Conditions: Advanced Solid Tumor
Keywords: Solid tumors
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 58
Healthy volunteers: no

Brief summary:
This clinical trial evaluated the safety and potential benefits of combining two cancer treatments, tislelizumab and lenvatinib, in Chinese participants with advanced or metastatic cancers, including lung, head and neck, bladder, kidney, and stomach cancer. The study included two parts: the first part assessed how safe the drug combination was, and the second part examined how well it worked.

A small group of participants initially received the drugs to determine the appropriate dose, and if the treatment was well tolerated, additional participants were treated at that dose. Participants remained on the treatment unless their cancer progressed, they experienced serious side effects, or they chose to stop.

Detailed description:

Arms:
arm 1: Participants with advanced or metastatic unresectable solid tumors were enrolled to receive 400 mg of tislelizumab administered on Day 1 of each 6-week cycle, along with 20 mg of lenvatinib self-administered orally once daily, to determine the recommended Part 2 dose (RP2D). arm 2: Participants with previously untreated, advanced or metastatic SCCHN received tislelizumab (400 mg administered intravenously \[IV\] every 6 weeks \[Q6W\]) in combination with lenvatinib (20 mg taken orally once daily \[QD\]) until disease progression, start of new anticancer therapy, unacceptable toxicity, withdrawal of consent, or study termination. arm 3: Systemic therapy naive participants with advanced or metastatic RCC received tislelizumab (400 mg IV Q6W) plus lenvatinib (20 mg orally QD) until disease progression, start of new anticancer therapy, unacceptable toxicity, withdrawal of consent, or study termination. arm 4: Participants with NSCLC expressing programmed cell death-ligand 1 (PD-L1) in ≥1% of tumor cells (TC ≥1%) and who had not received prior systemic therapy received tislelizumab (400 mg IV Q6W) and lenvatinib (20 mg orally QD) until disease progression, start of new anticancer therapy, unacceptable toxicity, withdrawal of consent, or study termination; this cohort was closed early based on emerging external data. arm 5: Participants with advanced GC who had received one prior line of systemic therapy were enrolled to receive tislelizumab and lenvatinib at the RP2D (tislelizumab 400 mg IV Q6W; lenvatinib 20 mg orally QD) until disease progression, start of new anticancer therapy, unacceptable toxicity, withdrawal of consent, or study termination; this cohort was closed early due to changes in the first-line standard of care. arm 6: Participants with cisplatin ineligible, systemic therapy naive advanced UC, were to be treated with tislelizumab (400 mg IV Q6W) and lenvatinib (20 mg orally QD). This cohort was closed prior to any participant enrollment based on emerging external data.

Interventions: intervention 1: lenvatinib intervention 2: Tislelizumab
Intervention descriptions: intervention 1: Administered at the dose of 20 mg orally, once daily. intervention 2: 400 mg administered intravenously on Day 1 of each 42-day cycle

Protocol document:
Prot_000.pdf: 
BGB-A317-212 
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03 November 2022 
 
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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 LENVATINIB IN 
PATIENTS WITH SELECTED SOLID TUMORS  
Protocol Number: 
BGB-A317-212 
Phase: 
2 
Investigational Product(s): 
Tislelizumab (BGB-A317), lenvatinib (a generic drug) 
Proposed Indication(s): 
Advanced Solid Tumors 
Sponsor: 
BeiGene (Shanghai) Co., Ltd. 
 
 
 
 
Sponsor Medical Monitor: 
 
Work Telephone:
 
Email: 
 
Original Protocol  
Protocol Amendment 1.0 
Protocol Amendment 2.0 
27 November 2020 
01 November 2021 
03 November 2022 
 
 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd., and its 
subsidiaries. This document is for use by individuals and their designated representatives for their 
confidential review, consideration, and/or participation in investigational trial(s). This document may not 
be copied or distributed for review by any unauthorized individuals without the prior written authorization 
of BeiGene, Ltd., or one of its subsidiaries. Your acceptance of this document constitutes agreement that 
you will not disclose the information contained herein to others without prior written authorization from 
BeiGene, Ltd., or one of its subsidiaries. 
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FINAL PROTOCOL APPROVAL SHEET  
 
A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF TISLELIZUMAB IN COMBINATION WITH 
LENVATINIB IN PATIENTS WITH SELECTED SOLID TUMORS 
BeiGene, Ltd., Approval: 
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INVESTIGATOR SIGNATURE PAGE  
 
Protocol Title: 
A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
TISLELIZUMAB IN COMBINATION WITH LENVATINIB IN 
PATIENTS WITH SELECTED SOLID TUMORS 
 
Protocol Identifier: 
BGB-A317-212 
 
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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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 ................................................................................22 
1. 
INTRODUCTION AND RATIONALES ..................................................................24 
1.1. 
Introduction .................................................................................................................24 
1.2. 
Lenvatinib ...................................................................................................................25 
1.2.1. 
Pharmacology .............................................................................................................25 
1.2.2. 
Clinical Experience .....................................................................................................26 
1.2.2.1. 
Clinical Pharmacology ................................................................................................26 
1.2.2.2. 
Clinical Efficacy and Safety .......................................................................................27 
1.3. 
Tislelizumab ...............................................................................................................29 
1.3.1. 
Pharmacology .............................................................................................................29 
1.3.2. 
Clinical Experience .....................................................................................................29 
1.3.2.1. 
Safety ..........................................................................................................................29 
1.3.2.2. 
Clinical Pharmacology ................................................................................................31 
1.3.2.3. 
Efficacy .......................................................................................................................32 
1.4. 
Study Rationale ...........................................................................................................33 
1.4.1. 
Rationale for the Dosing Regimen .............................................................................33 
1.4.1.1. 
Lenvatinib Starting Dose ............................................................................................33 
1.4.1.2. 
Tislelizumab ...............................................................................................................35 
1.4.2. 
Rationale for Combination of Tislelizumab and Lenvatinib in the Treatment 
of Advanced Solid Tumors .........................................................................................35 
1.4.3. 
Rationale for Tumor Type(s) ......................................................................................36 
1.4.3.1. 
Non-Small Cell Lung Cancer .....................................................................................36 
1.4.3.2. 
Squamous Cell Carcinoma of Head and Neck ...........................................................37 
1.4.3.3. 
Urothelial Carcinoma ..................................................................................................38 
1.4.3.4. 
Renal Cell Carcinoma .................................................................................................39 
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1.4.3.5. 
Gastric Cancer ............................................................................................................40 
1.4.4. 
Rationale for Biomarker Strategy ...............................................................................41 
1.5. 
Benefit-Risk Assessment ............................................................................................42 
1.6. 
Study Conduct ............................................................................................................43 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................44 
2.1. 
Study Objectives and Endpoints for Part 1 (Safety run-in) ........................................44 
2.2. 
Study Objectives and Endpoints for Part 2 (Expansion) ............................................44 
3. 
STUDY DESIGN .......................................................................................................45 
3.1. 
Summary of Study Design ..........................................................................................45 
3.2. 
Duration of Study .......................................................................................................47 
3.3. 
Study Design of Part 1 ................................................................................................47 
3.3.1. 
Starting Dose and Dose De-Escalation Approach ......................................................47 
3.3.2. 
Rules for Dose De-Escalation .....................................................................................47 
3.3.3. 
Assessment of Dose-Limiting Toxicity ......................................................................48 
3.3.4. 
Dose-Limiting Toxicity Definition .............................................................................48 
3.4. 
Study Design of Part 2 ................................................................................................49 
4. 
STUDY POPULATION .............................................................................................51 
4.1. 
Inclusion Criteria ........................................................................................................51 
4.2. 
Exclusion Criteria .......................................................................................................54 
5. 
STUDY TREATMENT ..............................................................................................58 
5.1. 
Formulation, Packaging, and Handling ......................................................................58 
5.1.1. 
Lenvatinib ...................................................................................................................58 
5.1.2. 
Tislelizumab ...............................................................................................................58 
5.2. 
Dosage, Administration, and Compliance ..................................................................58 
5.2.1. 
Part 1 ...........................................................................................................................58 
5.2.1.1. 
Tislelizumab ...............................................................................................................59 
5.2.1.2. 
Lenvatinib ...................................................................................................................59 
5.2.2. 
Part 2 ...........................................................................................................................60 
5.3. 
Overdose .....................................................................................................................60 
5.4. 
Dose Delay or Modification .......................................................................................60 
5.4.1. 
Dose Delay or Modification for Tislelizumab ............................................................60 
5.4.2. 
Dose Delay or Modification for Lenvatinib ...............................................................61 
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6. 
PRIOR AND CONCOMITANT THERAPY .............................................................65 
6.1. 
Prior Therapy ..............................................................................................................65 
6.2. 
Permitted Concomitant Medications/Procedures .......................................................65 
6.2.1. 
Systemic Corticosteroids ............................................................................................66 
6.2.2. 
Hepatitis B Treatment .................................................................................................66 
6.2.3. 
Radiation Therapy ......................................................................................................66 
6.3. 
Prohibited Concomitant Medications/Procedures ......................................................67 
6.4. 
Medications to Be Used with Caution ........................................................................67 
6.5. 
Drug-drug Interaction .................................................................................................68 
6.5.1. 
Drug-drug Interaction between Tislelizumab and Lenvatinib ....................................68 
6.5.2. 
Drug-drug Interaction between Lenvatinib and Other Drugs .....................................68 
7. 
STUDY PERIODS, VISITS, OR PROCEDURES ....................................................69 
7.1. 
Screening Period .........................................................................................................69 
7.1.1. 
Informed Consent and Screening Log ........................................................................69 
7.1.2. 
Demographics .............................................................................................................69 
7.2. 
Enrollment ..................................................................................................................69 
7.3. 
Treatment Period ........................................................................................................70 
7.4. 
End-of-Treatment Visit ...............................................................................................70 
7.5. 
Follow-up Periods .......................................................................................................70 
7.5.1. 
Safety Follow-up Period .............................................................................................70 
7.5.2. 
Efficacy Follow-up Period ..........................................................................................70 
7.5.3. 
Survival Follow-up Period ..........................................................................................71 
7.5.4. 
Lost to Follow-up .......................................................................................................71 
7.6. 
Discontinuation From Study Treatment or From the Study .......................................71 
7.6.1. 
Patient Discontinuation From Study Treatment (End of Treatment for an 
Individual Patient) ......................................................................................................71 
7.6.2. 
Patient Discontinuation From the Study (End of Study for an Individual 
Patient) ........................................................................................................................72 
7.7. 
End of Study ...............................................................................................................72 
8. 
STUDY ASSESSMENTS ..........................................................................................73 
8.1. 
Screening Assessments ...............................................................................................73 
8.1.1. 
Pulmonary Function Tests ..........................................................................................73 
8.2. 
Safety Assessments .....................................................................................................74 
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8.2.1. 
Vital Signs ..................................................................................................................74 
8.2.2. 
Physical Examinations ................................................................................................74 
8.2.3. 
Eastern Cooperative Oncology Group Performance Status ........................................74 
8.2.4. 
Laboratory Safety Tests ..............................................................................................74 
8.2.4.1. 
Cardiac Enzyme Monitoring .......................................................................................75 
8.2.5. 
Electrocardiograms .....................................................................................................75 
8.2.6. 
Adverse Events ...........................................................................................................75 
8.2.7. 
Hepatitis B and C Testing ...........................................................................................76 
8.3. 
Tumor and Response Evaluations ..............................................................................76 
8.4. 
Pharmacokinetic Assessment and Antidrug Antibody Testing ..................................78 
8.5. 
Biomarkers ..................................................................................................................78 
8.6. 
Visit Windows ............................................................................................................79 
8.7. 
Unscheduled Visits .....................................................................................................79 
9. 
SAFETY MONITORING AND REPORTING .........................................................80 
9.1. 
Risks Associated With study drugs ............................................................................80 
9.1.1. 
Risks Associated With Tislelizumab ..........................................................................80 
9.1.2. 
Risks Associated With Lenvatinib ..............................................................................80 
9.2. 
General Plan to Manage Safety Concerns ..................................................................80 
9.2.1. 
Eligibility Criteria .......................................................................................................80 
9.2.2. 
Abnormal Liver Function Tests ..................................................................................81 
9.2.3. 
Safety Monitoring Plan ...............................................................................................81 
9.3. 
Adverse Events ...........................................................................................................81 
9.3.1. 
Definitions and Reporting ...........................................................................................81 
9.3.2. 
Assessment of Severity ...............................................................................................82 
9.3.3. 
Assessment of Causality .............................................................................................83 
9.3.4. 
Follow-up of Adverse Events .....................................................................................83 
9.3.5. 
Laboratory Test Abnormalities ...................................................................................84 
9.4. 
Definition of a Serious Adverse Event .......................................................................85 
9.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................85 
9.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................86 
9.6.1. 
Adverse Event Recording Period ................................................................................86 
9.6.2. 
Reporting Serious Adverse Events .............................................................................87 
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9.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................87 
9.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................87 
9.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................87 
9.6.3. 
Eliciting Adverse Events ............................................................................................88 
9.6.4. 
Progressive Disease ....................................................................................................88 
9.6.5. 
Deaths .........................................................................................................................88 
9.6.6. 
Recording Pregnancies ...............................................................................................88 
9.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................89 
9.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................89 
9.6.9. 
Recording Infusion-Related Reactions .......................................................................89 
9.7. 
Management of Adverse Events of Special Interest for Tislelizumab .......................89 
9.7.1. 
Managing Infusion-Related Reactions .......................................................................90 
9.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................91 
9.7.3. 
Immune-Mediated Adverse Events ............................................................................91 
9.7.4. 
Renal Function Abnormalities ....................................................................................93 
9.8. 
Management of Adverse Events of Special Interest for Lenvatinib ...........................93 
9.8.1. 
The AE management guidance for risks for lenvatinib ..............................................93 
9.8.1.1. 
Management of Hypertension .....................................................................................93 
9.8.1.2. 
Management of Proteinuria ........................................................................................95 
9.8.1.3. 
Management of Hepatotoxicity ..................................................................................96 
9.8.1.4. 
Management of Thromboembolic Events ..................................................................96 
9.8.1.5. 
Management of Posterior Reversible Encephalopathy Syndrome (PRES) ................96 
9.8.1.6. 
Management of hypocalcemia ....................................................................................96 
10. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................97 
10.1. 
Statistical Analysis ......................................................................................................97 
10.1.1. 
Analysis Sets ...............................................................................................................97 
10.1.2. 
Patient Disposition ......................................................................................................98 
10.1.3. 
Demographic and Other Baseline Characteristics ......................................................98 
10.1.4. 
Prior and Concomitant Medications ...........................................................................98 
10.2. 
Efficacy Analyses .......................................................................................................98 
10.2.1. 
Primary Efficacy Analysis ..........................................................................................99 
10.2.2. 
Secondary Efficacy Analysis ......................................................................................99 
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10.3. 
Safety Analyses ..........................................................................................................99 
10.3.1. 
Extent of Exposure ...................................................................................................100 
10.3.2. 
Adverse Events .........................................................................................................100 
10.3.3. 
Laboratory Analyses .................................................................................................100 
10.3.4. 
Vital Signs ................................................................................................................101 
10.3.5. 
Pulmonary Function Test ..........................................................................................101 
10.4. 
Pharmacokinetic Analyses ........................................................................................101 
10.5. 
Immunogenicity Analyses ........................................................................................101 
10.6. 
Other Exploratory Analyses .....................................................................................101 
10.7. 
Sample Size Consideration .......................................................................................101 
11. 
STUDY COMMITTEES ..........................................................................................103 
11.1. 
Safety Monitoring Committee ..................................................................................103 
12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .............................................................................................104 
12.1. 
Access to Information for Monitoring ......................................................................104 
12.2. 
Access to Information for Auditing or Inspections ..................................................104 
13. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................105 
13.1. 
Regulatory Authority Approval ................................................................................105 
13.2. 
Quality Assurance .....................................................................................................105 
13.3. 
Study Site Inspections ...............................................................................................105 
13.4. 
Drug Accountability .................................................................................................105 
14. 
ETHICS/PROTECTION OF HUMAN PATIENTS ................................................107 
14.1. 
Ethical Standard ........................................................................................................107 
14.2. 
Institutional Review Board/Independent Ethics Committee ....................................107 
14.2.1. 
Protocol Amendments ..............................................................................................107 
14.3. 
Informed Consent .....................................................................................................108 
14.4. 
Patient and Data Confidentiality ...............................................................................108 
14.5. 
Financial Disclosure .................................................................................................110 
15. 
DATA HANDLING AND RECORD KEEPING ....................................................111 
15.1. 
Data Collection and Management Responsibilities ..................................................111 
15.1.1. 
Data Entry in the Electronic Case Report Form .......................................................111 
15.1.2. 
Data Collection .........................................................................................................111 
15.1.3. 
Data Management/Coding ........................................................................................111 
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15.2. 
Study Records Retention ..........................................................................................112 
15.3. 
Protocol Deviations ..................................................................................................113 
15.4. 
Study Report and Publications ..................................................................................113 
15.5. 
Study and Study Center Closure ...............................................................................114 
15.6. 
Information Disclosure and Inventions ....................................................................114 
16. 
REFERENCES .........................................................................................................116 
17. 
APPENDICES ..........................................................................................................123 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................124 
APPENDIX 1A. DOSE ESCALATION BLOOD AND TUMOR TISSUE 
BIOMARKER ANALYSIS ......................................................................................129 
APPENDIX 2. PHARMACOKINETIC AND IMMUNOGENICITY SAMPLING 
SCHEDULE FOR TISLELIZUMAB .......................................................................130 
APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS ..............................................131 
APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .....................................................................................132 
APPENDIX 5. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................133 
APPENDIX 6. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................134 
APPENDIX 7. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................136 
APPENDIX 8. FRIDERICIA’S FORMULA FOR CORRECTING QT INTERVALS ...........137 
APPENDIX 9. CHRONIC KIDNEY DISEASE-EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................138 
APPENDIX 10. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................139 
APPENDIX 11. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................154 
APPENDIX 12. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR USED 
WITH CAUTION DURING TREATMENT WITH LENVATINIB ......................164 
APPENDIX 13. CLINICAL STUDIES EVALUATING DRUG–DRUG 
INTERACTIONS WITH LENVIMA ......................................................................165 
 
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LIST OF TABLES  
Table 1: 
Summary of Tumor Response in Study BGB A317_Study_001 (Efficacy 
Evaluable Analysis Set) ..............................................................................................32 
Table 2: 
Summary of Tumor Response in Study BGB-A317-102 (Safety Analysis 
Set) ..............................................................................................................................33 
Table 3: 
Immune-Mediated AEs of Special Interest of Tislelizumab and 
Pembrolizumab ...........................................................................................................34 
Table 4: 
Planned Dose Levels for Lenvatinib and Tislelizumab ..............................................59 
Table 5: 
Recommended Dosage Modifications for Lenvatinib Related Adverse 
Events of Special Interest ...........................................................................................62 
Table 6: 
Dose Modifications for Lenvatinib Treatment-Related Toxicity ...............................63 
Table 7: 
Dose Reduction Recommendations for Lenvatinib ....................................................64 
Table 8: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Cohorts ................................................................................................86 
Table 9: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................87 
Table 10: Treatment Modifications for Symptoms of Infusion-Related Reactions Due 
to Study Drug(s) .........................................................................................................90 
Table 11: Examples of Immune-Mediated Adverse Events .......................................................92 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................46 
 
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SYNOPSIS  
Name of Sponsor/Company: BeiGene, Ltd 
Investigational Product(s): Tislelizumab (BGB-A317) and lenvatinib (a generic drug) 
Title of Study: A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF TISLELIZUMAB IN COMBINATION WITH LENVATINIB 
IN PATIENTS WITH SELECTED SOLID TUMORS 
Protocol Identifier: BGB-A317-212 
Phase of Development: 2 
Number of Patients: Approximately 70 patients in total 
Part 1 (Safety run-in stage): Approximately 6 to 18 patients with 5 prespecified tumor types 
Part 2 (Expansion): To enroll additional patients at RP2D up to approximately 30 patients in each of 
5 prespecified tumor type cohorts. Three cohorts were closed prior to planned enrollment. 
Study Centers: Approximately 14 centers in China 
Study Objectives: 
Part 1 (Safety run-in) 
Primary: 
• 
To assess the safety and determine the recommended Phase 2 dose (RP2D) of lenvatinib 
(20 mg or other dose once a day [QD]) in combination with tislelizumab (intravenous [IV], 
400 mg every six weeks [Q6W]) in patients with advanced solid tumors 
Part 2 (Expansion) 
Primary: 
• 
To assess the overall response rate (ORR) of tislelizumab (IV, 400 mg Q6W) in 
combination with lenvatinib in patients with selected advanced solid tumors 
Secondary: 
• 
To evaluate the preliminary anticancer activity of tislelizumab (IV, 400 mg Q6W) in 
combination with lenvatinib using progression-free survival (PFS), duration of response 
(DOR), disease control rate (DCR), and overall survival (OS) 
• 
To characterize the safety of tislelizumab (IV, 400 mg Q6W) in combination with 
lenvatinib 
Exploratory: 
• 
To explore potential biomarkers that may correlate with clinical responses/resistance to 
tislelizumab in combination with lenvatinib 
• 
To characterize the pharmacokinetics (PK) and immunogenicity of tislelizumab when 
given in combination with lenvatinib 
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Study Endpoints: 
Part 1 (Safety run-in)  
Primary: 
• 
Adverse events (AEs) and serious adverse events (SAEs) as characterized by type, 
frequency, severity (as graded by National Cancer Institute-Common Terminology Criteria 
for Adverse Events [NCI-CTCAE] Version 5.0), timing, seriousness, and relationship to 
study drug(s); physical examinations, electrocardiograms (ECGs), and laboratory 
assessments as needed; and AEs meeting protocol-defined dose-limiting toxicity (DLT) 
criteria. 
Part 2 (Expansion) 
Primary: 
• 
ORR, as assessed using Response Evaluation Criteria in Solid Tumors (RECIST) Version 
1.1 by investigator 
Secondary: 
• 
PFS, DOR, DCR, as assessed using RECIST Version 1.1 by investigator, and OS 
• 
AEs and SAEs as characterized by type, frequency, severity (as graded by NCI-CTCAE 
Version 5.0), timing, seriousness, and relationship to study drug(s); physical examinations, 
ECGs, and laboratory assessments as needed 
Exploratory: 
• 
Potential biomarkers including but not limited to PD‑L1 expression, TMB/DNA mutation/ 
microsatellite instability (MSI), blood tumor mutational burden (bTMB)/DNA 
mutation/MSI, and the association of biomarkers with disease status, response/resistance to 
tislelizumab in combination with lenvatinib 
• 
Serum concentrations of tislelizumab and the incidence of ADA 
Study Design 
This is an open-label, multicenter, Phase 2 study to evaluate the safety and preliminary anticancer 
activity of tislelizumab in combination with lenvatinib in Chinese patients with locally advanced or 
metastatic tumors including programmed cell death ligand-1 (PD-L1) positive non-small cell lung 
cancer (NSCLC), squamous cell carcinoma of head and neck (SCCHN), urothelial cancer (UC), renal 
cell carcinoma (RCC), and gastric cancer (GC). Lenvatinib (Lenvatinib Mesilate Capsules, brand name 
JIELIEN® [hereafter referred to as “lenvatinib”]), which will be used in this study, is a generic drug to 
the lenvatinib capsules (Lenvatinib Mesilate Capsules, brand name Lenvima® [hereafter referred to as 
“Lenvima”]). This study includes 2 parts, Part 1 as safety run-in stage and Part 2 as expansion stage to 
assess the efficacy and safety of tislelizumab in combination with lenvatinib. 
Six patients will receive lenvatinib 20 mg orally once daily as starting dose, administered in 
combination with tislelizumab 400 mg intravenously once every 6 weeks, and up to 18 patients will be 
dosed if lower dose(s) of lenvatinib in combination with tislelizumab need to be assessed to determine 
RP2D in Part 1. The Safety Monitoring Committee (SMC) will evaluate the safety of the combination 
therapy when the first 6 DLT-evaluable patients have completed the first 28 days of treatment. Once 
the SMC confirms that the combination therapy is tolerable to proceed, the current dose will be 
recommended by SMC as RP2D for Part 2, and enrollment for Part 2 will begin at this dose. Patients 
enrolled in Part 1 at the RP2D will be counted towards Part 2 by the diagnosed tumor type, and the 
total patient number including Part 1 and Part 2 will be approximately 30 at RP2D in the cohort of each 
tumor type. There will be a total of 5 cohorts in the study as NSCLC, SCCHN, UC, RCC, and GC, 
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respectively. Three cohorts were closed prior to planned enrollment due to emerging data (NSCLC and 
UC cohorts) and changes to first-line standard of care (GC cohort). Patients will receive the study 
drug(s) until occurrence of progressive disease (PD), starts new anticancer therapy, lost to follow-up, 
unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor. 
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 Version 5.0. 
 
Study Schema 
 
Abbreviations: TIS, tislelizumab; LEN, lenvatinib; NSCLC, non-small cell lung cancer; SCCHN, squamous cell 
carcinoma of head and neck; UC, urothelial cancer; RCC, renal cell carcinoma; GC, gastric cancer; PD-L1, 
programmed cell death ligand-1, QD, once daily; Q6W, once every 6 weeks. 
 
Part 1 
Tislelizumab will be administered at 400 mg Q6W for this study (including Part 1 and Part 2). For the 
drug combined with tislelizumab, lenvatinib will begin at dose of 20 mg QD. 
Lower dose levels of lenvatinib initiated from 20 mg QD will be explored as necessary depending on 
observed safety profile. Lenvatinib dose will begin with Dose level 0: lenvatinib at 20 mg/day orally 
and tislelizumab 400 mg Q6W, IV will be administrated to patients with selected solid tumors on a 42-
day treatment cycle. Dose de-escalation of lenvatinib includes Dose level -1: lenvatinib 16 mg/day 
orally and tislelizumab 400 mg Q6W, IV, and Dose level -2: lenvatinib 12 mg/day orally and 
tislelizumab 400 mg Q6W, IV. Once the dose has been reduced, re-escalation is not allowed. 
Six patients will be enrolled for lenvatinib (20 mg QD) in combination with tislelizumab (IV, 400 mg 
Q6W). An SMC will be established to review the safety data collected from patients in Part 1 of the 
study first 28 days after starting tislelizumab (intravenously, 400 mg once per 6 weeks) in combination 
with lenvatinib. Based on these data, the SMC will recommend whether a dose modification of 
lenvatinib is needed, or whether the next part of the study can be initiated. The decision about 
establishing the RP2D is made by the sponsor. 
If 0 or 1 in 6 patients experience a DLT at dose level of 20 mg QD lenvatinib combined with 
tislelizumab (IV, 400 mg Q6W) in select tumor type, then patients could be enrolled at this dose level 
subsequently for Part 2. 
If 2 or more in 6 patients experience a DLT at dose level of 20 mg QD lenvatinib combined with 
tislelizumab (IV, 400 mg Q6W), 6 more patients would be enrolled at a next lower dose level, with 
dose reduction of lenvatinib from 20 mg to 16 mg QD or from 16 mg to 12 mg QD in combination 
with 400 mg tislelizumab Q6W. 
If 2 or more in 6 patients experience a DLT at Dose level of 12 mg QD lenvatinib in combination with 
tislelizumab (IV, 400 mg Q6W), enrollment of patients will stop. 
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In the safety run-in period, safety information including but not limited to the DLTs, all treatment-
emergent adverse event (TEAEs), laboratory abnormalities, and/or pharmacology data of first 28 day 
from first 6 evaluable patients will be reviewed by SMC. Recruitment will be on hold until the data 
have been reviewed. 
A DLT is defined as 1 of the following toxicities occurring during the DLT assessment window (first 
28 study days) 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: 
• 
≥ Grade 4 toxicity 
• 
Grade 3 toxicity that is clinically significant and does not resolve to baseline or ≤ Grade 1 
within 7 days after optimal supportive care is initiated 
• 
≥ Grade 2 thromboembolic event 
Note: The following 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 
For safety run-in, patients who received <67% of scheduled tislelizumab and/or < 75% of scheduled 
lenvatinib during the DLT assessment window for any reason other than a DLT will be replaced. 
All patients enrolled in the safety run-in period will be assessed for DLTs during the DLT assessment 
window. Once they complete the DLT assessment, each subject still receiving study treatment will 
continue with the same dosage. Tumor assessments will be continued as scheduled. 
Part 2 
Part 2 of the study will begin once the recommended dose is confirmed by the sponsor. Approximately 
30 patients at RP2D will be enrolled in each cohort in parallel. 
Each cohort will be evaluated independently for study endpoints and may be closed due to lack of 
preliminary anticancer activity or other reasons. 
 
Study Assessments: 
Tumor assessments will be performed by the investigators based on RECIST v1.1. All scans for tumor 
assessments performed during the study should be archived in accordance with the standard local 
practice. Tumor imaging at Screening must be performed within 28 days before first dose of study 
drugs (Cycle 1 Day 1). 
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Tumor assessments will be carried out every 9 weeks (±7 days) (counting from C1D1) in the first year 
(54 weeks), then every 12 (±7 days) weeks thereafter. Computed tomography or magnetic resonance 
imaging (CT/MRI) scans of chest, abdomen, and pelvis and of other known sites of disease will be 
obtained at Screening (within 28 days before Cycle 1/ Day 1), at all tumor assessment timepoints, and 
as clinically indicated. Patients with squamous cell carcinoma of the head and neck must also have 
head and neck scans performed. 
MRI may be used instead of CT for head, neck, abdomen, and pelvis; however, the chest must be 
assessed using CT. Chest disease should not be followed using chest x-ray. 
Imaging of the brain (preferably MRI) at baseline is required for all screened patients with the 
diagnosis of NSCLC. It also should be performed for patients with solid tumors other than NSCLC if 
clinically indicated. For patients with previously treated eligible brain metastases, a brain scan must be 
performed at all tumor assessment timepoints. 
The tumor assessment schedule should not be affected by interruptions in study treatment. If a patient 
discontinues study treatment due to the reasons other than disease progression or death, tumor 
assessments will continue to be performed as scheduled until disease progression, begins subsequent 
anticancer therapy, loss to follow-up, withdrawal of consent, death, or until study termination, 
whichever occurs first. 
Patients will be evaluated for any AEs and SAEs occurring until up to 30 days after the last dose of 
study drug(s) (all severity grades, per NCI-CTCAE v.5.0) or initiation of new anticancer therapy, 
whichever occurs first, and immune-mediated AEs (imAEs) occurring up to 90 days after the last dose 
of tislelizumab regardless of initiation of subsequent anticancer therapy. 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. 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. 
Duration of Patient Participation:  
Patients will receive study drug(s) until PD, unacceptable toxicity, death, or another discontinuation 
criterion is met. 
Study Population:  
• 
NSCLC Cohort: Patients with advanced NSCLC who have no prior systemic anti-tumor 
therapy for advanced disease, and whose tumor expressed PD-L1 status as tumor cell (TC) 
≥ 1% by the Ventana SP263 assay, without EGFR mutation and/or known ALK gene 
translocation. 
• 
SCCHN Cohort: Patients with recurrent or metastatic (R/M) SCCHN who have no prior 
systemic anti-tumor therapy for advanced disease. Patients who have a primary tumor site 
of nasopharynx (any histology) are not eligible. 
• 
UC Cohort: Patients with locally advanced or metastatic UC who are cisplatin-ineligible 
and have no prior systemic anti-tumor therapy for advanced disease. 
• 
RCC Cohort: Patients with advanced RCC with clear cell as predominant component and 
have no prior systemic anti-tumor therapy for advanced disease. 
• 
GC Cohort: Patients with advanced gastric cancer/gastroesophageal junction 
adenocarcinoma (GC/GEJC) and have 1 line of prior systemic anti-tumor therapy for 
advanced disease. 
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Key Eligibility Criteria: 
Inclusion: 
1. Histologically and/or cytologically confirmed solid tumor types such as one of following: 
NSCLC, SCCHN, UC, RCC or GC. For patients with tumor types other than GC, should 
receive no prior systemic anti-cancer therapy for advanced disease. For GC cohort, patients 
should have had 1-line previous systemic treatment for advanced disease. 
• 
NSCLC Cohort: Advanced/metastatic NSCLC without EGFR mutation and/or known 
ALK gene translocation, and whose tumor expressed PD-L1 status as TC ≥ 1% confirmed 
by central laboratory utilizing Ventana SP263 assay. For non-squamous NSCLC patients 
without documented EGFR status, a tissue-based EGFR mutation assessment is required 
before enrollment. 
Note: Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
therapy is acceptable if therapy was completed ≥ 6 months before the diagnosis of 
advanced or metastatic disease. 
• 
SCCHN Cohort: Recurrent or metastatic (R/M) SCCHN, primary tumor locations need to 
be oropharynx, oral cavity, hypopharynx, or larynx. Patients who have a primary tumor 
site of nasopharynx (any histology) are not eligible. 
Note: Systemic therapy as part of multimodal treatment for locally advanced disease is 
acceptable if it was completed ≥ 6 months before diagnosis of recurrent/metastatic disease. 
Metastatic means M1 per American Joint Committee on Cancer (AJCC), Eighth Edition. 
• 
UC Cohort: Advanced/unresectable (inoperable) or metastatic UC, including renal pelvis, 
ureters, bladder, or urethra. In order to be enrolled, the patient has to be cisplatin-ineligible, 
defined as meeting any of the following criteria: 
- Creatinine clearance (calculated by Cockcroft-Gault formula or measured) < 60 
mL/min but >30 mL/min 
Note: Patients with a creatinine clearance (calculated or measured) < 30 mL/min or on 
dialysis are excluded from the study. 
- CTCAE, grade 2 or above audiometric hearing loss 
- CTCAE, grade 2 or above peripheral neuropathy 
Note: For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-
radiation for UC, a recurrence-free interval > 12 months since the last treatment 
administration is required. Prior local intravesical chemotherapy or immunotherapy is 
allowed if completed at least 4 weeks before the initiation of study treatment. Low-dose 
chemotherapy (eg., low dose cisplatin, cisplatin+5FU, mytomycin+5FU, or 
cisplatin+paclitaxel) given concurrent with radiation to the primary tumor site is not 
considered as systemic therapy. 
• 
RCC Cohort: Advanced/metastatic RCC with clear cell as predominantly component or 
have recurrent disease. 
Note: Prior neoadjuvant/adjuvant therapy of targeted agents to VEGF/VEGFR or mTOR is 
acceptable if it was completed > 12 months before recurrence. 
• 
GC Cohort: Confirmed diagnosis of GC or GEJC, which has been treated with 1 prior line 
of therapy for advanced disease. Patients need to have documented disease progression 
during/after previous first-line treatment. The disease progression needs to be confirmed 
by radiographic scan such as computed tomography (CT). 
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Note: Prior neoadjuvant or adjuvant therapy in which the interval between the completion 
of treatment and the occurrence of recurrence or metastatic disease was < 6 months will be 
counted as one line of treatment for advanced disease. External beam radiation therapy as 
neoadjuvant/adjuvant is acceptable, internal radioactive implant treatment is not allowed. 
- Any standard chemotherapy regimen recommended by local guideline as first-line 
treatment is allowed. As first-line treatment, the chemotherapy should be received 
at least one cycle by patient. The substitution of drug(s) for the drug(s) with the 
same mechanism of action due to any reason other than disease progression is not 
considered a new line of therapy and is allowed. However, if a new component, 
dissimilar to any of the original components, is added to the regimen, the new 
combination is considered a new regimen which is not eligible. Prior 
intraperitoneal chemotherapy is allowed if completed at least 4 weeks before the 
initiation of study treatment. 
- Patients with HER2 (+) must receive first-line anti-HER2 systemic therapy (anti-
HER2 plus chemotherapy recommended by local guideline) and had 
documentation of disease progression during/after first-line anti-HER2 treatment. 
Patients with unknown status must have their HER2 status determined locally. 
2. Tumor tissue (approximately 10 unstained slides) for central laboratory assessment of PD-L1 
status for the NSCLC cohort during the screening period, and for retrospective analysis of 
other exploratory biomarkers related to response and resistance for NSCLC, SCCHN, UC and 
GC cohorts in a BeiGene designated central or test laboratory. 
• 
For cohorts of NSCLC, SCCHN, UC and GC, a fresh biopsy is mandatory in the absence 
of archival tumor tissues. 
• 
Submission of < 10 unstained slides is not a protocol deviation. If patients cannot provide 
10 unstained slides, patients may be enrolled after confirmation with the sponsor. 
• 
For non-squamous NSCLC patients who could not provide EGFR documentation and 
complete EGFR test locally, 10 slides will be required additionally for central laboratory 
assessment of EGFR mutation. 
Note: 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. For biopsy-derived samples, 
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. 
3. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤ 150/90 mmHg at screening, and no change in antihypertensive medications 
within 1 week before the Cycle 1 Day 1. 
Exclusion: 
1. For the NSCLC cohort, active leptomeningeal disease or uncontrolled, untreated brain 
metastasis will be excluded. 
• 
Patients with a history of treated and, at the time of screening, stable central nervous 
system metastases are eligible, provided they meet all of the following: 
- Brain imaging at screening shows no evidence of interim progression, clinically stable 
for at least 2 weeks and, have no evidence of new brain metastases 
- Have measurable disease and/or evaluable disease outside of the central nervous 
system 
- No ongoing requirement for corticosteroids as therapy for central nervous system 
disease; anticonvulsants at a stable dose are allowed 
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- No stereotactic radiation or whole-brain radiation ≤ 14 days before the first dose of 
study drug(s) 
For other cohorts than NSCLC, known leptomeningeal disease or brain metastasis will be 
excluded. 
2. 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 ≤ 28 days 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 7) 
≤ 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. QTcF interval (QT interval corrected for heart rate by Fridericia’s formula [Appendix 8]) 
> 450 msec 
h. Cardiac left ventricular ejection fraction (LVEF) out of the institutional normal range as 
determined by multiplegated acquisition (MUGA) scan or echocardiogram. The same 
modality used at baseline must be applied for subsequent evaluations. 
i. 
Syncope or seizure ≤ 28 days before the first dose of study drug(s) 
3. Patients having >1+ proteinuria on urinalysis will undergo 24-hour urine collection for 
quantitative assessment of proteinuria. Patients with urine protein ≥1 g/24-hour will be 
ineligible 
4. Have clinically significant bleeding (such as CTCAE ≥ Grade 2) within 21 days before first 
dose 
Investigational Product, Dose, and Mode of Administration: 
In both Part 1 and Part 2, tislelizumab 400 mg will be administered intravenously on Day 1 of each 42-
day cycle. 
In Part 1, lenvatinib will be initially administered at the dose of 20 mg orally, once daily. 
In Part 2, lenvatinib will be taken at the RP2D from Part 1. 
Reference Therapy, Dose, and Mode of Administration: 
Not applicable  
Statistical Methods: 
Analysis Set 
• 
The Safety Analysis Set (SAF) 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 patients enrolled during safety run-in stage who 
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1) received ≥ 75% of scheduled lenvatinib and ≥ 67% (approximately two-thirds) of 
scheduled tislelizumab administration during the DLT assessment window, remained 
on study during the DLT observation period, and had sufficient safety evaluation OR 
2) experienced a DLT within the DLT observation period.  
The detailed calculation of scheduled dose intensity of tislelizumab/lenvatinib is 
documented in the Safety Monitoring Committee Operating Procedure and statistical 
analysis plan (SAP) of this study. 
• 
The PK Analysis Set includes all patients who received ≥ 1 dose of tislelizumab and have 
≥ 1 quantifiable postbaseline PK data. 
• 
The ADA Analysis Set includes all patients who received ≥ 1 dose of tislelizumab and 
have a baseline and at least 1 postbaseline ADA result. 
Efficacy Analysis 
Primary and/or secondary efficacy endpoints will be based on investigators’ tumor assessments per 
RECIST Version 1.1 (if applicable) and will be defined as follows: 
− ORR is defined as the proportion of patients who had confirmed complete response (CR) or 
partial response (PR). 
− Duration of response is defined as the time from the first confirmed objective response until the 
first documentation of progression or death, whichever comes first. 
− DCR is defined as the proportion of patients with best overall response, as defined in 
Appendix 11, of a CR, PR, or stable disease. 
− PFS is defined as the time from the date of the first dose of study drugs to the date of the first 
documentation of PD or death, whichever occurs first. 
− OS is defined as the time from the date of the first dose of study drugs to death due to any 
cause. 
The efficacy endpoints will be summarized by cohort. 
ORR assessed by the investigator and its 95% CI will be summarized by cohort based on the Safety 
Analysis Set and the Evaluable Analysis Set. 
PFS will be estimated using the Kaplan-Meier method. The median PFS and the cumulative probability 
of PFS at specific time points, if estimable, will be calculated and presented with 2-sided 95% CIs. PFS 
censoring rule will follow United States Food and Drug Administration Guidance for Industry Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics (US FDA, 2018). 
DOR will be analyzed using methods similar to those described for PFS in the responders. 
DCR will be analyzed using methods similar to those described for ORR based on the SAF and EAS. 
Waterfall plots of maximum tumor shrinkage per patient will be presented. 
OS will be analyzed in the SAF using methods similar to those described for PFS, except for censoring 
rules. For OS, patients will be censored either at the date that the patient was last known to be alive or 
the date of data cutoff, whichever comes earlier, in the absence of death. OS rates at specific timepoints 
will be calculated based on the Kaplan-Meier method. 
Safety Analysis 
Safety will be assessed by monitoring and recording of AEs and 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 Version 5.0. The incidence of DLT events and TEAEs will be reported as the number 
(percentage) of patients with TEAEs by Medical Dictionary for Regulatory Activities (MedDRA) 
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system organ class and preferred term. Descriptive summary statistics (eg, n, mean, standard deviation, 
median, minimum, and maximum for continuous variables; n [%] for categorical variables) and 
changes from baseline will be determined for laboratory parameters and vital signs. 
Extent of exposure to study drug will be summarized descriptively as the number of cycles received 
(number and percentage of patients), duration of exposure, cumulative total dose received per patient, 
dose intensity (mg/day) and relative dose intensity (%). 
The number (and percentage) of patients with dose reductions, dose delays, treatment interruptions, and 
study drug discontinuation will be summarized for each study drug. 
The AE verbatim descriptions (as recorded by the investigator on the electronic case report form 
[eCRF]) will be classified into standardized medical terminology using the MedDRA®. 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 after discontinuation of study drug(s), or 
initiation of new anticancer therapy, whichever occurs first. 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. Immune-mediated AEs will be identified from all AEs that had an 
onset date or a worsening in severity from baseline (pretreatment) on or after the first dose of 
tislelizumab and up to 90 days from the last dose of tislelizumab, regardless of whether the patient 
starts a new anticancer therapy. If an imAE occurs outside the above mentioned TEAE window, it will 
not be classified as a TEAE. All imAEs will be reported separately. 
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 Version 5.0 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). 
TEAEs include those events considered by the investigator to be related to study treatment or with 
missing assessment of the causal relationship. SAEs, deaths, ≥ Grade 3 TEAEs, immune-mediated 
AEs, treatment-related TEAEs, and TEAEs that led to treatment discontinuation, treatment 
interruption, or dose delay will be summarized. 
Safety data will be summarized using the Safety Analysis Set by cohort and in overall study population 
except for analysis of DLT which is only applicable to patients in DLT evaluable set. 
PK Analysis 
Blood samples will be collected for tislelizumab PK evaluation at predose and postdose; the serum 
concentration data will be tabulated and summarized by the visit/cycle at which these samples are 
collected. Descriptive statistics will include mean, median, range, and standard deviation as 
appropriate. 
Sample Size Consideration 
The study plans to enroll approximately 70 patients: 
− Part 1 (Safety run-in): Approximately 6 to 18 patients with 5 prespecified tumor types 
− Part 2 (Expansion): To enroll additional patients at RP2D up to approximately 30 patients in 
each of 5 prespecified tumor type cohorts 
Three cohorts were closed prior to planned enrollment due to emerging data (NSCLC and UC cohorts) 
and changes to first-line standard of care (GC cohort). In the SCCHN and RCC cohorts, approximately 
30 patients per cohort will be enrolled to evaluate the preliminary efficacy. No formal hypothesis 
testing will be performed in the efficacy evaluation. 
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BGB-A317 
tislelizumab 
BE 
bioequivalence  
bTMB 
blood tumor mutational burden 
CKD-EPI 
Chronic Kidney Disease-Epidemiology Collaboration 
Cmax 
maximum observed plasma concentration 
CR 
complete response 
CT 
computed tomography 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
End-of-Treatment (Visit) 
FDG 
fluorine-18 [F-18] fluorodeoxyglucose 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEJC 
gastroesophageal junction adenocarcinoma 
GFR 
glomerular filtration rate 
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 
IV 
intravenous 
LVEF 
left ventricular ejection fraction 
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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MUGA 
multiplegated acquisition 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NMPA 
(China) National Medical Product Administration 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death ligand-1 
PET 
positron-emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
PR 
partial response 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCCHN 
squamous cell carcinoma of head and neck 
SMC 
Safety Monitoring Committee 
TKI 
tyrosine kinase inhibitor 
TMB 
tumor mutational burden 
TEAE 
treatment-emergent adverse event 
TRAE 
treatment-related adverse event 
Tmax 
time to maximum plasma concentration 
UC 
urothelial cancer 
ULN 
upper limit of normal 
 
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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 et al, 2018) and has shown benefit in various therapeutic settings (Georganaki et al, 2018).  
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4-variant 
monoclonal antibody against programmed cell death protein-1 (PD-1) under clinical 
development for the treatment for of multiple human malignancies. Tislelizumab is approved for 
the treatment of patients for the following indications in China: 
• for use in combination with paclitaxel plus carboplatin or paclitaxel for injection 
(albumin-bound) plus carboplatin as first-line treatment in patients with unresectable, 
locally advanced, or metastatic squamous non-small cell lung cancer (NSCLC) 
• for use in combination with pemetrexed and platinum chemotherapy as first-line 
treatment in patients with unresectable, locally advanced, or metastatic non-squamous 
NSCLC with no EGFR genomic tumor aberrations negative and ALK genomic tumor 
negative 
• for use as monotherapy for the treatment of adult patients with locally advanced or 
metastatic non squamous NSCLC, with EGFR genomic tumor aberrations negative 
and ALK genomic tumor negative, that has progressed after or did not tolerate prior 
platinum-based chemotherapy and of adult patients with locally advanced or 
metastatic squamous NSCLC, with EGFR and ALK negative or unknown, that has 
progressed after or did not tolerate prior platinum-based chemotherapy 
• for use in treatment of patients with locally advanced or metastatic esophageal 
squamous cell carcinoma who have disease progression following or are intolerant to 
first-line standard chemotherapy 
• for use in combination with gemcitabine and cisplatin as first-line treatment in 
patients with recurrent or metastatic nasopharyngeal cancer 
In addition, tislelizumab is conditionally approved in China for the following based on data from 
pivotal clinical studies. 
• for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma 
who have received at least 2 lines of systemic chemotherapy regimens 
• for the treatment of patients with locally advanced or metastatic urothelial carcinoma 
with PD-L1 high expression whose disease progressed during or following platinum-
containing chemotherapy or who have disease progression within 12 months of 
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy 
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• for the treatment pf patients with hepatocellular carcinoma who have been previously 
treated with at least one systemic therapy 
• for the treatment of adult patients with advanced unresectable or metastatic 
microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid 
tumors: patients with advanced colorectal cancer (CRC) who had been treated with 
fluoropyrimidine, oxaliplatin, and irinotecan; and patients with other advanced solid 
tumors who develop disease progression after prior treatment and who have no 
satisfactory alternative treatment options. 
Lenvatinib (Lenvatinib Mesilate Capsules, brand name JIELIEN® [hereafter referred to as 
“lenvatinib”]) is a generic drug to the lenvatinib capsules (Lenvatinib Mesilate Capsules, brand 
name Lenvima® [hereafter referred to as “Lenvima”]). As a receptor tyrosine kinase (RTK) 
inhibitor that inhibits VEGFR1-3; fibroblast growth factor receptor (FGFR) 1, FGFR 2, FGFR 3, 
FGFR 4; platelet-derived growth factor receptor (PDGFR) alpha, KIT, and RET, Lenvima has 
been approved in the United State (US) for the treatment of patients with locally recurrent or 
metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, in 
combination with everolimus for patients with advanced renal cell carcinoma following 1 prior 
antiangiogenic therapy, for the first-line treatment of patients with unresectable hepatocellular 
carcinoma, and in combination with pembrolizumab, for the treatment of patients with advanced 
endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following 
prior systemic therapy and are not candidates for curative surgery or radiation. It is approved in 
China for the first-line treatment of patients with unresectable hepatocellular carcinoma.  
NSCLC, squamous cell carcinoma of head and neck (SCCHN), urothelial cancer (UC), renal cell 
carcinoma (RCC), and gastric cancer (GC) are selected tumor types which are intended to be 
investigated under the combination treatment of lenvatinib plus tislelizumab in this study. 
1.2. 
Lenvatinib  
1.2.1. 
Pharmacology  
RTK are essential components of signal transduction pathways that mediate cell-to-cell 
communication (Hubbard and Miller, 2007). They are a subclass of cell-surface growth-factor 
receptors with an intrinsic, ligand-controlled tyrosine-kinase activity. These single-pass 
transmembrane receptors, which bind polypeptide ligands - mainly growth factors - play key 
roles in processes such as cellular growth, differentiation, metabolism, and motility. In cancer, 
constitutive and aberrant activations of components of those pathways result in increased 
proliferation, survival, and metastasis. Therefore, these signaling pathways became prime targets 
for cancer therapy. 
A preclinical study with human thyroid cancer models (Tohyama et al, 2014) shown the half-
maximal inhibitory concentration (IC50) values of Lenvima for its targets are shown following: 
IC50 for VEGFR1, VEGFR2, VEGFR3, RET proto-oncogenes (RET), FGFR 1, FGFR 2, FGFR 
3, FGFR 4, platelet-derived growth factor receptor (PDGFR) alpha and KIT proto-oncogenes 
(KIT) is 4.7 nmol/L, 3.0 nmol/L, 2.3 nmol/L, 6.4 nmol/L, 61 nmol/L, 27 nmol/L, 52 nmol/L, 43 
nmol/L, 29 nmol/L and 85 nmol/L, respectively. 
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In preclinical studies, Lenvima showed inhibitory activities dose-dependently in VEGFR2-driven 
phosphorylation, tube formation and proliferation in human vascular endothelial cells (human 
umbilical vein endothelial cell – HUVEC) induced by VEGF. In in vivo studies where human 
cancer cells were transplanted in immune deficient mouse models, Lenvima also demonstrated 
high anticancer effect in a wide variety of cancers. In addition, safety results in nonclinical 
studies showed Lenvima to be well tolerated within the therapeutic range. 
In vitro binding of Lenvima to human plasma proteins ranged from 98% to 99% (0.3-30 μg/mL). 
The contributions of albumin, α1-acid glycoprotein, and γ-globulin to the human plasma protein 
binding of Lenvima were estimated to be 93.2%, 6.1%, and 0.7%, respectively. In vitro, the 
Lenvima blood-to-plasma concentration ratio ranged from 0.59 to 0.61 (0.1-10 μg/mL) 
(LENVIMA (lenvatinib) [prescribing information], 2020; EMA assessment report for lenvatinib, 
2015). 
1.2.2. 
Clinical Experience  
Use of Lenvima 24 mg QD for the treatment of differentiated thyroid cancer has been approved 
by the United States (US) Food and Drug Administration (FDA). The once daily combination of 
18 mg Lenvima and 5 mg everolimus for patients with advanced renal cell carcinoma following 
1 prior anti-angiogenic therapy was approved by the US FDA. Once daily Lenvima 12 mg (body 
weight ≥60 kg) or 8 mg (body weight <60 kg) QD orally as monotherapy has been approved by 
US FDA and China National Medical Product Administration (NMPA) for patients with 
unresectable hepatocellular carcinoma. In addition, Lenvima 20 mg orally once daily in 
combination with pembrolizumab 200 mg intravenously (IV) every 3 weeks or 400 mg every 6 
weeks has been approved by US FDA for the treatment of patients with advanced endometrial 
carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic 
therapy (Keytruda (pembrolizumab) [prescribing information], 2020).  
The pharmacokinetics and safety of lenvatinib has been studied in a study named “a single-
center, open-label, randomized, single-dose, 2 cycle, 2 sequence, cross-over design study to 
evaluate the bioequivalence of lenvatinib and Lenvima in healthy subjects under fasting/after the 
meal status” (hereafter referred to as the “bioequivalence [BE] study”). The BE study was 
carried out with the Lenvatinib Mesilate Capsules (JIELIEN, dosage form: 4 mg] produced by 
Simcere Co., Ltd. and Lenvatinib Mesilate Capsules (Lenvima, dosage form: 4 mg] produced by 
Patheon Inc.  
The results of the BE study suggested equivalency in in vivo metabolic processes of lenvatinib 
and Lenvima. Please refer to the lenvatinib Investigator’s Brochure for more detailed 
information (Simcere Investigator’s Brochure, 2021). 
1.2.2.1. 
Clinical Pharmacology  
The clinical BE study showed that concentration-time curves are similar between lenvatinib and 
Lenvima. The geometric mean ratio and 90% CI of the major pharmacokinetic (PK) parameters 
(AUC0-inf, AUC0-t, and Cmax) of lenvatinib were within the acceptable range (0.8 to 1.25), 
indicating that lenvatinib is bioequivalent to Lenvima. Administration with a high-fat meal did 
not change bioavailability of lenvatinib but delayed the median time to peak plasma 
concentration (Tmax) from 2.25 hours to 4.5 hours (Simcere Investigator’s Brochure, 2021).  
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In patients with solid tumors administered single and multiple doses of Lenvima QD, the 
maximum observed Lenvima plasma concentration (Cmax) and the AUC increased proportionally 
over the dose range of 3.2 to 32 mg with a median accumulation index varying between 0.96 (20 
mg) and 1.54 (6.4 mg). At clinically relevant doses (≥12 mg QD), mean accumulation ratios of 
Lenvima ranged between 0.96 and 1.28. Plasma Lenvima concentrations declined bi-
exponentially following Cmax. The terminal elimination half-life of Lenvima was approximately 
28 hours (LENVIMA (lenvatinib) [prescribing information], 2020).  
1.2.2.2. 
Clinical Efficacy and Safety  
The BE study assessed the safety of lenvatinib and compared it with that of Lenvima in healthy 
subjects. A total of 64 healthy subjects received a single dose, 4 mg of study drug (32 subjects in 
the lenvatinib group and 32 in the Lenvima group) under the fasting status. The study results 
showed that both drugs were safe and well tolerated. The overall incidence of treatment-
emergent adverse event (TEAE) in the lenvatinib group and Lenvima group was 6.3% and 
18.8%, respectively. All reported TEAEs were mild and none of them would lead to dose 
modification or dose delay. No death or serious adverse event (SAE) was reported throughout 
the study (Simcere Investigator’s Brochure, 2021). 
Lenvima has been approved for multiple advanced malignancies. Clinical data from the 
indications of RCC, NSCLC, SCCHN, UC, and GC are listed below. Refer to the prescribing 
information for detailed information of other approved indications regarding clinical efficacy 
(LENVIMA (lenvatinib) [prescribing information], 2020). 
1.2.2.2.1. Lenvima in Renal Cell Carcinoma  
The efficacy was evaluated in a multicenter, randomized (1:1:1) study (Study 205: 
NCT01136733), in which 153 patients with advanced or metastatic renal cell carcinoma who 
have previously received anti-angiogenic therapy received Lenvima 18 mg orally once daily with 
everolimus 5 mg orally once daily, Lenvima 24 mg orally once daily, or everolimus 10 mg orally 
once daily.  
Of the 101 patients randomized to the Lenvima + everolimus combination arm, or to the 
everolimus monotherapy arm, the treatment effect of the combination on progression-free 
survival (PFS) was supported by a retrospective independent review of radiographs with an 
observed hazard ratio (HR) of 0.43 (95% CI: 0.24, 0.75) compared with the everolimus arm. 
Median PFS was 14.6 months (95% CI: 5.9, 20.1) in the combination arm versus 5.5 months 
(95% CI: 3.5, 7.1) in the everolimus arm. 
The clinical efficacy and safety of Lenvima in combination with pembrolizumab was explored in 
the phase 3 Keynote-581 study (CLEAR: NCT02811861). In this study, 1069 patients with 
advanced renal cell carcinoma and no previous systemic therapy were randomly assigned (1:1:1) 
to receive Lenvima (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once 
every 3 weeks), Lenvima (18 mg orally once daily) plus everolimus (5 mg orally once daily), or 
sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without 
treatment). The combination therapy was associated with significantly prolonged PFS and 
overall survival (OS) than sunitinib. Grade 3 or higher TEAEs were reported in 82.4% of the 
patients who received Lenvima plus pembrolizumab, compared to 71.8% of those who received 
sunitinib. The most frequent Grade 3 or higher TEAEs occurring in the population receiving 
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Lenvima plus pembrolizumab included hypertension (27.6%), diarrhea (9.7%), and weight 
decrease (8.0%) (Motzer et al, 2021). 
1.2.2.2.2. Lenvima in Non-Small Cell Lung Cancer  
The clinical safety and efficacy of Lenvima in combination with pembrolizumab was evaluated 
in the Phase 3 LEAP-007 study (NCT03829332). In this study, 623 patients with PD-L1-
positive, treatment-naïve NSCLC were randomly assigned (1:1) to receive pembrolizumab 
(200 mg intravenously once every 3 weeks) in combination with Lenvima (20 mg orally once 
daily) or placebo. The pembrolizumab plus Lenvima arm showed significantly prolonged PFS 
with an observed HR of 0.78 (95% CI: 0.64, 0.95) compared with the pembrolizumab plus 
placebo arm. Median PFS was 6.6 months (95% CI: 6.1, 8.2) in the pembrolizumab plus 
Lenvima arm versus 4.2 months (95% CI:4.1, 6.2) in the pembrolizumab plus placebo arm. The 
overall response rate (ORR) was higher in the pembrolizumab plus Lenvima arm (40.5%, 95% 
CI: 34.9%, 46.2%) versus 27.7% (95% CI: 22.8%, 33.0%) in the pembrolizumab plus placebo 
arm. Median OS was 14.1 months in the pembrolizumab plus Lenvima arm versus 16.4 months 
in the pembrolizumab plus placebo arm. Grade 3 or higher treatment-related adverse events 
(TRAEs) occurred in 57.9% of patients in the pembrolizumab plus Lenvima arm and in 24.4% of 
the pembrolizumab plus placebo arm. The most frequent TRAEs occurring in the population 
receiving pembrolizumab plus Lenvima included hypertension (36.2%), hypothyroidism 
(36.2%), proteinuria (28.8%), and diarrhoea (27.8%). (Csoszi et al, 2021). 
1.2.2.2.3. Lenvima in Squamous Cell Carcinoma of Head and Neck  
In a Phase 1B/2 study (NCT02501096) of pembrolizumab plus Lenvima performed in patients 
with selected advanced solid tumors, 22 patients with advanced SCCHN were enrolled who had 
previously received several prior lines of systemic therapies (Taylor et al, 2020). ORR was 
reported as 46% (95% CI: 24.4% to 67.8%), and median PFS was 4.7 (95% CI: 4.0 to 9.8) 
months. Among a total of 137 patients with the selected solid tumor, TRAEs were reported in 
97% (133/137) of patients, in which Grade 3 to 4 TRAEs were reported in 67% (92/137) of 
patients. The most common TRAEs were fatigue (58%), diarrhoea (52%), hypertension (47%), 
and hypothyroidism (42%). 
1.2.2.2.4. Lenvima in Urothelial Cancer  
The efficacy and safety of Lenvima in combination with pembrolizumab as first-line treatment 
was explored in the Phase 3 LEAP-011 study (NCT03898180), which is a randomized (1:1), 
double-blind study. In LEAP-011, 441 patients were enrolled in total, randomly assigned to 
receive pembrolizumab (200 mg intravenously once every 3 weeks) in combination with 
Lenvima (20 mg orally once daily) or placebo. Median PFS was 4.2 months (95% CI: 3.8, 5.9) in 
the pembrolizumab plus Lenvima arm versus 4.0 months (95% CI: 2.7, 5.4) in the 
pembrolizumab plus placebo arm, with an observed HR of 0.91 (95% CI: 0.71, 1.16). Median 
OS was 11.2 months (95% CI: 7.4, 14.9) in the pembrolizumab plus Lenvima arm versus 
13.8 months (95% CI: 9.8, 18.8) in the pembrolizumab plus placebo arm. ORR was 31.2% in 
pembrolizumab plus Lenvima arm versus 26.5% in the pembrolizumab plus placebo arm. 
Grade 3 or higher TRAEs occurred in 50.0% of patients in the pembrolizumab plus Lenvima arm 
and 27.9% of patients in the pembrolizumab plus placebo arm. The most frequent TRAEs 
occurring in the population receiving pembrolizumab plus Lenvima included proteinuria 
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(37.8%), hypothyroidism (36.5%), hypertension (34.9%) and diarrhoea (20.7%). (Yohann et al, 
2022). 
1.2.2.2.5. Lenvima in Gastric Cancer  
A Phase 2 study of Lenvima plus pembrolizumab as first- and second-line treatment was 
performed in 29 Japanese patients with advanced gastric cancer (EPOC1706, NCT03609359) 
(Kawazoe et al, 2020). Median PFS was 7.1 months (95% CI: 5.4, 13.7), and the safety profile 
was acceptable. ORR was reported as 69% (95% CI: 49%, 85%) in the overall population, in 
which ORR was reported as 40% in patients whose tumor PD-L1 status Combined Positive 
Score (CPS) was < 1, and 84% in those whose PD-L1 status CPS was ≥ 1. Grade 3 TRAEs 
occurred in 14 patients (48%); the most common Grade 3 TRAEs were hypertension (in 
11 patients [38%]), proteinuria (5 patients [17%]), and platelet count decrease (2 patients [7%]). 
No Grade 4 TRAE, serious TRAE, or treatment-related death occurred. 
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 binds to the extracellular domain (ECD) of 
human PD-1 with high specificity and affinity (dissociation constant [KD] = 0.15 nM), as 
demonstrated by receptor binding assays based on surface plasmon resonance. Tislelizumab 
competitively blocks the binding of both PD-L1 and 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. 
Refer to the tislelizumab (BGB-A317) Investigator’s Brochure (BeiGene Investigator’s 
Brochure, 2021)for detailed information regarding pharmacology studies. 
1.3.2. 
Clinical Experience  
1.3.2.1. 
Safety  
The overall safety experience with tislelizumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in 2694 patients treated as of the cutoff date 20 May 2021. 
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the 
incidence, severity, or causality of adverse events (AEs) to tislelizumab dose level. The safety 
profile for single-agent tislelizumab is similar to that observed with other PD-1 inhibitors.  
Refer to the tislelizumab (BGB-A317) Investigator’s Brochure (BeiGene Investigator’s 
Brochure, 2021)for more detailed information. 
1.3.2.1.1. Pooled Safety Assessment of Monotherapy Studies  
There were 1992 patients treated in the 7 pooled solid tumor monotherapy studies. The patients 
in the solid tumor group of pooled monotherapy studies had a median treatment exposure 
duration of 4.07 months (range: 0.10 to 41.46) and median study follow-up duration of 
11.53 months (range: 0.07 to 58.91). The median age of the patients was 60 years and 72.1% 
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were male. These patients had a median of 1.0 prior systemic anticancer therapy regimens 
(range: 0 to 12) and their most common tumor types were NSCLC (639 of 1992 patients, 
32.1%), esophageal squamous cell carcinoma (15.9%), hepatocellular carcinoma (15.9%), 
urothelial bladder cancer (5.7%), and CRC (5.2%). 
1.3.2.1.2. Treatment-Emergent Adverse Events  
Of the 1992 patients in the solid tumor group of monotherapy studies, 1922 patients (96.5%) 
experienced ≥ 1 TEAE and 1391 patients (69.8%) experienced ≥ 1 TEAE considered treatment 
related. TEAEs ≥ Grade 3 in severity were experienced by 847 of 1992 patients (42.5%) and 
269 patients (13.5%) experienced a ≥ Grade 3 TEAE considered treatment related. Serious 
TEAEs were reported in 706 patients (35.4%) and 209 patients (10.5%) experienced ≥ 1 serious 
TEAE considered treatment related. A total of 141 patients (7.1%) experienced a TEAE leading 
to death. 
The most commonly occurring TEAEs were anaemia (502 of 1992 patients, 25.2%), aspartate 
aminotransferase (AST) increased (18.0%), alanine aminotransferase (ALT) increased (16.7%), 
decreased appetite (16.5%), and cough (15.1%). 
The most commonly occurring ≥ Grade 3 TEAEs were anaemia (87 of 1992 patients, 4.4%), 
pneumonia (4.3%), AST increased (2.3%), hyponatraemia (2.1%), gamma-glutamyltransferase 
increased (1.7%), and hypertension (1.7%). 
1.3.2.1.3. Treatment-Emergent Adverse Events Assessed as Related to Treatment  
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 1391 (69.8%) 
experienced ≥ 1 treatment-related TEAE. The most commonly occurring treatment-related 
TEAEs were AST increased (250 of 1992 patients, 12.6%), ALT increased (12.1%), 
hypothyroidism (9.9%), anaemia (9.3%), and rash (8.0%). 
269 (13.5%) experienced ≥ 1 tislelizumab-related TEAE of ≥ Grade 3 severity. The most 
commonly occurring ≥ Grade 3 TEAEs were AST increased (25 of 1992 patients, 1.3%), ALT 
increased (1.0%), and anaemia (1.0%). All other events occurred in < 1% of patients. 
1.3.2.1.4. Treatment-Emergent Serious Adverse Events  
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 706 (35.4%) 
experienced ≥ 1 treatment-emergent SAE. The most commonly occurring SAEs were pneumonia 
(95 of 1992 patients, 4.8%), pneumonitis (1.7%), dysphagia (1.2%), pleural effusion (1.0%), and 
pyrexia (1.0%). 
209 (10.5%) experienced ≥ 1 tislelizumab-related treatment-emergent SAE. The most commonly 
occurring treatment-related SAE was pneumonitis (31 of 1992 patients, 1.6%). All other events 
occurred in less than 1% of patients. 
1.3.2.1.5. Immune-Mediated Adverse Events  
The majority of monotherapy studies pooled have undergone an adjudication process for 
identifying immune-mediated adverse events (imAEs). Only adjudicated imAEs are presented in 
this section. Of the 1912 patients in the adjudicated solid tumor group of pooled monotherapy 
studies, 286 patients (15.0%) experienced ≥ 1 imAE of any grade. The most commonly 
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occurring imAEs of any grade were hypothyroidism (115 of 1912 patients, 6.0%), pneumonitis 
(2.1%), immune-mediated lung disease (0.7%), rash (0.7%), ALT increased (0.6%), and 
hyperthyroidism (0.6%). The categories of imAEs experienced by ≥ 1% of patients were 
immune-mediated hypothyroidism (118 of 1912 patients, 6.2%), immune-mediated pneumonitis 
(3.7%), immune-mediated hepatitis (1.8%), and immune-mediated skin adverse reaction (1.3%). 
73 patients (3.8%) experienced ≥ 1 imAE that was ≥ Grade 3 in severity. The most commonly 
occurring ≥ Grade 3 imAEs were pneumonitis (15 of 1912 patients, 0.8%), interstitial lung 
disease (0.4%), ALT increased (0.3%), AST increased (0.3%), and hepatitis (0.3%). 
1.3.2.1.6. Infusion-Related Reactions  
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 58 patients (2.9%) 
experienced ≥ 1 infusion-related reaction (IRR) of any grade. The most commonly occurring 
IRRs were “infusion-related reaction” (28 of 1992 patients, 1.4%), pyrexia (0.9%), rash (0.3%), 
hypotension (0.2%), nausea (0.2%), and pruritus (0.2%). 
5 patients (0.3%) experienced ≥ Grade 3 IRRs. The most common ≥ Grade 3 IRRs was 
“infusion-related reaction” (2 of 1992 patients, 0.1%). All other ≥ Grade 3 IRRs occurred in 
single patients. 
1.3.2.1.7. Fatal Adverse Events  
Of the 1992 patients in the solid tumor group of pooled monotherapy studies, 
163 patients (8.2%) died ≤ 30 days after their last dose of tislelizumab. The causes of death for 
these patients were adverse events (54 of 1992 patients, 2.7%), disease under study (2.6%), 
disease progression (2.5%), and “other” (0.4%). A total of 1230 patients (61.7%) died > 30 days 
after their last dose of tislelizumab. The causes of death for these patients were disease under 
study (664 of 1992 patients, 33.3%), disease progression (22.7%), “other” (4.5%), adverse events 
(1.1%), and “missing” (0.1%). 
141 patients (7.1%) experienced ≥ 1 TEAE leading to death. The most commonly occurring 
TEAEs leading to death were “death” (16 of 1992 patients, 0.8%), pneumonia (0.7%), multiple 
organ dysfunction syndrome (0.6%), general physical health deterioration (0.5%), hepatic failure 
(0.5%), and respiratory failure (0.5%). 
20 patients (1.0%) experienced ≥ 1 tislelizumab-related TEAE leading to death. The most 
commonly occurring tislelizumab-related TEAEs leading to death were pneumonia 
(3 of 1992 patients, 0.2%), “death” (0.1%), hepatic failure (0.1%), multiple organ dysfunction 
syndrome (0.1%), and pneumonitis (0.1%). All other events occurred in single patients. 
1.3.2.2. 
Clinical Pharmacology  
The PK of tislelizumab was characterized in 126 patients with solid tumors in the Phase 1 studies 
BGB-A317_Study_001 and BGB-A317-102 using serum concentrations from patients who 
received doses of 0.5, 2.0, 5.0, or 10 mg/kg once every 2 weeks and 2.0 mg/kg, 5.0 mg/kg, or 
200 mg once every 3 weeks (106 patients in BGB-A317_Study_001, 20 patients in Study 
BGB-A317-102). The drug exposure (Cmax and AUC) increased in a dose-proportional manner 
from 0.5 mg/kg to 10 mg/kg, following first dose administration. Preliminary PK data from 
27 patients administered 1 dose of 200 mg once every 3 weeks showed that tislelizumab 
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concentrations are between the range of concentrations observed from patients administered 
2 mg/kg and 5 mg/kg doses. 
The PK of tislelizumab was best characterized using a 3-compartmental model with linear 
clearance mechanism. No time-varying clearance was observed in tislelizumab PK. The typical 
estimates of clearance (CL), central volume of distribution (Vc), and peripheral volumes 2 and 3 
(V2 and V3, respectively), were 0.153 L/day, 3.05 L, 1.27 L, and 2.10 L, respectively, with 
interindividual variability in CL (26.3%), Vc (16.7%), V2 (74.7%), and V3 (99.9%). The 
terminal t1/2 was estimated to be approximately 23.8 days. The accumulation ratios were 
estimated to be 2.14 and 2.49 for AUCss and minimum serum concentration at steady state 
(Cmin,ss), respectively. Steady state is expected to be reached in approximately 12 weeks. 
1.3.2.3. 
Efficacy  
Efficacy data of two Phase 1/2 monotherapy studies in advanced solid tumors, 
BGB-A317_Study_001 and BGB-A317-102, are summarized below. 
1.3.2.3.1. Study BGB-A317_Study_001  
BGB-A317_Study_001 was a 2-stage study. Phase 1A consisted of a dose-escalation and dose 
finding component, and Phase 1B investigated efficacy and safety in select tumor types. 
Responses were assessed by the investigator per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 criteria. 
Of the 451 patients treated with tislelizumab in the study, best overall responses of complete 
response (CR) were reported in 6 patients (1.3%) and of partial response (PR) in 54 patients 
(12.0%). The resulting overall clinical response rate (CR + PR) was 13.3%. Additionally, there 
were 141 patients (31.3%) with a best overall response of stable disease. 
Of 451 patients in the Safety Analysis Set, 156 patients in total were enrolled into GC, NSCLC, 
SCCHN, UBC, and RCC cohorts. The key efficacy data is summarized in Table 1. Please refer to 
Study BGB-A317_Study_001 (Desai et al, 2020) for more information regarding clinical 
efficacy. 
Table 1: 
Summary of Tumor Response in Study BGB-A317_Study_001 (Safety 
Analysis Set) 
 
GC 
(N = 54) 
NSCLC 
(N = 49) 
SCCHN 
(N = 20) 
UC 
(N = 17) 
RCC 
(N = 16) 
ORR (CR, PR) 
% (95% CI) 
13.0 
(5.37, 24.90) 
12.2 
(4.63, 24.77) 
15.0 
(3.21, 37.89) 
29.4 
(10.31, 55.96) 
31.3 
(11.02, 58.66) 
Data cutoff: May 2019 
Abbreviations: CR, complete response; GC, gastric cancer; SCCHN, squamous cell carcinoma of head and neck; 
NSCLC, non-small cell lung cancer; ORR, overall response rate; PR, partial response; RCC, renal cell carcinoma; 
UC, urothelial carcinoma. 
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1.3.2.3.2. Study BGB-A317-102  
Study BGB-A317-102 is a 2-phase (Shen et al, 2020), nonrandomized, Phase 1/2 study of 
tislelizumab monotherapy in Chinese patients with advanced solid tumors. 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. There was 1 patient (0.4%) with a CR reported. A total of 44 
patients (17.7%) had a 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. 
Of 249 patients in the efficacy evaluable set, 84 patients in total were enrolled into GC, NSCLC, 
UC and RCC cohorts. The key efficacy was summarized in Table 2. Please refer to study BGB-
A317-102 (Shen et al, 2020) for more information regarding clinical efficacy. 
Table 2: Summary of Tumor Response in Study BGB-A317-102 (Safety Analysis Set) 
 
NSCLC 
(N = 56) 
GC 
(N = 24) 
RCC 
(N= 21) 
UC  
(N =22) 
ORR (CR, PR) 
%, (n/N) 
(Exact 95% CI) 
18% (10/56) 
(8.9, 30.4) 
17% (4/24) 
(4.7, 37.4) 
10% (2/21) 
(1.2, 30.4) 
14% (3/22) 
(2.9, 34.9) 
DCR (CR, PR, SD) 
% 
(Exact 95% CI) 
55% 
(41.5, 68.7) 
29% 
(12.6, 51.1) 
52% 
(29.8, 74.3) 
41% 
(20.7, 63.6) 
CBR (CR, PR, durable SD)* 
% 
(Exact 95% CI) 
52% 
(38.0, 65.3) 
25% 
(9.8, 46.7) 
52% 
(29.8, 74.3) 
27% 
(10.7, 50.2) 
Abbreviations: CBR, clinical benefit rate; CI, confidence interval; CR, complete response; DCR, disease control 
rate; GC, gastric cancer; NSCLC, non-small cell lung cancer; ORR, overall response rate; PR, partial response; 
RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; UC, 
urothelial carcinoma. 
*OR (objective response) is based on the confirmed CR or PR according to RECIST v1.1. Durable SD is defined as 
SD duration ≥ 16 weeks. 
1.4. 
Study Rationale  
1.4.1. 
Rationale for the Dosing Regimen  
1.4.1.1. 
Lenvatinib Starting Dose  
The starting dose of 20 mg lenvatinib once daily in combination with tislelizumab has been 
selected. Lenvima 20 mg orally once daily in combination with pembrolizumab 200 mg IV every 
3 weeks or 400 mg every 6 weeks has been approved by US FDA for the treatment of patients 
with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease 
progression following prior systemic therapy (Keytruda (pembrolizumab) [prescribing 
information], 2020). In a Phase 1B/2 study of pembrolizumab in combination with Lenvima in 
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selected advanced solid tumors, Lenvima 20mg daily dose was identified as the MTD and 
recommended Phase 2 dose (RP2D) for combination of pembrolizumab (Taylor et al, 2020). 
Two dose-limiting toxicity (DLTs) (Grade 3 arthralgia and grade 3 fatigue) were reported in the 
initial combination cohort of Lenvima 24mg and pembrolizumab. No DLT was then observed in 
the subsequent de-escalation cohort of Lenvima 20mg. Therefore, 20mg of Lenvima was 
confirmed as MTD and RP2D for combination with pembrolizumab. Of 137 total patients across 
several tumor types, Lenvima dose reduction and/or interruption occurred in 85% patients, 
however 13% patients discontinued from the treatment of Lenvima; in addition, there were 45% 
and 15% of the total patients, respectively, who had pembrolizumab dose interruption and 
discontinuation. From the clinical data as outlined in Section 1.3.2.1 , tislelizumab has 
demonstrated a similar safety profile as other PD-1 antibodies including pembrolizumab. As 
shown in Table 3, the published safety data of immune mediated AEs of special interest indicates 
a similar safety profile of tislelizumab as pembrolizumab. Please refer to tislelizumab IB 
(BeiGene Investigator’s Brochure, 2021) and prescribing information of pembrolizumab 
(Keytruda (pembrolizumab) [prescribing information], 2020) for details. Bioequivalence studies 
of lenvatinib suggested equivalency in in vivo metabolic processes of lenvatinib and Lenvima. 
Please refer to the lenvatinib Investigator’s Brochure for more detailed information (Simcere 
Investigator’s Brochure, 2021). 
Table 3: Immune-Mediated AEs of Special Interest of Tislelizumab and Pembrolizumab 
 
Immune-mediated Adverse Events  
Categories 
Preferred Term 
Tislelizumab 
monotherapy in 
Solid Tumors 
(N = 1912) 
Pembrolizumab monotherapy in various Tumors 
(N = 2799) 
Any 
Grade 
n (%) 
Grade ≥ 3 
n (%) 
Any 
Grade 
n (%) 
Grade 1 
 (%) 
Grade 2 
 (%) 
Grade 3 
 (%) 
Grade 4 
 (%) 
Grade 5 
 (%) 
Immune-mediated 
hypothyroidism 
118 
(6.2) 
1 (0.1) 
237(8.5)  
(6.2) 
(0.1) 
 
 
Immune-mediated 
hyperthyroidism 
12 (0.6) 1 (0.1) 
17(3.4)  
(0.8) 
0.1 
 
 
Immune-mediated 
hepatitis 
34 (1.8) 19 (1.0) 
19 (0.7)  
(0.1) 
(0.4) 
(<0.1) 
 
Immune-mediated 
pneumonitis 
70 (3.7) 28 (1.5) 
94 (3.4) (0.8) 
(1.3) 
(0.9) 
(0.3) 
(0.1) 
Immune-mediated 
myositis/rhabdomyolysis 
14 (0.7) 5 (0.3) 
(<1) 
 
 
 
 
 
Immune-mediated 
nephritis and renal 
dysfunction 
6 (0.3) 2 (0.1) 
9(0.3) 
 
(0.1) 
(0.1) 
(<0.1) 
 
Immune-mediated colitis 
17 (0.9) 6 (0.3) 
48(1.7)  
(0.4) 
(1.1) 
(<0.1) 
 
Source data: Tislelizumab IB v9.0, Table 17; Pembrolizumab prescribing information, Section 5.  
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Safety profile of the combination treatment of Lenvima plus pembrolizumab has been fully 
assessed in the Phase 1B/2 study of pembrolizumab in combination with Lenvima in selected 
advanced solid tumors (Taylor et al, 2020). The overall safety profile of the combination is 
acceptable. Based on available data, it is reasonable to select the starting dose of lenvatinib 20mg 
once daily in this study for NSCLC, SCCHN, UC, GC and RCC cohorts.  
1.4.1.2. 
Tislelizumab  
The clinical fixed dose of 200 mg intravenously once every 3 weeks was the approved 
tislelizumab dose in multiple indications. 
For this study, alternate dose regimen 400 mg once every 6 weeks is selected by matching dose 
and exposure (AUC) with the exposure of 200 mg once every 3 weeks regimen. Exposure-
response (E-R) assessments of available clinical data from Studies including BGB-
A317_Study_001, BGB-A317-102, and BGB-A317-203 suggest no clinically significant 
relationships between tislelizumab exposure and efficacy (ORR) or safety across tumor types, 
and the 400 mg once every 6 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 expected peak 
concentration of 400 mg once every 6 weeks regimen compared with the 200 mg once every 
3 weeks is well covered by the available safety data at the dose of 10 mg/kg every 2 weeks 
(Study BGB-A317_Study_001). Additionally, alternative 6-weekly dose administration is expected 
to increase patient compliance and offer additional convenience for care providers. Recently, the 
approval of the use of extended dosing regimen has also been reported for other PD-1 inhibitors such 
as nivolumab (240 mg Q2W and 480 mg Q4W) and pembrolizumab (200 mg Q3W and 400 mg 
Q6W), demonstrating the feasibility and utility of this approach (Long et al, 2018; Opdivo 
(nivolumab), 2018; Lala et al, 2018; Kenilworth, NJ, 2019; Press Release, 2019; Scot E, 2019; 
Peter H, 2019). 
The potential drug-drug interaction between tislelizumab and lenvatinib is considered to be low; 
details can be found in Section 6.5. 
1.4.2. 
Rationale for Combination of Tislelizumab and Lenvatinib in the Treatment of 
Advanced Solid Tumors  
Tislelizumab as an anti-PD-1 antibody has shown efficacy and well tolerated safety in several 
types of tumors in clinical studies. In the select tumor types of NSCLC, SCCHN, UC, RCC and 
GC, the clinical antitumor activities have been observed in the Phase 1 and 2 studies. 
Tislelizumab has also been approved by China healthy authority for patients with locally 
advanced or metastatic urothelial carcinoma with PD-L1 high expression whose disease has 
progressed during, following, or within 12 months of platinum-containing chemotherapy. The 
rationale for individual tumor types has been described in the below sections. 
Lenvima as a kinase inhibitor has shown efficacy in several types of tumors. As monotherapy, 
Lenvima has demonstrated preliminary antitumor activities in NSCLC and RCC from published 
phase 1 or 2 studies. In addition, Lenvima has been approved in advanced RCC following one 
prior anti-angiogenic therapy as combination therapy with everolimus.  
Combining an immunotherapeutic PD-1 checkpoint inhibitor with an agent that has both immune 
modulatory and antitumor properties could enhance the antitumor efficacy observed with either 
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agent alone. In addition, selected tyrosine kinase inhibitors have been shown to modulate the 
immunogenic status of tumors, improve tumor perfusion by reducing intratumoral pressure and 
modulate subsets of immune cells, thereby increasing the frequency and function of effector 
immune elements while decreasing the number and function of immune suppressor cells. 
1.4.3. 
Rationale for Tumor Type(s)  
1.4.3.1. 
Non-Small Cell Lung Cancer  
Worldwide, lung cancer has been the most common malignancy in the past few decades and the 
leading cause of cancer related death by far. In 2012, it was estimated that a total of 1.8 million 
new cases were diagnosed, accounting for 12.9% of all new cancer diagnoses (Wong et al, 
2017). Likewise, lung cancer is also the most common cancer and the leading cause of cancer 
death in China; about 782,000 new cases of lung cancer were diagnosed in 2014 (Chen et al, 
2015). According to statistics from the National Office on Tumor Cure and Prevention, about 
626,000 people die of lung cancer each year in China (Chen et al, 2018). 
Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancers (PDQ Adult 
Treatment Editorial Board, 2017). It includes 2 major pathological types: non-squamous 
carcinoma (including adenocarcinoma, large-cell carcinoma, and other subtypes) and squamous 
cell (epidermoid) carcinoma (NCCN Guidelines Version 4, 2019). 
The KEYNOTE-042 study (Mok et al, 2019) demonstrated that single-agent pembrolizumab in 
the first-line setting significantly improved overall survival (OS) compared with platinum-based 
chemotherapy for patients with locally advanced or metastatic NSCLC, with PD-L1 expression 
of 1% or more (by 22C3 assay), but without EGFR mutation or ALK rearrangement. 
Pembrolizumab was approved in US and China for the first line treatment of patients with 
NSCLC expressing PD-L1 (TPS ≥ 1%) with no EGFR or ALK genomic tumor aberrations. 
Although pembrolizumab has been approved in PD-L1 positive NSCLC, in the exploratory 
analysis, clinical benefit of pembrolizumab in the subset population who had TPS 1-49% PD-L1 
expressed tumor has not been demonstrated to be significantly prolonged over the standard of 
care chemotherapy (OS was 13.4 months in pembrolizumab versus 12.1 months in 
chemotherapy). It indicates that there is a need for a more robust effective and tolerable 
treatment for PD-L1 positive NSCLC. 
Tislelizumab as an anti-PD-1 antibody showed antitumor activity in NSCLC in BGB-A317-001 
and BGB-A317-102 studies (Desai et al, 2020; Shen et al, 2020). In those 2 studies, 49 patients 
(mostly Caucasian) and 56 Chinese patients with advanced NSCLC were evaluable for 
assessment respectively. ORR was reported as 12.2% and 18%, respectively. The additional two 
Phase 3 studies have also demonstrated superior efficacy for tislelizumab in combination with 
chemotherapy versus the backbone chemotherapy in squamous NSCLC and non-squamous 
NSCLC respectively. Overall, tislelizumab has shown clinical activity in NSCLC that is 
comparable to that of other marketed PD-1 antibodies globally.  
In a Phase 1B/2 study (Taylor et al, 2020) of pembrolizumab plus Lenvima performed in patients 
with selected advanced solid tumor, 21 patients with advanced NSCLC were enrolled, of whom 
52% has been treated with PD-1/L1 Abs previously. The ORR was reported as 33% (95% CI: 
14.6 to 57.0), and median PFS was 5.9 months (95% CI: 2.3 to 13.8). Overall, it is expected that 
tislelizumab in combination with lenvatinib as one of chemo-free regimens would derive 
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additional clinical benefit in PD-L1 positive NSCLC versus the current standard of care. The 
combination treatment would be a potentially more effective and tolerable chemo-free regimen 
based on the assessment of mechanism of action (MoA) synergistic effects and available clinical 
data. While the Phase 3 LEAP-007 study (NCT03829332), which investigated the clinical safety 
and efficacy of pembrolizumab in combination with Lenvima or placebo in first-line NSCLC 
patients, showed a PFS benefit, no OS benefit was observed in the intent-to-treat (ITT) 
population. The median OS was 14.1 months in the pembrolizumab plus Lenvima arm versus 
16.4 months in the pembrolizumab plus placebo arm. Based on results published at the European 
Society for Medical Oncology Immuno-Oncology (ESMO IO) Congress 2021 (Csoszi et al, 
2021), the enrollment of the NSCLC cohort to Study BGB-A317-212 was suspended after 
5 patients had enrolled. 
1.4.3.2. 
Squamous Cell Carcinoma of Head and Neck  
Squamous cell carcinoma of head and neck (SCCHN) is the 9th most common malignancy 
diagnosed world-wide accounts for 834,860 new patients and 8th in China (Bray et al, 2018). It 
was estimated that 64,000 new Chinese with SCCHN except nasopharynx cancer diagnosed in 
2014 (Chen et al, 2018). First-line treatment of cetuximab plus chemotherapy with platinum and 
5-fluorouracil is still the standard of care in China, which provides median overall survival of 
about 10 months (Vermorken et al, 2008). 
PD-1 antibody monotherapy in SCCHN has shown efficacy and manageable safety in several 
studies. KEYNOTE-048 is a Phase 3 study (Burtness et al, 2019) conducted in patients with 
recurrent or metastatic squamous cell carcinoma of the head and neck, to evaluate 
pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy as first-line 
treatment. In this study for patients received pembrolizumab monotherapy, median overall 
survival was 14.9 months in groups whose tumor PD-L1 CPS ≥ 20 and 12.3 months in groups 
whose PD-L1 CPS ≥1; ORR was reported as 23% in groups whose PD-L1 CPS ≥20 and 19% in 
PD-L1 CPS ≥1 group. The study also demonstrated a statistically significant improvement in OS 
for the patients with PD-L1 CPS ≥1 randomized to pembrolizumab as a single agent compared to 
those randomized to cetuximab in combination with chemotherapy. Additionally, it was 
observed that there was no significant difference in OS between pembrolizumab single agent arm 
and the control arm in total population.  
Tislelizumab as an anti-PD-1 antibody showed anti-cancer activity in SCCHN in a Phase 1A/1B 
clinical study (Desai et al, 2020). In this study, 20 patients with previously treated SCCHN were 
enrolled to receive tislelizumab single agent. ORR for this population was 15%, with an ORR of 
20% and 8.3% for PD-L1 positive and PD-L1 negative patients, respectively.  
PD-1 antibody in combination with Lenvima has shown efficacy and manageable safety in 
SCCHN. In a Phase 1B/2 study (Taylor et al, 2020) of pembrolizumab plus Lenvima performed 
in patients with selected advanced solid tumors, 22 patients with advanced SCCHN were 
enrolled who have received several prior lines of systemic therapies previously. ORR was 
reported as 46% (95% CI: 24.4 to 67.8), and median PFS was 4.7 (95% CI: 4.0 to 9.8) months. 
Tislelizumab in combination with lenvatinib is expected to show clinical benefit with a tolerable 
safety profile. For patients with SCCHN, a population with comparatively poor Eastern 
Cooperative Oncology Group (ECOG) performance and nutritional status, a chemo-free regimen 
could provide a more tolerable and efficient alternative to chemotherapy-based treatment. 
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1.4.3.3. 
Urothelial Carcinoma  
Urothelial carcinoma (UC), also known as transitional cell carcinoma, is an aggressive 
malignancy and the most common cancer of the urinary system. More than 90% of urothelial 
carcinoma originates in the bladder, while 8% may also originate at the renal pelvis and 2% in 
ureter or urethra. The epidemiology data found worldwide and in China are similar. It was 
estimated that there were 424,082 new cases and 148,270 deaths from bladder cancer in men and 
125,311 new cases and 51,652 deaths in women worldwide in 2018 (Bray et al, 2018). In China, 
bladder cancer is the sixth most common cancer in men and the thirteenth in women, with 
approximately 80,500 new cancer cases (62,100 men and 18,400 women) and 32,900 deaths 
(25,100 men and 7800 women) in China in 2015 (Chen et al, 2016). Of all locally advanced or 
metastatic UC patients, approximately 46.6% received platinum-based chemotherapy as first line 
treatment. Only 20.5% of patients received cisplatin-based chemotherapy based on baseline 
disease characteristics (Sonpavde et al, 2014). OS was 13 to 15 months for patients who received 
GC (gemcitabine and cisplatin) as first-line treatment (Kaufman et al, 2000; Maase et al, 2000); 
while 26.1% of patients received gemcitabine and carboplatin with an inferior OS of only 
9.3 months (Santis et al, 2012). 
Tislelizumab as an anti-PD-1 antibody showed anti-cancer activity in urothelial cancer in 2 
multi-cohort Phase 1/2 clinical studies (Desai et al, 2020; Shen et al, 2020). In those studies, 22 
Chinese patients and a population of 17 mostly Caucasian patients with advanced urothelial 
cancer were enrolled respectively to receive tislelizumab. The ORR was 14% and 29.4% 
respectively for Chinese patients and for Caucasian dominant population. Additionally, 
tislelizumab has been approved by China authority for patients with previously treated advanced 
or metastatic urothelial carcinoma with PD-L1 high expression based on a single arm Phase 2 
study (CTR20170071). In the study median PFS was 2.1 months (95% CI: 2.0-2.46) and median 
OS was 9.8 months (95% CI: 7.5-13.5). Overall response rate was reported as 23.1% in 
104 patients who were evaluable for efficacy assessment (Ye et al, 2019). 
In a Phase 1B/2 study (Taylor et al, 2020), pembrolizumab plus Lenvima was explored in 
patients with several selected advanced solid tumors, of which 20 patients with advanced 
urothelial carcinoma who had progressed after several lines of approved anti-cancer therapies 
enrolled. In urothelial carcinoma, anti-cancer activity of pembrolizumab in combination with 
Lenvima has demonstrated as an ORR was 25% (95% CI: 8.7 to 49.1), median PFS was 
5.4 months (95% CI: 1.3 to NE) which is similar with that of gemcitabine and carboplatin 
(median PFS: 5.8 months) as first-line treatment in patients who are cisplatin ineligible as 
reported in EORTC Study 30986 (Santis et al, 2012). 
Based on the available information, it is estimated that tislelizumab, which has a similar clinical 
activity as pembrolizumab, in combination with lenvatinib, which is a generic drug to Lenvima, 
could provide a similar efficacy as that reported from gemcitabine and carboplatin chemotherapy 
in first-line treatment setting for UC patients who are ineligible for cisplatin treatment. This 
chemo-free regimen would provide an additional option for this group of population for whom it 
is expected to have a relatively poor survival prognosis when compared to cisplatin eligible 
population. However, in the Phase 3 LEAP-011 Study (NCT03898180) of pembrolizumab in 
combination with Lenvima or placebo in patients with first-line UC, the resulting data showed no 
OS benefit in the ITT population. The median OS was 11.8 months in the pembrolizumab plus 
Lenvima arm versus 12.9 months in the pembrolizumab plus placebo arm. This result was 
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published at the American Society of Clinical Oncology Genitourinary (ASCO GU) Symposium 
in 2022 (Yohann et al, 2022). Therefore, the enrollment of the UC cohort to Study BGB-A317-
212 was suspended. 
1.4.3.4. 
Renal Cell Carcinoma  
Renal cell carcinoma (RCC) is the seventh most common cancer in men and the ninth most 
common cancer in women. Worldwide, there are an estimated 209,000 newly diagnosed cases of 
RCC and an estimated 102,000 deaths per year (Escudier et al, 2014). It is estimated that in 
2015, 66,800 new RCC cases were diagnosed, and 23,400 deaths occurred in China (Chen et al, 
2016). Approximately 90% of renal tumors are RCC and approximately 80% of these are of clear 
cell histology. 
In a Phase 2 study (Atkins et al, 2020), 159 patients with advanced or metastatic RCC who had 
no previous treatment were enrolled to receive nivolumab monotherapy as first-line treatment. 
Of all 123 treatment-naïve ccRCC (clear cell RCC) patients, median PFS was 8.3 months (95% 
CI, 5.5-10.9) in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) 
risk population, and median PFS in IMDC favorable and intermediate/poor population was 
19.3 months (95% CI, 8.1-NA) and 5.5 months (95% CI, 3.9-9.1) respectively. ORR was 
reported as 31.7% (39/123) in overall population. KEYNOTE-427, a Phase 2 study evaluated 
pembrolizumab monotherapy as first-line treatment in patients with advanced RCC. This study 
showed that ORR in cohort A of 110 ccRCC patients as 36.4% (40/110) [95% CI, 27.4-46.1], 
median PFS was 7.1 months (95% CI, 5.6-11.0), and median OS did not reach (McDermott et al, 
2020).  
Tislelizumab as an anti-PD-1 antibody has shown efficacy and well tolerated safety in several 
types of tumor in multi-cohort Phase 1/2 studies (Desai et al, 2020; Shen et al, 2020). 21 Chinese 
patients and 16 mostly Caucasian patients with previously treated advanced renal cell carcinoma 
were enrolled to receive tislelizumab monotherapy. The ORR was reported as 10% and 31.3% 
respectively. These results demonstrated as an anti-PD-1 antibody, tislelizumab monotherapy is 
an effective agent in advanced renal cell carcinoma. 
Lenvima monotherapy also showed encouraging efficacy in advanced renal cell carcinoma as 
second line treatment in a Phase 2 study (Motzer et al, 2015). This is a randomized, Phase 2, 
multicenter, open-label study enrolling patients with advanced clear-cell RCC who had received 
treatment with a VEGF-targeted therapy. In this study, patients who were randomized to receive 
Lenvima had median PFS of 7.4 months (95% CI, 5.6–10.2), median OS of 18.4 months 
(95% CI, 13.3–NE), and ORR of 27% (14/25, [95% CI, 16–41]).  
In a Phase 1B/2 study, pembrolizumab 200mg IV Q3W plus Lenvima oral 20mg/day was 
explored in patients with several selected advanced solid tumors, of which 30 patients with 
advanced renal cell carcinoma with predominantly clear cell who had progressed after several 
lines of approved anti-cancer therapies were enrolled. Among patients in RCC cohort, 
pembrolizumab in combination with Lenvima has demonstrated an ORR of 70% (21/30; 95% CI, 
50.6 to 85.3) and median PFS of 19.8 months (95% CI: 9.9-24.1) (Taylor et al, 2020). The 
CLEAR study published in 2021 confirmed the anti-tumor efficacy of this combination therapy 
in the first-line setting (Motzer et al, 2021). 
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Based on these results, we assume that tislelizumab monotherapy could provide similar efficacy 
as nivolumab or pembrolizumab and the combination treatment could have synergic effects in 
patients with advanced RCC.  
1.4.3.5. 
Gastric Cancer  
Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer 
mortality worldwide (Globocan 2018d, 2020). 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 2018d, 
2020). Stomach cancer is the second highest incidences and mortality in China. Patients with 
newly diagnosed inoperable locally advanced or metastatic disease generally receive 
chemotherapy regimens containing platinum and fluoropyrimidine (Smyth et al, 2016; NCCN, 
2017).  
Patients with advanced GC who failed first line standard treatment represent a population with a 
great unmet medical need. In the second-line setting, the treatment options are still limited, 
including cytotoxic chemotherapy with docetaxel, paclitaxel, or irinotecan and the VEGFR2 
monoclonal antibody ramucirumab based therapy, which is given as either monotherapy or in 
combination with paclitaxel. The prognosis remains poor, with the median overall survival being 
approximately 8 to 10 months. 
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 (Keytruda (pembrolizumab) [prescribing information], 2020). 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. 
Tislelizumab as an anti-PD-1 antibody has shown efficacy and well tolerated safety in several 
types of tumors in multi-cohort Phase 1/2 studies (Desai et al, 2020; Shen et al, 2020). In those 
studies, 52 and 24 patients with advanced gastric cancer were respectively enrolled into two 
studies, in which ORR was reported as 13.5% and 17% respectively and the median overall 
survival was reported as 4.7 months (95% CI, 2.4-NE) in the China study. 
A Phase 2 study of Lenvima plus pembrolizumab as first and second line treatment was 
performed in 29 Japanese patients with advanced gastric cancer (EPOC1706) (Kawazoe et al, 
2020). Median PFS was 7.1 months (95% CI: 5.4-13.7), median OS was not reached, and safety 
profile was acceptable. ORR was reported as 69% (95% CI: 49-85) in overall population, in 
which ORR as reported as 40% in patients whose tumor PD-L1 status CPS<1, and 84% in 
PD-L1 status CPS ≥ 1.  
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Based on the promising results from this Phase 2 study and available results from tislelizumab 
Phase 1/2 studies, it is expected tislelizumab in combination with lenvatinib would provide an 
efficient treatment option for this study population, for whom overall survival tends to be less 
than 12 months.  
Since nivolumab plus mFOLFOX (oxaliplatin, folinic acid, and 5-fluorouracil)/XELOX 
(oxaliplatin and capecitabine) was approved by the US FDA and the China NMPA in 2021 and 
sintilimab plus XELOX was approved by the NMPA in 2022 for first-line GC/gastroesophageal 
junction adenocarcinoma (GEJC), a combination of anti-PD-1 agents with chemotherapy is 
widely used in this population. The population of patients with PD-1-naïve second-line GC has 
significantly decreased due to the changes regarding first-line standard of care; thus, the 
enrollment of the GC cohort to Study BGB-A317-212 was suspended after 3 patients had been 
enrolled. 
1.4.4. 
Rationale for Biomarker Strategy  
A number of biomarkers have been identified that correspond with response to immunotherapy 
for patients with NSCLC, SCCHN, UC, RCC, and GC.  
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 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 mTKI has not 
been conclusive from limited data reported (MRTX-500, Keynote-146, COSMIC021). Thus, the 
correlation of PD-L1 with response needs further exploration. For SCCHN, PD-L1 expression is 
positively correlated with response to anti-PD-1 monotherapy (Keynote-048, Checkmate-141). 
One pilot study investigating the role of PD-L1 in predicting response to anti-PD-1 in 
combination with mTKI fail to come to a clear conclusion due to the high prevalence of PD-L1 
positive patients (82% PD-L1+) in this study. Thus, the correlation of PD-L1 with response 
needs further exploration. For UC, clinical results (1st line setting/maintenance) demonstrate that 
PD-L1 expression is positively correlated with response to anti-PD-L1therapy (IMvigor-130, 
JAVELIN). There are several clinical studies investigating anti-PD(L)-1 plus mTKI in UC 
ongoing, however, biomarker data in this context has not been extensively reported. 
Consequently, the correlation of PD-L1 with response needs further exploration (Xu et al, 2019; 
Kawazoe et al, 2020; Fukuoka et al, 2020). For RCC, clinical results demonstrate that patients 
can benefit from anti-PD-1 in combination with mTKI regardless of PD-L1 expression (Keynote-
426, Checkmate-9ER). For GC, the expression of PD-L1 is positively correlated with response to 
anti-PD-1 monotherapy (Keynote-061, Keynote-062). Additionally, 3 pilot studies have 
demonstrated the trend of patients who express PD-L1 benefiting from anti-PD-1 plus mTKI, 
compared to those negative for PD-L1 expression. This indicates that PD-L1 may be a potential 
biomarker predicting response to anti-PD(L)-1 in combination with mTKI in GC.  
Tumor mutational burden (TMB) works as the surrogate marker for neo-antigen prediction and 
has been reported to positively correlate with 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).There have been limited data 
reported so far regarding the clear role of TMB in predicting response to anti-PD(L)-1 in 
combination with mTKI in NSCLC, SCCHN, UC and GC. Consequently, the role of TMB 
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requires further exploration. 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 studies 
(POPLAR, OAK, MYSTIC studies, etc.) (Gandara et al, 2018). Apart from TMB, microsatellite 
instability (MSI), and DNA mutation can also be explored from the TMB detection panel, thus 
their role in predicting response/resistance can also be investigated. 
Consequently, in the NSCLC, SCCHN, UC and GC cohorts, PD-L1, TMB/DNA mutation/MSI, 
bTMB/DNA mutation/MSI 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 lenvatinib.  
1.5. 
Benefit-Risk Assessment  
More than 1000 patients have been treated with tislelizumab monotherapy at clinically relevant 
doses (≥ 2 mg/kg) and in combination. The safety profile is consistent with known class effects 
of anti-PD-1 antibodies including pembrolizumab and included mostly mild/moderate AEs. Very 
few Grade 3 or Grade 4 imAEs have been observed, which are generally reversible and 
manageable with study drug interruption and/or steroid treatment. Monotherapy of anti PD-1 
antibodies including tislelizumab or Lenvima monotherapy has shown anti-tumor activity from 
available data in selected tumor types of interest. Synergic effects of the combination of PD-1 
antibody with lenvatinib is expected based on pre-clinical studies. 
The safety profile of the combination regimen of pembrolizumab plus Lenvima has been fully 
assessed in the published two phase 2 studies in solid tumors. MTD and RP2D of the 
combination therapy is established, and overall safety profile is tolerable and acceptable. See 
Section 1.4.1.1. In addition, the combination treatment is approved in the US for not MSI-H or 
dMMR patients with previously pretreated advanced endometrial carcinoma. Tislelizumab 
presents a similar safety profile as pembrolizumab and lenvatinib shows equivalency in in vivo 
metabolic characteristic to Lenvima. Therefore, it is expected that the combination of 
tislelizumab plus lenvatinib would be tolerable for the patients with select tumor types of 
interest. 
In the phase 2 studies, pembrolizumab in combination with Lenvima showed promising results in 
selected, heavily treated solid tumors. Tislelizumab monotherapy as an anti PD-1 antibody 
presents similar efficacy as pembrolizumab based on available data. While the current standard 
of care in the select tumor types provides a moderate antitumor activity, however there is still an 
unmet medical need for an alternative treatment option for those patients who require a more 
tolerable and effective treatment. There is supportive evidence showing that 2 different 
mechanism of actions drugs combination would provide a synergistic clinical efficacy but still 
presents a tolerable safety profile. In consideration of unmet medical needs and expectation for 
effective chemo-free treatment for select tumor types, it is thought that tislelizumab in 
combination with lenvatinib would provide a favorable benefit risk profile for those patients. 
Tislelizumab 400 mg Q6W could provide a convenient choice of administration. It is expected 
that safety and efficacy are similar with tislelizumab 200 mg Q3W based on the results from 
Exposure-response (E-R) assessments of available clinical data. Also, the higher Cmax of 400 mg 
Q6W regimen compared with the 200 mg Q3W is well covered by the available safety data at 
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higher doses (up to 10 mg/kg Q2W doses were used in Study BGB-A317_Study_001). See 
Section 1.4.1.2. A Phase 3 study sponsored by BeiGene is ongoing to evaluate tislelizumab 400 
mg Q6W in adjuvant therapy setting in resectable stage II and IIIA NSCLC (NCT 04379635). 
A Safety Monitoring Committee (SMC) will be established consisting of the sponsor’s clinical, 
safety, and medical team representatives (eg, medical monitor, Clinical Pharmacology and Drug 
Safety) and investigators. SMC will assess the preliminary safety of lenvatinib in combination 
with tislelizumab and recommend the RP2D of lenvatinib in combination with tislelizumab 
based on the available data in this study. 
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 and Endpoints for Part 1 (Safety run-in)  
Objectives 
Endpoints 
Primary 
To assess the safety and determine the RP2D of 
lenvatinib (20 mg or other dose QD) in 
combination with tislelizumab (intravenous [IV], 
400 mg Q6W) in patients with advanced solid 
tumors 
AEs and SAEs as characterized by type, 
frequency, severity (as graded by NCI-CTCAE 
Version 5.0), timing, seriousness, and relationship 
to study drug(s); physical examinations, 
electrocardiograms (ECGs), and laboratory 
assessments as needed; and AEs meeting 
protocol-defined DLT criteria. 
 
2.2. 
Study Objectives and Endpoints for Part 2 (Expansion)  
Objectives 
Endpoints 
Primary 
To assess the ORR of tislelizumab (IV, 400 mg 
Q6W) in combination with lenvatinib at RP2D in 
patients with selected advanced solid tumors 
ORR, as assessed using RECIST Version 1.1 (as 
described in Section 10.2) by investigator 
Secondary 
To evaluate the preliminary anticancer activity of 
tislelizumab (IV, 400 mg Q6W) in combination 
with lenvatinib  
PFS, DOR, and DCR, as assessed using RECIST 
Version 1.1 (as described in Section 10.2) by 
investigator and OS 
To characterize the safety of tislelizumab (IV, 
400 mg Q6W) in combination with lenvatinib 
AEs and SAEs as characterized by type, 
frequency, severity (as graded by NCI-CTCAE 
Version 5.0), timing, seriousness, and relationship 
to study drug(s); physical examinations, ECGs, 
and laboratory assessments as needed 
Exploratory 
To explore potential biomarkers that may 
correlate with clinical responses/resistance to 
tislelizumab in combination with lenvatinib 
Potential biomarkers including but not limited to 
PD‑L1 expression, TMB/DNA mutation/ 
microsatellite instability (MSI), bTMB/DNA 
mutation/MSI, and the association of biomarkers 
with disease status, response/resistance to 
tislelizumab in combination with lenvatinib 
To characterize the PK and immunogenicity of 
tislelizumab when given in combination with 
lenvatinib 
Serum concentrations of tislelizumab and the 
incidence of ADA 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is an open-label, multicenter, Phase 2 study to evaluate the safety and preliminary 
anticancer activity of tislelizumab in combination with lenvatinib in Chinese patients with locally 
advanced or metastatic tumors including PD-L1-positive NSCLC, SCCHN, UC, RCC, and GC. 
This study includes 2 parts, Part 1 as safety run-in stage and Part 2 to assess the efficacy and 
safety of tislelizumab in combination with lenvatinib (Figure 1). 
Six patients will receive lenvatinib 20 mg orally once daily as starting dose in combination with 
tislelizumab 400 mg intravenously once every 6 weeks, and up to 18 patients will be dosed if 
lower dose(s) of lenvatinib in combination with tislelizumab need to be assessed to determine 
RP2D in Part 1. The SMC will evaluate the safety of the combination therapy when the first 6 
DLT-evaluable patients have completed the first 28 days of treatment. Once the SMC confirms 
that the combination therapy is tolerable to proceed, the current dose will be recommended by 
SMC as RP2D for Part 2, and enrollment for Part 2 will begin at this dose. Patients enrolled in 
Part 1 at the RP2D will be counted towards Part 2 by the diagnosed tumor type, and total patient 
number including Part 1 and Part 2 will be approximately 30 at RP2D in cohort of each tumor 
type. There will be a total of 5 cohorts in the study as NSCLC, SCCHN, UC, RCC and GC, 
respectively. Three cohorts were closed prior to planned enrollment due to emerging data 
(NSCLC and UC cohorts) and changes to first-line standard of care (GC cohort). Patients will 
receive the study drug(s) until occurrence of PD, starts new anticancer therapy, lost to follow-up, 
unacceptable toxicity, death, withdrawal of consent, or study termination by sponsor. 
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 Version 5.0. 
Refer to Section 9 for additional and specific information regarding AE monitoring and 
reporting. 
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. Specific details are described in 
the following sections. 
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Figure 1: 
Study Schema 
 
Abbreviations: TIS, tislelizumab; LEN, lenvatinib; NSCLC, non-small cell lung cancer; SCCHN, squamous cell 
carcinoma of head and neck; UC, urothelial cancer; RCC, renal cell carcinoma; GC, gastric cancer; PD-L1, 
programmed cell death ligand-1, QD, once daily; Q6W, once every 6 weeks. 
 
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3.2. 
Duration of Study  
The sponsor reserves the right to suspend or prematurely close the enrollment or to prematurely 
discontinue this study either at a single study center or at all study centers at any time for any 
reason. For the definition of end of study for individual patients or the entire protocol, please 
refer to Section 7.6 and Section 7.7, respectively. 
After the end of study for patients who are still receiving study drug(s), lenvatinib will not be 
provided further; however, tislelizumab may continue to be provided for patients by enrolling 
into a long-term extension study. 
3.3. 
Study Design of Part 1  
3.3.1. 
Starting Dose and Dose De-Escalation Approach  
Up to protocol development period, there is no safety data on lenvatinib in combination with 
tislelizumab 400 mg Q6W in Chinese patients with locally advanced or metastatic tumors, 
considering patient’s safety, a safety run-in part for combination dosages of lenvatinib and 
tislelizumab will be performed. Patients in this part will have one of the following tumors: non-
small cell lung cancer, squamous cell carcinoma of the head and neck, urothelial carcinoma, 
renal cell carcinoma, or gastric cancer. 
Tislelizumab will be administered at 400 mg Q6W for this study (including Part 1 and Part 2). 
For the drug combined with tislelizumab, lenvatinib will begin at dose of 20 mg QD. The 
rationale of starting doses of lenvatinib as combination treatment was summarized in Section 
1.4.1.1. 
Lower dose levels of lenvatinib initiated from 20 mg QD will be explored as necessary 
depending on observed safety profile. lenvatinib dose will begin with Dose level 0: lenvatinib at 
20mg/day orally and tislelizumab 400 mg Q6W, IV will be administrated to patients with 
selected solid tumors on a 42-day treatment cycle. Dose de-escalation of lenvatinib includes 
Dose level -1: lenvatinib 16 mg/day orally and tislelizumab 400 mg Q6W, IV and Dose level -2: 
lenvatinib 12 mg/day orally and tislelizumab 400 mg Q6W, IV. Once the dose has been reduced, 
re-escalation is not allowed. 
Six patients will be enrolled for lenvatinib (20 mg QD) in combination with tislelizumab (IV, 
400 mg Q6W). An SMC will be established to review the safety data collected from patients in 
Part 1 of the study first 28 days after starting tislelizumab (intravenously, 400 mg once per 6 
weeks) in combination with lenvatinib. Based on these data, the SMC will recommend whether a 
dose modification of lenvatinib is needed, or whether the next part of the study can be initiated. 
The decision about establishing the RP2D is made by the sponsor. 
3.3.2. 
Rules for Dose De-Escalation  
If 0 or 1 in 6 patients experience a DLT at dose level of 20 mg QD lenvatinib combined with 
tislelizumab (IV, 400 mg Q6W) in select tumor type, then patients could be enrolled at this dose 
level subsequently for Part 2.  
If 2 or more in 6 patients experience a DLT at dose level of 20 mg QD lenvatinib combined with 
tislelizumab (IV, 400 mg Q6W), 6 more patients would be enrolled at a next lower dose level, 
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with dose reduction of lenvatinib from 20 mg QD to 16 mg QD or from 16 mg QD to 12 mg QD 
in combination with 400 mg tislelizumab Q6W. 
If 2 or more in 6 patients experience a DLT at Dose level of 12 mg QD lenvatinib in combination 
with tislelizumab (IV, 400 mg Q6W), enrollment of patients will stop. 
In the safety run-in period, safety information including but not limited to the DLTs, all TEAEs, 
laboratory abnormalities, and/or pharmacology data of first 28 days from first 6 evaluable 
patients at each dose level will be reviewed by SMC. Recruitment will be on hold until the data 
have been reviewed. 
3.3.3. 
Assessment of Dose-Limiting Toxicity  
For initial dose-finding recommendations, AEs will be assessed per the DLT criteria below 
(Section 3.3.4) during the 28-day DLT assessment window, which starts with the first day of 
study drug administration. 
The DLT Evaluable Analysis Set includes patients enrolled during safety run-in stage who 
• Received ≥ 75% of scheduled lenvatinib and ≥ 67% (approximately two-thirds) of 
scheduled dose intensity of tislelizumab administration during the DLT assessment 
window, remained on study during the DLT observation period, and had sufficient safety 
evaluation OR  
• Experienced a DLT within the DLT observation period. 
Patients will be considered not evaluable for DLTs if they 1) did not receive ≥ 75% of scheduled 
lenvatinib or ≥ 67% (approximately two-thirds) of scheduled dose intensity of tislelizumab 
administration during the DLT assessment window, OR 2) received supportive care during the 
DLT assessment window that confounds the evaluation of DLTs (not including supportive care 
described as part of the DLT definition). Patients who are not DLT-evaluable must be replaced, 
if needed. 
The detailed calculation of scheduled dose intensity of tislelizumab/ lenvatinib is documented in 
the Safety Monitoring Committee Operating Procedure and statistical analysis plan (SAP) of this 
study. 
Clinically important or persistent AEs that are not part of the DLT criteria (Section 3.3.4) may 
also be considered a DLT following review by the sponsor in consultation with the investigators. 
Additionally, any clinically significant AEs that occur after the DLT assessment window (eg, 
late immune-mediated AE [imAE]) for a given dose level may be considered regarding 
subsequent decisions.  
Any patient who experiences a DLT may be withdrawn from treatment or may continue at a 
lower dose level or take one of study drugs following discussion with and approval by the 
medical monitor. 
3.3.4. 
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) 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: 
• ≥ Grade 4 toxicity 
• Grade 3 toxicity that is clinically significant and does not resolve to baseline or ≤ Grade 1 
within 7 days after optimal supportive care is initiated 
• ≥ Grade 2 any thromboembolic event 
Note: The following 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 
For safety run-in, patients who received <67% of scheduled tislelizumab and/or < 75% of 
scheduled lenvatinib during the DLT assessment window for any reason other than a DLT will 
be replaced. All patients enrolled in safety run-in period will be assessed for DLTs during the 
DLT assessment window. Once they complete the DLT assessment, each subject still receiving 
study treatment will continue with the same dosage. Tumor assessments will be continued as 
scheduled.  
3.4. 
Study Design of Part 2  
Part 2 of the study will begin once the recommended dose is confirmed by the sponsor. Three 
cohorts were closed prior to planned enrollment due to emerging data (NSCLC and UC cohorts) 
and changes to first-line standard of care (GC cohort). In the SCCHN and RCC cohorts, 
approximately 30 patients at RP2D will be enrolled per cohort in parallel. 
Each cohort will be evaluated independently for study endpoints and may be closed due to lack 
of preliminary anticancer activity or other reasons.  
NSCLC Cohort: Patients with advanced NSCLC who have no prior systemic anti-tumor therapy 
for advanced disease, and whose tumor expressed PD-L1 status as tumor cell (TC) ≥ 1% by the 
Ventana SP263 assay, without EGFR mutation and/or known ALK gene translocation. 
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SCCHN Cohort: Patients with recurrent or metastatic (R/M) SCCHN who have no prior systemic 
anti-tumor therapy for advanced disease. Patients have a primary tumor site of nasopharynx (any 
histology) are not eligible. 
UC Cohort: Patients with locally advanced or metastatic UC who are cisplatin-ineligible and 
have no prior systemic anti-tumor therapy for advanced disease. 
RCC Cohort: Patients with advanced RCC with clear cell as predominantly component and have 
no prior systemic anti-tumor therapy for advanced disease. 
GC Cohort: Patients with advanced GC/GEJC and have 1 line of prior systemic anti-tumor 
therapy for advanced disease. 
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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. No eligibility waivers will be granted. 
4.1. 
Inclusion Criteria  
Each patient must meet all 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. Histologically and/or cytologically confirmed solid tumor types such as one of following: 
NSCLC, SCCHN, UC, RCC or GC/ GEJC. For patients with tumor types other than 
GC/GEJC, should receive no prior systemic anti-cancer therapy for advanced disease. For 
GC/GEJC cohort, patients should have had 1-line previous systemic treatment for 
advanced disease. 
• NSCLC Cohort: Advanced/metastatic NSCLC without EGFR mutation and/or known 
ALK gene translocation, and whose tumor expressed PD-L1 status as TC ≥ 1% 
confirmed by central laboratory utilizing Ventana SP263 assay. For non-squamous 
NSCLC patients without documented EGFR status, a tissue-based EGFR mutation 
assessment is required before enrollment.  
Note: Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
therapy is acceptable if therapy was completed ≥ 6 months before the diagnosis of 
advanced or metastatic disease. 
• SCCHN Cohort: Recurrent or metastatic (R/M) SCCHN, primary tumor locations 
need to be oropharynx, oral cavity, hypopharynx, or larynx. Patients who have a 
primary tumor site of nasopharynx (any histology) are not eligible. 
Note: Systemic therapy as part of multimodal treatment for locally advanced disease 
is acceptable if it was completed ≥ 6 months before diagnosis of recurrent/metastatic 
disease. Metastatic means M1 per American Joint Committee on Cancer (AJCC) 
Eighth Edition (Amin et al, 2017). 
• UC Cohort: Advanced/unresectable (inoperable) or metastatic UC, including renal 
pelvis, ureters, bladder, or urethra. In order to be enrolled, the patient has to be 
cisplatin-ineligible, defined as meeting any of the following criteria (Galsky et al, 
2011): 
− Creatinine clearance (calculated by Cockcroft-Gault formula or measured) < 
60 mL/min but >30 mL/min 
Note: Patients with a creatinine clearance (calculated or measured) < 30 
mL/min or on dialysis are excluded from the study. 
− CTCAE, grade 2 or above audiometric hearing loss 
− CTCAE, grade 2 or above peripheral neuropathy 
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Note: For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-
radiation for UC, a recurrence-free interval > 12 months since the last treatment 
administration is required. Prior local intravesical chemotherapy or immunotherapy is 
allowed if completed at least 4 weeks before the initiation of study treatment. Low-
dose chemotherapy (eg., low dose cisplatin, cisplatin+5FU, mytomycin+5FU, or 
cisplatin+paclitaxel) given concurrent with radiation to the primary tumor site is not 
considered as systemic therapy. 
• RCC Cohort: Advanced/metastatic RCC with clear cell as predominantly component 
or have recurrent disease.  
Note: Prior neoadjuvant/adjuvant therapy of targeted agents to VEGF/VEGFR or 
mTOR is acceptable if it was completed > 12 months before recurrence.  
• GC Cohort: Confirmed diagnosis of GC or GEJC, which has been treated with 1 prior 
line of therapy for advanced disease. Patients need to have documented disease 
progression during/after previous first-line treatment. The disease progression needs 
to be confirmed by radiographic scan such as computed tomography (CT). 
Note: Prior neoadjuvant or adjuvant therapy in which the interval between the 
completion of treatment and the occurrence of recurrence or metastatic disease was 
< 6 months will be counted as one line of treatment for advanced disease. External 
beam radiation therapy as neoadjuvant/adjuvant is acceptable, internal radioactive 
implant treatment is not allowed. 
− Any standard chemotherapy regimen recommended by local guideline as first-
line treatment is allowed. As first-line treatment, the chemotherapy should be 
received at least one cycle by patient. The substitution of drug(s) for the 
drug(s) with the same mechanism of action due to any reason other than 
disease progression is not considered a new line of therapy and is allowed. 
However, if a new component, dissimilar to any of the original components, is 
added to the regimen, the new combination is considered a new regimen 
which is not eligible. Prior intraperitoneal chemotherapy is allowed if 
completed at least 4 weeks before the initiation of study treatment. 
− Patients with HER2 (+) must receive first-line anti-HER2 systemic therapy 
(anti-HER2 plus chemotherapy recommended by local guideline) and had 
documentation of disease progression during/after first-line anti-HER2 
treatment. Patients with unknown status must have their HER2 status 
determined locally. 
4. At least 1 measurable lesion per RECIST Version 1.1 
• A lesion in an area subjected to prior locoregional therapy, including previous 
radiotherapy, is not considered measurable unless there has been demonstrated 
progression in the lesion since the start of therapy as defined by RECIST Version 1.1 
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5. Tumor tissue (approximately 10 unstained slides) for central laboratory assessment of 
PD-L1 status for the NSCLC cohort during the screening period, and for retrospective 
analysis of other exploratory biomarkers related to response and resistance for NSCLC, 
SCCHN, UC, and GC cohorts in a BeiGene designated central or special laboratory. 
• For cohorts of NSCLC, SCCHN, UC, and GC, a fresh biopsy is mandatory in the 
absence of archival tumor tissues.  
• Submission of < 10 unstained slides is not a protocol deviation. If patients cannot 
provide 10 unstained slides, patients may be enrolled after confirmation with the 
sponsor. 
• For non-squamous NSCLC patients who could not provide EGFR documentation and 
complete EGFR test locally, 10 slides will be required additionally for central 
laboratory assessment of EGFR mutation. 
Note: 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. For biopsy-derived 
samples, 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. 
6. ECOG Performance Status ≤ 1 
7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤ 150/90 mmHg at screening, and no change in antihypertensive 
medications within 1 week before the Cycle 1 Day 1. 
8. Adequate organ function as indicated by the following laboratory values ≤ 7 days before 
the first dose of study drugs 
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. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated glomerular 
filtration rate (GFR) ≥ 40 mL/min/1.73 m2 by Chronic Kidney Disease-Epidemiology 
Collaboration (CKD-EPI) equation (Appendix 9) 
e. Serum total bilirubin ≤ 1.5 x ULN (less than 3 x ULN for patients with Gilbert 
syndrome) 
f. AST and ALT ≤ 2.5 x ULN or < 5 x ULN if hepatic metastases are present 
g. Adequate blood coagulation function as evidenced by an International Normalized 
Ratio (INR) ≤ 1.5. 
9. 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). 
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10. 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. 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from this study: 
1. For the NSCLC cohort, active leptomeningeal disease or uncontrolled, untreated brain 
metastasis will be excluded.  
Patients with a history of treated and, at the time of screening, stable central nervous 
system metastases are eligible, provided they meet all the following: 
− Brain imaging at screening shows no evidence of interim progression, clinically 
stable for at least 2 weeks and, have no evidence of new brain metastases 
− Have measurable disease and/or evaluable disease outside of the central nervous 
system 
− No ongoing requirement for corticosteroids as therapy for central nervous system 
disease; anticonvulsants at a stable dose are allowed 
− No stereotactic radiation or whole-brain radiation ≤ 14 days before the first dose 
of study drug(s) 
For other cohorts than NSCLC, patients with known leptomeningeal disease or brain 
metastasis will be excluded. 
2. Prior therapy with lenvatinib or an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other 
antibody or drug specifically targeting T-cell costimulation or checkpoint pathways 
3. Active autoimmune diseases or history of autoimmune diseases that may relapse, 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 
4. 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, or 
carcinoma in situ of the cervix or breast) 
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5. 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) 
6. History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung 
diseases including but not limited to pulmonary fibrosis, acute lung diseases, etc. 
7. 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) 
8. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence within 2 weeks of intervention). 
Note: Patients with symptomatic pleural effusion are excluded unless the patient 
undergoes a therapeutic thoracentesis or has had pleurodesis (more than 2 weeks prior) 
and has subsequently stable effusions. 
9. Severe chronic or active infection (including tuberculosis infection, etc) requiring 
systemic antibacterial, antifungal, or antiviral therapy before the first dose of study 
drug(s). 
a. Severe infections within 4 weeks before first dose, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
b. Received therapeutic oral or IV antibiotics within 2 weeks before first dose 
c. Antiviral therapy is permitted for patients with chronic hepatitis B virus (HBV) or 
hepatitis C virus (HCV) infection. 
10. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA > 500 IU/mL (or 
> 2500 copies/mL) 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). 
11. Patients with active hepatitis C. 
• Patients with a negative HCV antibody test result at screening or a positive HCV 
antibody test result followed by a negative HCV RNA test result at screening are 
eligible. The HCV RNA test will be performed only for patients testing positive for 
HCV antibody. Patients receiving antivirals at screening should have been treated for 
> 2 weeks before the first dose of study drug(s). 
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12. Known history of HIV infection 
13. 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 before the first dose of study drug(s). 
14. Immunodeficiency, allogeneic stem cell transplantation, or organ transplantation 
15. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days before the first dose of study drug(s) 
b. Pulmonary embolism ≤ 28 days 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 7) ≤ 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. QTcF interval (QT interval corrected for heart rate by Fridericia’s formula 
[Appendix 8]) > 450 msec 
h. Cardiac left ventricular ejection fraction (LVEF) out of the institutional normal range 
as determined by multiplegated acquisition (MUGA) scan or echocardiogram. The 
same modality used at baseline must be applied for subsequent evaluations. 
i. Syncope or seizure ≤ 28 days before the first dose of study drug(s) 
16. History of severe hypersensitivity reactions to other monoclonal antibodies 
17. Serious nonhealing wound, ulcer, or bone fracture 
18. Chemotherapy, immunotherapy (eg, interleukin, interferon, thymosin), or investigational 
therapy ≤ 14 days or 5 half-lives (whichever is shorter) before the first dose of study 
drug(s). Also, palliative radiation treatment or other locoregional therapies within 14 days 
before the first dose of study drug. 
19. 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) 
20. 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, 
and specific laboratory abnormalities) 
21. 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. 
22. 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. 
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23. 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. 
24. Women who are pregnant or are breastfeeding 
25. Inability to swallow capsules or disease/procedure significantly affecting gastrointestinal 
function, such as malabsorption syndrome, resection of the stomach or small bowel, 
bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or 
complete bowel obstruction 
• Gastroesophageal reflux disease under treatment with proton-pump inhibitors is 
allowed (assuming no drug interaction potential).  
26. Patients having >1+ proteinuria on urinalysis will undergo 24-hour urine collection for 
quantitative assessment of proteinuria. Patients with urine protein ≥1 g/24-hour will be 
ineligible 
27. Have clinically significant bleeding (such as CTCAE ≥ Grade 2) within 21 days before 
first dose 
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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Lenvatinib  
Management (ie, handling, storage, administration, and disposal) of lenvatinib will be in 
accordance with relevant local guidelines, prescribing information/summary of product 
characteristics. 
Refer to the Pharmacy Manual for details regarding administration, accountability, and disposal. 
5.1.2. 
Tislelizumab  
Tislelizumab is a monoclonal antibody formulated for IV injection in a single-use vial (20R 
glass, USP type I), containing a total of 100 mg antibody in 10 mL of isotonic solution. 
Tislelizumab has been aseptically filled in single-use vials with a Flurotec-coated butyl rubber 
stopper and an aluminum 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 stored at refrigerated conditions (2-8°C) and protected from light as 
specified on the label. 
Refer to the Pharmacy Manual for details regarding IV administration, accountability, and 
disposal. Please also refer to the tislelizumab IB (BeiGene Investigator’s Brochure, 2021) for 
other details regarding tislelizumab. 
5.2. 
Dosage, Administration, and Compliance  
Treatment with study drug(s) on Day 1 of Cycle 1 must begin within 2 business days after 
receiving the confirmation of 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 9.7 and 
Appendix 10. 
Accurate records of all study drug(s) received, dispensed, returned, and disposed should be 
maintained in the site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of study 
drug management, drug preparation, storage, and administration. 
5.2.1. 
Part 1  
Planned dose level(s) for lenvatinib and tislelizumab are presented in Table 4. 
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Table 4: 
Planned Dose Levels for Lenvatinib and Tislelizumab 
Study drug(s) 
Dose 
Lenvatinib 
20 mg QD, oral (Dose level 0) 
16 mg QD, oral (Dose level -1) 
12 mg QD, oral (Dose level -2) 
Tislelizumab 
400 mg every 6 weeks, IV 
This Part will review the safety profiles of the dosage of lenvatinib as 20 mg QD or other dose in 
combination with tislelizumab (intravenous [IV], at dose of 400 mg Q6W) in patients with 
selected types of solid tumor. 
5.2.1.1. 
Tislelizumab  
Tislelizumab 400 mg will be administered on Day 1 of each 42-day cycle (once every 6 weeks) 
by intravenous infusion through an intravenous line containing a sterile, nonpyrogenic, low-
protein-binding, 0.2- or 0.22-micron in-line or add-on filter. 
As a routine precaution, after infusion of tislelizumab on Day 1 of Cycle 1 and Cycle 2, patients 
must be monitored for at least 2 hours afterward in an area with resuscitation equipment and 
emergency agents. From Cycle 3 onward, at least 1 hour monitoring period is required in an area 
with resuscitation equipment and emergency agents. 
The initial infusion of tislelizumab (Cycle 1, Day 1) will be delivered over 90 minutes; the 
second infusion may be administered over 60 minutes if 90 minutes are tolerated; and for the 
following infusions, at least 30 minutes is required if 60 minutes infusion is tolerated, which is 
the shortest time period permissible for infusion. Tislelizumab must not be concurrently 
administered with any other drug. Study treatment with tislelizumab may be administered up to 3 
days before or after the scheduled Day 1 of each cycle. 
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of imAEs and infusion-related reactions are provided in detail in Section 9.7.3 and 
Section 9.7.1. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
5.2.1.2. 
Lenvatinib  
Starting on Day 1 of each Cycle, lenvatinib 20 mg will be administered orally once a day at 
approximately the same time each day. Patients will be instructed to swallow the capsules whole, 
in quick succession, with water. Lenvatinib can be administered with or without food. A dose of 
lenvatinib should be skipped if it is not taken within 12 hours of the scheduled time. An extra 
dose of lenvatinib should not be taken to make up for a missed dose. If vomiting occurs during 
treatment, no re-dosing of the patient is allowed before the next scheduled dose.  
On Day 1 of each cycle lenvatinib will be administered at least 1 hour after completion of 
tislelizumab administration.  
Compliance will be assessed by the investigator and/or study personnel at each patient visit along 
with information provided by the patient and documented accordingly. The investigator and/or 
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study personnel will keep accurate records of the quantities of capsules dispensed and used by 
each patient. This information must be captured in the source document at the end of each cycle. 
5.2.2. 
Part 2  
Patients enrolled in Part 2 will receive the study drug of the confirmed RP2D dose of lenvatinib 
in Part 1 and tislelizumab until occurrence of PD, unacceptable toxicity, death, withdrawal of 
consent, or study termination by sponsor. 
5.3. 
Overdose  
Any incorrect administration of study drug(s) or overdose of tislelizumab (defined as ≥ 600 mg 
in a 24-hour period) or lenvatinib (defined as any dose > 20 mg) 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 electronic case report form (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 9.6.2. Supportive care measures 
should be administered as appropriate. 
5.4. 
Dose Delay or Modification  
A dose delay due to the reason other than tolerability 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. 
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 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 ≤ 21 days, it should be administered in the current cycle. If 
tislelizumab needs to be withheld for > 21 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. 
Dose modification related to imAEs and infusion-related reactions are described in Section 9.7.3 
and Section 9.7.1, respectively. 
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5.4.2. 
Dose Delay or Modification for Lenvatinib  
Lenvatinib dose modification for patients who experience lenvatinib related adverse events of 
special interest should be in accordance with the guidelines provided in Table 5 and Table 6, 
while other related AEs which are not outlined in Table 5, dose modification for lenvatinib 
should follow guidelines provided in Table 6. Once the dose has been reduced, it should not be 
increased later. Any dose reduction below 4 mg/day must be discussed with the sponsor. If the 
administration of lenvatinib is interrupted for reasons other than toxicity, then treatment with the 
study drug may be resumed at the same dose. 
For management of AE of lenvatinib of special interest, the instructions are summarized in 
Section 9.8.1. It is recommended to discuss with the medical monitors if the investigators 
propose to manage the AEs with otherwise strategy which is not outlined in Table 5, Table 6 and 
Section 9.8.1. Dose reductions of lenvatinib in Part 2 occur in succession starting at the 
confirmed dose identified in safety run-in. 
For toxicity that is suspected of related to both tislelizumab and lenvatinib, the investigators 
should follow the recommendation referring to both instructions (Section 5.4.1 and 
Section 5.4.2) for dose delay and modification until the causality to individual agent is clearly 
identified. Lenvatinib may be resumed at the same dose if AE is assessed as not related to 
lenvatinib later. 
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Table 5: Recommended Dosage Modifications for Lenvatinib Related Adverse Events of 
Special Interest 
 
 
Adverse Reaction 
Severity 
Dosage Modifications for Lenvatinib 
Hypertension  
Grade 3 
Withhold for Grade 3 that persists despite optimal 
antihypertensive therapy. 
Resume at reduced dose when hypertension is controlled at 
less than or equal to Grade 2. 
Grade 4 
Permanently discontinue. 
Cardiac Dysfunction Grade 3 
Withhold until improves to Grade 0 to 1 or baseline. 
Resume at a reduced dose or discontinue depending on the 
severity and persistence of adverse reaction. 
Grade 4 
Permanently discontinue. 
Arterial 
Thromboembolic 
Event 
Any Grade 
Permanently discontinue. 
Hepatotoxicity 
Grade 3 or 4 
Withhold until improves to Grade 0 to 1 or baseline. 
Either resume at a reduced dose or discontinue depending on 
severity and persistence of hepatotoxicity. 
Permanently discontinue for hepatic failure. 
Renal Failure or 
Impairment 
Grade 3 or 4 
Withhold until improves to Grade 0 to 1 or baseline. 
Resume at a reduced dose or discontinue depending on severity 
and persistence of renal impairment. 
Proteinuria 
2 g or greater 
proteinuria in 
24 hours 
Withhold until less than or equal to 2 grams of proteinuria per 
24 hours. 
Resume at a reduced dose. 
Permanently discontinue for nephrotic syndrome. 
Gastrointestinal 
Perforation 
Any Grade 
Permanently discontinue. 
Fistula Formation 
Grade 3 or 4 
Permanently discontinue. 
QT Prolongation 
Greater than 
500 ms or 
greater than 60 ms 
increase from 
baseline 
Withhold until improves to less than or equal to 480 ms or 
baseline.  
Resume at a reduced dose. 
Reversible Posterior 
Leukoencephalopathy 
Syndrome 
Any Grade 
Withhold until fully resolved. 
Resume at a reduced dose or discontinue depending on severity 
and persistence of neurologic symptoms. 
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Table 6: 
Dose Modifications for Lenvatinib Treatment-Related Toxicity  
Lenvatinib Treatment-Related 
Toxicitya,b 
During Therapy 
Adjusted Dosef 
Grade 1, Tolerable Grade 2 
 
Continue treatment 
No change 
Intolerable Grade 2c,d and Grade 3g 
First occurrence 
Interrupt lenvatinib until 
resolved to tolerable Grade 2 or 
Grade 0-1 
Reduce lenvatinib by one dose 
levelb 
Second occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib until 
resolved to tolerable Grade 2 or 
Grade 0-1 
Reduce lenvatinib by one more 
dose level 
Third occurrence 
(same toxicity or new toxicity) 
Interrupt lenvatinib until 
resolved to tolerable Grade 2 or 
Grade 0-1 
Reduce lenvatinib by one more 
dose level 
Fourth occurrence  
(same toxicity or new toxicity) 
Interrupt lenvatinib until 
resolved to tolerable Grade 2 or 
Grade 0-1 
Reduce lenvatinib by one more 
dose level 
Grade 4e,g: Discontinue lenvatinib permanently 
a. 
An interruption of lenvatinib treatment for more than 21 days (due to lenvatinib treatment-related toxicities) 
will require a discussion with the sponsor before treatment can be resumed. 
b. Excluding alopecia. Initiate optimal medical management for nausea, vomiting, hypothyroidism, hypertension 
and/or diarrhea before any lenvatinib interruption or dose reduction. For treatment-related hypertension, refer to 
Management of Hypertension (Section 9.8.1) for dose modification guidelines. 
c. 
Applicable only to Grade 2 toxicities judged by subject and/or physician to be intolerable. 
d. Obese patients with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie, 
Grade 1 weight loss). These patients will restart the study drug(s) at a lower dose once their weight remains stable 
for at least 1 week and they reached the normal BMI (if the weight loss occurred but it is still above normal BMI, 
they can restart the study treatment at a lower dose once the weight has been stable for at least 1 week). Normal 
BMI should be used as the new baseline for further dose reductions. 
e. 
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
f.  
Refer to Table 7 for adjusted dose. 
g. For asymptomatic Grade ≥3 elevations of amylase and lipase, the sponsor’s medical monitor should be 
consulted to obtain permission to continue treatment. 
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Table 7: Dose Reduction Recommendations for Lenvatinib  
Initial 
Lenvatinib Dose 
(mg, QD) 
Adjusted Dose To Be Administered (mg, QD) 
Reduction 1 
Reduction 2 
Reduction 3 
Reduction 4 
20 
16 
12 
8 
4 
16 
12 
8 
4 
 
12 
8 
4 
 
 
QD = once daily. 
General guidelines for holding periods of lenvatinib due to procedures: 
For minor procedures, lenvatinib should be stopped 2 days before the procedure and restarted 2 
days after, once there is evidence of adequate healing and no risk of bleeding. Needle biopsies 
(fine needle aspirations and core needle aspirations) are usually considered minor procedures. 
For major procedures, lenvatinib should be stopped 1 week (5 half-lives) before the procedure 
and then restarted once there is clear wound healing and no risk of bleeding, but at least 1 week 
after the procedure. It is up to the investigator to determine if it is a major or minor procedure. 
Usually, a major procedure implies general anesthesia. 
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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 all patients 
will be collected at study entry and entered into the eCRF. 
Note: For patients without prior systemic anti-cancer therapy, planned neoadjuvant 
chemotherapy (to debulk the tumor before surgical intervention) plus postoperative adjuvant 
chemotherapy is considered 1 regimen.  
For GC patient who has had previous first-line therapy, if the treatment is interrupted for surgery 
or radiotherapy or any other reason than disease progression and then continues with an 
unchanged schedule and components, that treatment is considered as 1 regimen despite the 
interruption. 
6.2. 
Permitted Concomitant Medications/Procedures  
The potential for drug-drug interaction between the study drug tislelizumab and small-molecule 
drug products is very low because tislelizumab is a therapeutic monoclonal antibody. Because 
tislelizumab is expected to be degraded into amino acids and recycled into other proteins, it is 
unlikely to have an effect on drug-metabolizing enzymes or transporters. 
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. Additionally, all diagnostic, therapeutic, or surgical procedures relating to malignancy 
should be recorded. Any medication that is considered necessary for the subject’s health and that 
is not expected to interfere with the evaluation of or interact with lenvatinib or tislelizumab may 
be continued during the study. 
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. 
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation of 
(or to interact with) lenvatinib or tislelizumab. 
Prophylactic antiemetic, granulocyte colony stimulating factors, granulocyte macrophage colony 
stimulating factors, platelet simulating factors or erythropoietin are permitted as clinically 
indicated. 
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6.2.1. 
Systemic Corticosteroids  
Systemic corticosteroids administered for the control of imAEs must be tapered gradually (see 
Appendix 10 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.  
6.2.2. 
Hepatitis B Treatment  
Patients with active hepatitis B, defined as HBV DNA ≥ 500 IU/mL at screening, must initiate 
treatment 2 weeks before the first dose and continue until 6 months after the last dose of 
tislelizumab. Patients should continue effective antiviral treatment during the study to decrease 
potential viral reactivation risk. Tenofovir and entecavir are recommended in the American 
Association for the Study of Liver Disease guideline because they lack resistance with long-term 
use (Terrault et al, 2016; AASLD/IDSA HCV Guidance Panel, 2015). The investigator might use 
other antiviral agents, if appropriate, following local guidelines. Management of antiviral therapy 
is at the discretion of the investigator. However, interferon-based therapy for hepatitis B is not 
permitted on study.  
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 500 IU/mL) 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 
tislelizumab discontinuation. 
6.2.3. 
Radiation Therapy  
Palliative (limited-field) radiation therapy is permitted, but only for pain control or prophylaxis 
of bone fracture to sites of bone disease present at baseline 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 RECIST 
Version 1.1 
• 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. 
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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 herbal medicine 
and Chinese patent medicines for the treatment of cancer regardless of cancer type), 
≤ 14 days (or ≤ 5 half-lives, if applicable, whichever is shorter) before the first dose of 
study drug(s) and during the study. Chinese herbal and Chinese 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). 
• Medications that prolong QT interval during study treatment with lenvatinib.  
Note: please refer to Appendix 12 for more details of known risk of QT 
Prolongation/Torsades de Pointes 
• Live vaccines ≤ 28 days before the first dose of tislelizumab and ≤ 60 days following the 
last dose of tislelizumab. 
• Immunosuppressive agents (except to treat a drug-related AE) during study treatment 
with tislelizumab. 
• 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 
during study treatment with tislelizumab. 
Note: Inhaled steroids are allowed for management of asthma or seasonal allergies. 
• Patients should not abuse alcohol or other drugs. 
• 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) 
≤ 14 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 6.1.  
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. 
With the exception of diagnostic biopsy of tumor tissue or placement of a venous access device, 
the investigator should discuss with the sponsor medical monitor any patient who requires 
surgery during the study. 
Earlier studies have shown that Lenvima exposure is neither affected by food intake (Shumaker 
et al, 2014a) or coadministration of cytochrome P450 (CYP)3A4 inhibitors and inducers 
(Shumaker et al, 2015; Shumaker et al, 2014b).  
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Lenvima has been reported to prolong the QT/QTc interval. Monitor and correct electrolyte 
abnormalities at baseline and periodically during treatment. Please refer to Appendix 12 for a list 
of medications or substances to be avoided or used with caution during treatment with lenvatinib. 
6.5. 
Drug-drug Interaction  
6.5.1. 
Drug-drug Interaction between Tislelizumab and Lenvatinib  
The potential drug-drug interaction between tislelizumab and lenvatinib is expected to be low.  
Both drugs have different disposition pathways and are not overlapping. Tislelizumab is given by 
IV infusion has no impact on the oral absorption of lenvatinib. Like most therapeutic proteins, 
tislelizumab is eliminated from the body via non-specific proteolytic catabolism and target 
mediated elimination pathways, have no effect on drug-metabolizing enzyme, such as CYP3A4 
enzyme that are responsible for the metabolism of lenvatinib and vice versa. Tislelizumab is 
unrelated to the pro-inflammatory cytokines, has no potential DDI interactions for drugs, like 
lenvatinib, are substrate of CYP/transporter (FDA, 2020).  
6.5.2. 
Drug-drug Interaction between Lenvatinib and Other Drugs  
Nonclinical studies identified that Lenvima is mainly metabolized by CYP3A4 enzyme and it’s 
the substrate of P-glycoprotein (P-gp) and breast cancer resistance protein. However, the clinical 
drug-drug interaction study showed that co-administration of Lenvima with CYP3A4/P-
glycoprotein inhibitors/inducer is not of a clinical concern (details can be found in Appendix 13). 
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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. 
7.1.2. 
Demographics  
Demographic factors such as age, gender, race, and ethnicity could influence the effects (safety 
and efficacy) of medicines and the risk/benefit assessment in different populations. Race and 
ethnicity data are collected in accordance with ICH guidance (ICH E5 1998, ICH E17 2017) 
adopted by the European Medicines Agency (EMA) and the US FDA, to understand whether 
race/ethnicity could influence the PK, safety, and/or efficacy of the study drug. For example, 
population PK analysis is a well-established, quantitative method that can quantify and explain 
the variability in drug concentrations among patients. Such variability can be attributed to 
intrinsic factors (eg, body weight, age, gender, race/ethnicity), or to extrinsic factors (eg, 
concomitant medications), and can lead to clinically relevant changes in drug concentrations that 
require a change in the dose or dosing regimen. Results from race/ethnicity and other 
demographic analyses will be incorporated into drug product labeling to provide guidance on 
safety and efficacy variations (if any) linked to certain populations (eg, race or ethnic group) as 
well as any potential dose adjustment needed for those populations. Therefore, collecting 
race/ethnicity data in the study is essential to understand whether race/ethnicity could influence 
the PK, safety, and/or efficacy. 
7.2. 
Enrollment  
Prior to enrollment, the investigator is responsible for assessing and confirming that each patient 
meets all inclusion eligibility criteria for this study and that none of the exclusion criteria apply. 
All results from the screening procedures and relevant medical history must be available and 
reviewed by the investigator before eligibility can be determined. No eligibility waivers will be 
granted. 
Sponsor verification of patient eligibility will be managed by way of source data verification in 
accordance with International Council for Harmonisation (ICH) E6. 
The sponsor’s medical monitor will support the investigator and/or site staff by answering any 
queries or questions relating to protocol eligibility criteria. 
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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 Version 1.1 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 End-of-Treatment (Visit) (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. 
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. 
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, 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. 
All AEs, including SAEs, will be collected as described in Section 9.6. 
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) or death will 
continue to undergo tumor assessments following the original plan until the patient experiences 
PD, starts new anticancer therapy, is lost to follow-up, withdraws consent or until patient death 
or study terminates, 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. 
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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. If both EOT and safety follow up visits are missed, the first survival follow-up visit 
should be calculated based on the date PI decided to End Treatment. Please use an “Equal 
Interval” calculation to estimate the next survival follow up visit/contact for the subject. 
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 of 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. 
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 herbal 
medicine and Chinese 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 
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accountability. The investigator may, in consultation with the medical monitor, 
discontinue patients from treatment who are consistently noncompliant. 
If tislelizumab or lenvatinib is discontinued permanently for reasons other than disease 
progression, the other drug could be continued as originally scheduled. 
If the decision is made to continue lenvatinib monotherapy beyond initial progression, it should 
be confirmed with the sponsor and the patient will continue to be treated and monitored 
according to the schedule in Appendix 1. Lenvatinib monotherapy must be discontinued 
permanently upon documentation of further progression, either symptomatic or radiographic. 
The guidance for tislelizumab use beyond the first disease progression is provided in Section 8.3. 
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. 
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. 
After the end of study for the patients who are still receiving study drug(s), lenvatinib will not be 
provided afterwards, while tislelizumab may be continued for patients by enrolling into a long-
term extension study. 
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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 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  
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. 
For patients with NSCLC, pulmonary function testing including spirometry and assessment of 
oxygenation, at a minimum, pulse oximetry at rest and with exercise, or alternatively, assessment 
of diffusion capacity, are to be performed for all patients during the screening period to assist the 
determination of suitability on the study. Respective test results need to be submitted to the 
sponsor. 
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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. 
8.2. 
Safety Assessments  
8.2.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate, and blood pressure 
(systolic and diastolic). Pulse rate and blood pressure will be measured while the patient is in a 
seated position after resting for 10 minutes.  
Height should only be measured and recorded during screening. Weight will be measured before 
study drug administration in every cycle. 
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 Version 5.0 
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 9.3 regarding AE definitions and 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 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, urinalysis, and coagulation 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 3 days before study drug administration. 
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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. 
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 creatine kinase-muscle/brain (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 10 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 CK and CK-MB 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 3 days before study drug administration. 
8.2.5. 
Electrocardiograms  
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient’s permanent study 
file at the site. 
When coinciding with blood draws (eg, performed within 30 minutes of each other), ECG 
assessment should be performed prior to 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, etc.) before each ECG 
collection. If the ECG is not performed ≤ 3 days before the first dose of study drug(s), the test 
should be repeated and reviewed before study drug administration on Day 1 of Cycle 1. After 
Day 1 of Cycle 1, ECGs will be collected on Day 1 of each cycle and as clinically needed. 
During the screening period, 3 consecutive 12-lead ECGs will be performed within 10 minutes 
for each interval to determine the mean QTcF interval (see Appendix 8). At other timepoints, a 
single 12-lead ECG will be performed for determination. Repeated 12-lead ECG will be 
performed if clinically indicated (see Appendix 1). 
8.2.6. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE Version 5.0. 
Characterization of toxicities will include severity, duration, and time to onset.  
All AEs, including SAEs, will be collected as described in Section 9.6. 
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8.2.7. 
Hepatitis B and C Testing  
Testing will be performed by 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, the test will be followed 
by viral load assessment (HBV DNA). 
Patients who have detectable HBV DNA at screening will perform the respective viral load test 
every 2 cycles starting at Cycle 3. 
8.3. 
Tumor and Response Evaluations  
Tumor imaging must 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 9 weeks (± 7 days), from Day 1 of Cycle 1, for the first 54 weeks, then every 12 weeks 
(± 7 days) after 54 weeks based on RECIST Version 1.1. 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 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). 
Patients with squamous cell carcinoma of the head and neck must also have head and neck scans 
performed. MRI may be used instead of CT for head, neck, abdomen, and pelvis; however, the 
chest must be assessed using CT. Chest disease should not be followed using chest x-ray. 
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 (preferably MRI) at baseline is required for all screened patients 
with the diagnosis of NSCLC. It also should be performed for patients with solid 
tumors other than NSCLC if clinically indicated. Screening evaluations will be 
performed ≤ 28 days before the first dose of study drug(s). For patients with 
previously treated eligible brain metastases, a brain scan must be performed at all 
tumor assessment timepoints. 
• 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. 
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• 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 or when clinically indicated (eg. a CR is suspected in target lesion 
or when progression in bone is suspected), Tc-99m or PET bone scans should be 
repeated. 
• For patients other than SCCHN, 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 Version 1.1 (see Appendix 11). The 
same evaluator should perform assessments, if possible, to ensure internal consistency across 
visits.  
After first documentation of response (CR or PR), confirmation of tumor response should occur 
at 4 weeks or later after the first response or at the next scheduled assessment timepoint; 
confirmation 4 to 6 weeks after the first response is strongly recommended. 
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 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. Patients must be informed that they may be forgoing treatment that has shown 
benefit by continuing treatment beyond progression. 
• The decision to continue study drug(s) beyond initial investigator-assessed 
progression must be agreed 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. 
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The tumor assessment schedule should not be affected by interruptions in study treatment. If a 
patient discontinues study treatment due to the reasons other than disease progression or death, 
tumor assessments will continue to be performed as scheduled until the patient begins a 
subsequent anticancer treatment, experiences disease progression, is lost to follow-up, withdraws 
consent, death, or until study terminates, whichever occurs first. 
8.4. 
Pharmacokinetic Assessment and Antidrug Antibody Testing  
Blood sampling for PK will be collected at the timepoints specified in the Schedule of 
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. 
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  
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  
Shipping, storage, and handling of blood as well as archival tumor and/or fresh tumor tissue for 
the assessment of biomarkers will be managed through a central laboratory. Refer to the 
laboratory manual for details of sample handling and the Schedule of Assessments (Appendix 
1A) for sample collection timepoints. 
Archival tumor tissues (approximately 10 freshly cut unstained FFPE slides) need to be sent for 
central laboratory assessment of PD-L1 for the NSCLC cohort during the screening period, and 
for retrospective analysis of other exploratory biomarkers related to response and resistance for 
the NSCLC, SCCHN, UC and GC cohorts in a BeiGene-designated central or special laboratory. 
These exploratory biomarkers include but are not limited to PD‑L1 expression in SCCHN, UC 
and GC cohorts, TMB/DNA mutation/MSI for patients in NSCLC, SCCHN, UC and GC 
cohorts. Submission of < 10 unstained slides is not a protocol deviation. For non-squamous 
NSCLC patients who could not provide EGFR documentation and complete EGFR test locally, 
10 slides will be required additionally for central laboratory assessment of EGFR mutation. 
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A fresh tumor biopsy at a tumor lesion is mandatory for NSCLC, SCCHN, UC and GC cohorts if 
there are no available archival tumor samples during the screening period. 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. 
Blood samples will be obtained for the evaluation of exploratory biomarkers including, but not 
limited to bTMB/DNA mutation/MSI for patients in NSCLC, SCCHN, UC and GC cohorts, 
which will be collected at baseline (required), at the time of first confirmed tumor response 
(optional), 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 
tislelizumab administration (Day 1) of each cycle should be performed before study treatment 
infusion/dose unless otherwise noted. Laboratory results must be reviewed before dosing. 
Day 1 of Cycle 1 is defined as the day when initial infusion of tislelizumab administration or first 
lenvatinib dosage, which occur first. Study treatment of tislelizumab may be administered ± 3 
days from the scheduled Day 1 of each cycle due to administrative reasons. On Day1 of each 
cycle, lenvatinib will be administered at least 1 hour after completion of tislelizumab 
administration. 
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 6 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. 
Risks Associated With study drugs  
9.1.1. 
Risks Associated With Tislelizumab  
Tislelizumab is an investigational agent that is currently in clinical development. The following 
recommendation is based on results from nonclinical and clinical studies with tislelizumab and 
published data on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions. imAEs are presented in Section 9.7.3. 
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 10. 
9.1.2. 
Risks Associated With Lenvatinib  
Lenvatinib is a kinase inhibitor that inhibits the kinase activities of VEGF receptors VEGFR1 
(FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). It inhibits other kinases that have been 
implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their 
normal cellular functions, including fibroblast growth factor (FGF) receptors; PDGFRα, KIT, 
and RET. 
Lenvatinib may cause side effects like other kinase inhibitors, including: Hypertension, Cardiac 
Dysfunction, Arterial Thromboembolic Events, Hepatotoxicity, Renal Failure or Impairment, 
Proteinuria, Diarrhea, etc. 
9.2. 
General Plan to Manage Safety Concerns  
9.2.1. 
Eligibility Criteria  
Eligibility criteria were selected to guard the safety of patients in this study. Results from the 
nonclinical toxicology studies and clinical data with tislelizumab, as well as the 
nonclinical/clinical data from lenvatinib (both Lenvima and the generic drug) 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 lenvatinib 
treatment are also excluded from the study (see Section 4.2 for the full list of exclusion criteria). 
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9.2.2. 
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 or designee immediately 
(ie, no more than 24 hours after learning of the event). 
9.2.3. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE Version 5.0.  
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 8), 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. 
At the start of each cycle, tislelizumab 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 5.2). 
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 9.7. 
9.3. 
Adverse Events  
9.3.1. 
Definitions and Reporting  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
drug(s), whether considered related to study drug(s) or not. 
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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. 
9.3.2. 
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 
• 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 9.6.2. 
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9.3.3. 
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 and lenvatinib Investigator’s Brochure in the 
determination of his/her assessment (Simcere Investigator’s Brochure, 2021; BeiGene 
Investigator’s Brochure, 2021). 
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 one 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 
• 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). 
9.3.4. 
Follow-up of Adverse Events  
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
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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 9.6.2. 
9.3.5. 
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. 
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9.4. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in which 
the patient was at risk of death at the time of the AE. It does not refer to an AE that 
hypothetically might have caused death if it 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. 
• 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 
9.5. 
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 and lenvatinib Investigator’s Brochure (Simcere 
Investigator’s Brochure, 2021; BeiGene Investigator’s Brochure, 2021). 
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9.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
9.6.1. 
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 drug, 
will be reported until either 30 days after last dose of study drug(s) or initiation of new 
anticancer therapy, whichever occurs first. Immune-mediated AEs (serious or nonserious) should 
be reported until 90 days after the last dose of tislelizumab regardless of whether or not the 
patient starts a new anticancer therapy. All SAEs considered related to the study drug(s) that are 
brought to the attention of the investigator should be reported regardless of time since the last 
dose of treatment. 
AEs and SAEs should be recorded according to the details in Table 8. For the follow-up period 
for AEs, see Section 9.3.4. For the definition of TEAEs, see Section 10.3.2. 
Table 8: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Cohorts 
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 9.6.4) 
All nonserious AEs, except 
those due to PD 
First dose of study drug 
Up to 30 days after last dose, 
initiation of new anticancer 
therapy, death, withdrawal of 
consent, or loss to follow-up, 
whichever occurs first 
Immune-mediated AEs (serious 
or nonserious) 
First dose of study drug 
Up to 90 days after last dose of 
tislelizumab (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. 
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9.6.2. 
Reporting Serious Adverse Events  
9.6.2.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 9. 
Table 9: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Timeframe for 
sending initial 
report 
Documentation 
method 
Timeframe for 
sending follow-
up report 
Documentation 
method 
Reporting 
method 
All SAEs 
Within 24 hours 
of first 
knowledge of 
the SAE 
SAE report 
As expeditiously 
as possible 
SAE report 
Email or fax 
SAE report form 
Abbreviations: SAE, serious adverse event. 
9.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours, as outlined above in Section 9.6.2.1. 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 9.3.3. 
The sponsor will provide contact information for SAE receipt. 
9.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will report all SAEs to the sponsor in accordance with the procedures detailed in 
Section 9.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a 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 9.5) will be submitted 
to all applicable regulatory authorities and investigators for tislelizumab and lenvatinib studies. 
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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. 
9.6.3. 
Eliciting Adverse Events  
The investigator or designee will ask patients about AEs by asking the following standard 
questions: 
• How are you feeling? 
• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
9.6.4. 
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. 
9.6.5. 
Deaths  
Death is an outcome and not usually considered an AE. If the only information available is death 
and the cause of death is unknown, then the death is reported as an AE (eg, “death,” “death of 
unknown cause,” or “death unexplained”). 
9.6.6. 
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 drugs, 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. 
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9.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees  
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information documents: 
• Tislelizumab Investigator’s Brochure, (BeiGene Investigator’s Brochure, 2021) 
• Lenvatinib Investigator’s Brochure, (Simcere Investigator’s Brochure, 2021) 
9.6.8. 
Assessing and Recording Immune-Mediated Adverse Events  
Since treatment with anti-PD-1 therapy can cause autoimmune disorders, AEs considered by the 
investigator to be immune related (see Section 9.7.3) should be classified as imAEs and 
identified as such in the eCRF AE page. Not all tislelizumab studies include a section in the 
eCRF AE page where imAEs are clearly identified. Therefore, all studies will rely on the 
company list of Potential imAEs to identify all cases in each study to be further assessed as 
immune-mediated AEs by the sponsor, in addition to those imAEs reported by the investigator 
via the AE CRF page. 
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 10. 
An extensive list of potential imAEs appears in Table 11. 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 10. 
9.6.9. 
Recording Infusion-Related Reactions  
The symptoms of infusion-related reactions may include but are not limited to fever, chills/rigor, 
nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, 
myalgia, dizziness, or hypertension. Severe reactions may include acute respiratory distress 
syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. 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. 
9.7. 
Management of Adverse Events of Special Interest for Tislelizumab  
As a routine precaution, following completion of study drug(s) 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. 
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9.7.1. 
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 study drug(s) are 
provided in Table 10. 
Table 10: 
Treatment Modifications for Symptoms of Infusion-Related Reactions Due to 
Study Drug(s) 
NCI-CTCAE grade 
Treatment modification for <<tislelizumab or other 
infused drug>> 
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. 
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. 
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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. 
9.7.2. 
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 treatment. Systemic 
anaphylactic/anaphylactoid reactions typically manifest within minutes following administration 
of the drug/antigen and are characterized by respiratory distress; laryngeal edema; and/or intense 
bronchospasm; and 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. 
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. 
9.7.3. 
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 
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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 11. 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 10. For any AEs not included in Appendix 10, 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 11: 
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 
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 10. 
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. 
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9.7.4. 
Renal Function Abnormalities  
Patients with moderate renal dysfunction (estimated GFR > 30 mL/min/1.73 m2 and 
< 60 mL/min/1.73 m2 by CKD-EPI equation) may be enrolled into the study. For patients with 
baseline renal insufficiency, the following algorithm is proposed for the use of steroid treatment 
in the management of imAEs: 
• If the serum creatinine is normal at baseline, please see Section 9.7.3 and refer to 
Appendix 10 for the diagnosis and management of patients with abnormal renal 
laboratory values. 
• If the serum creatinine is Grade 1 at baseline and the increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 2 after starting treatment with study 
drug(s), refer to Appendix 10 for the diagnosis and management of patients with 
abnormal renal laboratory values. Check the estimated GFR using Appendix 9 and the 
estimated GFR calculator link. In the setting of a Grade 2 serum creatinine increase only, 
study treatment can continue unless the serum creatinine increases by ≥ 50% from the 
baseline value OR the estimated GFR falls below 20 mL/min/1.73 m2. 
• If the serum creatinine is Grade 2 at baseline and the increase in serum creatinine meets 
criteria for serum creatinine increase ≥ Grade 3 after starting treatment with study 
drug(s), refer to Appendix 10 for the diagnosis and management of patients with 
abnormal renal laboratory values. In the setting of a Grade 3 serum creatinine increase 
only, study treatment will be held until serum creatinine improves to baseline and 
treatment may resume only after discussion with the medical monitor. 
9.8. 
Management of Adverse Events of Special Interest for Lenvatinib  
9.8.1. 
The AE management guidance for risks for lenvatinib  
9.8.1.1. 
Management of Hypertension  
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that patients enrolled to receive treatment with lenvatinib 
have BP of ≤150/90 mm Hg at the time of study entry and, if known to be hypertensive, have 
been on a stable dose of antihypertensive therapy for at least 1 week before Cycle 1/Day 1. Early 
detection and effective management of hypertension are important to minimize the need for 
lenvatinib dose interruptions and reductions. 
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Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg or 
diastolic BP ≥90 mm Hg) is confirmed on 2 assessments a minimum of 1 hour apart. One BP 
assessment is defined as the mean value of 3 measurements at least 5 minutes apart. The choice 
of antihypertensive treatment should be individualized to the subject’s clinical circumstances and 
follow standard medical practice. For previously normotensive patients, appropriate 
antihypertensive therapy should be started when systolic BP ≥140 mm Hg or diastolic BP ≥90 
mm Hg is first observed on 2 assessments a minimum of 1 hour apart. For those patients already 
on antihypertensive medication, treatment modification may be necessary if hypertension 
persists. For patients with hypertension and proteinuria, appropriate therapy, eg, angiotensin-
converting enzyme inhibitor or angiotensin-II receptor antagonist, is preferred (Kilfoy et al, 
2009). 
Lenvatinib should be withheld in any instance where a subject is at imminent risk to develop a 
hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension (eg, BP ≥160/100 mm Hg, significant risk factors for cardiac disease, intracerebral 
hemorrhage, or other significant co-morbidities). Once the subject has been on the same 
hypertensive medications for at least 48 hours and the BP is controlled, lenvatinib should be 
resumed as described below. 
During the treatment period, patients with systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg 
must have their BP monitored on Day 15 or more frequently as clinical indicated until systolic 
BP has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 3 consecutive months. If a 
repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the subject must 
resume the Day 15 evaluation until systolic BP has been ≤150 mm Hg and diastolic BP has been 
≤95 mm Hg for 3 consecutive months. 
The following guidelines should be followed for the management of systolic BP ≥160 mm Hg or 
diastolic BP ≥100 mm Hg confirmed on repeat measurements after 1 hour: 
1. Continue lenvatinib and institute antihypertensive therapy for patients not already 
receiving antihypertensive medication 
2. For those patients already on antihypertensive medication, dose of the current agent may 
be increased, if appropriate, or 1 or more agents of a different class of antihypertensive 
should be added. 
3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted. It should 
be restarted at one lower dose level as specified in Table 7 only when systolic BP ≤150 
mm Hg and diastolic BP ≤95 mm Hg and the subject has been on a stable dose of 
antihypertensive medication for at least 48 hours 
− If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the first dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted. It should 
be restarted at an additional dose reduction as specified in Table 7 only when 
systolic BP ≤150 mmHg and diastolic BP ≤95 mmHg and the subject has been on 
a stable dose of antihypertensive medication for at least 48 hours. 
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− If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted. It should 
be restarted at a third dose reduction as specified in Table 7 only when systolic 
BP ≤150 mmHg and diastolic BP ≤95 mmHg and the subject has been on a stable 
dose of antihypertensive medication for at least 48 hours. 
The following guidelines should be followed for the management of Grade 4 hypertension (life-
threatening consequences): 
• Institute appropriate medical management 
• Discontinue study drug 
9.8.1.2. 
Management of Proteinuria  
Regular assessment of proteinuria should be conducted as detailed in the Schedule of 
Assessments (Appendix 1). Guidelines for assessment and management of proteinuria: 
1. Grading will be based on the 24-hour urinary protein result. Management of lenvatinib 
administration will be based on the grade of proteinuria according to instructions 
contained in Table 5, “Recommended Dosage Modifications for lenvatinib Related 
Adverse Events of Special Interest” 
2. A 24-hour urine collection (within 72 hours) to verify the grade of proteinuria for protein 
quantitation is required in the following situations: 
− The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on study 
drug 
− A subsequent increase in severity of urine dipstick proteinuria occurring on the 
same lenvatinib dose level 
− When there has been a lenvatinib dose reduction and at the new dose level the 
urine protein dipstick result is 2+, 3+, or 4+ 
3. Urine dipstick testing for patients with proteinuria ≥2+ should be performed on Day 15 
(or more frequently as clinically indicated) until the results have been 1+ or negative for 
3 consecutive months. 
Grading of proteinuria should be performed according to CTCAE v5.0 but will be based on the 
24-hour urine collection for total protein result, if a 24-hour urine was performed at that 
timepoint. 
For patients with lenvatinib-related toxicity, the dose reduction and/or interruption instructions 
provided in Table 5 and Table 6 of the study protocol should be followed. 
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9.8.1.3. 
Management of Hepatotoxicity  
Regular monitoring of liver function tests (eg, ALT, AST, bilirubin levels) should be conducted 
as detailed in the Schedule of Assessments (Appendix 1 ) and as clinically indicated. If signs 
occur indicating a decrease in liver function by 1 grade or more from baseline, the instructions 
contained in Table 5 of the protocol should be followed, “Recommended Dosage Modifications 
for lenvatinib Related Adverse Events of Special Interest”. Appropriate supportive care should 
be provided together with close monitoring. If hepatic failure occurs the study drug must be 
discontinued. 
9.8.1.4. 
Management of Thromboembolic Events  
Patients should be advised to pay attention to the symptoms suggestive of venous 
thromboembolic events, which include acute onset of dyspnea, chest pain, cough, hemoptysis, 
tachypnea, tachycardia, cyanosis, DVT signs including lower-extremity swelling, redness and 
warmth to touch or tenderness. In case any of these signs or symptoms appear, patients should be 
instructed to report such signs and symptoms promptly to the treating physician. If a 
thromboembolic event is confirmed, instructions contained in Table 5 of the protocol should be 
followed, “Recommended Dosage Modifications for Lenvatinib Related Adverse Events of 
Special Interest”. Appropriate supportive care should be provided together with close 
monitoring. If a subject experiences life-threatening (Grade 4) thromboembolic reactions, 
including pulmonary embolism, the study drug must be discontinued. 
9.8.1.5. 
Management of Posterior Reversible Encephalopathy Syndrome (PRES)  
In clinical studies with Lenvima, events of posterior reversible encephalopathy syndrome 
(PRES) were reported in less than 1% of Lenvima-treated patients (LENVIMA (lenvatinib) 
[prescribing information], 2020). PRES is a neurological disorder that can present with 
headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or 
neurological disturbances. Mild to severe hypertension may be present. MRI is necessary to 
confirm the diagnosis of PRES. Appropriate measures should be taken to control blood pressure. 
In patients with signs or symptoms of PRES, dose interruptions, reductions, or discontinuation 
may be required per instructions included in Table 5. 
9.8.1.6. 
Management of hypocalcemia  
Serum calcium should be monitored regularly per the Schedule of Assessments (Appendix 1). 
Hypocalcemia should be treated per institutional guidelines (eg, using, as appropriate, calcium, 
magnesium, and Vitamin D supplementation) until resolution. 
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10. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
As described in the study objectives, this study is designed to establish the safety and tolerability, 
and preliminary anticancer activities of tislelizumab in combination with lenvatinib in patients 
with advanced solid tumors as assessed in multiple expansion cohorts. 
The statistical analyses will be performed by the sponsor or designee after the data collection is 
completed and the database is locked and released. In general, data will be summarized by 
cohort, unless otherwise specified. 
Details of the statistical analyses will be included in a separate SAP.  
10.1. 
Statistical Analysis  
The following descriptive statistics will be used to summarize the study data on the basis of their 
nature unless otherwise specified: 
• Continuous variables: number of non-missing observations, mean, standard deviation, 
median, minimum, and maximum 
• Categorical variables: frequencies and percentages 
• Time-to-event variables: number of non-missing observations, median, minimum and 
maximum. Kaplan-Meier event rates may also be provided if applicable for specific time 
to event variables 
10.1.1. 
Analysis Sets  
The Safety Analysis Set (SAF) 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 patients enrolled during safety run-in stage who 
• Received ≥ 75% of scheduled lenvatinib and ≥ 67% (approximately two-thirds) of 
scheduled dose intensity of tislelizumab administration during the DLT assessment 
window, remained on study during the DLT observation period, and had sufficient safety 
evaluation OR. 
• Experienced a DLT within the DLT observation period. 
The detailed calculation of scheduled dose intensity of tislelizumab/ lenvatinib is documented in 
the Safety Monitoring Committee Operating Procedure and statistical analysis plan of this study. 
The PK Analysis Set includes all patients who received ≥ 1 dose of tislelizumab 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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10.1.2. 
Patient Disposition  
The number of patients treated, discontinued from study drug(s) and/or the study, and those with 
important/critical protocol deviations will be counted. 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) as of the data cutoff date 
will be summarized using the data from the eCRF. 
Important/critical protocol deviations will be summarized and listed by category. 
10.1.3. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized using descriptive statistics in 
the Safety Analysis Set. Continuous variables include age, weight, vital signs, time since initial 
cancer diagnosis, time since advanced/metastatic disease diagnosis, etc. Categorical variables 
include gender, ECOG Performance Status, region/country, race, prior systemic therapies 
received, stage of disease, metastatic site, etc. Other disease-specific parameters might be 
summarized in the relevant cohort as appropriate. 
10.1.4. 
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).  
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. A listing of prior and concomitant medications will be provided. 
10.2. 
Efficacy Analyses  
Efficacy Analyses will be provided by subgroups as appropriate, such as PD-L1 subgroups, etc. 
Per-patient listings may be generated with limited patients for analysis. 
Primary and/or secondary efficacy endpoints will be based on investigators’ tumor assessments 
per RECIST Version 1.1 (if applicable) and will be defined as follows: 
− ORR is defined as the proportion of patients who had confirmed CR or PR. 
− Duration of response is defined as the time from the first confirmed objective 
response until the first documentation of progression or death, whichever comes 
first. 
− DCR is defined as the proportion of patients with best overall response, as defined 
in Appendix 11,of a CR, PR, or stable disease.  
− PFS is defined as the time from the date of the first dose of study drugs to the date 
of the first documentation of PD or death, whichever occurs first. 
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− OS is defined as the time from the date of the first dose of study drugs to death 
due to any cause. 
General statistical considerations of efficacy analysis will be demonstrated in the following 
sections.  
More details will be provided in the SAP. 
10.2.1. 
Primary Efficacy Analysis  
ORR assessed by the investigator and its 95% CI will be summarized by cohort based on the 
Safety Analysis Set and the Evaluable Analysis Set. 
10.2.2. 
Secondary Efficacy Analysis  
PFS, duration of response, DCR, and OS will be summarized by cohort and in overall study 
population. 
PFS will be estimated using the Kaplan-Meier method. The median PFS and the cumulative 
probability of PFS at specific timepoints, if estimable, will be calculated and presented with 2-
sided 95% CIs. PFS censoring rule will follow United States Food and Drug Administration 
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(US FDA, 2018). 
Duration of response will be analyzed using methods similar to those described for PFS in the 
responders. 
DCR will be analyzed using methods similar to those described for ORR based on the SAF and 
EAS. 
Waterfall plots of maximum tumor shrinkage per patient will be presented. 
OS will be analyzed in the SAF using methods similar to those described for PFS, except for 
censoring rules. For OS, patients will be censored either at the date that the patient was last 
known to be alive or the date of data cutoff, whichever comes earlier, in the absence of death. OS 
rates at specific timepoints will be calculated based on the Kaplan-Meier method. 
10.3. 
Safety Analyses  
Safety will be assessed by monitoring and recording of AEs and 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 Version 5.0. The incidence of DLT events and TEAEs will be 
reported as the number (percentage) of patients with TEAEs by Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class and preferred term. Descriptive summary 
statistics (eg, n, mean, standard deviation, median, minimum, and maximum for continuous 
variables; n [%] for categorical variables) and changes from baseline will be determined for 
laboratory parameters and vital signs. 
Safety data will be summarized in the Safety Analysis Set by cohort and in overall study 
population except for analysis of DLT which is only applicable to patients in DLT Evaluable Set.  
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10.3.1. 
Extent of Exposure  
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity, and relative dose intensity. 
The number (and percentage) of patients with dose reductions, dose delays, treatment 
interruptions, and study drug discontinuation will be summarized for each study drug. Reasons 
for dose modifications and discontinuation will be summarized as well. 
Patient data listings will be provided for all dosing records. 
10.3.2. 
Adverse Events  
The AE verbatim descriptions (investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA lower level term, preferred term, and primary system 
organ class. 
DLTs will be summarized for the safety run-in stage. 
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 after discontinuation 
of study drug(s), or initiation of new anticancer therapy, whichever occurs first. Only those AEs 
that were treatment emergent will be included in summary tables. Immune-mediated AEs will be 
identified from all AEs that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of tislelizumab and up to 90 days from the last dose of 
tislelizumab, regardless of whether the patient starts a new anticancer therapy. If an imAE occurs 
outside the above mentioned TEAE window, it will not be classified as a TEAE. All imAEs will 
be reported separately. All AEs, treatment emergent or otherwise, will be presented in patient 
data listings.  
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
system organ class and preferred term. A patient will be counted only once by the highest 
severity grade per NCI-CTCAE Version 5.0 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). 
TEAEs include those events considered by the investigator to be related to study treatment or 
with missing assessment of the causal relationship. SAEs, deaths, ≥ Grade 3 TEAEs, immune-
mediated AEs, treatment-related TEAEs, and TEAEs that led to treatment discontinuation, 
treatment interruption, or dose delay will be summarized. 
10.3.3. 
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 
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categorical variables) for laboratory parameters and their changes from baseline will be 
calculated. Laboratory values will be summarized by visit and by maximum postbaseline change. 
Laboratory parameters that are graded by NCI-CTCAE Version 5.0 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. 
10.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse 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. 
10.3.5. 
Pulmonary Function Test  
Pulmonary function test results will be listed by patient and by visit if available. 
10.4. 
Pharmacokinetic Analyses  
Blood samples will be collected for tislelizumab PK evaluation at predose and postdose; the 
serum concentration data will be tabulated and summarized by the visit/cycle at which these 
samples are collected. Descriptive statistics will include mean, median, range, and standard 
deviation as appropriate.  
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. The effect of 
immunogenicity on PK, efficacy, and safety may be evaluated if data allow and reported 
separately from the main clinical study report. 
10.6. 
Other Exploratory Analyses  
Potential biomarkers including but not limited to PD‑L1 expression, TMB/DNA mutation/ 
microsatellite instability (MSI), bTMB/DNA mutation/MSI, and the association of biomarkers 
with disease status, response/resistance to tislelizumab in combination with lenvatinib. 
10.7. 
Sample Size Consideration  
The study plans to enroll approximately 70 patients: 
− Part 1 (Safety run-in): Approximately 6 to 18 patients with 5 prespecified tumor 
types 
− Part 2 (Expansion): To enroll additional patients at RP2D up to approximately 
30 patients in each of 5 prespecified tumor type cohorts 
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Three cohorts were closed prior to planned enrollment due to emerging data (NSCLC and UC 
cohorts) and changes to first-line standard of care (GC cohort). In the SCCHN and RCC cohorts, 
approximately 30 patients per cohort will be enrolled to evaluate the preliminary efficacy. No 
formal hypothesis testing will be performed in the efficacy evaluation. 
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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 review and 
evaluate the safety information including but not limited to DLTs, all TEAEs, and laboratory 
abnormalities when the first 6 evaluable patients administered lenvatinib at each dose level in 
combination with tislelizumab (400 mg, IV, Q6W) have completed the first 28 days of treatment. 
The SMC will make recommendations on safety management (including resumption of 
enrollment, or de-escalation of lenvatinib dose to the next level, or termination of enrollment) 
and will recommend the RP2D for Part 2. 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 specified in the Pharmacy Manual 
for disposal, arrangements will be made between the site and BeiGene or its representative for 
destruction or return of unused study drug supplies. 
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All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
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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 re-consented 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 investigator, institution, sponsor, and site will maintain confidentiality and privacy standards 
for the collection, storage, transmission, and processing of patients’ personal and medical 
information by following applicable laws and regulations related to the confidentiality, use, and 
protection of such information, including the ICH Good Clinical Practice Guideline, as 
implemented locally. Such laws may be more stringent than the requirements in this protocol. 
The investigator and site shall code the personal and medical information obtained during the 
study with a unique patient identification number assigned to each patient enrolled in the study. 
The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Unless required to be provided by laws or 
regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the investigator and site must ensure that any personal and medical information 
transmitted to sponsor or its service providers is: 1) required by the protocol, and 2) 
appropriately de-identified (eg, via redaction and/or coding with the patient identification 
number) to ensure the following information about patients are NOT shared: 
• names or initials (full or partial); 
• full dates of birth; 
• contact information (such as phone numbers or home or email addresses);  
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• numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part 
of this study; 
• geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  
• information about marital status, family, or household members; employment, sex 
life, sexual preference, or other sensitive data that is not relevant to the study. 
Patient personal and medical information obtained during this study is confidential and may only 
be disclosed to third parties as permitted by the signed ICF (or a separate authorization for the 
use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law. 
In limited circumstances, such as in connection with insurance purposes or patient support 
services ancillary to certain study sites (eg, for patient travel or reimbursement), the investigator 
and site may provide certain of this personal information to the sponsor or its representatives. 
Such personal information may not be provided as part of the study protocol (eg, as part of the 
eCRF, on samples or reports submitted to the central lab, on safety reporting forms [except in 
China], or on product dispensing logs provided to the sponsor, etc.). 
Investigator and site must use only the specific forms and clinical trial systems, (eg, the 
electronic data capture [EDC] system and any secure file transfer platforms [SFTPs]) designated 
by sponsor for sharing and transfers of personal and medical information.  
In the event of a breach of the confidentiality of a patient’s personal or medical information, the 
investigator, site, and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable laws. If the sponsor identifies personal or medical information that 
was not properly de-identified, it may be required to report the disclosure under local applicable 
laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes where allowed by local 
law or the patient’s signed ICF. 
Information generated during this study must be available for inspection upon request by 
representatives of the United States Food and Drug Administration (US FDA), the China 
National Medical Products Administration (China NMPA), and all other national and local 
health authorities; by sponsor monitors, representatives, and collaborators; and by the IRBs/IECs 
for each study site, as appropriate. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the tislelizumab Investigator’s Brochure (BeiGene Investigator’s Brochure, 2021) and 
lenvatinib Investigator’s Brochure (Simcere Investigator’s Brochure, 2021), this protocol, 
eCRFs, the investigational drugs, and any other study information, are confidential and remain 
the sole and exclusive property of the sponsor during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from the 
sponsor. The investigator further agrees to take all reasonable precautions to prevent the 
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disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 
If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
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 interest of the clinical investigators and/or disclose those 
financial interests, as required, to the appropriate health authorities. This is intended to ensure 
financial interests and arrangements of the clinical investigators with BeiGene that could affect 
reliability of data submitted to health authorities are identified and disclosed by the sponsor. 
Investigators are responsible for providing information about their financial interests before 
participation in the study and to update this information if any relevant changes occur during the 
study and for 1 year after completion of the study (ie, last patient, last visit). 
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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, 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 lower 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. 
Biological samples at the conclusion of this study 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. For 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 study master file filing according to GCP 
and local regulation 
• Shipment of samples (including but not limited to those for PK, ADA, and 
biomarkers) to the assay laboratory for central laboratory analysis according to 
protocol and laboratory manual requirements 
In addition, the sponsor reserves the right to suspend or prematurely close the enrollment or to 
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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Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive 
advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet 
Oncol. 2016;17(6):717-26.  
National Comprehensive Cancer Network (NCCN) Guidelines Version 4. (2019). Non-Small 
Cell Lung Cancer.  
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in 
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Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern 
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17. 
APPENDICES  
 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS  
Assessment 
Screeninga 
Treatment cycles 
Safety follow-
upc 
Survival 
follow-up 
d 
 
 
Cycle 1 
(42 days) 
Cycle 2-Cycle 3 
(every 42 days) 
≥ Cycle 4 
(every 42 
days) 
EOT 
Visitb 
 
 
Visit day 
-28 to -1 
1u 
8 
15 
29 
1 
22 
1 
0 to 7 
days 
30 days after 
last dose 
Every 3 
months 
Visit window 
 
 
±2 
± 2 
± 2 
± 3 
±3 
±3 
 
± 7 
± 14 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics/medical 
history/disease history 
X 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
Physical examinationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
12-lead ECGg 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Adverse eventsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior and concomitant 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematologyi 
Xi 
X 
 
X 
X 
Xi 
X 
X 
Xb 
X 
 
Clinical chemistryi 
Xi 
X 
X 
X 
X 
Xi 
X 
X 
Xb  
X 
 
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Assessment 
Screeninga 
Treatment cycles 
Safety follow-
upc 
Survival 
follow-up 
d 
 
 
Cycle 1 
(42 days) 
Cycle 2-Cycle 3 
(every 42 days) 
≥ Cycle 4 
(every 42 
days) 
EOT 
Visitb 
 
 
Visit day 
-28 to -1 
1u 
8 
15 
29 
1 
22 
1 
0 to 7 
days 
30 days after 
last dose 
Every 3 
months 
Visit window 
 
 
±2 
± 2 
± 2 
± 3 
±3 
±3 
 
± 7 
± 14 
CK and CK-MBj 
X 
X 
 
X 
X 
X 
X 
X 
Xb 
X 
 
Coagulation parametersi 
Xi 
X 
X 
X 
X 
X 
X 
X 
Xb 
X 
 
Urinalysisi 
Xi 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Pregnancy testk 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Thyroid functionl 
Xl  
X 
 
 
 
X 
 
X 
 
X 
 
HBV/HCV testsm 
X 
 
As clinically indicated m 
 
Pulmonary function testsn 
X 
 
As clinically indicated n 
 
Pharmacokinetics 
 
See Appendix 2  
 
Anti-tislelizumab antibodies 
 
See Appendix 2  
 
Blood biomarkerso 
 
X 
At the time of confirmed response and PD  
 
Tumor assessmentp 
X 
 
Every 9 weeks (± 7 days) from Cycle 1 Day 1, for the first 
54 weeks, then every 12 weeks (± 7 days)  
X b 
 
X 
Archival or fresh tumor 
tissueq 
X 
 
See Appendix 1A 
 
 
Tislelizumab administrationr 
 
X 
 
 
 
X 
 
X 
 
 
 
Lenvatinib administrations 
 
Daily 
 
 
 
LVEF examinationt 
X 
 
As clinically indicated 
X 
 
 
Survival status 
 
 
 
 
 
X 
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Abbreviations: AE, adverse event; CK, creatine kinase; CK-MB, creatine kinase-muscle/brain; CT, computed tomography; DLCO, diffusing capacity of the lungs 
for carbon monoxide; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, End-of-Treatment (Visit); FEV1, forced expiratory volume; 
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; NCI-CTCAE, National Cancer Institute-Common Terminology 
Criteria for Adverse Events; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; T3, triiodothyronine; 
T4, thyroxine; LVEF = left ventricular ejection fraction, MUGA = multiplegated acquisition. 
 
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. 
b The EOT Visit is conducted ≤ 7 days after the investigator determines that the patient must permanently discontinue tislelizumab and lenvatinib. 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 Vital signs will include measurements of body temperature (˚C), pulse 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 of 
tislelizumab, and if clinically indicated, during and 30 minutes after each tislelizumab infusion. Vital signs should also be recorded before administration of 
lenvatinib; recorded values may be used for post-tislelizumab assessment if vital signs are collected within 30 minutes after 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 When coinciding with blood draws (eg, performed within 30 minutes of each other), ECG assessment should be performed prior to 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. If the ECG is not performed ≤ 3 days before the first dose of study drug(s), the test should 
be repeated and reviewed before study drug administration on Day 1 of Cycle 1. After Day 1 of Cycle 1, ECGs will be collected on Day 1 of each cycle and as 
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clinically needed. During the screening period, 3 consecutive 12-lead ECGs will be performed within 10 minutes for each interval to determine the mean QTcF 
interval. At other timepoints, a single 12-lead ECG will be performed for determination. Repeated 12-lead ECG will be performed if clinically indicated. 
h The AEs and laboratory abnormalities will be graded per NCI-CTCAE Version 5.0. 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/or lenvatinib) or initiation of new 
anticancer therapy, whichever occurs first. Immune-mediated AEs (serious and nonserious) should be reported for tislelizumab 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, urinalysis, and coagulation 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 3 days before study drug administration. 
Clinical chemistry, coagulation, and urinalysis (data collected as specified in Appendix 3) will be performed for Days 1, 8, 15 and 29 of Cycle 1 and then Day 1 
and Day 22 for Cycle 2 and Cycle 3, then on Day 1 of each subsequent cycle. Hematology (data collected as specified in Appendix 3) will be performed for 
Days 1, 15 and 29 of Cycle 1 and then Day 1 and Day 22 for Cycle 2 and Cycle 3, then on Day 1 of each subsequent cycle. Refer to Section 9.3.5 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 CK and CK-MB 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 3 days before 
study drug administration. 
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 each cycle. A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
l Analysis of free T3, free T4, and thyroid stimulating hormone will be performed by the local study site laboratory. If the thyroid function test at screening is not 
performed ≤ 7 days before study drug administration on Day 1 of Cycle 1, the test should be repeated and reviewed before study drug administration. Thyroid 
function tests will be performed at Day 1 of each subsequent cycle and at the Safety Follow-up Visit. 
m Testing will be performed by a local 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. Patients who have detectable 
HBV DNA at screening will perform the respective viral load test every 2 cycles starting at Cycle 3 (ie, Day 1 of Cycles 3, 5, 7, etc) and the EOT Visit. 
n For patients with tumor type other than lung cancer 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. For 
patients with lung cancer, pulmonary function testing including spirometry and assessment of oxygenation, at a minimum pulse oximetry at rest and with 
exercise, or alternatively, assessment of diffusion capacity, are to be performed for all patients during the screening period to assist the determination of 
suitability for 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, FEV1 < 60% or DLCO (if performed) < 60% of age- and sex-adjusted 
predicted performance levels, the medical monitor needs to be consulted to confirm eligibility. Tests may be repeated as clinically indicated while on study. 
o Blood samples will be collected for all patients at baseline (required), at the time of first confirmed tumor response (optional), and at the time of PD (optional). 
Approximately 10 mL for each timepoint. Written patient consent is required for blood sample collections.  
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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 9 weeks (± 7 days), from Day 1 of Cycle 1, for the first 54 weeks, then every 12 weeks 
(± 7 days), based on RECIST Version 1.1. 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. 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 with squamous cell carcinoma of the head and neck must also have head and neck scans performed. MRI may be used instead of CT for 
head, neck, abdomen, and pelvis; however, the chest must be assessed using CT. Chest disease should not be followed using chest x-ray. If a patient 
discontinues study treatment due to the reasons other than disease progression or death, tumor assessments will continue to be performed as scheduled until the 
patient begins a subsequent anticancer treatment, experiences disease progression, is lost to follow-up, withdraws consent or until patient death or study 
terminates, whichever occurs first. See Section 8.3 for more information.  
q Archival tumor tissue (if available) must be sent to the central laboratory for PD-L1 assessment for the NSCLC cohort during the screening period and for 
retrospective analysis of exploratory biomarkers for NSCLC, SCCHN, UC and GC cohorts. If archival tumor tissues are not available during the screening 
period, a fresh tumor biopsy is mandatory for the NSCLC, SCCHN, UC and GC cohort. 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 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 42-day cycle (once every 6 weeks) (see Section 5.2 for details).  
s Lenvatinib will be self-administered orally once daily (see Section 5.2 for details). 
t During the study, MUGA scans or echocardiograms will be performed to assess LVEF at screening, EOT visit, and if clinically indicates assessed by 
investigator. 
u Cycle 1 Day 1 (C1D1) is defined as the day when initial infusion of tislelizumab administration or first dose of lenvatinib, whichever happens earlier. Study 
treatment of tislelizumab may be administered ± 3 days from the scheduled Day 1 of each cycle due to administrative reasons. On Day1 of each cycle, 
lenvatinib will be administered at least 1 hour after completion of tislelizumab administration. 
 
 
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APPENDIX 1A. DOSE ESCALATION BLOOD AND TUMOR TISSUE BIOMARKER ANALYSIS  
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response. 
a Blood samples will be collected for all patients at baseline (required), at the time of first confirmed tumor response (optional), and at the time of PD (optional). 
Approximately 10 mL for each timepoint. Written patient consent is required for blood sample collections. 
b Archival tumor tissue (if available) must be sent to the central laboratory for PD-L1 assessment for the NSCLC cohort during the screening period and for 
retrospective analysis of exploratory biomarkers for NSCLC, SCCHN, UC and GC cohorts. If archival tumor tissues are not available during the screening 
period, a fresh tumor biopsy is mandatory for the NSCLC, SCCHN, UC and GC cohort. 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 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. 
Biomarker assessment 
Screening 
Cycle 1 
Patients with 
confirmed PR or 
CR 
Patients with 
confirmed PD 
(End-of- 
treatment 
visit) 
Visit day 
-28 to ~ -1 
1 
2 
8 
15 
0 to 7 days 
Peripheral blood 
(≈ 10 mL)a  
 
X 
 
 
 
X 
(+ 14 days of 
confirmation) 
X 
Archival or fresh tumor 
tissueb 
X 
 
 
 
 
 
 
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APPENDIX 2. PHARMACOKINETIC AND IMMUNOGENICITY SAMPLING SCHEDULE FOR 
TISLELIZUMAB  
 
Study Visit 
Timepoint 
PKa 
ADAb 
Cycle 1, Day 1 
Predose (within 60 min before start of 
infusion) 
X 
X 
Within 30 min after end of infusion 
X 
 
Cycle 2, Day 1 
Predose (within 60 min before start of 
infusion) 
X 
X 
Cycle 3, Day 1 
Predose (within 60 min before start of 
infusion) 
X 
X 
Within 30 min after end of infusion 
X 
 
Cycle 5, Day 1 
Predose (within 60 min before start of 
infusion) 
X 
X 
Cycle 9, Day 1 
Predose (within 60 min before start of 
infusion) 
X 
X 
EOT/Safety Follow-up 
EOT Visit or Safety Follow-up Visit 
(30 days ± 7 days after last dose) 
X 
X 
Abbreviations: EOT, end of treatment; min, minutes; ADA, antidrug antibody 
Note: Sample collection must be from opposite arm of that used for study drug infusion. If drug was administered via a central venous catheter, sample collection 
for pharmacokinetic and antidrug antibody should be from a different site. Window: within 30 minutes after end of infusion for postdose samples and 
within 60 minutes before start of infusion for predose samples unless otherwise specified. 
a 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, 3, 5 and 9. A postdose (within 30 minutes after completing tislelizumab infusion) sample is required to be 
collected on Day 1 of Cycles 1 and 3. 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 safety follow-up. 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. 
b Blood used to test for anti-tislelizumab antibodies should be collected within 60 minutes before beginning the Day 1 infusion of Cycles 1, 2, 3, 5, and 9 and at 
the mandatory Safety Follow-up Visit. If tislelizumab is permanently discontinued, scheduled ADA sampling is no longer required except safety follow-up. 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  
Category 
Parameters 
Clinical 
chemistry 
Alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, albumin, total 
bilirubin, direct bilirubin, blood urea nitrogen or urea, amylase, lipase, potassium, sodium, 
total calciuma, creatinine, Glucose, lactate dehydrogenase, total protein, creatine kinaseb, 
CK-MBb, magnesium    
Hematology 
Red blood cell count, hematocrit, hemoglobin, platelet count, white blood cell count, 
lymphocyte count, neutrophil count 
Coagulation 
Prothrombin time, partial thromboplastin time or activated partial thromboplastin time, 
international normalized ratio 
Urinalysis 
Glucose, protein, blood, ketones, 24-hour proteinc, random urine protein to creatinine ratio    
Thyroid function 
Thyroid stimulating hormone, free T3, free T4 
Others 
HCV Ab, HCV RNAd, HBsAg, HBsAb, HBcAb, HBV DNAd, urine pregnancy teste, serum 
pregnancy teste 
Abbreviations: C1D1, Cycle 1 Day 1; CK-MB, creatine kinase-muscle/brain; HBcAb, hepatitis B core antibody; 
HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C 
virus. 
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 3 treatment cycles, all predose assessments from Cycle 4 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 or a 
random urine sample for total protein and creatinine to determine a protein to creatinine ratio. 
d. Refer to footnote m in Appendix 1 for detailed requirement. 
e. 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 each 
cycle. A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
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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 housework, 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. 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 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, 2020). 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 mIU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months have 
been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
Adapted from Clinical Trials Facilitation Group, 2020. 
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APPENDIX 7. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest. If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin et al, 1994. 
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. 
Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 
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APPENDIX 8. FRIDERICIA’S FORMULA FOR CORRECTING QT 
INTERVALS  
Prolongation of the QT interval reflects abnormalities in cardiac repolarization and is a risk 
factor for various cardiovascular events including ventricular arrhythmias, heart failure, coronary 
artery disease, and death in various populations. Assessment of the QT interval requires 
correction for the heart rate in order to enable comparisons with standard reference values. 
Fridericia’s formula is one of the most widely used method for correcting QT intervals 
(Fridericia, 1920). The formula is as follows: 
QTcF = 
QT
√RR
3
 
QT is the QT interval measured from the start of QRS wave to the end of T wave (not including 
U wave). 
RR is the RR interval, which could be calculated as 60 divided by heart rate (beats per minute). 
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APPENDIX 9. CHRONIC KIDNEY DISEASE-EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION  
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) 
equation (Levey et al, 2009) and the Modification of Diet in Renal Disease 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 10. 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 or 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, multiplegated 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 11. 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 
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or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
• Blastic bone lesions are nonmeasurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor 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 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 CR. 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. 
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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 
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 CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between 2 measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the 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 12. MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR 
USED WITH CAUTION DURING TREATMENT WITH 
LENVATINIB  
MEDICATIONS OR SUBSTANCES TO BE AVOIDED OR USED WITH CAUTION 
DURING TREATMENT WITH LENVATINIB 
The text below was obtained from the followings https://crediblemeds.org/ and 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
Bold font indicates medications or substances that might be relatively commonly used. 
Italic font indicates medications for indications that are exclusionary for the current study or 
would likely result in discontinuation from study treatment with lenvatinib for management of a 
concurrent illness. 
MEDICATIONS THAT SHOULD BE AVOIDED 
Drugs With a Known Risk of QT Prolongation/Torsades de Pointes 
Amiodarone, anagrelide, arsenic trioxide, astemizole (off United States [US] market), 
azithromycin, bepridil (off US market), chloroquine, chlorpromazine, cilostazol, 
ciprofloxacin, cisapride (off US market), citalopram, clarithromycin, cocaine, 
disopyramide, dofetilide, domperidone (not on US market), donepezil, dronedarone, 
droperidol, erythromycin, escitalopram, flecainide, fluconazole, gatifloxacin (off US 
market), grepafloxacin (not on US market), halofantrine (not on US market), haloperidol, 
ibogaine (not on US market), ibutilide, levofloxacin, levomepromazine / methotrimeprazine 
(not on US market), levomethadyl (off US market), levosulpiride (not on US market), 
mesoridazine (off US market), methadone, moxifloxacin, ondansetron, oxaliplatin, 
pentamidine, pimozide, probucol (off US market), procainamide, propofol, quinidine, 
roxithromycin (not on US market), sevoflurane, sotalol, sparfloxacin (off US market), 
sulpiride (not on US market), sultopride (non on US market), terfenadine (off US market), 
terlipressin (not on US market), terodiline (not on US market), thioridazine, vandetanib. 
CAUTION WHEN TAKING THE FOLLOWING MEDICATIONS 
Substrates with Narrow Therapeutic Index for CYP3A4 
Astemizole, terfenadine, cisapride, pimozide, quinidine, benazepril, or ergot alkaloids 
(ergotamine, dihydroergotamine) 
 
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APPENDIX 13. CLINICAL STUDIES EVALUATING DRUG–DRUG 
INTERACTIONS WITH LENVIMA  
Nonclinical studies identify CYP3A4 as a potentially important Cytochrome P450 isozyme 
responsible for metabolism of Lenvima. Clinical studies were conducted to test these findings. 
Simultaneous CYP3A4/P-glycoprotein (P-gp) inhibition by ketoconazole slightly (15% to 19%) 
increases systemic exposure to Lenvima (Shumaker et al, 2015). Since no change was observed 
in half-life, Tmax, or lag time (tlag), the slight increase in systemic exposure is probably related to 
a decrease in first pass metabolism. However, since the magnitude of change is small, co-
administration of Lenvima with CYP3A4/P-gp inhibitors is not of clinical concern. 
The influence of P-gp inhibition on Lenvima PK has been investigated. P-gp inhibition was 
accomplished by co-administering a single dose of rifampin with a single dose of Lenvima. 
Preliminary results suggest P-gp inhibition increases systemic exposure to Lenvima 26% to 32%. 
Thus, co-administration of Lenvima with P-gp inhibitors only causes a small increase in 
Lenvima exposure. 
The influence of simultaneous P-gp and CYP3A4 induction on Lenvima PK has been 
investigated. Examination of simultaneous P-gp and CYP3A4 induction on Lenvima PK was 
accomplished by administering rifampin QD for 21 days (Shumaker et al, 2014a). A single dose 
of Lenvima was coadministered with the 15th dose of rifampin. Based on preliminary data, 
simultaneous P-gp and CYP3A4 induction minimally altered Lenvima exposure as mean Cmax 
increased about 8% while AUC decreased about 7%. Coadministration of Lenvima with 
CYP3A4/P-gp inducers is not of clinical concern. 
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BGB-A317-212  
PROTOCOL AMENDMENT 2.0  
SUMMARY OF CHANGES 
Study Title: A MULTICENTER, OPEN-LABEL, PHASE 2 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
TISLELIZUMAB IN COMBINATION WITH LENVATINIB IN PATIENTS WITH SELECTED SOLID TUMORS 
BeiGene, Ltd., has updated the BGB-A317-212 protocol from Protocol Amendment 1.0 (01 November 2021) to Protocol 
Amendment 2.0 (03 November 2022).  The primary purposes for this amendment are as follows: 
• to terminate three cohorts (NSCLC, UC, and GC) 
• to update Section 1 based on the latest Tislelizumab Investigator Brochure 
• to decommission the treatment eligibility review process 
• to update patient and data confidentiality language 
• to update demographic language 
In addition, editorial and format changes have been made throughout to enhance clarity and readability. 
Key changes made from Protocol Amendment 1.0 to Protocol Amendment 2.0 are summarized in the table below. 
Section 
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on 
the Safety of 
Patients, Study 
Conduct, or 
Expectedness of 
Suspected Serious 
Adverse Effects 
Cover Page, Headers, 
Final Protocol Approval 
Sheet 
• 
Changed protocol edition and dates 
• 
Changed sponsor medical monitor 
To update the protocol 
edition 
To update the contact 
information of the sponsor 
medical monitor 
N 
N/A 
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Section 
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on 
the Safety of 
Patients, Study 
Conduct, or 
Expectedness of 
Suspected Serious 
Adverse Effects 
Throughout the 
protocol 
• 
Revised the cohort names from 
“Cohort A/B/C/D/E” to 
“NSCLC/SCCHN/UC/RCC/GC 
Cohort,” respectively 
To define the cohort more 
clearly and to correspond to 
the termination of 3 cohorts 
(NSCLC, UC, and GC 
cohorts) in Part 2 
N 
N/A 
Synopsis 
• 
Revised the number of study centers 
from “Approximately 20 centers” to 
“Approximately 14 centers” 
• 
The synopsis was updated as 
appropriate to reflect changes made 
throughout the protocol 
To update the number of 
study centers in China 
To be consistent with full  
protocol text 
N 
N/A 
Section 1.1 Introduction 
Section 1.3.2 Clinical 
Experience 
Section 1.4.1 Rationale 
for the Dosing Regimen 
• 
Updated the approved indications for 
tislelizumab in China 
• 
Updated the clinical safety data of 
tislelizumab 
• 
Updated the approved dose for 
tislelizumab 
• 
Updated efficacy data from 
BGB-A317_Study_001 
To update the clinical data 
of tislelizumab to align 
with Tislelizumab 
Investigator Brochure 
Version 9.0 and 
Tislelizumab United States 
Prescribing Information 
N 
N/A 
Section 1.2.2.2. Clinical 
Efficacy and Safety 
• 
Deleted the wording “Administration 
with a high-fat meal did not change 
safety results significantly” 
To align with Lenvima 
(lenvatinib) Investigator’s 
Brochure 
N 
N/A 
Section 1.2.2.2. Clinical 
Efficacy and Safety 
• 
Added the clinical efficacy and 
safety data of Lenvima for NSCLC, 
SCCHN, UC, and GC patients 
To strengthen the rationale 
for the selection of tumor 
types in this study and the 
N 
N/A 
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Section 
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on 
the Safety of 
Patients, Study 
Conduct, or 
Expectedness of 
Suspected Serious 
Adverse Effects 
Section 1.2.2.2.2 
Lenvima in Non-Small 
Cell Lung Cancer 
Section 1.2.2.2.3 
Lenvima in Squamous 
Cell Carcinoma of Head 
and Neck 
Section 1.2.2.2.4 
Lenvima in Urothelial 
Cancer 
Section 1.2.2.2.5 
Lenvima in Gastric 
Cancer 
termination of three cohorts 
(NSCLC, UC, and GC) in 
Part 2 
Section 1.4.1.1 
Lenvatinib Starting 
Dose 
• 
Added wording about the approved 
dose for Lenvima in combination 
with pembrolizumab 
To strengthen the rationale 
for the starting dose of 
lenvatinib 
N 
N/A 
Section 1.4.3.1 
Non-Small Cell Lung 
Cancer 
Section 1.4.3.3 
Urothelial Carcinoma 
Section 1.4.3.5 Gastric 
Cancer 
• 
Added the latest study results 
(LEAP-007 study and LEAP-011 
study) and the changes of first-line 
SoC for patients with GC in China 
To strengthen the rationale 
for the termination of three 
cohorts (NSCLC, UC, and 
GC) in Part 2 
N 
N/A 
Section 2.2 Study 
Objectives and 
• 
Deleted specific tumor type 
information in the ORR and 
biomarker analysis 
To increase the flexibility 
of ORR and biomarker 
analysis and to correspond 
Y 
Potential impact on 
study conduct 
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Section 
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on 
the Safety of 
Patients, Study 
Conduct, or 
Expectedness of 
Suspected Serious 
Adverse Effects 
Endpoints for Part 2 
(Expansion) 
• 
Deleted wording “time-pairing” in 
the exploratory objectives and 
endpoints 
to the termination of 3 
cohorts (NSCLC, UC, and 
GC) in Part 2 
To increase the flexibility 
of post-dose PK sample 
analysis 
Section 3.1 Summary of 
Study Design 
Section 3.4 Study Design 
of Part 2 
• 
Added wording “Three cohorts 
were closed prior to planned 
enrollment due to emerging data 
(NSCLC and UC cohorts) and 
changes to first-line standard of 
care (GC cohort)” 
To correspond to the 
termination of 3 cohorts 
(NSCLC, UC, and GC) in 
Part 2 
Y 
Potential impact on 
study conduct 
Figure 1 Study Schema 
• 
Added the wording about specific 
tumor types 
To clarify the tumor types 
included in this study 
N 
N/A 
Section 3.2 Duration of 
Study 
• 
Added wording about enrollment 
closure, study discontinuation, and 
the continuation of providing study 
drug(s) 
To clarify the sponsor’s 
right to close enrollment or 
discontinue the study 
N 
N/A 
Section 4 Study 
Population 
• 
Revised wording “The sponsor will 
not grant any eligibility waivers” to 
“No eligibility waivers will be 
granted.” 
To correspond to the 
discontinuation of 
eligibility review by the 
sponsor’s medical monitor 
prior to enrollment 
N 
N/A 
Section 4.1 Inclusion 
Criteria 
• 
Deleted wording “primary” in the 
note of the SCCHN cohort 
To clarify the inclusion 
criteria of SCCHN patients 
N 
N/A 
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Section 
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on 
the Safety of 
Patients, Study 
Conduct, or 
Expectedness of 
Suspected Serious 
Adverse Effects 
• 
Added clarification of the term 
“metastatic” in the note of the 
SCCHN cohort 
Section 5.2 Dosage, 
Administration, and 
Compliance 
• 
Deleted wording “medical monitor 
or designee’s” 
To correspond to the 
discontinuation of 
eligibility review by the 
sponsor’s medical monitor 
prior to enrollment 
N 
N/A 
Section 7.1.2 
Demographics 
• 
Added content regarding 
demographic factors and the 
justifying collection of race/ethnicity 
data 
To update per sponsor’s 
current process 
N 
N/A 
Section 7.2 Enrollment 
• 
Removed Treatment Eligibility Form 
language 
• 
Added wording that sponsor 
verification of patient eligibility will 
be managed by source data 
verification in accordance with ICH 
E6 
To discontinue Treatment 
Eligibility review 
conducted by medical 
monitors prior to patient 
enrollment 
To update per sponsor’s 
current process 
Y 
Potential impact on 
study management 
with no expected 
impact on patient 
safety 
Section 8.2.4 
Laboratory Safety Tests 
Appendix 1 Schedule of 
Assessments 
• 
Added wording “urinalysis” 
To clarify the clinical 
practice of urinalysis 
N 
N/A 
Section 8.2.4.1 Cardiac 
Enzyme Monitoring 
• 
Added wording about the 
performance of CK and CK-MB 
To clarify the clinical 
practice of CK and CK-MB 
N 
N/A 
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Protocol Amendment 2.0 Summary of Changes 
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CONFIDENTIAL 
Page 6 
Section 
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on 
the Safety of 
Patients, Study 
Conduct, or 
Expectedness of 
Suspected Serious 
Adverse Effects 
Appendix 1 Schedule of 
Assessments 
during the screening period and 
result review while on study 
Section 8.2.5 
Electrocardiograms 
Appendix 1 Schedule of 
Assessments 
• 
Revised the frequency of 12-lead 
ECGs during the study 
To increase the flexibility 
of 12-lead ECGs in clinical 
practice 
N 
N/A 
Section 8.3 Tumor and 
Response Evaluations 
• 
Added wording “confirmation 4 to 
6 weeks after the first response is 
strongly recommended” 
To clarify the 
recommended timeslot for 
the tumor response 
confirmation 
N 
N/A 
Section 10.2.1 Primary 
Efficacy Analysis 
• 
Revised the ORR analysis method 
To increase the flexibility 
of efficacy analysis 
N 
N/A 
Section 10.3.2 Adverse 
Events 
• 
Updated the imAE definition 
To be consistent with the 
new AE definition for 
tislelizumab 
N 
N/A 
Section 10.6 Other 
Exploratory Analyses 
• 
Deleted tumor type information in 
the biomarker analysis 
To correspond to the 
termination of three cohorts 
(NSCLC, UC, and GC) in 
Part 2 
Y 
Potential impact on 
study conduct 
Section 10.7 Sample Size 
Consideration 
• 
Revised the number of patients from 
“Approximately 150” to 
“Approximately 70” 
• 
Added wording “Three cohorts 
were closed prior to planned 
enrollment due to emerging data 
To correspond to the 
termination of three cohorts 
(NSCLC, UC, and GC) in 
Part 2 
Y 
Potential impact on 
study conduct 
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Section 
Key Changes 
Rationale for the Change 
Substantial 
Change 
(Y/N) 
Potential Impact on 
the Safety of 
Patients, Study 
Conduct, or 
Expectedness of 
Suspected Serious 
Adverse Effects 
(NSCLC and UC cohorts) and 
changes to first-line standard of 
care (GC cohort). In the SCCHN 
and RCC cohorts, approximately” 
Section 14.4 Patient and 
Data Confidentiality 
• 
Updated the confidentiality language 
To update per sponsor’s 
current legal language 
N 
N/A 
Section 15.5 Study and 
Study Center Closure 
• 
Added wording “or to prematurely 
close” 
To increase the flexibility 
of enrollment closure 
N 
N/A 
Appendix 2 
Pharmacokinetic and 
Immunogenicity 
Sampling Schedule for 
Tislelizumab 
• 
Added wording “EOT Visit or 
Safety Follow-up Visit” 
To clarify the timepoint of 
EOT/Safety Follow-up 
N 
N/A 
Appendix 3 Clinical 
Laboratory Assessments 
• 
Revised wording “and” to “or” in 
footnote c 
To increase the flexibility 
of routine urinalysis 
N 
N/A 
Appendix 6 
Contraception 
Guidelines and 
Definitions of "Women 
of Childbearing 
Potential, "No 
Childbearing Potential" 
• 
Revised the postmenopausal follicle-
stimulating hormone concentration 
from “> 30 IU/mL” to 
“> 30 mIU/mL” 
To update the definition of 
postmenopausal to align 
with Clinical Trials 
Facilitation Group 
guideline 
N 
N/A 
Abbreviations: AE, adverse event; CK, creatine kinase; CK-MB, creatine kinase-muscle/brain; ECG, electrocardiogram; EOT, End-of-Treatment (Visit); GC, 
gastric cancer; ICH, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; imAE, immune-mediated adverse 
event; N, no; N/A, not applicable; NSCLC, non-small cell lung cancer; ORR, overall response rate; PK, pharmacokinetic(s); RCC, renal cell carcinoma; SCCHN, 
squamous cell carcinoma of head and neck; SoC, standard of care; UC, urothelial cancer; Y, yes. 
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SAP_001.pdf: 
Synoptic Clinical Study Report (data cutoff date: 10 July 2024) 
BGB-A317-212 
BeiGene 
 
CONFIDENTIAL 
Page 1 
16.1.9 
DOCUMENTATION OF STATISTICAL METHODS  


 
 
Page 1 of 27 
Statistical Analysis Plan 
Company Confidential 
Document No.: VV-QDOC-11461 Version: 2.0, Effective Date: 12 Nov 2021 
 
BGB-A317-212 
BeiGene 
Statistical Analysis Plan 1.0 
09 Nov 2023 
 
CONFIDENTIAL 
Page 1 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Protocol Number: 
BGB-A317-212 
Study Protocol Title: 
A Multicenter, Open-Label, Phase 2 Study to Evaluate the Efficacy 
and Safety of Tislelizumab in Combination with Lenvatinib in 
Patients with Selected Solid Tumors  
Date: 
09 Nov 2023 
Version: 
1.0 
DocuSign Envelope ID: 947179AE-FB74-485F-BD6C-2E207FFAC099
 
 
 
Page 2


Page 2 of 27
Statistical Analysis Plan
Company Confidential
Document No.: VV-QDOC-11461 Version: 2.0, Effective Date: 12 Nov 2021
BGB-A317-212
BeiGene
Statistical Analysis Plan 1.0
09 Nov 2023
CONFIDENTIAL
Page 2
SIGNATURE PAGE
DocuSign Envelope ID: 947179AE-FB74-485F-BD6C-2E207FFAC099
 
 
Page 3


 
Page 3 of 27 
Statistical Analysis Plan 
Company Confidential 
Document No.: VV-QDOC-11461 Version: 2.0, Effective Date: 12 Nov 2021 
BGB-A317-212
BeiGene
Statistical Analysis Plan 1.0 
09 Nov 2023 
CONFIDENTIAL
Page 3
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
1. .................. INTRODUCTION ........................................................................................................8 
2. .................. STUDY OVERVIEW ...................................................................................................8 
2.1. .............. Study Design .................................................................................................................8 
2.2. .............. Study Assessments........................................................................................................9 
3. .................. STUDY OBJECTIVES ..............................................................................................10 
3.1. .............. Primary Objective .......................................................................................................10 
3.2. .............. Secondary Objective ...................................................................................................10 
3.3. .............. Exploratory Objective .................................................................................................10 
4. .................. STUDY ENDPOINTS ................................................................................................10 
4.1. .............. Primary Endpoint(s) ....................................................................................................10 
4.2. .............. Secondary Endpoints ..................................................................................................11 
4.3. .............. Exploratory Endpoints ................................................................................................11 
5. .................. SAMPLE SIZE CONSIDERATIONS .......................................................................11 
6. .................. STATISTICAL METHODS .......................................................................................12 
6.1. .............. Analysis Sets ...............................................................................................................12 
6.2. .............. Multiplicity Adjustment..............................................................................................12 
6.3. .............. Data Analysis General Considerations .......................................................................12 
6.3.1. ........... Definitions and Computations ....................................................................................12 
6.3.2. ........... Conventions ................................................................................................................13 
6.3.3. ........... Handling of Missing Data ...........................................................................................13 
6.4. .............. Patient Characteristics ................................................................................................14 
6.4.1. ........... Patient Disposition ......................................................................................................14 
6.4.2. ........... Protocol Deviations ....................................................................................................14 
6.4.3. ........... Demographic and Other Baseline Characteristics ......................................................14 
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6.4.4. ........... Disease History ...........................................................................................................14 
6.4.5. ........... Prior Anticancer Drug Therapies and Surgeries .........................................................15 
6.4.6. ........... Prior and Concomitant Medications ...........................................................................15 
6.4.7. ........... Medical History ..........................................................................................................15 
6.4.8. ........... Subsequent Anti-cancer Therapy ................................................................................15 
6.5. .............. Efficacy Analysis ........................................................................................................16 
6.5.1. ........... Primary Efficacy Endpoint(s) .....................................................................................16 
6.5.2. ........... Secondary Efficacy Endpoints ....................................................................................16 
6.6. .............. Safety Analyses ..........................................................................................................18 
6.6.1. ........... Extent of Exposure .....................................................................................................18 
6.6.2. ........... Adverse Events ...........................................................................................................19 
6.6.3. ........... Laboratory Values ......................................................................................................20 
6.6.4. ........... Vital Signs ..................................................................................................................21 
6.6.5. ........... Eastern Cooperative Oncology Group (ECOG) Performance Status .........................22 
6.7. .............. Pharmacokinetic Analyses ..........................................................................................22 
6.8. .............. Immunogenicity Analyses ..........................................................................................22 
6.9. .............. Other Analyses ............................................................................................................22 
7. .................. INTERIM ANALYSES ..............................................................................................22 
8. .................. CHANGES IN THE PLANNED ANALYSIS ...........................................................22 
9. .................. REFERENCES ...........................................................................................................23 
APPENDIX 1. IMPUTATION OF MISSING OR PARTIALLY MISSING DATES ...............24 
1. Impute partial dates for concomitant medication.......................................................................24 
2. Impute partial dates for adverse events ......................................................................................24 
 
 
 
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LIST OF TABLES 
Table 1: ..... Censoring Rules for Progression-free Survival Per RECIST Version 1.1 ......... Error! 
Bookmark not defined. 
Table 2: ..... Serum Chemistry and Hematology Laboratory Tests 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA  
Antidrug Antibody 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
 Alanine Aminotransferase 
AST  
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
CI 
Confidence Interval 
CR 
Complete Response 
CT 
Computed Tomography 
DCR  
Disease Control Rate 
DLT  
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DOR  
Duration of Response 
ECG  
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
eCRF  
Electronic Case Report Form 
imAE 
immune-mediated Adverse Event 
GC 
Gastric Cancer  
LDH 
Lactate Dehydrogenase 
MedDRA  
Medical Dictionary for Regulatory Activities 
MRI  
Magnetic Resonance Imaging 
MSI  
Microsatellite Instability 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NSCLC 
Non-Small Cell Lung Cancer 
ORR  
Overall Response Rate 
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Abbreviation 
Definition 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-1  
Programmed cell Death protein-1 
PD-L1 
Programmed cell Death Ligand-1 
PFS  
Progression-Free Survival 
PK 
Pharmacokinetic  
PR 
Partial Response 
PT 
Preferred Term 
RCC 
Renal Cell Carcinoma  
RECIST  
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SAE  
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCCHN 
Squamous Cell Carcinoma of Head and Neck  
SD 
Stable Disease 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
TA 
Tumor Assessment 
TEAE  
Treatment-Emergent Adverse Event 
TMB  
Tumor Mutational Burden 
TTR 
Time To Response  
UC 
Urothelial Cancer  
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-A317-212: a multicenter, open-
label, phase 2 study to evaluate the efficacy and safety of Tislelizumab in combination with 
Lenvatinib in patients with selected solid tumors. This SAP is based on BGB-A317-212 Protocol 
Amendment 2.0, dated on November 03, 2022. The focus of this SAP is for the primary and final 
analysis specified in the study protocol.  
2. 
STUDY OVERVIEW 
2.1. 
Study Design 
This is an open-label, multicenter, Phase 2 study to evaluate the safety and preliminary 
anticancer activity of Tislelizumab in combination with Lenvatinib in Chinese patients with 
locally advanced or metastatic tumors including PD-L1 positive non-small cell lung cancer 
(NSCLC), squamous cell carcinoma of head and neck (SCCHN), urothelial cancer (UC), renal 
cell carcinoma (RCC) and gastric cancer (GC). This study includes 2 parts, Part 1 as safety run-
in stage and Part 2 to assess the efficacy and safety of Tislelizumab in combination with 
Lenvatinib (Figure 1). 
Six patients will receive Lenvatinib 20 mg orally once daily as starting dose in combination with 
Tislelizumab 400 mg intravenously once every 6 weeks, and up to 18 patients will be dosed if 
lower dose(s) of Lenvatinib in combination with Tislelizumab need to be assessed to determine 
RP2D in Part 1. The SMC will evaluate the safety of the combination therapy when the first 6 
DLT-evaluable patients have completed the first 28 days of treatment. Once the SMC confirms 
that the combination therapy is tolerable to proceed, the current dose will be recommended by 
SMC as RP2D for Part 2, and enrollment for Part 2 will begin at this dose. Patients enrolled in 
Part 1 at the RP2D will be counted towards Part 2 by the diagnosed tumor type, and total patient 
number including Part 1 and Part 2 will be approximately 30 at RP2D in cohort of each tumor 
type. There will be a total of 5 cohorts in the study as NSCLC, SCCHN, UC, RCC and GC, 
respectively. Patients will receive the study drug(s) until occurrence of PD, starts new anticancer 
therapy, lost to follow-up, unacceptable toxicity, death, withdrawal of consent, or study 
termination by sponsor. 
All patients will be closely monitored for adverse events (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 National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. 
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Figure 1:
Study Schema
Abbreviations: TIS, Tislelizumab; LEN, Lenvatinib; NSCLC, non-small cell lung cancer; SCCHN, squamous cell 
carcinoma of head and neck; UC, urothelial cancer; RCC, renal cell carcinoma; GC, gastric cancer; PD-L1, 
programmed cell death ligand-1, QD, once daily; Q6W, once every 6 weeks.
2.2.
Study Assessments
Tumor assessments will be performed by the investigators based on RECIST v1.1. All scans for 
tumor assessments performed during the study should be archived in accordance with the 
standard local practice. Tumor imaging at Screening must be performed within 28 days before 
first dose of study drugs (Cycle 1 Day 1).
Tumor assessments will be carried out every 9 weeks (±7 days) (counting from C1D1) in the first 
year (54 weeks), then every 12 (±7 days) weeks thereafter until disease progression, begins 
subsequent anticancer therapy, loss to follow-up, withdrawal of consent, death, or until study 
termination, whichever occurs first.
Patients will be evaluated for any AEs and SAEs occurring until up to 30 days after the last dose 
of study drug(s) (all severity grades, per NCI-CTCAE v.5.0) or initiation of new anticancer 
therapy, whichever occurs first, and immune-mediated AEs (imAEs) occurring up to 90 days 
after the last dose of tislelizumab regardless of initiation of subsequent anticancer therapy. 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. 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.
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3. 
STUDY OBJECTIVES 
3.1. 
Primary Objective 
Part 1 (Safety run-in) 
• 
To assess the safety and determine RP2D) of Lenvatinib (20 mg or other dose once a day 
[QD]) in combination with Tislelizumab (intravenous [IV], 400 mg every six weeks [Q6W]) 
in patients with advanced solid tumors. 
Part 2 (Expansion) 
• 
To assess the overall response rate (ORR) of Tislelizumab (IV, 400 mg Q6W) in 
combination with Lenvatinib in patients with selected advanced tumors. 
3.2. 
Secondary Objective 
Part 2 (Expansion) 
• 
To evaluate the preliminary anticancer activity of Tislelizumab (IV, 400 mg Q6W) in 
combination with Lenvatinib using progression-free survival (PFS), duration of response 
(DOR), disease control rate (DCR), and overall survival (OS). 
• 
To characterize the safety of Tislelizumab (IV, 400 mg Q6W) in combination with 
Lenvatinib. 
3.3. 
Exploratory Objective 
Part 2 (Expansion)  
• 
To explore potential biomarkers that may correlate with clinical responses/resistance to 
Tislelizumab in combination with Lenvatinib. 
• 
To characterize the pharmacokinetics and immunogenicity of Tislelizumab when given in 
combination with Lenvatinib. 
4. 
STUDY ENDPOINTS 
4.1. 
Primary Endpoint(s) 
Part 1 (Safety run-in) 
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• 
Adverse events (AEs) and serious adverse events (SAEs) as characterized by type, 
frequency, severity (as graded by NCI-CTCAE Version 5.0), timing, seriousness, and 
relationship to study drug(s); physical examinations, electrocardiograms (ECGs), and 
laboratory assessments as needed; and AEs meeting protocol-defined DLT criteria. 
Part 2 (Expansion) 
• 
ORR, as assessed using Response Evaluation Criteria in Solid Tumors (RECIST) Version 
1.1 by investigator. 
4.2. 
Secondary Endpoints 
Part 2 (Expansion) 
• 
PFS, DOR, DCR, as assessed using RECIST Version 1.1 by investigator, and OS. 
• 
AEs and SAEs as characterized by type, frequency, severity (as graded by NCI-CTCAE 
Version 5.0), timing, seriousness, and relationship to study drug(s); physical examinations, 
ECGs, and laboratory assessments as needed. 
4.3. 
Exploratory Endpoints 
Part 2 (Expansion) 
• 
Potential biomarker of PD- L1 expression and its association with response to Tislelizumab 
in combination with Lenvatinib. 
• 
Serum concentrations of tislelizumab and the incidence of ADA. 
5. 
SAMPLE SIZE CONSIDERATIONS 
The study plans to enroll approximately 70 patients: 
 Part 1 (Safety run-in): Approximately 6 to 18 patients with 5 prespecified tumor types 
 Part 2 (Expansion): To enroll additional patients at RP2D up to approximately 30 patients 
in the prespecified tumor type  
Three cohorts were closed prior to planned enrollment due to emerging data (NSCLC and UC 
cohorts) and changes to first-line standard of care (GC cohort). In the SCCHN and RCC cohorts, 
approximately 30 patients per cohort will be enrolled to evaluate the preliminary efficacy. No 
formal hypothesis testing will be performed in the efficacy evaluation. 
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6. 
STATISTICAL METHODS 
6.1. 
Analysis Sets 
The Safety Analysis Set 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 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 patients enrolled during safety run-in stage who 
x Received ≥ 75% of scheduled Lenvatinib and ≥ 67% (approximately two-thirds) of 
scheduled dose intensity of Tislelizumab administration during the DLT assessment 
window, remained on study during the DLT observation period, and had sufficient 
safety evaluation OR  
x Experienced a DLT within the DLT observation period. 
The PK Analysis Set includes all patients who received ≥ 1 dose of Tislelizumab 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 include Tislelizumab in combination with Lenvatinib. 
Reference date: Reference date is defined as the date of the first dose of study drug and will 
appear in every listing where an assessment date or event date appears. 
Study Day: Study day will be calculated in reference to the date of the first dose of 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 
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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. 
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: 
x 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
significant digit. 
x 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded 
up to 1 significant digit. 
x Age will be calculated as the integer part of (date of informed consent – date of birth 
+ 1)/365.25. 
x 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. 
x For laboratory results collected as in numerical range, if lab results >= x or >x then set as 
x; if < x or <=x, then x/2. 
x For by-visit observed data analyses, percentages will be calculated based on the 
number of patients with non-missing data as the denominator, unless otherwise 
specified. 
x For continuous endpoints, summary statistics will include n, mean, standard 
deviation, median, Q1, Q3 and range (minimum and maximum). 
x For discrete endpoints, summary statistics will include frequencies and percentages. 
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. 
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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 duration of study follow-up 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. 
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: 
x Age (continuously and by categories [≤65 or >65 years]) 
x Sex 
x Race 
x Weight 
x ECOG performance status at baseline 
6.4.4. 
Disease History 
The number (percentage) of patients reporting a history of disease and characteristics, as 
recorded on the eCRF, will be summarized in the safety analysis set. Disease characteristics 
include disease stage at initial diagnosis, patients with metastatic disease at study entry, time 
from initial diagnosis to first dose date, time from initial diagnosis of metastatic disease to first 
dose date, time from initial diagnosis of locally advanced disease to first dose date, 
histology/cytology, histologic grade.  
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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 
anticancer drug therapy,  best overall response to the last anticancer drug therapy, time from end 
of last anticancer drug therapy to first dose date, time from last disease progression to first dose 
date, treatment setting for prior anti-cancer drug therapies and number of patients with any prior 
anticancer surgery, time from last anticancer surgery to first dose date for prior surgeries. The 
therapies and surgeries with the same sequence/regimen number are counted as one prior 
therapy/surgery. 
6.4.6. 
Prior and Concomitant Medications 
Prior medications are defined as medications that stopped before the first dose of study drug.  
Concomitant medication is defined as medications that received (started before, on or after the 
date of the first dose of the treatment) during study treatment period from initialization of 
treatment up to 30 days after treatment, regardless of whether to receive any subsequent anti-
cancer therapy. 
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.  
6.4.8. 
Subsequent Anti-cancer Therapy 
Subsequent anti-cancer therapy is defined as the anti-cancer therapy started after the last dose 
date of study treatment. A summary of number (percentage) of patients who receive subsequent 
anti-cancer therapy in procedure/surgery or radiotherapy or systematic anti-cancer therapy will 
be provided based on safety analysis set. A listing of subsequent anti-cancer therapy will be 
provided. 
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6.5. 
Efficacy Analysis 
Primary and/or secondary efficacy endpoints will be based on investigators’ tumor assessments 
per RECIST Version 1.1. 
6.5.1. 
Primary Efficacy Endpoint(s) 
The primary analysis is planned in around 9 months after the last patient received the first dose 
of study drug. The investigator assessment will be used for the analysis. Patients without 
postbaseline tumor assessment will be considered as non-responders. The number and proportion 
of patients who achieve the objective response (CR/PR) will be summarized. Associated 2-sided 
95% Clopper-Pearson confidence interval (CI) of ORR (defined as the proportion of patients 
who had CR or PR) will be calculated by cohort based on Safety Analysis Set and Evaluable 
Analysis Set. 
Best Overall Response (BOR) which is defined as the best response recorded from the start of 
the study drug until data cut or start of new antineoplastic treatment. Patients with no post-
baseline response assessment (due to whatever reason) will be considered non-responders for 
BOR. The number and proportion for each of the response categories (complete response [CR], 
partial response [PR], stable disease [SD], and progressive disease [PD]) will be presented. 
A swimmer plot of time on treatment (ie, duration of exposure), with indicators for the start and 
end of each response episode classified by CR or PR, will also be provided for the cohorts with 
at least 10 patients. The patients will be ordered by the duration of exposure. Patients with the 
longest duration will be presented at the top of the plot. 
Forest plot for selected cohorts in the expansion stage with sufficient sample size will be 
provided. 
6.5.2. 
Secondary Efficacy Endpoints 
Progression Free Survival (PFS)  
PFS is defined as the time from the date of the first dose of study drugs to the date of the first 
documentation of PD or death, whichever occurs first. 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 constructed to provide a visual description of 
the PFS change with time for the cohorts with at least 10 patients. PFS censoring rule will follow 
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the US FDA Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics (2018). The censoring rules for the primary analysis of PFS are presented in 
Error! Reference source not found.. 
Table 1. 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  
Last adequate disease assessment before the new 
anticancer therapy  
Censored  
No baseline or post-baseline tumor 
assessments without death within 
19 weeks after the first dose after 
the first dose 
Date of the first dose 
Censored  
No baseline or post-baseline tumor 
assessments and died within 19 
weeks after the first dose 
Date of death 
Event  
Death or progression after more 
than one missed visit 
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  
Death before first PD assessment  
Date of death  
Event  
 
Duration of Response (DOR)  
Duration of response analysis will only include responders. 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 
Evaluable Analysis Set. 
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Disease control rate (DCR), defined as the proportion of patients with best overall response of a 
CR, PR, or SD, will be analyzed using methods similar to those described for ORR based on the 
Safety Analysis Set and Evaluable 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 the 
cohorts with at least 10 patients.  
Overall survival (OS) 
OS, defined as the time from the date of the first dose of study drugs to death due to any cause, 
will be analyzed in the Safety Analysis Set using methods similar to those described for PFS, 
except for censoring rules. For OS, patients will be censored either at the date that the patient 
was last known to be alive or the date of data cutoff, whichever comes earlier, in the absence of 
death. OS rates at specific timepoints will be calculated based on the Kaplan-Meier method. 
Time to Response (TTR) will be analyzed using sample statistics such as mean, median and 
standard deviation in the responders. 
6.6. 
Safety Analyses 
All safety analyses will be performed by cohorts 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, 
coagulation, and urinalysis), vital signs, ECG findings and physical examination.  
6.6.1. 
Extent of Exposure 
The following measures of the extent of exposure will be summarized for Tislelizumab and 
Lenvatinib (One cycle is defined as 42 days for Tislelizumab): 
x Duration of exposure (months) is defined as last date of exposure – first dose date + 
1:  
For Tislelizumab Q6W, it is calculated as (min (cutoff date, death date, last dose date 
+ 41) – first dose date + 1)/30.4375.  
For Lenvatinib QD, it is calculated as (min (cutoff date, death date, last dose date) – 
first dose date + 1)/30.4375. 
x 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. 
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Statistical Analysis Plan 1.0 
09 Nov 2023 
 
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x Total dose received per patient (mg): defined as the cumulative dose of the study drug 
during the treatment period of the study. 
x 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 
 total cumulative dose × 42
last dose date up to cutoff date +  42 –  first dose date 
For Lenvatinib (mg/day), it will be calculated as 
cumulative dose
last dose date up to cutoff date + 1 –  first dose date 
x 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 dose on study 
day 1 by a patient divided by the duration of exposure. 
x Number (%) of patients with dose delay 
x Number (%) of patients with dose missing 
x Number (%) of patients with dose interruptions 
x Number (%) of patients with dose modifications 
x Reasons for dose delay 
x Reasons for dose interruptions 
x Reasons for dose modifications 
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 26.1 or above) lowest 
level term closest to the verbatim term, along with the linked MedDRA preferred term (PT) and 
primary system organ class (SOC). 
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 (permanent discontinuation of study drug) or the initiation of new anti-cancer therapy, 
whichever is earlier. Summary tables will generally focus on those AEs that were treatment-
emergent (TE). All AEs, treatment-emergent or otherwise, will be presented in patient data 
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listings. 
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 treatment modification, 
treatment-related TEAEs, treatment-related TEAEs serious adverse events (SAEs), treatment-
related TEAEs with Grade 3 or above, treatment-related TEAEs that led to death, treatment-
related TEAEs that led to treatment discontinuation, treatment-related TEAEs that led to 
treatment modification will be provided. Treatment-related AEs include those events considered 
by the investigator to be related to study drug or with a missing assessment of the causal 
relationship.  
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. The 
number (percentage) of patients with treatment-related TEAEs, treatment-emergent SAEs, 
TEAEs with grade 3 or above, treatment-related SAEs, TEAEs that led to death, and TEAEs that 
led to treatment discontinuation, dose modification will be summarized by SOC and PT. TEAEs 
with grade 3 or above will also be summarized by SOC and PT in descending order. 
Immune-mediated adverse events (imAE) will be reported until 90 days after the last dose of 
tislelizumab regardless of initiation of a new anti-cancer therapy. All imAE (serious, grade>=3, 
leading to death, leading to treatment discontinuation, leading to treatment modification) will be 
summarized reported separately. ImAE outcome, time to onset, and duration by category will 
also be summarized in table. 
Infusion related AE also will be summarized and reported. 
All deaths and causes of death will be summarized by cohorts, including those occurred during 
the study treatment period and those reported during the survival follow-up period after 
treatment completion/discontinuation. 
6.6.3. 
Laboratory Values 
Laboratory safety tests will be evaluated for selected parameters described in Table 2. Parameters 
selected from Table 2 will be summarized as appropriate. 
Laboratory parameters (e.g. ALP, ALT, AST, total bilirubin, albumin, hemoglobin, platelet 
counts, WBC count, neutrophil and lymphocyte) that are graded in NCI CTCAE Version 5.0 or 
higher will be summarized by shifts from baseline CTCAE grades to maximum post-baseline 
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grades. In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE 
grading in both high and low directions will be summarized separately. 
Box-whisker plots will be generated for parameters of interest.  
Patient data listings of selected list of lab parameters will be provided as appropriate. 
Table 2: 
Serum Chemistry and Hematology Laboratory Tests 
Serum Chemistry 
Hematology 
Alkaline Phosphatase (ALP) 
Red Blood Cell Count 
Alanine Aminotransferase (ALT) 
Hematocrit 
Aspartate Aminotransferase (AST) 
Hemoglobin 
Albumin 
Platelet Count 
Total Bilirubin 
White Blood Cell Count 
Direct Bilirubin 
Lymphocytes Count 
Blood Urea Nitrogen or Urea 
Neutrophils Count 
Amylase 
 
Lipase 
 
Potassium 
 
Sodium  
 
Total Calcium 
 
Creatinine  
 
Glucose 
 
Lactate Dehydrogenase (LDH) 
 
Total Protein 
 
CK 
 
CK-MB 
 
Magnesium 
 
6.6.4. 
Vital Signs 
Descriptive statistics for vital sign parameters (e.g. systolic and diastolic blood pressure [BP], 
pulse rate, temperature, and weight) and changes from baseline will be presented by visit. 
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Shift tables assessing the toxicity grade at baseline versus worst toxicity recorded post-baseline 
will be presented. 
6.6.5. 
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. 
6.7. 
Pharmacokinetic Analyses 
Blood samples will be collected for Tislelizumab PK evaluation at predose and postdose; the 
serum concentration data will be tabulated and summarized by the visit/cycle at which these 
samples are collected. Descriptive statistics will include mean, median, range, and standard 
deviation as appropriate. 
6.8. 
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. The effect of 
immunogenicity on PK, efficacy, and safety may be evaluated if data allow and reported 
separately from the main clinical study report. 
6.9. 
Other Analyses 
Biomarker of PD- L1 expression in squamous cell carcinoma of the head and neck (SCCHN), 
and its association with response to Tislelizumab in combination with Lenvatinib will be 
analyzed. 
7. 
INTERIM ANALYSES 
No formal interim analysis will be conducted. Summaries of efficacy and safety data may be 
generated to inform subsequent clinical development planning. 
8. 
CHANGES IN THE PLANNED ANALYSIS 
Not applicable.  
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9. 
REFERENCES 
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. 
US Food and Drug Administration Center for Drug Evaluation Research (CDER) and Center for 
Biologics Evaluation and Research. FDA Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. 2018. 
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APPENDIX 1. IMPUTATION OF MISSING OR PARTIALLY MISSING 
DATES 
Please note: all the imputed date should be prior to/or by last known alive date.  The last known 
alive date only is based on complete dates without imputation.   
1. Impute partial dates for concomitant medication  
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute partial dates for medications.   
If start date of a medication/therapy/procedure is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
x If the imputed start date > death date, then set to death date 
If end date of a medication/therapy/procedure is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed end date > death date, then set to death date 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
2. Impute partial dates for adverse events 
If year of the start date is missing or start date is completely missing, do not impute.  Impute AE 
end date first if both AE start date and end date are partially missing. 
If end date of an adverse event is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed end date > 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. 
 
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If start date of an adverse event is partially missing, impute as follows: 
x If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
x If both month and day are missing and year ≠ year of treatment start date, then set to 
January 01 
x If day is missing and month and year = month and year of treatment start date, the set 
to treatment start date 
x If day is missing and month and year ≠ month and year of treatment start date, the set 
to first of the month 
x If the imputed AE start date is after AE end date (maybe imputed), then update AE 
start date  
with AE end date as final imputed AE start date 
x If the imputed end date > min (death date, end of study date), then set to min (death 
date, end of study date) 
 
3. Impute partial dates related to disease history and prior therapy (Drug, 
surgery/procedure, radiotherapy) 
The following rules will be applied to impute partial dates such as as initial diagnosis date, initial 
BCLC staging date, relapse date, therapy date (start/end date), or surgery date etc. 
Impute end date first. If end date is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to the last day of the month 
If start date is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
x If the imputed start date > end date, then set to the end date 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute.  
 
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4. Impute partial dates for subsequent anti-cancer therapy as collected in the post-
treatment page (same rule applies to safety and efficacy flag)
If start date of subsequent anti-cancer therapy is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed start date > min (death date, study discontinuation date, data cutoff 
date, start date of the 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: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed stop date > min (death date, study discontinuation date, data cutoff date, 
start date of the next subsequent 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. 
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