 
Summaries of the number (%) of patients with the below types of TEAE will be generated by tumor 
types: 
 All TEAEs  
o TEAEs by SOC and PT (Any Grade and ≥Grade 3) 
o TEAEs by PT 
o Tislelizumab related TEAEs by SOC and PT (Any Grade and ≥Grade 3) 
o Fruquintinib related TEAEs by SOC and PT (Any Grade and ≥Grade 3) 


 
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o Tislelizumab related TEAEs by PT 
o Fruquintinib related TEAEs by PT 
 Serious TEAEs  
o Serious TEAEs by SOC and PT 
o Tislelizumab related serious TEAEs by SOC and PT 
o Fruquintinib related serious TEAEs by SOC and PT 
o Serious TEAEs by PT 
 TEAEs leading to death  
o TEAEs leading to death by SOC and PT 
o Tislelizumab-related TEAEs leading to death by SOC and PT 
o Fruquintinib related TEAEs leading to death by SOC and PT 
 TEAEs leading to treatment discontinuation by SOC and PT 
o TEAEs leading to discontinuation of tislelizumab by SOC and PT 
o TEAEs leading to discontinuation of fruquintinib by SOC and PT 
 TEAEs leading to treatment modification by SOC and PT 
o TEAEs leading to dose modification of tislelizumab by SOC and PT 
o TEAEs leading to dose modification of fruquintinib by SOC and PT 
In addition, Dose-Limiting Toxicity Treatment-Emergent Adverse Events will be summarized by 
tumor types in DLT Evaluable Analysis Set. 
Patient data listings of all AEs, treatment-emergent or otherwise will be provided. 
6.6.2.2        Immune- Mediated Adverse Event 
Immune-mediated AEs (imAE) 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 study drug and up to 90 days 
from the last dose of tislelizumab, regardless of whether the patient starts a new anticancer therapy. If 
an imAE occurs outside of the above-mentioned TEAE window, it will not be classified as a TEAE. 
An overall summary table and separate summaries of the following incidence of immune-mediated 
adverse events will be provided: 
 imAEs by category and PT (Any Grade and ≥Grade 3) 
 Summary of imAEs Treated with Systemic Corticosteroids by Category 
 imAEs Outcome, Time to Onset, and Duration by Category 
Patient data listings of imAEs will be provided. 
 


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6.6.2.3        Infusion-related Adverse Event 
For infusion related reaction (IRR)s, a summary of incidence by SOC and PT (Any Grade and 
≥Grade 3) will be provided.   
6.6.2.4        Death 
All deaths and causes of death will be summarized by tumor types, including those occurred 
during the study treatment period and those reported during the survival follow-up period after 
treatment completion/discontinuation. 
Patient data listings of deaths will be provided. 
6.6.3. 
Laboratory Values 
Laboratory safety tests will be evaluated for selected parameters described in Table 3. 
Laboratory parameters (e.g., hematology, chemistry, and coagulation) that are graded in NCI 
CTCAE Version 5.0 or higher will be summarized by shifts from baseline CTCAE grades to 
maximum post-baseline grades. In the summary of laboratory parameters by CTCAE grade, 
parameters with CTCAE grading in both high and low directions will be summarized separately. 
The summary tables will report laboratory assessments up to 30 days of the last dose date. 
Box-whisker plots will be generated for parameters of interest. 
Laboratory parameters for potential Hy’s Law for liver injury and abnormal thyroid function will 
also be summarized.  
Table 3:      Clinical Laboratory Assessment 
Serum 
Chemistry 
Hematology 
Coagulation a 
Thyroid 
Function 
Alkaline 
phosphatase 
Hemoglobin 
Prothrombin time 
TSH 
Alanine 
aminotransferase 
Platelet counts 
Partial thromboplastin 
time or activated 
partial thromboplastin 
time  
T3 
Aspartate 
aminotransferase 
White blood cell 
count  
International 
normalized ratio 
T4 
Albumin 
Lymphocyte 
count 
Total bilirubin 
Neutrophil 


 
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count 
Direct bilirubin 
 
 
 
Potassium 
 
 
 
Sodium  
 
 
 
Total calcium a 
 
 
 
Creatinine 
 
 
 
Lactate 
dehydrogenase 
 
 
 
Total protein 
 
 
 
Creatine Kinase 
(CK) b 
 
 
 
CK-MB b 
 
 
 
Abbreviations: CK-MB, creatine kinase cardiac isoenzyme;  
a Total calcium values will be corrected for patients with hypoproteinemia. 
b All patients will have creatine kinase and CK-MB testing at screening, and to be repeated at all 
scheduled visits during the first 2 treatment cycles, all predose assessments from Cycle 3 
onwards, and at the End-of-Treatment/Safety Follow-up visit. If CK-MB fractionation is not 
available, assess troponin I and/or troponin T instead.  
6.6.4. 
Vital Signs 
Patient data listings of vital signs will be provided. 
6.6.5. 
Electrocardiograms (ECG) 
The number and percentage of patients satisfying the following QTcF conditions at any time 
post-baseline will be summarized: 
 > 450, > 480, or > 500 msec   
 > 30 or > 60 msec maximum increase from baseline 
6.6.6. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
A shift table from baseline to worst post-baseline in ECOG performance status will be 
summarized. ECOG status will be summarized by visit. 


 
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6.7. 
Pharmacokinetic Analyses 
The following analysis plan provides the framework for the summarization of the PK data from 
this study. The objective is to assess serum tislelizumab and plasma fruquintinib and its major 
metabolite M11 (also known as HM5025423) PK profile. The PK analysis will be performed on 
PK analysis set. 
6.7.1. 
Pharmacokinetic Analysis of Fruquintinib 
For fruquintinib and its major metabolite M11 (also called HM5025423), serial and sparse PK 
samples will be collected for part 1 and sparse samples will be collected for part 2. 
• 
Part 1 serial PK: pre-dose, 1h, 2h, 4h, 6h, 8h post dosing on C1D1 
• 
Part 1 sparse PK: pre-dose on C1D15, C2D1, C2D15, C4D1, C7D1, and C13D1 
• 
Part 2 sparse PK: pre-dose and 4h post dosing of C1D1; pre-dose on C1D15, C2D1, 
C2D15, C4D1, C7D1, and C13D1 
Pharmacokinetic Concentrations Analysis 
The concentration and time data of fruquintinib and M11 will be listed individually and 
summarized using descriptive statistics for both serial and sparse PK samples. The PK analyst 
will appropriately flag and annotate treatment of any anomalous concentrations, exclusions and 
any special treatment for descriptive statistics and plots.  
The following conventions will be used for reporting descriptive statistics for concentration data.  
 
PK concentrations should be reported in listings at the same level of precision as that in the 
source data. 
 
If a concentration at a given time point is below the assay quantification limit (BLQ), the 
concentration shall be reported as the term “BLQ” with the lower limit of quantitation 
(LLOQ) defined in the footnotes. BLQ values shall be treated as zero for computation of 
descriptive statistics. BLQ values will not be included for calculations of geometric mean 
and geometric coefficient of variation (CV%). 
 
If a concentration at a given time point is missing, it shall be reported as a missing value. 
Missing values may be defined in a bioanalytical source as “NS” (no sample), “NR” (no 
result), “IS” (insufficient sample), etc. If missing data are not identified in the bioanalytical 
source (i.e., the record is missing), the reporting convention of “NS" shall be utilized. 
 
If the calculated mean concentration is BLQ, the mean value shall be reported in outputs 
(such as tables) as BLQ and SD and geometric CV% shall be reported as ND (not 
determined). Minimum, median, and maximum may be reported. 
Plots of Pharmacokinetic Plasma Concentrations  
For patients with serial plasma samples, plasma concentration versus time data will be plotted 
individually (using actual time) and summarized (using plan time) graphically using arithmetic 
mean (±SD) plots by analyst, respectively. Each plot will be showed in linear (i.e., original) scale 
and semi-logarithmic scale of time. Arithmetic mean concentrations that are BLQ shall be set to 
zero for plotting on linear scale but not shown on log-linear scale. 


 
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PK Parameters Analysis 
Actual dose and blood draw times will be used to calculate the PK parameters. Parameters will 
be listed individually and summarized using descriptive statistics. PK parameters will be 
estimated based on non-compartmental analysis methods and will be computed using Phoenix 
WinNonlin® Version 8.0. or higher. Calculation and presentation of PK parameters will be 
based on the Work Instruction: Best Practice Guidance: Non-Compartmental Pharmacokinetic 
Data Analysis for Clinical Studies. Version 1.0, Document Number VV-QDOC-13140. 
The PK parameter estimates profile includes but is not limited to the following. 
Parameter 
(Units) 
Definition 
Method of Determination 
AUCt  
(ng*h/mL) 
Area under the concentration-time 
curve from time zero to time t (8 
hour) 
Calculated using the linear up/log down 
variant of the trapezoidal rule 
AUCinf  
(ng*h/mL) 
Area under the concentration-time 
curve from time zero to infinite time 
with extrapolation of the terminal 
phase 
Calculated using the linear up/log down 
variant of the trapezoidal rule 
Cmax  
(ng/mL) 
Maximum observed concentration  
Reported value 
Tmax (h) 
Time of the maximum observed 
concentration  
Actual elapsed time for observed Cmax 
Tlast (h) 
Time of the last quantifiable 
concentration 
Actual elapsed time for observed the 
last quantifiable concentration 
t1/2 (h) 
Apparent terminal elimination half-
life  
ln(2)/λz, where λz is the first-order rate 
constant of drug associated with the 
terminal portion of the curve 
CL/F (L/h) 
Apparent drug clearance 
Calculated as Dose/(AUCinf*F), where 
F is the fraction of dose absorbed 
Vz/F (L) 
Apparent volume 
Calculated as CL/F/λz, where λz is the 
first-order rate constant of drug 
associated with the terminal portion of 
the curve 
%AUCextrap 
(%) 
 
Percentage of AUC due to 
extrapolation from the last 
quantifiable concentration to infinity 
Calculated as (AUCinf-
AUClast)/AUCinf*100 
The parameters Cmax, Tmax and Tlast will be obtained directly from the concentration-time profiles. 
If Cmax occurs at more than 1 timepoint, Tmax will be assigned to the first occurrence of Cmax. 
 


 
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The PK analyst will appropriately flag and annotate treatment of any anomalous PK parameters, 
exclusions and any special treatment for descriptive statistics. The following conventions will be 
used for reporting descriptive statistics for PK parameters data: 
 
All the PK parameters except Tmax, Tlast and t1/2 should have at least the following summary 
statistics: sample size (n), mean, standard deviation (SD), coefficient of variance (CV%), 
median, minimum, maximum, geometric mean, geometric CV%. 
 
For in-text tables, geometric mean (geometric CV%) will be the default method of reporting 
PK parameters. Tmax and Tlast should be presented as median, range (minimum, maximum), 
when presenting the summary statistics.  
 
For any parameters that n ≤ 2, SD should not be presented. 
 
The units for all PK parameters will be provided. 
 
It is recognized that the number of decimals in reported concentrations, for example: 
“9632.94401 ng/mL” or “9.963294401 ug/mL" are highly improbable and will be queried 
(since bioanalytical assays generally do not have this level of precision). Usually the first-in-
human dose escalation trial will provide the numerical range of PK parameters e.g., AUC 
range from 10 to 10,000 ng.hr/mL and Cmax range from 1 to 1000 ng/mL. 
 
In this scenario, for reporting PK parameters such as AUC and Cmax, the following guidance 
is provided for rounding: 
- If the numerical value is below 100 then one decimal place may be used e.g., 0.1 or 99.9. 
- For values ranging from >100, whole numbers should be used e.g., 100 or 9999. 
- If > 10,000 the clinical pharmacologist may decide on changing units e.g., from ng/ml to 
μg /ml. 
- For reporting times e.g., for Tmax, Tlast or t1/2, if <1 hour uses 2 decimals; time up to 24 hour 
should be reported to one decimal place e.g., 23.5 hour, time >24 hour should be rounded to 
nearest whole number e.g. 105 hr. 
6.7.2. 
Pharmacokinetic Analysis of Tislelizumab 
Blood samples will be collected for tislelizumab PK evaluation at predose (Ctrough) and postdose 
(Cmax); the serum concentration data will be tabulated and summarized using descriptive 
statistics by the visit/cycle at which these samples are collected.  
6.8. 
Immunogenicity Analyses 
In part 1 and part 2, ADA samples for tislelizumab should be collected on Day 1 (Predose of 
tislelizumab, -60 min) of Cycles 1, 2, 4, 7 and 13, and at the mandatory safety follow-up visit. 
All samples should be drawn at the same time as the PK blood collection for pre-dose of 
tislelizumab. 
The scope of ADA calculations used for characterizing clinical immunogenicity depend on the 
incidence and kinetics of detected (ADA). Therefore, not all parameters described below may be 
derived or additional parameters may be added. 


 
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The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of subjects who develop detectable ADAs.  The incidence of positive and neutralizing 
ADAs will be reported for ADA-evaluable subjects according to the following definitions: 
 ADA-evaluable patient: Number of patients with reportable non-missing baseline result 
and at least one reportable sample taken after tislelizumab administration during the 
treatment or follow-up observation period with reportable result (used for computing 
treatment-induced ADA incidence). Baseline-positive ADA-evaluable patient is an ADA-
evaluable patient with positive ADA result. 
 Treatment-emergent ADA: The sum of both treatment-boosted and treatment-induced 
ADA-positive patients. Synonymous with “ADA Incidence”. 
 Treatment-induced ADA: ADA-evaluable patients that were ADA-negative at baseline 
and ADA-positive following administration of tislelizumab. 
 Treatment-boosted ADA: Baseline-positive ADA-evaluable patient with significant 
increases (4-fold or higher) in ADA titer after tislelizumab administration.  
 Persistent ADA response: Treatment-induced ADA detected at two or more sampling 
time points during the treatment (including follow-up period if any), where the first and 
last ADA-positive samples (irrespective of any negative samples in between) are 
separated by a period of 16 weeks or longer, or treatment induced ADA incidence in the 
last sampling time point. 
 Transient ADA response: Treatment-induced ADA that is not considered as persistent 
ADA.  
 Neutralizing ADA: patients with positive NAb. 
The individual immunogenicity results will also be listed. 
Additional ADA analyses (such as the effect of immunogenicity on PK, efficacy, and safety) 
may be conducted if deemed necessary and will be described in a separate analysis plan. 
7. 
INTERIM ANALYSES 
No interim analysis is planned.  
8. 
CHANGES IN THE PLANNED ANALYSIS 
Table 4 summarizes the major changes in the planned analyses from BGB-A317-fruquintinib-
201 Protocol Amendment 1.0, dated on 16 December 2020. The changes are all made before 
database lock and not based on any comparative data. 
Table 4: 
Statistical Analysis Plan Changes 
SAP 
version  
Approval 
date  
Change made 
from  
Rationale of the change  Description of the change  
1.0  
This version  Protocol 
To clarify the definition Change the “death occurred before the first 


 
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Amendment 1.0 of the evaluable analysis 
set.   
 
postbaseline tumor assessment” from the 
definition of evaluable analysis set in the 
protocol into “early death (within 17 weeks 
of the first dose date)” in the SAP. 
1.0  
This version  Protocol 
Amendment 1.0 
To align with BeiGene’s 
current standard. 
The definition of TEAE is different between 
protocol and SAP. In the protocol, “TEAE 
classification also applies to imAEs recorded 
up to 90 days after the last dose of 
tislelizumab, regardless of whether or not the 
patient starts a new anticancer therapy.” In 
this SAP, “If an imAE occurs outside of the 
above-mentioned TEAE window, it will not 
be classified as a TEAE”. The update of 
TEAE window streamlines the TEAE 
derivation so all TEAEs can be identified 
programmatically instead of relying on the 
manual medically review of imAE.  
 
9. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (Version 1.1). Eur J Cancer. 2009;45(2):228-47. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 
1982;38:29-41. 
Greenwood M. The Natural Duration of Cancer. Reports on Public health and medical subjects. 
1926;33:1-26. 
Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best 
supportive care in Asian patients with previously treated metastatic colorectal cancer 
(CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 
2015;16(6):619-29. 
Li J, Qin S, Xu RH, et al. Effect of Fruquintinib vs Placebo on Overall Survival in Patients With 
Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial. 
JAMA. 2018;319(24):2486-2496. 
Mok TSK, Wu YL, Kudaba I et al. Pembrolizumab versus chemotherapy for previously 
untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung  cancer 
(KEYNOTE-042): a randomised, open-label, controlled, Phase III trial. 2019; 393(10183):1819-
1830. 
Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus 
paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction 
adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol. 
2014;15(11):1224-35. 


 
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APPENDIX 1. IMPUTATION OF MISSING OR PARTIALLY MISSING 
DATES 
In general, missing or partial dates will not be imputed at the data level. The following rules will 
apply for the specific analysis and summary purposes mentioned below only. 
1.1 Prior/concomitant medications/procedures  
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute partial dates for medications.   
If start date of a medication/therapy/procedure is partially missing, impute as follows: 
 If both month and day are missing, then set to January 01 
 If only day is missing, then set to the first of the month 
 If the imputed start date > death date, then set to death date 
If end date of a medication/therapy/procedure is partially missing, impute as follows: 
 If both month and day are missing, then set to December 31 
 If only day is missing, then set to last day of the month 
 If the imputed end date > death date, then set to death date 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
1.2 Adverse events  
If year of the start date is missing or start date is completely missing, do not impute.  Impute AE 
end date first if both AE start date and end date are partially missing. 
If end date of an adverse event is partially missing, impute as follows: 
 If both month and day are missing, then set to December 31 
 If only day is missing, then set to last day of the month 
 If the imputed end date > min(death date, end of study date), then set to min (death 
date, end of study date) 
If year of the end date is missing or end date is completely missing, do not impute. 
 
If start date of an adverse event is partially missing, impute as follows: 
 If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
 If both month and day are missing and year ≠ year of treatment start date, then set to 


 
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January 01 
 If day is missing and month and year = month and year of treatment start date, the set 
to treatment start date 
 If day is missing and month and year ≠ month and year of treatment start date, the set 
to first of the month 
 If the imputed AE start date is after AE end date (maybe imputed), then update AE 
start date  
with AE end date as final imputed AE start date 
 If the imputed end date > min (death date, end of study date), then set to min (death 
date, end of study date) 
 
1.3 Disease history and prior therapy (drug, surgery/procedure, radiotherapy)  
For prior therapy, impute end date first.  
If end date of a prior therapy is partially missing, impute as follows: 
 If both month and day are missing, then set to December 31 
 If only day is missing, then set to last day of the month 
 If the imputed end date > first dose date, then set to first dose date -1 
If start date of a prior therapy is partially missing, impute as follows: 
 If both month and day are missing, then set to January 01 
 If only day is missing, then set to the first of the month 
 If the imputed start date > end date, then set to end date  
The following rules will be applied to impute partial dates such as initial diagnosis date, initial 
BCLC staging date, relapse date, therapy date (start/end date), or surgery date etc. 
If date of a disease history is partially missing, impute as follows: 
 If both month and day are missing, then set to January 01 
 If only day is missing, then set to the first of the month 
 If the imputed date > first dose date, then set to first dose date – 1 
If diagnosis date of metastatic disease/locally advanced is partially missing, impute as follows: 
 If both month and day are missing, then set to January 01 
 If only day is missing, then set to the first of the month 
 If the imputed date > first dose date, then set to first dose date – 1 
 If the imputed date < (imputed) date of initial diagnosis date, then set to initial diagnosis 


 
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date. 
If the date of response to prior therapy is partially missing, impute as follows: 
 If both month and day are missing, then set to January 01 
 If only day is missing, then set to the first of the month 
 If the imputed date > first dose date, then set to first dose date – 1 
If the imputed date < the start date of prior therapy, then set to the start date of prior therapy 
+1. 
 
1.4 Subsequent anti-cancer therapy  
If start date of subsequent anti-cancer therapy is partially missing, impute as follows: 
 If both month and day are missing, then set to December 31 
 If only day is missing, then set to last day of the month 
 If the imputed start date > min (death date, study discontinuation date, data cutoff 
date, start date of the next subsequent anti-cancer therapy), then set to min (death 
date, study discontinuation date, data cutoff date, start date of the next subsequent 
therapy) 
If stop date of is partially missing, impute as follows:  
 If both month and day are missing, then set to December 31  
 If only day is missing, then set to last day of the month  
 If the imputed stop date > min (death date, study discontinuation date, data cutoff date, 
start date of the next subsequent anti-cancer therapy), then set to min (death date, study 
discontinuation date, data cutoff date, start date of the next subsequent therapy)  
The (imputed) stop date must be after or equal to the (imputed) start date  
 
If year of the start date/stop date is missing, do not impute. 
 
Note: if the imputed subsequent anti-cancer therapy date collected from CRF “post-treatment 
discontinuation anti-cancer systemic therapy” or “post-treatment discontinuation anti-cancer 
procedure” page is before the last dosing date, send data query. 
 
1.5 Fruquintinib administration date and actual dose 
If end dose date of fruquintinib for certain cycle is missing, set to start dose date of this cycle. 
If actual dose is ‘other’, but other dose is not specified, set actual dose as 0. 
 


 
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27 February 2024 
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APPENDIX 2. RULES FOR IDENTIFYING MISSING TUMOR 
ASSESSMENTS 
Identifying two missing tumor assessments 
1) Input scheduled TA visit list
a.
(8wk-16wk-24wk-32wk-40wk-48wk-58wk) for this study with TA as every 8
weeks for the first 56 weeks, then every 12 weeks thereafter
2) Identify last evaluable TA before PD or death (--LPTADT) and map it to the closest
scheduled visit (--LPTADT_WK).
a.
In the event of unscheduled TA, choose the closest scheduled visit number (e.g.,
8wk) as –LPTADT_WK. It can be achieved programmatically by following the
classification rule (e.g., defining thresholds) depicted in Table 5 below.  (The
team can consider mapping all tumor visits if the scheduled visits are uncleaned
or questionable)
b. Otherwise, assign the scheduled visit number (assuming it is coded correctly) to --
LPTADT_WK
3) Find the 2nd TA visit after LPTADT_WK according to the list in step 1 (-
LPTADT_WK_2)
a.
If LPTADT_WK_2+1wk (assuming 1 week TA window) < earliest of PD/death
date, then censor PFS at the –LPTADT
b. Otherwise, PFS event at the earliest of PD/death date
Table 5 shows how to assign unscheduled TA to a schedule visit. The threshold column is 
defined as the mid-point between current and next visit (except for baseline); it is the upper limit 
for LPTADT to be mapped to the prior scheduled assessment (step 2a above). For example, if 
LPTADT is Week 44 for an unscheduled visit, it will be mapped to Week 40 TA since it is 
within the threshold for Week 40. Assuming it is SD and the subsequent TA of the patient is PD 
after Week 57, PFS will be censored at LPTADT (Week 40); had the PD occurred prior to Week 
57, it would be counted as an PFS event. 
Table 5:      Example of scheduled tumor assessments with time window 
Weeks 
Scheduled week -
1 
Scheduled 
week 
Scheduled 
week+1 
Threshold 
Baseline 
Baseline 
Every 8 weeks 
for the first 56 
weeks 
Week 7 
Week 8 
Week 9 
Week 12 
Week 15 
Week 16 
Week 17 
Week 20 
Week 23 
Week 24 
Week 25 
Week 28 
Week 31 
Week 32 
Week 33 
Week 36 
Week 39 
Week 40 
Week 41 
Week 44 
Week 47 
Week 48 
Week 49 
Week 52 
Week 55 
Week 56 
Week 57 
Week 62 
 Every 12 
weeks 
Week 67 
Week 68 
Week 69 
Week 74 
Week 79 
Week 80 
Week 81 
Week 86 


 
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thereafter 
  
Week 91 
Week 92 
Week 93 
… 
 … 
 … 
 … 
 …