A Phase 2, Multicenter, Randomized, 3-Arm, Open-Label Study to Investigate the Preliminary Efficacy and Safety of the Anti-TIGIT Monoclonal Antibody Ociperlimab (BGB-A1217) Plus Tislelizumab Plus Concurrent Chemoradiotherapy in Patients With Untreated Limited-Stage Small Cell Lung Cancer
Phase: PHASE2
Conditions: Limited Stage Small Cell Lung Cancer
Sponsor: BeiGene

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CLINICAL STUDY PROTOCOL 
Protocol Title:  
A Phase 2, Multicenter, Randomized, 3-Arm, Open-
Label Study to Investigate the Preliminary Efficacy 
and Safety of the Anti-TIGIT Monoclonal Antibody 
Ociperlimab (BGB-A1217) Plus Tislelizumab Plus 
Concurrent Chemoradiotherapy in Patients With 
Untreated Limited-Stage Small Cell Lung Cancer 
Protocol Identifier: 
AdvanTIG-204 
Phase: 
2 
Investigational Products: 
Ociperlimab (BGB-A1217) and tislelizumab 
(BGB-A317) 
Indication: 
Untreated limited-stage small cell lung cancer 
(LS-SCLC) 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, California 94403 
USA 
Sponsor Medical Monitor: 
 
Telephone: 
 
Email: 
 
Original Protocol Version 0.0: 
25 February 2021 
Protocol Amendment Version 1.0: 
18 June 2021 
Protocol Amendment Version 2.0: 
23 September 2021 
Protocol Amendment Version 3.0: 
08 October 2021 
 
 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, 
Ltd., and its subsidiaries. This document is for use by individuals and their designated 
representatives for their confidential review, consideration, and/or participation in investigational 
trial(s). This document may not be copied or distributed for review by any unauthorized 
individuals without the prior written authorization of BeiGene, Ltd., or one of its subsidiaries. 
Your acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without the prior written authorization from BeiGene, 
Ltd., or one of its subsidiaries. 
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INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 2, Multicenter, Randomized, 3-Arm, Open-Label Study to 
Investigate the Preliminary Efficacy and Safety of the Anti-TIGIT 
Monoclonal Antibody Ociperlimab (BGB-A1217) Plus Tislelizumab Plus 
Concurrent Chemoradiotherapy in Patients With Untreated Limited-Stage 
Small Cell Lung Cancer 
Protocol Identifier: 
AdvanTIG-204 
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 
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 ................................................................................21 
1. 
INTRODUCTION ......................................................................................................23 
1.1. 
Background Information on Limited-Stage Small Cell Lung Cancer ........................23 
1.2. 
Current Treatment of Limited-Stage Small Cell Lung Cancer and Unmet 
Clinical Needs .............................................................................................................24 
1.2.1. 
Concurrent Chemoradiotherapy With or Without Prophylactic Cranial 
Irradiation as First-Line Therapy for Limited-Stage Small Cell Lung Cancer ..........24 
1.2.2. 
Anti-PD-1/PD-L1 Therapy for Limited-Stage Small Cell Lung Cancer ....................25 
1.3. 
Background Information on Ociperlimab (BGB-A1217) ...........................................29 
1.3.1. 
Nonclinical Summary .................................................................................................29 
1.3.1.1. 
Pharmacology .............................................................................................................29 
1.3.1.2. 
Toxicology ..................................................................................................................29 
1.3.2. 
Prior Clinical Experience With Ociperlimab ..............................................................30 
1.3.3. 
Ociperlimab Clinical Pharmacology and Pharmacodynamics ...................................33 
1.4. 
Background Information on Tislelizumab ..................................................................34 
1.4.1. 
Pharmacology .............................................................................................................34 
1.4.2. 
Toxicology ..................................................................................................................34 
1.4.3. 
Clinical Pharmacology ................................................................................................34 
1.4.4. 
Prior Clinical Experience With Tislelizumab .............................................................35 
1.4.4.1. 
Treatment-Emergent Adverse Events Assessed as Related to Tislelizumab ..............35 
1.4.4.2. 
Treatment-Emergent Serious Adverse Events ............................................................35 
1.4.4.3. 
Immune-Mediated Adverse Events ............................................................................36 
1.4.4.4. 
Infusion-Related Reactions .........................................................................................36 
1.4.4.5. 
Liver Laboratory Abnormalities .................................................................................36 
1.4.4.6. 
Fatal Adverse Events ..................................................................................................37 
1.4.5. 
Efficacy Assessment of Tislelizumab .........................................................................37 
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1.5. 
Study Rationales .........................................................................................................38 
1.5.1. 
Rationale for Combination of Ociperlimab and Tislelizumab in the 
Treatment of Limited-Stage Small Cell Lung Cancer ................................................38 
1.5.2. 
Rationale for the Selection of Ociperlimab Dose .......................................................39 
1.5.3. 
Rationale for Selection of Tislelizumab Dose ............................................................39 
1.5.4. 
Rationale for Chemoradiotherapy as the Component of the Combination 
Treatment ....................................................................................................................40 
1.5.5. 
Rationale for Combination of Concurrent Chemoradiotherapy and 
Immunotherapy ...........................................................................................................40 
1.5.6. 
Rationale for Chemotherapy Regimens ......................................................................41 
1.5.7. 
Rationale for Radiation Therapy Dose .......................................................................42 
1.5.8. 
Rationale for Biomarker Strategy ...............................................................................42 
1.6. 
Benefit-Risk Assessment ............................................................................................43 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................45 
2.1. 
Study Objectives .........................................................................................................45 
2.1.1. 
Primary Objective .......................................................................................................45 
2.1.2. 
Secondary Objectives .................................................................................................45 
2.1.3. 
Exploratory Objectives ...............................................................................................45 
2.2. 
Study Endpoints ..........................................................................................................45 
2.2.1. 
Primary Endpoint ........................................................................................................45 
2.2.2. 
Secondary Endpoints ..................................................................................................46 
2.2.3. 
Exploratory Endpoints ................................................................................................46 
3. 
STUDY DESIGN .......................................................................................................47 
3.1. 
Summary of Study Design ..........................................................................................47 
3.2. 
Screening Period .........................................................................................................50 
3.3. 
Treatment Period ........................................................................................................50 
3.4. 
End of Treatment/Safety Follow-up ...........................................................................51 
3.5. 
Survival Follow-up .....................................................................................................52 
3.6. 
Discontinuation From the Study Treatment or From the Study .................................52 
3.6.1. 
Patient Discontinuation From Study Treatment .........................................................52 
3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........53 
3.7. 
End of Study ...............................................................................................................53 
4. 
STUDY POPULATION .............................................................................................54 
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4.1. 
Inclusion Criteria ........................................................................................................54 
4.2. 
Exclusion Criteria .......................................................................................................55 
5. 
STUDY TREATMENT ..............................................................................................58 
5.1. 
Formulation, Packaging, and Handling ......................................................................58 
5.1.1. 
Ociperlimab ................................................................................................................58 
5.1.2. 
Tislelizumab ...............................................................................................................58 
5.1.3. 
Chemotherapy .............................................................................................................58 
5.2. 
Dosage, Administration, and Compliance ..................................................................58 
5.2.1. 
Ociperlimab and Tislelizumab ....................................................................................60 
5.2.2. 
Chemotherapy .............................................................................................................61 
5.2.2.1. 
Cisplatin + Etoposide ..................................................................................................61 
5.2.2.2. 
Carboplatin + Etoposide .............................................................................................62 
5.2.3. 
Thoracic Radiation Therapy .......................................................................................62 
5.2.3.1. 
Radiation Dose Specifications ....................................................................................62 
5.2.3.2. 
Variations of Dose Prescription ..................................................................................63 
5.2.3.3. 
Localization, Simulation, and Immobilization ...........................................................64 
5.2.3.4. 
Radiation Treatment Planning ....................................................................................65 
5.2.4. 
Prophylactic cranial irradiation (PCI) .........................................................................66 
5.3. 
Incorrect Administration or Overdose ........................................................................66 
5.4. 
Investigational Medicinal Product Accountability .....................................................66 
5.5. 
Dose Delay or Modification .......................................................................................66 
5.5.1. 
Dose Delay or Modification for Ociperlimab or Tislelizumab ..................................67 
5.5.2. 
Dose Delay, Interruption, or Modifications for Radiation Therapy ...........................68 
5.5.3. 
Dose Delay, Interruption, or Modifications for Chemotherapy .................................69 
5.5.4. 
Criteria for Discontinuing Chemotherapy Regimens .................................................71 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................72 
6.1. 
Prior Therapy ..............................................................................................................72 
6.2. 
Concomitant Therapy .................................................................................................72 
6.2.1. 
Permitted Concomitant Medications/Procedures .......................................................72 
6.2.1.1. 
Systemic Corticosteroids ............................................................................................72 
6.2.1.2. 
Hepatitis B Treatment .................................................................................................72 
6.2.1.3. 
Hepatitis C Treatment .................................................................................................73 
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6.2.2. 
Prohibited Concomitant Medications/Procedures ......................................................73 
6.2.3. 
Restricted Concomitant Medications/Procedures .......................................................73 
6.3. 
Potential Interactions Between Study Drugs and Concomitant Medications .............73 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................75 
7.1. 
Screening ....................................................................................................................75 
7.1.1. 
Informed Consent and Screening Log ........................................................................75 
7.1.2. 
Patient Numbering ......................................................................................................75 
7.1.3. 
Demographic Data and Medical History ....................................................................76 
7.1.4. 
Female Patients of Childbearing Potential and Contraception ...................................76 
7.1.5. 
Pulmonary Function Tests ..........................................................................................76 
7.2. 
Enrollment ..................................................................................................................76 
7.2.1. 
Confirmation of Eligibility .........................................................................................76 
7.2.2. 
Enrollment/Randomization .........................................................................................77 
7.3. 
Study Drug Dispensation ............................................................................................77 
7.4. 
Safety Assessments .....................................................................................................77 
7.4.1. 
Vital Signs, Height, and Weight .................................................................................77 
7.4.2. 
Physical Examinations ................................................................................................78 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status ........................................78 
7.4.4. 
Laboratory Safety Tests ..............................................................................................78 
7.4.4.1. 
Cardiac Enzyme Monitoring .......................................................................................78 
7.4.5. 
Electrocardiograms .....................................................................................................79 
7.4.6. 
Adverse Events ...........................................................................................................79 
7.4.7. 
Hepatitis B and C Testing ...........................................................................................79 
7.5. 
Tumor and Response Evaluations ..............................................................................79 
7.6. 
Pharmacokinetic and Antidrug Antibody Testing ......................................................81 
7.7. 
Biomarkers ..................................................................................................................81 
7.8. 
Patient-Reported Outcomes ........................................................................................82 
7.9. 
Visit Windows ............................................................................................................82 
7.10. 
Unscheduled Visits .....................................................................................................83 
8. 
SAFETY MONITORING AND REPORTING .........................................................84 
8.1. 
Risks Associated With Study Drugs ...........................................................................84 
8.1.1. 
Risks Associated With Ociperlimab and Tislelizumab ..............................................84 
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8.1.2. 
Risks Associated With Chemotherapy .......................................................................84 
8.1.3. 
Risks Associated With Radiation Therapy .................................................................85 
8.2. 
General Plan to Manage Safety Concerns ..................................................................85 
8.2.1. 
Eligibility Criteria .......................................................................................................85 
8.2.2. 
Safety Monitoring Plan ...............................................................................................85 
8.3. 
Adverse Events ...........................................................................................................85 
8.3.1. 
Definitions and Reporting ...........................................................................................85 
8.3.2. 
Assessment of Severity ...............................................................................................86 
8.3.3. 
Assessment of Causality .............................................................................................86 
8.3.4. 
Follow-up of Adverse Events .....................................................................................87 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................88 
8.4. 
Definition of a Serious Adverse Event .......................................................................88 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................89 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................89 
8.6.1. 
Adverse Event Recording Period ................................................................................89 
8.6.2. 
Reporting Serious Adverse Events .............................................................................90 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................90 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................91 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................91 
8.6.3. 
Eliciting Adverse Events ............................................................................................92 
8.6.4. 
Disease Progression ....................................................................................................92 
8.6.5. 
Deaths .........................................................................................................................92 
8.6.6. 
Pregnancies .................................................................................................................92 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................92 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................93 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................93 
8.7. 
Management of Adverse Events of Special Interest ...................................................93 
8.7.1. 
Managing Infusion-Related Reactions .......................................................................93 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................95 
8.7.3. 
Immune-Mediated Adverse Events ............................................................................95 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................97 
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9.1. 
Statistical Analysis ......................................................................................................97 
9.1.1. 
Randomization Methods .............................................................................................97 
9.1.2. 
Analysis Sets ...............................................................................................................97 
9.1.3. 
Patient Disposition ......................................................................................................97 
9.1.4. 
Demographic and Other Baseline Characteristics ......................................................97 
9.1.5. 
Prior and Concomitant Medications ...........................................................................98 
9.2. 
Efficacy Analyses .......................................................................................................98 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................98 
9.2.2. 
Secondary Efficacy Analysis ......................................................................................98 
9.2.3. 
Exploratory Efficacy Analysis ....................................................................................99 
9.3. 
Safety Analyses ........................................................................................................100 
9.3.1. 
Extent of Exposure ...................................................................................................100 
9.3.2. 
Adverse Events .........................................................................................................100 
9.3.3. 
Laboratory Analyses .................................................................................................101 
9.3.4. 
Vital Signs ................................................................................................................101 
9.3.5. 
Pulmonary Function Test ..........................................................................................101 
9.4. 
Pharmacokinetic Analysis ........................................................................................101 
9.5. 
Immunogenicity Analysis .........................................................................................102 
9.6. 
Sample Size Consideration .......................................................................................102 
9.7. 
Interim Analyses .......................................................................................................102 
10. 
STUDY COMMITTEES AND COMMUNICATION ............................................103 
10.1. 
Safety Monitoring Committee ..................................................................................103 
10.1.1. 
Study Safety Stopping Criteria .................................................................................103 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS .............................................................................................105 
11.1. 
Access to Information for Monitoring ......................................................................105 
11.2. 
Access to Information for Auditing or Inspections ..................................................105 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................106 
12.1. 
Regulatory Authority Approval ................................................................................106 
12.2. 
Quality Assurance .....................................................................................................106 
12.3. 
Study Site Inspections...............................................................................................106 
12.4. 
Drug Accountability .................................................................................................106 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ................................................108 
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13.1. 
Ethical Standard ........................................................................................................108 
13.2. 
Institutional Review Board/Independent Ethics Committee ....................................108 
13.2.1. 
Protocol Amendments ..............................................................................................108 
13.3. 
Informed Consent .....................................................................................................109 
13.4. 
Patient and Data Confidentiality ...............................................................................109 
13.5. 
Financial Disclosure .................................................................................................110 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................111 
14.1. 
Data Collection and Management Responsibilities ..................................................111 
14.1.1. 
Data Entry in the Electronic Case Report Form .......................................................111 
14.1.2. 
Data Collection .........................................................................................................111 
14.1.3. 
Data Management/Coding ........................................................................................111 
14.2. 
Data Integrity and In-house Blinding .......................................................................112 
14.3. 
Study Records Retention ..........................................................................................112 
14.4. 
Protocol Deviations ..................................................................................................113 
14.5. 
Study Report and Publications..................................................................................113 
14.6. 
Study and Study Center Closure ...............................................................................114 
14.7. 
Information Disclosure and Inventions ....................................................................114 
15. 
REFERENCES .........................................................................................................116 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................122 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ..............................................129 
APPENDIX 3. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .....................................................................................130 
APPENDIX 4. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................131 
APPENDIX 5. PREEXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................141 
APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................142 
APPENDIX 7. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................143 
APPENDIX 8. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................156 
APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................157 
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APPENDIX 10. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE (EORTC-QLQ-C30) ................................................................159 
APPENDIX 11. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE QUESTIONNAIRE 
LUNG CANCER (QLQ-LC13) ................................................................................161 
APPENDIX 12. COCKROFT-GAULT FORMULA AND CALVERT FORMULA ..............162 
APPENDIX 13. DOSE MODIFICATION OF CHEMOTHERAPY .......................................163 
APPENDIX 14. MANAGEMENT OF RADIATION ESOPHAGITIS ...................................167 
 
LIST OF TABLES 
Table 1: 
Ongoing PD-1 Pathway-Targeting Immunotherapy Studies in Limited-Stage 
Small Cell Lung Cancer ..............................................................................................28 
Table 2: 
Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term and Maximum Severity (Safety Analysis Set) ..................................................31 
Table 3: 
Planned Dose, Frequency of Administration, and Route of Administration 
for Study Drugs ...........................................................................................................59 
Table 4: 
Administration of Ociperlimab and Tislelizumab and Monitoring Time ...................61 
Table 5 
Normal Tissue Dose-Volume Constraints for Conventionally Fractionated 
Radiation Therapy with Concurrent Chemotherapy a .................................................63 
Table 6: 
Summary of Dose Prescription Variations .................................................................63 
Table 7: 
The Summary of the Commonly and Specific Reported Toxicity of the 
Chemotherapeutic Agents ...........................................................................................84 
Table 8: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Arms ....................................................................................................90 
Table 9: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................91 
Table 10: Treatment Modifications for Symptoms of Infusion-Related Reactions Due 
to Study Drug(s) .........................................................................................................94 
Table 11: Examples of Immune-Mediated Adverse Events .......................................................96 
 
LIST OF FIGURES 
Figure 1: 
Cycle 1 Mean (± SD) Serum Concentration-Time Profiles of Ociperlimab in 
Study BGB-900-105 ...................................................................................................33 
Figure 2: 
Study Schema .............................................................................................................49 
 
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SYNOPSIS 
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Products: Ociperlimab (BGB-A1217) and tislelizumab (BGB-A317) 
Title of Study: A Phase 2, Multicenter, Randomized, 3-Arm, Open-Label Study to Investigate the 
Preliminary Efficacy and Safety of the Anti-TIGIT Monoclonal Antibody Ociperlimab (BGB-A1217) 
Plus Tislelizumab Plus Concurrent Chemoradiotherapy in Patients With Untreated Limited-Stage 
Small Cell Lung Cancer 
Protocol Identifier: AdvanTIG-204 
Phase of Development: 2 
Number of Patients: Approximately 120 
Study Centers: Approximately 30 to 40 centers internationally 
Study Objectives: 
Primary: 
• 
To compare progression-free survival (PFS) between Arm A (ociperlimab [BGB-A1217] plus 
tislelizumab plus concurrent chemoradiotherapy [cCRT]) and Arm C (cCRT only) and between 
Arm B (tislelizumab plus cCRT) and Arm C as assessed by the investigator according to 
Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the 
Intent-to-Treat (ITT) Analysis Set 
Secondary: 
• 
To compare the following between Arm A and Arm C and between Arm B and Arm C as 
assessed by the investigator according to RECIST v1.1 in the ITT Analysis Set: 
- 
Complete response (CR) rate 
- 
Overall response rate (ORR) 
- 
Duration of response (DOR)  
- 
Overall survival (OS) 
- 
Distant metastasis-free survival (DMFS) 
• 
To evaluate the correlation of programmed cell death ligand-1 (PD-L1) and T-cell 
immunoglobulin and ITIM domain (TIGIT) expression with ORR, PFS, and OS  
• 
To evaluate the safety and tolerability of ociperlimab combined with tislelizumab plus cCRT 
and tislelizumab plus cCRT 
Exploratory: 
• 
To explore prognostic and predictive effects of tissue- and blood-based biomarkers on efficacy 
and their association with mechanisms of resistance  
• 
To evaluate health-related quality of life (HRQoL) 
• 
To assess the utility of circulating tumor DNA (ctDNA) level change as a surrogate marker for 
efficacy  
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• 
To assess the pharmacokinetics (PK) of ociperlimab and tislelizumab 
• 
To assess the immunogenicity of ociperlimab and tislelizumab 
Study Endpoints: 
Primary: 
• 
PFS, defined as the time from the date of randomization to the date of the first documented 
disease progression as determined by the investigator per RECIST v1.1 or death from any 
cause (whichever occurs first), in the ITT Analysis Set of Arms A, B, and C 
Secondary Endpoints:  
• 
CR rate, defined as the proportion of patients who had CR as assessed by the investigator per 
RECIST v1.1, in the ITT Analysis Set of Arms A, B, and C 
• 
ORR, defined as the proportion of patients who had CR or partial response (PR) as assessed by 
the investigator per RECIST v1.1, in the ITT Analysis Set of Arms A, B, and C 
• 
DOR, defined as the time from the date of the first occurrence of a documented objective 
response to the date of documented disease progression as assessed by the investigator per 
RECIST v1.1 or death from any cause (whichever occurs first), in the ITT Analysis Set of 
Arms A, B, and C 
• 
OS, defined as the time from the date of randomization to the date of death due to any cause, in 
the ITT Analysis Set of Arms A, B, and C 
• 
DMFS, defined as the time from the date of randomization to the date of the first documented 
distant metastasis as assessed by the investigator per RECIST v1.1 or death from any cause 
(whichever occurs first), in the ITT Analysis Set of Arms A, B, and C 
• 
ORR, PFS, and OS in subgroups based on PD-L1 and TIGIT expression levels 
• 
The incidence and severity of treatment-emergent adverse events (TEAEs) graded according to 
National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 
(NCI-CTCAE v5.0). 
Exploratory Endpoints:  
• 
Biomarkers from patient-derived tumor tissue(s) and/or blood samples obtained before, during, 
and/or after treatment including but not limited to gene expression profile, tissue- or 
blood-based gene mutations and tumor mutational burden (TMB)/microsatellite instability 
(MSI), CD155/CD226 expression, and small cell lung cancer (SCLC) subtyping 
(ASCL1/NEUROD1/POU2F3/YAP1)  
• 
HRQoL assessment using 2 patient-reported outcomes (PROs) including the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 
(EORTC QLQ-C30) and its lung cancer module Quality of Life Questionnaire Lung Cancer 13 
(QLQ-LC13) 
• 
The ctDNA level change before, during, and after treatment as a surrogate marker for efficacy 
• 
Serum concentrations of ociperlimab and tislelizumab at specified timepoints 
• 
Assessment of immunogenicity of ociperlimab and tislelizumab by determining the incidence 
of antidrug antibodies (ADAs)  
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Study Design 
This is a Phase 2, multicenter, randomized, 3-arm, open-label study to investigate the preliminary 
efficacy and safety of the anti-TIGIT monoclonal antibody ociperlimab plus tislelizumab plus cCRT 
followed by ociperlimab plus tislelizumab (Arm A) and tislelizumab plus cCRT followed by 
tislelizumab only (Arm B) compared with cCRT only (Arm C) in patients with previously untreated 
limited-stage small cell lung cancer (LS-SCLC). 
The primary endpoint is investigator-assessed PFS in the ITT Analysis Set for the comparisons of 
Arm A versus Arm C and Arm B versus Arm C.  
Approximately 120 patients will be randomized in a 1:1:1 ratio to receive the study treatment in the 
following 3 arms: 
• 
Arm A: Ociperlimab 900 mg intravenously once every 3 weeks plus tislelizumab 200 mg 
intravenously once every 3 weeks combined with cCRT for 4 cycles, followed by ociperlimab 
900 mg intravenously once every 3 weeks plus tislelizumab 200 mg intravenously once every 
3 weeks  
• 
Arm B: Tislelizumab 200 mg intravenously once every 3 weeks combined with cCRT for 
4 cycles, followed by tislelizumab 200 mg intravenously once every 3 weeks  
• 
Arm C: cCRT only for 4 cycles 
Randomization will be stratified by disease stage (I/II versus III) by the American Joint Committee on 
Cancer staging system, 8th edition.  
The chemotherapy regimen is cisplatin 75 mg/m2 on Day 1 of each cycle for 4 cycles. If the patient is 
unable to tolerate the 1-day administration of cisplatin 75 mg/m2, at the investigator’s discretion (eg, 
patients had concurrent superior vena cava syndrome) cisplatin 25 mg/m2 dosed on Days 1, 2, and 3 is 
allowed. Etoposide is administered at 100 mg/m2 on Days 1, 2, and 3 for 4 cycles. Dose adjustment is 
allowed to address potential renal, hematologic, or other toxicities after the first cycle.  
If cisplatin is contraindicated or not tolerated, carboplatin and etoposide will be the alternative regimen 
(Section 5.2.2.1). Carboplatin at a dose of area under the plasma or serum concentration-time curve 5 
(AUC 5) should be administered as an intravenous infusion once every 3 weeks on Day 1 of each cycle 
for 4 cycles and etoposide 100 mg/m2 should be administered on Days 1, 2, and 3 of each cycle for 4 
cycles. 
For Arm A and Arm B, investigational drug(s) (ociperlimab plus tislelizumab [Arm A] or tislelizumab 
alone [Arm B]) will be given starting on Cycle 1 Day 1 (C1D1) before chemotherapy and continued for 
a duration of up to 12 months (a maximum of 17 cycles of treatment) or until disease progression 
according to RECIST v1.1, unacceptable toxicity, death, or another discontinuation criterion is met, 
whichever occurs first.  
Radiation therapy (RT) should start early within cycle 1 or 2 of systemic therapy. The total dose of RT 
will be 60 to 70 Gy, given in once-daily fractions over 6 to 7 weeks.  
Prophylactic cranial irradiation (PCI) is permitted at the investigator’s discretion. The preferred total 
dose for PCI to the whole brain is 25 Gy in 10 daily fractions. 
 
 
 
 
Study Schema 
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Study Assessments: 
Tumor Assessments: 
Tumor imaging will be performed ≤ 28 days before randomization. During the study, tumor imaging 
will be performed at approximately 12 weeks (± 7 days) from the date of randomization (an additional 
tumor assessment is allowed if clinically indicated), then every 6 weeks (± 7 days) for the next 
54 weeks, and then every 12 weeks (± 7 days) thereafter based on RECIST v1.1.  
Administration of study treatment will continue for up to 12 months (17 cycles maximum) for Arms A 
and B and for 4 cycles for Arm C, or until disease progression as assessed by the investigator according 
to RECIST v1.1, unacceptable toxicity, death, or another discontinuation criterion is met, whichever 
occurs first. 
A patient who discontinues study treatment early for reasons other than disease progression (eg, 
toxicity) will continue to undergo tumor assessments following the original schedule until disease 
progression according to RECIST v1.1, withdrawal of consent, loss to follow-up, start of a new 
anticancer therapy, death, or study termination, whichever occurs first. 
In Arms A and B, treatment with ociperlimab plus tislelizumab or with tislelizumab alone beyond the 
initial investigator-assessed, RECIST v1.1-defined disease progression is permitted provided that the 
patient has investigator-assessed clinical benefit and is tolerating the study drug(s). The following 
criteria must be met in order to treat patients who may continue to benefit from study drugs after 
disease progression:  
• 
Absence of clinical symptoms and signs of disease progression (including clinically significant 
worsening of laboratory values). 
• 
Stable Eastern Cooperative Oncology Group (ECOG) Performance Status (≤ 2). 
• 
Absence of rapid progression of disease or of progressive tumor at critical anatomical sites (eg, 
cord compression) that requires urgent alternative medical intervention. 
• 
Investigators must obtain written informed consent for treatment beyond radiologic disease 
progression and inform patients that this practice is not considered standard in the treatment of 
cancer. 
Tumor assessments are required to be performed on schedule regardless of whether the study treatment 
has been administered or held; that is, tumor assessments should not be adjusted for delays in cycles. 
Safety Assessments: 
Patients will be evaluated for any AEs and serious adverse events (SAEs) occurring up to 30 days after 
the last dose of study treatment (all severity grades, per NCI-CTCAE v5.0) or initiation of a new 
anticancer therapy, whichever occurs first, and immune-mediated AEs (imAEs) occurring up to 
90 days after the last dose of ociperlimab or tislelizumab, regardless of initiation of a new anticancer 
therapy. All treatment-related SAEs will be recorded by the investigator after treatment discontinuation 
until patient death, withdrawal of consent, or loss to follow-up, whichever occurs first. All study 
treatment-related SAEs will be followed until they resolve to baseline or ≤ Grade 1, the investigator 
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assesses the AE as stable and unlikely to improve, the patient is lost to follow-up, or the patient 
withdraws consent, whichever occurs first. 
Safety assessments will also include laboratory values (eg, hematology, clinical chemistry, coagulation, 
urinalysis), vital signs, electrocardiograms (ECGs), ECOG Performance Status, and physical 
examinations. 
Patient-Reported Outcomes: 
Patient-reported outcomes will be collected using the EORTC QLQ-C30 and QLQ-LC13 questionnaires 
will be completed at predose on Day 1 of every cycle from Cycle 1 (baseline) through Cycle 4, and then 
to coincide with scheduled tumor assessments (every 6 weeks [± 7 days]) until the EOT Visit (Arms A, 
B, and C). 
Safety Monitoring Committee: 
A Safety Monitoring Committee (SMC) consisting of qualified investigators who are taking part in the 
study will be implemented to support the study and structure the scientific input. The SMC will 
conduct safety assessments at the following timepoints:  
• 
After approximately 6 patients (≥ 2 patients per arm) have completed 2 cycles of study 
treatment  
• 
After approximately 18 patients (≥ 6 patients per arm) have completed 2 cycles of study 
treatment or no later than 6 months after the first SMC evaluation, whichever occurs first  
• 
After the scheduled SMC assessments, the SMC will review data approximately every 
6 months for the first 18 months of the study and yearly thereafter  
The SMC could review data more frequently if indicated or requested by the medical monitor or SMC 
based on ongoing safety monitoring of patients on study. The SMC may recommend study 
modifications including early termination of the study due to safety concerns. Full details of the SMC 
procedures and processes can be found in the SMC Charter.  
Enrollment may continue during these SMC safety reviews. 
The study will be conducted in compliance with International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) guidelines. 
Duration of Patient Participation: 
Duration of treatment will be up to 12 months for Arms A and B (17 cycles maximum), including 
approximately 3 months (4 cycles) for concurrent administration of chemoradiotherapy, and 
approximately 3 months (4 cycles) for Arm C. Each patient’s study course will include: 
• 
Screening period of up to 28 days before randomization 
• 
Treatment for durations described above or until disease progression (or any other reasons for 
discontinuation before progression) 
• 
Safety Follow-up Visit to occur within 30 days (± 7 days) after the last dose of study treatment 
Survival follow-up information will be collected every 3 months after the Safety Follow-up Visit until 
death, withdrawal of consent, loss to follow-up, or study completion. The end of study is defined as the 
timepoint when the final data for the study has been collected, which is after the last study patient has 
made the final visit to the study location. The duration from the first enrolled patient to the final 
analysis for PFS is estimated to be approximately 30 months. 
 
 
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Study Population:  
The study will enroll approximately 120 patients (randomized at a 1:1:1 ratio) who meet the 
inclusion/exclusion criteria outlined below. 
Key Eligibility Criteria: 
Key Inclusion Criteria: 
The population under study consists of adult patients (≥18 years of age or the legal age of consent in 
the jurisdiction in which the study is taking place) with histologically or cytologically confirmed 
diagnosis of LS-SCLC that is considered unresectable and can be safely treated with definitive 
radiation doses. Patients must not have received prior treatment for LS-SCLC. Patients must submit 
qualified archival tumor tissue with an associated pathology report or agree to a tumor biopsy. All 
patients are also required to have measurable disease per RECIST v1.1 within 28 days before 
randomization, an ECOG Performance Status ≤ 2, life expectancy ≥ 12 weeks, and adequate organ 
function. For full inclusion criteria, see Section 4.1. 
Key Exclusion Criteria: 
Patients will not have mixed SCLC histology (except for mixed SCLC with neuroendocrine carcinoma 
origin) and will not have received surgical resection for LS-SCLC. Patients must not have received 
prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, TIGIT or any other antibody or drug 
specifically targeting T-cell costimulation or checkpoint pathways. For full exclusion criteria, see 
Section 4.2. 
Investigational Product, Dose, and Mode of Administration: 
• 
Ociperlimab will be administered at a dose of 900 mg intravenously once every 3 weeks on 
Day 1 of each cycle  
• 
Tislelizumab will be administered at a dose of 200 mg intravenously once every 3 weeks on 
Day 1 of each cycle 
Reference Therapy, Dose, and Mode of Administration: 
Allowed chemotherapy regimens: 
• 
Cisplatin plus etoposide 
− 
Cisplatin 75 mg/m2 should be administered as an intravenous infusion once every 3 
weeks on Day 1 of each cycle for 4 cycles; If the patient is unable to tolerate the 1-day 
administration of cisplatin 75 mg/m2, at the investigator’s discretion (eg, patients had 
concurrent superior vena cava syndrome) 
− 
cisplatin 25 mg/m2 dosed on Days 1, 2, and 3 is allowed.  
− 
Etoposide (100 mg/m2) should be administered as an intravenous infusion on Days 1, 
2, and 3 of each cycle for 4 cycles. 
• 
Carboplatin plus etoposide. To be used if cisplatin is contraindicated. Also, patients will be 
allowed to switch from cisplatin to carboplatin if they exhibit intolerance to cisplatin after 
completing ≥ 1 cycle of cisplatin treatment (Section 5.2.2.1) 
− 
Carboplatin at a dose of AUC 5 should be administered as an intravenous infusion 
once every 3 weeks on Day 1 of each cycle for 4 cycles. 
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− 
Etoposide (100 mg/m2) should be administered as an intravenous infusion on Days 1, 
2, and 3 of each cycle for 4 cycles. 
Thoracic radiation therapy (TRT): 
• 
Once-daily fractions for 6 to 7 weeks for a total dose of 60 to 70 Gy  
Statistical Methods: 
Analysis sets: 
The ITT Analysis Set includes all randomized patients. Patients will be analyzed according to their 
randomized treatment arm. This will be the primary analysis set for all efficacy analysis. 
The Safety Analysis Set includes all patients who have received ≥ 1 dose of any component of study 
drug; it will be the analysis set used for the safety analyses.  
The PK Analysis Set includes all patients who receive ≥ 1 dose of tislelizumab/ociperlimab per the 
protocol and for whom any quantifiable postbaseline PK data are available.  
The ADA Analysis Set, which includes all patients who receive ≥ 1 dose of tislelizumab/ociperlimab 
and for whom both baseline and ≥ 1 postbaseline ADA result are available. 
The Biomarker Analysis Set includes all patients who have ≥ 1 evaluable biomarker measurement; it 
will be used for the biomarker analysis.  
Efficacy analysis: 
The efficacy endpoints including PFS, CR rate, ORR, DOR, and OS will be summarized by arm in the 
ITT Analysis Set. The efficacy endpoints will be compared in Arm A versus Arm C and Arm B versus 
Arm C. These analyses are descriptive and exploratory; no formal testing was designed for this study. 
The primary endpoint is PFS assessed by investigators. PFS per investigator is defined as the time from 
the date of randomization to the date of the first documented disease progression as assessed by the 
investigator according to RECIST v1.1 or death from any cause, whichever occurs first. Kaplan-Meier 
methodology will be used to estimate median or other quartiles of PFS along with its 95% confidence 
interval (CI); constructed using Brookmeyer and Crowley method). Kaplan-Meier curves will be 
constructed to provide a visual description of the PFS distribution. Event-free rate at selected 
timepoints will be estimated with 95% CI estimated using Greenwood formula. The hazard ratio (HR) 
for PFS for each comparison (ie, Arm A versus Arm C, Arm B versus Arm C) will be estimated using a 
stratified Cox regression model. The 95% CI for the HR will be provided. Unstratified analysis will 
also be presented. 
CR rate is the proportion of patients who had a CR as assessed by the investigator per RECIST v1.1 in 
all randomized patients with measurable disease at baseline. Patients without any postbaseline 
assessment will be considered as nonresponders. CR rate and its Clopper-Pearson 95% CI will be 
calculated for each arm. The comparison of CR rate between arms will be evaluated using the Cochran-
Mantel-Haenszel (CMH) Χ2 test with the actual stratification factors as strata. Odds ratio and the 
difference in CR rate, as well as their 2-sided 95% CIs, will be calculated. 
ORR is the proportion of patients who had a CR or PR as assessed by the investigator per RECIST v1.1 
in all randomized patients with measurable disease at baseline. Patients without any postbaseline 
assessment will be considered as nonresponders. Similar methodology used to evaluate CR rate will be 
applied to the analysis of ORR. 
DOR is defined for patients with an objective response as the time from the date of the first 
documented objective response to the date of documented disease progression as assessed by the 
investigator using RECIST v1.1 or death from any cause, whichever occurs first. Only patients who 
have achieved objective responses will be included in the analysis of DOR. Similar methodology used 
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to evaluate PFS will be applied to the analysis of DOR. 
DMFS is defined as the time from the date of randomization to the date of the first documented distant 
metastasis as assessed by the investigator per RECIST v1.1 or death from any cause, whichever occurs 
first. Similar methodology used to evaluate PFS will be applied to the analysis of DMFS. 
OS is defined as the time from the date of randomization to the date of death from any cause. OS will 
be analyzed in the ITT Analysis Set. Data for patients who are not reported as having died at the time 
of analysis will be censored at the date the patient was last known to be alive. Data for patients who do 
not have postbaseline information will be censored at the date of randomization. Similar methodology 
used to evaluate PFS will be applied to the analysis of OS. 
HRQoL is defined as changes from baseline in PRO measures. Summary statistics (mean, standard 
deviation, median, and range) of the postbaseline scores and the changes from baseline will be reported 
for the EORTC QLQ-C30 and QLQ-LC13 questionnaires. Line charts depicting the mean changes (and 
standard errors) over time from the baseline assessment will be provided for each treatment arm.  The 
clinically meaningful changes postbaseline and a mixed model analysis will be performed using the 
global health status, physical function and fatigue domains of QLQ-C30, and dyspnoea, coughing, 
haemotysis and pain in chest, pain in arms and shoulders and peripheral neuropathy domains of 
QLQ-LC13. Completion and compliance rates will be summarized at each timepoint by treatment arm. 
Only patients in the ITT Analysis Set with a nonmissing baseline assessment and ≥ 1 in-study 
nonmissing postbaseline assessment will be included in the analyses. 
Safety analysis: 
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE v5.0. Safety 
will also be assessed by laboratory values (eg, hematology, clinical chemistry, coagulation, urinalysis), 
vital signs, ECGs, ECOG Performance Status, and physical examinations. Descriptive statistics will be 
used to analyze all safety data overall and by arm in the Safety Analysis Set. 
Pharmacokinetic Analysis: 
Ociperlimab and tislelizumab serum concentration data will be tabulated and summarized by the 
visit/cycle at which these concentrations are collected. Descriptive statistics will include means, 
medians, ranges, and standard deviations, as appropriate.  
Immunogenicity Analysis: 
The anti-ociperlimab and anti-tislelizumab antibody results will be summarized using descriptive 
statistics by the number and percentage of patients who develop detectable ADAs. The incidence of 
positive ADAs and neutralizing ADAs will be reported for evaluable patients.  
Biomarker Analysis 
Raw biomarker data will be normalized to adjust for batch effect, if applicable, for any biomarker 
analyses. Receiver operating characteristics curves will be generated and AUC will be calculated based 
on a logistic regression model to evaluate the association between continuous biomarkers and ORR. 
Youden Index-based optimal cutoffs or/and clinically meaningful cutoffs will be used to divide the 
biomarker-evaluable population into subgroups. Logistic regression and Cox regression will be used to 
evaluate the prognostic and predictive effects of the biomarkers on response and survival with 
treatment, biomarker status, and their interaction as the main factors. The potential utility of ctDNA 
level change as a surrogate predictor of efficacy and the mechanisms of resistance will also be 
assessed.  
Sample size: 
This study is not designed to make explicit power and type I error consideration but rather to obtain 
preliminary efficacy and safety data for ociperlimab plus tislelizumab and tislelizumab monotherapy 
for patients with untreated LS-SCLC. This study will enroll approximately 120 subjects into 3 arms, 
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with approximately 40 patients in each arm. The contribution of tislelizumab to the efficacy results will 
be demonstrated by descriptive analysis of PFS, ORR, and DOR in the comparison of Arm B versus 
Arm C. The contribution of adding ociperlimab will be demonstrated by similarly descriptive analysis 
in the comparison of Arm A versus Arm B. With a sample size of 40 patients in each arm, the binomial 
probabilities of detecting ≥ 1 TEAEs with a frequency of 5% and 1% are approximately 0.87 and 0.33, 
respectively. The final analysis for PFS is estimated to happen approximately 30 months after the 
enrollment of the first patient. 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma or serum concentration-time curve 
cCRT 
concurrent chemoradiotherapy 
CR 
complete response 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
DMFS 
distant metastasis-free survival 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Core 30 
EOT 
End-of-Treatment 
EP 
etoposide plus cisplatin 
ES-SCLC 
extensive-stage small cell lung cancer 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HRQoL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
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Abbreviation 
Definition 
LS-SCLC 
limited-stage small cell lung cancer 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PCI 
prophylactic cranial irradiation 
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) 
PR 
partial response 
PRO 
patient-reported outcomes 
PT 
preferred term 
PVR 
poliovirus receptor 
QLQ-LC13 
Quality of Life Questionnaire Lung Cancer 13 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RT 
radiation therapy 
SAE 
serious adverse event 
SCLC 
small cell lung cancer 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TIGIT 
T-cell immunoglobulin and ITIM domain 
TMB 
tumor mutational burden 
TNM 
Tumor size, Lymph nodes affected, Metastases 
ULN 
upper limit of normal 
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1. 
INTRODUCTION 
1.1. 
Background Information on Limited-Stage Small Cell Lung Cancer 
Lung cancer was the most commonly diagnosed cancer and the leading cause of cancer-related 
death (Bray et al 2018) in the world for many years. As of 2020, the newest data from Globocan 
showed that lung cancer is the second most common cancer worldwide with approximately 2.2 
million new diagnoses and 1.8 million deaths globally. In China, lung cancer is the leading cause 
of cancer-related death in both men and women, with an estimated 610,200 deaths and an 
estimated 733,300 new cases in the year 2015 (Chen et al 2016).  
Small cell lung cancer (SCLC) is an aggressive form of lung cancer that accounts for 
approximately 15% of all lung cancers (PDQ Adult Treatment Editorial Board [NSCLC] 2020). 
Histologically, it is a high-grade neuroendocrine tumor, which originates from neuroendocrine 
cells in the bronchial epithelium. The disease typically presents as bulky symptomatic masses, 
and mediastinal involvement is common. There is a strong association between smoking and 
SCLC; nearly all cases of SCLC are attributable to cigarette smoking. An important prognostic 
factor for SCLC is the extent of disease progression. At the time of diagnosis, approximately 
30% of patients with SCLC will have tumors confined to the hemithorax of origin, the 
mediastinum, or the supraclavicular lymph nodes, which can be safely encompassed within a 
radiation field; these patients are designated as having limited-stage SCLC (LS-SCLC). Patients 
with disease beyond the ipsilateral hemithorax, including malignant pleural or pericardial 
effusion or hematogenous metastases, are designated as having extensive-stage SCLC 
(ES-SCLC). The Veterans Administration (VA) Study Group’s 2-stage classification scheme has 
historically been used to define the extent of disease progression in patients with SCLC and is 
often used for clinical decision-making. The National Comprehensive Cancer Network (NCCN) 
SCLC Panel adopted a combined approach for staging SCLC using both the American Joint 
Committee on Cancer (AJCC) Tumor size, Lymph nodes affected, Metastases (TNM) staging 
system and the VA classification scheme for SCLC. When the TNM classifications are applied 
to the VA system, LS-SCLC is defined as stage I to III (T any, N any, M0), excluding T3-4 due 
to multiple lung nodules that are too extensive or that have tumor/nodal volume that is too large 
to be encompassed in a tolerable radiation plan. ES SCLC is defined as stage IV (T any, N any, 
M1a/b/c) or T3-4 due to multiple lung nodules that cannot be safely treated with definitive 
radiation therapy (RT). The TNM system is useful for selecting patients who are eligible for 
surgery and for radiation treatment planning. Clinical research studies normally recommend the 
TNM system because it allows for more precise assessments of prognosis and specific therapy. 
SCLC clinically differentiates itself from the more prevalent non-small cell lung cancer 
(NSCLC) by having rapid doubling time, high growth rate, and early appearance of widespread 
metastases. In addition, even if a majority of patients are sensitive to initial chemotherapy and 
RT, most of them have rapid occurrence of tumor relapse or metastasis within months of 
completing initial therapy. A long period of disease-free survival is rare and there have not been 
significant improvements in the management of resistance to subsequent second-line therapies. 
Despite some notable progress over the past few decades, the prognosis for patients with LS-
SCLC remains unsatisfactory, with median survival times of 16 to 30 months and 2-year survival 
rates of 44% to 56%. The median survival ranges from 8 to 13 months for patients with 
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ES-SCLC and the 2-year survival rate is approximately 5% (Murray et al 1993; Turrisi et al 
1999; Faivre-Finn et al 2017; Lally et al 2007). 
1.2. 
Current Treatment of Limited-Stage Small Cell Lung Cancer and 
Unmet Clinical Needs 
1.2.1. 
Concurrent Chemoradiotherapy With or Without Prophylactic Cranial Irradiation 
as First-Line Therapy for Limited-Stage Small Cell Lung Cancer 
Patients with LS-SCLC are a heterogeneous population who have early (TNM stages I-II) and 
locally advanced (TNM stage III) tumors. The treatment for all stages of LS-SCLC can be briefly 
categorized as resectable therapy and unresectable therapy.  
Briefly, the NCCN guidelines state that surgery with lobectomy and mediastinal nodal sampling 
is recommended only for patients with stage I to IIA (T1-2, N0) SCLC in whom mediastinal 
staging has confirmed that mediastinal lymph nodes are not involved. Note that fewer than 5% of 
patients with SCLC have true stage I to IIA disease. In most patients with SCLC, survival rates 
are much lower due to aggressive malignant characteristics and more advanced disease with 
lymph node involvement. There is a paucity of prospective evidence in very early stage SCLC; 
most of the data regarding the role of surgery in SCLC are from retrospective reviews. For 
patients with medically inoperable cT1-2 N0 disease, concurrent chemoradiotherapy (cCRT) has 
been the historical standard. Considering the encouraging results in early-stage NSCLC, 
stereotactic ablative radiotherapy (SABR) is increasingly being utilized for well-staged 
medically inoperable SCLC (Verma et al 2017). 
The current standard of care for most patients with advanced LS-SCLC is cCRT with etoposide 
plus cisplatin (EP) along with thoracic radiation therapy (TRT). Patients who have attained a 
complete or partial response to initial therapy can be considered for prophylactic cranial 
irradiation (PCI). 
EP is the most commonly used initial combination chemotherapy regimen for patients with 
LS-SCLC. In clinical practice, carboplatin is used as a substitute for cisplatin to reduce the risk 
of emesis, neuropathy, and nephropathy. However, the use of carboplatin carries a greater risk of 
myelosuppression. According to a meta-analysis of individual patient data from 4 randomized 
studies comparing cisplatin-based versus carboplatin-based regimens in patients with SCLC, 
which included 32% of 663 patients with limited-stage disease, no significant difference was 
observed in efficacy outcomes (Rossi et al 2012). 
TRT improves local control rates by 25% in patients with limited-stage disease and is associated 
with improved survival (Pignon et al 1992; Warde and Payne 1992). The current standard of care 
in patients with LS-SCLC is based on a randomized controlled trial that compared once-daily 
(45 Gy in 25 fractions over 5 weeks) to twice-daily (45 Gy in 30 fractions over 3 weeks) RT 
delivered concurrently with EP, showing the superiority of twice-daily RT in terms of survival 
(Turrisi et al 1999). However, there has been a lack of consensus regarding the routine use of 
twice-daily RT, despite its superiority, due to concerns regarding toxicity and logistical issues. 
More recently, the CONVERT trial (Faivre-Finn et al 2017) compared twice-daily RT (45 Gy in 
30 fractions over 3 weeks) to a higher dose of RT delivered once daily (66 Gy in 33 fractions 
over 6.5 weeks), both given concurrently with chemotherapy; overall survival (OS) outcomes did 
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not significantly differ between the 2 groups. This trial supports once-daily RT concurrently with 
chemotherapy as a standard of care for LS-SCLC. For once-daily RT, the recommended 
schedule is once daily up to a total dose of 60 to 70 Gy.  
Several systematic reviews and meta-analyses of the timing of RT in LS-SCLC have reported 
that early concurrent RT results in a small but significant improvement in OS when compared 
with late concurrent or sequential RT. Concurrent chemoradiotherapy where RT starts with an 
early cycle (1st or 2nd) of chemotherapy is more effective compared with delayed-start RT or 
sequential chemoradiotherapy. Early RT yielded better survival than delayed RT (eg, at Cycle 4 
of chemotherapy), about 10% improvement in survival rate at 2 years (Fried et al 2004). 
In SCLC with early and extensive metastatic spread, intracranial metastases occur in more than 
50% of patients. The role of PCI in SCLC has evolved over time; PCI confers an OS benefit in 
patients with LS-SCLC and is considered the standard of care. In a meta-analysis (Aupérin et al 
1999) comparing PCI versus no PCI in 987 patients in 7 clinical trials, the data demonstrated that 
PCI reduced the risk of brain metastasis by 54% and improved the 3-year survival rate by 5.4%. 
In general, little significant progress has been made in the treatment of SCLC for more than 
3 decades, with the exception of the approval of atezolizumab and durvalumab in combination 
with EP chemotherapy in the first-line setting for patients with ES-SCLC. LS-SCLC has the 
same characteristics of high metastatic potential and invariable recurrence after initial treatment 
as ES-SCLC. Despite several current clinical trials to investigate novel treatment paradigms for 
LS-SCLC, there are no approved novel agents, including immunotherapy, for LS-SCLC. There is 
thus a significant unmet clinical need for new agents with novel mechanisms of action and 
nonoverlapping toxicity that can be combined with established treatments. 
1.2.2. 
Anti-PD-1/PD-L1 Therapy for Limited-Stage Small Cell Lung Cancer 
Immunotherapy with checkpoint inhibitors and antibodies against programmed cell death 
protein-1 (PD-1) and its ligand, programmed cell death ligand-1 (PD-L1), is an active area of 
research. In cancer tissues, PD-1 is upregulated on tumor-infiltrating lymphocytes, while PD-L1 
is expressed on many types of cancer cells. Cancer cells express PD-L1 to escape immune 
surveillance via ligation to PD-1 expressed in an adaptive immune response (Pardoll 2012). 
SCLC has a strong association with smoking and consequently has a high load of somatic 
mutations induced by tobacco carcinogens. Importantly, the high tumor mutational burden 
(TMB) of SCLC might provide opportunities for therapeutic intervention, owing to its positive 
correlation with response to immune checkpoint therapy, which has been demonstrated in the 
CheckMate-032 trial (Antonia et al 2016). TMB is defined as the total number of 
nonsynonymous mutations within a tumor genome and can be considered as a surrogate for the 
load of neoantigens expressed by the tumor. Of note, in the IMpower-133 trial, a blood-based 
TMB measurement did not correlate with outcomes with the addition of atezolizumab; so, 
prospective confirmation is needed (Horn et al 2018). Little is known about the best way to 
assess TMB, and available data suggest that it may behave as a continuum biomarker and that a 
cutoff may be identified. 
PD-L1 expression shows a statistically significant association with response to checkpoint 
inhibitors in NSCLC, but the same has not been observed in SCLC. A meta-analysis 
(Acheampong et al 2020) including 2792 patients from 27 studies showed large inter-study 
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differences in the rates of PD-L1 expression in SCLC tumors, with rates varying from 0% to 
82.8%. The pooled estimate of PD-L1 expression was 22.0% (after removing outlying studies), 
which is consistent with the low prevalence of PD-L1 expression in this disease. Although the 
meta-analysis indicated that expression of PD-L1 appears to confer longer OS in SCLC patients, 
the correlation was not statistically significant, a result that is also consistent with previous 
reports (Zhang et al 2017). 
Strategies targeting the PD-1 pathway alone or in combination with other anticancer agents, 
including chemotherapy, RT, or anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) 
agents, have been tested in the front-line setting as maintenance therapy or as late-line palliative 
treatment. 
Until now, as for checkpoint inhibitor monotherapy, the United States Food and Drug 
Administration (US FDA) has approved pembrolizumab and nivolumab monotherapies as the 
third-line or later-line treatment in pretreated ES-SCLC. In the KEYNOTE-028 trial (Ott et al 
2017), pembrolizumab showed a response rate of 33.3%, with a median duration of response 
(DOR) of 19.4 months, a median progression-free survival (PFS) of 1.9 months, and median OS 
of 9.7 months for patients with PD-L1-expressing tumors (tumor proportion score ≥ 1% as 
measured using the 22C3 antibody). In the KEYNOTE-158 trial (Chung et al 2019), 
pembrolizumab showed an overall response rate (ORR) of 18.7%, median PFS of 2.0 months, 
and median OS of 9.1 months regardless of PD-L1 expression. Nivolumab demonstrated similar 
efficacy in the CheckMate 032 study for treating patients with metastatic SCLC whose cancer 
had progressed after platinum-based chemotherapy and ≥ 1 other line of therapy (Antonia et al 
2016). Other single agents tested as monotherapies include durvalumab for pretreated SCLC, 
where it showed an ORR of 9.5% and median OS of 4.8 months (Goldman et al 2018) and 
atezolizumab tested in a randomized study compared with cCRT, where atezolizumab did not 
increase ORR or PFS (Pujol et al 2019).  
Based on the observed anticancer activity and survival benefit of checkpoint inhibitor 
monotherapy in SCLC, anti-PD-1/PD-L1 antibodies are being investigated in combination with 
chemotherapy or cCRT in SCLC.  
In the past several decades, only atezolizumab and durvalumab, PD-L1 inhibitors, have been 
approved by the US FDA for use in the first-line setting for patients with ES-SCLC. The 
IMpower133 study demonstrated improvements in PFS and OS when atezolizumab was added to 
first-line chemotherapy and continued into the maintenance phase. The median PFS by 
investigator was 5.2 months with atezolizumab combined with cCRT compared with 4.3 months 
with cCRT alone; the median OS was 12.3 months versus 10.3 months, respectively. The rate of 
Grade 3 or 4 adverse events (AEs) was similar in both groups (56%) (Horn et al 2018). The 
CASPIAN study also showed durvalumab plus chemotherapy significantly improved median OS 
compared with the chemotherapy arm (13.0 versus 10.3 months; HR0.73, 95%CI: 0.59–0.91; 
p = 0.0047) (Paz-Ares et al 2019).  
Given the positive results of trials adding immunotherapy to standard of care treatment in 
stage III NSCLC (Antonia et al 2018) and ES-SCLC, an ongoing question is whether 
immunotherapy could improve survival in the limited-stage setting.  
There are currently several studies, either planned or active, that are investigating the role of 
checkpoint inhibitors in limited-stage disease; these studies include two therapeutic models: 
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checkpoint inhibitors to complement standard cCRT as sequential consolidation therapy, and 
incorporation of checkpoint inhibitors in the standard concurrent regimen. These ongoing clinical 
trials are included in the list of currently ongoing studies shown in Table 1. 
 
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Table 1: 
Ongoing PD-1 Pathway-Targeting Immunotherapy Studies in Limited-Stage Small Cell Lung Cancer 
IO + cCRT  
IO + cCRT 
IO after cCRT 
IO after cCRT 
IO after cCRT 
IO after cCRT 
Study name 
NRG-LU005 
(NCT03811002) 
NCT02402920 
ADRIATIC  
(NCT03703297) 
ML41257 
(NCT04308785) 
STIMULI 
(NCT02046733) 
ACHILES 
(NCT03540420) 
Sponsor 
NCI 
Merck 
AstraZeneca 
Roche 
Bristol-Myers Squibb 
Roche 
Phase 
Phase 2/3  
Phase 1 
Phase 3 
Phase 2 
Phase 2 
Phase 2 
Study design 
Randomized,  
open-label 
Open-label 
Randomized, double-blind 
Randomized,  
open-label 
Randomized,  
open-label 
Open-label 
Target 
enrollment 
506 
80 
600 
242 
264 
212 
Inclusion 
Must have 1 pre-
registration cycle 
of chemotherapy  
LS-SCLC, 
ES-SCLC 
After 4 cycles of cCRT 
After 4 cycles of 
cCRT 
After 4 cycles of 
cCRT 
After 4 cycles of 
cCRT 
Study 
treatment 
• cCRT + 
atezolizumab for 
3 cycles followed 
by atezolizumab 
(17 cycles; 1 
year) 
• cCRT for 3 
cycles followed 
by observation 
LS-SCLC: 
pembrolizumab + 
cCRT for 4 cycles 
followed by 
pembrolizumab 
for 12 cycles 
 
• Durvalumab + placebo for 4 
cycles followed by 
durvalumab for 2 years 
• Durvalumab + tremelimumab 
for 4 cycles followed by 
durvalumab for 2 years 
• Placebo for 4 cycles followed 
by placebo maintenance 
• 2 cycles 
chemotherapy + 
atezolizumab for 
12 months 
• 2 cycles 
chemotherapy + 
placebo 
• Nivolumab + 
ipilimumab for 4 
cycles followed 
by nivolumab for 
12 months 
 
• Atezolizumab 
for 12 months 
 
Primary 
endpoint 
Phase 2: PFS 
Phase 3: OS 
Safety 
PFS + OS  
PFS + OS 
PFS + OS 
2-year survival 
Status 
Recruiting (US 
only) 
Recruiting (US 
only) 
Recruiting (global, including 
China and US) 
Not yet recruiting 
(China only) 
Ongoing (AUS, EU) 
Recruiting (EU) 
Start to 
estimated 
primary 
completion 
28 May 2019 to 
Dec 2026 
22 Jul 2015 to 31 
July 2023 
27 Sep 2018 to Feb 2024 
NA to Sep 2022 
28 Jul 2014 to Dec 
2020 
31 Jul 2018 to 
Dec 2023 
Abbreviations: AUS, Australia; cCRT, concurrent chemoradiotherapy; ES-SCLC, extensive-stage small cell lung cancer; EU, European Union; 
IO, immuno-oncology; LS-SCLC, limited-stage small cell lung cancer; NA, not applicable; NCI, National Cancer Institute; OS, overall survival; 
PD-1, programmed cell death protein-1; PFS, progression-free survival, US, United States.
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The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab and 
ipilimumab consolidation after cCRT, the study closed early in 2019 due to slow accrual 
(Peters et al 2020). Another clinical trial testing the role of immunotherapy is the Phase 3, 
randomized, double-blind, international ADRIATIC study sponsored by AstraZeneca 
(ClinicalTrials.gov Identifier: NCT03703297). This is a 3-arm studying evaluating the efficacy 
of durvalumab or durvalumab with tremelimumab compared with placebo for consolidation in 
patients with LS-SCLC that has not progressed after cCRT. The primary endpoints of this 
Phase 3 study are PFS and OS.  
Overall, there are no approved novel agents/immunotherapy in LS-SCLC. Even if there is a high 
response in initial cCRT, most responses are transient, and most patients experience disease 
recurrence after a few months. Relapsed SCLC is often resistant to second-line therapies. Median 
survival ranges from 15 to 20 months for LS-SCLC. Because of the dismal prognosis and 
relative resistance to salvage therapies, there is an urgent need for therapeutic innovations with 
novel mechanisms of action and nonoverlapping toxicity, which can be combined with 
established treatments to manage this disease. 
1.3. 
Background Information on Ociperlimab (BGB-A1217) 
1.3.1. 
Nonclinical Summary 
1.3.1.1. 
Pharmacology 
Ociperlimab (BGB-A1217) is a humanized immunoglobulin G (IgG) 1 monoclonal antibody 
against T-cell immunoglobulin and ITIM domain (TIGIT) under clinical development for the 
treatment of human malignancies. 
Ociperlimab binds to the extracellular domain of human TIGIT with high specificity and affinity 
(equilibrium dissociation constant [KD] = 0.135 nM), as demonstrated by target-binding assays 
and surface plasmon resonance characterization. Ociperlimab has shown antitumor activity in 
both the GL261 mouse glioma tumor model and the CT26.WT mouse colon cancer model in 
humanized TIGIT knock-in mice. In the MC-38 mouse colon cancer model in humanized TIGIT 
knock-in mice, ociperlimab in combination with anti-mouse PD-1 significantly inhibited tumor 
growth compared with either therapy alone. 
Ociperlimab has the constant region of a wild-type human immunoglobulin G1 (IgG1) to enable 
Fc-mediated effector functions. Ociperlimab has demonstrated competent binding to C1q and all 
Fc gamma receptors (FcγRs) and induces antibody-dependent cellular cytotoxicity (ADCC) 
against a TIGIT-overexpressing cell line, but no ADCC or complement-dependent cytotoxicity 
against primary T cells in cell-based assays. 
Refer to the Ociperlimab (BGB-A1217) Investigator’s Brochure for detailed information 
regarding pharmacology studies. 
1.3.1.2. 
Toxicology 
Humanized TIGIT knock-in mice containing human TIGIT gene and cynomolgus monkeys were 
selected for nonclinical safety evaluation of ociperlimab based on the homology of the TIGIT 
amino acid sequence, binding affinity, and efficacy studies.  
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Ociperlimab demonstrated a comparable binding affinity in TIGIT receptor occupancy assays 
with CD3+ splenocytes from humanized TIGIT knock-in mice compared with CD3+ human 
peripheral blood mononuclear cells (with EC50 of 48.8 ng/mL versus 63.2 ng/mL, respectively). 
In addition, ociperlimab showed a significant inhibition of GL261 tumor growth in humanized 
TIGIT knock-in mice at a dose of ≥ 0.4 mg/kg via weekly intraperitoneal dosing. 
The toxicity and safety profile of ociperlimab was characterized in a 4-week repeated-dose 
toxicology study in humanized TIGIT knock-in mice and a 13-week repeated-dose toxicology 
study in cynomolgus monkeys. Ociperlimab was also evaluated in a 4-week repeated-dose study 
in humanized TIGIT knock-in mice with subcutaneous MC-38 tumors. The cynomolgus monkey 
was considered the relevant species for toxicity studies based upon the target sequence homology 
and cross-species TIGIT-binding activities of ociperlimab. 
No apparent toxicity was noted in monkeys following repeated dosing at 10, 30, or 100 mg/kg 
once every 2 weeks for 13 weeks. The toxicokinetic profile in the monkey study showed that 
systemic exposure appeared to be dose proportional with no sex difference. No accumulation 
was observed over the 13-week dosing period in monkeys. No immunotoxicity was apparent as 
no changes in clinical pathology or histopathology were observed. Positive antidrug antibodies 
(ADAs) against ociperlimab were observed in 6/10, 3/10, and 4/10 animals during the dosing 
period, and 3/4, 2/4, and 2/4 animals during the recovery period, at dose levels of 10, 30, and 
100 mg/kg, respectively. The anti-ociperlimab antibodies showed a rapid clearance of 
ociperlimab in serum in a few individual animals but did not appear to have an effect on the 
overall systemic exposure (area under the plasma or serum concentration-time curve [AUC]) or 
toxicity assessment. 
No specific binding of ociperlimab was noted with normal human tissues. A variety of factors 
might contribute to the negative results, including negligible target expression in normal tissues 
(Yang 2016; Human Protein Atlas) and sensitivity of the immunohistochemistry method. 
No significant increase in cytokine release was observed from an in vitro cytokine release assay 
following treatment of nonactivated peripheral blood mononuclear cells with ociperlimab when 
compared with human IgG. The results suggest that ociperlimab has potentially low probability 
of causing acute cytokine release syndrome. 
Overall, no apparent toxicity was noted in the monkey toxicity study. No unexpected tissue 
cross-reactivity was found in human or monkey tissues. The toxicokinetic profile showed dose-
proportional increases in systemic exposure without apparent accumulation or sex difference. 
Immunogenicity was observed without apparent immunotoxicity or effect on the systemic 
exposure. The no-observed-adverse-effect level (NOAEL) of ociperlimab was 100 mg/kg in the 
13-week monkey toxicity study. The safety profile of ociperlimab is considered adequate to 
support first-in-human dosing. 
Refer to the Ociperlimab (BGB-A1217) Investigator’s Brochure for detailed information 
regarding toxicology studies. 
1.3.2. 
Prior Clinical Experience With Ociperlimab  
As of 16 June 2020, a Phase 1 study (BGB-900-105) was investigating the safety/tolerability, 
pharmacokinetics (PK), and preliminary antitumor activity of ociperlimab in combination with 
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tislelizumab with or without chemotherapy in patients with unresectable locally advanced or 
metastatic solid tumors. 
Patients enrolled in Study BGB-900-105 were treated with escalating doses of ociperlimab 
(50, 150, 450, or 900 mg) in combination with tislelizumab 200 mg once every 3 weeks; all 
patients cleared the dose-limiting toxicity (DLT) period without DLTs. The maximum tolerated 
dose was not reached and the recommended Phase 2 dose (RP2D) was determined to be 900 mg 
ociperlimab in combination with 200 mg tislelizumab once every 3 weeks. The most commonly 
reported treatment-emergent adverse events (TEAEs; Table 2) were fatigue (3 out of 11 patients) 
and diarrhoea and aspartate aminotransferase (AST) increased (2 patients each out of 11 
patients). Most TEAEs were Grade 1 or Grade 2, with the exception of three Grade 3 TEAEs of 
atrial flutter, pericardial effusion malignant and dyspnea, which were serious and deemed not 
related to study drugs (1 patient each).  
Treatment-related TEAEs (ociperlimab, tislelizumab, or both) occurred in 3 patients and 
included influenza, AST increased, and dry skin in 1 patient; abdominal pain, dry eye, and 
diarrhea in 1 patient; and fatigue in 1 patient. All treatment-related TEAEs were Grade 1. No 
infusion reactions were reported. 
The study is currently enrolling patients at the RP2D. Ociperlimab continues to appear to be safe 
and well-tolerated. Preliminary results also show that 100% receptor occupancy was achieved at 
50 mg. 
Refer to the Ociperlimab (BGB-A1217) Investigator’s Brochure for detailed information 
regarding clinical experience with ociperlimab. 
Table 2: 
Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term and Maximum Severity (Safety Analysis Set) 
System Organ Class 
Preferred Term 
Tislelizumab 200 mg 
Total 
(N = 11) 
n (%) 
Ociperlimab 
50 mg 
(N = 1) 
n (%) 
Ociperlimab 
150 mg 
(N = 3) 
n (%) 
Ociperlimab 
450 mg 
(N = 4) 
n (%) 
Ociperlimab 
900 mg 
(N = 3) 
n (%) 
Patients with ≥ 1 TEAE 
1 (100.0) 
3 (100.0) 
3 (75.0) 
1 (33.3) 
8 (72.7) 
Gastrointestinal disorders 
1 (100.0) 
1 (33.3) 
2 (50.0) 
0 (0.0) 
4 (36.4) 
Diarrhoea 
0 (0.0) 
1 (33.3) 
1 (25.0) 
0 (0.0) 
2 (18.2) 
Abdominal pain 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Constipation 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Dry mouth 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
General disorders and 
administration site conditions 
1 (100.0) 
0 (0.0) 
1 (25.0) 
1 (33.3) 
3 (27.3) 
Fatigue 
1 (100.0) 
0 (0.0) 
1 (25.0) 
1 (33.3) 
3 (27.3) 
Musculoskeletal and connective 
tissue disorders 
0 (0.0) 
1 (33.3) 
1 (25.0) 
1 (33.3) 
3 (27.3) 
Back pain 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Flank pain 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (33.3) 
1 (9.1) 
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System Organ Class 
Preferred Term 
Tislelizumab 200 mg 
Total 
(N = 11) 
n (%) 
Ociperlimab 
50 mg 
(N = 1) 
n (%) 
Ociperlimab 
150 mg 
(N = 3) 
n (%) 
Ociperlimab 
450 mg 
(N = 4) 
n (%) 
Ociperlimab 
900 mg 
(N = 3) 
n (%) 
Groin pain 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Infections and infestations 
1 (100.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
2 (18.2) 
Influenza 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Otitis externa 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Investigations 
1 (100.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
2 (18.2) 
Aspartate aminotransferase 
increased 
1 (100.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
2 (18.2) 
Nervous system disorders 
1 (100.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
2 (18.2) 
Neuralgia 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Somnolence 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Respiratory, thoracic, and 
mediastinal disorders 
0 (0.0) 
1 (33.3) 
1 (25.0) 
0 (0.0) 
2 (18.2) 
Cough 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Dyspnoea 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Skin and subcutaneous tissue 
disorders 
1 (100.0) 
0 (0.0) 
0 (0.0) 
1 (33.3) 
2 (18.2) 
Drug eruption 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (33.3) 
1 (9.1) 
Dry skin 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Blood and lymphatic system 
disorders 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Anaemia 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Cardiac disorders 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Atrial flutter 
1 (100.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Ear and labyrinth disorders 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Ear discomfort 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Eye disorders 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Dry eye 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Neoplasms benign, malignant 
and unspecified (incl cysts and 
polyps) 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Cancer pain 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Pericardial effusion 
malignant 
0 (0.0) 
0 (0.0) 
1 (25.0) 
0 (0.0) 
1 (9.1) 
Psychiatric disorders 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
Confusional state 
0 (0.0) 
1 (33.3) 
0 (0.0) 
0 (0.0) 
1 (9.1) 
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Abbreviations: AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities; N, total patients treated; 
NCI-CTCAE v5.0, National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0; TEAE, 
treatment-emergent adverse event. 
Notes: A patient with multiple occurrences of an AE is counted only once in the AE category. MedDRA Version 22.0 was used 
to code AEs. AEs were graded using NCI-CTCAE v5.0. Events are sorted in descending order of the number of patients for 
System Organ Class and Preferred Term in the Total column. 
1.3.3. 
Ociperlimab Clinical Pharmacology and Pharmacodynamics 
As of the data cutoff date of 16 June 2020, preliminary PK data of ociperlimab are available 
from a total of 11 patients treated with ociperlimab at the 50 mg (n = 1), 150 mg (n = 3), 450 mg 
(n = 4), and 900 mg (n = 3) dose levels in combination with tislelizumab 200 mg in the 
dose-escalation portion of Study BGB-900-105. Ociperlimab serum concentrations declined in a 
biexponential manner after intravenous infusion and ociperlimab exposures (maximum observed 
concentration and AUC) increased approximately dose-proportionally from 50 mg to 900 mg 
(Figure 1).  
Peripheral TIGIT receptor occupancy data were available for 11 enrolled patients treated with 
ociperlimab at the 50 mg (n = 1), 150 mg (n = 3), 450 mg (n = 4), and 900 mg (n = 3) dose levels 
in Study BGB-900-105. Complete TIGIT receptor occupancy (100%) was observed on CD8, 
CD4, natural killer (NK), and T regulatory cells in peripheral blood at all the tested dose levels. 
Figure 1: 
Cycle 1 Mean (± SD) Serum Concentration-Time Profiles of Ociperlimab in 
Study BGB-900-105 
 
Abbreviations: conc, concentration; n, number of patients; SD, standard deviation. 
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1.4. 
Background Information on Tislelizumab 
1.4.1. 
Pharmacology 
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against PD-1 under clinical development for the treatment of several 
human malignancies. 
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity 
and affinity (KD = 0.15 nM). It competitively blocks the binding of both PD-L1 and programmed 
cell death protein ligand-2 (PD-L2), thus inhibiting PD-1-mediated negative signaling in T cells. 
In in vitro cell-based assays, tislelizumab was observed to dose-dependently enhance the 
functional activity of human T cells and pre-activated primary peripheral blood mononuclear 
cells. Tislelizumab has also demonstrated in vivo antitumor activity in several allogeneic 
xenograft models, in which peripheral blood mononuclear cells were coinjected with human 
cancer cells (A431 [epidermoid carcinoma]) or tumor fragments (BCCO-028 [colon cancer]) into 
immunocompromised mice.  
In vitro assays with tislelizumab suggest either low or no ADCC, antibody-dependent cellular 
phagocytosis, or complement-dependent cytotoxicity effects in humans (Labrijn et al 2009; 
Zhang et al 2018). Tislelizumab was specifically engineered to abrogate these potential 
mechanisms of T-cell clearance and potential resistance to anti-PD-1 therapy. 
Please refer to the Tislelizumab Investigator’s Brochure for additional details regarding 
nonclinical studies of tislelizumab. 
1.4.2. 
Toxicology 
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology 
studies in mice and cynomolgus monkeys and in a 13-week, repeated-dose toxicology study in 
cynomolgus monkeys. Cynomolgus monkey was the only relevant species based on the target 
sequence homology and binding activity. 
Overall, no apparent toxicity was noted in the mice or monkey toxicity studies. No tissue 
cross-reactivity was found in either human or monkey tissues, nor was any effect on cytokine 
release observed in the human whole-blood assay. The toxicokinetic profile showed dose-
proportional increases in systemic exposure without apparent accumulation or sex difference. 
Immunogenicity was observed without apparent immunotoxicity or effect on the systemic 
exposure. The NOAEL of tislelizumab in the 13-week monkey toxicity study was considered to 
be 30 mg/kg. The safety profile of tislelizumab is considered adequate to support the current 
study, AdvanTIG-204. 
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on the 
toxicology of tislelizumab. 
1.4.3. 
Clinical Pharmacology 
Population PK analysis was conducted using data from 798 patients with solid tumors or 
classical Hodgkin lymphoma who received doses of 0.5, 2.0, 5.0, and 10 mg/kg once every 
2 weeks, 2.0 and 5.0 mg/kg once every 3 weeks, and 200 mg once every 3 weeks. The PK of 
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tislelizumab was best characterized using a 3-compartmental linear population PK model with 
linear clearance mechanisms. No time-varying clearance was observed in tislelizumab PK. The 
typical estimates of clearance (CL), central volume (Vc), and peripheral volumes (V2, V3) were 
0.164 L/day, 2.92 L, 0.928 L, and 1.39 L, respectively, with moderate inter-individual variability 
in CL (32.2%), Vc (16.7%), V2 (56.6%), and V3 (94.2%). The volume of distribution at steady 
state (Vss) was 5.238 L, which is typical of monoclonal antibodies with limited distribution and 
consistent with a standard IgG monoclonal antibody (Deng et al 2012; Dirks and Meibohm 2010; 
Keizer et al 2010; Ryman and Meibohm 2017). Based on population PK analysis, tislelizumab 
PK was characterized by a terminal half-life of approximately 25.5 days. 
Although tumor size, albumin, and tumor type were significant covariates on CL and body 
weight, sex, and tumor type were significant covariates on Vc, these covariates are not expected 
to have a clinically relevant impact on tislelizumab exposure. Exposure-response analysis 
indicated a lack of clinically significant exposure-response relationships for ORR and safety 
endpoints across a variety of advanced solid tumors and classical Hodgkin lymphoma for 
tislelizumab. Population PK analysis supports fixed dosing across different ethnic groups. 
1.4.4. 
Prior Clinical Experience With Tislelizumab 
As of 20 May 2020, 1181 patients with solid tumors had been treated with tislelizumab 
monotherapy in 5 clinical studies. 
A pooled monotherapy analysis was conducted to provide a comprehensive review of the 
tislelizumab safety profile. Patients included in this analysis (N = 1181) had a median age of 
60.0 years, with 67.1% of them being male. Median treatment exposure duration was 3.7 (range: 
0.1 to 55.3) months and median study follow-up duration was 9.9 (range: 0.1 to 58.9) months. 
Refer to the Tislelizumab Investigator's Brochure for more detailed information on tislelizumab 
safety data when given as monotherapy or in combination with chemotherapy. 
1.4.4.1. 
Treatment-Emergent Adverse Events Assessed as Related to Tislelizumab 
Of the 1181 patients with solid tumors treated with tislelizumab monotherapy, 788 (66.7%) 
experienced ≥ 1 treatment-related TEAE. The most commonly occurring TEAEs (≥ 5% of 
patients) assessed as related to tislelizumab irrespective of grade were AST increased 
(136 patients, 11.5%), alanine aminotransferase (ALT) increased (125 patients, 10.6%), 
hypothyroidism (106 patients, 9.0%), rash (97 patients, 8.2%), and pruritus and fatigue 
(95 patients each, 8.0%). 
A total of 167 patients (14.1%) experienced at least 1 ≥ Grade 3 TEAE assessed as related to 
tislelizumab. The most frequent ≥ Grade 3 TEAEs that occurred in ≥ 1% of the patients were 
AST increased (21 patients, 1.8%), ALT increased (17 patients, 1.4%), and anaemia (13 patients, 
1.1%). 
1.4.4.2. 
Treatment-Emergent Serious Adverse Events 
Of the 1181 patients with solid tumors treated with tislelizumab monotherapy, 415 (35.1%) 
experienced ≥ 1 treatment-emergent serious adverse event (SAE). The most commonly occurring 
treatment-emergent SAEs (irrespective of relationship to study drug) were pneumonia 
(41 patients, 3.5%), and pyrexia and ascites (15 patients each, 1.3%). 
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A total of 107 patients (9.1%) experienced ≥ 1 tislelizumab-related treatment-emergent SAE. 
The most common treatment-emergent SAEs deemed related to tislelizumab were pneumonitis 
(11 patients, 0.9%); AST increased (6 patients, 0.5%); and colitis, ALT increased, and pyrexia 
(5 patients each, 0.4%). All other tislelizumab-related treatment-emergent SAEs occurred in 
< 5 patients. 
1.4.4.3. 
Immune-Mediated Adverse Events  
Anti-PD-1 therapies are known to cause immune-mediated adverse events (imAEs) in some 
patients and therefore have been defined as adverse events (AEs) of special interest (AESI) in 
tislelizumab clinical studies and as such are being monitored closely. 
Immune-mediated AEs are consistent with an immune-related mechanism or immune-related 
component for which noninflammatory etiologies (eg, infection or tumor progression) have been 
ruled out. Immune-mediated AEs can include events with an alternate etiology that were 
exacerbated by the induction of autoimmunity. There is a potential temporal relationship 
between the initiation of tislelizumab treatment and the onset of an imAE that spans a window of 
days to several months. 
All imAEs presented here are assessed as related to the study drug by the investigator and 
categorized and adjudicated by the sponsor clinical team. Certain imAEs have multiple Medical 
Dictionary for Regulatory Activities (MedDRA) terms associated with the same category. 
Special categories have been created to group patients experiencing these events. 
Of the 1113 patients with solid tumors included in the pooled analysis of imAEs, 233 (20.9%) 
experienced ≥ 1 imAE of any grade. The most commonly occurring imAEs of any grade were 
hypothyroidism (69 patients, 6.2%), hyperthyroidism (37 patients, 3.3%), and rash (34 patients, 
3.1%). A total of 52 patients (4.7%) experienced at least 1 ≥ Grade 3 imAE. The most commonly 
occurring ≥ Grade 3 imAEs were ALT increased (9 patients, 0.8%) and AST increased and 
pneumonitis (7 patients each, 0.6%). 
1.4.4.4. 
Infusion-Related Reactions 
Infusion-related reactions, including high-grade hypersensitivity reactions, following 
administration of tislelizumab are uncommon. Of the 1181 patients treated with tislelizumab 
monotherapy, 45 (3.8%) experienced ≥ 1 infusion-related reaction of any grade. The most 
commonly occurring infusion-related reactions of any grade were infusion-related reactions 
(28 patients, 2.4%), pyrexia (10 patients, 0.8%), and nausea (4 patients, 0.3%). Two patients 
(0.2%) had ≥ Grade 3 infusion-related reactions and all other events occurred in single instances; 
these included rash, flushing, hypotension, and spinal pain. 
1.4.4.5. 
Liver Laboratory Abnormalities 
Of the 932 patients with solid tumors included in the analysis of drug-induced liver injury, 
34 patients (3.6%) experienced increases in ALT or AST levels > 5 x upper limit of normal 
(ULN) but ≤ 10 x ULN, 11 patients (1.2%) had ALT or AST elevations >10 x ULN but 
≤ 20 x ULN, and 1 patient (0.1%) had ALT or AST elevations > 20 x ULN. Bilirubin 
elevation > 2 x ULN was observed in 43 patients (4.6%). 
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Concomitant ALT/AST and bilirubin elevation in the absence of alkaline phosphatase increases 
were observed in 2 patients (0.2%). These patients had diagnoses of advanced metastatic gastric 
or liver cancer and both presented with extensive hepatic involvement and confirmed hepatic 
disease progression at the time of the observed abnormalities in liver laboratory values; these 
cases therefore did not meet the criteria for Hy’s law. 
1.4.4.6. 
Fatal Adverse Events 
Out of 1181 patients treated with tislelizumab monotherapy who were included in the analysis, 
18 patients (1.5%) experienced a fatal AE ≤ 30 days after the last study drug dose. A total of 
9 patients (0.8%) experienced fatal AEs that were deemed related to tislelizumab, including 
hepatic failure (2 patients, 0.2%); and large intestinal obstruction, pneumonitis, respiratory arrest, 
respiratory failure, hepatitis acute, brain oedema, and death (1 patient each, 0.1%). 
1.4.5. 
Efficacy Assessment of Tislelizumab 
Efficacy data are available from 2 of the ongoing Phase 1 monotherapy studies in solid tumors, 
BGB-A317_Study_001 and BGB-A317-102, which are summarized below (data cut-off 
20 May 2019) and from a Phase 3 combination study, BGB-A317-304, in NSCLC (data cut-off 
06 December 2019; Wang et al 2020).  
Study BGB-A317_Study_001 is a Phase 1a/1b study consisting of a dose-escalation phase (1a) 
and a dose-expansion phase (1b) designed to establish the maximum tolerated dose and schedule, 
determine the RP2D, and investigate the preliminary efficacy of tislelizumab in previously 
treated patients with select tumor types. 
The RP2D and schedule for tislelizumab was determined to be 200 mg administered once every 
3 weeks. Across all disease cohorts (N = 441), 5 patients (1.1%) experienced a CR and 
55 patients (12.5%) had a confirmed PR, yielding an ORR of 13.6%. Stable disease was 
observed in 142 patients (32.2%). The disease control rate was 45.8% (95% CI: 41.1, 50.6) and 
clinical benefit rate (CBR) was 26.5% (95% CI: 22.5, 30.9). 
Study BGB-A317-102 is a nonrandomized, Phase 1/2 study of tislelizumab monotherapy 
evaluating the activity and safety of tislelizumab at the RP2D and schedule of 200 mg given once 
every 3 weeks in previously treated Chinese patients with select advanced solid tumors. It 
showed the recommended dose of tislelizumab 200 mg every 3 weeks was generally well 
tolerated and demonstrated a manageable safety profile in Chinese patients with advanced solid 
tumors. Preliminary antitumor activities were observed in the overall patient population and 
across multiple indications. Across all tumor types, the ORR was 17.0% (51 patients; 95% 
CI:12.9%, 21.7%). There was 1 patient with a confirmed CR, who was diagnosed with squamous 
cell carcinoma of the larynx. The CBR (CR + PR + durable stable disease ≥ 24 weeks) was 32% 
and the DCR was 44.7%. 
Study BGB-A317-206 (data on file) was investigating tislelizumab in combination with 
chemotherapy as first-line treatment in patients with lung cancer. One of the cohorts enrolled 
17 ES-SCLC patients who were treated with tislelizumab combined with etoposide plus cisplatin 
or carboplatin for 4-6 cycles followed by tislelizumab maintenance treatment. As of 25 Feb 
2019, the confirmed ORR was 76.5% (95% CI: 50.1, 93.2) and the disease control rate was 
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88.2% (95% CI: 63.6, 98.5). The median DOR was 6.5 months and the median PFS was 6.9 
months (95% CI: 4.90,10.09).  
1.5. 
Study Rationales  
1.5.1. 
Rationale for Combination of Ociperlimab and Tislelizumab in the Treatment of 
Limited-Stage Small Cell Lung Cancer 
SCLC is typically characterized by high TMB, unstable TP53 and RB1 genes, and high mutation 
rate of the DNA damage response pathway. However, SCLC has lower PD-L1 expression than 
other lung cancers. Certain advances have been made in the use of immune checkpoint inhibitors 
for the treatment of SCLC. Combination of first-line immune checkpoint inhibitors with 
chemotherapy for ES-SCLC has shown improved clinical benefit. Besides atezolizumab, which 
has been approved in combination with standard chemotherapy, durvalumab combined with EP 
has also shown significant survival improvement and long-term clinical benefit in the CASPIAN 
trial (Paz-Ares et al 2019). Pembrolizumab also demonstrated significantly improved PFS in the 
KEYNOTE 604 study (Rudin et al 2020). However, the role of PD-1/PD-L1 antibodies in 
LS-SCLC has not been determined. Further investigations on novel strategies of immune 
checkpoint inhibitors combined with other agents may be helpful in overcoming the treatment 
challenges in SCLC. Other agents that may be investigated for the treatment of SCLC include 
those that target immune checkpoints other than PD-1/PD-L1 or those that modulate the immune 
metabolism of the tumor microenvironment. 
TIGIT is a receptor found on the surface of NK cells, T regulatory cells, and activated T cells, 
and it has a high-affinity ligand CD155, also known as poliovirus receptor (PVR) (Hu et al 
2020). Upregulation of TIGIT expression in tumor infiltrating lymphocytes has been reported in 
NSCLC (Tassi et al 2017). Blockade of the TIGIT receptor has been shown both in vitro and in 
vivo to rescue functionally “exhausted” T cells (Johnston et al 2014).  
A recent study using SCLC samples showed that PVR, an immune checkpoint protein expressed 
on tumor cells, is highly expressed in SCLC cell lines and tumor tissues (Yu et al 2018). 
According to the same group, PVR mediates the inhibition of T cells by competitively binding to 
TIGIT, which indicates that the PVR-TIGIT pathway may be a promising target for 
immunotherapy in SCLC and also highlights the potential for the combination of checkpoint 
blocking agents (eg, PD-L1) for improved SCLC immunotherapy.  
Although targeting TIGIT could eliminate immune suppression by reactivating T effector cells 
and NK cells, TIGIT blockade alone (ie, ociperlimab monotherapy) is unlikely to result in an 
effective antitumor response according to existing anti-TIGIT clinical data.  
Ociperlimab and tislelizumab have nonoverlapping anticancer mechanisms and are likely to have 
synergistic and/or added activity. Therefore, the combination use of ociperlimab and tislelizumab 
concurrent with standard cCRT is designed to evaluate the effect of ociperlimab in combination 
with tislelizumab in maximizing the potential therapeutic benefit while simultaneously achieving 
clinical benefit for patients.  
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1.5.2. 
Rationale for the Selection of Ociperlimab Dose 
Ociperlimab doses ranging from 50 mg to 900 mg administered once every 3 weeks, in 
combination with 200 mg of tislelizumab once every 3 weeks, were explored in the ongoing 
Phase 1/1b Study BGB-900-105. All the tested ociperlimab dose levels cleared the DLT window 
without any significant safety or tolerability events. Ociperlimab exposures increased in an 
approximately dose-proportional manner (Ociperlimab (BGB-A1217) Investigator’s Brochure). 
As of 07 August 2020, the maximum administered ociperlimab dose of 900 mg was selected as 
the RP2D. 
Complete TIGIT receptor occupancy was observed in circulating T cells and NK cells in 
peripheral blood at all the tested doses in the BGB-900-105 study. However, since the correlation 
between TIGIT receptor occupancy in peripheral blood and receptor occupancy in tumor tissues 
is unknown, quantitative systems pharmacology modeling was performed to predict the 
occupancy in tumor tissues. Preliminary results show that near complete TIGIT receptor 
occupancy in tumor tissues is predicted at doses ≥ 450 mg. Due to the lack of information on the 
impact of immunogenicity on the ociperlimab PK and based on the emerging safety and 
tolerability data, a dose of 900 mg was selected. This dose level is expected to increase the 
likelihood of efficacious concentrations and saturation of TIGIT receptors in tumor tissues 
completely over the entire dosing interval. The absence of any dose-dependent safety events in 
the ongoing study additionally supports the selection of this dose for further evaluation. The 
preliminary ociperlimab PK data from the ongoing BGB-900-105 study indicate a lack of a 
significant relationship between ociperlimab exposure and the patient’s body weight and support 
the selection of a fixed dose for ociperlimab. 
1.5.3. 
Rationale for Selection of Tislelizumab Dose 
The clinical fixed dose of 200 mg intravenously once every 3 weeks was selected based on 
comparable safety and efficacy profiles between 2 and 5 mg/kg in BGB-A317_Study_001. 
Rates of treatment-related AEs and SAEs observed in patients receiving 2 mg/kg and 5 mg/kg 
once every 2 weeks and once every 3 weeks were comparable, suggesting no clear 
dose-dependence across these regimens. Additionally, PK data also showed no relationship 
between exposure and treatment-emergent imAEs (Wu et al 2019a; Wu et al 2019b). 
Confirmed response rates in patients treated with tislelizumab once every 3 weeks were 
favorable compared with those in patients treated once every 2 weeks. While there are 
differences in response rates between dose levels, this is more likely a reflection of the small 
sample size and patient heterogeneity than of dose response. 
Clearance of tislelizumab was not dependent on body weight, and the observed serum exposure 
of a 200 mg dose fell between the serum exposures observed after 2 mg/kg and 5 mg/kg doses. 
Therefore, clinical activity with a manageable and tolerable safety profile is expected to be 
maintained in patients receiving tislelizumab 200 mg once every 3 weeks. 
Exposure-response analysis indicated a lack of clinically significant exposure-response 
relationships for ORR and safety endpoints across a variety of advanced solid tumors and 
classical Hodgkin lymphoma for tislelizumab. These findings support the use of the 200 mg once 
every 3 weeks dose regimen for pivotal studies. 
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In conclusion, the observed clinical activity in patients with advanced tumors, coupled with a 
manageable safety profile and supportive data, support the use of the proposed tislelizumab dose 
of 200 mg intravenously once every 3 weeks as the recommended dose for pivotal studies; please 
refer to the Tislelizumab Investigator’s Brochure for further details. 
1.5.4. 
Rationale for Chemoradiotherapy as the Component of the Combination 
Treatment 
Platinum-based chemotherapy is the standard of care for first-line therapy in LS-SCLC. The 
platinum agents most commonly used are cisplatin and carboplatin, which are often combined 
with the non-platinum agent etoposide. The addition of RT to standard combination 
chemotherapy improves both local control and OS. Early cCRT is recommended for patients 
with LS-SCLC based on the longer survival time reported in patients treated concurrently 
compared with the survival times for those treated sequentially. For the comparator arm and the 
2 study arms in this study, cCRT represents the current standard of care. Patients will receive 
4 cycles of EP (or carboplatin plus etoposide if cisplatin is contraindicated or not tolerated) 
concurrent with RT as backbone treatment. 
1.5.5. 
Rationale for Combination of Concurrent Chemoradiotherapy and 
Immunotherapy 
The rationale for immunotherapy in combination with cCRT has been shown in a multitude of 
preclinical studies, including xenograft models of some solid tumors (Deng et al 2014). Both 
chemotherapy and RT can upregulate major histocompatibility complex class I antigens, increase 
tumor antigen release, drive a polyclonal T-cell response, enhance CD8þ T-cell infiltration, limit 
T-cell exhaustion, modulate the immune environment, provoke an interferon gamma response, 
and upregulate the expression of PD-L1 (Gandhi et al 2018; Kordbacheh et al 2018), which 
could make such tumors sensitive to a PD-1/PD-L1-directed therapy. In this setting, 
chemotherapy and RT act as priming agents for immunotherapy; elimination of cancer cells by 
chemotherapy and/or RT triggers release of antigens, which can turn poorly immunogenic or 
immunosuppressive tumors into an immunogenic environment (Vanneman and Dranoff 2012). 
The PACIFIC trial was the first randomized Phase 3 study to clinically validate these findings. 
This is a global Phase 3 trial of the anti-PD-L1 agent, durvalumab, being compared with placebo 
as consolidation therapy following ≥ 2 cycles of platinum-based chemotherapy administered 
concurrently with RT without progression in patients with unresectable stage III NSCLC. The 
trial demonstrated that median PFS was significantly longer with durvalumab than with placebo 
(median PFS 16.8 months versus 5.6 months, stratified HR for disease progression or death 
0.52), with a similar safety profile in the 2 groups (Antonia et al 2017). 
In SCLC, both the IMpower133 (Horn et al 2018) and the CASPIAN (Paz-Ares et al 2019) trials 
reported that the addition of an immune checkpoint inhibitor to chemotherapy modestly 
improved survival. The BGB-A317-206 study that is investigating tislelizumab in combination 
with chemotherapy has also demonstrated confirmed anticancer activity and was well tolerable 
as first-line treatment for patients with ES-SCLC (see Section 1.4.5). Although immune 
checkpoint inhibition in combination with chemotherapy demonstrated clinical benefits, survival 
curves separated late in randomized trials, and patients who would benefit could not be 
identified. Given that radiation to a primary tumor leads to tumor-antigen release and a tumor-
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specific adaptive immune response, which is enhanced by immune-stimulating agents, it is 
possible that the addition of RT to a chemotherapy and immune checkpoint inhibitor regimen 
could make SCLC more immunogenic. As for LS-SCLC, the result from a Phase 1/2 trial of 
pembrolizumab combined with cCRT for patients with LS-SCLC showed that cCRT and 
pembrolizumab was well tolerated and yielded favorable outcomes, providing a basis for 
randomized studies (Welsh et al 2020).  
More insight into the biological mechanisms underlying treatment resistance is needed to 
improve patient outcome. Combination with PD-1/PD-L1 and TIGIT blockade might rescue 
functionally “exhausted” T cells and result in a durable control of cancer. This trial will evaluate 
whether the addition of an anti-PD-1 therapy and anti-TIGIT therapy to combined modality 
therapy can benefit patients with LS-SCLC. 
In addition, improvement in antitumor effects has been observed preclinically when RT is given 
concurrently with or immediately after anti-PD-L1 rather than sequentially (Dovedi et al 2014). 
However, sequential delivery of checkpoint inhibitors did not improve response to RT at local or 
distant sites (Dovedi et al 2017). The results of the PACIFIC trial, which suggested that the OS 
was better when durvalumab was given within 2 weeks after the end of cCRT, was consistent 
with preclinical data (Antonia et al 2017). Therefore, the earlier introduction of tislelizumab + 
ociperlimab given simultaneously with cCRT may lead to further enhancement of 
immune-mediated antitumor efficacy. 
As a novel immunotherapy combination, anti-PD-L1 plus anti-TIGIT given concurrently with 
RT has been evaluated in a mouse model (Grapin et al 2019). The experiment compared the 
tumor response during treatment with anti-PD-L1 plus anti-TIGIT plus RT with single agent 
therapy plus RT or RT alone. In the CT26 model, 3 x 8 Gy hypofractionated RT was 
dramatically more effective in combination with anti-TIGIT and anti-PD-L1 therapy, with a CR 
rate of 90% (9/10 mice) compared with that of 20% (2/10 mice), 30% (3/10 mice), and 0% 
(0/10 mice) for anti-TIGIT, anti-PD-L1, and RT alone, respectively. A CR with anti-TIGIT and 
anti-PD-L1 therapy in combination with 18 x 2 Gy normofractionated RT was observed in 7/12 
(58.3%) mice compared with 3/12 (25%), 8/12 (66.7%), and 1/10 (10%) mice for anti-TIGIT, 
anti-PD-L1, and RT alone with the same fractionated RT, respectively.  
Based on those preclinical and clinical supportive data, this study is designed to study cCRT 
combined with anti-PD-1 or anti-PD-1 plus anti-TIGIT therapies to investigate the addition of 
immunotherapy to cCRT in LS-SCLC. Ideally, these therapeutic strategies will continue to 
improve long-term survival and quality of life for patients with LS-SCLC. 
1.5.6. 
Rationale for Chemotherapy Regimens 
Four cycles of EP is the standard of care of systemic therapy for patients with LS-SCLC. It has 
been widely applied for initial treatment in LS-SCLC for over 3 decades. In clinical practice, 
carboplatin is used as a substitute for cisplatin to reduce the risk of emesis, neuropathy, and 
nephropathy. However, it also carries a greater risk of myelosuppression. During systemic 
therapy concurrent with RT, EP is recommended (category 1) as the preferred regimen. In this 
study, patients in each cohort will receive 4 cycles of EP; if cisplatin is contraindicated or not 
tolerated, carboplatin may be used. 
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1.5.7. 
Rationale for Radiation Therapy Dose 
The total dose of RT will be 60 to 70 Gy in once-daily fractions given within 6 to 7 weeks, 
which is a standard RT procedure according to NCCN SCLC Panel recommendations. The RT 
dose in LS-SCLC therapy may be given as a once-daily or twice-daily regimen; both regimens 
have shown improved survival outcome for patients with LS-SCLC and there is no significant 
difference between the 2 options. The Phase 3 CONVERT trial compared total doses of 66 Gy 
with once-daily fractionation and 45 Gy with twice-daily fractionation in 547 patients with 
LS-SCLC; OS outcomes did not significantly differ between the 2 groups.  
Based on this study, the higher doses of 60 to 70 Gy with once-daily fractionation became 
another acceptable option (Miller et al 2003; Roof et al 2003; Bogart et al 2004). The once-daily 
regimen was selected for this study because the twice-daily regimen carries some concerns about 
tolerance, presents logistic issues for the RT department, and is inconvenient for patients. 
The PCI regimen was standardized at 25 Gy in 10 fractions in patients with LS-SCLC who have 
a good response to initial therapy. It became a component of the standard of care based on a 
meta-analysis (Aupérin et al 1999) that reported decreased incidence of brain metastases (relative 
risk = 0.46, p < 0.001) and a 5.4% absolute improvement in 3-year OS (20.7% versus 15.3%) 
with the addition of PCI. 
1.5.8. 
Rationale for Biomarker Strategy 
Biomarker assays will be performed using patient-derived tumor tissue(s) and/or blood samples 
to evaluate the predicative biomarkers associated with tislelizumab plus ociperlimab. These 
biomarkers will include but not limit to gene expression profile, tissue- or blood-based gene 
mutations and TMB/microsatellite instability (MSI), PD-L1/TIGIT/CD155/CD226 expression, 
and SCLC subtyping (ASCL1/NEUROD1/POU2F3/YAP1).  
Despite the progress in clinical treatment of SCLC using anti-PD-1/PD-L1 inhibitors, predictive 
biomarkers for SCLC clinical efficacy are yet to be well-established and biomarker research for 
LS-SCLC is very scarce. PD-L1 expression is under investigation in ES-SCLC immunotherapy 
and its correlation with clinical efficacy has not been well-established, which might be due to 
different scoring algorithms and combination treatment regimens. In Keynote 158, improved 
ORR was observed in the PD-L1 combined positive score ≥ 1 subgroup treated with 
pembrolizumab monotherapy for second-line or further-line treatment of SCLC 
(Chung et al 2018). Other studies investigating PD-L1 tumor cell expression or immune cell 
expression showed no association with clinical benefit (Hellmann et al 2017). More data are 
needed to further evaluate the predictive power of PD-L1 expression using different scoring 
algorithms in SCLC. Another potential predictive biomarker reported in SCLC immunotherapy 
was tissue and blood TMB. Improved ORR was observed in the Checkmate 032 trial in 
TMB-high SCLC patients treated with nivolumab (Antonia et al 2016). However, in the 
IMpower 133 trial, no correlation of TMB with OS was observed in patients with SCLC treated 
with atezolizumab plus chemotherapy (Horn et al 2018). The predictive value of TMB will be 
further evaluated in the current study. Moreover, there is a lack of evidence indicating whether 
genetic mutations could have a correlation with the benefit of immunotherapy in patients with 
SCLC. SCLC is characterized by relatively high TIGIT and PVR expression and high PVR 
expression is correlated with poor prognosis (Yu et al 2018). The expression of TIGIT pathway 
molecules including TIGIT, CD226, CD155, and CD112 will be measured to explore their 
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relationship with clinical response to ociperlimab plus tislelizumab. Other immune-related 
factors will also be assessed in this study, including immune-related gene expression and tumor 
infiltrating immune cells, which could reflect the status of the tumor immune microenvironment 
in SCLC and potentially unveil the mechanisms of response or resistance to immunotherapy. 
Moreover, 4 molecular subtypes of SCLC have been increasingly clearly defined (A/N/P/I) in 
recent years, and SCLC-I subtype is characterized by an inflamed tumor microenvironment, 
suggesting its sensitivity to immunotherapy (Gay et al 2019). Therefore, SCLC subtyping and its 
correlation with immunotherapy response will also be explored. 
1.6. 
Benefit-Risk Assessment 
Tislelizumab monotherapy and in combination with chemotherapy have shown meaningful 
antitumor activity and manageable safety profiles in various types of tumors including 
ES-SCLC. Other immune checkpoint inhibitors combined with first-line chemotherapy have also 
shown improved efficacy in ES-SCLC in both the IMpower 133 trial (Horn et al 2018) and the 
CASPIAN trial (Paz-Ares et al 2019). Based on increased evidence for the combination of 
immunotherapy and RT, the synthetic anticancer activity of immunotherapy has been proven by 
preclinical and clinical data. Checkpoint inhibitors with cCRT have provided favorable benefit-
risk profiles in the PACIFIC trial for patients with unresectable stage III NSCLC (Antonia et al 
2017). Earlier treatment with potentially more effective treatment options might further improve 
the clinical benefit. 
As discussed earlier, there is extensive evidence supporting TIGIT’s role in regulating immune 
response and the interaction between the TIGIT and PD-1 pathways has been shown to promote 
tumor immune escape. The clinical efficacy demonstrated for tislelizumab and preliminary 
results with an anti-TIGIT/anti-PD-L1 competitor combination suggest that ociperlimab has the 
potential to improve and/or extend the therapeutic benefits of tislelizumab in the treatment-naïve 
setting. The novel therapeutic strategy of using ociperlimab and tislelizumab combined with 
cCRT seeks to augment the current modest improvement in SCLC, especially in LS-SCLC, 
which still only has cCRT as the standard initial therapy.  
PD-1 blockade by tislelizumab has been evaluated in more than 1350 patients with a safety and 
efficacy profile similar to what has been reported for other anti-PD-1/PD-L1 therapies such as 
nivolumab and pembrolizumab. Based on the mechanism(s) of action and the nonclinical and 
preliminary clinical data, the combined blockade of TIGIT and PD-1 by ociperlimab and 
tislelizumab, respectively, is expected to result in immune-mediated toxicities similar to what has 
been observed with tislelizumab alone. Preliminary safety results from the CITYSCAPE trial 
(N = 135) support this hypothesis and demonstrate that patients treated with the 
anti-TIGIT/anti-PD-L1 combination experienced < 10% increase in overall and Grade 3 or 
4 TEAEs compared with patients treated with anti-PD-1 and placebo (Rodriguez-Abreu et al 
2020). 
As for the safety profile of immunotherapy combined with cCRT, the Phase 3 PACIFIC trial and 
the Phase 2 trials NICOLAS (Peters et al 2019) and DETERRED (Lin et al 2020) have released 
preliminary safety data of anti-PD-1/PD-L1 administered at the same time as cCRT. Most of 
AEs were Grade 1 or 2 and all immune-mediated toxicities were reversible with steroids and 
supportive care. 
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The risk of augmented safety signals, as has been shown for other anti-PD-1-based immuno-
oncology combinations, still remains. Therefore, the European Society for Medical Oncology 
and the American Society for Clinical Oncology have established a monitoring plan to monitor, 
diagnose, and manage imAEs. A Safety Monitoring Committee (SMC) will be established to 
regularly monitor the safety of ociperlimab plus tislelizumab and tislelizumab alone in 
combination with cCRT (Section 10.1). 
Given the unmet medical need and limited treatment options in this indication, the benefit/risk 
assessment for this study is favorable, based on strong scientific rationale indicating that the 
blockade of PD-1 pathway with or without the blockade of the TIGIT pathway combined with 
standard cCRT may result in enhanced antitumor activity as compared with cCRT alone without 
a major increase in the risk of immune-mediated toxicities. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective  
• To compare progression-free survival (PFS) between Arm A (ociperlimab plus 
tislelizumab plus cCRT) and Arm C (cCRT only) and between Arm B (tislelizumab 
plus cCRT) and Arm C as assessed by the investigator according to Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Intent-to-Treat 
(ITT) Analysis Set 
2.1.2. 
Secondary Objectives  
• To compare the following between Arm A and Arm C and between Arm B and Arm 
C as assessed by the investigator according to RECIST v1.1 in the ITT Analysis Set: 
− Complete response (CR) rate 
− Overall response rate (ORR) 
− Duration of response (DOR)  
− Overall survival (OS) 
− Distant metastasis-free survival (DMFS) 
• To evaluate the correlation of PD-L1 and TIGIT expression with ORR, PFS, and OS 
• To evaluate the safety and tolerability of ociperlimab combined with tislelizumab 
plus cCRT and tislelizumab plus cCRT 
2.1.3. 
Exploratory Objectives  
• To explore prognostic and predictive effects of tissue- and blood-based biomarkers on 
efficacy and their association with mechanisms of resistance  
• To evaluate health-related quality of life (HRQoL)  
• To assess the utility of circulating tumor DNA (ctDNA) level change as a surrogate 
marker for efficacy 
• To assess the PK of ociperlimab and tislelizumab 
• To assess the immunogenicity of ociperlimab and tislelizumab 
2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoint 
• PFS, defined as the time from the date of randomization to the date of the first 
documented disease progression as determined by the investigator per RECIST v1.1 
or death from any cause (whichever occurs first), in the ITT Analysis Set of Arms A, 
B, and C 
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2.2.2. 
Secondary Endpoints 
• CR rate, defined as the proportion of patients who had CR as assessed by the 
investigator per RECIST v1.1, in the ITT Analysis Set of Arms A, B, and C 
• ORR, defined as the proportion of patients who had CR or partial response (PR) as 
assessed by the investigator per RECIST v1.1, in the ITT Analysis Set of Arms A, B, 
and  
• DOR, defined as the time from the date of the first occurrence of a documented 
objective response to the date of documented disease progression as determined by 
the investigator per RECIST v1.1 or death from any cause (whichever occurs first), in 
the ITT Analysis Set of Arms A, B, and C 
• OS, defined as the time from the date of randomization to the date of death due to any 
cause in the ITT Analysis Set, in the ITT Analysis Set of Arms A, B, and C  
• DMFS, defined as the time from the date of randomization to the date of the first 
documented distant metastasis as assessed by the investigator per RECIST v1.1 or 
death from any cause (whichever occurs first), in the ITT Analysis Set of Arms A, B, 
and C 
• ORR, PFS, and OS in subgroups based on PD-L1 and TIGIT expression levels 
• The incidence and severity of treatment-emergent adverse events (TEAEs) graded 
according to National Cancer Institute-Common Terminology Criteria for Adverse 
Events Version 5.0 (NCI-CTCAE v5.0). 
2.2.3. 
Exploratory Endpoints 
• Biomarkers from patient-derived tumor tissue(s) and/or blood samples obtained 
before, during, and/or after treatment including but not limited to gene expression 
profile, tissue- or blood-based gene mutations and TMB/MSI, CD155/CD226 
expression, SCLC subtyping (ASCL1/NEUROD1/POU2F3/YAP1)  
• HRQoL assessment using 2 patient-reported outcomes (PROs) including the 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30 (EORTC QLQ-C30) and its lung cancer module Quality of 
Life Questionnaire Lung Cancer 13 (QLQ-LC13) 
• The ctDNA level change before, during, and after treatment as a surrogate marker for 
efficacy 
• Serum concentrations of ociperlimab and tislelizumab at specified timepoints 
• Assessment of immunogenicity of ociperlimab and tislelizumab by determining the 
incidence of ADAs 
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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is a Phase 2, multicenter, randomized, 3-arm, open-label study to investigate the 
preliminary efficacy and safety of ociperlimab plus tislelizumab plus cCRT followed by 
ociperlimab plus tislelizumab (Arm A) and tislelizumab plus cCRT followed by tislelizumab 
only (Arm B) compared with cCRT only (Arm C) in patients with previously untreated 
LS-SCLC.  
The primary endpoint is investigator-assessed PFS in the ITT Analysis Set for the comparisons 
of Arm A versus Arm C and Arm B versus Arm C.  
Approximately 120 patients will be randomized in a 1:1:1 ratio to receive the study treatment in 
the following 3 arms: 
• Arm A: Ociperlimab 900 mg intravenously once every 3 weeks plus tislelizumab 200 
mg intravenously once every 3 weeks combined with cCRT for 4 cycles, followed by 
ociperlimab 900 mg intravenously once every 3 weeks plus tislelizumab 200 mg 
intravenously once every 3 weeks  
• Arm B: Tislelizumab 200 mg intravenously once every 3 weeks combined with cCRT 
for 4 cycles, followed by tislelizumab 200 mg intravenously once every 3 weeks  
• Arm C: cCRT only for 4 cycles 
Randomization will be stratified by disease stage (I/II versus III) by the AJCC staging system, 
8th edition.  
The chemotherapy regimen is cisplatin 75 mg/m2 on Day 1 of each cycle for 4 cycles. If the 
patient is unable to tolerate the 1-day administration of cisplatin 75 mg/m2, at the investigator’s 
discretion (eg, patients had concurrent superior vena cava syndrome), cisplatin 25 mg/m2 dosed 
on Days 1, 2, and 3 is allowed. Etoposide is administered at 100 mg/m2 on Days 1, 2, and 3 for 4 
cycles. Dose adjustment is allowed to address potential renal, hematologic, or other toxicities 
after the first cycle.  
If cisplatin is contraindicated or not tolerated (Section 5.2.2.1), carboplatin and etoposide will be 
the alternative chemotherapy regimen. Carboplatin at a dose of area under the plasma or serum 
concentration-time curve 5 (AUC 5) should be administered as an intravenous infusion once 
every 3 weeks on Day 1 of each cycle for 4 cycles and etoposide 100 mg/m2 should be 
administered on Days 1, 2, and 3 of each cycle for 4 cycles. 
For Arm A and Arm B, investigational drug(s) (ociperlimab plus tislelizumab [Arm A] or 
tislelizumab alone [Arm B]) will be given starting on Cycle 1 Day 1 (C1D1) before 
chemotherapy and continued for a duration of up to 12 months (a maximum of 17 cycles of 
treatment) or until disease progression according to RECIST v1.1, unacceptable toxicity, death, 
or another discontinuation criterion is met, whichever occurs first. 
RT should start early within cycle 1 or 2 of systemic therapy. The total dose of RT will be 60 to 
70 Gy, given in once-daily fractions over 6 to 7 weeks.  
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PCI is permitted at the investigator’s discretion. The preferred total dose for PCI to the whole 
brain is 25 Gy in 10 daily fractions. 
The study design schematic is presented in Figure 2.
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Figure 2: 
Study Schema 
 
Abbreviations: AJCC, American Joint Committee on Cancer; cCRT, concurrent chemoradiotherapy; CR, complete response; D1, Day 1; DMFS, distant 
metastasis-free survival; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; LS-SCLC, limited-stage small cell lung cancer; ORR, overall 
response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; Q3W, once every 3 weeks; R, randomization. 
For all study procedures, see Section 7 and Appendix 1. 
 
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3.2. 
Screening Period 
Screening evaluations will be performed within 28 days before randomization. Patients who 
agree to participate in this study will sign the informed consent form (ICF) before undergoing 
any screening procedure. Patients who are suspected to have concurrent serious respiratory 
illness or exhibit significant respiratory symptoms unrelated to underlying cancer will also take a 
pulmonary function test (refer to Section 7.1.5 and Appendix 1 for details). Screening 
evaluations may be repeated as needed within the screening period; the investigator is to assess 
preliminary patient eligibility according to the latest screening assessment results. 
Archival tumor tissue must be collected for the purpose of biomarker analysis. If no archival 
samples are available, a fresh tumor biopsy at baseline is required. Refer to Section 7.7 for 
details. 
3.3. 
Treatment Period 
After completing all screening activities, eligible patients will be randomized in a 1:1:1 ratio to 
receive either ociperlimab plus tislelizumab plus cCRT followed by ociperlimab plus 
tislelizumab (Arm A), tislelizumab plus cCRT followed by tislelizumab only (Arm B), or cCRT 
only (Arm C). Randomization will be stratified according to stage (stage I/II versus stage III). 
Patients will receive open-label treatment with one of the following: 
• Arm A: Ociperlimab 900 mg intravenously once every 3 weeks plus tislelizumab 200 
mg intravenously once every 3 weeks combined with cCRT for 4 cycles, followed by 
ociperlimab 900 mg intravenously once every 3 weeks plus tislelizumab 200 mg 
intravenously once every 3 weeks  
• Arm B: Tislelizumab 200 mg intravenously once every 3 weeks combined with cCRT 
for 4 cycles, followed by tislelizumab 200 mg intravenously once every 3 weeks  
• Arm C: cCRT only for 4 cycles 
For Arm A and Arm B, investigational drug(s) will be given starting on Cycle 1 Day 1 (C1D1) 
before chemotherapy and continued for a duration of up to 12 months, or until disease 
progression per RECIST v1.1, unacceptable toxicity, death, or another discontinuation criterion 
is met, whichever occurs first. 
In Arms A and B, treatment with ociperlimab plus tislelizumab or with tislelizumab alone 
beyond the initial investigator-assessed, RECIST v1.1-defined disease progression is permitted 
provided that the patient has investigator-assessed clinical benefit and is tolerating study drug. 
Specific requirements for patients with disease progression to be able to continue treatment with 
ociperlimab and tislelizumab are described in Section 7.5. 
During the study, tumor imaging will be performed at approximately 12 weeks (± 7 days) from 
the date of randomization (an additional tumor assessment is allowed if clinically indicated), then 
every 6 weeks (± 7 days) for the next 54 weeks, and then every 12 weeks (± 7 days) thereafter 
based on RECIST v1.1. Tumor response will be assessed by investigators. Details are provided 
in Section 7.5. 
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Safety will be assessed throughout the study by monitoring AEs/SAEs (toxicity grades assigned 
per NCI-CTCAE v5.0 and laboratory results. Vital signs, physical examinations, Eastern 
Cooperative Oncology Group (ECOG) Performance Status change, electrocardiogram (ECG) 
results, and other examinations will also be used for safety assessment. Safety assessments are 
further detailed in Section 7.4 and the Schedule of Assessments (Appendix 1). 
3.4. 
End of Treatment/Safety Follow-up 
The End-of-Treatment (EOT) Visit and Safety Follow-up Visit are planned to be conducted 
when the investigator determines that study treatment will no longer be used. The EOT Visit 
should be conducted within 7 days after the decision to discontinue study treatment or upon 
completion of study treatment. If routine laboratory tests (eg, hematology, serum chemistry) are 
completed within 7 days before the planned EOT or Safety Follow-up Visit, these tests need not 
to be repeated. Tumor assessment is not specifically required at the EOT or Safety Follow-up 
Visit and should follow the regular tumor evaluation schedule detailed in Section 7.5. However, 
in some cases, the time window of tumor assessment might overlap with the EOT and/or Safety 
Follow-up Visit. 
Patients who discontinue study treatment for any reason will be asked to return to the clinic for 
the Safety Follow-up Visit, which is required to be conducted 30 days (± 7 days) after the last 
dose/last day of study treatment (including cCRT), or initiation of new anticancer therapy, 
whichever occurs first.  
For Arms A and B, patients should return to the site or 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 (± 7 days) after the last dose of 
ociperlimab or tislelizumab, regardless of whether patients start 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. 
The EOT Visit may be used as the Safety Follow-up Visit if it occurred 30 days (± 7 days) after 
the last dose of study treatment, eg, at an EOT Visit right after a response assessment showed 
disease progression resulting in patient discontinuation. Patients who discontinue study treatment 
or complete study treatment before disease progression will have their tumors assessed as 
outlined in Section 7.5. If the EOT Visit is used as the Safety Follow-up Visit, the assessment 
that has been performed at the EOT Visit does not need to be repeated. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
Patients who discontinue or complete study treatment before disease progression will need to 
undergo tumor assessments as outlined in Section 7.5. 
For patients who have disease progression during the study, an optional biopsy will also be taken 
at the EOT or Safety Follow-up Visit from accessible tumor sites, which could be used for 
exploratory study including, but not limited to, study of the resistance mechanism. If feasible, 
any follow-up biopsy should be ideally taken from the same tumor lesion as the baseline biopsy. 
Written informed consent is required before fresh tumor biopsies. 
See Appendix 1 for assessments to be performed at the EOT and Safety Follow-up Visits. 
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3.5. 
Survival Follow-up 
Patients will be followed for survival and to obtain information on subsequent anticancer therapy 
after discontinuation of study treatment via telephone calls, patient medical records, and/or clinic 
visits approximately every 3 months (± 14 days) after the Safety Follow-up Visit or as directed 
by the sponsor until death, withdrawal of consent, loss to follow-up, or end of study. 
3.6. 
Discontinuation From the Study Treatment or From the Study 
3.6.1. 
Patient Discontinuation From Study Treatment 
Patients have the right to discontinue study treatment at any time for any reason. In addition, the 
investigator has the right to discontinue a patient from the study treatment at any time. Patients 
who discontinue study treatment for reasons other than disease progression should be followed 
for assessments of antitumor activity (Section 7.5), safety (Section 7.4) and survival 
(Section 3.5), if possible. 
The primary reason for discontinuation from the study treatment should be documented in source 
documents and on the appropriate electronic case report form (eCRF). Patients may discontinue 
study treatment for reasons which include, but are not limited to, the following: 
• Radiographic disease progression per RECIST v1.1 
• Adverse event 
• Patient decision 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety, if he or she were to continue the study treatment 
• Use of any concurrent anticancer therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese (or other 
Country) herbal medicine and Chinese (or other Country) patent medicines] for the 
treatment of cancer) 
• Patient noncompliance 
Investigative site staff should first counsel patients who are significantly 
noncompliant (eg, missing 2 treatment cycles) on the importance of study drug 
compliance and drug accountability. The investigator may, in consultation with the 
medical monitor, discontinue patients from treatment who are consistently 
noncompliant. 
• Completion of study treatment 
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3.6.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) 
Patients may discontinue study for reasons which include, but are not limited to, the following:  
• Patient withdrawal of consent 
• Death 
• Loss to follow-up 
3.7. 
End of Study 
The end of study is defined as the timepoint when the final data point is collected from the last 
patient in the study. This is when the last patient dies, withdraws consent, completes all study 
assessments, or is lost to follow-up. Alternatively, the end of study is when the sponsor decides 
to terminate the study. 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
early may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
• Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients should be seen as soon as possible for an EOT 
Visit and Safety Follow-up Visit. 
The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) of the early termination of the study. 
The sponsor has the right to close a site at any time. The decision will be notified to the site in 
advance. Reasons for closing a site may include but are not limited to the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Good Clinical Practice (GCP) noncompliance 
• Study activity is completed (ie, all patients have completed, and all obligations have 
been fulfilled) 
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4. 
STUDY POPULATION 
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all the following criteria: 
1. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the schedule of assessments 
2. Age ≥ 18 years (or the legal age of consent in the jurisdiction in which the study is taking 
place) on the day of signing the informed consent form 
3. Patient has pathologically (histologically or cytologically) proven diagnosis of small cell 
lung cancer  
4. Has limited-stage disease (stage Tx, T1-T4, N0-3, M0; AJCC staging, 8th edition), and 
can be safely treated with definitive radiation doses. Note: Patients with stage T3-4 
disease due to multiple lung nodules that are too extensive or that have tumor/nodal 
volume that is too large to be encompassed in a tolerable radiation plan are ineligible 
5. Patient has not received any prior treatment for LS-SCLC 
6. Patient has measurable disease as assessed according to RECIST v1.1 that is appropriate 
for selection as a target lesion for repeat measurement, as determined by local site 
investigator/radiology review 
7. Patients must agree to provide an archival tumor tissue with an associated pathology 
report or agree to perform a fresh tumor biopsy during screening (formalin-fixed 
paraffin-embedded block or approximately 15 unstained slides [8 slides minimum]) 
Note: If < 8 unstained slides are available, a discussion with the sponsor is required 
8. ECOG Performance Status ≤ 2 assessed within 7 days before the first administration of 
study intervention 
9. Patients must have a life expectancy of ≥ 12 weeks 
10. Adequate organ function as indicated by the following screening laboratory values 
obtained within 7 days before randomization: 
a. Absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin 
≥ 90 g/L. Note: Patients must not have undergone a blood transfusion or received 
growth factor support ≤ 14 days before sample collection at screening 
b. International normalized ratio or prothrombin time ≤ 1.5 x ULN 
c. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN 
d. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients 
with Gilbert’s syndrome) 
e. AST and ALT ≤ 2.5 x ULN 
f. Calculated creatinine clearance (CrCl) ≥ 45 mL/min (Cockcroft-Gault formula) 
(Appendix 12) 
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11. Females of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study; and for ≥ 120 days after the last dose of 
ociperlimab and tislelizumab in Arm A or tislelizumab in Arm B, or ≥ 180 days after the 
last dose of radiotherapy or chemotherapy (except for cisplatin), or ≥ 14 months after the 
last dose of cisplatin, whichever occurs later; and have a negative urine or serum 
pregnancy test ≤ 7 days before randomization. See Appendix 9. 
12. Non-sterile males must be willing to use a highly effective method of birth control for the 
duration of the study; and for ≥ 120 days after the last dose of ociperlimab and 
tislelizumab in Arm A or tislelizumab in Arm B, or ≥ 180 days after the last dose of 
radiotherapy or chemotherapy (except for cisplatin), or ≥ 11 months after the last dose of 
cisplatin, whichever occurs later. 
• 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 “sub-fertility”) are not to be 
considered sterile for purposes of this study. 
4.2. 
Exclusion Criteria 
Patients who meet any of the following criteria are not eligible to enroll: 
1. Mixed small cell lung cancer histology. Note: mixed SCLC with the component of 
neuroendocrine carcinoma origin is considered eligible 
2. Have received surgical resection for LS-SCLC 
3. Any patient for whom the tumor is considered resectable by surgery or stereotactic body 
radiation therapy/stereotactic ablative radiotherapy should be considered ineligible 
4. Is expected to require any other form of antineoplastic therapy while on study. 
5. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-TIGIT, or any other 
antibody or drug specifically targeting T-cell costimulation or checkpoint pathways 
6. Receipt of interleukin, interferon, thymosin, or any investigational therapies within 
14 days or 5 half-lives (whichever is longer) before randomization 
7. Patient’s radiation treatment plans are likely to encompass a volume of whole lung 
receiving ≥ 20 Gy in total (V20) of > 38% of lung volume. Prior tangent fields for breast 
cancer with minimal overlap with target volumes are allowed per approval of the 
principal investigators 
8. Active autoimmune diseases or history of autoimmune diseases that may relapse 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening: 
a. Controlled type I diabetes 
b. Hypothyroidism (provided it is managed with hormone replacement therapy only) 
c. Controlled celiac disease 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
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e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
9. Any active malignancy ≤ 2 years before randomization except for the specific cancer 
under investigation in this study and any locally recurring cancer that has been treated 
curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, 
carcinoma in situ of the cervix or breast) 
10. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
randomization 
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) 
b. Topical, ocular, intra-articular, intranasal, or inhaled 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 
11. Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or 
corrected calcium despite standard medical management or ≥ Grade 3 hypoalbuminemia 
≤ 14 days before randomization 
12. History of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung 
diseases including pulmonary fibrosis, acute lung diseases, etc. Patients with significantly 
impaired pulmonary function or who require supplemental oxygen at baseline must 
undergo an assessment of pulmonary function at screening (see Section 7.1.5) 
13. Infection (including tuberculosis infection, etc) requiring systemic antibacterial, 
antifungal, or antiviral therapy within 14 days before randomization 
Note: Antiviral therapy is permitted for patients with hepatocellular carcinoma or chronic 
hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. 
14. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA > 500 IU/mL (or 
> 2500 copies/mL) at screening 
Note: Inactive hepatitis B surface antigen (HBsAg) carriers and those with treated and 
stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. 
Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA 
should be managed per treatment guidelines. Patients receiving antiviral therapy at 
screening should have been treated for > 2 weeks before randomization. 
15. Patients with active hepatitis C 
Note: Patients with a negative HCV antibody test at screening or a positive HCV 
antibody test followed by a negative HCV RNA test at screening are eligible. The HCV 
RNA test will be performed only for patients testing positive for HCV antibody. Patients 
receiving antiviral therapy at screening should have been treated for > 2 weeks before 
randomization. 
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16. Known history of HIV infection 
17. Any major surgical procedure ≤ 28 days before randomization (except for placement of 
vascular access). Patients must have recovered adequately from the toxicity and/or 
complications from the intervention before randomization 
18. Prior allogeneic stem cell transplantation or organ transplantation 
19. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days before randomization 
b. Pulmonary embolism ≤ 28 days before randomization 
c. Any history of acute myocardial infarction ≤ 6 months before randomization 
d. Any history of heart failure meeting New York Heart Association Classification III 
or IV (Appendix 6) ≤ 6 months before randomization 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
randomization  
f. Any history of cerebrovascular accident ≤ 6 months before randomization 
g. Uncontrolled hypertension that cannot be managed by standard anti-hypertension 
medications ≤ 28 days before randomization 
h. Any episode of syncope or seizure ≤ 28 days before randomization 
20. A history of severe hypersensitivity reactions to other monoclonal antibodies 
21. A history of allergic reactions to cisplatin, carboplatin, other platinum-containing 
compounds, or etoposide. 
22. Patients with toxicities (as a result of prior anticancer therapy) which have not recovered 
to baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, 
neuropathy and specific laboratory abnormalities) 
23. Was administered a live vaccine ≤ 28 days before randomization 
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines and are not allowed. 
24. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study drug, or 
affect the explanation of drug toxicity or AEs, or result in insufficient or impaired 
compliance with study conduct 
25. Women who are pregnant, breastfeeding, or planning to get pregnant during the study. 
26. Concurrent participation in another therapeutic clinical study 
 
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5. 
STUDY TREATMENT 
5.1. 
Formulation, Packaging, and Handling 
5.1.1. 
Ociperlimab 
Ociperlimab is a monoclonal antibody formulated for intravenous injection in a single-use vial 
(20 mL glass vial, USP Type I) containing a total of 300 mg antibody in 15 mL of buffered 
isotonic solution as available. Ociperlimab 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 kept at the temperature condition as specified on the label. Shaking 
should be avoided. 
Refer to the pharmacy manual for details regarding intravenous administration, accountability, 
and disposal. Refer to the Ociperlimab (BGB-A1217) Investigator’s Brochure for other details 
regarding ociperlimab. 
5.1.2. 
Tislelizumab 
Tislelizumab is a monoclonal antibody formulated for intravenous injection in a single-use vial 
(20R glass, United States Pharmacopeia [USP] type I), containing a total of 100 mg of antibody 
in 10 mL of isotonic solution. Tislelizumab has been aseptically filled in a single-use glass vial 
with a rubber stopper and capped by an aluminum flip-off seal cap. Each vial is packaged into a 
single carton box. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature condition as specified on the label. Shaking 
should be avoided. 
Refer to the pharmacy manual for details regarding intravenous administration, accountability, 
and disposal. Please also refer to the Tislelizumab Investigator’s Brochure for other details 
regarding tislelizumab. 
5.1.3. 
Chemotherapy 
Management (ie, handling, storage, administration, and disposal) of cisplatin, carboplatin, and 
etoposide will be in accordance with the relevant local guidelines and/or prescribing 
information/summary of product characteristics.  
For further details, see the manufacturer’s prescribing information for the respective 
chemotherapeutic agents. 
5.2. 
Dosage, Administration, and Compliance 
Dosing schedules for all treatment arms, broken out by individual arm, are provided in Table 3. 
The first dose of study drug is to be administered within 3 business days of randomization.  
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C1D1 is defined as the day of the administration of the first dose of ociperlimab or tislelizumab. 
Ociperlimab and tislelizumab and will be given starting from C1D1 in the cCRT phase and 
continued for a duration of up to 12 months after C1D1. During the cCRT phase, ociperlimab 
and tislelizumab should be administered before chemotherapy; in case the logistical 
circumstances do not allow for all of the intravenous study drugs (including ociperlimab, 
tislelizumab, and platinum-based doublet chemotherapy) to be administered on the same day, 
ociperlimab and tislelizumab administration on the same day should be guaranteed and then 
chemotherapy should start as soon as possible within the following 3 days. For Arm C (cCRT 
only), C1D1 is defined as the day of administration of the first dose of chemotherapy. 
All patients will be monitored continuously for AEs. Treatment modifications (eg, dose delay, 
reduction, interruption, or discontinuation) will be based on specific laboratory and AE criteria, 
as described in Section 5.5. 
Table 3: 
Planned Dose, Frequency of Administration, and Route of Administration 
for Study Drugs 
Study drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Duration of 
treatment 
Ociperlimab 
900 mg 
Day 1 of each cycle 
(3-week cycles) 
Intravenous 
See Section 3.3 
Tislelizumab 
200 mg 
Day 1 of each cycle 
(3-week cycles) 
Intravenous 
See Section 3.3 
Cisplatin + 
Etoposide 
Cisplatin 
75 mg/m2  
 
75 mg/m2: Day 1 of 
each cycle  
If the patient is 
unable to tolerate 
the 1-day 
administration of 
cisplatin 75 mg/m2, 
at the investigator’s 
discretion cisplatin 
25 mg/m2 dosed on 
Days 1, 2 and 3 is 
allowed. 
(3-week cycles) 
Intravenous 
First 4 cycles 
Etoposide 
100 mg/m2 
Days 1, 2, and 3 of 
each cycle  
(3-week cycles) 
Intravenous 
First 4 cycles 
Carboplatin + 
Etoposide 
Carboplatin 
AUC 5 
Day 1 of each cycle 
(3-week cycles) 
Intravenous 
First 4 cycles 
Etoposide 
100 mg/m2 
Days 1, 2, and 3 of 
each cycle  
(3-week cycles) 
Intravenous 
First 4 cycles 
Abbreviation: AUC, area under the plasma or serum concentration-time curve. 
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5.2.1. 
Ociperlimab and Tislelizumab 
In Arm A, tislelizumab 200 mg followed by ociperlimab 900 mg will be administered on Day 1 
of each cycle (once every 3 weeks). In Arm B tislelizumab 200 mg will be administered on 
Day 1 of each cycle (once every 3 weeks),  
Ociperlimab and tislelizumab and will be administered by intravenous infusion through an 
intravenous line containing a sterile, non-pyrogenic, low-protein-binding 0.2 or 0.22 micron in-
line or add-on filter. Specific instructions for product preparation and administration are 
provided in the Pharmacy Manual. 
The initial 2 infusions for Arms A and B (Day 1 of Cycles 1 and 2) will be delivered over 
60 (± 5) minutes each for ociperlimab and tislelizumab (Table 4); if these infusions are well 
tolerated, then the subsequent infusions may be administered over 30 (± 5) minutes, which is the 
shortest time period permissible for infusion. Ociperlimab and tislelizumab and must not be 
concurrently administered with any other drug (refer to Section 6). 
Use of a volumetric pump is recommended to control the infusion speed and to avoid potential 
infusion reactions associated with too rapid administration. The pump may not be needed if the 
infusion speed is controlled through alternative means and consistent with approved institutional 
procedures.  
At the end of the infusion period, the line will be flushed with enough normal saline to make sure 
the complete doses of ociperlimab and tislelizumab are administered. 
As a routine precaution, after infusion of tislelizumab followed by ociperlimab (Arm A) and 
tislelizumab (Arm B) on Day 1 of Cycles 1 and 2, patients must be monitored in an area with 
resuscitation equipment and emergency agents for ≥ 120 minutes. From Cycle 3 onwards, a 
≥ 60-minute monitoring period in an area with resuscitation equipment and emergency agents is 
required (Table 4). 
Guidelines for dose modification, treatment interruption, or discontinuation and for the 
management of imAEs and infusion-related reactions are provided in detail in Section 8.7 and 
Appendix 7. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation, storage, and 
administration. 
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Table 4: 
Administration of Ociperlimab and Tislelizumab and Monitoring Time 
Arm 
Cycle 
Ociperlimab in combination with tislelizumab or 
tislelizumab alone a 
Arm A 
Cycle 1 Day 1 
Tislelizumab infusion over 60 (± 5) minutes followed by 
ociperlimab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 120 minutes  
Cycle 2 Day 1  
Tislelizumab infusion over 60 (± 5) minutes followed by 
ociperlimab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 120 minutes  
Cycle 3 Day 1 
onwards 
Tislelizumab infusion over 30 (± 5) minutes followed by 
ociperlimab infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 60 minutes  
Arm B 
Cycle 1 Day 1 
Tislelizumab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 120 minutes 
Cycle 2 Day 1 
Tislelizumab infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 120 minutes 
Cycle 3 Day 1 
onwards 
Tislelizumab infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 60 minutes 
a  There is no required monitoring period between tislelizumab infusion and ociperlimab infusion. 
5.2.2. 
Chemotherapy 
5.2.2.1. 
Cisplatin + Etoposide  
Cisplatin 75 mg/m2 will be administered on Day 1 for 4 cycles. If the patient is unable to tolerate 
the 1-day administration of cisplatin 75 mg/m2, at the investigator’s discretion (eg, patients had 
concurrent superior vena cava syndrome) cisplatin 25 mg/m2 dosed on Days 1, 2, and 3 is 
allowed. Etoposide 100 mg/m2 will be administered on Days 1, 2, and 3 of each of the first 4 
cycles by intravenous infusion.  
For cisplatin, all patients should receive adequate hydration (including pretreatment hydration) 
and diuretics. Urinary output > 2000 mL must be maintained in the 24 hours following the 
infusion. 
For etoposide, extravasation of infusion should be avoided. 
Additional premedications should be administered as per standard practice. 
If a patient is contraindicated for cisplatin, carboplatin plus etoposide is the alternative 
chemotherapy regimen. Also, patients will be allowed to switch from cisplatin to carboplatin if 
they exhibit intolerance to cisplatin after completing ≥ 1 cycle of cisplatin treatment 
(Section 5.2.2.2). 
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Contraindication or intolerance to cisplatin is indicated if the patient has a history of allergy or 
hypersensitivity to cisplatin, has had intolerable toxicity to cisplatin, has met Hy’s law criteria 
after receiving cisplatin-containing treatment, or has blood creatinine clearance < 60 mL/min. 
5.2.2.2. 
Carboplatin + Etoposide 
If patients have contraindication or intolerance to cisplatin, carboplatin will be used in the 
chemotherapy regimen in place of cisplatin. 
Carboplatin at a dose of AUC 5 will be administered on Day 1 and etoposide 100 mg/m2 will be 
administered on Days 1, 2, and 3 of each of the first 4 cycles by intravenous infusion. 
Carboplatin dose should be calculated before each dose using actual weight if the patient’s body 
weight changes by more than 10% from baseline (or the newly referred body weight) and current 
serum creatinine level according to local prescribing information and local practice. 
5.2.3. 
Thoracic Radiation Therapy 
Before enrolling a patient in this study, the radiation oncologist will evaluate the thoracic CT 
scan or MRI to ensure that the treatment volumes are unlikely to significantly exceed the 
specified normal tissue constraints and that it is feasible to administer the RT dose at the range as 
allowed in the protocol for a patient. A patient will be excluded if his/her radiation treatment 
plans are likely to encompass a volume of the whole lung receiving ≥ 20 Gy in total (V20) of 
more than 38% of lung volume. All patients will receive RT using either a standardized 
3-dimensional conformal RT technique or intensity-modulated radiotherapy or volumetric 
modulated arc therapy on a linear accelerator delivering a beam energy of ≥ 6 MV. 
RT should start early within cycle 1 or 2 of systemic therapy. The total dose of RT will be 60 to 
70 Gy to the initial primary tumor target volume and be delivered once daily over 6 to 7 weeks.  
While 60 to 70 Gy in 6 to 7 weeks is the target dose of radiation, concern about patient tolerance 
discovered during treatment planning or delivery, for example, a V20 exceeding that 
recommended in the protocol, may dictate that a lower dose be administered after consulting 
with sponsor medical monitor. Definitive RT will be considered as receiving a minimum of 
56 Gy to the planning target volume (PTV). 
Contouring of normal tissues and organs for radiotherapy planning will be in accordance with the 
NCCN guideline or local institutional guidelines.  
5.2.3.1. 
Radiation Dose Specifications 
Patients will receive treatment for 5 days per week, in once-daily fractions, to a target dose of 
60 to 70 Gy in 6 to 7 weeks. Normalization of the treatment plan will cover 95% of the PTV with 
the prescription dose. The minimum PTV dose should ideally not fall below 93% of the 
prescription dose. All radiation doses will be calculated with inhomogeneity corrections that take 
into account the density differences within the irradiated volume (ie, air in the lung and bone). 
The maximum and minimum point doses (within the PTV) will be reported.  
For patients with LS-SCLC who experience tumor shrinkage with chemotherapy, treating all 
involved nodal stations (at time of diagnosis) and post-chemotherapy lung parenchymal tumor is 
recommended.  
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Organs at Risk 
Normal tissue constraints are prioritized in Table 5 for treatment planning.  
Table 5 
Normal Tissue Dose-Volume Constraints for Conventionally Fractionated 
Radiation Therapy with Concurrent Chemotherapy a 
Organ at risk  
Constraints in 30–35 fractions 
Spinal cord 
Max ≤ 50 Gy 
Lung 
V20 ≤ 35%–40%b,c; MLD ≤ 20 Gy d 
Heart 
V50 ≤ 25%; Mean ≤ 20 Gy 
Esophagus 
Mean ≤ 34 Gy; Max ≤105% of prescription dose; V60 ≤ 17%; 
contralateral sparing is desirable 
Brachial plexus 
Max ≤ 66 Gy 
Abbreviations: DLCO, diffusing capacity of the lung;; FEV1, forced expiratory volume in 1 second; Gy, Gray; max, 
maximum; MLD, mean lung dose; NCCN, National Comprehensive Cancer Network; OAR, organ at risk; PFT, 
pulmonary function test 
a These constraints represent doses that generally should not be exceeded, based on a consensus survey of NCCN 
Member Institutions. Because the risk of toxicity increases progressively with dose to normal tissues, a key principle 
of radiation treatment planning is to keep normal tissue doses "as low as reasonably achievable" while adequately 
covering the target. The doses to any given organ at risk should typically be lower than these. 
b Use V20 < 35%, especially for the following: elderly ≥ 70 years, and poor PFTs (such as FEV1 or DLCO < 50% 
normal). Use more conservative limits with a diagnosis or radiologic evidence of idiopathic pulmonary fibrosis 
(IDP)/usual interstitial pneumonia (UIP) (the tolerance of these patients is lower though not well characterized). 
c Vxx = % of the whole OAR receiving ≥ xx Gy 
d MLD, being the volumes of both lungs minus the gross tumor volume 
5.2.3.2. 
Variations of Dose Prescription 
The variations in dose prescription are described below, and also summarized in Table 6 (NCCN 
2021). 
Per Protocol: ≥ 99% of the PTV receives at least 93% of the prescribed dose, and no volume 
≥ 1 cm3 within the PTV receives > 110% of the prescribed dose, and no more than a contiguous 
volume of 1 cm3 outside the PTV receives a maximum of 110% of the prescribed dose, and the 
percent volume of both lungs (excluding PTV) receiving a dose of 5 Gy or higher (V5) is ≤ 60%. 
Variation Acceptable: Deviations of this magnitude are not desirable but are acceptable. 
Between < 99% but ≥ 95% of the PTV receives at least 93% of the prescribed dose, or a 
contiguous volume of > 1 cm3 within the PTV receives > 110% but ≤ 115% of the prescribed 
dose, or a contiguous volume of >1cm3 outside the PTV receives > 110% but ≤ 115% of the 
prescribed dose, or V5 is > 60% but ≤62%.  
Table 6: 
Summary of Dose Prescription Variations  
Per Protocol 
Acceptable Variation  
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PTV volume  coverage ≥ 99% of PTV receives 
at least 93% of prescribed dose 
≥ 95% but < 99% of PTV receives at 
least 93% of prescribed dose 
Excessive dose  within 
PTV 
No contiguous volume 
> 1 cm3 within the PTV receives > 
107% of prescribed dose 
> 1 cm3 contiguous volume within PTV 
receives > 107% but 
≤ 110% of prescribed 
dose 
Excessive dose  outside 
PTV 
No contiguous volume 
> 1 cm3 outside PTV receives > 105% 
of prescribed dose 
> 1 cm3 contiguous volume outside 
PTV receives > 105% but 
≤ 107% of prescribed 
dose 
Spinal Cord 
Dmax  ≤ 50 Gy 
50 Gy < Dmax ≤ 52 Gy 
Excessive Lung 
V5 ≤60% 
V5 > 60% but ≤ 62% 
V5/V20 /mean dose 
V20 ≤ 38% 
Mean dose ≤ 20 Gy 
Heart 
V50 ≤ 25% 
Mean dose ≤ 20 Gy 
25% < V50 ≤ 33% 
20 Gy < Mean dose ≤22Gy 
Esophagus 
Mean dose ≤ 34 Gy 
Dmax ≤105% of prescription dose; V60 
≤ 17%; 
contralateral sparing is desirable 
34 Gy < Mean dose ≤ 36 Gy 
V60 ≤ 19%; 
contralateral sparing is desirable 
Brachial Plexus 
Dmax ≤ 66 Gy 
Dmax ≤ 68 Gy 
Abbreviations: Dmax, Maximum dose; Gy, Gray; PTV, planning target volume; Vxx, percentage of the whole organ 
at risk receiving ≥ xx Gy 
5.2.3.3. 
Localization, Simulation, and Immobilization 
Each patient will be positioned in an institution-specific immobilization device in the treatment 
position on a flat table. All planning CT scans should be performed in the treatment position 
using the same immobilization device for setup as is used at the linear accelerator. Optimal 
immobilization is critical for this protocol in order to ensure reproducibility of the daily setup. 
Either a conventional (non-4D CT) treatment planning CT study or a 4-dimensional computed 
tomography (4DCT) will be performed. Conventional CT scans will be performed during quiet, 
uncoached respiration while the patient undertakes a normal respiration, using at least 5-mm 
slices through the entire target volume. The whole thorax (cricoid to L2) should be covered using 
< 1 cm slices in order to generate dose-volume histograms to be calculated of the lungs, spinal 
cord, heart, and esophagus. A treatment planning FDG-PET/CT scan (or FDG-PET alone) with 
the patient in the treatment position can be used for treatment planning. Where a PET/CT is 
obtained in the treatment position, the CT from this study may be used as the planning CT scan. 
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The gross tumor volume (GTV), internal target volume (ITV) and PTV will be defined on all 
appropriate slices (see definitions in Section 5.2.3.4 ). Intravenous contrast (if no 
contraindication exists) during the planning CT is optional, provided that a recent diagnostic 
chest CT was done with contrast to delineate the major blood vessels. If not, intravenous contrast 
can be administered during the planning CT, if this is considered necessary in the view of the 
radiation oncologist. If contrast is used, the densities can be overridden or the contrast scan could 
be registered to a non-contrast scan for planning purposes. Acceptable methods of accounting for 
tumor motion include design of the PTV to cover the excursion of the lung primary cancer and 
nodes during breathing such as an ITV approach, breath-holds (eg, Eleckta ABC device), or 
respiratory gating (for example, Varian RPM system). 
During patient treatment, daily image guided radiation therapy (IGRT) using orthogonal X-ray, 
cone beam CT, CT on rails, or MR guidance must be used for all patients, regardless of radiation 
techniques. Daily image guidance that allows for 3D shifts is the minimum requirement for this 
trial. Most advanced imaging techniques can be utilized as long as they also allow for 3D shifts. 
The setup margin in this trial is tied to the use of daily image guidance. Registering anatomy 
using soft tissue will be most effective for localization. Other soft tissues in the lung such as the 
carina can help for mediastinal alignment. Fiducial markers can be used for localization as 
needed. Any linear shifts seen that are ≥2 mm should be applied prior to treatment. 
5.2.3.4. 
Radiation Treatment Planning 
Three-Dimensional Conformal Radiotherapy (3DCRT) 
The PTV is to be treated with any combination of coplanar or noncoplanar 3D conformal fields 
shaped to deliver the specified dose while restricting the dose to the normal tissues. The 
treatment plan used for each patient will be based on an analysis of the volumetric dose, 
including dose-volume histogram analyses of the PTV and critical normal structures. Each field 
is to be treated daily. 
Intensity Modulated Radiation Therapy (IMRT) 
The use of IMRT is recommended, provided that the institution has been using this technique for 
treating lung cancer for at least 6 months before study activations, as IMRT results in a greater 
proportion of out of target lung receiving radiation outside the PTV. 
Detailed Specification 
Target volumes: the definitions of volumes will be in accordance with the ICRU 50 (1999) for 
3DCRT and ICRU 83 (2010) for IMRT. 
GTV: The primary tumor and clinically positive lymph nodes seen on the planning CT (> 1 cm 
short axis diameter) or pre-treatment PET scan (SUV > 3) will constitute the GTV. This 
volume(s) may be disjointed. In the event of a collapsed lobe or lung segment, the use of PET to 
distinguish tumor from fluid/atelectasis is encouraged. 
CTV: The CTV is defined to be the GTV plus a 0.5 cm margin as appropriate to account for 
microscopic tumor extension. The CTV should be adjusted to not expand into other organs such 
as esophagus, heart, major blood vessels, or bone unless clinically indicated. If an ITV approach 
is used, then the ITV plus 0.5 cm margin forms the CTV. 
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PTV: The PTV will be equal to the CTV plus 0.5 cm setup margin in all directions. 
5.2.4. 
Prophylactic cranial irradiation (PCI) 
For patients with stage II-III LS-SCLC who are less than 70 years of age with good performance 
status (ECOG 0 to 2), without impaired neurocognitive function, and attain a complete or partial 
response to initial systemic therapy, PCI is recommended.  
The preferred dose for PCI to the whole brain is 25 Gy in 10 daily fractions. The decision for 
PCI administration should be made according to investigator’s discretion and local institutional 
guidelines. 
Only standard prophylactic whole brain radiation therapy is allowed in the trial. Memantine may 
be used for prevention of brain irradiation-induced cognitive toxicity at the investigator’s 
discretion.  
During the PCI treatment period (about 2 weeks), the immunotherapy, including tislelizumab 
monotherapy and the combination of ociperlimab plus tislelizumab, will be temporarily 
suspended. 
5.3. 
Incorrect Administration or Overdose 
Any incorrect administration of any study drug or overdose of tislelizumab (defined as ≥ 600 mg 
in a 24-hour period), ociperlimab, cisplatin, carboplatin, or etoposide should be noted in the 
patient’s chart and on the appropriate eCRF. 
AEs associated with an overdose or incorrect administration of study drug will be recorded on 
the AE eCRF. Any SAEs associated with an overdose or incorrect administration must be 
reported within 24 hours of awareness via the SAE reporting process described in Section 8.6.2. 
Supportive care measures should be administered as appropriate. 
5.4. 
Investigational Medicinal Product Accountability 
The investigational medicinal products (IMPs) required for completion of this study 
(ociperlimab, tislelizumab, cisplatin, carboplatin, and etoposide) will be provided by the sponsor 
or sourced by the site and reimbursed by the sponsor, as required by local or country-specific 
guidance. The investigational site will acknowledge receipt of IMPs. Any damaged shipments 
will be replaced. 
Accurate records of all IMPs received, dispensed, returned, and disposed of should be recorded 
on the site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of IMP management. 
5.5. 
Dose Delay or Modification 
A dose delay is a deviation from prescribed dosing schedule (ie, the drug is withheld beyond 
visit window). A dose interruption is an interruption of an infusion. 
Every effort should be made to administer the study drug(s) according to the planned dose and 
schedule. In the event of significant toxicities, dosing may be delayed and/or reduced based on 
the guidelines below. Reasons for dose modifications or delays, the supportive measures taken, 
and the outcome will be documented in the patient's chart and recorded in the eCRF. 
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The dose modification guidelines in this section are not intended to be a substitute for clinical 
judgment. Investigators may delay or modify doses for other reasons (eg, AEs, declining weight, 
laboratory findings) as appropriate. 
5.5.1. 
Dose Delay or Modification for Ociperlimab or Tislelizumab 
There will be no dose reduction for ociperlimab or tislelizumab in this study. 
If a dose delay is required, ociperlimab and tislelizumab will be delayed for Arm A (ie, 
ociperlimab and tislelizumab must both be delayed in Arm A and, if applicable, restarted at the 
same time) and tislelizumab will be delayed in Arm B.  
Ociperlimab and tislelizumab in Arm A or tislelizumab in Arm B may be temporarily suspended 
if the patient experiences a toxicity that is considered related to ociperlimab or tislelizumab and 
requires a dose to be withheld. Investigational drug(s) should resume as soon as possible after the 
AEs recover to baseline or Grade 1, whichever is more severe, except for AEs that, in the 
opinion of the investigator, are not considered a safety risk to the patient. If a treatment delay is 
due to laboratory results worsening, eg, hematologic or biochemical parameters, the frequency of 
relevant blood tests should be increased as clinically indicated.  
In general, dose delays for reasons other than management of AEs are prohibited. A dose delay 
of ≤ 12 weeks is allowed under the following guidance and at the discretion of the investigator 
after consultation with the medical monitor or designee. 
If the administration of the study drug(s) can resume within ≤ 10 days, the drug(s) should be 
administered in the current cycle. If the study drug needs to be withheld for > 10 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 ociperlimab plus tislelizumab or tislelizumab alone 
≤ 12 weeks after the last dose of study treatment, then the patient should be discontinued from 
treatment. If the patient is not able to resume ociperlimab plus tislelizumab or tislelizumab alone 
≤ 12 weeks after the last dose for unforeseen non-drug-related reasons, continued treatment may 
be allowed if approved by the medical monitor. 
If imAEs are persistent without any improvement for >12 weeks, permanent discontinuation of 
the study drugs should be considered. In Arm A, the treatment discontinuation in response to 
imAEs should be applied to both ociperlimab and tislelizumab because the causality of imAEs 
may not be distinguished from one study drug to the other. 
If the patient recovers from the treatment-related AE after 12 weeks, reinitiation of the study 
drugs is permitted only in patients who are deemed to be deriving clinical benefit per the opinion 
of the investigator following agreement between the investigator and the medical monitor. 
The tumor assessment schedule will not be altered even if the administration of the study drug is 
delayed. 
If one component of chemotherapy is discontinued permanently during the first 4 cycles of 
treatment for reasons other than disease progression, the other component of chemotherapy may 
be continued per the guidelines in the study protocol and as per local practice. Ociperlimab plus 
tislelizumab (Arm A) or tislelizumab alone (Arm B) may continue as indicated. 
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If both components of the chemotherapy are withheld because of toxicity for > 6 weeks, 
chemotherapy should be discontinued; ociperlimab plus tislelizumab or tislelizumab alone may 
be continued if the toxicity resulting in chemotherapy discontinuation is not considered by the 
investigator to be related to ociperlimab plus tislelizumab or tislelizumab alone. Exceptions 
based on clinical benefit require the prior approval of the medical monitor. 
Specific treatment modifications to manage tislelizumab- or ociperlimab-related toxicities, such 
as imAEs and infusion-related reactions, are described in Section 8.7.1 and Appendix 7.  
5.5.2. 
Dose Delay, Interruption, or Modifications for Radiation Therapy 
Investigators will be advised to suspend the use of chemotherapy and/or ociperlimab plus 
tislelizumab or tislelizumab alone given with RT if they believe that continuing administration of 
chemotherapy and/or ociperlimab plus tislelizumab or tislelizumab alone will compromise 
delivery of full-dose RT in a timely manner. 
Reversible or permanent alopecia, bone marrow toxicity, esophagitis, and skin pigmentation are 
expected side effects of RT. Radiation-induced myocarditis and spinal cord injury rarely occur at 
doses lower than 50 Gy. Radiographic evidence of radiation-induced changes and subsequent 
fibrosis of the lung may occur within lung volumes receiving ≥ 20 Gy. It is essential to spare as 
much normal lung as possible in order to avoid symptomatic lung injury. 
• In case of radiation dose delay due to machine breakdown or public holidays or any 
dose delay of RT up to 7 days, radiation should be completed to the prescribed doses. 
Total number of fractions and elapsed days should be carefully reported. 
• During the cCRT phase, esophagitis is managed according to Appendix 13 and 
Appendix 14 with regard to RT. During this cCRT period, chemotherapies and/or 
ociperlimab plus tislelizumab or tislelizumab alone should be withheld if the 
investigator believes that continued use will jeopardize the delivery of full-dose RT 
and RT is to be continued. Retreatment with chemotherapies and/or ociperlimab plus 
tislelizumab or tislelizumab alone is permitted if there is resolution of the esophagitis 
to ≤ Grade 2. 
• If Grade 4 esophagitis related to RT, chemotherapies, or ociperlimab plus 
tislelizumab or tislelizumab alone occurs, RT, chemotherapies, and/or ociperlimab 
plus tislelizumab or tislelizumab alone should be held until resolution of the 
esophagitis to ≤ Grade 2. 
• During the cCRT phase, in case of Grade 3 or Grade 4 radiation pneumonitis/lung 
infiltrates related to RT, the recommendation is to hold RT, chemotherapies and 
ociperlimab plus tislelizumab or tislelizumab alone. Retreatment with RT, 
chemotherapies and ociperlimab plus tislelizumab or tislelizumab alone is acceptable 
if symptoms resolve to ≤ Grade 1 or are controlled on prednisolone ≤ 10 mg/day (or 
equivalent corticosteroids). Discontinue study treatment if symptoms persist with 
corticosteroid treatment. 
Radiation toxicities will be assessed according to NCI-CTCAE v5.0 criteria and reported per 
Section 8.3. Note that radiation toxicities can arise more than 90 days after the completion of RT. 
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Esophagitis 
The first symptoms of acute esophagitis usually start in the second or third week of RT, 
commonly at the dose of 18.0 to 21.0 Gy of standard fractionated RT (Wei et al 2006), and 
include a sensation of difficult swallowing (dysphagia). This may progress to painful swallowing 
of food and saliva (odynophagia) and later to constant pain not necessarily related to swallowing. 
In severe cases, patients may not be able to swallow at all and may require intravenous 
hydration, feeding through a gastric tube and, in rare cases, parenteral nutrition. Symptomatic 
esophagitis is common with combined modality therapy (Werner-Wasik 2005) and it does not 
constitute a reason to delay RT or chemotherapy, provided oral intake is sufficient to maintain 
hydration. Symptoms of acute esophagitis may persist for 1 to 3 weeks after completion of RT. If 
CTCAE Grade 4 esophagitis occurs and treatment is delayed, every effort should be made to 
limit the radiation dose delay to 3 treatment days or less. Patients requiring hospitalization, 
placement of a feeding tube in the stomach, or intravenous feedings because of esophagitis may 
have their treatment dose delayed in order to allow for healing of the esophageal mucosa. 
Recommended dose modifications of the chemotherapy regimens in cases of Grade 3 or 4 
esophagitis are presented in Appendix 13. 
Information regarding esophagitis grading according to NCI-CTCAE v5.0 and management of 
radiation esophagitis through diet and medications is presented in Appendix 14. 
Pneumonitis 
Pneumonitis has been reported in association with use of anti-PD-L1/anti-PD-1 antibodies. It is 
also seen in 5% to 15% of patients irradiated for breast, lung, and mediastinal tumors. Thus, 
pneumonitis may be immune-related or as a result of late toxicity to RT. The risk of developing 
radiation pneumonitis is directly related to the volume of irradiated lung, the amount of radiation 
given, and the use of cCRT. Additional risk factors include comorbid lung disease, poor baseline 
pulmonary function testing, and low performance status.  
Symptoms of radiation pneumonitis, including low-grade fever, congestion, dry cough, pleuritic 
chest pain, and a sensation of chest fullness, usually develop 1 to 3 months after completion of 
RT. Diagnosis is difficult, often complicated by comorbid conditions and radiation injury to 
adjacent structures (eg, esophagus, pericardium). Prednisone, in dosages of at least 50 to 60 mg 
per day for 1 week followed by an extended taper, has been shown to abate symptoms and 
improve lung function. Bronchodilators and supplemental oxygen may be necessary. 
5.5.3. 
Dose Delay, Interruption, or Modifications for Chemotherapy 
Dose modifications for chemotherapy should be performed per applicable local prescribing 
information and per local practice according to the investigator’s clinical judgment. 
Recommended dose modifications for key chemotherapy toxicities are outlined in Appendix 13. 
If chemotherapy-related toxicities warrant a dosing delay, chemotherapy administration may 
restart as soon as is feasible. Chemotherapy may be delayed up to 3 weeks to allow sufficient 
time for recovery. Upon recovery, chemotherapy is recommended to be administered according 
to the dose as described in Appendix 13.  
These serve as guidelines and do not replace investigator judgment and applicable local label 
recommendations if more stringent. 
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Baseline body weight is used to calculate the required chemotherapy doses. Dose modifications 
are required if the patient’s body weight changes by ≥ 10% from baseline (or the new reference 
body weight). Chemotherapy doses should not be modified for any body weight change of 
˂ 10%.  
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion of 
the investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of the 
investigator, the toxicity is related to the combination of both chemotherapy agents, both drugs 
should be held/modified according to recommended dose modifications. 
Study drug-related toxicities must be resolved to baseline or Grade 1 (whichever is more severe) 
before administering the next dose, except for alopecia or ≤ Grade 2 fatigue or neuropathy. A 
maximum of 2 dose reductions for each chemotherapeutic agent, except for carboplatin, are 
permitted. Only 1 dose reduction is permitted for carboplatin. Once the dose has been decreased, 
it should remain reduced for all subsequent administrations or further reduced if necessary. There 
will be no dose escalations in this study. If additional reductions are required, that 
chemotherapeutic agent must be discontinued. 
The interval between the start of 2 consecutive chemotherapy regimens should be ≥ 3 weeks. If 
chemotherapy-related toxicities warrant a dosing delay, chemotherapy administration may restart 
as soon as is feasible. For example, chemotherapy administration can occur during an 
unscheduled visit and resynchronize with ociperlimab plus tislelizumab or tislelizumab alone at 
subsequent cycle(s), if possible. Dosing intervals of subsequent cycles of ociperlimab plus 
tislelizumab or tislelizumab alone may be shortened or extended as clinically feasible to allow 
for resynchronization, but the time between 2 consecutive doses of ociperlimab plus tislelizumab 
or tislelizumab alone should be at least 10 days. If clinically appropriate, the investigator may 
delay all treatment components up to a maximum of 7 days to allow synchronized administration 
of all agents and realigned dosing of treatment cycles according to the original schedule. 
If the patient is unable to resume chemotherapy treatment ≤ 6 weeks after the last dose of 
chemotherapy, then the patient should be discontinued from treatment. If the patient is not able 
to resume chemotherapy ≤ 6 weeks after the last dose because of unforeseen non-drug-related 
reasons, continued treatment may be allowed if approved by the medical monitor. 
SELECTED PRECAUTIONS FOR CHEMOTHERAPY: 
• Neutropenia: Fever or other evidence of infection must be assessed promptly and treated 
aggressively following the local clinical practice and/or the guidelines. 
• Renal Toxicity:  
o Nephrotoxicity is common with cisplatin. Encourage oral hydration.  Avoid 
nephrotoxic drugs such as aminoglycoside antibiotics. 
o Patients should not be given cisplatin or carboplatin if their creatinine clearance is 
< 60 mL/min or < 45 mL/min, respectively. 
o Etoposide dosage should be reduced to 75% of dose in patients with a creatinine 
clearance from 15 to 50 mL/min.  
o Patients will be allowed to switch from cisplatin to carboplatin if patients become 
ineligible for cisplatin due to toxicity related to cisplatin if they have completed 
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≥ 1 cycle of cisplatin treatment. Reasons for platinum switch should be documented 
in source documents and eCRF. 
• Ototoxicity and sensory neural damage should be assessed before each cycle. Cisplatin is 
contraindicated in patients with a preexisting hearing deficit. 
For toxicities not listed above, dose modifications are permitted per local standards. 
5.5.4. 
Criteria for Discontinuing Chemotherapy Regimens 
Except where specified above, both chemotherapy drugs in the platinum-based doublet regimen 
should be discontinued for any of the following: 
• Any Grade 4 peripheral neuropathy 
• Persistent Grade 3 paresthesia 
• Grade 3 or 4 drug-related thrombocytopenia associated with clinically significant 
bleeding 
• Any drug-related liver function test abnormality value that meets any of the following 
criteria requires discontinuation: 
− AST or ALT > 5 x ULN for > 2 weeks 
− AST or ALT > 10 x ULN or 
− Total bilirubin > 5 x ULN or 
− Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• Any drug-related AE that recurs after 2 prior dose reductions (1 dose reduction for 
carboplatin) for the same drug-related AE requires discontinuation of the drug(s). 
• Any Grade 3 or 4 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) assessed to be causing the reaction. The drug assessed 
as not related to the hypersensitivity reaction or infusion reaction may be continued. 
• Any Grade 4 AE that the investigator considers related to study drug and 
inappropriate to be managed by dose reduction(s) requires discontinuation of drug(s). 
The drug not assessed to be related to the event may be continued. 
• If any significant toxicity does not resolve within 21 days, that component will be 
discontinued.  
For toxicities not listed above, the investigator would determine whether the chemotherapy 
regimen should be discontinued per clinical judgment, patient’s well-being, and local standards. 
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6. 
PRIOR AND CONCOMITANT THERAPY 
6.1. 
Prior Therapy 
The eligibility criteria (Section 4) specify that patients should not have received any prior 
treatment for LS-SCLC; prior therapies targeting PD-1, PD-L1, PD-L2, TIGIT, T-cell 
costimulation or checkpoint pathways; immunotherapy (eg, interleukin, interferon, or thymosin); 
or investigational therapy ≤ 14 days or 5 half-lives (whichever is longer) before randomization. 
6.2. 
Concomitant Therapy 
6.2.1. 
Permitted Concomitant Medications/Procedures 
Unless otherwise noted, most concomitant medications and therapies deemed necessary and in 
keeping with local standards of medical care at the discretion of the investigator for supportive 
care (eg, antiemetics, antidiarrheals) and in a patient’s interest are allowed. Opiates and other 
medication required for palliative management of patients are allowed. Patients must notify the 
investigator of all concurrent medications used during the study. 
All concomitant medications will be recorded on the eCRF including all prescription and 
over-the-counter medications, herbal supplements, and intravenous medications and fluids.  
6.2.1.1. 
Systemic Corticosteroids 
Systemic corticosteroids given for the control of imAEs must be tapered gradually (see 
Appendix 7) and given at nonimmunosuppressive doses (≤ 10 mg/day of prednisone or 
equivalent) before the next administration of ociperlimab plus tislelizumab or tislelizumab alone. 
The short-term use of steroids as prophylactic treatments (eg, for patients with contrast allergies 
to diagnostic imaging contrast dyes) is permitted. 
6.2.1.2. 
Hepatitis B Treatment 
Patients with active hepatitis B, defined as HBV DNA ≥ 500 IU/mL at screening, must initiate 
treatment 2 weeks before randomization and continue until 6 months after the last dose of study 
drug(s). Patients should continue effective antiviral treatment during the study to decrease 
potential viral re-activation risk. Tenofovir and entecavir are recommended in the American 
Association for the Study of Liver Disease (AASLD) guideline because patients are unlikely to 
develop resistance to these drugs with long-term use (Terrault et al 2016; AASLD/IDSA HCV 
Guidance Panel 2015). The investigator may approve the use of other antiviral agents, if 
appropriate, following local guidelines. However, interferon-based therapy for hepatitis B is not 
permitted on study. 
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 500 IU/mL) is at the discretion of the investigator, in accordance with 
local guidance. Such medications must be documented in the patient’s chart and recorded in the 
eCRF. Patients receiving antiviral therapy at screening should be treated for > 2 weeks before 
randomization and continue treatment during the study and for 6 months after study treatment 
discontinuation. 
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6.2.1.3. 
Hepatitis C Treatment 
Patients who are receiving treatment for hepatitis C at screening should remain on continuous, 
effective antiviral therapy during the study. Investigators can consider treatment with sofosbuvir 
alone or in combination with other antivirals following the AASLD guideline or local guidelines 
as appropriate. However, interferon-based therapy for HCV is not permitted on study. Patients 
who are given antiviral therapy must initiate treatment > 2 weeks before randomization. 
6.2.2. 
Prohibited Concomitant Medications/Procedures 
Live vaccines ≤ 28 days before randomization and ≤ 60 days after the last dose of study drug(s) 
are prohibited. 
The following medications are prohibited during screening, through the EOT Visit or disease 
progression, whichever occurs later:  
• Any concurrent anticancer therapy, including chemotherapy, hormonal therapy, 
immunotherapy, standard anticancer agents, or investigational anticancer agents 
• Any investigational anticancer therapy 
• Herbal remedies for the treatment of cancer or Chinese patent medicines with 
approval from the China National Medical Products Administration (NMPA) for use 
as anticancer treatment (regardless of cancer type)  
• Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or that 
are known to potentially interfere with liver or other major organ functions (eg, 
hypericin)  
Patients must notify the investigator of all herbal remedies used during the study. 
6.2.3. 
Restricted Concomitant Medications/Procedures 
The following medications are restricted during screening and through the EOT Visit: 
• Immunosuppressive agents (except to treat a drug-related AE) 
• Systemic corticosteroids > 10 mg daily (prednisone or equivalent), except to treat or 
control a drug-related AE (per protocol) or for short-term use as prophylactic 
treatment. In addition, use of inhaled and intranasal corticosteroids is permitted 
• Patients should not abuse alcohol or other drugs during the study 
• Use of potentially hepatotoxic drugs in patients with impaired hepatic function should 
be carefully monitored 
6.3. 
Potential Interactions Between Study Drugs and Concomitant 
Medications 
Information regarding clinical drug interactions with ociperlimab is not available and no 
dedicated drug-drug interaction studies are planned. However, the potential for drug-drug 
interaction between the study drugs (ociperlimab and tislelizumab) and small molecule drug 
products is very low because ociperlimab and tislelizumab are therapeutic monoclonal 
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antibodies. Additionally, ociperlimab and tislelizumab are unlikely to have an effect on 
drug-metabolizing enzymes or transporters because they are expected to be degraded into amino 
acids and recycle into other proteins. 
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7. 
STUDY ASSESSMENTS AND PROCEDURES 
A table of scheduled study assessments is provided in Appendix 1. Patients will be closely 
monitored for safety and tolerability throughout the study. All assessments must be performed 
and documented in the medical record for each patient. 
Dosing will occur only if the clinical assessment and local laboratory test values (that must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines.  
7.1. 
Screening 
Screening evaluations will be performed within 28 days before randomization. Patients who 
agree to participate will sign the ICF before undergoing any screening procedure. The screening 
period begins on the first day a screening procedure is conducted. Screening evaluations may be 
repeated as needed within the screening period; the investigator is to assess patient eligibility 
according to the latest screening assessment results. 
Results of standard-of-care tests or examinations performed before obtaining informed consent 
and ≤ 28 days before randomization may be used for the purposes of screening rather than 
repeating the standard-of-care tests unless otherwise indicated. 
Procedures conducted during the Screening Visit only are described in this section. Patients who 
are suspected or known to have concurrent serious respiratory illness or exhibit significant 
respiratory symptoms unrelated to underlying cancer should take a pulmonary function test (refer 
to Appendix 1 for details) based upon the treatment physician’s judgement. For the description 
of other assessments that are conducted during screening, as well as throughout the study, refer 
to Safety Assessments (Section 7.4), Tumor and Response Evaluations (Section 7.5) and 
Biomarkers (Section 7.7) sections. The PK sampling schedule is shown in Appendix 1. 
Rescreening under limited conditions may be allowed after consultation with the sponsor, eg, 
when a patient narrowly misses a laboratory criterion and it is correctable and not due to rapidly 
deteriorating condition or disease progression. Rescreening is allowed only once. 
7.1.1. 
Informed Consent and Screening Log 
Voluntary, written informed consent for participation in the study must be obtained before 
performing any study-specific procedures. Informed consent forms for enrolled patients and for 
patients who are screened but not enrolled will be maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization. The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable. 
7.1.2. 
Patient Numbering 
After obtaining informed consent, study site personnel will access the Interactive Response 
Technology (IRT) system to assign a unique patient number to each potential study participant. 
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7.1.3. 
Demographic Data and Medical History 
Demographic data will include age or year of birth, sex, and self-reported race/ethnicity.  
Medical history includes any history of clinically significant disease, surgery, or cancer; 
reproductive status (ie, of childbearing potential or no childbearing potential); history of alcohol 
consumption and tobacco (ie, former or current or never); and all medications (eg, prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by 
the patient within 28 days before randomization.  
Cancer history will include an assessment of prior surgery, prior, RT and prior drug therapy 
including start and stop dates, best response, and reason for discontinuation. Data from 
radiographic studies performed before study entry may be collected for review by the 
investigator. 
Preexisting AEs at baseline should be recorded as medical history. 
7.1.4. 
Female Patients of Childbearing Potential and Contraception 
Childbearing potential is defined as the physiological ability to become pregnant. Refer to 
Appendix 9 for contraception guidelines and definitions of “women of childbearing potential” 
and “no childbearing potential.” 
A urine or serum pregnancy test (for women of childbearing potential, including women who 
have had a tubal ligation) must be performed and documented as negative within 7 days before 
the first dose of study treatment. Urine pregnancy tests will be performed at the timepoints 
indicated in Appendix 1. A serum pregnancy test must be performed if the urine pregnancy test 
is positive or equivocal. 
7.1.5. 
Pulmonary Function Tests 
Pulmonary function testing including spirometry and assessment of oxygenation, at a minimum, 
pulse oximetry at rest and with exercise, or alternatively, assessment of diffusion capacity, are to 
be performed as clinically indicated (eg, patient is having symptoms of lung problems or has 
medical history of chronic lung disease) during the Screening Period to assist the determination 
of suitability on the study. Respective test results need to be submitted to the sponsor. 
For test results indicative of significantly impaired pulmonary function, eg, resting pulse 
oximetry < 90% on room air and further desaturation upon exercise, forced expiratory volume 
(FEV1) < 60% or diffusing capacity of the lungs for carbon monoxide (DLCO) (if performed) 
< 60% of age- and sex-adjusted predicted performance levels (Pellegrino et al 2005), the medical 
monitor needs to be consulted to confirm eligibility. 
Tests may be repeated as clinically indicated while on study. 
7.2. 
Enrollment 
7.2.1. 
Confirmation of Eligibility 
The investigator is responsible for ensuring that each patient meets the eligibility criteria for this 
study. The investigator will assess and confirm the eligibility of each patient. All results from the 
screening procedures and relevant medical history must be available before eligibility can be 
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determined. All inclusion criteria must be met and none of the exclusion criteria may be met. No 
eligibility waivers will be granted.  
After a patient is screened and the investigator determines that the patient is eligible, study site 
personnel will complete the Treatment Eligibility Form (TEF) by transcribing information on 
inclusion/exclusion criteria, significant medical history, concomitant medications, disease 
history, pathology diagnosis, information from relevant imaging reports (as applicable), prior 
anticancer therapies and screening safety laboratory results requested in the TEF.  
To confirm eligibility, the TEF will be sent by the site to the medical monitor or designee, via 
secure transmission, for review during the screening period. Per the patient 
privacy/confidentiality provisions in this protocol, the TEF should be coded with the patient’s 
screening ID number to protect the patient’s personal data in accordance with local laws and 
regulations and BeiGene requirements (eg, direct identifiers such as names, initials and full date 
of birth should never be shared, and personal data not specifically required by the protocol 
should never be included or otherwise provided).  
The medical monitor will review the TEF and confirm the investigator has accurately assessed 
that all inclusion criteria have been met and none of the exclusion criteria apply and 
communicate their conclusion to the site.  If the medical monitor raises concerns about the 
eligibility of a potential patient or the contents of the TEF, the investigator is responsible for 
reviewing and responding to the medical monitor’s concerns and/or correcting the contents of the 
TEF, as appropriate. A patient cannot be started on study drug until confirmation of eligibility 
from the medical monitor or designee is received and filed in the patient’s records. 
7.2.2. 
Enrollment/Randomization 
Site personnel will access the IRT system to randomize patients to treatment assignment and to 
enable study drug dispensation. Study treatment must commence within 3 business days after 
randomization/treatment assignment. 
7.3. 
Study Drug Dispensation 
All study drugs will be dispensed and administered as described in Section 5.2. 
7.4. 
Safety Assessments 
7.4.1. 
Vital Signs, Height, and Weight 
Vital signs will include measurements of body temperature, pulse rate, and blood pressure 
(systolic and diastolic).  
Vital signs will be assessed in Arms A, B, and C at screening, before study drug administration 
on Days 1, 8, and 15 in the first 2 cycles for all patients at the beginning of each subsequent 
cycle, at the EOT Visit, and at the Safety Follow-up Visit (Appendix 1).  
The patient’s vital signs must be recorded within 60 minutes before, during, and 30 minutes after 
the first infusion of ociperlimab plus tislelizumab (as a whole infusion) in Arm A or tislelizumab 
alone in Arm B at each cycle visit for 2 cycles. For subsequent cycles, vital signs will be 
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collected within 60 minutes before the infusion, if clinically indicated, during and 30 minutes 
after the infusion.  
Pulse rate and blood pressure should be collected while the patient is in a seated position after 
resting for 10 minutes and before the start of any treatment. Weight will be assessed at screening, 
before study drug administration on Day 1 of each cycle, at the EOT Visit, and at the Safety 
Follow-up Visit. Height will be recorded at screening only. 
7.4.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted including 
evaluations of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) dermatological, 4) 
musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) neurological systems. Any 
abnormality identified during screening will be graded according to NCI-CTCAE v5.0 and 
recorded on the eCRF with appropriate disease/condition terms. 
At subsequent visits (and as clinically indicated), limited (especially for respiratory and 
cardiovascular systems), symptom-directed physical examinations will be performed. New or 
worsened clinically significant abnormalities are to be recorded as AEs on the eCRF. Refer to 
Section 8.3 regarding AE definitions and reporting and follow-up requirements. 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG Performance Status (Appendix 3) will be assessed during the study as outlined in 
Appendix 1. 
7.4.4. 
Laboratory Safety Tests 
Local laboratory assessments of serum chemistry, hematology, coagulation, and urinalysis will 
be conducted as outlined in Appendix 2. 
If laboratory tests at screening are not performed within 7 days before the administration of study 
drug(s) on Day 1 of Cycle 1, these tests should be repeated and reviewed before administration 
of study drug(s).  
Hematology, serum chemistry (including liver function tests), and coagulation assessments will 
be performed at the timepoints specified in Appendix 1. 
Urinalysis is to be conducted at screening and during the treatment period only if clinically 
warranted. 
Thyroid assessments (free or total triiodothyronine [T3]; free or total thyroxine [T4], and 
thyroid-stimulating hormone [TSH]) will be performed at the timepoints specified in 
Appendix 1. 
7.4.4.1. 
Cardiac Enzyme Monitoring 
Although immune-related myocarditis is a rare complication of immune checkpoint inhibitors, 
serum creatinine kinase (CK) and CK cardiac isoenzyme (CK-MB) will be monitored to protect 
study participants and to quantify the risk of muscle inflammation (see Appendix 1 for the blood 
collection schedule and Appendix 7 for guidelines for management of suspected immune-related 
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myocarditis). Serum troponins may be substituted per local guidelines if used consistently 
throughout the study. 
7.4.5. 
Electrocardiograms 
The 12-lead ECG recordings will be obtained during screening, as clinically indicated during the 
treatment period, at the EOT Visit, and at the Safety Follow-up Visit (Appendix 1). 
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. 
Patients should rest in semirecumbent supine position for ≥ 10 minutes before ECG collection. 
When coinciding with blood draws at the same timepoint, ECG assessment should be performed 
before blood draws and study treatment infusions. 
7.4.6. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0. 
Characterization of toxicities will include severity, duration, and time to onset. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
7.4.7. 
Hepatitis B and C Testing 
Testing will be performed by the local laboratory at screening and will include screening 
HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody). After screening, viral load 
assessment (HBV DNA and HCV RNA) may be performed if clinically indicated. Patients who 
have detectable HBV DNA at screening or upon repeat testing will undergo the respective viral 
load test every 4 cycles (eg, Cycles 4, 8, and 12) (Appendix 1). 
7.5. 
Tumor and Response Evaluations 
Tumor imaging will be performed within 28 days before randomization. During the study, tumor 
imaging will be performed at approximately 12 weeks (± 7 days) from the date of randomization 
(an additional tumor assessment is allowed if clinically indicated), then every 6 weeks (± 7 days) 
for the next 54 weeks, and then every 12 weeks (± 7 days) thereafter based on RECIST v1.1. If a 
tumor assessment is missed or conducted outside of the specified assessment window, all 
subsequent scans should be conducted on the planned schedule. 
Screening assessments and each subsequent assessment of the tumor must include computed 
tomography (CT) scans (with oral/intravenous contrast, unless contraindicated) or magnetic 
resonance imaging (MRI) of the chest, abdomen, and pelvis. Other known or suspected sites of 
disease must be included in the imaging assessments (neck, brain, etc). 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit 
and reassessed at each subsequent tumor evaluation. The same radiographic procedure used to 
assess disease sites at screening must be used throughout the study (eg, the same contrast 
protocol for CT scans). 
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• Imaging of the brain (preferably MRI) at baseline is required for all screened patients. 
Screening evaluations will be performed within 28 days before randomization and 
additional evaluations may also be performed as clinically indicated during the study. 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a non-contrast CT of the chest plus a 
contrast-enhanced MRI (if possible) of the abdomen and pelvis should be performed. 
• If a CT scan for tumor assessment is performed on a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards of a 
diagnostic CT scan. 
• Bone scans (Technetium-99m [Tc-99m]) or PET should be performed at screening if 
clinically indicated.  
• CT scans of the neck or extremities should be performed at screening only if 
clinically indicated. 
• At the investigator’s discretion, other methods of assessment of target lesions and 
nontarget lesions per RECIST v1.1 may be used. 
Response will be assessed by the investigator using RECIST v1.1 (see Appendix 4). The same 
evaluator should perform assessments, if possible, to ensure internal consistency across visits. 
Administration of study treatment will continue until up to12 months after randomization for 
Arms A and B and for 4 cycles for Arm C, or until disease progression as assessed by the 
investigator per RECIST v1.1, unacceptable toxicity, death, or another discontinuation criterion 
is met, whichever occurs first. 
A patient who discontinues study treatment early for reasons other than disease progression (eg, 
toxicity) or completes study treatment will continue to undergo tumor assessments following the 
original schedule until disease progression per RECIST v1.1, withdrawal of consent, loss to 
follow-up, the start of a new anticancer therapy, death, or study termination, whichever occurs 
first. 
In Arms A and B, treatment with ociperlimab plus tislelizumab or with tislelizumab alone 
beyond the initial investigator-assessed, RECIST v1.1-defined disease progression is permitted 
provided that the patient has investigator-assessed clinical benefit and is tolerating the study 
drug(s). The following criteria must be met in order to treat patients who may continue to benefit 
from study drugs after disease progression: 
• Absence of clinical symptoms and signs of disease progression (including clinically 
significant worsening of laboratory values) 
• Stable ECOG Performance Status (≤ 2) 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention 
• Investigators must obtain written informed consent for treatment beyond radiologic 
disease progression and inform patients that this practice is not considered standard in 
the treatment of cancer  
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The investigator should obtain written agreement from the sponsor medical monitor on 
continuing study drug(s) beyond the initial investigator-assessed progression, and the decision 
must be documented in the study records. 
Tumor assessments should continue as planned in patients receiving study drug(s) beyond initial 
investigator-assessed progression. Tumor assessments in such patients should continue until 
study treatment discontinuation.  
Tumor assessments are required to be performed on schedule regardless of whether study 
treatment has been administered or held; that is, tumor assessments should not be adjusted for 
delays in cycles. 
7.6. 
Pharmacokinetic and Antidrug Antibody Testing 
Checkpoint inhibitor drugs may elicit an immune response. Patients with signs of any potential 
immune response to ociperlimab or tislelizumab will be closely monitored. Validated screening 
and confirmatory assays will be employed to detect ADAs at multiple timepoints throughout the 
study (Appendix 1). The immunogenicity evaluation will utilize a risk-based immunogenicity 
strategy (Koren et al 2008; Worobec and Rosenberg 2004a; Worobec and Rosenberg 2004b) to 
characterize ADA responses to ociperlimab and tislelizumab in support of the clinical 
development program. In addition, blood samples will be collected for characterization of 
ociperlimab and tislelizumab PK at the timepoints specified in the Schedule of Assessments 
(Appendix 1).  
The following assessments will be performed at a central laboratory: 
• ADA assays: serum samples will be tested for the presence of ADAs to ociperlimab 
or tislelizumab using a validated immunoassay 
• PK assay: serum samples will be assayed for ociperlimab or tislelizumab 
concentration using a validated immunoassay 
Shipping, storage, and handling of samples for the assessment of ociperlimab and tislelizumab 
PK and ADA assays will be managed through a central laboratory. Instruction manuals and 
supply kits will be provided for all central laboratory assessments. 
7.7. 
Biomarkers 
Shipping, storage, and handling of blood, archival tumor, fresh tumor, and leftover tumor tissue 
for the assessment of biomarkers will be managed through a central laboratory. Refer to the 
laboratory manual for details of sample handling. 
Patients must agree to provide an archival tumor tissue with an associated pathology report or 
agree to perform a fresh tumor biopsy during screening (formalin-fixed paraffin-embedded block 
or approximately 15 unstained slides [8 slides minimum]). Note: If < 8 unstained slides are 
available, a discussion with the sponsor is required. PD-L1 and TIGIT expression by 
immunohistochemistry will be tested in the central laboratory and their association with clinical 
efficacy with be analyzed for the secondary endpoint analysis. In addition to PD-L1 and TIGIT 
expression, other exploratory predictive biomarkers, including but not limited to gene expression 
profile, tissue- or blood-based gene mutations and TMB/MSI, CD155/CD226 expression, and 
SCLC subtyping by the expression of transcription factors 
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(ASCL1/NEUROD1/POU2F3/YAP1), which may be related to the clinical benefit of 
ociperlimab and tislelizumab, may also be evaluated. If no archival samples are available, a fresh 
tumor biopsy at baseline is required. For fresh biopsy specimens, acceptable samples include 
core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies 
for cutaneous, subcutaneous, or mucosal lesions.  
For patients who have confirmed disease progression during the study, optional biopsies will also 
be taken from accessible tumor sites to obtain samples to explore resistance mechanisms. If 
feasible, any follow-up biopsy should be ideally taken from the same tumor lesion as the baseline 
biopsy. Written patient consent is required for fresh tumor biopsies. Biomarker testing for 
optional biopsy samples will include PD-L1 and TIGIT as well as other exploratory biomarkers. 
(Note: for the sites in China mainland, tissue and blood samples will be obtained to test the 
expression of PD-L1 and TIGIT, gene expression profile, tissue- or blood-based gene mutations 
and TMB/MSI and ctDNA level change, CD155/CD226 expression, and SCLC subtyping by the 
expression of transcription factors (ASCL1/NEUROD1/POU2F3/YAP1). 
Tumor tissue should be of good quality based on total and viable tumor content. Cytology 
samples including fine-needle aspiration, brushing, cell pellets from pleural effusion, and lavage 
samples are not acceptable. 
Blood samples will be collected at screening and at defined timepoints during treatment as well 
as at the time of confirmed disease progression (see Appendix 1 for the specified timepoints) for 
assessment of blood-based tumor mutation profile and ctDNA level change before and after 
treatment. The association of ctDNA level change with ORR, PFS, and OS will be analyzed to 
evaluate the potential utility of ctDNA as a surrogate marker for clinical efficacy. 
Sample collection and biomarker testing will be performed after relevant regulatory approval. 
7.8. 
Patient-Reported Outcomes 
Patients will be asked to complete questionnaires before any clinical activities (including blood 
draws or imaging scans) are performed during on-study clinic visits according to the schedule in 
Appendix 1. These questionnaires will include the EORTC-QLQ-C30 (Appendix 10) and its 
lung cancer module QLQ-LC13 (Appendix 11). The questionnaires will be provided in the 
patient’s preferred language. 
7.9. 
Visit Windows 
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see 
Appendix 1). All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed before study treatment infusion/dose 
unless otherwise noted. Laboratory results are required to be reviewed before dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
event, the visit should be scheduled on the nearest feasible date (the visit window is provided in 
Appendix 1), with subsequent visits conducted according to the planned schedule every 3 weeks 
from Day 1 of Cycle 1. 
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7.10. 
Unscheduled Visits 
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include vital signs/focused physical examination; ECOG Performance Status; AE 
review; concomitant medications and procedures review; radiographic assessments; physical 
examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms; and 
hematology and chemistry laboratory assessments. The date and reason for the unscheduled visit 
must be recorded in the source documentation. 
If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, then 
diagnostic tests may be performed based on the investigator assessment as appropriate, and the 
results of these tests should be entered on the unscheduled visit eCRF. 
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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol. 
8.1. 
Risks Associated With Study Drugs 
8.1.1. 
Risks Associated With Ociperlimab and Tislelizumab 
Ociperlimab and tislelizumab are investigational agents that are currently in clinical 
development. Limited safety data are available in patients, and the full safety profile has not been 
characterized. The following recommendation is based on results from nonclinical and clinical 
studies with ociperlimab and tislelizumab and published data on other molecules within the same 
biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions. AEs observed with anti-PD-1 therapy are presented in Section 8.7.3. 
Ociperlimab-mediated TIGIT inhibition may increase the risk of imAEs. However, no apparent 
immunotoxicity, or toxicity in general, have been observed in animal models treated with 
ociperlimab. Furthermore, in the absence of activation, peripheral effector T cells do not 
typically express TIGIT, thereby minimizing any potential negative additive affect as it relates to 
peripheral immune tolerance. 
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 7. 
8.1.2. 
Risks Associated With Chemotherapy 
Please refer to Table 7 for the reported toxicity for the respective chemotherapeutic agents. The 
investigator should refer to the package insert for a complete list of potential side effects. 
Table 7: 
The Summary of the Commonly and Specific Reported Toxicity of the 
Chemotherapeutic Agents 
Agents 
Specific toxicity 
Common toxicity 
Cisplatin 
Nephrotoxicity; ototoxicity; peripheral 
neuropathies 
Myelodepression with leukopenia, 
thrombocytopenia and anemia; 
infectious complications; 
nausea/vomiting and other 
gastrointestinal toxicity; hepatic 
impairment; fatigue; anorexia; 
constipation 
Carboplatin 
Ototoxicity, peripheral neuropathies 
Etoposide 
Hypersensitivity reactions; ocular; 
respiratory; skin; neurologic 
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8.1.3. 
Risks Associated With Radiation Therapy 
AEs related to RT include nausea/vomiting, diarrhea, weight loss, fatigue, hematological 
toxicity, skin erythema, subcutaneous fibrosis, esophagitis, esophageal stricture, esophageal 
fistula, carditis, myelitis, acute radiation pneumonitis, and late pulmonary fibrosis. 
8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this study. Results from the 
nonclinical toxicology studies and clinical data with ociperlimab and tislelizumab, as well as the 
nonclinical/clinical data from other TIGIT and PD-L1/PD-1 inhibitors, were considered. 
Specifically, patients at risk for study-emergent active autoimmune diseases or with a history of 
autoimmune diseases that may relapse, patients who have undergone allogeneic stem cell or 
organ transplantation, and patients who have received a live vaccine ≤ 28 days before 
randomization are excluded from the study. Refer to Section 4.2 for the full list of exclusion 
criteria. 
8.2.2. 
Safety Monitoring Plan 
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v5.0. All enrolled patients will be evaluated clinically and with 
standard laboratory tests at regular intervals during their participation in this study. Safety 
evaluations will consist of medical interviews, recording of AEs (see Table 8), physical 
examinations, laboratory measurements (hematology, chemistry, etc) and other assessments, 
including those listed in Appendix 1. In addition, patients will be closely monitored for the 
development of any signs or symptoms of infections or autoimmune conditions. 
At the start of each cycle, study drug(s) will 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 (see Section 5.2). 
Serum samples will be drawn for determination of ADAs to ociperlimab and tislelizumab in 
patients randomized to Arms A and B. 
Investigators are instructed to report all AEs (including pregnancy-related AEs). 
The potential safety issues anticipated in this study, as well as measures intended to avoid or 
minimize such toxicities, are outlined in Section 8.7. 
8.3. 
Adverse Events 
8.3.1. 
Definitions and Reporting 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study 
drug, whether considered related to study drug or not. 
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Examples of AEs include the following: 
• Worsening of a chronic or intermittent preexisting condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome 
• Detection or diagnosis of a new condition after study drug administration, even 
though the condition may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. However, there may be instances when copies of medical records for certain 
cases are requested by the sponsor. In this instance, all patient identifiers will be blinded on the 
copies of the medical records before submission to the sponsor. 
8.3.2. 
Assessment of Severity 
The investigator will assess the severity of each AE and SAE reported during the study. AEs and 
SAEs should be assessed and graded based upon the NCI-CTCAE v5.0. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• 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 8.6.2. 
8.3.3. 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug and the occurrence 
of each AE or SAE, using best clinical judgment. Alternative causes, such as natural history of 
the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of 
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the AE or SAE to the study drug should be considered and investigated. The investigator should 
consult the Tislelizumab Investigator’s Brochure, Ociperlimab (BGB-A1217) Investigator’s 
Brochure, chemotherapy prescribing information, or radiation manual in the determination of 
his/her assessment. 
There may be situations when an SAE has occurred, and the investigator has only limited 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always assesses causality for every SAE before transmission of the SAE report to 
the sponsor, because the causality assessment is 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 
(ie, there are facts, evidence, or arguments to suggest possible causation). A number of factors 
should be considered in making this assessment, including the following: 
• Temporal relationship of the AE to the administration of study treatment/study 
procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study drug 
• Biological plausibility 
• An AE should be considered “related” to study drug if any of the following criteria 
are met; otherwise, the event should be assessed as “not related”: 
− There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out 
− There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely 
− There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of the study drug).  However, the 
influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs). 
8.3.4. 
Follow-up of Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts.  
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up or the patient 
withdraws consent. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
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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 8.6.2. 
8.3.5. 
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 dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or further diagnostic 
investigation. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 x ULN associated with cholestasis), only the diagnosis (ie, 
cholestasis) should be recorded on the Adverse Event eCRF. 
If the laboratory abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE. For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event eCRF unless the etiology changes. The initial 
severity of the event should be recorded, and the severity or seriousness should be updated any 
time the event worsens. 
8.4. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death. 
• Is life-threatening. 
Note: The term “life-threatening” in the definition of “serious” refers to an AE from 
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which the patient was at risk of death at the time of the AE. It does not refer to an AE 
that hypothetically might have caused death if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization. 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
• Results in disability/incapacity. 
Note: The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
• Is a congenital anomaly/birth defect. 
• Is considered a significant medical AE by the investigator based on medical 
judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
The following are NOT considered to be SAEs: 
• Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information) 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 Investigator’s Brochure, Ociperlimab (BGB-A1217) 
Investigator’s Brochure, chemotherapy prescribing information, or radiation manual. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events 
8.6.1. 
Adverse Event Recording Period 
After informed consent has been signed but before the administration of study drug, only SAEs 
should be reported. 
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After initiation of study treatment, all AEs and SAEs, regardless of relationship to study 
treatment, will be reported until either 30 days after the last dose of study treatment or initiation 
of new anticancer therapy, whichever occurs first. 
For patients in Arm A and Arm B, immune-mediated AEs (serious or nonserious) should be 
reported until 90 days after the last dose of ociperlimab plus tislelizumab or tislelizumab alone, 
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. 
All AEs ongoing at the time of treatment discontinuation which worsen in severity to Grade 5 
should be reported regardless of time from treatment stop. 
AEs and SAEs should be recorded according to the details in Table 8. For the follow-up period 
for AEs, see Section 8.3.4. For the definition of TEAEs, see Section 9.3.2. 
Table 8: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Arms 
Event type 
Record new or worsening events that occur during this period 
Begin 
End 
SAEs a 
Signing of informed 
consent 
Up to 30 days after last dose, initiation 
of new anticancer therapy, death, 
withdrawal of consent, or loss to 
follow-up, whichever occurs first 
Nonserious AEs due to disease 
progression 
Do not record (see Section 8.6.4) 
All nonserious AEs, except 
those due to PD 
First dose of study 
treatment 
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-related AEs (serious 
or nonserious) 
First dose of study 
treatment 
Up to 90 days after last dose 
(regardless of initiation of new 
anticancer therapy), death, withdrawal 
of consent, or loss to follow-up, 
whichever occurs first 
Abbreviations: AE, adverse event; PD, disease progression; SAE, serious adverse event. 
a All SAEs considered related to the study drug(s) that are brought to the attention of the investigator should be 
reported regardless of time since the last dose of treatment. 
8.6.2. 
Reporting Serious Adverse Events 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events 
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 9. 
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Table 9: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee 
 
Timeframe for sending 
initial/follow-up a report 
Documentation 
method 
Reporting method 
All SAEs  
Within 24 hours of first 
knowledge of the SAE 
SAE Report 
Electronic submission of 
SAE form to safety portal b 
Abbreviations: EDC, electronic data capture; IMP, investigational medicinal product; SAE, serious adverse event. 
a Report follow-up information that is clinically relevant and pertains to the SAE; this includes, but is not limited to, 
the following: Update to the SAE, new additional SAE, outcome, seriousness criteria, investigator causality, event 
start date/date of onset, date of death, relationship to each IMP. Follow-up information will also be reported at the 
discretion of the investigator if the new or updated information changes the medical assessment of the case. 
b SAE reports should be submitted to the sponsor’s safety database electronically from within the EDC. If the 
electronic submission is not available for any reason, a paper SAE form should be submitted by email or fax. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above in Section 8.6.2.1. The SAE Report 
will always be completed as thoroughly as possible with all available details of the event, and 
forwarded to the sponsor or designee within the designated 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 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will report all SAEs to the sponsor in accordance with the procedures detailed in 
Section 8.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation. 
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
All SUSARs (as defined in Section 8.5) will be submitted to all applicable regulatory authorities 
and investigators for ociperlimab and tislelizumab studies. 
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC. The investigator should place copies of 
Safety Reports from the sponsor in the Investigator Site File. 
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8.6.3. 
Eliciting Adverse Events 
The investigator or designee will ask patients about AEs by asking the following standard 
questions: 
• How are you feeling? 
• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
8.6.4. 
Disease Progression 
Disease progression, which is expected in this study population and is measured as an efficacy 
endpoint, should not be recorded as an AE term. Similarly, nonserious AEs that are clearly 
consistent with the pattern of progression of the underlying disease and are considered 
unequivocally due to disease progression should not be recorded. However, if there is any 
uncertainty as to whether a nonserious AE is due to disease progression, it should be recorded as 
an AE. All SAEs and deaths regardless of relatedness to disease progression should be recorded 
and reported (see Section 8.6.2). 
8.6.5. 
Deaths 
Death is an outcome and not usually considered an event. If the only information available is 
death and the cause of death is unknown, then the death is reported as an AE, eg, “death,” “death 
of unknown cause,” or “death unexplained.” 
8.6.6. 
Pregnancies 
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy, or within 120 days after the last dose of ociperlimab and tislelizumab in 
Arm A or tislelizumab in Arm B, or within 180 days after the last dose of radiotherapy or 
chemotherapy (except for cisplatin), or within 14 months after the last dose of cisplatin (for the 
female patient), or within 11 months after the last dose of cisplatin (for the partner of the male 
patient), a pregnancy report form is required to be completed and expeditiously submitted to the 
sponsor to facilitate outcome follow-up. Information on the status of the mother and child will be 
forwarded to the sponsor. Generally, follow-up will be no longer than 6 to 8 weeks after the 
estimated delivery date. Any premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should be always reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as an SAE. 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees 
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
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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  
• Ociperlimab (BGB-A1217) Investigator’s Brochure 
• Cisplatin prescribing information 
• Carboplatin prescribing information 
• Etoposide prescribing information 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events 
Because treatment with anti-PD-1 therapy or immune checkpoint inhibitors can cause 
autoimmune disorders, AEs considered by the investigator to be immune-mediated (see 
Section 8.7.3) should be classified as imAEs and identified as such on the eCRF AE page until 
90 days after the last dose of study treatment. 
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly described with immune checkpoint inhibitors, in Appendix 7. 
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 7. 
8.6.9. 
Recording Infusion-Related Reactions 
The symptoms of infusion-related reactions may include, but are not limited to, fever, 
chills/rigor, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness, or hypertension. Severe reactions may include acute respiratory 
distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Each 
individual sign and symptom of an infusion-related reaction should be recorded as a separate AE 
in the eCRF and identified as an infusion-related reaction. Refer to the eCRF completion 
guidelines for details. 
8.7. 
Management of Adverse Events of Special Interest 
As a routine precaution, after infusion of ociperlimab and tislelizumab (Arm A) and tislelizumab 
(Arm B) on Day 1 of Cycles 1 and 2, patients must be monitored for ≥ 120 minutes afterward in 
an area with resuscitation equipment and emergency agents. From Cycle 3 onward, a 
≥ 60-minute monitoring period is required in an area with resuscitation equipment and 
emergency agents. 
The management of infusion-related reactions, severe hypersensitivity reactions, and imAEs 
according to the NCI-CTCAE criteria are outlined below. 
8.7.1. 
Managing Infusion-Related Reactions 
Patients should be closely monitored for infusion-related reactions. Immediate access to an 
Intensive Care Unit (ICU) or equivalent environment and appropriate medical therapy (including 
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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 ociperlimab and 
tislelizumab 
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Any worsening is 
closely monitored. Medical management as 
needed. 
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 2 - moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, intravenous 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Stop infusion. Infusion may be resumed at 50% of 
previous rate once infusion-related reaction has 
resolved or decreased to Grade 1 in severity. Any 
worsening is closely monitored. Proper medical 
management should be instituted as described 
below. 
Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3 - severe 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
clinical sequelae. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Grade 4 - life-threatening 
Life-threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described 
below. 
The patient should be withdrawn from study 
drug(s) treatment. 
Hospitalization is recommended. 
Abbreviations: NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Event; NSAIDs, 
nonsteroidal anti-inflammatory drugs. 
Once the ociperlimab or tislelizumab infusion rate has been decreased by 50% or suspended due 
to an infusion-related reaction, it must remain decreased for all subsequent infusions and be 
administered with premedication. If the patient has a second infusion-related reaction 
(≥ Grade 2) on the slower infusion rate, infusion should be discontinued, and the patient should 
be withdrawn from treatment with ociperlimab plus tislelizumab or tislelizumab alone. 
NCI-CTCAE Grade 1 or 2 infusion-related 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), 
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and if considered indicated, oral or intravenous glucocorticoids, epinephrine, bronchodilators, 
and oxygen. In the next cycle, patients should receive oral premedication with an antihistamine 
(eg, diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or equivalent), and they 
should be closely monitored for clinical signs and symptoms of an infusion-related reaction. 
NCI-CTCAE Grade 3 or 4 infusion-related reaction: Proper medical management should be 
instituted immediately, as indicated per type and severity of the reaction. This includes, but is not 
limited to, oral or intravenous antihistamines, antipyretics, glucocorticoids, epinephrine, 
bronchodilators, and oxygen. 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms 
If a hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (UK) (Soar et al 2008). 
Patients should be instructed to report any delayed reactions to the investigator immediately. 
In the event of a systemic anaphylactic/anaphylactoid reaction the infusion must be immediately 
stopped and the patient discontinued from the study. Systemic anaphylactic/anaphylactoid 
reactions typically manifest within minutes after administration of the drug/antigen and are 
characterized by respiratory distress; laryngeal edema; and/or intense bronchospasm; and often 
followed by vascular collapse or shock without antecedent respiratory difficulty; cutaneous 
manifestations such as pruritus and urticaria with/without edema; and gastrointestinal 
manifestations such as nausea, vomiting, crampy abdominal pain, and diarrhea. 
The patient will be administered epinephrine injection and dexamethasone infusion if a 
hypersensitivity reaction is observed. The patient should then be placed on monitor immediately, 
and the ICU should be alerted for possible transfer if needed. 
For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drug infusion. 
Alternative treatments for fever (ie, paracetamol) may be given to patients at the discretion of the 
investigator. 
8.7.3. 
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, disease progression, or other neoplastic causes) with 
appropriate diagnostic tests that may include, but are not limited to, serologic, immunologic, and 
histologic (biopsy) data. If alternative causes have been ruled out; the AE required the use of 
systemic steroids, other immunosuppressants, or endocrine therapy; and is consistent with an 
immune-mediated mechanism of action, the imAE indicator on 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 ociperlimab or tislelizumab to determine whether they 
are immune mediated. 
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Recommendation for diagnostic evaluation and management of imAEs is based on European 
Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) 
guidelines (Haanen et al 2017; Brahmer et al 2018), and common immune-related toxicities are 
detailed in Appendix 7. For any AEs not included in Appendix 7, please refer to the ASCO 
Clinical Practice Guideline (Brahmer et al 2018) for further guidance on diagnostic evaluation 
and management of immune-related toxicities. 
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, myositis 
Blood 
anemia; leukopenia; thrombocytopenia 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Neurologic 
encephalitis, meningitis, meningoradiculitis, meningoencephalitis 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Recommendations for managing imAEs are detailed in Appendix 7. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drug(s) should be discontinued 
after consultation with the sponsor. Patients who experience a recurrence of any event at the 
same or higher severity grade after restart of study drug should permanently discontinue 
treatment. 
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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
The statistical analyses will be performed by the sponsor or designee after the data collection is 
completed and the database is locked and released. Details of the statistical analyses will be 
included in a separate Statistical Analysis Plan. 
9.1. 
Statistical Analysis 
9.1.1. 
Randomization Methods 
As discussed in Section 7.2.2, patients will be randomized using the IRT system for this study by 
permuted block stratified randomization with a stratification factor of disease stage 
(stage I/II versus stage III). 
9.1.2. 
Analysis Sets 
The ITT Analysis Set includes all randomized patients. Patients will be analyzed according to 
their randomized treatment arm. This will be the primary analysis set for all efficacy analysis. 
The Safety Analysis Set includes all patients who have received ≥ 1 dose of any component of 
study drug; it will be the analysis set for the safety analyses.  
The PK Analysis Set includes all patients who receive ≥ 1 dose of tislelizumab/ociperlimab per 
the protocol and for whom any quantifiable postbaseline PK data are available. 
The ADA Analysis Set, which includes all patients who receive ≥ 1 dose of 
tislelizumab/ociperlimab and for whom both baseline and ≥ 1 postbaseline ADA result are 
available. 
The Biomarker Analysis Set includes all patients who have ≥ 1 evaluable biomarker 
measurement; it will be used for biomarker analysis. 
9.1.3. 
Patient Disposition 
The number of patients randomized, treated, or discontinued from study drug and/or study, and 
those with important protocol deviations will be counted. The primary reason for study drug 
and/or study discontinuation will be summarized according to the categories in the eCRF. The 
end-of-study status (alive, dead, withdrew consent, or lost to follow-up) at the data cutoff date 
will be summarized using the data from the eCRF. 
Important protocol deviations will be summarized and listed by each category. 
9.1.4. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics of the ITT population will be summarized using 
descriptive statistics. Continuous variables include age, weight, vital signs, and time since initial 
cancer diagnosis. Categorical variables include gender, ECOG Performance Status, geographical 
region, country, race, disease stage, smoking history, and PET-CT done or not done. 
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9.1.5. 
Prior and Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary drug codes.  
Concomitant medications will be further coded to the appropriate Anatomical Therapeutic 
Chemical (ATC) code indicating therapeutic classification. Prior and concomitant medications 
will be summarized and listed by drug and drug class in the Clinical Study Report (CSR) for this 
protocol. Prior medications will be defined as medications that were stopped before the day of 
the first dose of study drug. Concomitant medications will be defined as medications that 1) were 
started before the first dose of study drug and were continuing at the time of the first dose of 
study drug, or 2) were started on or after the date of the first dose of study drug up to 30 days 
after the patient’s last dose (as of the Safety Follow-up 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 (± 7 days) after the 
last dose of study drugs regardless of whether or not the patient starts a new anticancer therapy.  
9.2. 
Efficacy Analyses 
The efficacy endpoints including PFS, CR rate, ORR, DOR, and OS will be summarized by arm 
in the ITT Analysis Set. The efficacy endpoints will be compared in Arm A versus Arm C and 
Arm B versus Arm C. These analyses are descriptive and exploratory; no formal testing was 
designed for this study. 
9.2.1. 
Primary Efficacy Analysis 
The primary endpoint is PFS as assessed by investigators. PFS per investigator is defined as the 
time from randomization to the first documented disease progression as assessed by the 
investigator according to RECIST v1.1, or death from any cause, whichever occurs first. 
Kaplan-Meier methodology will be used to estimate median or other quartiles of PFS along with 
its 95% confidence interval (CI; constructed using the Brookmeyer and Crowley method). 
Kaplan-Meier curves will be constructed to provide a visual description of PFS distribution. 
Event-free rate at selected timepoints will be estimated with 95% CI using Greenwood formula. 
The hazard ratio (HR) for PFS for each comparison (ie, Arm A versus Arm C, Arm B versus 
Arm C) will be estimated using a stratified Cox regression model. The 95% CI for the HR will 
be provided. Unstratified analysis will also be presented. 
Subgroup analysis of primary endpoint of PFS per investigator will be conducted to determine 
whether the treatment effect is consistent across various subgroups. Subgroup factors include but 
are not limited to PD-L1 expression in tumor cells (clinical meaningful cutoffs), TIGIT 
expression level (clinical meaningful cutoffs), region, race, disease stage, gender, and age. 
9.2.2. 
Secondary Efficacy Analysis 
Complete Response Rate 
CR rate is the proportion of patients who had a CR as assessed by investigator per RECIST v1.1 
in all randomized patients with measurable disease at baseline. Patients without any postbaseline 
assessment will be considered nonresponders. CR rate and its Clopper-Pearson 95% CI will be 
calculated for each arm. The comparison in CR rate between arms will be evaluated using the 
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Cochran-Mantel-Haenszel (CMH) Χ2 test with the actual stratification factors as strata. Odds 
ratio and the difference in CR rate, as well as their 2-sided 95% CIs, will be calculated. 
Overall Response Rate  
ORR is the proportion of patients who had a CR or PR as assessed by the investigator per 
RECIST v1.1 in all randomized patients with measurable disease at baseline. Patients without 
any postbaseline assessment will be considered nonresponders. Similar methodology used to 
evaluate CR rate will be applied to the analysis of ORR. 
Duration of Response  
DOR is defined for patients with an objective response as the time from the first documented 
objective response to documented disease progression as assessed by the investigator using 
RECIST v1.1, or death from any cause, whichever occurs first. Only patients who have achieved 
objective responses will be included in the analysis of DOR. Similar methodology used to 
evaluate PFS will be applied to the analysis of DOR. 
Overall Survival  
OS is defined as the time from randomization to death from any cause. OS will be analyzed in 
the ITT Analysis Set. Data for patients who are not reported as having died at the time of 
analysis will be censored at the date the patients were last known to be alive. Data for patients 
who do not have postbaseline information will be censored at the date of randomization. Similar 
methodology used to evaluate PFS will be applied to the analysis of OS. 
Distant Metastasis-Free Survival 
DMFS is defined as the time from the date of randomization to the date of the first documented 
distant metastasis as assessed by the investigator per RECIST v1.1, or death from any cause, 
whichever occurs first. Similar methodology used to evaluate PFS will be applied to the analysis 
of DMFS. 
The distant metastasis includes separate tumor nodule(s) in a contralateral lobe, tumor with 
pleural or pericardial nodules or malignant pleural or effusion pericardial, single extrathoracic 
metastasis in a single organ (including involvement of a single nonregional node), and multiple 
extrathoracic metastases in a single organ or in multiple organs. 
ORR, PFS, and OS in PD-L1 and TIGIT Subgroups 
Clinically meaningful cutoffs of PD-L1 and TIGIT expression level will be selected to divide the 
biomarker-evaluable patients into subgroups. ORR, PFS, and OS analysis by PD-L1 and TIGIT 
expression subgroups will be performed to investigate the predictive value of these biomarkers. 
9.2.3. 
Exploratory Efficacy Analysis 
Biomarker Analysis 
Raw biomarker data will be normalized to adjust for batch effect, if applicable, for exploratory 
statistical analyses. Receiver operating characteristics curves will be generated and AUC will be 
calculated based on a logistic regression model to evaluate the association between continuous 
biomarkers and ORR. Biomarker cutoffs (PD-L1 and TIGIT expression levels) used in subgroup 
analyses will be explored in this study using the Youden method. The cutoffs from the Youden 
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method or/and clinically meaningful cutoffs will be used in subgroup analyses. Logistic 
regression and Cox regression will be used to evaluate the prognostic and predictive effects of 
the biomarkers on response and survival endpoints with treatment, biomarker status, and their 
interaction as the main factors.  
The potential utility of ctDNA level change as a surrogate predictor of efficacy and the 
mechanisms of resistance will also be assessed. 
Health-Related Quality of Life 
Summary statistics (mean, standard deviation, median, and range) of the postbaseline scores and 
changes from baseline will be reported for the EORTC QLQ-C30 and QLQ-LC13 
questionnaires. Line charts depicting the mean changes (and standard errors) over time from the 
baseline assessment will be provided for each treatment arm. The clinically meaningful changes 
postbaseline and a mixed model analysis will be performed using the global health status, 
physical function and fatigue domains of QLQ-C30, and dyspnoea, coughing, haemotysis and 
pain in chest, pain in arms and shoulders and peripheral neuropathy domains of QLQ-LC13. 
Completion and compliance rates will be summarized at each timepoint by treatment arm. Only 
patients in the ITT Analysis Set with a nonmissing baseline assessment and ≥ 1 in-study 
nonmissing postbaseline assessment will be included in the analyses. 
9.3. 
Safety Analyses 
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE v5.0. 
Laboratory values (eg, hematology, clinical chemistry, coagulation, urinalysis), vital signs, 
ECGs, and physical examinations will also be used to assess safety. Descriptive statistics will be 
used to analyze all safety data overall and by arm in the Safety Analysis Set. 
9.3.1. 
Extent of Exposure 
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (number and percentage of patients), duration of exposure (days), cumulative total dose 
received per patient (mg), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose reduction, interruption, dose delay, and drug 
discontinuation due to AEs will be summarized for each study drug. Frequency of the above dose 
adjustments and discontinuation will be summarized by category. 
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
9.3.2. 
Adverse Events 
The AE verbatim descriptions (investigator’s description from the eCRF) will be classified into 
standardized medical terminology using MedDRA. AEs will be coded according to MedDRA 
(Version 22.0 or higher) lowest level term closest to the verbatim term, Preferred Term (PT), and 
primary System Organ Class (SOC). 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug and up to 30 days after study treatment 
discontinuation or initiation of new anticancer therapy, whichever occurs first. The TEAE 
classification also applies to imAEs that are recorded up to 90 days after discontinuation of 
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ociperlimab or tislelizumab, regardless of whether the patient starts a new anticancer therapy. 
Only those AEs that were treatment-emergent will be included in summary tables. All AEs, 
treatment-emergent or otherwise, will be presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and PT. A patient will be counted only once by the highest severity grade per 
NCI-CTCAE v5.0 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 TEAEs will also be summarized by relationship to the 
study drug. Treatment-related AEs include those events considered by the investigator to be 
related to a study drug or with missing assessment of the causal relationship.  
SAEs, deaths, TEAEs ≥ Grade 3 severity, imAEs, treatment-related TEAEs, and TEAEs that led 
to treatment discontinuation, dose interruption, dose reduction, or dose delay will be 
summarized. 
9.3.3. 
Laboratory Analyses 
Clinical laboratory (eg, hematology, serum chemistry, 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, maximum for continuous variables; n [%] for categorical 
variables) for laboratory parameters and their changes from baseline will be calculated. 
Laboratory values will be summarized by visit and by worst postbaseline visit. 
Laboratory parameters that are graded by NCI-CTCAE v5.0 will be summarized by 
NCI-CTCAE grade. In the summary of laboratory parameters by NCI-CTCAE grade, parameters 
with NCI-CTCAE grading in both high and low directions (eg, glucose, potassium, sodium) will 
be summarized separately. 
9.3.4. 
Vital Signs  
Descriptive statistics for vital signs parameters (body temperature, pulse rate, and systolic and 
diastolic blood pressure) and changes from baseline will be presented by visit for all visits. Vital 
signs will be listed by patient and visit. 
9.3.5. 
Pulmonary Function Test 
Pulmonary function test results will be listed by patient if available. 
9.4. 
Pharmacokinetic Analysis 
Ociperlimab and tislelizumab serum concentration data will be tabulated and summarized by the 
visit/cycle at which these concentrations are collected. Descriptive statistics will include means, 
medians, ranges, and standard deviations, as appropriate. Additional PK analyses may be 
conducted as appropriate. 
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Additional PK analyses, including population PK analyses and exposure-response analyses 
(efficacy or safety endpoints) may be conducted as appropriate and the results of such analysis 
may be reported separately from the clinical study report. 
9.5. 
Immunogenicity Analysis 
The anti-ociperlimab antibody and anti-tislelizumab antibody results will be summarized using 
descriptive statistics by the number and percentage of patients who develop detectable ADAs. 
The incidence of positive ADAs and neutralizing ADAs will be reported for evaluable patients. 
The effect of immunogenicity on PK, efficacy, and safety may be evaluated if data allow and 
will be reported separately from the main study report. 
9.6. 
Sample Size Consideration 
This study is not designed to make explicit power and type I error considerations but rather to 
obtain preliminary efficacy and safety data for ociperlimab plus tislelizumab and tislelizumab 
monotherapy for patients with untreated LS-SCLC. This study will enroll approximately 120 
subjects into 3 arms with approximately 40 patients in each arm. The contribution of tislelizumab 
to the efficacy results will be demonstrated by descriptive analysis of PFS, ORR, and DOR in the 
comparison of Arm B versus Arm C. The contribution of adding ociperlimab will be 
demonstrated by similarly descriptive analysis in the comparison of Arm A versus Arm B. With 
a sample size of 40 patients in each arm, the binomial probabilities of detecting 1 or more 
TEAEs with a frequency of 5% and 1% are approximately 0.87 and 0.33, respectively. The final 
analysis for PFS is estimated to happen approximately 30 months after the enrollment of the first 
patient. 
9.7. 
Interim Analyses 
No interim analyses are planned. 
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10. 
STUDY COMMITTEES AND COMMUNICATION 
10.1. 
Safety Monitoring Committee 
An SMC consisting of qualified investigators who are taking part in the study will be 
implemented to support the study and structure the scientific input. The SMC will conduct safety 
assessments at the following timepoints:  
• After approximately 6 patients (≥ 2 patients per arm) have completed 2 cycles of 
study treatment  
• After approximately 18 patients (≥ 6 patients per arm) have completed 2 cycles of 
study treatment or no later than 6 months after the first SMC evaluation, whichever 
occurs first 
• After the scheduled SMC assessments, the SMC will review data approximately 
every 6 months for the first 18 months of the study and yearly thereafter  
The SMC could review data more frequently if indicated or requested by the medical monitor or 
the SMC based on ongoing safety monitoring of patients on study. The SMC may recommend 
study modifications including early termination of the study due to safety concerns. Full details 
of the SMC procedures and processes can be found in the SMC Charter.  
Enrollment may continue during these SMC safety reviews. 
10.1.1. 
Study Safety Stopping Criteria  
During the ongoing trial, early stopping for safety will be assessed according to a prespecified 
stopping rule. The early stopping rule will be based on the number of patients who experience 
≥ Grade 3 pneumonitis, serious TEAE with life-threatening outcome, or TEAE leading to death. 
If the patients have more than one AEs as defined above, the patients will be counted only once. 
If the early stopping boundary is met, enrollment will be suspended to wait for the 
recommendation of the SMC. Based on the SMC recommendation, the sponsor may choose to:  
1. terminate the treatment arm or arms meeting the stopping rule; 
2. amend the protocol to improve the benefit/risk for patients; 
3. continue without any changes.  
The stopping rule is established by using the Bayesian approach proposed by Thall, Simon, and 
Estey (Thall et al 1995). The sponsor may consider terminating the treatment arm if the posterior 
probability of the AE rate of greater than 30% is at least 80% for that treatment arm. 
Noninformative prior of Beta (1,1) is used to calculate the Bayesian posterior probability. Two 
evaluations of early stopping are planned in accordance with the scheduled SMC review. 
1. The first one is planned when approximately 18 patients (≥ 6 patients per arm) have 
completed 2 cycles of study treatment. Based on the prespecified early stopping rule, the 
early stopping boundary is observing ≥ 3 patients with the above AEs among 6 patients in 
Arm A or Arm B. 
2. The second one is planned approximately 6 months later after the first early stopping 
review or when approximately 60 patients (≥ 20 patients per arm) have completed 2 
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cycles of study treatment, whichever is earlier. Based on the prespecified early stopping 
rule, the early stopping boundary is observing ≥ 8 patients with the above AEs among 20 
patients in Arm A or Arm B. 
The stopping boundary will be adjusted according to the actual patients enrolled in Arm A or 
Arm B at the analysis timing of early stopping evaluation. 
Besides the stopping rule with Bayesian approach, the sponsor will further evaluate the trend of 
the AE rates between experimental arm (Arm A or Arm B) and control arm (Arm C). The safety 
evaluation will be continued by regular SMC review after the two stopping rule review. An 
ad-hoc SMC review will be triggered for further safety evaluation if necessary to address 
emerging safety concerns.  
 
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study may be fully documented. Such records include, but are not limited to, the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals. In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data. 
11.1. 
Access to Information for Monitoring 
In accordance with International Council for Harmonisation (ICH) GCP guidelines, the study 
monitor must have direct access to the investigator’s source documentation in order to verify the 
data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately. The investigator agrees to provide access to records, facilities, and personnel to 
representatives of a regulatory agency or the sponsor for the effective conduct of any inspection 
or audit. 
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12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
the appropriate regulatory agency before the study is initiated at a study center in that country. 
12.2. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Site Inspections 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study.  
12.4. 
Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient drug dispensation records, and returned or 
destroyed study product. Dispensation records will document quantities received from the 
sponsor’s designated depot or its designee and quantities dispensed to patients, including 
batch/lot number, date dispensed, patient identifier number, and the initials of the person 
dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with the sponsor’s requirements specified in 
the Pharmacy Manual. At appropriate times during the conduct of the study or at the end of the 
study 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 the sponsor’s requirements specified in the Pharmacy Manual 
for disposal, arrangements will be made between the site and the sponsor or its representative for 
destruction or return of unused study drug supplies. 
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All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
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13. 
ETHICS/PROTECTION OF HUMAN PATIENTS 
13.1. 
Ethical Standard 
This study will be conducted by the principal investigator and the study center in full 
conformance with the ICH 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 ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). 
13.2. 
Institutional Review Board/Independent Ethics Committee 
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted, reviewed, and approved by the IRB/IEC before the study is 
initiated. In addition, any patient recruitment materials must be approved by the IRB/IEC.  
Copies of the IEC/IRB correspondence and approval of the amended ICF/other information and 
the approved amended ICF/other information must be forwarded to the sponsor promptly. 
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments. In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and IRB/IEC. Investigators may receive written 
investigational new drug (IND) safety reports or other safety-related communications from the 
sponsor. Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures established by 
their IRB/IEC and archived in the site’s study file. 
13.2.1. 
Protocol Amendments 
Any protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements. Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming their willingness to remain in the study. 
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13.3. 
Informed Consent  
The sponsor’s sample ICF will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. The final IRB/IEC-approved ICFs must be provided to 
the sponsor for health authority submission purposes according to local requirements. 
The ICFs must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained before participation in the study. 
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate. The 
final revised IRB-/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes. 
Patients must reconsent to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study. For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
13.4. 
Patient and Data Confidentiality 
The principal investigator and sponsor will maintain confidentiality and privacy standards by 
following applicable data privacy laws covering the collection, storage, transmission, and 
processing of patients’ personal and medical information. 
The principal investigator shall code the medical information obtained during the study with a 
unique patient identification number assigned to each patient enrolled in the study. This approach 
ensures that patients’ names are not included in any dataset transmitted to any sponsor location. 
Patient medical information obtained during this study is confidential and may be disclosed only 
to third parties as permitted by the signed ICF (or a separate authorization for the use and 
disclosure of personal health information that has been signed by the patient), unless permitted or 
required by law. 
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
principal investigator and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable data privacy laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes. 
Data generated during this study must be available for inspection upon request by representatives 
of the US FDA, the China NMPA, and all other national and local health authorities; by sponsor 
monitors, representatives, and collaborators; and by the IRBs/IECs for each study site, as 
appropriate. 
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The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. The investigator agrees that all information 
received from the sponsor, including but not limited to, the Investigator's Brochure, this protocol, 
eCRFs, the IND, and any other study information, remain the sole and exclusive property of the 
sponsor during the conduct of the study and thereafter. This information is not to be disclosed to 
any third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from the sponsor. The investigator further agrees 
to take all reasonable precautions to prevent the disclosure by any employee or agent of the study 
site to any third party or otherwise into the public domain. 
If a written contract for the conduct of the study is executed, and that contract includes 
confidentiality provisions inconsistent with this section, that contract’s provisions shall apply to 
the extent they are inconsistent with this section. 
13.5. 
Financial Disclosure 
Investigators are required to provide the sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interests of the clinical investigators, and/or disclose those 
financial interests, as required, to the appropriate health authorities. This is intended to ensure 
that financial interests and arrangements of the clinical investigators with the sponsor that could 
affect reliability of data submitted to health authorities are identified and disclosed by the 
sponsor. Investigators are responsible for providing information about their financial interests 
before participation in the study and for updating this information if any relevant changes occur 
during the study and for 1 year after completion of the study (ie, last patient, last visit). 
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14. 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Data Collection and Management Responsibilities 
14.1.1. 
Data Entry in the Electronic Case Report Form 
All study-related data collected or received by the investigator or study team shall be promptly 
entered into the eCRFs. In no event should the entry of the study data into the eCRF be later than 
what is stipulated in the site contract after the data is collected or received by the investigator or 
study team without prior communication with and approval by the sponsor. 
14.1.2. 
Data Collection 
Data required by the protocol will be entered into an electronic data capture (EDC) system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The e-signature of the investigator or designee must be 
provided in the EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of the sponsor and should not be made 
available in any form to third parties without written permission from the sponsor, except for 
authorized representatives of the sponsor or appropriate regulatory authorities. 
14.1.3. 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol will be stored by the sponsor at the end of the study. 
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file that includes all database modifications) will 
be followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the study, a study monitor (clinical research associate) will make site visits to review 
protocol compliance, compare eCRFs against individual patient’s medical records, and ensure 
that the study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. Checking the 
eCRFs for completeness, clarity, and cross-checking with source documents is required to 
monitor the progress of the study. Direct access to source data is also required for inspections 
and audits and will be carried out with due consideration given to data protection and medical 
confidentiality. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA by lower level term, PT, and primary SOC. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. Concomitant diseases/medical history will be coded using MedDRA. 
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14.2. 
Data Integrity and In-house Blinding 
Functions/persons with access to the EDC system shall be prohibited from using the EDC system 
to generate unnecessary listings/summaries that may introduce unwanted bias or to share such 
outputs from the EDC system with other functions/persons who do not have access to the EDC 
system. In addition, the central imaging vendor will perform the central imaging review without 
knowledge of treatment arm assignment. Although the study is open-label, analyses or 
summaries generated by randomized treatment assignment and actual treatment received will be 
limited and documented. 
14.3. 
Study Records Retention 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least 1 of the following 2 categories: 1) investigator’s study file, and/or 2) 
patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent forms, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include documents such as 
(although not be limited to) the following: patient hospital/clinic records, physician’s and nurse’s 
notes, appointment book, original laboratory reports, ECG, electroencephalogram, x-ray, 
pathology and special assessment reports, consultant letters, screening and enrollment logs, etc. 
After closure of the study, the investigator must maintain all study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval when needed (eg, 
audit or inspection) and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel. Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating a hard copy, if required. Furthermore, the investigator must 
ensure there is an acceptable backup of these reproductions and that an acceptable quality control 
process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements, local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including 
but not limited to the following: archival at an off-site facility, or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
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If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 
store these in sealed containers 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. 
14.4. 
Protocol Deviations 
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert they will apply due 
diligence to avoid protocol deviations and shall report all protocol deviations to sponsor. 
The investigator is to document and explain any deviations from the approved protocol. The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures. 
14.5. 
Study Report and Publications 
A clinical study report will be prepared and provided to the regulatory agency(ies). The sponsor 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study. The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential. As this is a multicenter study, the first publication or disclosure 
of study results shall be a complete, joint multicenter publication or disclosure coordinated by 
the sponsor. Thereafter, any secondary publications will reference the original publication(s). 
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of Medical 
Journal Editors 2018). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this trial will be presented in the investigator’s clinical study agreement. Each investigator 
agrees that, in accordance with the terms of the clinical study agreement, a further delay of the 
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publication/presentation may be requested by the sponsor to allow for patent filings in advance 
of the publication/presentation. 
14.6. 
Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Collection of all study documents for the trial master file filing according to GCP and 
local regulation 
• Shipment of samples (including, but not limited to, those for PK, ADA, and 
biomarkers) to the assay lab for central lab analysis according to protocol and lab 
manual requirements  
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for any reason. 
Potential reasons for suspension or discontinuation include but are not limited to safety or ethical 
issues or noncompliance with this protocol, GCP, the sponsor’s written instructions, the clinical 
study agreement, or applicable laws and regulations. If the sponsor determines such action is 
needed, the sponsor will discuss this with the investigator (including the reasons for taking such 
action) at that time. When feasible, the sponsor will provide advance notification to the 
investigator of the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons. The sponsor will also inform the 
regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action. If required by applicable regulations, the investigator must inform the IEC/IRB promptly 
and provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor. In 
addition, arrangements will be made for the return of all unused study drug(s) in accordance with 
the applicable sponsor procedures for the study.  
Financial compensation to the investigators and/or institutions will be in accordance with the 
clinical study agreement established between the investigator and/or institutions and the sponsor. 
14.7. 
Information Disclosure and Inventions 
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial 
property rights that are conceived or reduced to practice by the study center personnel during the 
course of or as a result of the study are the sole property of the sponsor and are hereby assigned 
to the sponsor. 
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If a written contract for the conduct of the study, which includes ownership provisions 
inconsistent with this statement, is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel. 
This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor. 
These restrictions do not apply to the following: 
• Information that becomes publicly available through no fault of the investigator or 
study center personnel 
• Information that is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information that is necessary to disclose to provide appropriate medical care to a 
patient 
• Study results that may be published as described in Section 14.5 
If a written contract for the conduct of the study, which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
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15. 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
 
Assessment 
Screening 
a 
Treatment Cycles 
 
EOT Visit b Safety Follow-up 
Visit 
60-Day and 90-Day 
Follow-up c 
Survival Follow-up 
d 
Cycles 1 to 2 
≥ Cycle 3 and up to 
Cycle 17 (approximately 
12 months) 
Days (Window) 
-28 to -1 
1 (+ 3) e 
8 (±3) 
15 (±3) 
1 (±3) 
0 to 7 days 
after last 
dose 
30 (±7) days after
last dose 
60 and 90 (±7) days 
after last dose 
Every 3 months 
(±14 days) after 
Safety Follow-up 
STUDY ENTRY AND GENERAL ASSESSMENTS 
Informed consent a 
X 
Inclusion/exclusion 
criteria  
X 
Randomization f 
X 
Medical history 
(including cancer 
history) g  
X 
 
 
 
 
 
 
 
 
Demographics g 
X 
Prior /concomitant 
medication evaluation g 
Continuous from ≤ 28 days before randomization until 30 days after the last dose of study treatment 
SAFETY ASSESSMENTS 
AE evaluation h 
Continuous from informed consent until 30 days after the last dose of study treatment for AEs; 90 days after the last dose of ociperlimab plus 
tislelizumab or tislelizumab alone for imAEs. 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. 
Physical examination i 
X 
X 
X 
X 
X 
X 
X 
Vital signs/weight j 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance 
Status w 
X 
X 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
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Assessment 
Screening 
a 
Treatment Cycles 
 
EOT Visit b Safety Follow-up 
Visit 
60-Day and 90-Day 
Follow-up c 
Survival Follow-up 
d 
Cycles 1 to 2 
≥ Cycle 3 and up to 
Cycle 17 (approximately 
12 months) 
Days (Window) 
-28 to -1 
1 (+ 3) e 
8 (±3) 
15 (±3) 
1 (±3) 
0 to 7 days 
after last 
dose 
30 (±7) days after
last dose 
60 and 90 (±7) days 
after last dose 
Every 3 months 
(±14 days) after 
Safety Follow-up 
Pulmonary function 
test k 
Only if clinically indicated 
12-lead ECG l 
X 
Only if clinically indicated 
X 
X 
Hematology m 
X 
X 
X 
X 
X (also Day 8 [± 3 days] 
in Cycles 3 and 4) m 
X 
X 
Chemistry m 
X 
X 
X 
 
X (also Day 8 [± 3 days] 
in Cycles 3 and 4) m 
X 
X 
 
 
Coagulation 
laboratory (PT, PTT, 
INR) m 
X 
X 
X 
X 
X 
Thyroid function n 
X 
 
 
 
Cycles 4, 7, 10, 13, and 
16 
 
X 
 
 
HBV/HCV test o 
X 
As clinically indicated 
 
 
Urinalysis m 
X 
As clinically indicated 
Serum β-hCG 
pregnancy test p 
X 
Urine β-hCG 
pregnancy test p  
X 
X 
X 
X 
X 
EFFICACY ASSESSMENTS 
Tumor assessment 
CT/MRI 
X 
Tumor imaging will be performed at approximately 12 weeks (± 7 days) from the date of randomization (an additional tumor assessment is 
allowed if clinically indicated), then every 6 weeks (± 7 days) for the next 54 weeks, and then every 12 weeks (± 7 days) thereafter based 
on RECIST v1.1. (Section 7.5). 
Brain MRI with contrast 
or CT scan, with contrast, 
of the head 
X 
Only if clinically indicated 
PRO q 
 
X 
X 
X 
 
 
 
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Assessment 
Screening 
a 
Treatment Cycles 
 
EOT Visit b Safety Follow-up 
Visit 
60-Day and 90-Day 
Follow-up c 
Survival Follow-up 
d 
Cycles 1 to 2 
≥ Cycle 3 and up to 
Cycle 17 (approximately 
12 months) 
Days (Window) 
-28 to -1 
1 (+ 3) e 
8 (±3) 
15 (±3) 
1 (±3) 
0 to 7 days 
after last 
dose 
30 (±7) days after
last dose 
60 and 90 (±7) days 
after last dose 
Every 3 months 
(±14 days) after 
Safety Follow-up 
PHARMACOKINETIC ASSESSEMENTS 
Pharmacokinetics r 
 
X 
Cycles 5, 9, and 17 
X 
Anti-ociperlimab and 
anti-tislelizumab 
antibody blood samples s 
X 
Cycles 5, 9, and 17 
X 
BIOMARKER ASSESSMENTS 
Archived tumor t 
X 
Fresh tumor biopsy t 
X 
At the time of disease progression or at EOT Visit (optional) 
 
 
 
Blood u 
 
X 
(C1D1 
predose) 
 
 
C3D1, C5D1, disease progression or 
EOT Visit 
 
 
 
Investigational Product (s) 
Arm A: 
ociperlimab + 
tislelizumab 
administration v 
X 
X 
Arm B:  
tislelizumab 
administration v 
X 
X 
 
 
 
Concurrent CRT (chemotherapy every 3 weeks for 4 cycles) 
Radiation therapy 
administration v  
Given once daily for a total dose of 60 to 70 Gy  
over 6 to 7 weeks  
 
Chemotherapy v 
X 
X (through Cycle 4) 
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Assessment 
Screening 
a 
Treatment Cycles 
 
EOT Visit b Safety Follow-up 
Visit 
60-Day and 90-Day 
Follow-up c 
Survival Follow-up 
d 
Cycles 1 to 2 
≥ Cycle 3 and up to 
Cycle 17 (approximately 
12 months) 
Days (Window) 
-28 to -1 
1 (+ 3) e 
8 (±3) 
15 (±3) 
1 (±3) 
0 to 7 days 
after last 
dose 
30 (±7) days after
last dose 
60 and 90 (±7) days 
after last dose 
Every 3 months 
(±14 days) after 
Safety Follow-up 
FOLLOW-UP 
Survival status 
X 
X 
X 
Disease therapy since IP 
discontinuation 
 
 
 
 
 
 
X 
X 
X 
Abbreviations: ADA, antidrug antibody; AE, adverse event; β-hCG, beta human chorionic gonadotropin; CxDy, Cycle x Day y; cCRT, concurrent 
chemoradiotherapy; CT, computed tomography; D, day; DLCO, diffusing capacity of the lungs for carbon monoxide; ECOG, Eastern Cooperative Oncology 
Group; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer-Quality of Life C30 questionnaire; EOT, End of Treatment; FEV, 
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; imAE, immune-mediated adverse event; INR, international normalized ratio; IEC, Independent Ethics Committee; IP, investigational 
product; IRB, Institutional Review Board; IRC, Independent Review Committee; IRT, integrated response technology; QLQ-LC13, Lung Cancer Module of 
EORTC QLQ-C30; MRI, magnetic resonance imaging; NCI, National Cancer Institute; PK, pharmacokinetics; PR, partial response; PRO, Patient-Reported 
Outcome; PT, prothrombin time; PTT, partial thromboplastin time; RT, radiation therapy; SAE, serious adverse event; T3, triiodothyronine; T4, thyroxine. 
 
a Written informed consent is required before performing any study-specific tests or procedures. Screening evaluations must be completed within 28 days of 
randomization. Results of standard-of-care tests or examinations performed before obtaining informed consent and within 28 days before randomization may 
be used for screening assessments rather than repeating such tests. 
b The EOT Visit (Section 3.4) is to be completed within 7 days after the decision to discontinue study treatment or upon completion of study treatment. If routine 
laboratory tests (eg, hematology, serum chemistry) are completed within 7 days before the EOT Visit, these tests need not be repeated. Tumor assessment is not 
specifically required at the EOT Visit. Patients who discontinue study treatment before disease progression confirmed by the investigator will need to undergo 
tumor assessments as outlined in Section 7.5; however, in some cases, the time window of tumor assessment might overlap with the EOT and/or Safety 
Follow-up Visit. 
c The 60-day and 90-day follow-up visits may be completed at the site or by telephone. 
d Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months after the Safety 
Follow-up Visit until death, loss to follow-up, withdrawal of consent, or end of study by sponsor. All patients will be followed up for survival and subsequent 
anticancer therapy information unless a patient requests to be withdrawn from follow-up. 
e Cycle 1 Day 1 (C1D1) dosing should be initiated within 3 business days of randomization. 
f Patients will be randomized into Arm A, Arm B, or Arm C via IRT. All patients must receive study treatment within 3 business days of randomization. 
g Includes age or year of birth, sex, and self-reported race/ethnicity; medical history includes any history of clinically significant disease, surgery, or cancer; 
cancer history will include an assessment of prior surgery, prior RT, and prior drug therapy including start and stop dates, best response, and reason for 
discontinuation. Information on radiographic studies performed before study entry may be collected for review by the investigator. Preexisting AEs at baseline 
should be recorded as medical history. Refer to Section 7.1.3 for additional information. 
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h The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0. All AEs will also be evaluated for seriousness. After the informed consent form 
has been signed, but before the first administration of study treatment, only SAEs should be recorded. After initiation of study treatment, all AEs and SAEs, 
regardless of relationship to study treatment, will be reported until either 30 days after last dose of study treatment or initiation of new anticancer therapy, 
whichever occurs first. For patients in Arm A and Arm B, immune-mediated AEs (serious or nonserious) should be reported until 90 days after the last dose of 
ociperlimab plus tislelizumab or tislelizumab alone 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. Refer to Section 8.6 for 
additional information. 
i A complete physical examination will be performed at the Screening Visit. At subsequent visits and as clinically indicated, limited, symptom-directed physical 
examinations will be performed. Refer to Section 7.4.2 for additional information. 
j Vital signs collected on study include temperature, pulse rate, and blood pressure (systolic and diastolic). Vital signs will be assessed in Arms A, B, and C at 
screening, before study drug administration on Days 1, 8, and 15 in the first 2 cycles for all patients, at the beginning of each subsequent cycle, at the EOT 
Visit, and at the Safety Follow-up Visit (Section 7.4.1). The patient’s vital signs should be recorded within 60 minutes before, during, and 30 minutes after the 
first infusion of ociperlimab plus tislelizumab (as a whole infusion) in Arm A or tislelizumab alone in Arm B at each cycle visit for 2 cycles. For subsequent 
cycles, vital signs will be collected within 60 minutes before infusion and, if clinically indicated, during and 30 minutes after the infusion. Pulse rate and blood 
pressure should be collected while the patient is in a seated position after resting for 10 minutes. Weight will be assessed at screening, before study drug 
administration on Day 1 of each cycle, at the EOT Visit, and at the Safety Follow-up Visit. Height will be recorded at screening only. 
k 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, is to be performed as clinically indicated during the screening period to assist the determination of suitability on the study. 
Respective test results need to be submitted to the sponsor. For test results indicative of significantly impaired pulmonary function, eg, resting pulse oximetry 
< 90% on room air and further desaturation upon exercise, FEV1 < 60% or DLCO (if performed) < 60% of age- and sex-adjusted predicted performance levels 
(Pellegrino et al 2005), the medical monitor needs to be consulted to confirm eligibility. Tests may be repeated as clinically indicated while on study. 
l The ECG recordings will be obtained during screening, as clinically indicated during the treatment period, at the EOT Visit, and at the Safety Follow-up Visit. 
Patients should rest in semirecumbent supine position for ≥ 10 minutes before ECG collection. 
m Local laboratory assessments of serum chemistry, hematology, coagulation, and urinalysis will be conducted as outlined in Appendix 2. If laboratory tests at 
screening are not performed within 7 days before the administration of study drug(s) on Day 1 of Cycle 1, these tests should be repeated and reviewed before 
administration of study drug(s). Hematology and serum chemistry assessments (including liver function tests) are specified in Appendix 2. Hematology 
assessments should be performed at Day 1 (± 3 days), Day 8 (± 3 days), and Day 15 (± 3 days) of the first 2 cycles, at Day 1 (± 3 days) and Day 8 (± 3 days) of 
the third and the fourth cycles, on Day 1 (± 3 days) of each subsequent cycle, at the EOT Visit, and at the Safety Follow-up Visit. Serum chemistry assessments 
(including liver function tests) should be performed on Day 1 (± 3 days) and Day 8 (± 3 days) of the first 4 cycles, on Day 1 (± 3 days) of each subsequent 
cycle, at the EOT Visit, and at the Safety Follow-up Visit. Coagulation assessments should be performed at screening, on Day 1 (± 3 days) of each cycle, at the 
EOT Visit, and at the Safety Follow-up Visit. Urinalysis is to be conducted during the treatment period only if clinically warranted. Refer to Section 8.3.5 for 
additional information regarding clinical assessment and management of clinical laboratory abnormalities. 
n Analysis of free T3 or total T3, free T4 or total T4, and thyroid-stimulating hormone will be performed by the local study site laboratory. Thyroid function tests 
will be performed at screening and every 3 cycles (ie, Cycles 4, 7, 10, etc.), and at the Safety Follow-up Visit. 
o Testing will be performed by the local laboratory at screening and will include screening HBV/HCV serology (HBsAg, HBsAb, HBcAb, and HCV antibody). 
After screening, viral load assessment (HBV DNA and HCV RNA) may be performed if clinically indicated. Patients who have detectable HBV DNA at 
screening or upon repeat testing will undergo the respective viral load test every 4 cycles (, Cycles 4, 8, and 12).  
 
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p Urine or serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as 
negative within 7 days before the first dose of study treatment. Urine pregnancy tests will be performed at each cycle before dosing, and at the EOT and Safety 
Follow-up Visits. A serum pregnancy test must be performed if the urine pregnancy test is positive or equivocal. 
q To be completed before any clinical activities during on-study site visits. EORTC QLQ-C30 and QLQ-LC13 questionnaires will be completed at predose on 
Day 1 of every cycle from Cycle 1 (baseline) through Cycle 4, and then to coincide with scheduled tumor assessments (every 6 weeks [± 7 days]) until the EOT 
Visit (Arms A, B, and C).  
r PK blood samples will be collected from patients who randomized to receive ociperlimab plus tislelizumab or tislelizumab alone (Arms A and B). Procedures 
for collection of ociperlimab and tislelizumab PK and ADA samples are described in the Laboratory Manual. Predose (within 60 minutes before starting the 
first study drug infusion)PK samples (Arm A: 2 samples collected at the same time [1 for ociperlimab, another for tislelizumab]; Arm B: 1 sample for 
tislelizumab) will be collected on Day 1 of Cycles 1, 2, 5, 9 and 17. Postdose (within 30 minutes after completing the last study drug infusion) PK samples 
(2 samples collected at the same time [1 sample for ociperlimab; another for tislelizumab] in Arm A; 1 sample for tislelizumab in Arm B) will be collected on 
Day 1 of Cycles 1 and 5. An additional PK sample is required to be collected at the Safety Follow-up Visit (Arm A: 2 samples collected at the same time [1 for 
ociperlimab, another for tislelizumab]; Arm B: 1 sample for tislelizumab). Should a patient present with any ≥ Grade 3 imAE, an additional blood PK sample 
may be taken to determine the serum concentration of ociperlimab and tislelizumab (Arm A: 2 samples collected at the same time [1 for ociperlimab, another 
for tislelizumab]; Arm B: 1 sample for tislelizumab). These tests are required when it is allowed by local regulations/IRBs/IECs. 
s ADA blood samples will be collected from patients who randomized to receive ociperlimab plus tislelizumab or tislelizumab alone (Arms A and B). Blood 
samples will be collected at predose (within 60 minutes before dose) on Day 1 of Cycles 1, 2, 5, 9, 17, and at the Safety Follow-up Visit for ociperlimab and 
tislelizumab (Arm A: 2 samples collected at the same time [1 for ociperlimab, another for tislelizumab]; Arm B: 1 sample for tislelizumab). 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/IECs. 
t Patients must agree to provide an archival tumor tissue with an associated pathology report or agree to perform a fresh biopsy during screening (formalin-fixed 
paraffin-embedded block or approximately 15 unstained slides [8 slides minimum]). Note: If < 8 unstained slides are available, a discussion with the sponsor is 
required. If the baseline archival tumor tissues are not collected during the screening period due to unspecified reasons, archival tissue collection after screening 
period is applicable. If baseline archival tumor tissue is not available, a fresh biopsy of a tumor lesion at baseline (within 28 days before randomization) is 
required. Optional biopsies will also be taken for the patients at confirmed disease progression or EOT for the assessment of mechanism of resistance. Written 
informed consent is required before collecting fresh tumor biopsies. If at any time during the study a patient undergoes a medically indicated procedure that has 
the likelihood of yielding tumor tissue, any remaining sample or a portion of the sample not necessary for medical diagnosis (leftover tumor tissue) may be 
obtained for exploratory analysis.  
u For Arm A and Arm B: Blood samples (about 10 mL at each timepoint) will be collected predose at C1D1, C3D1, C5D1, EOT visit or at the time of confirmed 
disease progression (whichever occurs first).  For Arm C: Blood samples (about 10 mL at each timepoint) will be collected predose at C1D1, C3D1, EOT visit 
or at the time of confirmed disease progression (whichever occurs first). 
v The schedule of RT and chemotherapy administrations is detailed in the specific section. The recommendation is to start RT on C1D1 of chemotherapy. 
Ociperlimab plus tislelizumab or tislelizumab alone should be given intravenously once every 3 weeks. The initial 2 infusions (Cycles 1 and 2) will be 
delivered over 60 (± 5) minutes, and administration can then occur over 30 (± 5) minutes for subsequent infusions if well-tolerated. Patients must be monitored 
for 2 hours after infusion of tislelizumab followed by ociperlimab (Arm A) and tislelizumab (Arm B) on Day 1 of Cycles 1 and 2; from Cycle 3 onward, at least 
a 60-minute monitoring period is required. The first dose will be given on C1D1and subsequent dosing will continue on the scheduled 3-week intervals. The 
chemotherapy regimens will be given intravenously on a 3-week cycle for the first 4 cycles. On Day 1 of Cycles 1 to 4, chemotherapy drugs will be 
administered in a sequential manner separately after the infusion of ociperlimab plus tislelizumab or tislelizumab alone; cisplatin 75 mg/m2 will be administered 
on Day 1 of each cycle. If the patient is unable to tolerate the 1-day administration of cisplatin 75 mg/m2, at the investigator’s discretion (eg, patients had 
concurrent superior vena cava syndrome) cisplatin 25 mg/m2 dosed on Days 1, 2 and 3 is allowed; carboplatin will be administered on Day 1 of each cycle; 
etoposide will be administered on Days 1, 2, and 3 of each cycle. 
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w ECOG Performance Status will be assessed in Arms A, B, and C at screening, before study drug administration on Day 1 of each cycle, at the EOT Visit, and at 
the Safety Follow-up Visit.
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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS 
Serum chemistry 
Hematology 
Coagulation 
Urinalysis  
Alkaline phosphatase 
Hemoglobin 
Prothrombin time 
pH 
Alanine aminotransferase 
Hematocrit 
Partial thromboplastin 
time or activated partial 
thromboplastin time 
Specific gravity 
Aspartate aminotransferase 
White blood cell count 
International 
normalized ratio 
Glucose 
Albumin 
Neutrophil count 
 
Protein 
Total bilirubin 
Lymphocyte count 
 
Ketones 
Direct bilirubin 
Platelet count 
 
Blood 
Blood urea nitrogen or urea 
 
 
24-hour protein a 
Potassium 
 
 
 
Sodium 
 
 
 
Calcium b 
 
 
 
Creatinine 
 
 
 
Glucose 
 
 
 
Lactate dehydrogenase 
 
 
 
Total protein 
 
 
 
Magnesium 
 
 
 
Phosphorus 
 
 
 
Chloride 
 
 
 
Creatine kinase/ 
CK-MB c 
 
 
 
Abbreviations: CK-MB, creatine kinase cardiac muscle isoenzyme. 
a 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. 
b Calcium values will be corrected for patients with hypoalbuminemia. 
 c Cardiac enzyme testing has been added to monitor for potential event of immune-related myocarditis. If CK-MB 
fractionation is not available, assess troponin I and/or troponin T instead. Investigators should make every effort to 
test either CK-MB, troponin I, and/or troponin T consistently at screening and at follow-up visits. 
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APPENDIX 3. 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 4. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1 
Source: Eisenhauer et al 2009. 
Definitions 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (v1.1). Changes in 
only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria. 
Note: Lesions are either measurable or nonmeasurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by computed tomography (CT) and magnetic resonance imaging (MRI) (no 
less than double the slice thickness and a minimum of 10 mm). Assumes a scan slice 
thickness no greater than 5 mm. 
• 10 mm caliper measurement by clinical exam (when superficial) 
• 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 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, and abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by reproducible imaging 
techniques are all nonmeasurable. 
Bone lesions: 
• Bone scan, positron-emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
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• 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 
locoregional 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, add lend themselves to reproducible repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. Pathological nodes that are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image 
is obtained (for CT scan, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node that is reported as being 20 mm by 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) 
should be considered nontarget lesions. Nodes that have a short axis < 10 mm are considered 
nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
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progression” (more details to follow). In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”). 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules). For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. As noted above, when lesions can be 
evaluated by both clinical examination and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the trial. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in 
identifying new lesions. However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
• CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. 
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (eg, for body scans). 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date, and because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response (CR) or surgical resection is an 
endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, they must normalize 
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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 that 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. 
Response Criteria 
Evaluation of Target Lesions 
• Complete response: Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or nontarget) must have reduction in short axis to < 10 mm. 
• Partial response: At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters 
• Progressive disease: At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or 
more new lesions is also considered progression). 
• Stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for progressive disease, taking as reference the smallest sum diameters while 
on study 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study. This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if 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 progressive 
disease, the actual short axis measurement of the nodes is to be included in the sum of 
target lesions. 
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• Target lesions that become “too small to measure.” While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (eg, 2 mm). However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure.” 
When this occurs, it is important that a value be recorded on the electronic case report 
form (eCRF). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. (Note: It is less likely that this rule will be used for lymph nodes 
since they usually have a definable size when normal and are frequently surrounded 
by fat, such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well). This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially nonreproducible; therefore, providing this 
default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that measurement should be recorded, even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion.” 
Evaluation of Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker level. 
All lymph nodes must be nonpathological in size (< 10 mm short axis). 
• Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
• PD: Unequivocal progression (as detailed below) of existing nontarget lesions. (Note: 
The appearance of one 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 one or more 
nontarget lesions is usually not sufficient to qualify for unequivocal progression 
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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 
progressive disease 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 progressive disease at 
that point. While it would be ideal to have objective criteria to apply to 
nonmeasurable disease, the very nature of that disease makes it impossible to do so; 
therefore, the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of preexisting lesions). This is particularly important 
when the patient’s baseline lesions show partial or complete response. For example, necrosis of a 
liver lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is a 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 progressive 
disease 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 fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
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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 
progressive disease 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 
progressive disease. 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 progressive disease will be 
the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at 
follow-up corresponds to a preexisting site of disease on CT that is not progressing on 
the basis of the anatomic images, this is not progressive disease. 
• Timepoint Response 
• It is assumed that at each protocol-specified time point, a response assessment occurs. 
The following table provides a summary of the overall response status calculation at 
each time point 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 
Stable disease 
Non-PD or not all evaluated 
No 
Stable disease 
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. 
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 
Stable disease  
(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. 
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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 CR or PR IS NOT required: Best 
response in these trials is defined as the best response across all time points (for example, a 
patient who has stable disease at first assessment, PR at second assessment, and progressive 
disease 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 time point response, the 
patient’s best response depends on the subsequent assessments. For example, a patient who has 
stable disease at first assessment, progressive disease at second and does not meet minimum 
duration for stable disease, will have a best response of progressive disease. The same patient 
lost to follow-up after the first stable disease assessment would be considered inevaluable. 
Best response determination in trials where confirmation of CR or PR IS required: CR or PR 
may be claimed only if the criteria for each are met at a subsequent time point 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" (not evaluable) time point 
assessments may complicate best response determination. The analysis plan for the trial must 
address how missing data/assessments will be addressed in determination of response and 
progression. For example, in most trials it is reasonable to consider a patient with time point 
responses of PR-NE-PR as having a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping trial therapy. 
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Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR. FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring. The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease-specific medical literature for the indication. However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
progression is confirmed at the next scheduled assessment, the date of progression should be the 
earlier date when progression was suspected. 
Confirmation of Measurement/Duration of Response 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure that 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 that 
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 the measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall CR is measured from the time the measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
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The clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between 2 measurements for determination of stable disease. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity, and standard practice. 
However, these limitations of the precision of the measured endpoint should be taken into 
account if comparisons between trials are to be made. 
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APPENDIX 5. PREEXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES 
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease. 
Please contact the medical monitor regarding any uncertainty about immune 
deficiency/autoimmune disease exclusions. 
Acute disseminated encephalomyelitis 
Addison disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet’s disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating polyneuropathy 
Chung-Strauss syndrome 
Crohn disease 
Dermatomyositis 
Dysautonomia 
Epidermolysis bullosa acquisita 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture syndrome 
Granulomatosis with polyangiitis 
Graves’ disease 
Guillain-Barré syndrome 
Hashimoto disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki disease 
Lambert-Eaton myasthenic syndrome 
Lupus erythematosus 
Lyme disease (chronic) 
Mooren ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus syndrome 
Optic neuritis 
Ord thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodosa 
Polyarthritis 
Polyglandular autoimmune syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter syndrome 
Rheumatoid arthritis 
Sarcoidosis  
Sjögren syndrome 
Stiff person syndrome 
Takayasu arteritis 
Ulcerative colitis 
Vogt-Kovangai-Harada disease 
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APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION 
Class 
Symptoms 
I 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort.  Symptoms of heart failure 
at rest.  If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin et al 1994. 
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels. 
Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p114. 
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APPENDIX 7. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT 
The recommendations below for the diagnosis and management of any immune-mediated AEs 
(imAEs) 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 or tislelizumab 
plus ociperlimab and the AE? 
• How did the patient respond to withdrawal of tislelizumab or tislelizumab plus 
ociperlimab? 
• Did the event recur when tislelizumab or tislelizumab plus ociperlimab 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-related Adverse Events 
Immune-related 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-related Adverse Events 
Immune-related Toxicity 
Diagnostic Evaluation Guideline 
Neurological Toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications. Conduct a diabetic 
screen and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology. Consider the need for brain/spine MRI/MRA and nerve conduction study 
for peripheral neuropathy. Consult with a neurologist if there are abnormal 
findings. 
Colitis 
Review dietary intake and exclude steatorrhea. Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 
culture, viral PCR, Clostridium difficile toxin, 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-Related Adverse Events 
• Immune-related AEs can escalate quickly. Study treatment interruption, close 
monitoring, timely diagnostic work-up, and treatment intervention as appropriate is 
required. 
• Immune-related AEs should improve promptly after introduction of 
immunosuppressive therapy. If this does not occur, review the diagnosis, seek further 
specialist advice, and contact the study medical monitor. 
• For some Grade 3 toxicities that resolve quickly, rechallenge with study drug may be 
considered if there is evidence of a clinical response to study treatment, after 
consultation with the study medical monitor. 
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone. 
Equivalent dosages of other corticosteroids can be substituted. For steroid-refractory 
imAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]). 
• Consider prophylactic antibiotics for opportunistic infections if the patient is 
receiving long-term immunosuppressive therapy. 
 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
Thyroid 
Disorders 
1-2 
Asymptomatic TFT abnormality or 
mild symptoms 
Replace thyroxine if 
hypothyroid until TSH/T4 
levels return to normal 
range. 
Thyrotoxic patients should 
be referred to an 
endocrinologist. In cases 
with systemic symptoms: 
withhold study treatment, 
treat with a beta blocker, 
and consider oral 
prednisolone 0.5 mg/kg/day 
for thyroid pain. 
Taper corticosteroids over 
2-4 weeks. Monitor thyroid 
function regarding the need 
for hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
3-4 
Severe symptoms, hospitalization 
required 
Refer patient to an 
endocrinologist. 
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day 
(for the elderly or those with 
comorbidities, the suggested 
starting dose is 
0.5 µg/kg/day). Add oral 
prednisolone 0.5 mg/kg/day 
for thyroid pain. 
Thyrotoxic patients require 
treatment with a beta 
blocker and may require 
carbimazole until thyroiditis 
resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
Hypophysitis 
1-2 
Mild-moderate symptoms 
Refer patient to an 
endocrinologist for hormone 
replacement. 
Add oral prednisolone 
0.5-1 mg/kg/day for patients 
with pituitary inflammation.  
Taper corticosteroids over at 
least 1 month. 
If there is no improvement 
in 48 hours, treat as Grade 
3-4. 
Continue study 
treatment. 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if 
infection suspected. Add 
oral prednisolone 
1 mg/kg/day if 
symptoms/appearance 
persist for 48 hours or 
worsen. 
Consider Pneumocystis 
infection prophylaxis.  
Taper corticosteroids over at 
least 6 weeks. 
Consider prophylaxis for 
adverse steroid effects: eg, 
blood glucose monitoring, 
vitamin D/calcium 
supplement. 
Hold study treatment.  
Retreatment is 
acceptable if symptoms 
resolve completely or 
are controlled on 
prednisolone 
≤ 10 mg/day. 
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
3-4 
Severe or life-threatening 
symptoms: breathless at rest 
Admit to a hospital and 
initiate treatment with 
intravenous 
methylprednisolone 
2-4 mg/kg/day. If there is no 
improvement, or worsening 
after 48 hours, add 
infliximab 5 mg/kg (if no 
hepatic involvement). 
Convert to oral prednisolone 
and taper over at least 
2 months. 
Cover with empiric 
antibiotics and consider 
prophylaxis for 
Pneumocystis infection and 
other adverse steroid 
effects, eg, blood glucose 
monitoring, vitamin 
D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
Toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
3-4 
Severe/life-threatening symptoms 
Initiate treatment with oral 
prednisolone or intravenous 
methylprednisolone 
1-2 mg/kg/day, depending 
on symptoms. Taper 
corticosteroids over at least 
4 weeks. 
Consider azathioprine, 
MMF, cyclosporine if no 
response within 
72-96 hours. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: ≤ 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. 
Hepatitis 
1 
ALT or AST > ULN to 3 x ULN 
Check LFTs within 1 week 
and before the next dose; 
check LFTs to verify that 
there has been no 
worsening. 
If LFTs are worsening, 
recheck every 48-72 hours 
until improvement is seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
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. 
 
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 worsening 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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
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. 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
3 
Fasting glucose value 
250-500 mg/dL; 13.9-27.8 mmol/L 
Admit patient to hospital 
and refer to a diabetologist 
for hyperglycemia 
management. 
Corticosteroids may 
exacerbate hyperglycemia 
and should be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline or 
Grade 0-1. 
 
4 
Fasting glucose 
value > 500 mg/dL; > 27.8 mmol/L 
Admit patient to hospital 
and institute local 
emergency diabetes 
management. 
Refer the patient to a 
diabetologist for insulin 
maintenance and 
monitoring. 
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. 
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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines 
(Subject to Clinical 
Judgement) 
Study Drug 
Management 
3 
Abdominal pain, nausea and 
vomiting 
Admit to hospital for urgent 
management.  Initiate 
intravenous 
(methyl)prednisolone 
1-2 mg/kg/day. Convert to 
oral prednisolone when 
amylase/lipase improved to 
Grade 2 and taper over at 
least 4 weeks. 
Hold study treatment; 
reintroduce only after 
discussion with the 
study medical monitor. 
 
4 
Acute abdominal pain, surgical 
emergency 
Admit to hospital for 
emergency management and 
appropriate referral. 
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with inflammation, 
swelling 
Management per local 
guideline. 
Continue study 
treatment. 
2 
Moderate pain with inflammation, 
swelling, limited instrumental (fine 
motor) activities 
Management as per local 
guideline.  Consider 
referring patient to a 
rheumatologist. 
If symptoms worsen on 
treatment, manage as a 
Grade 3 event. 
Continue treatment or, 
if symptoms continue 
to worsen, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with inflammation or 
permanent joint damage, daily 
living activity 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 
related, permanently 
discontinue study 
treatment in patients 
with moderate or severe 
symptoms. 
Patients with no 
symptoms or mild 
symptoms may not 
restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline and 
after discussion with 
the study medical 
monitor. 
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 antithymocyte 
globulin. 
3 
Severe symptoms with mild 
exertion 
Hold study treatment. 
If a diagnosis of 
myocarditis is 
confirmed and 
considered immune 
related, permanently 
discontinue study 
treatment in patients 
with moderate or severe 
symptoms. 
Patients with no 
symptoms or mild 
symptoms may not 
restart tislelizumab 
unless cardiac 
parameters have 
returned to baseline and 
after discussion with 
the study medical 
monitor. 
 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CHF, congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; ECG, 
electrocardiogram; INR, international normalized ratio; LFT, liver function test; MMF, mycophenolate mofetil; 
MUGA, multigated acquisition scan; NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, 
thyroid function test; TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 
a If clinically significant cardiac enzyme abnormalities are detected during laboratory assessment and serial cardiac 
enzyme assessments pose logistical hardship for the patient, then patient hospitalization should strongly be 
considered until immune-related myocarditis has been ruled out. 
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APPENDIX 8. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
equation (Levey et al 2009) and the Modification of Diet in Renal Disease (MDRD) Study 
equation. The National Kidney Disease Education Program (NKDEP) calculators rely on 
creatinine determinations, which are isotope dilution mass spectrometry (IDMS) traceable. All 
laboratories should be using creatinine methods calibrated to be IDMS traceable. 
This CKD-EPI equation calculator should be used when serum creatinine (Scr) is reported in 
mg/dL. This equation is recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 x min (Scr /κ, 1)α x max(Scr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found here: 
https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-
evaluation/glomerular-filtration-rate-calculators 
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APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL” 
Contraception Guidelines 
The Clinical Trials Facilitation Group recommendations related to contraception and pregnancy 
testing in clinical trials include the use of highly effective forms of birth control (Clinical Trials 
Facilitation Group 2014). These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation 
− Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
− Oral, injectable, implantable 
Note: Oral birth control pills are not considered a highly effective form of birth 
control, and if they are selected, they must be used with a second, barrier method 
of contraception such as condoms with or without spermicide. 
• An intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
Note: This is only considered a highly effective form of birth control when the 
vasectomized partner is the sole partner of the study participant and there has been a 
medical assessment confirming surgical success. 
− A sterile male is one for whom azoospermia in a semen sample has been 
demonstrated as definitive evidence of infertility. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment) 
Note: Total sexual abstinence should only be used as a contraceptive method if it is in 
line with the patients’ usual and preferred lifestyle. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, postovulation methods), declaration of abstinence for the 
duration of exposure to study drug, and withdrawal are not acceptable methods of 
contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception, and if used, this method must be 
used in combination with one of the highly effective forms of birth control listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant. 
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Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• Postmenopausal, defined as: 
− ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
− < 55 years of age with no spontaneous menses for ≥ 12 months AND with 
postmenopausal follicle-stimulating hormone (FSH) concentration > 30 IU/mL 
and all alternative medical causes for the lack of spontaneous menses for ≥ 12 
months have been ruled out, such as polycystic ovarian syndrome, 
hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of 
hormonal contraception or hormonal replacement therapy should be excluded. 
Adapted from Clinical Trials Facilitation Group (CTFG) 2014. 
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APPENDIX 10. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE CANCER 
QUESTIONNAIRE (EORTC-QLQ-C30) 
 
 
 
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APPENDIX 11. EUROPEAN ORGANISATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY OF LIFE 
QUESTIONNAIRE LUNG CANCER (QLQ-LC13) 
 
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APPENDIX 12. COCKROFT-GAULT FORMULA AND CALVERT 
FORMULA 
CALVERT FORMULA: 
 
a Age in years and weight in kilograms. 
b Recommend using ideal body weight if the patient is obese (> 30% over ideal body weight) in calculation of 
estimated CLCr. Calculating by actual body weight is acceptable. 
(GFR* + 25) x AUC = dose (in mg). 
*GFR calculation formula is same as ClCr formula as shown above. 
 
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APPENDIX 13. DOSE MODIFICATION OF CHEMOTHERAPY 
Dose Reduction Level of Etoposide, Cisplatin and Carboplatin 
Dose Lever 
Etoposide (mg/m2)a 
Cisplatin (mg/m2)a 
Carboplatin (mg/m2)a 
Full Dose 
100 mg/m2, on Days 1, 2, 
and 3 of each cycle for 4 
cycles 
75 mg/m2, on Day 1 of 
each cycle for 4 cycles  
If the patient is unable to 
tolerate the 1-day 
administration of cisplatin 
75 mg/m2, at the 
investigator’s discretion, 
cisplatin 25 mg/m2 dosed 
on Days 1, 2 and 3 is 
allowed 
AUC 5 on Day 1 of each 
cycle for 4 cycles 
First Dose 
Reduction  
(-1 dose level) 
75% of initial starting 
dose 
75% of initial starting 
dose 
75% of initial starting 
dose 
Second Dose 
Reduction b 
(-2 dose level) 
50% of initial starting 
dose 
50% of initial starting 
dose 
NA c 
Abbreviations: AUC, area under the plasma or serum concentration-time curve; NA, not applicable.  
a Dose reductions may or may not be concomitant, refer to the tables below.  
b Including the second appearance of the toxicity needs 1 dose reduction. A maximum of 2 dose level reductions are 
allowed.  
c Only 1 dose reduction is permitted for carboplatin. 
 
In patients with impaired renal function, the following initial dose modification should be 
considered based on measured creatinine clearance: 
Measured Creatinine Clearance 
>50 mL/min 
15 to 50 mL/min 
Etoposide 
100% of dose 
75% of dose 
Subsequent etoposide dosing should be based on patient tolerance and clinical effect. The 
minimum dose of etoposide should be 50% of dose. 
 
Recommended Dose Modifications for Hematologic Toxicity 
Dose adjustments are based on nadir blood counts since the preceding chemotherapy 
administration. Dose level adjustments are relative to those of the preceding administration. 
Recommended dose modifications for hematologic toxicity are provided in the following table.  
 
 
 
 
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Chemotherapy Dose Modification for Hematological Toxicity a 
Adverse event 
Treatment 
Febrile neutropenia; documented 
infection 
1) The first episode of febrile neutropenia or documented 
infection will result in antibiotic treatment and 1 dose level 
reduction in the dose of both drugs.  
2) If there is a second episode despite dose reduction, the patient 
must receive prophylactic antibiotics during the subsequent 
cycle. 
3) If there is a third episode, the chemotherapy will be 
discontinued. 
Neutropenia 
Grade 3 
(0.5-1.0 x 109/L) 
Chemotherapy delay until ≤ Grade 1 (≥ 1.5 x 109/L); restart with 
the full dose 
Grade 4 
(< 0.5 x 109/L) 
Chemotherapy delay until recovered to ≤ Grade 1; 1 dose 
reduction of all further doses  
Thrombo-
cytopenia 
Grade 1 
Chemotherapy delay until recovered to normal; restart with the 
full dose 
Grade 2 or Grade 3 
without bleeding 
Chemotherapy delay until recovered to normal; 1 dose reduction 
of all further doses  
Grade 4 
Chemotherapy delay until recovered to normal; 2 dose reduction 
of all further doses (the lowest dose level)  
Grade 3 or 4 
associated 
with clinically 
significant bleeding 
Discontinue chemotherapy 
Recurrence of Grade 3 or 4 after 2 
dose reductions (with either 
neutropenia or thrombo cytopenia) 
Discontinue chemotherapy 
a If considered in the best interest of the patient and consistent with local practice, investigators may decide to use 
supportive measures/treatment and/or secondary prophylaxis instead of dose reductions for the next cycle. The 
provided triggers for dose modifications are recommendations only.  
 
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Recommended Dose Modifications for Nonhematologic Toxicities 
The dose adjustments of chemotherapy for nonhematologic toxicity are described in the 
following table. All dose modifications should be made based on the worst grade toxicity.  
In general, for ≥ Grade 3 nonhematologic toxicities, chemotherapy should be delayed until 
resolution to less than or equal to the patient’s baseline value before resuming treatment at a 
reduced dose. However, exceptions may be made for Grade 3 neurotoxicity or esophagitis. In the 
case of neurotoxicity, the investigator and patient may decide to continue treatment at a reduced 
dose, with no delay required, as neurotoxicity may not resolve to baseline values. Adjustments 
for esophagitis are recommended to follow dose modifications as described in the table below. 
Chemotherapy Dose Modifications a for Nonhematologic Toxicities 
Toxicity 
Grade 
Treatment  
Renal toxicity 
≥ Grade 1 
Delay chemotherapy until recovered to Grade 0 or baseline, change cisplatin 
to carboplatin, if possible; 1 dose reduction for other drug; if recur, 
discontinue chemotherapy. 
Etoposide dosage should be reduced one dose level in patients with a 
creatinine clearance from 15 to 50 mL/min. 
Ototoxicity  
Grade 2 
1 Reduction of all further doses of cisplatin  
Grade 3-4 
Delay chemotherapy until recovered to ≤ Grade 2, change cisplatin to 
carboplatin 
Sensory 
neuropathy b, c 
Grade 2 
1 Reduction for all further doses of cisplatin 
For carboplatin + paclitaxel regimen, delay paclitaxel until ≤ Grade 1 while 
continuing carboplatin 
Grade 3 
Discontinue cisplatin, change cisplatin to carboplatin; 1 dose reduction for 
etoposide 
For carboplatin + paclitaxel regimen, discontinue paclitaxel while continuing 
carboplatin 
Grade 4 
Discontinue cisplatin, carboplatin, paclitaxel, and etoposide 
Hepatic toxicity 
(transaminase 
elevation) 
Grade 3 or 4 
1 dose reduction for cisplatin and etoposide 
Diarrhea 
Grade 4 
Discontinue chemotherapy 
Oral mucositis 
or stomatitis 
≥ Grade 3 
 Reduction for further doses of etoposide  
Discontinue chemotherapy for Grade 4 
Esophagitis d, e 
≥ Grade 3 
Hold chemotherapy until ≤ Grade 2 
Delay chemotherapy at the discretion of investigator for Grade 3; delay 
chemotherapy for Grade 4 
Other organ 
toxicity 
Grade 2 
Delay chemotherapy until ≤ Grade 1 or baseline f 
Grade 3-4 
Delay chemotherapy until recovered to ≤ Grade 1 or baseline e; 1 reduction 
of all further doses 
a If considered in the best interest of the patient and consistent with local practice, investigators may decide to use 
supportive measures/treatment and/or secondary prophylaxis instead of dose reductions for the next cycle. The 
provided triggers for dose modifications are recommendations only. 
b Delay until resolution of toxicity to baseline value is not required for Grade 3 neurotoxicity. 
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c At the discretion of the attending physician, patients experiencing Grade 3 neurologic toxicity as a transient 
ischemic attack that has completely resolved may not require dose reduction or discontinuation. 
d Grade 3 esophagitis will occur in a significant number of patients toward the end of radiation therapy. For patients 
who experience this event earlier than anticipated in the course of their treatment, the advice would be to hold 
chemotherapy and assess at weekly intervals. If symptoms do not progress at the time of assessment, chemotherapy 
can be resumed; chemotherapy can be resumed at 80% of previous dose for both drugs. 
e Grade 4 esophagitis results in holding chemotherapy until toxicity resolves to ≤ Grade 2, and then chemotherapy 
may be resumed; chemotherapy can be resumed at 80% of previous dose for both drugs. 
f Skin reactions, paronychia, alopecia, fatigue, nausea/vomiting, which may have resolved to Grade 2 or baseline. 
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APPENDIX 14. MANAGEMENT OF RADIATION ESOPHAGITIS 
CTCAE Scale: Acute Esophagitis Related to Radiation 
Grade 
Clinical state 
1 
Asymptomatic; clinical or diagnostic observations only; intervention not indicated 
2 
Symptomatic; altered eating/swallowing; oral supplements indicated 
3 
Severely altered eating/swallowing; tube feeding, TPN, or hospitalization indicated 
4 
Life-threatening consequences; urgent operative intervention indicated 
5 
Death 
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; TPN, total parenteral nutrition. 
Dietary and Nutritional Support Recommendations for Acute Radiation Esophagitis 
Supportive measure 
Recommendation 
Dietary modification 
• 
Consider dietician referral 
• 
Avoid potentially irritant foods (tobacco, alcohol, coffee, and 
spicy foods) 
• 
Soft, bland diet 
• 
Small, frequent meals 
Nutritional support 
• 
Liquid meal replacements/supplements 
• 
Intravenous hydration 
• 
Electrolyte correction 
• 
For prolonged symptoms, enteral feeding or total parenteral 
nutrition may be required, although former is preferred 
• 
Antiemetics may be beneficial 
Modified from Baker and Fairchild 2016 
Recommendations for Medication Management of Radiation Esophagitis 
Treatment 
option 
Management of esophagitis 
1 
Ketoconazole 200 mg PO QD 
2 
Fluconazole 100 mg PO QD until the completion of radiation 
3 
Mixture of viscous lidocaine 60 mL + Mylanta (or generic equivalent 
antacid) 30 mL + sucralfate (1 gm/mL) 10 mL. Take 15 to 30 mL PO q3 to 4 h PRN 
4 
Ranitidine 150 mg PO BID (or other histamine-2 [H2] receptor blocker or a proton-
pump inhibitor such as omeprazole) until completion of radiation 
5 
Grade 4 esophagitis: hold CRT until Grade 2 or less 
Abbreviations: BID, twice daily; CRT, chemoradiotherapy; h, hour; PO, oral; PRN, when necessary; q, every; QD, 
once daily. 
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