A Randomized, Open-Label, Multicenter, Phase 2, Umbrella Study to Evaluate the Preliminary Efficacy, Safety, and Pharmacodynamics of Tislelizumab Monotherapy and Multiple Tislelizumab-based Immunotherapy Combinations With and Without Chemotherapy as Neoadjuvant Treatment in Chinese Patients With Resectable Stage II to IIIA Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer
Sponsor: BeiGene

BGB-LC-202 
BeiGene 
Protocol Amendment Version 2.0 
18 July 2023 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
TITLE PAGE  
Protocol Title: 
Protocol Identifier: 
Phase: 
NCT Number
Investigational Product(s): 
Indication: 
Sponsor: 
Sponsor Medical Monitor: 
Original Protocol Version 0.0: 
Protocol Amendment Version 1.0: 
Protocol Amendment Version 2.0: 
A Randomized, Open-Label, Multicenter, Phase 2, 
Umbrella Study to Evaluate the Preliminary Efficacy, 
Safety, and Pharmacodynamics of Tislelizumab 
Monotherapy and Multiple Tislelizumab-based 
Immunotherapy Combinations With or Without 
Chemotherapy as Neoadjuvant Treatment in Chinese 
Patients with Resectable Stage II to IIIA Non-Small 
Cell Lung Cancer 
BGB-LC-202 
2 
NCT05577702
Tislelizumab (BGB-A317) and other investigational 
agents  
Neoadjuvant treatment for resectable Stage II to IIIA 
non-small cell lung cancer 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
1840 Gateway Drive, 3rd Floor 
San Mateo, CA 94404 
USA 
 
Telephone: 
 
Email: 
 
18 July 2022 
10 November 2022 
18 July 2023 
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 affiliates. 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 affiliates. 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 affiliates. 
Approved Date
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FINAL PROTOCOL APPROVAL SHEET  
A Randomized, Open-Label, Multicenter, Phase 2, Umbrella Study to Evaluate the Preliminary 
Efficacy, Safety, and Pharmacodynamics of Tislelizumab Monotherapy and 
Multiple Tislelizumab-based Immunotherapy Combinations With or Without Chemotherapy as 
Neoadjuvant Treatment in Chinese Patients with Resectable Stage II to IIIA Non-Small Cell 
Lung Cancer 
BeiGene, Ltd., Approval: 
 
See electronic signature 
 
 
See electronic signature 
Sponsor Medical Monitor 
 
Date 
 
Approved Date
7/18/2023

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Protocol Amendment Version 2.0  
18 July 2023 
 
CONFIDENTIAL 
Page 3 
INVESTIGATOR SIGNATURE PAGE  
Protocol Title: 
A Randomized, Open-Label, Multicenter, Phase 2, Umbrella Study to 
Evaluate the Preliminary Efficacy, Safety, and Pharmacodynamics of 
Tislelizumab Monotherapy and Multiple Tislelizumab-based 
Immunotherapy Combinations With or Without Chemotherapy as 
Neoadjuvant Treatment in Chinese Patients with Resectable Stage II to 
IIIA Non-Small Cell Lung Cancer 
Protocol Identifier: 
BGB-LC-202  
This protocol is a confidential communication of BeiGene, Ltd., and its affiliates. 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 affiliates. 
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 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
TITLE PAGE ...................................................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
LIST OF TABLES .........................................................................................................................10 
SYNOPSIS ....................................................................................................................................11 
LIST OF ABBREVIATIONS AND TERMS ................................................................................22 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Background Information on Non-Small Cell Lung Cancer and Unmet 
Clinical Needs .............................................................................................................24 
1.1.1. 
Background Information on Early-Stage Non-Small Cell Lung Cancer ....................24 
1.1.2. 
Current Treatment Options for Patients With Resectable NSCLC Stage II to 
IIIA .............................................................................................................................24 
1.1.3. 
Unmet Medical Need ..................................................................................................27 
1.1.4. 
Background Information on Investigational Agents ...................................................28 
1.2. 
Study Rationale ...........................................................................................................28 
1.2.1. 
Rationale for Patient Population and Treatment Setting ............................................28 
1.2.2. 
Rationale for Tislelizumab or Tislelizumab-Based Immunotherapy 
Combinations as Neoadjuvant Treatment in Patients With NSCLC ..........................29 
1.2.3. 
Rationale for Study Design .........................................................................................31 
1.2.4. 
Rationale for Selection of Investigational Agents ......................................................31 
1.2.5. 
Rationale for Major Pathological Response and Pathological Complete 
Response as Efficacy Endpoints .................................................................................31 
1.2.6. 
Biomarker Strategy Rationale.....................................................................................32 
1.3. 
Benefit-Risk Assessment ............................................................................................34 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................36 
2.1. 
Study Objectives and Endpoints .................................................................................36 
3. 
STUDY DESIGN .......................................................................................................38 
3.1. 
Summary of Study Design ..........................................................................................38 
3.2. 
Screening Period .........................................................................................................40 
3.3. 
Neoadjuvant Treatment Phase ....................................................................................40 
3.4. 
End of Treatment and Safety Follow-up Visit ............................................................41 
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3.5. 
Surgery ........................................................................................................................42 
3.6. 
Survival Follow-up .....................................................................................................42 
3.7. 
Discontinuation From the Study Treatment or From the Study .................................43 
3.7.1. 
Patient Discontinuation From Study Treatment .........................................................43 
3.7.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........43 
3.7.3. 
End of Study ...............................................................................................................44 
4. 
STUDY POPULATION .............................................................................................45 
4.1. 
Inclusion Criteria ........................................................................................................45 
4.2. 
Exclusion Criteria .......................................................................................................46 
5. 
STUDY TREATMENT ..............................................................................................50 
5.1. 
Formulation, Packaging, Labeling, and Handling ......................................................50 
5.2. 
Dosage, Administration, and Compliance ..................................................................50 
5.2.1. 
Treatment Administration ...........................................................................................50 
5.2.2. 
Surgical Treatment Plan .............................................................................................50 
5.3. 
Overdose .....................................................................................................................51 
5.4. 
Investigational Medicinal Product Accountability .....................................................51 
5.5. 
Dose Modification ......................................................................................................52 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................53 
6.1. 
Prior Therapy ..............................................................................................................53 
6.2. 
Concomitant Therapy .................................................................................................53 
6.2.1. 
Permitted Concomitant Medications/Procedures .......................................................53 
6.2.1.1. 
Systemic Corticosteroids ............................................................................................53 
6.2.1.2. 
Hepatitis B Treatment .................................................................................................53 
6.2.1.3. 
Hepatitis C Treatment .................................................................................................54 
6.2.1.4. 
COVID-19 Vaccines ...................................................................................................54 
6.2.2. 
Prohibited Concomitant Medications/Procedures ......................................................54 
6.2.3. 
Restricted Concomitant Medications/Procedures .......................................................54 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................55 
7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................57 
7.1. 
Screening ....................................................................................................................57 
7.1.1. 
Informed Consent and Screening Log ........................................................................57 
7.1.2. 
Patient Numbering ......................................................................................................58 
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7.1.3. 
Demographic Data and Medical History ....................................................................58 
7.1.4. 
Women of Childbearing Potential and Contraception ................................................58 
7.1.5. 
HIV Serology Test ......................................................................................................58 
7.2. 
Enrollment ..................................................................................................................58 
7.2.1. 
Confirmation of Eligibility .........................................................................................58 
7.2.2. 
Enrollment/Randomization .........................................................................................59 
7.3. 
Study Drug Dispensation ............................................................................................59 
7.4. 
Safety Assessments .....................................................................................................59 
7.4.1. 
Vital Signs ..................................................................................................................59 
7.4.2. 
Physical Examinations ................................................................................................59 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status ........................................59 
7.4.4. 
Laboratory Safety Tests ..............................................................................................60 
7.4.5. 
Cardiac Enzyme Monitoring .......................................................................................60 
7.4.6. 
Electrocardiograms .....................................................................................................60 
7.4.7. 
Adverse Events ...........................................................................................................60 
7.4.8. 
Presurgical Visit and Surgical Complications ............................................................60 
7.4.9. 
Hepatitis B and C Testing ...........................................................................................61 
7.5. 
Tumor and Response Evaluations ..............................................................................61 
7.6. 
Pharmacokinetic and Antidrug Antibody Testing ......................................................62 
7.7. 
Biomarkers ..................................................................................................................63 
7.7.1. 
Tissue Biomarkers ......................................................................................................63 
7.7.2. 
Blood Biomarkers .......................................................................................................64 
7.8. 
Visit Windows ............................................................................................................64 
7.9. 
Unscheduled Visits .....................................................................................................65 
8. 
SAFETY MONITORING AND REPORTING .........................................................66 
8.1. 
Risks Associated With Study Treatment ....................................................................66 
8.2. 
General Plan to Manage Safety Concerns ..................................................................66 
8.2.1. 
Eligibility Criteria .......................................................................................................66 
8.3. 
Adverse Events ...........................................................................................................66 
8.3.1. 
Definitions and Reporting ...........................................................................................66 
8.3.2. 
Assessment of Severity ...............................................................................................67 
8.3.3. 
Safety Monitoring Plan ...............................................................................................67 
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8.3.4. 
Assessment of Causality .............................................................................................68 
8.3.5. 
Follow-up of Adverse Events .....................................................................................68 
8.3.6. 
Laboratory Test Abnormalities ...................................................................................69 
8.4. 
Definition of a Serious Adverse Event .......................................................................70 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................70 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................71 
8.6.1. 
Adverse Event Recording Period ................................................................................71 
8.6.2. 
Reporting Serious Adverse Events .............................................................................71 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................71 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................72 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................72 
8.6.3. 
Eliciting Adverse Events ............................................................................................73 
8.6.4. 
Disease Progression ....................................................................................................73 
8.6.5. 
Deaths .........................................................................................................................73 
8.6.6. 
Pregnancies .................................................................................................................73 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................74 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................74 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................74 
8.6.10. 
Recording Anaphylaxis ..............................................................................................74 
8.7. 
Management of Events to be Monitored ....................................................................75 
8.7.1. 
Infusion-Related Reactions and Anaphylaxis .............................................................75 
8.7.2. 
Immune-Mediated Adverse Events ............................................................................75 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................77 
9.1. 
Statistical Analysis ......................................................................................................77 
9.1.1. 
Randomization Methods .............................................................................................77 
9.1.2. 
Analysis Sets ...............................................................................................................77 
9.1.3. 
Patient Disposition ......................................................................................................78 
9.1.4. 
Demographic and Other Baseline Characteristics ......................................................78 
9.1.5. 
Prior and Concomitant Medications ...........................................................................78 
9.2. 
Efficacy Analysis ........................................................................................................78 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................78 
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9.2.2. 
Secondary Efficacy Analysis ......................................................................................79 
9.2.3. 
Exploratory Efficacy Analysis ....................................................................................79 
9.3. 
Safety Analyses ..........................................................................................................80 
9.3.1. 
Extent of Exposure .....................................................................................................80 
9.3.2. 
Adverse Events ...........................................................................................................80 
9.3.3. 
Laboratory Analyses ...................................................................................................81 
9.3.4. 
Vital Signs ..................................................................................................................81 
9.3.5. 
Electrocardiograms .....................................................................................................81 
9.3.6. 
Eastern Cooperative Oncology Group Performance Status ........................................82 
9.3.7. 
Feasibility of Surgery .................................................................................................82 
9.4. 
Biomarker Analysis ....................................................................................................82 
9.5. 
Pharmacokinetic Analysis ..........................................................................................82 
9.6. 
Immunogenicity Analyses ..........................................................................................82 
9.7. 
Sample Size Consideration .........................................................................................83 
9.8. 
Interim Analysis ..........................................................................................................83 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................84 
10.1. 
Blinded Independent Pathology Review ....................................................................84 
10.2. 
Steering Committee ....................................................................................................84 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................85 
11.1. 
Access to Information for Monitoring ........................................................................85 
11.2. 
Access to Information for Auditing or Inspections ....................................................85 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................86 
12.1. 
Regulatory Authority Approval ..................................................................................86 
12.2. 
Quality Assurance .......................................................................................................86 
12.3. 
Study Site Inspections.................................................................................................86 
12.4. 
Drug Accountability ...................................................................................................86 
13. 
ETHICS/PROTECTION OF HUMAN PATIENTS ..................................................88 
13.1. 
Ethical Standard ..........................................................................................................88 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................88 
13.2.1. 
Protocol Amendments ................................................................................................88 
13.3. 
Informed Consent .......................................................................................................89 
13.4. 
Patient and Data Confidentiality .................................................................................89 
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13.5. 
Financial Disclosure ...................................................................................................91 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................92 
14.1. 
Data Collection and Management Responsibilities ....................................................92 
14.1.1. 
Data Entry in the Electronic Case Report Form .........................................................92 
14.1.2. 
Data Collection ...........................................................................................................92 
14.1.3. 
Data Management/Coding ..........................................................................................92 
14.2. 
Data Integrity and In-House Blinding ........................................................................93 
14.3. 
Study Records Retention ............................................................................................93 
14.4. 
Protocol Deviations ....................................................................................................94 
14.5. 
Study Report and Publications....................................................................................94 
14.6. 
Study and Study Center Closure .................................................................................95 
14.7. 
Information Disclosure and Inventions ......................................................................95 
15. 
REFERENCES ...........................................................................................................97 
APPENDIX 1. SCHEDULE OF ASSESSMENTS (FOR ARMS 1A, 1B, 1C, 2A, AND 
2C) 108 
APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS ..............................................116 
APPENDIX 3. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS (ECOG PS) ...............................................................................................117 
APPENDIX 4. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................118 
APPENDIX 5. PREEXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................128 
APPENDIX 6. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................130 
APPENDIX 7. INFUSION-RELATED REACTIONS, HYPERSENSITIVITY 
REACTIONS AND IMMUNE-MEDIATED ADVERSE EVENTS: 
EVALUATION AND MANAGEMENT .................................................................131 
APPENDIX 8. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION EQUATION ...........................................................................150 
APPENDIX 9. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................151 
APPENDIX 10. LIST OF RESTRICTED CHINESE HERBAL AND PATENT 
MEDICINES .............................................................................................................153 
APPENDIX 11. TISLELIZUMAB ...........................................................................................155 
APPENDIX 12. OCIPERLIMAB .............................................................................................163 
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APPENDIX 13. LBL-007 .........................................................................................................173 
APPENDIX 14. CHEMOTHERAPY .......................................................................................188 
APPENDIX 15. PREGNANCY REPORTING PERIOD .........................................................194 
 
LIST OF TABLES  
Table 1: 
Preliminary Efficacy and Safety Data of PD-1 Pathway-Targeting 
Immunotherapy or  in combination with chemotherapy in Resectable 
NSCLC Neoadjuvant Treatment .................................................................................27 
Table 2: 
Objectives and Endpoints ...........................................................................................36 
Table 3: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
All Treatment Arms ....................................................................................................71 
Table 4: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................72 
Table 5: 
Examples of Immune-Mediated Adverse Events .......................................................75 
 
LIST OF FIGURES 
Figure 1: 
Overall Survival by Clinical Response and by Pathological Response ......................32 
Figure 2: 
Study Schema .............................................................................................................39 
 
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SYNOPSIS  
Name of Sponsor/Company: BeiGene, Ltd. 
Investigational Medicinal Product(s): Tislelizumab (BGB-A317) and other investigational agents 
Title of Study: A Randomized, Open-Label, Multicenter, Phase 2, Umbrella Study to Evaluate the 
Preliminary Efficacy, Safety, and Pharmacodynamics of Tislelizumab Monotherapy and 
Multiple Tislelizumab-based Immunotherapy Combinations With or Without Chemotherapy as 
Neoadjuvant Treatment in Chinese Patients with Resectable Stage II to IIIA Non-Small Cell Lung 
Cancer 
Protocol Identifier: BGB-LC-202 
Phase of Development: 2 
Number of Patients: 
In the current protocol, approximately 120 patients will be enrolled. Roughly 60 patients with tumor 
programmed death protein ligand-1 (PD-L1) expression ≥ 50% will be randomly assigned into 
Substudy 1 including Arm 1A (tislelizumab monotherapy), Arm 1B (tislelizumab in combination with 
ociperlimab), and Arm 1C (LBL-007 in combination with tislelizumab) in a 1:1:1 randomization ratio. 
Roughly 60 patients with tumor PD-L1 expression < 50% will be randomly assigned into Substudy 2 
including Arm 2A (tislelizumab in combination with chemotherapy) and Arm 2C (LBL-007 in 
combination with tislelizumab and chemotherapy) in a 1:2 randomization ratio. With the addition of 
other investigational agents in combination with tislelizumab over the course of the study, the patient 
number and randomization ratio can be adjusted. 
Study Centers: Approximately 14 centers in China 
Study Objectives and Endpoints: 
Efficacy Objectives and Endpoints: 
Objectives 
Endpoints 
To evaluate the major pathological 
response (MPR) rate as assessed by the 
Blinded Independent Pathology Review 
(BIPR) in patients receiving 
investigational agents as neoadjuvant 
treatment 
• 
The MPR rate as assessed by the BIPR and defined as 
the proportion of patients with ≤ 10% residual viable 
tumor in the resected primary tumor and all resected 
lymph nodes 
To evaluate the pathological complete 
response (pCR) rate of neoadjuvant 
treatment with investigational agents as 
assessed by the BIPR 
• 
The pCR rate as assessed by the BIPR and defined as 
the proportion of patients with absence of residual 
tumor in the resected primary tumor and all resected 
lymph nodes  
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To evaluate the survival related endpoints 
including event-free survival (EFS), 
overall survival (OS), disease-free 
survival (DFS), and milestone endpoints 
• 
EFS is defined as the time from randomization until 
any of the following events, whichever occurs first: 
radiographic disease progression that precludes 
definitive surgery, local or distant recurrence, as 
assessed by investigator per Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1, or death due 
to any cause. The 1-year and 2-year EFS rates will be 
provided as milestone endpoints. 
• 
OS is defined as the time from the date of 
randomization to the date of death due to any cause. 
The 1-year and 2-year OS rates will be provided as 
milestone endpoints.  
• 
DFS is defined as the time from the first date of no 
disease (ie, patients who underwent margin-negative 
[R0] resection) to local or distant recurrence, as 
assessed by the investigator according to RECIST 
v1.1, or death due to any cause, whichever occurs first. 
The 1-year and 2-year DFS rates will be provided as 
milestone endpoints. 
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Safety Objectives and Endpoints: 
Objectives 
Endpoints 
To assess the safety and tolerability of 
neoadjuvant treatment with 
investigational agents 
• 
Incidence and severity of treatment-emergent adverse 
events, including serious adverse events and 
immune-mediated adverse events (imAEs), with 
severity determined according to National Cancer 
Institute Common Terminology Criteria for Adverse 
Events Version 5.0 (NCI-CTCAE v5.0) 
To assess the feasibility of surgery in 
patients receiving neoadjuvant treatment 
with investigational agents 
• 
Proportion of patients who undergo surgical resection 
within a scheduled period after receiving any dose of 
investigational agents, delayed or canceled surgery, 
duration of surgery and surgical approach  
Pharmacodynamic/Exploratory Objectives and Endpoints: 
Objectives 
Endpoints 
To evaluate intratumoral, blood-based or 
draining lymph node-based 
pharmacodynamics, prognostic 
biomarkers, and response- or 
resistance-associated biomarkers seen 
with neoadjuvant treatment with 
investigational agents 
• 
Biomarkers assessed in baseline and post-treatment 
tumor tissue, blood, or draining lymph node samples, 
which include:  
- 
Immune cell quantification and phenotyping via 
multiplex immunohistochemistry or flow 
cytometry 
- 
Gene expression profile 
- 
Gene mutations/tumor mutation burden 
(TMB)/microsatellite instability (MSI) 
- 
T-cell receptor (TCR) profile 
- 
Soluble proteins such as cytokines/chemokines 
- 
Circulating tumor DNA (ctDNA) or minimal 
residual disease (MRD) 
- 
Target or ligands expression of each 
investigational agent 
To characterize the pharmacokinetics 
(PK) of the investigational agents 
• 
Serum or plasma concentrations of the investigational 
agents at specified timepoints 
To assess the host immunogenicity to 
investigational protein therapeutics 
• 
Immunogenic responses to investigational protein 
therapeutics, evaluated through detection of antidrug 
antibodies (ADAs) 
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Study Design: 
This is a randomized, open-label, multicenter, Phase 2, umbrella study to evaluate the preliminary 
efficacy, safety, and pharmacodynamics of tislelizumab as monotherapy and in combination with other 
investigational agents as neoadjuvant treatment in Chinese patients with resectable Stage II to IIIA 
non-small cell lung cancer (NSCLC). 
The study is designed with the flexibility of adding treatment arms as new treatments become available 
or discontinuing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, and 
of modifying the patient population (eg, regarding biomarker status). In the current protocol, 
Substudy 1 includes Arm 1A (tislelizumab monotherapy), Arm 1B (tislelizumab in combination with 
ociperlimab), and Arm 1C (LBL-007 in combination with tislelizumab) in patients with tumor PD-L1 
expression ≥ 50%; Substudy 2 includes Arm 2A (tislelizumab in combination with chemotherapy) and 
Arm 2C (LBL-007 in combination with tislelizumab and chemotherapy) in patients with tumor PD-L1 
expression < 50%. New tislelizumab-based combination arm(s) may be added in accordance with 
emerging preclinical or clinical evidence via a protocol amendment. 
The total number of patients will depend on the number of experimental arms and the timing when they 
are added to the study. Arm 1A and Arm 2A may stay open with the corresponding randomization ratio 
whenever there is at least one combination arm open for enrollment. With the addition of new 
investigational agents, the patient number and randomization ratio will be adjusted based on the 
number of experimental arms that are open for enrollment (eg, if an arm is added or enrollment in an 
arm is suspended for pending analysis of results from the preliminary phase).  
The study schema is presented below: 
  
Abbreviations: ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; EOT, End-of-
Treatment; FFPE, formalin-fixed paraffin-embedded; NSCLC, non-small cell lung cancer; PD-L1, programmed 
death protein ligand-1; R, randomization ratio. 
*Tumor assessments should be conducted per protocol until disease recurrence or progression that precludes 
definitive surgery, initiation of new anticancer therapy except the prespecified adjuvant therapy, withdrawal of 
consent, death, loss to follow-up, or study termination by the sponsor, whichever occurs first. Survival status 
should be followed per protocol until death, loss to follow-up or the end of study. 
Neoadjuvant treatment: 
Eligible patients will be assigned randomly in a fixed ratio into one of the active treatment arms. 
Substudy 1: 
In the current version protocol, eligible patients with tumor PD-L1 expression ≥ 50% will be 
randomized in a 1:1:1 ratio to 1 of the following treatment arms: 
• 
Arm 1A: tislelizumab on a 3-week cycle for 2 to 4 cycles, followed by surgical resection 
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• 
Arm 1B: tislelizumab + ociperlimab on a 3-week cycle for 2 to 4 cycles, followed by surgical 
resection 
• 
Arm 1C: LBL-007 + tislelizumab on a 3-week cycle for 2 to 4 cycles, followed by surgical 
resection 
Patients randomized to Arm A, Arm B, and Arm C in the original protocol (0.0) and protocol 
amendment 1.0 will be mapped to Arm 1A, Arm 1B, and Arm 1C in this protocol amendment 2.0, 
respectively. 
Substudy 2: 
Eligible patients with tumor PD-L1 expression < 50% will be randomized in a 1:2 ratio to 1 of the 
following treatment arms: 
• 
Arm 2A: tislelizumab + chemotherapy on a 3-week cycle for 2 to 4 cycles, followed by 
surgical resection 
• 
Arm 2C: LBL-007 + tislelizumab + chemotherapy on a 3-week cycle for 2 to 4 cycles, 
followed by surgical resection 
The following platinum-based doublet chemotherapy options are permitted for this study: 
• 
Cisplatin/carboplatin + pemetrexed (nonsquamous) 
• 
Cisplatin/carboplatin + paclitaxel (squamous) 
For patients with tumors of mixed histology (squamous and nonsquamous), appropriate chemotherapy 
regimen will be decided by investigators based on the major histological components assessed by 
pathologists. Carboplatin can replace cisplatin per the investigator’s discretion in consideration of 
patient’s tolerability to cisplatin. The reasons for intolerability should be documented. After 
discontinuation from study treatment due to any reasons (completion of planned neoadjuvant treatment, 
adverse event, patient’s withdrawal, or investigator’s decision), the End-of-Treatment (EOT)/Safety 
Follow-up Visit should be conducted ≤ 30 days (± 7 days) after the last dose of study treatment (refer 
to Section 3.4 for details). Before surgery, the resectability assessment which is composed of tumor 
response and safety assessments will be conducted at Presurgical Visit, and the eligible patients will 
proceed to surgery. Based on the investigator’s discretion, patients who are found to have disease 
progression at scheduled tumor assessments or at any time during neoadjuvant treatment or who 
discontinued early from neoadjuvant treatment due to intolerable AEs, patient’s withdrawal, or 
investigator’s decision may still proceed to undergo surgery if patients are assessed as likely being able 
to tolerate surgery and their tumor is deemed resectable and nonmetastatic.  
For patients who are responding to neoadjuvant therapy but cannot proceed to surgery (eg, because of 
pulmonary embolism or myocardial infarction), the medical monitor should be consulted. 
Surgery: 
Upon completion of the neoadjuvant treatment, patients will undergo surgical resection of their tumor. 
Surgical specimens (primary tumor tissue and dissected lymph nodes) will be assessed for pathological 
response (MPR and pCR) by the BIPR and biomarker analysis will be performed. 
At Presurgical Visit, the investigator will reassess the patient to reconfirm the disease resectability 
based on tumor response and safety assessments. The Presurgical Visit and associated assessments can 
be incorporated into the EOT/Safety Follow-up Visit in accordance with local institutional practice. 
The tumor assessment and other safety assessments at Presurgical Visit should be completed ≤ 14 days 
before surgery. The surgical procedure should be performed ≤ 14 days after the EOT/Safety Follow-up 
Visit. If surgery cannot be performed within this time window (eg, because of a prolonged AE), 
investigator should inform sponsor medical monitor regarding the determination of surgery beyond 
pre-specified time window as well as the corresponding considerations  (refer to Section 5.2.2 for 
details). 
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Survival Follow-up: 
During the Survival Follow-up period, based on the investigator’s benefit-risk assessment for each 
patient, optional adjuvant regimens per local guideline are allowed after surgery. Disease recurrence 
status and survival status will be followed periodically during this period. 
Blinded Independent Pathology Review: 
Independent pathology review will be established for central review of pathologic responses. Tumor 
and lymph node samples will be submitted for central review. Sites will be trained before enrolling the 
first patient. Pathology sample acquisition guidelines and the submission process will be outlined in the 
Pathology Manual for the study, which will be provided by the vendors. For histologic assessment, all 
tumor and associated lymph node tissues should be sectioned at 1-cm intervals. For assessments of 
pathological response, the percentage of viable tumor cells in ≥ 1 section per centimeter of the tumor 
and lymph node tissue resected should be evaluated. The assessment by the BIPR will be used for 
reporting of the endpoints of MPR and pCR. 
Study Assessments 
Efficacy assessments: 
MPR and pCR will be assessed by the BIPR. Each tumor assessment will include computed 
tomography (CT) scans (with oral/intravenous contrast, unless contraindicated) of the chest and 
abdomen (including liver and adrenal glands). In addition, patients will undergo whole body by 
positron emission tomography (PET) at screening, followed by tumor assessments by CT scans (with 
oral/intravenous contrast, unless contraindicated) at the EOT/Safety Follow-up Visit after neoadjuvant 
treatment phase. Tumor assessment at the Presurgical Visit may not be repeated if there is a standard 
tumor assessment per protocol performed ≤ 14 days before surgery. The first disease follow-up tumor 
assessment after surgery will be performed at 3 months (± 2 weeks) after surgery, then every 6 months 
(± 4 weeks) for the first 2 years, and then annually (± 8 weeks) thereafter. Tumor assessments must be 
conducted per protocol until disease recurrence or progression that precludes definitive surgery, 
initiation of new anticancer therapy except the prespecified adjuvant therapy, withdrawal of consent, 
death, loss to follow-up, or study termination by the sponsor, whichever occurs first. Tumor assessment 
should be performed by investigator per RECIST v1.1, and disease resectability should be assessed by 
attending thoracic surgeon per local guidelines and best clinical experience. Disease progression that 
does not preclude definitive surgery is not a criterion for tumor assessment discontinuation. Patients 
precluded from planned surgery for any reason except disease progression or death will continue to 
undergo tumor assessment every 6 weeks (± 1 week) until disease progression, death, initiation of new 
anticancer therapy, withdrawal of consent, loss to follow-up, or study termination by the sponsor, 
whichever occurs first.  
Pharmacodynamic and exploratory assessments:  
For biomarker evaluation, formalin-fixed paraffin-embedded (FFPE) specimens (FFPE blocks 
[preferred] or unstained slides) of the primary tumor and optional lymph node samples will be collected 
at Screening. If patients undergo surgery, representative tissue samples of the primary tumor will be 
collected. If accessible, a surgical lymph node sample is recommended to be provided. The surgical 
specimen for biomarker evaluation is optional for patients who achieve pCR after neoadjuvant 
treatment. Blood samples will be collected at predose on Day 1 of Cycle 1, on Day 8 of Cycle 1 and at 
predose on Day 1 of Cycle 2 during the first 2 cycles of the neoadjuvant treatment phase to evaluate PK 
and ADA biomarkers. Blood samples will also be collected at EOT/Safety Follow-up Visit, 7 days after 
surgery, and then at the visits for disease follow-up tumor assessment after surgery. Patients who have 
disease progression/recurrence will be asked to provide an optional biopsy from accessible tumor sites 
to explore mechanisms of resistance. Biomarker analysis (including PD-L1, immune cell quantification 
and phenotyping, gene expression profile, gene mutations/TMB/MSI, TCR sequencing and target or 
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ligands expression of each investigational agent, soluble proteins such as cytokines and chemokines, 
and ctDNA or MRD) will be performed. 
PK samples will be collected for PK characterization of tislelizumab and/or other investigational 
agents. ADA samples will be collected to detect the development of any ADAs against tislelizumab 
and/or other investigational agents as appropriate. PK and ADA samples will be collected at times 
specified in the schedule of assessments. 
Safety assessments: 
All patients will be assessed for safety and tolerability on Day 1 of each cycle during the neoadjuvant 
treatment period. Patients will return to the clinic for the EOT/Safety Follow-up Visit as described in 
Section 3.4. 
AEs will be evaluated according to the latest version of National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0). After the informed consent 
form (ICF) has been signed but before the administration of the study treatment, only serious adverse 
events should be reported. After initiation of study treatment, all AEs (serious or nonserious), 
regardless of relationship to treatment, will be reported until either 30 days after the last dose of study 
treatment or until initiation of prespecified adjuvant treatment or other new anticancer therapy, 
whichever occurs first. Immune-mediated adverse events (serious or nonserious) should be reported 
until 90 days after the last dose of study treatment, regardless of whether the patient starts a new 
anticancer therapy or prespecified adjuvant treatment. All serious adverse events 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. 
After the EOT/Safety Follow-up Visit, survival status and any additional anticancer treatment will be 
evaluated every 6 months (± 4 weeks) via phone contact or in-person contact.  
Details about the study assessments are presented in Section 7 and in Appendix 1. 
Study Duration: 
The study duration varies for each individual patient. After enrollment, each patient is planned to 
receive neoadjuvant treatment for 2 to 4 cycles, followed by surgery; adjuvant therapy is allowed after 
surgery at the discretion of the investigator according to local guidelines. A survival follow-up phase is 
also planned for each patient. Patients have the right to discontinue from the study at any time and for 
any reason.  
Study Population: Patients with resectable, histologically confirmed Stage II to IIIA NSCLC. In the 
current protocol, approximately 60 patients will be randomly assigned into Substudy 1, including Arm 1A 
(tislelizumab monotherapy), Arm 1B (tislelizumab in combination with ociperlimab), and Arm 1C 
(LBL-007 in combination with tislelizumab), for patients with tumor PD-L1 expression ≥ 50% in a 
1:1:1 randomization ratio. Approximately 60 patients with tumor PD-L1 expression < 50% will be 
randomly assigned into Substudy 2, including Arm 2A (tislelizumab in combination with 
chemotherapy) and Arm 2C (LBL-007 in combination with tislelizumab and chemotherapy), in a 
1:2 randomization ratio. 
Key Eligibility Criteria: 
Key Inclusion Criteria: 
• 
Age ≥ 18 years on the day of signing the informed consent form 
• 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 
• 
Histologically confirmed Stage II-IIIA NSCLC (per the Eighth American Joint Committee on 
Cancer/Union Internationale Contre le Cancer NSCLC staging system) 
• 
Measurable disease as assessed by the investigator per RECIST v1.1 
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• 
Evaluation by an attending thoracic surgeon to confirm eligibility for an R0 resection with 
curative intent 
• 
Adequate cardiopulmonary function to be eligible for surgical resection with curative intent 
assessed by investigator 
• 
Adequate hematologic and organ function, defined by protocol-specified laboratory test results, 
obtained ≤ 7 days before randomization 
• 
Patients must provide at least 15 freshly cut, unstained FFPE slides of the primary tumor, or 
FFPE block containing equivalent tumor tissues (preferred), for central PD-L1 evaluation 
during screening and other exploratory biomarker assessments. Only patients with evaluable 
PD-L1 status assessed by central laboratory are eligible. If local result of epidermal growth 
factor receptor (EGFR) mutation status (nonsquamous only) is not available, 3 additional slides 
for central EGFR testing are required. 
Key Exclusion Criteria: 
• 
Any prior antineoplastic therapy(ies) for current lung cancer (eg, radiotherapy, targeted 
therapies, ablation, or other systemic or local antineoplastic treatment) 
• 
Patients with large cell neuroendocrine carcinoma (LCNEC) 
• 
Known EGFR sensitizing mutations and/or anaplastic lymphoma kinase (ALK) rearrangement 
• 
The presence of locally advanced unresectable NSCLC regardless of stage or metastatic 
disease. Mediastinal lymph node samples are required for clinical staging to assess nodal 
involvement in patients with contralateral mediastinal adenopathy on CT scan. 
• 
Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone or equivalent) or other immunosuppressive medications ≤ 14 days before 
randomization 
- Adrenal replacement steroids (dose ≤ 10 mg daily of prednisone or equivalent); 
topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption; and short course (≤ 7 days) of corticosteroid prescribed 
prophylactically or for the treatment of a nonautoimmune condition are permitted 
• 
Active autoimmune diseases or history of autoimmune diseases that may relapse 
- Patients with controlled type I diabetes, hypothyroidism only requiring hormone 
replacement, controlled celiac disease by diet alone, skin diseases (such as vitiligo, 
psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger are permitted to enroll 
• 
History of interstitial lung disease, pneumonitis, or uncontrolled lung diseases including 
pulmonary fibrosis, acute lung diseases, etc. 
• 
Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral 
therapy, including tuberculosis infection, etc. 
- Severe infections ≤ 4 weeks before randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
- Received therapeutic oral or intravenous antibiotics for severe chronic or active 
infections ≤ 2 weeks before randomization 
If applicable, investigational agent-specific eligibility criteria will be provided corresponding to the 
respective agent-specific appendix. 
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Investigational Product, Dose, and Mode of Administration: 
Substudy 1: 
Arm 1A: 
Tislelizumab: Day 1 of each 3-week cycle, administered as an intravenous infusion 
Arm 1B: 
Tislelizumab: Day 1 of each 3-week cycle, administered as an intravenous infusion 
Ociperlimab: Day 1 of each 3-week cycle, administered as an intravenous infusion 
Arm 1C: 
LBL-007: Day 1 of each 3-week cycle, administered as an intravenous infusion 
Tislelizumab: Day 1 of each 3-week cycle, administered as an intravenous infusion 
Substudy 2: 
Arm 2A: 
Tislelizumab: Day 1 of each 3-week cycle, administered as an intravenous infusion 
Chemotherapy: Day 1 of each 3-week cycle, Cisplatin (75 mg/m2) (or Carboplatin area under the curve 
(AUC) = 5 mg/mL/min] + Pemetrexed (nonsquamous, 500 mg/m2)/Paclitaxel (squamous, 175 mg/m2), 
administered as an intravenous infusion. 
Arm 2C: 
LBL-007: Day 1 of each 3-week cycle, administered as an intravenous infusion 
Tislelizumab: Day 1 of each 3-week cycle, administered as an intravenous infusion 
Chemotherapy: Day 1 of each 3-week cycle, cisplatin (75 mg/m2) (or carboplatin 
[AUC = 5 mg/mL/min)] + pemetrexed (nonsquamous, 500 mg/m2)/paclitaxel (squamous, 175 mg/m2), 
administered as an intravenous infusion. 
Carboplatin can replace cisplatin per the investigator’s discretion in consideration of patient’s 
tolerability to cisplatin. The reasons for intolerability should be documented.  
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Statistical Methods: 
Descriptive statistics will be used to summarize the demographic, disease characteristic, efficacy, and 
safety data. No statistical hypotheses are planned for this exploratory study.  
Analysis sets: 
• 
The Intent-to-Treat (ITT) analysis set includes all enrolled patients. Patients will be analyzed 
according to their randomized treatment arm.  
• 
The Intent-to-Treat with tumor PD-L1 expression ≥ 50% (ITT-1) analysis set includes all 
enrolled patients with tumor PD-L1 expression ≥ 50% in Substudy 1. Patients will be analyzed 
according to their randomized treatment arm. It will be the primary analysis set for the efficacy 
analysis for patients with tumor PD-L1 expression ≥ 50%. 
• 
The Intent-to-Treat with tumor PD-L1 expression < 50% (ITT-2) analysis set includes all 
enrolled patients with tumor PD-L1 expression < 50% in Substudy 2. Patients will be analyzed 
according to their randomized treatment arm. It will be the primary analysis set for the efficacy 
analysis for patients with tumor PD-L1 expression < 50%. 
• 
The Safety (SAF) analysis set includes all enrolled patients who received ≥ 1 dose of 
neoadjuvant treatment. Patients will be analyzed according to the treatment they actually 
received. It will be the analysis set for the safety analyses.  
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• 
The Efficacy Evaluable (EE) analysis set includes all patients from the SAF analysis set who 
have completed surgery as planned; it will be used as supportive analysis set. 
• 
The Biomarker analysis set includes all patients from the SAF analysis set who have 
≥ 1 evaluable biomarker measurement; it will be used for the biomarker analysis. 
Efficacy analyses: 
Primary efficacy analysis of MPR rate will be based on the ITT-1 and ITT-2 analysis sets. All analyses 
will be descriptive. The rate of MPR along with its 95% Clopper-Pearson CI will be calculated for each 
arm in each analysis set. In addition, the rate difference between the tislelizumab monotherapy and 
other tislelizumab-based immunotherapy combinations in the ITT-1 analysis set and the rate difference 
between tislelizumab in combination with chemotherapy and tislelizumab in combination with 
LBL-007 and chemotherapy in the ITT-2 analysis set will also be provided using Fisher’s exact test. 
The efficacy analysis of pCR rate will be summarized similarly to the MPR rate in the ITT-1 and ITT-2 
analysis sets.  
DFS, EFS, and OS will be estimated using the Kaplan-Meier method in the ITT-1 and ITT-2 analysis 
sets. The event-free rates at selected timepoints along with 95% CI will be estimated using the 
Greenwood formula (Greenwood 1926). Hazard ratio and corresponding two-sided 95% CI will be 
estimated using a Cox proportional hazards model if necessary. Statistical methods will be described in 
detail in the Statistical Analysis Plan. 
Safety analyses: 
Safety will be determined by monitoring and recording of AEs and laboratory values (hematology, 
clinical chemistry, coagulation, and urinalysis). Vital signs, physical examinations, and 
electrocardiogram findings will also be used in determining the safety profile. The severity of AEs will 
be graded according to the NCI-CTCAE v5.0. The incidence of treatment-emergent adverse events will 
be reported as the number (percentage) of patients with treatment-emergent adverse events by system 
organ class and preferred term. Descriptive summary statistics (eg, n, mean, SD, median, minimum, 
maximum for continuous variables; n [%] for categorical variables) and changes from baseline will be 
determined for laboratory parameters and vital signs. 
Biomarker analysis: 
Exploratory biomarkers will be assessed. Analyses may examine the association between relevant 
biomarkers and clinically relevant outcomes including patient prognosis, response, and resistance. 
Pharmacokinetic Analyses: 
The serum/plasma 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 SDs, 
as appropriate. 
Immunogenicity Analyses: 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADAs. The incidence of positive ADAs and neutralizing 
ADAs will be reported for evaluable patients. 
Sample size considerations: 
This study is designed for the preliminary evaluation of the pharmacodynamics, safety, and efficacy of 
tislelizumab monotherapy and multiple tislelizumab-based immunotherapy combinations with or 
without chemotherapy in patients with resectable Stage II to IIIA NSCLC. It is not designed to allow 
explicit power and Type I error considerations, so there is no formal statistical hypothesis. 
Approximately 60 patients will be randomly assigned into Substudy 1, including Arm 1A (tislelizumab 
monotherapy), Arm 1B (tislelizumab in combination with ociperlimab), and Arm 1C (LBL-007 in 
combination with tislelizumab), in patients with tumor PD-L1 expression ≥ 50% in a 
1:1:1 randomization ratio. Approximately 60 patients with tumor PD-L1 expression < 50% will be 
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randomly assigned into Substudy 2, including Arm 2A (tislelizumab in combination with 
chemotherapy) and Arm 2C (LBL-007 in combination with tislelizumab and chemotherapy), in a 
1:2 randomization ratio. With the defined sample size, the expected 95% CI of the MPR rate difference 
in patients with tumor PD-L1 expression ≥ 50% between the tislelizumab-based immunotherapy 
combination arms and the tislelizumab monotherapy arm would be 1% to 59% if the true MPR for 
tislelizumab-based immunotherapy combinations arm and monotherapy arm is 70% and 40%, 
respectively. The expected 95% CI of the MPR rate difference in patients with PD-L1 expression 
< 50% between LBL-007 in combination with tislelizumab and chemotherapy arm and tislelizumab in 
combination with chemotherapy arm would be -11% to 41% if the true MPR for tislelizumab in 
combination with LBL-007 and chemotherapy arm and tislelizumab in combination with chemotherapy 
arm is 49% and 34%, respectively.  
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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
AUC 
area under the curve 
BGB-A1217 
ociperlimab 
BGB-A317 
tislelizumab 
BIPR 
Blinded Independent Pathology Review 
COVID-19 
Coronavirus disease 2019 
CT 
computed tomography 
CYP 
cytochrome P-450 
DFS 
disease-free survival 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EFS 
event-free survival 
EOT 
End-of-Treatment 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intention-to-Treat 
ITT-1 
Intent-to-Treat with tumor PD-L1 expression ≥ 50% 
ITT-2 
Intent-to-Treat with tumor PD-L1 expression < 50% 
MPR 
major pathological response 
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Abbreviation 
Definition 
MSI 
microsatellite instability 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NK 
natural killer 
NMPA 
National Medical Products Administration 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
pCR 
pathological complete response 
PD-1 
programmed death protein-1  
PD-L1 
programmed death protein ligand-1  
PET 
positron emission tomography  
PK 
pharmacokinetic(s) 
R0 
margin-negative 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
TCR 
T cell receptor 
TEAE 
treatment-emergent adverse event 
TIL 
tumor-infiltrating lymphocytes 
TMB 
tumor mutation burden 
TPS 
Tumor Proportion Score 
Treg 
regulatory T cell 
ULN 
upper limit of normal 
 
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1. 
INTRODUCTION  
1.1. 
Background Information on Non-Small Cell Lung Cancer and 
Unmet Clinical Needs  
1.1.1. 
Background Information on Early-Stage Non-Small Cell Lung Cancer  
Lung cancer is the second most commonly diagnosed cancer worldwide, with an estimated 2.2 
million new cases and 1.8 million deaths in 2020. During that same year, lung cancer accounted 
for 1 in 10 (11.4%) cancers diagnosed and for 1 in 5 (18.0%) cancer deaths, making it the 
leading cause of cancer deaths in 2020 (Siegel et al 2021). Approximately 80% to 85% of lung 
cancers are non-small cell lung cancer (NSCLC), which includes adenocarcinoma (40%), 
squamous cell carcinoma (25%), and large cell carcinoma (10%). A few other subtypes of 
NSCLC, such as adenosquamous carcinoma and sarcomatoid carcinoma, are much less common. 
The prognosis for lung cancer patients is relatively poor, although it greatly depends on the stage 
at which the cancer is detected. Lung cancer staging is performed worldwide according to the 
tumor, lymph node, and metastasis (TNM) Classification of Malignant Tumors, Eighth Edition 
(Amin et al 2017).  At diagnosis, about 30% of NSCLC patients have Stage II to IIIA disease. 
The median 5-year overall survival (OS) rate ranges from 36% to 60% of these patients (defined 
by the American Joint Committee on Cancer Eighth Edition [Goldstraw et al 2016]). The 
treatment goal for patients with resectable stage lung cancer is curing their cancer; however, up 
to 60% of male and up to 50% of female patients with Stage II NSCLC die within 3 years after 
diagnosis (Araghi et al 2021). As a single modality, surgery for early-stage or locally advanced 
NSCLC remains associated with high rates of recurrence (Huynh et al 2021a). 
1.1.2. 
Current Treatment Options for Patients With Resectable NSCLC Stage II to 
IIIA  
The most common cause of treatment failure in resectable NSCLC is tumor recurrence (Cruz et 
al 2017). Local recurrence is associated with poor OS. In Stage I to III NSCLC patients, the local 
recurrence rate after surgery was 9.4% (median follow-up time 59 months), and the most 
significant risk factor for local recurrence within 5 years after resection was lymph node 
metastasis. 
The goal of neoadjuvant treatment is to achieve downstaging to enable or facilitate complete 
resection while preserving lung parenchyma and function to a greater extent, and for an earlier 
eradication of micrometastases to prevent disease recurrence (Huynh et al 2021a). In the past, 
chemotherapy was recommended by international treatment guidelines as neoadjuvant or 
adjuvant treatment for resectable NSCLC (NCCN 2022; CSCO Guidelines 2020). Despite 
administration of the chemotherapy preoperative treatment, the tumor recurrence and long-term 
benefit in event-free survival (EFS)/disease-free survival (DFS) or OS in patients with 
early-stage resectable NSCLC remain unsatisfactory and are associated with significant toxicity, 
especially hematologic toxicities which may lead to delay of surgical procedures with curative 
intent or impact the postoperative recovery. According to published clinical studies, the median 
OS ranged from 93 to 33 months, and the median DFS ranged from 48 to 32 months, and the 
incidence rate of hematologic toxicity of ≥ Grade 3 ranged from 40% to 85% in patients with 
early-stage resectable NSCLC treated with preoperative chemotherapy (Douillard et al 2006; Ou 
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et al 2010; Pisters et al 2010; Scagliotti et al 2012). The major pathological response (MPR) rate 
achieved from neoadjuvant chemotherapy was only 8.9% to 20% and pathological complete 
response (pCR) rate ranged from 2.2% to 4% (Hellmann et al 2014).  
Anti-programmed cell death protein-1 (PD-1) therapy has emerged as an effective treatment for 
patients with tumors expressing varying degrees of PD-L1 (Hanna et al 2017). Anti-PD-1 and 
anti-PD-L1 therapies target the programmed death receptor pathway of T lymphocytes; this 
checkpoint has been found to be activated in cancers allowing tumors to evade the host immune 
system. Since the successful development of cancer immunotherapy in advanced NSCLC, 
creative perioperative treatment regimens containing PD-1/PD-L1 have been conducted in 
clinical studies recently (Table 1). With emerging data from several pivotal studies in resectable 
NSCLC recently, the treatment landscape for this patient population is changing. Immune 
checkpoint inhibitors in combination with platinum-based chemotherapy as neoadjuvant 
treatment followed by immune checkpoint inhibitors as adjuvant treatment are now 
recommended as the preferred treatment in the latest international treatment guidelines (NCCN 
2023).  
For the neoadjuvant treatment setting, patients with resectable NSCLC treated with neoadjuvant 
immunotherapy plus chemotherapy had higher rates of pathological tumor response and longer 
EFS compared to chemotherapy alone, which may predict clinical benefit and correlates with 
improved outcomes (Forde et al 2022; Wakelee et al 2023). Checkmate 816 is the first Phase 3 
study to evaluate nivolumab plus chemotherapy as neoadjuvant treatment for Stage IB to IIIA 
disease. Preliminary result showed a statistically significant and clinically meaningful 
improvement in the primary endpoint of pCR rate (24% with nivolumab + platinum-doublet 
chemotherapy versus 2.2% with chemotherapy alone), and the benefit was consistent across 
disease stages, histologies, tumor mutation burden (TMB), and PD-L1 expression levels. The 
addition of the neoadjuvant nivolumab to chemotherapy did not impede the feasibility of surgery. 
The long-term follow-up data appeared that the long-term endpoint was consistently met and the 
study treatment resulted in a significant improvement in EFS with a 37% risk reduction 
compared with chemotherapy alone as neoadjuvant (median EFS: 31.6 months versus 20.8 
months, hazard ratio [HR] 0.63; 95% CI 0.45 to 0.87; p=0.0052). However, the toxicity of study 
treatment in the Checkmate 816 study should not be overlooked: treatment-related AEs of any 
grade were reported in 82.4% and 88.6% of patients in the treatment arm and in the 
chemotherapy arm, respectively; Grade 3 or 4 treatment-related AEs were reported in 33.5% and 
36.9% of patients in the treatment arm and in the chemotherapy arm, respectively (Forde et al 
2021; Forde et al 2022). Chemotherapy plus nivolumab is strongly recommended by 
international treatment guidelines as neoadjuvant treatment for resectable NSCLC, especially for 
those patients with tumors ≥ 4 cm or node positive and no contraindications to immune 
checkpoint inhibitors (NCCN 2023). Nivolumab plus platinum-based chemotherapy was granted 
approval by China National Medical Products Administration (NMPA) as neoadjuvant treatment 
for operable NSCLC patients in January 2023.  
KEYNOTE-671 is a randomized, double-blind Phase 3 trial evaluating neoadjuvant 
pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab as a single agent 
versus placebo plus neoadjuvant chemotherapy followed by adjuvant placebo in patients with 
resectable Stage II-IIIB NSCLC. Compared with neoadjuvant chemotherapy alone, adding 
perioperative pembrolizumab was associated with a significant improvement in EFS (HR 0.58; 
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95% CI: 0.46 to 0.72; p < 0.001). Patients who received pembrolizumab plus neoadjuvant 
chemotherapy were also significantly more likely than those who received placebo plus 
neoadjuvant chemotherapy to attain significantly better MPR (30.2% versus 11.0%; p < 0.0001) 
and pCR (18.1% versus 4.0%; p < 0.0001) (Wakelee et al 2023). 
The AEGEAN study is a randomized, double-blind, multi-center, placebo-controlled, global 
Phase 3 trial evaluating durvalumab as perioperative treatment for patients with resectable 
Stage IIA-IIIB NSCLC. Patients treated with the durvalumab plus chemotherapy regimen before 
and after surgery showed a 32% reduction in EFS versus chemotherapy alone (HR 0.68; 95% CI: 
0.53 to 0.88; p = 0.003902). Treatment with neoadjuvant durvalumab plus chemotherapy before 
surgery resulted in a pCR and MPR rate of 17.2% and 33.3% versus 4.3% and 12.3% for patients 
treated with neoadjuvant chemotherapy alone (Heymach et al 2023).  
The Neotorch study is a randomized, double-blind, placebo-controlled, Phase 3 trial evaluating 
the efficacy and safety of perioperative toripalimab plus chemotherapy followed by toripalimab 
maintenance versus chemotherapy alone in patients with resectable Stage II and III NSCLC. 
With a median follow-up of 18.3 months, interim analysis from the Neotorch trial showed a 
significant improvement in EFS for patients treated with toripalimab arm (HR 0.40; 95% CI: 
0.277 to 0.565; p < 0.0001). In combination with perioperative chemotherapy, toripalimab 
demonstrated more favorable pCR and MPR of 24.8% versus 1.0% and 48.5% versus 8.4% 
compared to chemotherapy alone, respectively (Lu et al 2023). 
For the adjuvant treatment setting, the IMpower 010 study is a Phase 3 clinical study to 
investigate adjuvant therapy with atezolizumab versus best supportive care in patients with 
early-stage NSCLC who had received radical resection followed by adjuvant platinum-based 
chemotherapy. The results showed that DFS was significantly improved in the study treatment 
arm compared with best supportive care (HR 0.66; 95% CI: 0.5 to 0.88; p = 0.0039) in patients 
with resected Stage II to IIIA NSCLC and PD-L1 of 1% or more, and the safety profile was 
tolerable with an incidence of Grade 3 and 4 treatment-related adverse events of 11% (Felip et al 
2021). In March 2022, China NMPA officially approved the use of Atezolizumab as an adjuvant 
therapy after surgical resection in patients with Stage II-IIIA resectable NSCLC who were 
evaluated to be PD-L1 positive (Tumor Proportion Score [TPS] ≥ 1%). 
Keynote 091 is a multicenter, randomized, triple-blind, placebo-controlled trial in patients with 
completely resected Stage IB-IIIA NSCLC regardless of tumor PD-L1 expression. 
Pembrolizumab was shown to significantly improve DFS versus placebo. Median DFS was 53.6 
months (95% CI: 39.2 to not reached) in the pembrolizumab group versus 42.0 months (95% CI: 
31.3 to not reached) in the placebo group (HR 0.76; 95% CI: 0.63-0.91; p = 0.0014). 
Atezolizumab and pembrolizumab are both recommended for patients with completely resected 
NSCLC (Atezolizumab in patients with PD-L1 ≥1%) and negative for EGFR exon 19 deletion or 
exon 21 L858R mutations or ALK rearrangements who received previous adjuvant 
chemotherapy and with no contraindications to immune checkpoint inhibitors (NCCN 2023). 
Apart from above pivotal studies, some early Phase 1/2 studies exploring neoadjuvant 
immunotherapy in NSCLC also showed promising outcomes especially in PD-L1 high 
population, compared with neoadjuvant regimens containing chemotherapy, the PD-1/PD-L1 
monotherapy or in combination with other immunotherapy showed notably better safety profile 
in terms of ≥ Grade 3 treatment-emergent adverse events (TEAEs) (4.5-13% versus 32.3-44.9% ) 
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(Table 1) , which supports the notion that PD-1/PD-L1 monotherapy or in combination with 
other immunotherapy as neoadjuvant in resectable NSCLC is expected to bring comparable 
clinical benefit with less safety concern compared with regiments containing chemotherapy in 
PD-L1 high population. 
Table 1: 
Preliminary Efficacy and Safety Data of PD-1 Pathway-Targeting 
Immunotherapy or  in combination with chemotherapy in Resectable 
NSCLC Neoadjuvant Treatment  
Study name 
Phase 
Populati
on 
Treatment(s) 
N  
MPR 
rate 
pCR 
rate 
≥ Gr.3 
TRAE 
Checkmate 159 
(Forde et al 2018) 
2 
I-IIIA 
Nivolumab 
21 
45% 
10% 
4.5% 
NEOSTAR 
(Cascone et al 
2021) 
2 
I-IIIA 
Nivolumab; 
Nivolumab + ipilimumab 
23 
21 
22% 
38% 
9% 
29% 
13% 
10% 
LCMC3 
(Lee JM et al 
2021) 
2 
I-IIIB 
Atezolizumab 
181 
21% 
7% 
6% 
ChiCTR-OIC-
17013726 
(Gao et al 2020) 
1b 
IA-IIIB 
Sintilimab 
40 
40.5% 
16.2% 
10% 
NEOpredict-Lung 
(Schuler et al 
2022) 
2 
I-IIIA 
Nivolumab,  
Nivolumab + Relatlimab 
60 
27% 
30% 
13% 
17% 
N/A 
Checkmate 816 
(Forde et al 2022) 
3 
IB-IIIA 
Chemotherapy, 
Nivolumab + 
Chemotherapy 
358 
8.9% 
36.9% 
2.2% 
24% 
36.9% 
33.5% 
AEGEAN 
(Heymach et al 
2023) 
3 
II-IIIB 
Chemotherapy, 
Durvalumab + 
chemotherapy 
799 
12.3% 
33.3% 
4.3% 
17.2% 
33.1% 
32.3% 
KEYNOTE-671 
(Wakelee et al 
2023) 
3 
II-IIIB 
Chemotherapy, 
Pembrolizumab + 
Chemotherapy 
797 
11% 
30.2% 
4% 
18.1% 
37.3% 
44.9% 
Neotorch 
(Lu et al 2023) 
3 
II-IIIB 
Chemotherapy, 
Toripalimab + 
chemotherapy 
404 
8.4% 
48.5% 
1% 
24.8% 
N/A 
Abbreviations: Gr, grade; MPR, major pathological response; N/A, not applicable; NSCLC, non-small cell lung 
cancer; pCR, pathological complete response; PD-1, programmed death protein-1; TRAE, treatment related adverse 
event. 
1.1.3. 
Unmet Medical Need  
Overall, early-stage NSCLC, despite being potentially curable, has a high risk of relapse, or 
death due to disease progression and unsatisfying current standard of care; exploring neoadjuvant 
containing novel therapeutic agents is still needed in order to retain the efficacy outcome and 
minimize safety risk, which may provide more clinical options for patients with early-stage 
resectable NSCLC. 
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1.1.4. 
Background Information on Investigational Agents  
Background information on each investigational agent is presented in the appendices: 
• Tislelizumab: Appendix 11 
• Ociperlimab: Appendix 12 
• LBL-007: Appendix 13 
• Chemotherapy: Appendix 14 
1.2. 
Study Rationale  
1.2.1. 
Rationale for Patient Population and Treatment Setting  
This study will enroll patients with resectable, histologically confirmed Stage II to IIIA NSCLC 
as determined at screening. In early-stage NSCLC, the 5-year OS rate is only 19% to 43% 
(Goldstraw et al 2007) with disease recurrence often seen in 30% to 70% of patients who 
undergo surgical resection (Ponn et al 2005). A rational approach to improve survival in these 
patients is to eradicate micrometastatic disease and to minimize the risk of relapse with adjuvant 
or neoadjuvant chemotherapy and immunotherapy. The currently available standard of care in 
China, including neoadjuvant chemotherapy plus immunotherapy with adjuvant immunotherapy 
are provided in Section 1.1.2. Despite improvements resulting from the addition of neoadjuvant 
immunotherapy to chemotherapy agent, the high toxicity should still not be overlooked. 
Therefore, exploring neoadjuvant therapy containing novel therapeutic agents is still needed in 
order to retain the efficacy outcome while minimizing the safety risk, which may provide more 
clinical options for patients with early-stage resectable NSCLC.  
Patients with PD-L1 low expression  
With nivolumab plus platinum-based chemotherapy approval by China NMPA as neoadjuvant 
treatment for operable NSCLC patients and results from several other Phase 3 studies of 
anti-PD-1/PD-L1 inhibitors in combination with chemotherapy as neoadjuvant being conducted 
in resectable NSCLC, which showed a promising pCR/MPR improvement, neoadjuvant 
immunotherapy plus chemotherapy is now a preferred regimen over neoadjuvant chemotherapy 
alone.  
Patients with PD-L1 high expression 
Previous studies have established the predictive value of tumor PD-L1 expression for evaluating 
efficacy of anti-PD-1 and anti-PD-L1 therapy in the advanced-stage NSCLC (Borghaei et al 
2015, Fehrenbacher et al 2016, Herbst et al 2014, Herbst et al 2016, Rosenberg et al 2016, 
Topalian et al 2012). Pembrolizumab monotherapy has been approved by the United States (US) 
Food and Drug Administration (FDA) as the first-line treatment of patients with NSCLC 
expressing a PD-L1 TPS ≥ 50% in 2016. The approval was expanded to TPS ≥ 1% in 2019 
(Keytruda [pembrolizumab] US prescribing information 2021). In February 2021, the FDA 
approved another checkpoint inhibitor monotherapy, cemiplimab-rwlc, for the first-line 
treatment of patients with advanced NSCLC whose tumors have high PD-L1 expression (TPS 
> 50%), which suggests that regimens containing PD-1 inhibitor without chemotherapy may be a 
potential choice for NSCLC patients with high PD-L1 expression. 
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Although anti-PD-1/PD-L1 inhibitors in combination with chemotherapy as neoadjuvant showed 
a promising pCR/MPR improvement, they also showed high toxicity with ≥ Grade 3 AEs 
assessed as related to the study treatment ranging between 32.3% to 44.9%. On the other hand, 
several Phase 1b-2 studies evaluating PD-1/PD-L1 inhibitors as monotherapy or in combination 
with another immunotherapeutic regimen as neoadjuvant in a similar population showed a 
comparable pCR/MPR, especially in PD-L1 high population, with the incidence of treatment-
related adverse events of ≥ Grade 3 only between 4.5% and 13% (Table 1), which suggests that 
PD-1/PD-L1 monotherapy or in combination with other immunotherapy as neoadjuvant in 
resectable NSCLC is expected to bring comparable clinical benefit with fewer safety concerns 
compared with regimens containing chemotherapy in PD-L1 high population.  
NEOpredict-Lung was a Phase 2 study that looked at the use of relatlimab plus nivolumab versus 
nivolumab alone in patients with resectable NSCLC. A total of 60 patients were enrolled in this 
study and were randomized in a 1:1 ratio to receive nivolumab or in combination with relatlimab 
prior to surgical resection. MPR was 27% in nivolumab arm versus 30% in nivolumab plus 
relatlimab arm and was 40% versus 71% in PD-L1 TPS ≥ 50% patients in the 2 arms (Schuler et 
al 2022). Administering the LAG-3 targeted antibody with PD-1 antibody prior to resection 
could offer additional clinical benefit for patients with resectable NSCLC, especially patients 
with PD-1 high expression, which indicates that PD-1 inhibitor or combined immunotherapy 
regimens containing PD-1 inhibitor may be a potential choice for resectable NSCLC patients, 
meriting further research on preoperative immune checkpoint inhibitor therapy in the 
neoadjuvant setting. Besides that, utilizing novel combinations containing other 
immunotherapeutic agents to improve PD-1/PD-L1 antibody monotherapy is also considered as a 
promising strategy to identify an optimal neoadjuvant treatment, which could further enhance the 
recognition and elimination of tumor cells by the host immune system and reduce the impact of 
the immunosuppressive tumor microenvironment.  
1.2.2. 
Rationale for Tislelizumab or Tislelizumab-Based Immunotherapy 
Combinations as Neoadjuvant Treatment in Patients With NSCLC  
Cancer cells have been found to have intrinsic mechanisms bypassing every step in the cancer 
immunity cycle to evade anticancer immunity. Across the cancer-immunity cycle, diverse 
mechanisms of immune escape have been reported, including defective cancer antigen 
presentation, immune checkpoint mediated exhaustion, decreased sensitivity to immune killing, 
and enriched immunosuppressive cells/cytokines (Gao et al 2017, Huang et al 2016, Koyama et 
al 2016, Shayan et al 2016, Topalian et al 2015, Zhu et al 2021). Overcoming above pathways of 
tumor immune escape may provide a mechanism justification to explore different kinds of 
immunotherapies or combinations. Several preclinical studies have shown that immunotherapy 
combinations may bring an additional synergistic effect, eg, PD-1/PD-L1 in combination with 
TIGIT or LAG-3 (Zhu et al 2021), and in combination therapies are currently being extensively 
explored in emerging clinical studies to target multiple defects along the immunity cycle and 
cancer intrinsic alterations and improve the anticancer efficacy. 
NSCLC histology is associated with a high frequency of mutation with multiple novel tumor 
antigens, which may make it more sensitive to immune recognition (Brahmer et al 2010, Iwai et 
al 2002).  Regarding to neoadjuvant treatment for early-stage NSCLC, immunotherapy allows 
the activated T cells to release cytokines, perforins, granzymes, and others to kill tumor cells. In 
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terms of mechanisms involved, when the tumor volume is relatively large, antigen presentation 
cell bears a relatively large antigen load, which elicits a stronger antitumor T cell response, as 
well as immune memory formation. Therefore, neoadjuvant immunotherapy could theoretically 
be better than adjuvant immunotherapy and may yield an even greater survival long-term benefit, 
which is supported by preclinical studies: in animal models, compared with adjuvant 
immunotherapy, neoadjuvant immunotherapy resulted in better ability to eradicate distant 
metastases after primary tumor resection, prevent metastasis and lead to greater prolongation of 
median survival time (Cascone et al 2018, Liu et al 2016). 
Breakthrough results from treatment with immune checkpoint inhibitors such as 
anti-PD-1/PD-L1 antibodies in patients with many types of solid tumors have paved the way to a 
new era of cancer immunotherapy, leading to a paradigm shift in cancer treatment. The 
up-regulation of immune checkpoint ligands such as PD-L1 on tumor cells can be induced by 
tumorigenic alterations and can lead to a prominent immune evasion mechanism. In NSCLC 
tumors, PD-L1 expression is relatively enriched, with PD-L1 positivity rates ranging from 24% 
to 60% (Yu et al 2016), and it is associated with poor survival. Since the successful development 
of cancer immunotherapy, several PD-1/PD-L1 regimens as antibody monotherapy and in 
combination with chemotherapy have been approved by FDA as standard of care for advanced 
NSCLC (Gandhi et al 2018, Herbst et al 2020, Langer et al 2016, Reck et al 2016, West et al 
2019). The COAST study, a Phase 2, umbrella study investigating efficacy and safety of 
durvalumab monotherapy or durvalumab-based novel combinations in unresectable, Stage III 
NSCLC, demonstrated the improved clinical outcomes with durvalumab-based novel 
combinations, indicating the additional immunomodulation of PD-L1 in combination with other 
novel biological pathways including anti-CD73 and anti-NKG2A may bring promising clinical 
benefit (Herbst et al 2022). 
Results from several clinical studies including BGB-A317-001, BGB-A317-102, 
BGB-A317-303, BGB-A317-304 and BGB-A317-307 revealed that tislelizumab and 
tislelizumab in combination with standard-of-care chemotherapy regimens were generally well 
tolerated and had favorable efficacy in patients with advanced NSCLC, 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. Besides that, the BGB-A317-315 study, a Phase 3 pivotal study 
investigating tislelizumab or placebo in combination with chemotherapy as neoadjuvant 
treatment followed by adjuvant tislelizumab or placebo in patients with Stage II or IIIA NSCLC 
is in progress. The study already met its primary endpoint (MPR) and key secondary endpoint 
(pCR) at interim analysis. Significant improvement in MPR and pCR was observed for the 
tislelizumab in combination with chemotherapy group versus placebo in combination with 
chemotherapy group. No unexpected safety signals have been observed. Taken together, this 
evidence supports that tislelizumab could serve as the backbone in novel combinations based on 
the assessment of its safety and efficacy profile. 
The particular rationale of tislelizumab or tislelizumab-based combinations is presented in the 
investigational agent-specific appendix.   
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1.2.3. 
Rationale for Study Design  
The BGB-LC-202 study is designed as an umbrella study. Usually, an umbrella study is designed 
with multiple substudies which may have a similar objective. The study design involves 
coordinated efforts and a highly efficient manner of initiating/terminating investigational agents 
according to emerging nonclinical or clinical data, to evaluate multiple investigational agents in 
the same treatment setting of one disease subtype, as it is supported by FDA guidelines in 
general, considering the potential advantages in term of flexibility and efficiency in clinical 
development (US FDA 2022). In comparison, executing multiple individual Phase 2 studies 
would require longer time and a greater number of patients.  
Tislelizumab monotherapy or tislelizumab-based combination therapy arms may be closed or 
opened during the study based on internal available data from the study or external emerging 
data. 
1.2.4. 
Rationale for Selection of Investigational Agents  
The rationales for selection of investigational agents and corresponding dose selection for each 
investigational agent are provided in the following agent-specific appendices as follows:  
• Tislelizumab: Appendix 11 
• Ociperlimab: Appendix 12 
• LBL-007: Appendix 13 
• Chemotherapy: Appendix 14 
1.2.5. 
Rationale for Major Pathological Response and Pathological Complete Response 
as Efficacy Endpoints  
In its accelerated approval process, the FDA has adopted a definition of surrogacy, which 
requires that a surrogate endpoint be reasonably likely to predict clinical benefit (Johnson et al 
2003). Pathological response after surgical resection of NSCLC has been proposed as a surrogate 
endpoint based on 3 findings: 1) pathological response strongly correlates to OS; 2) pathological 
response is reflective of neoadjuvant treatment; and 3) the degree of pathological response 
correlates with the degree of OS benefit (Hellmann et al 2014). 
The endpoint of pCR, defined as absence of residual tumor in the resected primary tumor and all 
resected lymph nodes, was widely utilized as an independent or co-primary survival surrogate 
endpoint in most of recent Phase 3 clinical studies of neoadjuvant treatment in the NSCLC 
disease field (Huynh et al 2021b). A prospective study of neoadjuvant chemotherapy in NSCLC 
patients showed a 5-year survival of 54% in patients with Stage IIIA disease who achieved pCR, 
which is striking when compared with the historical standard (Pisters et al 1993). A randomized, 
long-term follow-up study which included 179 patients with Stage Ib-IIIa NSCLC treated with 
neoadjuvant chemotherapy showed that 11% of patients achieved a pCR and had a relative risk 
of death of 0.42 (p<0.001) compared with patients without pCR (Depierre et al 2002). The 
surrogate endpoint of pCR is adopted from regulatory agencies such as the FDA as an acceptable 
endpoint for accelerated approval in breast cancer (US FDA 2012). Taken together, this evidence 
supports the notion that pCR as surrogate endpoint may reasonably predict survival benefit in 
patients with resectable NSCLC under the neoadjuvant treatment setting.  
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MPR, defined as ≤ 10% residual viable tumor tissue, was also proposed as a survival surrogate 
for patients with resectable NSCLC receiving neoadjuvant chemotherapy treatment (Hellmann et 
al 2014). This is based on studies in which investigators, in acknowledgment of the rarity of pCR 
in NSCLC, considered other definitions of pathological response, including residual viable tumor 
as a surrogate survival endpoint. Junker et al performed pathological analysis of 40 tumors from 
patients with Stage IIIA and IIIB disease who were given sequential neoadjuvant chemotherapy 
treatment, chemoradiotherapy, and surgical resection (Junker et al 1997). Patients with ≤ 10% 
residual tumor in this group had a median survival of 36 months, while patients who had > 10% 
residual viable tumor tissue had a median survival of 14 months. A retrospective study from the 
MD Anderson Cancer Center by William and colleagues (William et al 2013) showed that in 
160 patients who received neoadjuvant platinum-based doublet chemotherapy, MPR was a 
stronger predictor of OS than the clinical Response Evaluation Criteria in Solid Tumors 
(RECIST) response (Figure 1). 
Figure 1: 
Overall Survival by Clinical Response and by Pathological Response 
 
Abbreviations: CT RECIST, computed tomography Response Evaluation Criteria in Solid Tumors; CR/PR, 
complete response/partial response; SD/PD, stable disease/progressive disease (William et al 2013). 
Thus, the sponsor believes that there is significant rationale for the use of pCR and MPR because 
of their correlation to the magnitude of improvement in OS, with the potential to increase the 
efficacy benefit of clinical studies and accelerate new treatment options for NSCLC patients. 
1.2.6. 
Biomarker Strategy Rationale  
Biomarker analyses will be performed to explore pharmacodynamics of tislelizumab alone or in 
combination with other investigational agents, as well as the association of biomarkers with 
patient prognosis, response, and potential resistance to the treatment.  
Biomarker analyses in tumor and draining lymph node tissues will include analysis of immune 
cell quantification and phenotyping, gene expression profiling (GEP), gene 
mutations/TMB/microsatellite instability (MSI) status, T-cell receptor (TCR) sequencing, and 
target or ligands expression in each investigational arm at baseline, surgery, and/or disease 
progression/reoccurrence. In addition, blood-based biomarkers will include periphery immune 
cell quantification and phenotype change, concentration, and dynamic changes of soluble 
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proteins such as cytokines/chemokines in blood, circulating tumor DNA (ctDNA) or minimal 
residual disease (MRD), and TCR sequencing.  
Accumulating evidence from mouse models and human patients with cancer has demonstrated 
the importance of the immune system in recognizing and eliminating transformed malignant 
cells, as well as the contradictory role in promoting tumor progression by immune system (Yang 
2015). Therefore, multiple immunotherapy strategies have been proposed to harness the immune 
system to battle cancer, including activating antitumor effector cells and/or removing 
immunosuppressive components. Therefore, the pharmacodynamics will be studied mainly 
focusing on phenotype changes of immune cells (including effector T cells, regulatory T cells 
[Tregs], NK cells, myeloid cell, etc) in the tumor microenvironment, peripheral blood, and 
draining lymph node during treatment based on mechanisms of action of each investigational 
agent (see the agent-specific appendix). Soluble proteins like cytokines/chemokines released 
from immune cells, as well as target or ligands of each investigational agent will be investigated. 
In addition to immune phenotyping, gene expression profile analysis offers an opportunity to 
dissect the tumor microenvironment (TME), a crucial mediator of cancer progression and 
therapeutic outcome. For example, 29 gene signatures covering both anti- and pro-tumor immune 
cells, angiogenesis/fibrosis and malignant cell properties classified tumors into four distinct TME 
subtypes and correlated the subtypes with patient response to immunotherapy in multiple cancers 
(Bagaev et al 2021). Other biomarkers such as TMB (Cristescu et al 2018) may reflect 
tumor-intrinsic neoantigen generation and the capability to evoke the immune response. In the 
Phase 2 clinical study of nivolumab neoadjuvant therapy in early-stage NSCLC, a higher TMB 
level was observed in patients with MPR. Therefore, TMB along with the gene mutations and 
MSI status should be further explored to understand the clinically relevant genetic biomarkers.  
More recently, ctDNA or MRD derived from peripheral blood has shown incredible potential as 
a highly sensitive and specific cancer biomarker. Particularly, studies of the anti-PD-L1 antibody 
durvalumab in patients with NSCLC or urothelial carcinoma revealed a correlation between 
quantitative variations in ctDNA levels and tumor response or patient outcome (Kuziora et al 
2017). Therefore, ctDNA of blood samples will be analyzed in this study to provide valuable 
information on several aspects of exploratory biomarkers, such as prognosis, detection of 
theranostic mutations, predictive biomarkers, early detection of treatment efficacy or disease 
relapse, and potential mechanisms of resistance (Cabel et al 2018). 
TCR sequencing allows for sensitive tracking of dynamic changes in antigen-specific T cells at 
the clonal level, giving unprecedented insight into the mechanisms by which immune checkpoint 
therapy alters T cell responses. Expansion of a greater number of TCRβ clonotypes between 
pre-- and on-treatment samples was observed in responders compared to a smaller number of 
expanded clonotypes in nonresponders, suggesting antigen-specific T-cell proliferation as a 
likely to be a key feature of successful responses to immunotherapy (Kidman et al 2020). Some 
studies have described dynamic changes of TCR repertoire in tumor, blood and draining lymph 
node, providing insight into how the T cell response changes when immunotherapy is 
administered. However, the utility of the TCR repertoire as a dynamic biomarker is still limited 
and requires further exploration. 
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1.3. 
Benefit-Risk Assessment  
The BGB-LC-202 study will evaluate the efficacy, pharmacodynamics, and safety of the 
tislelizumab alone and of tislelizumab-based combinations as neoadjuvant treatment in patients 
with previously untreated, resectable Stage II to IIIA NSCLC. Based on general assessment, the 
sponsor believes neoadjuvant tislelizumab alone or in combination with novel agents may 
provide clinical benefit by enhancing the tumor response and reducing disease recurrence after 
surgery. 
Blockade of the PD-1 pathway has demonstrated strong antitumor efficacy either alone or in 
combination with standard of care chemotherapy in multiple cancer indications. As of the data 
cutoff date of 20 July 2022, tislelizumab has been evaluated in 3220 patients (2173 patients 
treated with monotherapy and 1047 patients treated with combination therapy), 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, which supports the assessment that the efficacy and safety 
profile of tislelizumab could serve as backbone therapy in novel combinations. 
The risk of observing augmented safety signals, as has been shown for other anti-PD-1-based 
immuno-oncology combinations, still remains; therefore, a monitoring plan derived from the 
European Society for Medical Oncology and American Society for Clinical Oncology has been 
established to monitor, diagnose, and manage immune-medicated adverse events (Appendix 7). 
As shown in Appendix 1, this study includes a comprehensive plan to monitor patient safety. 
Safety data will be continuously monitored by the sponsor’s study team in consultation with 
investigator(s) as needed. Refer to Section 7.4 and Section 8 for information regarding additional 
safeguards and considerations related to potential risk.  
The design of the current study aims to minimize potential risks to patients, and specifies the 
rules and procedures to add tislelizumab-based combination arms as follows: 
• A rationale for potential synergistic activity of the novel candidate agent in 
combination with tislelizumab or other PD-1/PD-L1 antibody based on its mechanism 
of action and supported by nonclinical or clinical evidence at the concept level 
• Preliminary evidence of clinical activity of the novel agent in combination with 
tislelizumab or other PD-1/PD-L1 antibody in certain solid tumor settings 
• An established preliminarily, recommended combination dose for the novel agent in 
combination with tislelizumab with an acceptable safety profile for the target 
population in this study 
• Requirement of a protocol amendment and respective health authority and local 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approvals 
prior to implementing any new experimental arm 
• Updated informed consent form (ICF) with relevant information on the new 
tislelizumab-based combination arm 
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The agent-specific benefit-risk assessment is presented in the respective appendix: 
• Tislelizumab: Appendix 11  
• Ociperlimab: Appendix 12  
• LBL-007: Appendix 13  
• Chemotherapy：Appendix 14 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives and Endpoints  
Table 2: 
Objectives and Endpoints 
Efficacy objectives and endpoints 
Objectives 
Endpoints 
To evaluate the major pathological response 
(MPR) rate as assessed by the Blinded 
Independent Pathology Review (BIPR) in 
patients receiving investigational agents as 
neoadjuvant treatment 
• 
MPR rate as assessed by the BIPR and defined as 
the proportion of patients with ≤ 10% residual viable 
tumor in the resected primary tumor and all resected 
lymph nodes  
To evaluate the pathological complete 
response (pCR) rate of neoadjuvant 
treatment with investigational agents as 
assessed by the BIPR 
• 
The pCR rate as assessed by the BIPR and defined 
as the proportion of patients with absence of residual 
tumor in the resected primary tumor and all resected 
lymph nodes 
To evaluate the survival related endpoints 
including event-free survival (EFS), overall 
survival (OS), disease-free survival (DFS), 
and milestone endpoints 
• 
EFS is defined as the time from randomization until 
any of the following events, whichever occurs first: 
radiographic disease progression that precludes 
definitive surgery, local or distant recurrence, as 
assessed by investigator per RECIST v1.1, or death 
due to any cause. The 1-year and 2-year EFS rates 
will be provided as milestone endpoints. 
• 
OS is defined as the time from the date of 
randomization to the date of death due to any cause. 
The 1-year and 2-year OS rates will be provided as 
milestone endpoints.  
• 
DFS is defined as the time from the first date of no 
disease (ie, patients who underwent margin-negative 
[R0] resection) to local or distant recurrence, as 
assessed by the investigator according to RECIST 
v1.1, or death due to any cause, whichever occurs 
first. The 1-year and 2-year DFS rates will be 
provided as milestone endpoints. 
Safety Objectives and Endpoints: 
To assess the safety and tolerability of 
neoadjuvant treatment with investigational 
agents 
• 
Incidence and severity of treatment-emergent 
adverse events (TEAEs), including serious adverse 
events (SAEs) and immune-mediated adverse events 
(imAEs), with severity determined according to 
National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 5.0 
(NCI-CTCAE v5.0) 
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Table 2: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
To assess the feasibility of surgery in 
patients receiving neoadjuvant treatment 
with investigational agents 
• 
Proportion of patients who undergo surgical 
resection within a scheduled period after receiving 
any dose of investigational agents, delayed or 
canceled surgery, duration of surgery and surgical 
approach  
Pharmacodynamics/exploratory Objective and Endpoints 
To evaluate intratumoral, blood-based or 
draining lymph node-based 
pharmacodynamics, prognostic biomarkers, 
and response- or resistance-associated 
biomarkers seen with neoadjuvant treatment 
with investigational agents 
• 
Biomarkers assessed in baseline and post-treatment 
tumor tissue, blood, or draining lymph node 
samples, which include:  
- 
Immune cell quantification and phenotyping via 
multiplex immunohistochemistry or flow 
cytometry 
- 
Gene expression profile 
- 
Gene mutations/tumor mutation burden 
(TMB)/microsatellite instability (MSI) 
- 
T cell receptor (TCR) profile 
- 
Soluble proteins such as cytokines/chemokines 
- 
Circulating tumor DNA (ctDNA) or minimal 
residual disease (MRD) 
- 
Target or ligands expression of each 
investigational agent 
To characterize the pharmacokinetics (PK) 
of the investigational agents 
Serum or plasma concentrations of the investigational 
agents at specified timepoints 
To assess the host immunogenicity to 
investigational protein therapeutics 
Immunogenic responses to investigational protein 
therapeutics, evaluated through detection of antidrug 
antibodies (ADAs) 
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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is a randomized, multi-center, open-label, Phase 2, umbrella study to evaluate the efficacy, 
safety, and pharmacodynamics of tislelizumab as monotherapy and in combination with other 
investigational agents as neoadjuvant treatment in Chinese patients with resectable Stage II to 
IIIA NSCLC. 
The study is designed with the flexibility of adding treatment arms when new treatments become 
available or discontinuing treatment arms that demonstrate minimal clinical activity or 
unacceptable toxicity, or modifying the patient population (eg, regarding biomarker status). New 
tislelizumab-based combination arm(s) may be added in accordance with emerging preclinical or 
clinical evidence via a protocol amendment. The current protocol includes the following 
treatment arms: 
Substudy 1: 
• Arm 1A: tislelizumab monotherapy 
• Arm 1B: tislelizumab in combination with ociperlimab 
• Arm 1C: LBL-007 in combination with tislelizumab  
Substudy 2: 
• Arm 2A: tislelizumab in combination with chemotherapy 
• Arm 2C: LBL-007 in combination with tislelizumab and chemotherapy 
This study consists of a screening phase, a neoadjuvant treatment phase, the End-of-Treatment 
(EOT)/safety follow-up visit, a surgery phase, and the survival follow-up phase. 
Patients will be required to sign an ICF to undergo screening procedures. Local PD-L1 
expression results will be acceptable for randomization/enrollment into this study. Patients will 
also be required to provide tissue samples of the primary tumor and optional lymph node for 
biomarker evaluation.  
The total number of patients depends on the number of experimental arms and the timing when 
they are added to the study. Arm 1A and Arm 2A may be kept open with the corresponding 
randomization ratio whenever at least 1 combination arm is open for enrollment. The patient 
number and randomization ratio will be adjusted based on the number of experimental arms that 
are open for enrollment (eg, if a new arm is added or enrollment in an existing arm is suspended 
for pending analysis of results from the preliminary phase). In the current protocol, Substudy 1 
includes Arm 1A (tislelizumab monotherapy), Arm 1B (tislelizumab in combination with 
ociperlimab), and Arm 1C (LBL-007 in combination with tislelizumab) in patients with tumor 
PD-L1 expression ≥ 50%; Substudy 2 includes Arm 2A (tislelizumab in combination with 
chemotherapy) and Arm 2C (LBL-007 in combination with tislelizumab and chemotherapy) in 
patients with tumor PD-L1 expression < 50%. 
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The study design schematic is presented in Figure 2. Eligible patients will be assigned randomly 
in a certain ratio into 1 of the active treatment arms. In this current version of the protocol, 
eligible patients with tumor PD-L1 expression ≥ 50% will be randomized in a 1:1:1 ratio to 
Substudy 1: 
• Arm 1A: tislelizumab on a 3-week cycle for 2 to 4 cycles, followed by surgical 
resection 
• Arm 1B: tislelizumab + ociperlimab on a 3-week cycle for 2 to 4 cycles, followed by 
surgical resection 
• Arm 1C: LBL-007 + tislelizumab on a 3-week cycle for 2 to 4 cycles, followed by 
surgical resection 
Eligible patients with tumor PD-L1 expression < 50% will be randomized in a 1:2 ratio to 
Substudy 2: 
• Arm 2A: tislelizumab + chemotherapy on a 3-week cycle for 2 to -4 cycles, followed 
by surgical resection 
• Arm 2C: LBL-007 + tislelizumab + chemotherapy on a 3-week cycle for 2 to 
4 cycles, followed by surgical resection 
Figure 2: 
Study Schema 
 
Abbreviations: ALK, anaplastic lymphoma kinase; EOT, End-of-Treatment; EGFR, epidermal growth factor 
receptor; FFPE, formalin fixed paraffin-embedded; NSCLC, non-small cell lung cancer; PD-L1, programmed death 
protein ligand-1; R, randomization ratio. 
*Tumor assessments should be conducted per protocol until disease recurrence or progression that precludes 
definitive surgery, initiation of new anticancer therapy except the prespecified adjuvant therapy, withdrawal of 
consent, death, loss to follow-up, or study termination by the sponsor, whichever occurs first. Survival status should 
be followed per protocol until death, loss to follow-up or the end of study 
Crossover between the experimental arms will not be allowed in this study. After the 
neoadjuvant treatment, patients will undergo surgical resection and then will enter the Survival 
Follow-up phase, in which patient may receive optional adjuvant treatment per local guideline at 
the discretion of investigator. 
For a description of all study procedures, see Section 7 and Appendix 1. 
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3.2. 
Screening Period  
Screening evaluations will be performed ≤ 28 days before randomization (see Appendix 1). 
Patients who agree to participate in this study will sign the ICF before undergoing any screening 
procedure. 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. For rescreening requirements, see Section 7.1. 
Patients are required to provide formalin-fixed paraffin-embedded (FFPE) block (preferred) or 
unstained slides of the primary tumor and optional lymph node sample for biomarker evaluation 
during screening. Refer to Section 7.7 for more details. 
3.3. 
Neoadjuvant Treatment Phase  
Eligible patients will be assigned randomly in a certain ratio into one of the active treatment 
arms. 
In this current version of the protocol, eligible patients with tumor PD-L1 expression ≥ 50% will 
be randomized in a 1:1:1 ratio to 1 of the following treatment arms in Substudy 1: 
• Arm 1A: tislelizumab on a 3-week cycle for 2 to 4 cycles, followed by surgical 
resection 
• Arm 1B: tislelizumab + ociperlimab on a 3-week cycle for 2 to 4 cycles, followed by 
surgical resection 
• Arm 1C: LBL-007 + tislelizumab on a 3-week cycle for 2 to 4 cycles, followed by 
surgical resection 
Eligible patients with tumor PD-L1 expression < 50% will be randomized in a 1:2 ratio to 1 of 
the following treatment arms in Substudy 2: 
• Arm 2A: tislelizumab + chemotherapy on a 3-week cycle for 2 to 4 cycles, followed 
by surgical resection 
• Arm 2C: LBL-007 + tislelizumab + chemotherapy on a 3-week cycle for 2 to 
4 cycles, followed by surgical resection 
The following platinum-based doublet chemotherapy options are permitted for this study: 
• Cisplatin/Carboplatin + Pemetrexed (nonsquamous) 
• Cisplatin/Carboplatin + Paclitaxel (squamous) 
For patients with tumors of mixed histology (squamous and nonsquamous), appropriate 
chemotherapy regimen will be decided by investigators based on the major histological 
components assessed by pathologists. Carboplatin can replace cisplatin per the investigator’s 
discretion in consideration of patient’s tolerability to cisplatin. The reasons for intolerability 
should be documented.  
After completion of planned neoadjuvant treatment or discontinuation from study treatment due 
to any reasons (AE, patient’s withdrawal, or investigator’s decision), the EOT/Safety Follow-up 
Visit should be conducted ≤ 30 days (± 7 days) after the last dose of the study treatment (refer to 
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Section 3.4 for details). The surgical procedure should be performed ≤ 14 days after the 
EOT/Safety Follow-up Visit. Before surgery, the resectability assessment that composed of 
tumor response and safety assessments will be conducted at Presurgical Visit, and the eligible 
patients will proceed to surgery. Based on the investigator’s discretion, patients who are found to 
have disease progression at scheduled tumor assessments or at any time during neoadjuvant 
treatment or who discontinued early from neoadjuvant treatment due to intolerable AEs, patient’s 
withdrawal, or investigator’s decision may still proceed to undergo surgery if patients are 
assessed as likely being able to tolerate surgery and their tumor is deemed resectable and 
nonmetastatic. For patients who are responding to neoadjuvant therapy but cannot proceed to 
surgery (eg, because of pulmonary embolism or myocardial infarction), the medical monitor 
should be consulted. 
A tumor response assessment will be performed at the EOT/Safety Follow-up Visit after the 
neoadjuvant treatment period. Tumor assessment at the Presurgical Visit may not be repeated if 
there is a standard tumor assessment per protocol performed ≤ 14 days before surgery (refer to 
Section 7.5 and Appendix 1 Schedule of Assessments for details). 
Safety will be assessed throughout the study by monitoring AEs/SAEs (toxicity grades assigned 
per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE 
v5.0]) and laboratory results. Vital signs, physical examinations, Eastern Cooperative Oncology 
Group Performance Status (ECOG PS) change, electrocardiogram (ECG) results, and other 
examinations will also be used for safety assessment. Safety assessments are further detailed in 
Section 7.4 and in the Schedule of Assessments (Appendix 1).  
Note: requirements for treatment administration and on-treatment procedures to be performed for 
a specific experimental arm will be presented in the agent-specific appendix, as applicable. 
3.4. 
End of Treatment and Safety Follow-up Visit  
The EOT/Safety Follow-up Visit will be conducted for patients who complete planned 
neoadjuvant or discontinue from study treatment due to any reason including AE, patient’s 
withdrawal, investigator’s decision, and others. Patients will be asked to return to the clinic for 
the EOT/Safety Follow-up Visit which should occur ≤ 30 (±7) days after the last dose of 
neoadjuvant treatment or before surgery procedure or the initiation of any new anticancer 
therapy after neoadjuvant therapy, whichever occurs first.  
If routine laboratory tests (eg, hematology, serum chemistry) are performed ≤ 7 days before an 
EOT/Safety Follow-up Visit, these tests will not need to be repeated. Tumor assessment is not 
required at the EOT/Safety Follow-up Visit provided that ≤ 2 weeks have passed since the last 
assessment. However, if the Presurgical Visit has been incorporated into the EOT/Safety 
Follow-up Visit to assess resectability before surgery, the safety assessment and tumor 
assessment at this visit should be performed ≤ 14 days before surgery.  
In addition, telephone contacts with patients should be conducted to assess immune-mediated 
adverse events (imAEs) and relevant concomitant medications (ie, those associated with an 
imAE or any new anticancer therapy), or if a pregnancy test is also required. These contacts 
should be made at 60 days (± 14 days), and 90 days (± 14 days) after the last dose of study 
treatment, regardless of whether the patient starts a new anticancer therapy or prespecified 
adjuvant treatment. Phone contacts should be documented in the patient’s source documentation. 
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If a patient reports a suspected imAE at a telephone follow-up contact, the investigator should 
arrange an unscheduled visit if further assessment is indicated. For women of childbearing 
potential (see Appendix 9), additional pregnancy tests will be required on 90 days (±14 days) and 
120 days (±14 days) after the last dose of study drug(s) (in clinic or over the phone, as needed 
based on assessments required). The timepoint for the additional pregnancy follow-up visit is 
specified in agent-specified appendix (as applicable). 
All AEs, including SAEs, will be collected as described in Section 8.6. 
Patients who discontinue study treatment before disease progression will have their tumors 
assessed as outlined in Section 7.5.  
See Appendix 1 for assessments to be performed at the EOT/Safety Follow-up Visit. 
3.5. 
Surgery  
Upon completion of neoadjuvant treatment, patients will undergo surgical resection of their 
tumor. Surgical specimens (primary tumor tissue and dissected lymph nodes) will be assessed for 
pathological response (MPR and pCR) by the BIPR and biomarker analysis will be performed. 
Refer to Section 7.7 and Section 10.1 for more details. 
At Presurgical Visit, the investigator will reassess the patient to reconfirm disease resectability 
based on tumor response and safety assessments. The safety assessment and tumor assessment at 
Presurgical Visit should be completed and reviewed by the investigator ≤ 14 days before surgery. 
The Presurgical Visit and associated assessments can be incorporated into the EOT/Safety 
Follow-up Visit if applicable and in accordance with local institutional practice (refer to 
Section 7.4.8 for details). 
The surgical procedure should be performed ≤ 14 days after the EOT/Safety Follow-up Visit. If 
surgery cannot be performed ≤ this time window (eg, because of a prolonged AE), investigator 
should inform sponsor medical monitor regarding the determination of surgery beyond 
pre-specified time window as well as corresponding considerations (refer to Section 5.2.2). 
3.6. 
Survival Follow-up  
Patients will be followed for survival status and for information on subsequent anticancer 
therapy after the EOT/Safety Follow-up Visit. This follow-up will be conducted via telephone 
call, patient medical records review, and/or clinic visits approximately every 6 months 
(± 4 weeks) after the EOT/Safety Follow-up Visit or as directed by the sponsor until death, 
withdrawal of consent, loss to follow-up, or the end of study (see Section 3.7.3). 
During the survival follow-up period, based on the investigator’s benefit/risk assessment for 
patients and determination, optional adjuvant therapy per local guidelines is allowed after 
surgery. 
Recurrence status will be monitored and assessed by the investigator per RECIST v1.1 during 
this period. See Section 7.5 and Appendix 1 for details.  
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3.7. 
Discontinuation From the Study Treatment or From the Study  
3.7.1. 
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 recurrence status 
(Section 3.6), if possible. 
The primary reason for discontinuation from the study treatment should be documented on the 
appropriate electronic case report form (eCRF). Patients may discontinue study treatment for 
reasons which include, but are not limited to, the following: 
• Radiographic disease progression assessed by the investigator per RECIST v1.1 
• AE 
• Patient withdrawal from study treatment 
• 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 
• Except for prespecified study treatment(s) as neoadjuvant, use of any other concurrent 
antineoplastic therapy(ies) (eg, any systemic anticancer therapy including 
chemotherapy, targeted therapies, hormonal therapy, immunotherapy, standard 
anticancer agents and investigational anticancer agents, or any local antineoplastic 
treatment including radiotherapy, ablation and other resection surgery for any cancer) 
• Patient noncompliance: 
Investigative site staff should first counsel patients who are significantly 
noncompliant on the importance of study treatment compliance and drug 
accountability. The investigator may, in consultation with the medical monitor, 
discontinue patients from treatment who are consistently noncompliant. 
• Completion of planned neoadjuvant treatment(s) 
Patients who discontinue study treatment prior to disease progression will continue to undergo 
tumor assessments as outlined in Section 7.5. 
3.7.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient)  
Patients will discontinue from the study for reasons which include, but are not limited to, the 
following: 
• Patient withdrawal of consent  
• Noncompliance 
• Death 
• Loss to follow-up 
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• Patients have completed all study assessments 
The sponsor has the right to terminate any of the experimental arms at any time based on the 
available data. 
3.7.3. 
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 and/or severity of AEs in this or other studies indicates a potential 
health hazard to patients 
• Overall patient enrollment is unsatisfactory 
• A rollover study becomes available 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients should be seen as soon as possible for an 
EOT/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 the IRBs/ IECs of the early termination of the study. 
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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. 
If applicable, additional inclusion/exclusion criteria for a specific experimental arm will be 
presented in the investigational agent-specific appendix. In addition to the inclusion and 
exclusion criteria in the protocol body, investigational agent-specific inclusion and exclusion 
criteria should be met based on patient assignment. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all the following criteria: 
1. Patient must sign a written ICF and understand and agree to comply with the 
requirements of the study and the schedule of assessments 
2. Age ≥ 18 years on the day of signing the ICF 
3. Histologically confirmed Stage II to IIIA NSCLC of squamous or nonsquamous 
histology (staging should be based on the Eighth Edition American Joint Committee on 
Cancer/Union Internationale Contre le Cancer NSCLC staging system [Goldstraw et al 
2016]): 
a. T4 primary NSCLC will be allowed only on the basis of size (tumors > 7 cm). 
Invasion of the diaphragm, mediastinum, heart, great vessels, trachea, recurrent 
laryngeal nerve, esophagus, vertebral body, carina, and separate tumor nodules in a 
different ipsilateral lobe is not permitted. 
b. Patients with mixed NSCLC histology (squamous and nonsquamous) or NSCLC not 
otherwise specified are eligible. 
c. Patients may be enrolled based on clinical stage, but pre-operative documentation of 
nodal involvement by endobronchial ultrasound or mediastinoscopy is strongly 
encouraged. 
4. Patients must provide at least 15 freshly cut unstained FFPE slides of the primary tumor, 
or FFPE block containing equivalent tumor tissues (preferred), for central PD-L1 
evaluation during screening and other exploratory biomarker assessment. Only patients 
with evaluable PD-L1 status assessed by central laboratory are eligible. If local result of 
EGFR mutation status (nonsquamous only) is not available, 3 additional slides for central 
EGFR testing are required.  
5. Solid or subsolid appearance of NSCLC on computed tomography (CT) scan with no 
appearance of purely ground-glass opacity: 
a. For subsolid lesions, the tumor size (ie, clinical T stage) should be measured based on 
the solid component only, without including the ground-glass opacity component. 
6. Evaluation by an attending thoracic surgeon to confirm eligibility for an R0 resection 
with curative intent (Section 5.2.2) 
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7. Adequate cardiopulmonary function assessed by an attending thoracic surgeon to be 
eligible for surgical resection with curative intent 
• If clinically indicated, patients with underlying ischemic, valvular, or other significant 
heart diseases should be evaluated preoperatively by a cardiologist. 
8. Measurable disease as assessed by the investigator per RECIST v1.1  
9. ECOG PS ≤ 1 
10. Adequate hematologic and organ function, as indicated by the following laboratory 
values obtained ≤ 7 days before randomization: 
a. Patients must not have required blood transfusion or growth factor support ≤ 7 days 
before sample collection at screening for the following: 
i. 
Absolute neutrophil count ≥ 1.5 x 109/L 
ii. 
Platelets ≥ 100 x 109/L 
iii. 
Hemoglobin ≥ 90 g/L 
b. Estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 using the Chronic Kidney 
Disease Epidemiology Collaboration equation (Appendix 8) 
c. Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) (total bilirubin must be 
< 3 x ULN for patients with Gilberts syndrome) 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN 
e. For patients not receiving therapeutic anticoagulation: international normalized ratio 
or activated partial thromboplastin time ≤1.5 x ULN 
11. Women of childbearing potential must be willing to use a highly effective method of 
birth control (Appendix 9) for the duration of the study or for ≥ 6 months after the last 
dose of tislelizumab or other investigational agent or chemotherapy, whichever occurs 
later. They must also have a negative urine or serum pregnancy test result ≤ 7 days before 
randomization.  
12. Nonsterile men must be willing to use a highly effective method of birth control 
(Appendix 9) for the duration of the study or for ≥ 6 months after the last dose of 
tislelizumab or other investigational agent or chemotherapy, whichever occurs later. 
a. A sterile man is defined as one for whom azoospermia has been previously 
demonstrated in a semen sample examination as definitive evidence of infertility. 
b. Men with known “low sperm count” (consistent with “sub-fertility”) are not to be 
considered sterile for the purposes of this study. 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria are not eligible to enroll: 
1. Any prior antineoplastic therapy(ies) for current lung cancer (eg, radiotherapy, targeted 
therapies, ablation, or other systemic or local antineoplastic treatment) 
2. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-cell 
immunoglobulin and ITIM domain (TIGIT), anti-lymphocyte activation gene-3 (LAG-3), 
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or any other antibody or drug specifically targeting T-cell costimulation or checkpoint 
pathways 
3. Has mixed small cell lung cancer  
4. Patients with large cell neuroendocrine carcinoma (LCNEC) 
5. Known EGFR sensitizing mutations and/or ALK rearrangement. 
a. Patients with nonsquamous NSCLC must have been tested for EGFR mutational 
status locally using a tissue-based or endobronchial ultrasound-guided transbronchial 
needle aspiration [EBUS-TBNA]–based EGFR test at screening. Patients found to 
have EGFR-sensitizing mutations are not eligible.    
6. Presence of locally advanced unresectable NSCLC regardless of stage or distant 
metastatic disease. Mediastinal lymph node samples are required for clinical staging to 
assess nodal involvement in patients with contralateral mediastinal adenopathy on CT 
scan. 
7. Patient with symptomatic coronavirus disease 2019 (COVID-19) infection or 
asymptomatic patients who tested positive for COVID-19 (through a licensed reverse 
transcription-polymerase chain reaction [RT-PCR] or antigen testing) during screening 
should recover from infection or test negative to be eligible for enrollment. 
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. Celiac disease controlled by diet alone 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) 
e. Any other disease that is not expected to recur in the absence of external triggering 
factors 
9. Any 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 
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c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast 
dye allergy) or for the treatment of a nonautoimmune condition (eg, delayed-type 
hypersensitivity reaction caused by contact allergen) 
11. Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium or sodium 
despite standard medical management or ≥ Grade 3 hypoalbuminemia ≤ 14 days before 
randomization 
12. History of interstitial lung disease, pneumonitis or uncontrolled lung diseases including 
pulmonary fibrosis, or acute lung diseases.  
13. Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral 
therapy, including tuberculosis infection, etc. 
a. Severe infections ≤ 4 weeks before randomization, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
b. Received therapeutic oral or intravenous antibiotics for severe chronic or active 
infections ≤ 2 weeks before randomization 
Note: Antiviral therapy is permitted for patients with chronic hepatitis B virus (HBV) 
or hepatitis C virus (HCV) infection. Patients receiving prophylactic antibiotics (eg, 
for the prevention of urinary tract infection, chronic obstructive pulmonary disease, or 
for dental extraction) are eligible. 
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 patients with treated and 
stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) may be enrolled. 
Patients with detectable HBsAg or detectable HBV DNA should be managed per 
treatment guidelines (see Section 6.2.1.2). 
15. Patients with active hepatitis C 
Note: Patients with a negative HCV antibody test at screening or positive HCV antibody 
test followed by a negative HCV RNA test at screening are eligible. The HCV RNA test 
will be performed only for patients with a testing positive test result for HCV antibody. 
For treatment guidance, see Section 6.2.1.3. 
16. Known history of human immunodeficiency virus (HIV) infection. If the status is 
unknown, an HIV test at screening is required. 
17. Any major surgical procedure ≤ 28 days before randomization. Patients must have 
recovered adequately from the toxicity and/or complications from the intervention prior 
to randomization. 
18. Prior allogeneic stem cell transplantation or organ transplantation 
19. Any of the following cardiovascular and cerebrovascular 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 
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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 ≥ Grade 2 ventricular arrhythmia ≤ 6 months before randomization 
f. Any history of cerebrovascular accident ≤ 6 months before randomization 
g. Uncontrolled hypertension that cannot be managed with standard antihypertensive 
medications ≤ 28 days before randomization 
h. Any episode of syncope or seizure ≤ 28 days before randomization 
20. A history of severe hypersensitivity or intolerance to chimeric or humanized antibodies, 
fusion proteins, chemotherapy agents, or any of the excipients of study treatment  
21. Has received any immunotherapy (eg, interleukin, interferon, thymosin, etc) or any 
investigational therapies ≤ 14 days or ≤ 5 half-lives (whichever is shorter) before the first 
dose of study drug 
22. Patients with toxicities caused by prior anticancer therapy that have not recovered to 
baseline or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, 
neuropathy, and specific laboratory abnormalities) 
23. Was administered a live vaccine ≤ 28 days before randomization 
Note: Vaccines for COVID-19 are allowed except for any live vaccine that may be 
developed. Seasonal vaccines for influenza are generally inactivated vaccines and are 
allowed. Intranasal vaccines are live vaccines and are not allowed. 
24. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study drug or that 
will affect the explanation of drug toxicity or AEs or result in insufficient or impaired 
compliance with study conduct 
25. Women who are pregnant or who are breastfeeding 
26. Concurrent participation in another therapeutic clinical study 
Note: Concurrent participation in observational or noninterventional studies is allowed. 
In addition, patients who have completed active treatment in a clinical study and are in 
the follow-up period can be enrolled in this study. 
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5. 
STUDY TREATMENT  
The specific stipulations of the study treatment for experimental arms including formulation, 
packaging, handing dosage, administration, dose modification, and overdose are provided in 
each investigational agent-specific appendix. Only common requirements for study treatment are 
presented in this section, unless otherwise specified. 
5.1. 
Formulation, Packaging, Labeling, and Handling  
• Tislelizumab: Appendix 11 
• Ociperlimab: Appendix 12 
• LBL-007: Appendix 13 
• Chemotherapy: Appendix 14 
5.2. 
Dosage, Administration, and Compliance  
5.2.1. 
Treatment Administration  
• Tislelizumab: Appendix 11 
• Ociperlimab: Appendix 12 
• LBL-007: Appendix 13  
• Chemotherapy: Appendix 14 
5.2.2. 
Surgical Treatment Plan  
A thoracic surgeon with experience in early-stage resectable NSCLC should evaluate patients at 
screening to determine eligibility for surgical resection. Patients should be eligible for an R0 
resection with curative intent at the time of screening (Rami-Porta et al 2005). Before surgery, 
the investigator will reassess the patient to reconfirm disease resectability at the Presurgical 
Visit. The tumor assessment and other safety assessments at Presurgical Visit should be 
completed ≤ 14 days before surgery. The Presurgical Visit and associated assessments can be 
incorporated into the EOT/Safety Follow-up Visit if applicable and in accordance with local 
institutional practice. Safety assessments at the Presurgical Visit, including but not limited to 
blood tests, coagulation, cardiac or pulmonary tests (if indicated), anesthesia assessment, and 
other evaluation procedures, should be performed per local standard of care.  
The surgical procedure should be performed ≤ 14 days after the EOT/Safety Follow-up Visit. If 
the surgery cannot be performed within this time window (eg, because of a prolonged AE), 
investigator should inform sponsor medical monitor regarding the determination of surgery 
beyond pre-specified time window as well as corresponding considerations. Patients will 
undergo tumor assessment by CT scan (with oral/intravenous contrast, unless contraindicated) at 
the EOT/Safety Follow-up Visit after the neoadjuvant treatment period. Tumor assessment at the 
Presurgical Visit may not be repeated if there is a standard tumor assessment per protocol 
performed ≤ 14 days before surgery. Resection may be accomplished via an open or minimally 
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invasive procedure (eg, video-assisted thoracic surgery or robotic video-assisted thoracic 
surgery). 
A complete resection must meet all 4 of the following criteria (Rami-Porta et al 2005):  
a. Free resection margins including the bronchial, venous, and arterial stumps, 
peribronchial soft tissue, and any peripheral margin near the tumor proved 
microscopically. 
b. Systematic nodal dissection in its wider form or, if it is not performed, lobe-specific 
systematic nodal dissection. Lobe-specific nodal dissection involves dissection and 
histological examination of intrapulmonary (lobar, interlobar, and segmental) and 
hilar nodes and ≥ 3 of the following mediastinal nodal stations depending on the lobar 
location of the primary tumor. The lymph node specimen should include ≥ 6 nodes, 
≥ 3 of which should be removed from intrapulmonary and/or hilar stations and ≥ 3 of 
which should be removed from mediastinal stations. One of the 3 lymph nodes 
removed from mediastinal stations must be from the subcarinal station.  
c. There should be no extracapsular extension of tumor in nodes removed separately or 
those at the margin of the main lung specimen. 
d. The highest mediastinal node that has been removed must be negative 
microscopically.  
Anatomic resection via lobectomy, bilobectomy, or pneumonectomy is strongly preferred. 
Wedge resections are not allowed. 
The performed surgical procedure should be documented and reported in the eCRF. If, after 
neoadjuvant treatment or during the surgery, the surgeon determines that the patient should not 
proceed with the planned surgery, the reason should be documented and reported in the eCRF as 
well. 
5.3. 
Overdose  
AEs associated with an overdose or incorrect administration of study drug will be recorded in the 
AE eCRF. Any SAEs associated with an overdose or incorrect administration must be reported 
≤ 24 hours after awareness via the SAE reporting process described in Section 8.6.2. Supportive 
care measures should be administered as appropriate. 
Refer to each investigational agent-specific appendix for details. 
5.4. 
Investigational Medicinal Product Accountability  
The investigational medicinal products (IMPs) required for completion of this study will be 
provided or sourced by the sponsor, as required by local or country-specific guidance. The 
investigational site will acknowledge receipt of the IMPs. Any damaged shipments will be 
replaced as appropriate. 
Accurate records of all IMPs received, dispensed, returned, and disposed of should be recorded 
in the site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of IMP management. 
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5.5. 
Dose Modification  
Every effort should be made to administer the study drugs according to the planned dose and 
schedule. In the event of significant toxicities, dose modification may be taken. Reasons for dose 
modification, the supportive measures taken, and the outcome will be documented in the 
patient’s source documents and recorded in the eCRF. 
The dose modification guidelines in the protocol are not intended to be a substitute for clinical 
judgment. Investigators may delay doses for other reasons (eg, AEs or laboratory findings) as 
appropriate. 
Treatment-specific dose modification guidance is presented in Appendix 11 (tislelizumab), 
Appendix 12 (ociperlimab), Appendix 13 (LBL-007), and Appendix 14 (chemotherapy). 
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6. 
PRIOR AND CONCOMITANT THERAPY  
6.1. 
Prior Therapy  
The exclusion criteria specify that patients must not have received prior therapy for current lung 
cancer, including chemotherapy and radiotherapy, and prior treatment with an antibody or drug 
against immune checkpoint pathways, including but not limited to, anti-PD-1, anti-PD-L1, or 
anti-CTLA-4 (Section 4.2). All prior cancer related treatments, treatments for underlying active 
medical conditions, and all medications (eg, prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the patient ≤ 30 days before 
randomization must be recorded in the appropriate eCRF. 
6.2. 
Concomitant Therapy  
If applicable, additional requirements with respect to concomitant therapy for a particular 
experimental arm will presented in the investigational agent-specific appendix. In addition to the 
common stipulations stated this section in the protocol body, investigational agent-specific 
requirements for concomitant therapy should be met based on patient assignment. 
6.2.1. 
Permitted Concomitant Medications/Procedures  
Most concomitant medications and therapies deemed necessary and in keeping with the local 
standards of medical care at the discretion of the investigator for the supportive care (eg, 
antiemetics, antidiarrheals, pain medications, and nutritional support) and for a patient’s 
wellbeing are allowed. All concomitant medications will be recorded in the eCRF including all 
prescriptions, over-the-counter drugs, herbal supplements, and intravenous medications and 
fluids. If changes (dose, stop, or start) in concomitant medication occur during the study, 
documentation of drug dosage, frequency, route, date, and reason for use will be recorded in the 
eCRF. All concomitant medications received ≤ 30 days before the first dose of study drug and 30 
days after the last infusion or dose of study treatment should be recorded. 
6.2.1.1. 
Systemic Corticosteroids  
Systemic corticosteroids for management of imAEs must be tapered gradually (see Appendix 7) 
and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) before the 
next study treatment administration. The short-term use of steroids as prophylactic treatments 
(eg, for patients with allergies to diagnostic imaging contrast dyes) is permitted. 
6.2.1.2. 
Hepatitis B Treatment  
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 500 IU/mL) is at the discretion of the investigator, as aligned with 
local guidance. Such medications must be documented in the patient’s chart and recorded in the 
eCRF. Patients receiving antivirals at screening should be managed per treatment guidelines. 
Once initiated, antiviral treatment should continue until 6 months after the last dose of study 
treatment or as permitted by local guidance. 
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6.2.1.3. 
Hepatitis C Treatment  
Patients with detectable HCV RNA who are receiving treatment at screening must meet the 
criterion of negative HCV RNA to be eligible. If the patients are treated and eligible, they should 
remain on continuous, effective antiviral therapy during the study. Investigators can consider 
treatment with antivirals following the international or local guidelines as appropriate. 
6.2.1.4. 
COVID-19 Vaccines  
Vaccines for COVID-19 are allowed except for any live vaccine (ie, live SARS-CoV-2 virus) 
that may be developed. Attenuated (vector) COVID-19 vaccines are inactivated vaccines and as 
such, are permitted. It is recommended to avoid COVID-19 vaccination ≤ 72 hours before or 
after study drug administration during the 2 to 4 treatment cycles. Vaccinations are considered a 
concomitant medication and hence should be entered in the eCRF. The specific COVID-19 
vaccine should be recorded instead of generic language, eg, mRNA-1273 vaccine (Moderna), 
BioNTech vaccine (Pfizer), etc. 
6.2.2. 
Prohibited Concomitant Medications/Procedures  
The following medications are prohibited from screening to the EOT/Safety Follow-up Visit: 
• Except for study treatment(s), any concurrent antineoplastic therapy(ies) (eg, any 
systemic anticancer therapy including chemotherapy, targeted therapies, hormonal 
therapy, immunotherapy, standard anticancer agents and investigational anticancer 
agents, or any local antineoplastic treatment including radiotherapy, ablation and 
other resection surgery for any cancer) 
• Live vaccines ≤ 28 days before randomization and ≤ 60 days after the last dose of 
study treatment(s) are prohibited. 
6.2.3. 
Restricted Concomitant Medications/Procedures  
The following medications/procedures are restricted during the study: 
• 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 
• Herbal remedies for the treatment of cancer or Chinese patent medicines with 
approval from the China NMPA for use as anticancer treatment (regardless of cancer 
type) (Appendix 10) 
• Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or that 
are known to potentially interfere with the liver or other major organ functions 
(eg, hypericin) (Appendix 10) 
• 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. 
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• Opiates and other medications required for palliative management of patients are 
allowed. Patients must notify the investigator of all concurrent medications used 
during the study. 
Patients must notify the investigator of all herbal remedies used during the study. 
6.3. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
Information on potential interactions between study drug and concomitant medications are 
provided in each investigational agent-specific appendix. The potential for drug-drug interaction 
between the study drugs (tislelizumab, ociperlimab, or LBL-007), standard chemotherapy, and 
small-molecule drug products is very low, given tislelizumab, ociperlimab, and LBL-007 are all 
therapeutic monoclonal antibodies. They are unlikely to have an effect on drug-metabolizing 
enzymes or transporters because they are expected to be degraded into amino acids and recycled 
into other proteins. The effect on drug-metabolizing enzymes or transporters for chemotherapy is 
summarized below. 
Cisplatin 
During cisplatin use, concurrent therapy with drugs having a potential ototoxic or nephrotoxic 
effect (eg, aminoglycosides, cefalotin, furosemide, and amphotericin B) should be avoided or 
closely monitored because this may lead to increased or exacerbated toxicity due to 
platin-induced changes in renal clearance of these substances. 
Carboplatin 
The major route of elimination of carboplatin is renal excretion. The renal effects of nephrotoxic 
compounds may be potentiated by carboplatin.  
Pemetrexed 
Renal function decreases would result in an increase in systemic exposure of pemetrexed. 
Pemetrexed should not be administered to patients whose creatinine clearance is < 45 mL/min. 
Caution should be exercised when administering pemetrexed concurrently with non-steroidal 
anti-inflammatory drugs to patients whose creatinine clearance is < 80 mL/min. Ibuprofen has 
been shown to increase pemetrexed exposure and poses a potential risk in patients with 
mild/moderate renal impairment. Hence, ibuprofen usage is discouraged in those patients. 
Paclitaxel 
The metabolism of paclitaxel is catalyzed by cytochrome P-450 (CYP) 2C8 and CYP3A4. 
Caution should be exercised when administering paclitaxel concomitantly with medicines known 
to inhibit or induce either CYP2C8 or CYP3A4 (eg, inhibitors ketoconazole and other imidazole 
antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, 
and nelfinavir or inducers rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine). 
When strong CYP2C8 and CYP3A4 inhibitors are co-administered with nab-paclitaxel, the 
toxicities may be exacerbated and the investigator should closely monitor for them. Please refer 
to the list of strong CYP2C8 and CYP3A4 inhibitors (Flockhart 2007; FDA Drug Development 
and Drug Interactions) and the prescribing information of paclitaxel for more information. 
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Refer to manufacturer’s prescribing information for the respective chemotherapy agents for 
drug-drug interaction information on the influence of drug-metabolizing enzymes or transporters. 
 
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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. In addition to the common 
assessments and procedures stated in this section, additional assessment requirements for each 
particular experimental arm are provided in the respective agent-specific appendix, if applicable. 
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 ≤ 28 days before randomization. Patients who agree to 
participate will sign the ICF before undergoing any screening procedure. The screening period 
begins on the date the ICF is signed. Screening evaluations may be repeated as needed within the 
screening period; the investigator will assess patient eligibility according to the latest screening 
assessment results. 
Results of standard of care tests or examinations performed prior to obtaining informed consent 
and ≤ 28 days prior to randomization may be used for the purposes of screening rather than 
repeating the standard of care tests unless otherwise indicated. 
For the description of other assessments that are conducted during screening, see Section 7.4 for 
the safety assessments, Section 7.5 for tumor and response evaluations, and Section 7.7 for 
biomarkers evaluations.  
Patients are required to provide FFPE block (preferred) or unstained slides of the primary tumor 
and optional lymph node sample for biomarker evaluation during screening. Only patients with 
evaluable PD-L1 status assessed by central laboratory are eligible. Refer to Section 7.7 for more 
details. 
Rescreening under limited conditions may be allowed after consultation with the sponsor. For 
example, rescreening may be considered when a patient narrowly misses a laboratory criterion 
that is correctable and not due to a rapidly deteriorating condition or disease progression. 
Rescreening is allowed only once. If a patient is rescreened, the patient must provide new 
informed consent as described in Section 7.1.1, and a new patient number assigned as described 
in Section 7.1.2. 
7.1.1. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before any 
study-specific procedures are performed. ICFs 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. 
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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 a potential study participant. 
Patients who are rescreened (see Section 7.1) will be assigned a new patient number. Screening 
numbers assigned to the same patient within the IRT system will be linked. Rescreening is 
allowed one time per patient. 
7.1.3. 
Demographic Data and Medical History  
Demographic data will include age or date of birth, sex, and self-reported race/ethnicity.  
Medical history includes any history of clinically significant disease, surgery, or cancer history; 
reproductive status (ie, of childbearing potential or no childbearing potential); history of 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 ≤ 30 days 
before randomization. Pre-existing AEs at baseline should be recorded as medical history.  
Cancer history will include pathologic diagnosis, stage at screening, and tumor location. 
Radiographic studies performed prior to study entry may be collected for review by the 
investigator. 
7.1.4. 
Women of Childbearing Potential and Contraception  
Childbearing potential is defined as being physiologically capable of becoming pregnant. Refer 
to Appendix 9 for contraception guidelines and definitions of “women of childbearing potential” 
and “no childbearing potential.” Refer to Appendix 1 for details about pregnancy testing for 
women of childbearing potential. 
7.1.5. 
HIV Serology Test  
An HIV serology test (antigen and/or antibodies) will be conducted at baseline for the patients 
with unknown HIV status. 
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 
determined. All inclusion criteria must be met and none of the exclusion criteria may be met. No 
eligibility waivers will be granted. 
Sponsor verification of patient eligibility will be managed by way of source data verification in 
accordance with International Council for Harmonisation (ICH) E6. 
The sponsor’s medical monitor will support the investigator and/or site staff by answering any 
queries or questions in relation to the eligibility criteria. 
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7.2.2. 
Enrollment/Randomization  
All eligible patients will be randomized to a treatment arm after enrollment according to the 
randomization ratio specified in Section 9.1.1 to a treatment arm after enrollment.  
Site personnel will access the IRT system to randomize patients to a treatment arm and to assign 
the study drugs. Study treatment must commence ≤ 2 business days after randomization. 
7.3. 
Study Drug Dispensation  
Study treatment will be dispensed and administered as described in Section 5.2. 
7.4. 
Safety Assessments  
In addition to the common safety assessments described in this section, additional requirements 
for safety assessments for each particular experimental arm are provided in the respective 
investigational agent-specific appendix, if applicable. 
7.4.1. 
Vital Signs  
See Appendix 1 for vital signs to be collected and the timing of their collection.  
Vital signs and weight measurements are required at screening, on Day 1 of the first cycle, on 
Day 1 of each subsequent cycle, at the EOT/Safety Follow-up Visit, and at the Presurgical Visit. 
Height measurements are only required at screening. 
Vital signs are required to be recorded ≤ 60 minutes before, during, and 30 minutes after the first 
infusion of study drug(s). For subsequent infusions, vital signs will be collected within 60 
minutes before infusion and if clinically indicated, during and 30 minutes after the infusion. 
7.4.2. 
Physical Examinations  
At the Screening Visit, the EOT/ Safety Follow up Visit and Presurgical Visit, a complete 
physical examination will be conducted, including evaluations of 1) the 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 in the eCRF with the appropriate 
disease/condition terms. 
At other visits (and as clinically indicated), limited, symptom-directed physical examinations 
will be performed. New or worsened clinically significant abnormalities are to be recorded as 
AEs in the eCRF. Refer to Section 8.2.1 regarding AE definitions and reporting and follow-up 
requirements. 
7.4.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG PS (Appendix 3) will be assessed during the study. 
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7.4.4. 
Laboratory Safety Tests  
Local laboratory assessments of serum chemistry, hematology, coagulation, urinalysis, and 
thyroid function will be conducted as described in Appendix 1. Specific assessments to be 
performed are listed in Appendix 2.  
If laboratory tests at screening are not performed ≤ 7 days before the administration of study 
drug(s) on Day 1 of Cycle 1, these tests should be repeated and reviewed before the 
administration of study drug(s). Hematology and serum chemistry (including liver function tests) 
as specified in Appendix 2 should be performed weekly for the first 2 cycles and within 3 days 
before Day 1 during Cycle 3 to 4 of neoadjuvant treatment and at EOT/Safety Follow-up Visit 
and Presurgical Visit. After Cycle 1, the results will be reviewed ≤ 48 hours before the 
administration of the study drug(s). 
Thyroid assessments will be performed as specified in Appendix 1. 
7.4.5. 
Cardiac Enzyme Monitoring  
Although immune-mediated 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 the management of suspected 
immune-mediated myocarditis). Serum troponins may be substituted per local guidelines if used 
consistently throughout the study. 
7.4.6. 
Electrocardiograms  
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient’s source documents 
at the site. 
When coinciding with blood draws at the same timepoint, the ECG assessment should be 
performed prior to the blood draws. Patients should rest in a semirecumbent supine position for 
≥ 10 minutes prior to the ECG collection. 
7.4.7. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0. 
Characterization of toxicities will include severity, duration, and time to onset. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
7.4.8. 
Presurgical Visit and Surgical Complications  
Before surgery, the investigator will reassess the eligibility of each patient to reconfirm disease 
resectability as assessed by tumor response and safety assessments at the Presurgical Visit and in 
accordance with local institutional practice. Evaluations at the Presurgical Visit will include 
blood tests, coagulation, cardiac, or pulmonary tests (if indicated), anesthesia assessment, tumor 
assessment, and other evaluation procedures, that should be performed per local standard of care. 
The Presurgical Visit and associated assessments could be incorporated into EOT/Safety 
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Follow-up Visit. The tumor assessment and other safety assessments at the Presurgical Visit 
should be completed ≤ 14 days before surgery (refer to Appendix 1 and Section 5.2.2 for details). 
Data on perioperative complications, including a delay in planned surgery, pneumonitis, acute 
respiratory distress syndrome, re-admission to the intensive care unit, atrial fibrillation or other 
supraventricular tachycardias, potential immune-mediated toxicities, and postoperative 
complications will be collected. Surgical complications occurring ≤ 90 days after surgery will be 
documented and followed until resolution. Surgical procedure complications will be monitored 
and recorded at the investigator or designee’s discretion. 
7.4.9. 
Hepatitis B and C Testing  
Viral hepatitis B and C serologic markers and viral load (if applicable) will be tested by the local 
laboratory. HBV testing will include hepatitis B surface antibody (HBsAb), HBsAg, and 
hepatitis B core antibody (HBcAb). In addition, HBV DNA will be quantified in patients with 
positive test results for HBsAg. HCV testing will consist of HCV antibody plus HCV RNA in 
patients with positive test results for HCV antibody. 
For patients who have detectable HBV DNA or HCV RNA at screening or upon repeat testing, 
the respective viral load testing will be performed every 12 weeks. A detailed schedule is 
provided in Appendix 1. 
7.5. 
Tumor and Response Evaluations  
Tumor imaging will be performed ≤ 28 days before randomization. Results of standard of care 
tests or examinations performed prior to obtaining informed consent and ≤ 28 days before 
randomization may be used for the purposes of screening rather than repeating the standard of 
care tests. Tumor response will be assessed by the investigator using RECIST v1.1 (see 
Appendix 4). 
Each tumor assessment will include CT scans (with oral/intravenous contrast, unless 
contraindicated) of the chest and abdomen (including liver and adrenal glands). In addition, 
patients will undergo whole body positron emission tomography (PET) at screening. Other 
known or suspected sites of disease must be included in the imaging assessments (bone, brain, 
etc). A CT scan of the chest, abdomen, and pelvis along with a bone scan can be used as an 
alternative for whole body PET/CT at the investigator’s discretion. 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 is required to be used throughout the study (eg, the same contrast protocol for CT 
scans).  
After the screening period, tumor assessments using CT scans (with oral/intravenous contrast, 
unless contraindicated) will be performed in EOT/Safety Follow-up Visit after the neoadjuvant 
treatment phase. Tumor assessments for the Presurgical Visit may not be repeated if there was a 
standard tumor assessment per protocol performed ≤ 14 days before surgery. After surgery, each 
tumor assessment will be performed by CT scans (with oral/intravenous contrast, unless 
contraindicated) of the chest and abdomen (including liver and adrenal glands), and biopsy (if 
disease progression is suspected). The first disease follow-up tumor assessment after surgery will 
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be performed after 3 months (± 2 weeks) postsurgery, then every 6 months (± 4 weeks) for the 
first 2 years, and annually (± 8 weeks) thereafter.  
Tumor assessments must continue according to the schedule until disease recurrence or 
progression that precludes definitive surgery, withdrawal of consent, initiation of new anticancer 
therapy except the prespecified adjuvant treatment, death, loss to follow-up, or study termination 
by the sponsor, whichever occurs first. Tumor assessment should be performed by investigator 
per RECIST v1.1, and disease resectability should be assessed by attending thoracic surgeon per 
local guideline and best clinical experience. Disease progression that does not preclude definitive 
surgery or initiation of prespecified adjuvant treatment is not a criterion of tumor assessment 
discontinuation. Patients precluded from planned surgery for any reasons except disease 
progression or death will continue to undergo tumor assessment every 6 weeks (± 1 week) until 
disease progression, death, initiation of new anti-cancer therapy, withdrawal of consent, loss to 
follow-up, or study termination by the sponsor, whichever occurs first. If a CT scan with contrast 
is contraindicated (eg, in patients with impaired renal clearance), a noncontrast CT scan of the 
chest may be performed and contrast-enhanced MRI scans (if possible) of the abdomen should 
be performed. If a CT scan for tumor assessment is performed using a PET/CT scanner, the CT 
scan acquisition must be consistent with the standards of a diagnostic CT scan. 
With immunotherapies, pseudoprogression may occur due to immune-cell infiltration and other 
mechanisms leading to apparent increase of existing tumor masses or appearance of new tumor 
lesions. Also, some patients may benefit from additional immunotherapies despite evidence of 
disease progression. Optional biopsy is highly recommended for patients with suspected 
pseudoprogression, who may not be able to tolerate the surgical procedure. The following 
criteria must be met to continue neoadjuvant treatment of patients with disease progression 
assessed by investigator per RECIST v1.1: 
• Absence of clinical symptoms and signs of disease progression (including clinically 
significantly worsening of laboratory values)  
• ECOG PS 0 or 1 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) that requires urgent alternative medical intervention 
• Investigators must obtain written informed consent for treatment after radiologic 
disease progression and inform patients that this practice is not considered standard in 
the treatment of cancer.  
• The decision to continue study drug(s) beyond initial investigator-assessed 
progression per RECIST v1.1 must be agreed on the medical monitor and 
documented in the study records. 
7.6. 
Pharmacokinetic and Antidrug Antibody Testing  
Blood samples will be collected for PK characterization of tislelizumab and/or other 
investigational agents in the original protocol. The serum or plasma (as appropriate) samples will 
be assayed for tislelizumab and/or other investigational agent concentrations using validated 
bioanalytical methods. Validated screening and confirmatory assays will be employed to detect 
ADAs for tislelizumab and other protein therapeutics investigational agents as appropriate.  
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PK and ADA samples will be collected at the timepoints indicated in Appendix 1. Requirements 
for collecting PK/ADA of investigational agents included in any new tislelizumab-based 
combination arm(s) that may be added in the future will be described in the respective protocol 
amendment(s). 
Shipping, storage, and handling of samples for the assessment of PK and ADA assays will be 
managed through a central laboratory. Refer to the laboratory manual for instructions.  
7.7. 
Biomarkers  
Shipping, storage, and handling of blood, archival tumor, fresh tumor, and leftover tumor tissue 
for the assessment of biomarkers will be managed through a central laboratory. Refer to the 
laboratory manual for details of sample handling. 
7.7.1. 
Tissue Biomarkers  
See Appendix 1 for the tissue biomarker sample collection schedule. 
Baseline tissue samples collected during screening and surgery will be shipped to a central 
laboratory for biomarker testing after local regulatory approval. This may occur after the start of 
study treatment if necessary. 
Patients must provide at least 15 freshly cut unstained FFPE slides of the primary tumor or FFPE 
block containing equivalent tumor tissues (preferred) for central PD-L1 evaluation during 
screening and other exploratory biomarker assessments. Only patients with evaluable PD-L1 
status as assessed by the central laboratory are eligible. If the local result of EGFR mutation 
status (nonsquamous only) is not available, 3 additional FFPE slides are required for central 
EGFR testing. If the first attempt of PD-L1 testing by the central laboratory fail, 3 additional 
slides may be required for repeat testing. If sufficient baseline tumor tissue is available, around 
35 unstained FFPE slides or equivalent FFPE block are strongly recommended to be provided to 
ensure exploration of all planned biomarkers. If accessible, a baseline lymph node sample (6 to 
10 FFPE slides) is recommended to be provided. If fewer slides are available, please contact the 
sponsor for recommendations. 
If patients undergo surgery, tumor tissue and lymph node tissue obtained from surgical resection 
are required and sent to a central laboratory according to study pathology manuals for 
pathological response analysis as assessed by BIPR. In addition, representative tissue samples of 
the primary tumor (at least 20 freshly cut unstained FFPE slides or FFPE block containing 
equivalent tumor tissues [preferred]) will be collected and sent to a central laboratory for 
biomarker evaluation. If sufficient tumor tissue is available, around 40 FFPE slides of surgery 
tumor tissue are recommended to be provided to ensure exploration of all planned biomarkers. If 
accessible, a surgical lymph node sample is recommended to be provided. The surgical specimen 
for biomarker evaluation is optional for patients who achieve pCR after neoadjuvant treatment. 
Acceptable fresh biopsy samples include core needle biopsies from deep tumor tissue or 
excisional, incisional, punch, or forceps biopsies from cutaneous, subcutaneous, or mucosal 
lesions. Tumor tissue should be of good quality based on total and viable tumor content. Fine-
needle aspiration, brushing, cell pellets from pleural effusion, lavage samples, and bone/bone 
marrow aspirates are not acceptable.  
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Biomarker analyses in tumor and lymph node tissues will include analyses of PD-L1, immune 
cell quantification and phenotyping, GEP, gene mutations/TMB/MSI, TCR sequencing and 
target or ligands expression in each investigational arm, at baseline, surgery, and/or at disease 
progression/reoccurrence to explore the pharmacodynamics of the therapeutic drugs, as well as 
potential predictive and prognostic biomarkers and mechanisms of resistance. The analysis may 
include the association between these biomarkers and clinically relevant outcomes including 
clinical efficacy, disease status, and resistance. 
Patients who have disease progression/recurrence will be asked to provide an optional biopsy 
(Appendix 1) from accessible tumor sites to explore the mechanism of resistance. If feasible, any 
follow-up biopsies should ideally be collected from the same tumor lesion used at baseline. 
Written patient consent is required for fresh tumor biopsies. 
7.7.2. 
Blood Biomarkers  
See Appendix 1 for the blood biomarker sample collection schedule. 
Blood samples will be collected at predose on Day 1 of Cycle 1, on Day 8 of Cycle 1 and at 
predose on Day 1 of Cycle 2 of neoadjuvant phase to evaluate PK and ADA biomarkers 
(Appendix 1). Blood samples will also be collected at the EOT/Safety Follow-up visit; 7 days 
after surgery, and then at the same visits for disease follow-up tumor assessment after surgery.  
Blood-based biomarkers will include periphery immune-cell quantification and phenotype 
change, concentration and dynamic changes of cytokines/chemokines or soluble proteins such as 
cytokine/chemokine in the blood, ctDNA or MRD, and TCR sequencing. Changes in those 
biomarkers may provide evidence of biologic activity of therapeutic drug combination treatment 
in human. Correlations between these biomarkers and efficacy endpoints will be explored to 
identify blood-based biomarkers that may help identify patients that are more likely to benefit 
from investigational agent combination treatment. Analysis may include the association between 
these biomarkers and clinically relevant outcomes including response, resistance, and prognosis. 
7.8. 
Visit Windows  
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see 
Appendix 1). All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed prior to study treatment administration 
unless otherwise noted. Laboratory results should be reviewed before study treatment 
administration. The radiograph results from scheduled or unscheduled tumor assessment must be 
reviewed by the investigator before dosing at the next cycle. 
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. 
A cycle is defined as having a duration of 21 days. Subsequent visits should be conducted 
according to the planned schedule every 21 days from Day 1 of last cycle. 
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7.9. 
Unscheduled Visits  
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include assessment of vital signs/focused physical examination, ECOG PS, AE review, 
review of concomitant medications and procedures, radiographic assessments, physical 
examination of the liver, spleen, and lymph nodes, review of 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’s assessment as appropriate, and the 
results of the diagnostic tests and images 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 Treatment  
The information on the risks associated with each investigational agent is provided in the 
corresponding appendix: 
• Tislelizumab: Appendix 11 
• Ociperlimab: Appendix 12  
• LBL-007: Appendix 13  
• Chemotherapy: Appendix 14 
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 investigational agent(s) as well as the 
nonclinical/clinical data from other immunotherapy combination(s) containing PD-L1/PD-1 
inhibitors, were considered. Specifically, patients at risk for developing study-emergent active 
autoimmune diseases or who have 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 (see 
Section 4.2 for the full list of exclusion criteria). 
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 the study treatment or not. 
Examples of AEs include: 
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome 
• Detection or diagnosis of a new condition after study treatment 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 
treatment or a concurrent medication (overdose per se should not be reported as an 
AE or SAE) 
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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 must be blinded or 
redacted on the copies of the medical records prior to submission to the sponsor. 
8.3.2. 
Assessment of Severity  
The investigator will assess the severity of each AE and SAE reported during the study. AEs and 
SAEs should be assessed and graded based upon the NCI-CTCAE v5.0. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
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. 
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 (except as noted in Section 8.6.4). 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; physical 
examinations; laboratory measurements (hematology, chemistry, etc); imaging; consultations (as 
needed); and other assessments, including those listed in Appendix 1 (Schedule of Assessments) 
and those listed in each investigational agent-specific appendix, if appliable. 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 treatment will only be administered after clinical laboratory 
results have been reviewed. Administration of study treatment will be performed in a setting 
where emergency medical equipment and staff who are trained to respond to medical 
emergencies are available (see Appendix 11, Appendix 12, Appendix 13, and Appendix 14). 
Investigators are instructed to report all AEs (including pregnancy-related AEs). 
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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. 
8.3.4. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study treatment and the 
occurrence of each AE or SAE, using best clinical judgment. Alternative causes, such as natural 
history of the underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the AE or SAE to the administration of study treatment should be considered and 
investigated. The investigator should consult the Investigator’s Brochure of each study drug in 
the determination of his/her assessment. 
There may be situations when an SAE has occurred and the investigator only has 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 transmitting the SAE report to the 
sponsor, because the causality assessment is one of the criteria used in determining regulatory 
reporting requirements. After considering follow-up information, the investigator may 
subsequently change his/her opinion of causality 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 
treatment (ie, there are facts, evidence, or arguments to suggest possible causation). The 
following factors should be considered in making this assessment, including the following: 
• Temporal relationship of the AE to the administration of study treatment or study 
procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study treatment 
• Biological plausibility 
• An AE should be considered “related” to study treatment 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 treatment). However, 
the influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs). 
8.3.5. 
Follow-up of Adverse Events  
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide the sponsor with further information on the patient’s condition. 
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All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts.  
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient 
withdraws consent. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultations with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.6. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, clinical chemistry, complete blood count [CBC], coagulation, 
or urinalysis) or other abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen during the study. The definition of clinically significant is left 
to the judgment of the investigator. In general, these are the laboratory test abnormalities or other 
abnormal assessments that: 
• are associated with clinical signs or symptoms, or 
• require active medical intervention, or 
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or further diagnostic 
investigation. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 x ULN associated with cholestasis), only the diagnosis (ie, 
cholestasis) should be recorded on the Adverse Event eCRF. Clinically associated events can be 
reported as a single event (eg, simultaneous occurrence of anemia, thrombocytopenia, and 
leukopenia may be reported as myelosuppression). 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 (or mmol/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 
grade of the event should be recorded, and the grade and seriousness should be updated any time 
the event changes. 
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8.4. 
Definition of a Serious Adverse Event  
A SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE 
that hypothetically might have caused death if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency department 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 or sponsor based on 
medical judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above) 
The following are not considered to be SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the product’s Reference Safety Information [RSI]) and meets 
the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is 
not consistent with that noted in the corresponding Investigator’s Brochure for the respective 
investigational agent(s). 
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8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
8.6.1. 
Adverse Event Recording Period  
After informed consent has been signed but before the administration of the study treatment, 
only SAEs associated with protocol-defined procedure should be reported to the sponsor. 
After initiation of study treatment, all AEs and SAEs, regardless of relationship to the study 
treatment, will be reported until either 30 days after the last dose of study treatment or until 
initiation of prespecified adjuvant treatment or other new anticancer therapy, whichever occurs 
first. Surgical procedure complications will be monitored and recorded at the investigator or 
designee’s discretion. Immune-mediated AEs (serious or nonserious) should be recorded until 
90 days after the last dose of study treatment, regardless of whether the patient starts prespecified 
adjuvant treatment or other new anticancer therapy. SAEs assessed as related to the study 
treatment that are brought to the attention of the investigator should be reported regardless of 
time since the last dose of treatment. 
AEs and SAEs should be as outlined in Table 3. For the follow-up period for AEs, see 
Section 8.3.5. For the definition of TEAEs, see Section 9.3.2. 
Table 3: 
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 
SAE associated with 
protocol-defined procedure 
Signing of informed 
consent 
First dose of study drug 
All AEs, SAEs a      
First dose of study drug 
Up to 30 days after last dose, initiation of 
new anticancer therapy, death, withdrawal 
of consent, or loss to follow-up, whichever 
occurs first 
Immune-mediated AE 
First dose of study drug 
Up to 90 days after last dose (regardless of 
initiation of new anticancer therapy), death, 
withdrawal of consent, or loss to follow-up, 
whichever occurs first 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
a All SAEs considered related to the study treatment(s) that are brought to the attention of the investigator should be 
reported regardless of time since the last dose of treatment until death, withdrawal of consent, or loss to follow-up, 
whichever occurs first. 
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 (≤ 24 hours after determination) to the sponsor or designee as 
described in Table 4. 
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Table 4: 
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee  
 
Timeframe for sending 
initial/follow-up report a    
Documentation method 
Reporting method 
All SAEs 
≤ 24 hours after first 
knowledge of the SAE 
SAE report 
Electronic submission of 
SAE form to portal b            
Abbreviations: AE, adverse event; SAE, serious adverse event. 
a. Report follow-up information that is clinically relevant and pertains to the SAE, which includes but is not limited 
to the following: Update to the SAE, new additional SAE, outcome, seriousness criteria, investigator-assessed 
causality, event start date/date of onset, date of death, relationship to each study drug. Follow-up information will 
also be reported, as per the discretion of the investigator if the new or updated information changes the medical 
assessment of the case. 
b. SAE reports should be submitted to the sponsor electronically from within the electronic data capture system. 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 or she is to report 
the information to the sponsor ≤ 24 hours as outlined above in Section 8.6.2.1. The SAE Report 
will always be completed as thoroughly as possible with all available details of the event and 
forwarded to the sponsor or designee within the designated time frames.  
If the investigator does not have all information regarding an SAE, he or she must not wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator 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 investigational agent 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. Events that are clearly consistent with the pattern of 
progression of the underlying disease and are considered unequivocally due to disease 
progression should not be reported as AEs. However, if there is any uncertainty as to whether an 
event is due to disease progression, it should be recorded as an AE (see Section 8.6.2). 
8.6.5. 
Deaths  
Deaths that occur during the adverse event recording period and which are attributed by the 
investigator solely to disease progression should not be reported as an AE but recorded on the 
End of Study eCRF page. For other deaths that occurred during the study safety reporting period 
(refer to Section 8.6.1), regardless of relationship to study drug, the primary cause of death must 
be reported as a fatal SAE on the Adverse Event eCRF and immediately reported to the sponsor 
(see Section 8.6.2). 
Death should be considered an outcome and not a distinct event. The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the Adverse Event eCRF. Generally, only one such event should be reported. If the cause of 
death is unknown, then the death could be reported as an AE, eg, “Death NOS.” 
8.6.6. 
Pregnancies  
If a female patient or the female partner of a male patient becomes pregnant during the 
pregnancy reporting period, a pregnancy report form must be submitted to the sponsor. The 
pregnancy reporting period for each arm is specified in Appendix 15. The pregnancy report form 
is a type of SAE report and must follow the same prompt reporting guidelines described in 
Section 8.6.2.1. The outcome of the pregnancy, including any premature termination of the 
pregnancy will also be reported to the sponsor. 
While pregnancy itself is not considered an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. An abortion, 
whether accidental, therapeutic, or spontaneous, should always be reported as an SAE. Similarly, 
any congenital anomaly or birth defect in a child born to a patient exposed to the study treatment 
should be recorded and reported as an SAE. 
Patients who become pregnant must immediately discontinue treatment (see Section 3.7). For 
patients who are no longer pregnant, resumption of treatment may be discussed with the medical 
monitor. 
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In addition to the common stipulations with respect to pregnancy in this section, additional 
requirements for the treatment with a particular agent are provided in the investigational 
agent-specific appendix, if applicable. 
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 treatment experience to 
identify and expeditiously communicate new safety findings to regulatory authorities, 
investigators, IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using reference safety information (RSI) in the Investigator’s 
Brochure of each study drug. 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events  
Treatment with anti-PD-1 therapy and immune checkpoint inhibitors can cause autoimmune 
disorders. All AEs considered by the investigator to be immune-mediated (see Section 8.7.2) 
should be classified as imAEs and identified as such in the eCRF adverse event page. 
8.6.9. 
Recording Infusion-Related Reactions  
Most anticancer treatments carry a risk for infusion reactions; the incidence may increase when 
different agents are administered concomitantly. The majority of infusion reactions are 
characterized by non-specific symptoms, including headache, nausea, fever or chills, dizziness, 
flush, pruritus, and chest or back pain. These may occur more frequently on initial exposure with 
less frequent or less severe reactions observed on re-exposure. Severe reactions are uncommon, 
but may be fatal without appropriate intervention. Any signs or symptoms experienced by 
patients during the infusion of pharmacologic or biologic agents or any event occurring on the 
first day of drug administration should be evaluated accordingly.  
Any event occurring during or within 24 hours of study drug administration and considered 
related to the infusion of study treatment should be recorded as a diagnosis (Infusion-related 
reaction) on the Adverse Event eCRF. 
Refer to the eCRF completion guidelines for details. See Appendix 7 for management of 
infusion-related reactions. 
8.6.10. 
Recording Anaphylaxis  
Anaphylaxis is a serious systemic hypersensitivity reaction that is usually rapid in onset and may 
cause death. It is characterized by the rapid development of airway and/or breathing and/or 
circulation problems. Intramuscular adrenaline is the most important treatment. Rechallenge is 
contraindicated. The definition currently accepted by the Agency relies on clinical diagnostic 
criteria and does not specify a particular immunologic mechanism (US FDA 2014). 
It is acknowledged that the distinction between an infusion reaction (refer to Section 8.6.9) and 
anaphylaxis can be challenging, but nevertheless such distinction is necessary due to the different 
clinical consequences and the potential option of being rechallenged. 
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To capture all potential adverse events, it is recommended to report all cases meeting the clinical 
diagnostic criteria of anaphylaxis as a diagnosis of “Anaphylaxis” with appropriate NCI-CTCAE 
grading (only Grade 3 through 5 is applicable). 
8.7. 
Management of Events to be Monitored  
In addition to the common statements with respect to events to be monitored presented in this 
section, additional requirements regarding AEs of interest for each particular agent are provided 
in the investigational agent-specific appendix, if applicable.  
8.7.1. 
Infusion-Related Reactions and Anaphylaxis  
Patients should be closely monitored during and after study drug administration for 
infusion-related reactions and anaphylaxis reactions. See Section 5.2.1 for the monitoring periods 
required. Immediate access to an intensive care unit or equivalent environment and appropriate 
medical therapy (including epinephrine, corticosteroids, antihistamines, bronchodilators, and 
oxygen) must be available to treat infusion-related reactions. 
See Appendix 7 for the management of infusion-related reactions and anaphylaxis reactions as 
well as treatment modifications. 
8.7.2. 
Immune-Mediated Adverse Events  
In this study, imAEs are events to be monitored. Potential imAEs are listed in Table 5 below. All 
AEs similar to those listed in the table should be evaluated in patients receiving the study 
agent(s) to determine whether the AE is immune-mediated. 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 
may not be limited to serologic, immunologic, and histologic (biopsy) data (see Appendix 7). If 
alternative causes have been ruled out and the AE required the use of systemic steroids, other 
immunosuppressants, or endocrine therapy, and it is consistent with an immune-mediated 
mechanism of action, the imAE indicator in the eCRF AE page should be checked. 
Recommendations for managing imAEs are detailed in Appendix 7. 
Table 5: 
Examples of Immune-Mediated Adverse Events  
Body system affected 
Events 
Skin  
Rash, vitiligo, follicular or urticarial dermatitis, 
erythematous/lichenoid rash, sweet syndrome, full-thickness 
necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
Colitis (includes diarrhea with abdominal pain or 
endoscopic/radiographic evidence of inflammation), pancreatitis, 
hepatitis 
Endocrine 
Thyroiditis, hypothyroidism, hyperthyroidism, hypophysitis with 
features of hypopituitarism, insulin-dependent diabetes mellitus, 
diabetic ketoacidosis, adrenal insufficiency 
Respiratory 
Pneumonitis/diffuse alveolitis 
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Body system affected 
Events 
Eye 
Episcleritis, conjunctivitis, iritis/uveitis 
Musculoskeletal 
Arthritis, arthralgia, myalgia, myasthenic syndrome/myasthenia 
gravis, myositis 
Blood 
Anemia, leukopenia, thrombocytopenia 
Renal 
Interstitial nephritis, glomerulonephritis  
Cardiac 
Pericarditis, myocarditis 
Neurologic 
Encephalitis, Guillain-Barré syndrome, meningitis, 
meningoradiculitis, meningoencephalitis, neuropathy 
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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. Data will be listed and summarized per 
sponsor agreed reporting standards, where applicable. Details of the statistical analyses will be 
included in a separate statistical analysis plan (SAP). 
9.1. 
Statistical Analysis  
9.1.1. 
Randomization Methods  
Patients will be randomly assigned to treatment arms using the IRT system for this study by 
block randomization. 
The randomization ratio will be adjusted to account for fluctuation in the number of experimental 
arms that are open for enrollment over the course of the study. Arm 1A and Arm 2A may stay 
open with the corresponding randomization ratio whenever there is at least 1 combination arm 
open for enrollment.  
In the current protocol, approximately 60 patients will be randomly assigned to Substudy 1, 
including Arm 1A (tislelizumab monotherapy), Arm 1B (tislelizumab in combination with 
ociperlimab), and Arm 1C (LBL-007 in combination with tislelizumab) in patients with tumor 
PD-L1 expression ≥ 50% in a 1:1:1 randomization ratio. Patients randomized to Arm A, Arm B, 
and Arm C in original protocol (0.0) and protocol amendment 1.0 will be mapped to Arm 1A, 
Arm 1B, and Arm 1C in this protocol amendment 2.0, respectively. Approximately 60 patients 
with tumor PD-L1 expression < 50% will be randomly assigned to Substudy 2, including 
Arm 2A (tislelizumab in combination with chemotherapy) and Arm 2C (LBL-007 in 
combination with tislelizumab and chemotherapy) in a 1:2 randomization ratio. 
9.1.2. 
Analysis Sets  
The Intent-to-Treat (ITT) analysis set includes all enrolled patients. Patients will be analyzed 
according to their randomized treatment arm.  
The Intent-to-Treat with tumor PD-L1 expression ≥ 50% (ITT-1) analysis set includes all 
enrolled patients with tumor PD-L1 expression ≥ 50% in Substudy 1. Patients will be analyzed 
according to their randomized treatment arm. It will be the primary analysis set for the efficacy 
analysis of patients with tumor PD-L1 expression ≥ 50%. 
The Intent-to-Treat with tumor PD-L1 expression < 50% (ITT-2) analysis set includes all 
enrolled patients with tumor PD-L1 expression < 50% in Substudy 2. Patients will be analyzed 
according to their randomized treatment arm. It will be the primary analysis set for the efficacy 
analysis of patients with tumor PD-L1 expression < 50%. 
The Safety (SAF) analysis set includes all enrolled patients who received ≥ 1 dose of 
neoadjuvant treatment. Patients will be analyzed according to the treatment they actually 
received. It will be the analysis set for the safety analyses.  
The Efficacy Evaluable (EE) analysis set includes all patients from the SAF analysis set who 
have completed surgery as planned; it will be used as supportive analysis set. 
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The Biomarker analysis set includes all patients from the SAF analysis set who have 
≥ 1 evaluable biomarker measurement; it will be used for the biomarker analysis. 
9.1.3. 
Patient Disposition  
The number of patients randomized, treated, and discontinued from any study treatment and/or 
from the study, and those with important protocol deviations will be counted. The primary reason 
for study treatment 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 
database 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 in the ITT analysis set, ITT-1 analysis set, and 
ITT-2 analysis set will be summarized using descriptive statistics. Continuous variables include 
age, weight, and vital signs. Categorical variables include sex, ECOG PS, race, histology, stage 
of disease, PD-L1 expression level, smoking status, and number of lesion sites. 
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 for this protocol. 
Prior medications will be defined as medications that were stopped before the day of the first 
dose of study treatment. Concomitant medications will be defined as medications that 1) started 
before the first dose of study treatment and were continuing at the time of the first dose of study 
treatment, or 2) started on or after the date of the first dose of study treatment and up to 30 days 
after the patient’s last dose of the study drug (s) (as of the Safety Follow-up Visit).  
9.2. 
Efficacy Analysis  
9.2.1. 
Primary Efficacy Analysis  
MPR rate as assessed by the BIPR 
MPR rate is defined as the proportion of patients with ≤ 10% residual viable tumor in the 
resected primary tumor and all resected lymph nodes as assessed by BIPR. The primary analysis 
of MPR rate will be based on the ITT-1 and ITT-2 analysis sets. Patients that do not have the 
planned surgery will be considered as failures/non-responders, and will therefore be counted in 
the denominator, but not in the numerator of the MPR rate. The MPR rate and its 
Clopper-Pearson 95% CI will be calculated for each arm in each analysis set. The difference in 
MPR rate will be evaluated using Fisher’s exact test between each combination arm and 
monotherapy arm in the ITT-1 analysis set, and between LBL-007 in combination with 
tislelizumab and chemotherapy arm and tislelizumab in combination with chemotherapy arm in 
the ITT-2 analysis set separately. The odds ratio and the difference in MPR rate in each analysis 
set, as well as their 2-sided 95% CIs, will also be calculated. 
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The monotherapy arm in the primary efficacy analysis for the ITT-1 analysis set will only 
include patients randomized to the monotherapy arm who also had the opportunity to be 
randomized to other combination therapy arms in order to conduct rigorous between-arm 
comparisons. The tislelizumab in combination with chemotherapy arm in the primary efficacy 
analysis for the ITT-2 analysis set will only include patients randomized to the tislelizumab in 
combination with chemotherapy arm who also had the opportunity to be randomized to other 
immunotherapy in combination with tislelizumab and chemotherapy arms in order to conduct 
rigorous between-arm comparisons. 
9.2.2. 
Secondary Efficacy Analysis  
pCR rate as assessed by the BIPR 
pCR rate is defined as the proportion of patients with absence of residual tumor in the resected 
primary tumor and all resected lymph nodes. The pCR rate will be summarized similarly as the 
MPR rate in the ITT-1 and ITT-2 analysis sets.  
EFS as assessed by the investigator 
EFS is defined as the time from randomization until any of the following events, whichever 
occurs first: radiographic disease progression that precludes definitive surgery, local or distant 
recurrence, as assessed by the investigator according to RECIST v1.1, or death due to any cause. 
The efficacy analysis of EFS will be conducted in the ITT-1 and ITT-2 analysis sets separately. 
Hazard ratio and corresponding two-sided 95% CI will be estimated using a Cox proportional 
hazards model. Kaplan-Meier methodology will be used to estimate median and other quartiles 
of EFS for each treatment arm. EFS rates at selected timepoints (1-year and 2-year) will be 
estimated using the Kaplan-Meier method with the corresponding 95% CI constructed using 
Greenwood’s formula (Greenwood 1926). Kaplan-Meier curve will be constructed to provide a 
visual description of the difference among treatment arms.  
OS  
OS is defined as the time from the date of randomization to the date of death due to any cause. 
The OS will be summarized similarly as the EFS in the ITT-1 and ITT-2 analysis sets 
DFS as assessed by the investigator 
DFS is defined as the time from the first date of no disease to local recurrence or distant 
metastasis or death due to any cause, whichever occurs first, as determined by the investigator. 
DFS will be analyzed only for patient who have undergone R0 resection in ITT-1 and ITT-2 
analysis sets separately. If patients are alive without recurrence, DFS will be determined from the 
first date of no disease to the date they were last known to be alive, and data will be censored on 
the date they were last known to be alive. DFS will be summarized similarly as the EFS in the 
ITT-1 and ITT-2 analysis sets. 
9.2.3. 
Exploratory Efficacy Analysis  
The first exploratory efficacy analysis will be based on the EE analysis set with patients with 
tumor PD-L1 expression ≥ 50% who completed the planned surgery. This analysis set will be 
used to evaluate the MPR and pCR of the patients with tumor PD-L1 expression ≥ 50%. 
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The second exploratory efficacy analysis will be conducted by including all patients with tumor 
PD-L1 expression ≥ 50% from the monotherapy arm for treatment comparison, regardless of 
whether a monotherapy arm patient had the opportunity or not to be randomized to other 
experimental arms. Such analysis will be applied to evaluate the difference in MPR and pCR of 
the patients with tumor PD-L1 expression ≥ 50%. 
The third exploratory efficacy analysis will be based on the EE analysis set with patients with 
tumor PD-L1 expression < 50% who completed the planned surgery. This analysis set will be 
used to evaluate the MPR and pCR of the patients with tumor PD-L1 expression < 50%. 
The fourth exploratory efficacy analysis will be conducted by including all patients with tumor 
PD-L1 expression < 50% from the tislelizumab in combination with chemotherapy arm for 
treatment comparison, regardless of whether a tislelizumab in combination with chemotherapy 
arm patient had the opportunity or not to be randomized to other experimental arms. Such 
analysis will be applied to evaluate the difference in MPR and pCR of the patients with tumor 
PD-L1 expression < 50%. 
The fifth exploratory efficacy analysis will be an across-study indirect comparison based on the 
ITT-2 analysis set combined with patients treated with tislelizumab in combination with 
chemotherapy from Study BGB-A317-315. This analysis set will be used to evaluate the MPR 
and pCR of the patients with tumor PD-L1 expression< 50%. 
9.3. 
Safety Analyses  
Safety will be assessed by monitoring and recording all AEs graded by NCI-CTCAE v5.0. 
Laboratory values (eg, hematology, clinical chemistry, coagulation, and urinalysis), dosing, vital 
signs, ECGs, and physical examinations will also be evaluated. All safety data in the SAF 
analysis set will be summarized descriptively. 
9.3.1. 
Extent of Exposure  
The extent of exposure to each study treatment will be summarized descriptively as the number 
of doses 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 interruption, dose delay, and drug 
discontinuation due to AEs will be summarized for each study drug. The frequency of the above 
dose adjustments and discontinuation will be summarized by category. 
Patient level listings will be provided for all dosing records and for calculated summary 
statistics. 
9.3.2. 
Adverse Events  
The AE verbatim descriptions (as recorded by the investigator on the eCRF) will be classified 
into standardized medical terminology using the MedDRA. AEs will be coded to the MedDRA 
lowest level term closest to the verbatim term, preferred term, and primary System Organ Class 
(SOC). 
A TEAEs is defined as an AE that has an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of the study treatment and during up to 30 days after 
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study treatment discontinuation, or initiation of new anticancer therapy, or prespecified adjuvant 
treatment, whichever occurs first. Only those AEs that were treatment-emergent will be included 
in the summary tables of TEAEs. All AEs, treatment-emergent or otherwise, will be presented in 
patient-level listings. 
Immune-mediated AEs will be identified from all AEs that had an onset date or a worsening in 
severity from baseline (pretreatment) on or after the first dose of experimental immunotherapy 
and up to 90 days after the last dose of study treatment, regardless of whether the patient starts a 
new anticancer therapy or prespecified adjuvant treatment.  
The incidence of TEAEs will be reported by SOC and Preferred Term as the number 
(percentage) of patients with TEAEs. A patient will be counted only once by the highest severity 
grade per NCI-CTCAE v5.0 within an SOC and Preferred Term, even if the patient experienced 
≥ 1 TEAE within a specific SOC and Preferred Term.  
The number (percentage) of patients with TEAEs will also be summarized by relationship to the 
study treatment. Treatment-related TEAEs include those events considered by the investigator to 
be related to a study drug or with missing assessment of the causal relationship.  
All TEAEs, SAEs, deaths, TEAEs ≥ Grade 3, infusion-related reactions, treatment-related 
TEAEs, TEAEs that lead to treatment discontinuation, dose interruption, or dose delay, and 
imAEs will be summarized. 
9.3.3. 
Laboratory Analyses  
Clinical laboratory (eg, hematology, serum chemistry, urinalysis) values will be evaluated for 
each laboratory parameter. 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, SD, median, minimum, maximum 
for continuous variables; n [%] for categorical variables) for laboratory parameters will be 
calculated.  
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 sign parameters (body temperature, pulse rate, 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. 
Electrocardiograms  
ECG will be performed at the baseline and at multiple time points after the start of treatment.  
Clinically significant abnormalities on ECG findings will be presented in a frequency table by 
visit and arm as appropriate. 
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9.3.6. 
Eastern Cooperative Oncology Group Performance Status  
A shift table from baseline to worst postbaseline in ECOG PS will be summarized by arm.  
ECOG PS scores will be summarized by visit and arm, as appropriate. 
9.3.7. 
Feasibility of Surgery   
The proportion of patients who undergo surgical resection within the scheduled period after 
receiving any dose of the investigational agent(s), will be summarized in the ITT-1 and ITT-2 
analysis sets. Delayed or canceled surgery, duration of surgery, and surgical approach will also 
be summarized in ITT-1 and ITT-2 analysis sets. 
9.4. 
Biomarker Analysis  
For the analysis of the biomarker endpoint, which is pharmacodynamic biomarker change (eg, 
Treg reduction) based on mechanisms of action of each investigational agents (see agent-specific 
appendix) between combination arms versus monotherapy arm, a two-sample t test will be used 
to compare percentage of biomarker change from baseline to surgery between arms in the 
Biomarker analysis set. Equal variance assumption will be checked. The percentage of biomarker 
change within each arm is defined as the change of biomarker at post-treatment from baseline 
divided by that at baseline. If considerable missing occurs, a linear mixed model with random 
intercept will be used to estimate biomarker change per arm in the Biomarker analysis set. 
Treatment assignment, visit, and the interaction of the two will be included as main effects while 
patient is considered as random effect. Other important demographic or baseline characteristics 
can be also adjusted, if necessary. Biomarker change will be compared between combination 
arms and the monotherapy arm using likelihood ratio test (LRT) from linear mixed model. 
Non-parametric test will be used if the normality assumption is severely violated. 
Associations between biomarkers and efficacy endpoints will be examined using logistics 
regression for binary endpoint, and Cox proportional hazards model for survival endpoints. More 
details will be provided in Statistical Analysis Plan. 
9.5. 
Pharmacokinetic Analysis  
Serum/plasma concentration data will be tabulated and summarized by visit/cycle at which these 
concentrations are collected. Descriptive statistics will include means, medians, ranges, and SDs, 
as appropriate. Pharmacokinetic analysis will be conducted. 
Additional PK analyses, including population PK analyses and exposure-response analyses 
(efficacy or safety endpoints), may be conducted as appropriate and the results of these analyses 
may be reported separately from the CSR. 
9.6. 
Immunogenicity Analyses  
ADA samples will be collected for tislelizumab and protein therapeutic investigational agents in 
this study as outlined in Appendix 1. The immunogenicity results will be summarized using 
descriptive statistics by the number and percentage of patients who develop detectable ADAs. 
The incidence of positive ADAs and neutralizing ADAs will be reported for evaluable patients.  
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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. 
9.7. 
Sample Size Consideration  
This study is designed for the preliminary evaluation of the pharmacodynamics, safety, and 
efficacy of tislelizumab monotherapy and multiple tislelizumab-based immunotherapy 
combinations with or without chemotherapy in patients with resectable Stage II to IIIA NSCLC. 
It is not designed to allow explicit power and Type I error considerations so there is no formal 
statistical hypothesis.  
Approximately 60 patients will be randomly assigned to Substudy 1, including Arm 1A 
(tislelizumab monotherapy), Arm 1B (tislelizumab in combination with ociperlimab), and 
Arm 1C (LBL-007 in combination with tislelizumab) in patients with tumor PD-L1 expression 
≥ 50% in a 1:1:1 randomization ratio. Approximately 60 patients with tumor PD-L1 expression 
< 50% will be randomly assigned to Substudy 2, including Arm 2A (tislelizumab in combination 
with chemotherapy) and Arm 2C (LBL-007 in combination with tislelizumab and chemotherapy) 
in a 1:2 randomization ratio. For the further emerging experimental drugs to be added into the 
study, roughly 20 patients with tumor PD-L1 expression ≥ 50% are planned to be enrolled for 
each corresponding tislelizumab-based immunotherapy combination arm, and roughly 40 
patients with tumor PD-L1 expression < 50% are planned to be enrolled for each corresponding 
tislelizumab in combination with immunotherapy and chemotherapy arm.  
Twenty patients in Arms 1A, 1B, 1C, and 2A, and 40 patients in Arm 2C will provide adequate 
information for estimation precision and safety evaluation. With the defined sample size, the 
expected 95% CI of the MPR rate difference in patients with tumor PD-L1 expression ≥ 50% 
between the tislelizumab-based immunotherapy combination arms and the tislelizumab 
monotherapy arm would be 1% to 59% if the true MPR for the tislelizumab-based 
immunotherapy combinations arm and monotherapy arm is 70% and 40%, respectively. The 
expected 95% CI of the MPR rate difference in patients with PD-L1 expression < 50% between 
the LBL-007 in combination with tislelizumab and chemotherapy arm and the tislelizumab in 
combination with chemotherapy arm would be -11% to 41% if the true MPR for the LBL-007 in 
combination with tislelizumab and chemotherapy arm and the tislelizumab in combination with 
chemotherapy arm is 49% and 34%, respectively. Patients in each arm will be followed for 
approximately 24 months. 
9.8. 
Interim Analysis  
No interim analysis is planned for this study. 
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10. 
STUDY COMMITTEES AND COMMUNICATION  
10.1. 
Blinded Independent Pathology Review  
A BIPR will be established for central review of pathologic responses. Tumor and lymph node 
samples will be submitted for central review. Sites will be trained before enrolling the first study 
patient. Pathology sample acquisition guidelines and the submission process will be outlined in 
the study pathology manuals to be provided by the vendors. For the histologic assessment, all 
tumor and associated lymph node tissues should be sectioned at 1-cm intervals. For assessments 
of pathological response, the percentage of viable tumor cells (TC) in ≥ 1 section per centimeter 
of the tumor and lymph node tissue resected should be evaluated. The assessment by the BIPR 
will be used for reporting of MPR and pCR. 
10.2. 
Steering Committee  
A steering committee will be established to provide recommendations on safety management and 
provide guidance to assure that the study is conducted in accordance with GCP and high 
scientific standards. This Steering Committee meeting will consist of BeiGene representatives 
and all Steering Committee members (Steering Committee Charter).  
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study can 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 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 the representatives of a regulatory agency or 
representatives of the sponsor with access to records, facilities, and personnel for the effective 
conduct of any inspection or audit. 
 
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12. 
QUALITY ASSURANCE AND QUALITY CONTROL  
12.1. 
Regulatory Authority Approval  
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements. Alternatively, the 
sponsor will 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 acknowledging 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 after 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 reviewed periodically 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 investigator and the study center in full conformance with 
the guidelines for Good Clinical Practice (ICH E6) 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 Definitions and 
Standards for Expedited Reporting (ICH E2A). 
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 IRB/IEC correspondence and approval of the amended ICF or other information and the 
approved amended ICF or other information must be forwarded to the sponsor promptly. 
The 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 the 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). The sponsor may utilize a protocol amendment to add new experimental 
arms to this study when new treatments become available, for discontinuing treatment arms that 
demonstrate minimal clinical activity or unacceptable toxicity, or modifying the patient 
population (eg, regarding biomarker status). Prior to implementing any new experimental arm, 
protocol amendment, and respective health authority and IRB/IEC approvals should be obtained.  
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, institution, sponsor, and site will maintain confidentiality and privacy 
standards for the collection, storage, transmission, and processing of patients’ personal and 
medical information by following applicable laws and regulations related to the confidentiality, 
use, and protection of such information, including the ICH Good Clinical Practice Guideline, as 
implemented locally. Such laws may be more stringent than the requirements in this protocol. 
The principal investigator and site shall code the personal and medical information obtained 
during the study with a unique patient identification number assigned to each patient enrolled in 
the study. The investigator must ensure that patients’ anonymity will be strictly maintained and 
that their identities are protected from unauthorized parties. Unless required to be provided by 
laws or regulations or specifically requested in exceptional circumstances by the sponsor or its 
representatives, the principal investigator and site must ensure that any personal and medical 
information transmitted to the sponsor or its service providers is: 1) required by the protocol, and 
2) appropriately de-identified (eg, via redaction and/or coding with the patient identification 
number) to ensure that the following information about patients are NOT shared: 
• names or initials (full or partial); 
• full dates of birth; 
• contact information (such as phone numbers or home or email addresses);  
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• numerical identifiers (eg, hospital or medical record, government, health insurance, or 
financial account numbers) other than patient identification numbers assigned as part 
of this study; 
• geographic identifiers smaller than a state, province, or local equivalent (such as city, 
county, zip code, or other equivalent geographic identifiers); or  
• information about marital status, family, or household members; employment, sex 
life, sexual preference, or other sensitive data that are not relevant to the study. 
Patient personal and medical information obtained during this study is confidential and may only 
be disclosed to third parties as permitted by the signed ICF (or a separate authorization for the 
use and disclosure of personal health information that has been signed by the patient), unless 
permitted or required by law. In limited circumstances, such as in connection with insurance 
purposes or patient support services ancillary to certain study sites (eg, for patient travel or 
reimbursement), the principal investigator and site may provide certain of this personal or 
medical information to the sponsor or its representatives.  Such personal or medical information 
may not be provided as part of the protocol (eg, as part of the eCRF or on samples or reports 
submitted to the central laboratory). 
The investigator and site personnel must use only the specific forms and clinical study systems, 
(eg, the electronic data capture [EDC] system and any secure file transfer platforms [SFTPs]) 
designated by the sponsor for sharing and transferal of personal and medical information.  
In the event of a breach of the confidentiality of a patient’s personal or medical information, the 
principal investigator, site personnel, and sponsor, as appropriate, shall fulfill all mediation steps 
and reporting obligations under applicable laws.  If the sponsor identifies personal or medical 
information that was not properly de-identified, it may be required to report the disclosure under 
local applicable laws. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes where allowed by local 
law or the patient’s signed ICF. 
Data generated during this study must be available for inspection upon request by representatives 
of the China NMPA and all other national and local health authorities; by sponsor monitors, 
representatives, and collaborators; and by the IRBs/IECs for each study site, as appropriate. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator’s Brochure(s), this protocol, eCRFs, the investigational drugs, and any other 
study information, are confidential and remain the sole and exclusive property of the sponsor 
during the conduct of the study and thereafter. This information is not to be disclosed to any third 
party (except employees or agents directly involved in the conduct of the study or as required by 
law) without prior written consent from the sponsor. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
If a written contract for the conduct of the study that includes confidentiality or privacy 
provisions inconsistent with this section is executed, that contract’s provisions shall apply to the 
extent they are inconsistent with this section. 
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13.5. 
Financial Disclosure  
Investigators (including any subinvestigators and coinvestigators) are required to provide the 
sponsor with sufficient accurate financial information in accordance with regulations to allow the 
sponsor to submit complete disclosure or certification to the absence of certain financial interest 
of the clinical investigators, and/or disclose those financial interests, as required, to the 
appropriate health authorities. This is intended to ensure financial interests and arrangements of 
the clinical investigators with 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 to 
update this information if any relevant changes occur during the study and for 1 year after 
completion of the study (ie, last patient, last visit). 
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14. 
DATA HANDLING AND RECORD KEEPING  
14.1. 
Data Collection and Management Responsibilities  
14.1.1. 
Data Entry in the Electronic Case Report Form  
All study-related data collected or received by the investigator or study team shall be promptly 
entered into the eCRFs. In no event should the entry of the study data into the eCRF be later than 
what is stipulated in the site contract after the data is collected or received by the investigator or 
study team without prior communication with and approval by the sponsor. 
14.1.2. 
Data Collection  
Data required by the protocol will be entered into an electronic data capture (EDC) system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF. The e-signature of the investigator or designee must be 
provided in the EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of 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 the lowest-level term, Preferred Term, 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. 
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 ≥ 1 of the following categories: 1) investigator’s study file, and/or 2) patient 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, ICFs, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include 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 that there is an acceptable backup of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements, local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to ≥ 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including 
but not limited to the following: archival at an off-site facility, or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 
store these in sealed containers away from the site so that they can be returned sealed to the 
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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 away from the site. 
Subject to patient consent, or as otherwise allowed under applicable law, biological samples at 
the conclusion of this study may be retained for ≤ 10 years or as allowed by your IRB/IEC, 
whichever is shorter. 
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 that they will apply 
due diligence to avoid protocol deviations and shall report all protocol deviations to the sponsor. 
The investigator is to document and explain any deviations from the approved protocol. Any 
major deviations that might impact patient safety and/or data integrity must be promptly reported 
by the investigator 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 Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance, and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study. The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential. As this is a multicenter study, the first publication or disclosure 
of study results shall be a complete, joint multicenter publication or disclosure coordinated by 
the sponsor. Thereafter, any secondary publications will reference the original publication(s). 
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of Medical 
Journal Editors 2018). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this study will be presented in the investigator’s clinical study agreement. Each investigator 
agrees that, in accordance with the terms of the clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 
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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 laboratory for central laboratory analysis according to 
protocol and laboratory manual requirements 
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for any reason. 
Potential reasons for suspension or discontinuation include but are not limited to safety or ethical 
issues or noncompliance with this protocol, GCP, the sponsor’s written instructions, the clinical 
study agreement, or applicable laws and regulations. If the sponsor determines such action is 
needed, the sponsor will discuss this with the investigator (including the reasons for taking such 
action) at that time. When feasible, the sponsor will provide advance notification to the 
investigator of the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons. The sponsor will also inform the 
regulatory authorities of the suspension or termination of the study and the reason(s) for the 
action. If required by applicable regulations, the investigator must inform the IRB/IEC 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. 
If a written contract for the conduct of the study, which includes ownership provisions 
inconsistent with this statement, is executed between the sponsor and the study center, that 
contract’s ownership provisions shall apply rather than this statement. 
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All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel. 
This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor. 
These restrictions do not apply to 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 IRB/IEC 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 is executed and it includes provisions 
inconsistent with this statement, that contract’s provisions shall apply rather than this statement. 
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15. 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS (FOR ARMS 1A, 1B, 1C, 
2A, AND 2C)  
Assessment 
Screeni
ng a 
Neoadjuvant Treatment 
EOT/ Safety 
Follow-up 
Visit b, c 
Surgery c 
Survival 
Follow-up 
 
Cycle 1 to 2   
(Every 21 days) 
Cycle 3 to 4 
(Every 21 
days) 
 
 
 
Days (window) -28 to -1 1 (± 3) 8 (± 2
) 
15 (± 2
) 
1 (± 3) 
30 (± 7) 
after the 
last dose 
Within 14 
days from 
EOT/Safety 
Follow-up 
Visit 
Every 6 months 
(± 4 weeks) or 
annual (± 8 
weeks)  cc 
Informed 
consent d 
X 
 
 
 
 
 
Inclusion/exclus
ion criteria 
X 
 
 
 
 
 
Randomization e 
Xd 
 
 
 
 
 
EGFR 
assessment (if 
status is 
unknown) f 
X 
 
 
 
 
 
Baseline tumor 
tissue and 
optional lymph 
node sample g 
X 
 
 
 
 
 
Surgical tumor 
tissue and 
lymph node 
sample h 
 
 
 
 
X 
 
Pathological 
response 
assessment 
 
 
 
 
X 
 
Demographic 
data 
X 
 
 
 
 
 
Medical history 
and baseline 
conditions 
X 
 
 
 
 
 
Thoracic 
surgery 
evaluation 
X 
 
 
X 
(Presurgical) 
 
 
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Assessment 
Screeni
ng a 
Neoadjuvant Treatment 
EOT/ Safety 
Follow-up 
Visit b, c 
Surgery c 
Survival 
Follow-up 
 
Cycle 1 to 2   
(Every 21 days) 
Cycle 3 to 4 
(Every 21 
days) 
 
 
 
Days (window) -28 to -1 1 (± 3) 8 (± 2
) 
15 (± 2
) 
1 (± 3) 
30 (± 7) 
after the 
last dose 
Within 14 
days from 
EOT/Safety 
Follow-up 
Visit 
Every 6 months 
(± 4 weeks) or 
annual (± 8 
weeks)  cc 
Vital 
signs/height and 
weight i 
X 
X 
 
 
X 
X 
 
 
Complete 
physical 
examination j 
X 
 
 
X 
 
 
Limited 
physical 
examination k 
 
X 
 
 
X 
 
 
 
ECOG PS 
X 
 
 
X 
 
 
ECG l 
X 
 
 
X 
 
 
Hematology m 
X 
X n 
X
 
X
 
X 
X 
 
 
Chemistry o 
X 
X n 
X 
X 
X 
X 
 
 
Pregnancy test p 
X 
X 
 
 
X 
X 
(EOT/Safety 
follow-up 
visit) 
 
 
Coagulation q  
X 
X n 
 
 
X 
X 
 
 
TSH, free T3 (or 
total T3), free 
T4 r 
X 
X r 
 
 
 
X 
 
 
Viral serology s 
X 
 
 
 
 
 
COVID-19 
testing t 
X 
 
 
 
 
 
Urinalysis u 
X 
X n,u 
X 
 
 
Pharmacokinetic
s v 
 
X 
X 
(Cycl
e 1 
only) 
 
 
X 
(EOT/Safety 
follow-up 
visit) 
 
 
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Assessment 
Screeni
ng a 
Neoadjuvant Treatment 
EOT/ Safety 
Follow-up 
Visit b, c 
Surgery c 
Survival 
Follow-up 
 
Cycle 1 to 2   
(Every 21 days) 
Cycle 3 to 4 
(Every 21 
days) 
 
 
 
Days (window) -28 to -1 1 (± 3) 8 (± 2
) 
15 (± 2
) 
1 (± 3) 
30 (± 7) 
after the 
last dose 
Within 14 
days from 
EOT/Safety 
Follow-up 
Visit 
Every 6 months 
(± 4 weeks) or 
annual (± 8 
weeks)  cc 
Antidrug 
antibodies w 
 
X 
 
 
 
X 
(EOT/Safety 
follow-up 
visit) 
 
 
Periphery 
immune cell 
quantification 
and phenotyping 
x 
 
X 
(predo
se) 
X 
(Cycl
e 1 
only) 
 
 
 
 
 
ctDNA/MRD x 
(optional) 
 
X 
(predo
se) 
 
 
 
X 
(EOT/Safety 
follow-up 
visit) 
 
X 
(7 days after surgery 
& the same visits of 
disease follow-up 
tumor assessment) 
Soluble proteins 
such as 
cytokine/chemo
kine in blood x 
 
X 
(predo
se) 
X 
(Cycl
e 1 
only) 
 
 
X 
(EOT/Safety 
follow-up 
visit) 
 
 
TCR profile in 
blood x 
 
X 
(predo
se) 
 
 
 
X 
(EOT/Safety 
follow-up 
visit) 
 
 
Optional tumor 
biopsy at the 
time of disease 
progression or 
recurrence y 
 
 
 
 
 
X 
Tumor response 
and disease 
recurrence 
assessments 
X z 
 
 
X aa 
 
X bb 
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Assessment 
Screeni
ng a 
Neoadjuvant Treatment 
EOT/ Safety 
Follow-up 
Visit b, c 
Surgery c 
Survival 
Follow-up 
 
Cycle 1 to 2   
(Every 21 days) 
Cycle 3 to 4 
(Every 21 
days) 
 
 
 
Days (window) -28 to -1 1 (± 3) 8 (± 2
) 
15 (± 2
) 
1 (± 3) 
30 (± 7) 
after the 
last dose 
Within 14 
days from 
EOT/Safety 
Follow-up 
Visit 
Every 6 months 
(± 4 weeks) or 
annual (± 8 
weeks)  cc 
Prior and 
concomitant 
medications cc 
X 
X 
 
X 
X 
(EOT/Safety 
Follow-up 
Visit) 
 
 
Adverse events 
dd 
X 
X 
X 
X 
(EOT/Safety 
Follow-up 
Visit) 
 
 
Study treatment 
administration ee 
 
X 
 
 
X 
 
 
 
Survival follow-
up and 
anticancer 
treatment 
 
 
 
 
 
X ff 
Abbreviations: ADA, antidrug antibody; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate 
aminotransferase; AUC, area under the curve; C#D#, Cycle # Day #; CK-MB, creatine kinase cardiac isoenzyme; 
COVID-19, Coronavirus disease 2019; CT, computed tomography; ECG, electrocardiogram; eCRF, electronic case 
report form; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EOT, End-of-Treatment; FFPE, 
formalin-fixed paraffin-embedded; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency 
virus; imAE, immune-mediated adverse event; IRT, Interactive Response Technology; MPR, major pathological 
response; MRI, magnetic resonance imaging; NSCLC, non-small cell lung cancer; pCR, pathological complete 
response; PD-L1, programmed death protein ligand-1; PET, positron emission tomography; PK, pharmacokinetics; 
RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; T3, triiodothyronine; T4, 
thyroxine; TSH, thyroid-stimulating hormone. 
Note: On treatment days, all assessments should be performed before dosing, unless otherwise specified. 
a. 
Results of standard of care tests or examinations performed before obtaining informed consent and 
≤ 28 days before randomization may be used for screening assessments rather than repeating these tests 
unless otherwise indicated (Section 3.2).  
b. 
The EOT/Safety Follow-up Visit will be conducted for patients who discontinue from study treatment due 
to any reason including completion of planned neoadjuvant, AE, patient’s withdrawal, investigator’s 
decision, and others. Patients will be asked to return to the clinic for the EOT/Safety Follow-up Visit which 
should occur within 30 (±7) days after the last dose of neoadjuvant treatment or before surgery procedure 
or the initiation of other new anticancer therapy, whichever occurs first. If routine laboratory tests (eg, 
hematology, serum chemistry) are performed ≤ 7 days before the EOT/Safety Follow-up Visit, these tests 
will not need to be repeated. Tumor assessment is not required at an EOT/Safety Follow-up Visit provided 
that ≤ 2 weeks have passed since the last assessment. However, if the Presurgical visit has been 
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incorporated in to EOT/Safety Follow-up Visit to assess resectability before surgery, the safety assessment 
and tumor assessment at this visit should be performed ≤ 14 days before surgery.  
c. 
The Presurgical Visit and associated assessments can be incorporated into the EOT/Safety Follow-up Visit 
and in accordance with local institutional practices. Unless otherwise specified, the assessments for 
Presurgical Visit are incorporated and presented in the schedule under the EOT/Safety Follow-up Visit. 
Besides that, per local standard of care the evaluations at Presurgical Visit could also include assessments 
of blood tests, coagulation, cardiac or pulmonary tests (if indicated), anesthesia assessment, and other 
evaluation procedures. The safety assessment and tumor assessment at the Presurgical Visit for resectability 
evaluation should be completed ≤ 14 days before surgery respectively (Section 3.4). Surgery should be 
performed ≤ 14 days after the EOT/Safety Follow-up Visit (Section 3.5). 
d. 
Informed consent must be documented before any study-specific screening procedure is performed and 
may be obtained up to 28 days before randomization. 
e. 
Patients with tumor PD-L1 expression ≥ 50% will be randomized into Arm 1A, Arm 1B, or Arm 1C in 
Substudy 1 via IRT in a 1:1:1 randomization ratio. Patients with tumor PD-L1 expression < 50% will be 
randomized into Arm 2A and Arm 2C in Substudy 2 via IRT in a 1:2 randomization ratio. The 
randomization ratio will be adjusted based on the number of experimental arms that are open for 
enrollment. Study treatment must commence ≤ 2 days after randomization. 
f. 
Patients with nonsquamous NSCLC histology with unknown EGFR status, will be required to be tested 
locally or at a central laboratory prior to enrollment. Fresh or archival tumor tissues (≥ 3 unstained slides) 
are required for the assessment of EGFR mutation if at a central laboratory. If archival tissues are 
insufficient for EGFR testing, a tumor biopsy is mandatory. 
g. 
Patients must provide at least 15 freshly cut unstained FFPE slides of the primary tumor or FFPE block 
containing equivalent tumor tissues (preferred) for central PD-L1 evaluation during screening and other 
exploratory biomarker assessments. Only patients with evaluable PD-L1 status as assessed by the central 
laboratory are eligible. If the local result of EGFR mutation status (nonsquamous only) is not available, 
3 additional FFPE slides are required for central EGFR testing. If the first attempt of PD-L1 testing by the 
central laboratory fail, 3 additional slides may be required for repeat. If sufficient baseline tumor tissue is 
available, around 35 unstained FFPE slides or equivalent FFPE block are strongly recommended to be 
provided to ensure exploration of all planned biomarkers. If accessible, a baseline lymph node sample (6 to 
10 FFPE slides) is recommended to be provided. If fewer slides are available, please contact sponsor for 
recommendations. Refer to Section 7.7.1 for more details. 
h. 
If patients undergo surgery, tumor tissue and lymph node tissue obtained from surgical resection are 
required and sent to a central laboratory according to study pathology manuals for pathological response 
analysis as assessed by BIPR. In addition, representative tissue samples of the primary tumor (at least 20 
freshly cut unstained FFPE slides or FFPE block containing equivalent tumor tissues [preferred]) will be 
collected and sent to a central laboratory for biomarker evaluation. If sufficient tumor tissue is available, 
around 40 FFPE slides of surgery tumor tissue are recommended to be provided to ensure exploration of all 
planned biomarkers. If accessible, a surgical lymph node sample is recommended to be provided. The 
surgical specimen for biomarker evaluation is optional for patients who achieve pCR after neoadjuvant 
treatment.  
i. 
Vital signs collected during the study include body temperature, pulse rate, and blood pressure (systolic and 
diastolic) while the patient is in a seated position after resting for 10 minutes. The patient’s vital signs are 
required to be recorded ≤ 60 minutes before, during, and 30 minutes after the first infusion completed of 
study drug(s). For subsequent infusions, vital signs will be collected within 60 minutes before infusion and 
if clinically indicated, during and 30 minutes after the infusion. Height will be recorded at screening only. 
Weight will be recorded on Day 1 of the first cycle, on Day 1 of each subsequent cycle, at the EOT/Safety 
Follow-up Visit, and at the Presurgical Visit. Vital signs collected at the Presurgical Visit include 
temperature, pulse rate, and blood pressure (systolic and diastolic), and weight.  
j. 
At the Screening Visit and at the EOT/ Safety Follow-up Visit and the Presurgical Visit, a complete 
physical examination will be conducted, including evaluations of 1) the head, eyes, ears, nose, and throat; 
and of the 2) cardiovascular, 3) dermatological, 4) musculoskeletal, 5) respiratory, 6) gastrointestinal, and 
7) neurological systems. For any abnormality noted at other visits (and as clinically indicated), limited, 
symptom-directed physical examinations will be performed.  
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k. 
Limited, symptom-directed examination should be performed on Day 1 of each cycle and as clinically 
indicated at other timepoints. New or worsened clinically significant abnormalities should be recorded in 
the adverse event eCRF. 
l. 
The ECG recordings will be obtained during screening, at the EOT/Safety Follow-up Visit, at the 
Presurgical Visit, and as clinically indicated at other timepoints. When coinciding with blood draws at the 
same timepoint, the ECG assessment should be performed before blood draws. Patients should be resting in 
a semirecumbent supine position for ≥ 10 minutes before ECG recording. 
m. 
Hematology assessments should be performed at screening, during the neoadjuvant phase (weekly during 
Cycle 1 to 2, ≤ 3 days before Day 1 during Cycle 3 to 4), and at the EOT/Safety Follow-up Visit and the 
Presurgical Visit. Hematology includes hemoglobin, hematocrit, white blood cell count, platelet count, and 
differential count (neutrophils, lymphocytes) (Appendix 2). 
n. 
If screening laboratory assessments were performed ≤ 7 days before Day 1 of Cycle 1, they do not have to 
be repeated. Otherwise, these tests must be repeated and reviewed before study drug administration on 
Day 1 of Cycle 1. 
o. 
Serum chemistry assessments (including liver function tests) should be performed at screening, during the 
neoadjuvant phase (weekly during Cycle 1 to 2, ≤ 3 days before Day 1 during Cycle 3 to 4), at the 
EOT/Safety Follow-up Visit and at the Presurgical visit. The chemistry panel includes sodium, potassium, 
chloride, glucose, blood urea nitrogen or urea, creatinine, total protein, albumin, total calcium, total and 
direct bilirubin, alkaline phosphatase, ALT, AST, lactate dehydrogenase, creatinine kinase, and CK-MB 
(Appendix 2). If CK-MB fractionation is not available, troponin I and/or troponin T should be assessed 
instead. Refer to Section 8.3.6 for additional information regarding clinical assessment and management of 
clinical laboratory abnormalities. 
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 ≤ 7 days before randomization. Urine 
pregnancy tests will be performed at each visit before study drug(s) administration, at the EOT/Safety 
Follow-up Visit. Additional pregnancy tests will be required at 90 (±14) days and 120 (±14) days after the 
last dose of study treatments for all experimental arms, and at 6 months (±14 days) after the last dose of 
LBL-007 for Arm 1C and Arm 2C (in the clinic or over the phone, as needed based on assessments 
required). If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
q. 
Coagulation parameters should be tested at Screening, ≤ 3 days before Day 1 of each cycle, at the 
EOT/Safety Follow-up Visit and at the Presurgical Visit. Please refer to Appendix 2 for a list of detailed 
assessment parameters of coagulation. 
r. 
TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at 
screening, ≤ 3 days before Day 1 of Cycle 2, at the EOT/Safety Follow-up Visit and at Presurgical Visit. 
s. 
At screening, patients will be tested for HIV serology (antigen and/or antibodies). Patients will be tested for 
hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody (HBcAb), and HCV 
antibody. If a patient has a positive hepatitis B surface antigen at screening, an HBV DNA test must also be 
performed to determine if the patient has an HBV infection. If a patient has a positive HCV antibody test at 
screening, an HCV RNA test must also be performed to determine if the patient has an HCV infection. For 
patients who have detectable HBV DNA or HCV RNA at screening or upon repeat testing, respective viral 
load testing will be performed every 12 weeks. 
t. 
COVID-19 testing should be performed by a certified local laboratory, which may be located at the study 
site. Testing may alternatively be performed at a certified offsite laboratory, clinic, or hospital, with the 
agreement of the investigator. A COVID-19 antigen test should be conducted ≤ 48 hours before Cycle 1 
Day 1 if clinically indicated 
u. 
Includes glucose, protein, ketones, and blood; dipstick permitted. Urinalysis should be performed at 
screening, as clinically indicated during neoadjuvant treatment, at EOT/Safety Follow-up visit and 
Presurgical Visit (Appendix 2). 
v. 
PK samples for investigational agents will be collected at sites that are able to adequately perform PK 
sampling and handling. During the neoadjuvant phase, PK samples are required at the following time 
points: predose Cycle 1 Day 1 (≤ 60 minutes before starting infusion); postdose Cycle 1 Day 1 
(≤ 30 minutes after completing infusion); Cycle 1 Day 8; and predose Cycle 2 Day 1 (≤ 60 minutes before 
starting infusion). A PK sample is required at the EOT/Safety Follow-up Visit during the visit. Should a 
patient present with any ≥ Grade 3 imAE, an additional blood PK sample may be taken to determine the 
concentrations. These tests are required when it is allowed by local regulations/IRBs/IECs. 
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w. 
ADA samples for protein therapeutic investigational agents will be collected at sites that are able to 
adequately perform ADA sampling and handling. During the neoadjuvant phase, ADA samples are 
required at the following time points: predose Cycle 1 Day 1 (≤ 60 minutes before starting infusion), and 
predose Cycle 2 Day 1 (≤ 60 minutes before starting infusion). An ADA sample is required at the 
EOT/Safety Follow-up Visit during the visit. All samples should be collected at the same time as blood 
collection for predose PK analysis. These tests are required when it is allowed by local 
regulations/IRBs/IECs. 
x. 
Blood samples for biomarker analysis will be collected as follows: 
1) 
For periphery immune cell quantification and phenotyping analysis: samples will be collected at 
predose on C1D1, on C1D8, and at predose on C2D1 during the neoadjuvant phase 
2) 
(Optional) For ctDNA or MRD analysis: samples will be collected at predose on C1D1 and C2D1 
during the neoadjuvant phase; at the EOT/Safety Follow-up Visit; at 7 days after surgery; and then 
at the same visits of disease follow-up tumor assessments after surgery. 
3) 
For soluble proteins such as cytokine/chemokine analysis: samples will be collected at predose on 
C1D1, C1D8, predose on C2D1 during the neoadjuvant phase, and at EOT/Safety Follow-up Visit. 
4) 
For TCR profile analysis: Samples will be collected at predose on C1D1 and C2D1 during the 
neoadjuvant phase; and at the EOT/Safety Follow-up Visit. 
y. 
Patients will undergo an optional tumor biopsy sample collection, if deemed clinically feasible by the 
investigator, at the time of first evidence of radiographic disease progression per RECIST v1.1 
(Appendix 4) during survival follow-up phase. Biopsies should be performed ≤ 40 days after 
progression/recurrence or before the prespecified adjuvant or new anticancer therapy, whichever is sooner. 
Patients must sign a separate Optional Biopsy Informed Consent Form to undergo optional biopsies. See 
Section 7.1.1 for tissue sample requirements. 
z. 
All measurable and evaluable lesions should be assessed and documented at screening. Tumor assessments 
performed as standard of care before obtaining informed consent and ≤ 28 days before randomization do 
not have to be repeated at screening. Screening assessments must include scans of the chest and abdomen 
by CT scan of the whole body by PET. Tumor assessments after randomization should include CT scans 
(with oral/intravenous contrast, unless contraindicated) of the chest and abdomen (including liver and 
adrenal glands). If a CT scan with contrast is contraindicated (eg, in patients with impaired renal clearance), 
a noncontrast CT scan of the chest may be performed and contrast-enhanced MRI scans (if possible) of the 
abdomen should be performed. Refer to Section 7.1 for additional details.  
aa. Patients will undergo tumor assessments per RECIST v1.1 (Appendix 4) at screening, at the EOT/Safety 
Follow-up Visit after the neoadjuvant phase and Presurgical Visit. All measurable and evaluable lesions 
should be reassessed at each subsequent tumor evaluation. The investigator must review radiograph results 
before dosing at the next cycle. The same radiographic procedures used to assess disease sites at screening 
should be used for subsequent tumor assessments (eg, the same contrast protocol for CT scans). The 
investigator will reassess the patient to reconfirm disease resectability, which includes a tumor response 
assessment and a safety assessment before surgery at the Presurgical Visit. Tumor assessment at the 
Presurgical Visit may not be repeated if there is standard tumor assessment per protocol performed 
≤ 14 days before surgery. Patients precluded from planned surgery for any reason except disease 
progression or death will undergo tumor assessments every 6 weeks (± 1 week) per RECIST v1.1 until any 
of the following events, whichever occurs first: radiographic disease progression assessed by the 
investigator, withdrawal of consent, initiation of new anticancer therapy, death, loss to follow-up, or study 
termination by the sponsor. 
bb. After surgery, disease follow-up tumor assessment will be performed using chest and upper abdominal CT. 
The first disease follow-up tumor assessment will be performed 3 months (± 2 weeks) after surgery, then 
every 6 months (± 4 weeks) for the first 2 years, and annually (± 8 weeks) thereafter (Appendix 4). Tumor 
assessments must continue according to the schedule until disease recurrence or progression that precludes 
definitive surgery, withdrawal of consent, initiation of new anticancer therapy with the exception of the 
prespecified adjuvant treatments, death, loss to follow-up, or study termination by the sponsor, whichever 
occurs first. Tumor assessment should be performed by investigator per RECIST v1.1, and disease 
resectability should be assessed by attending thoracic surgeon per local guideline and best clinical 
experience. Disease progression that does not preclude definitive surgery or initiation of prespecified 
adjuvant treatment is not criterion of tumor assessment discontinuation.  
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cc. Information regarding medications (eg, prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by a patient in addition to protocol-mandated 
treatment will be collected from 30 days before randomization until 30 days after the last dose of study 
drug(s) (as of EOT/Safety Follow-up Visit) (Section 6). 
dd. After informed consent has been signed but before the administration of the study drug(s), only SAEs 
associated with protocol-defined procedure should be reported to the sponsor. After initiation of the study 
treatment, all AEs and SAEs, regardless of relationship to the study treatment, will be reported until either 
30 days after the last dose of study treatment or until initiation of prespecified adjuvant treatment or other 
new anticancer therapy, whichever occurs first. Surgical procedure complications will be monitored and 
recorded at the investigator or designee’s discretion. Immune-mediated AEs (serious or nonserious) should 
be recorded until 90 days after the last dose of study treatment, regardless of whether the patient starts pre-
specified adjuvant treatment or other new anticancer therapy. 
ee. Tislelizumab 200 mg (Arm 1A), tislelizumab 200 mg plus ociperlimab 900 mg (Arm 1B), LBL-007 
600 mg plus tislelizumab 200 mg (Arm 1C), tislelizumab 200 mg plus chemotherapy (cisplatin [75 mg/m2] 
or carboplatin [AUC=5 mg/mL/min] + pemetrexed [nonsquamous, 500 mg/m2]/paclitaxel [squamous, 
175 mg/m2]) (Arm 2A), or LBL-007 600 mg plus tislelizumab 200 mg plus chemotherapy (cisplatin 
[75 mg/m2] or carboplatin [AUC=5 mg/mL/min] + pemetrexed [nonsquamous, 500 mg/m2]/paclitaxel 
[squamous, 175 mg/m2]) (Arm 2C) will be given intravenously once every 3 weeks during the neoadjuvant 
phase (Section 3.3). The specific stipulations of the study treatment of experimental arms including 
formulation, packaging, dosage handling, administration, dose modification, and overdose are provided in 
each investigational agent-specific appendix. 
ff. 
After the EOT/Safety Follow-up Visit, information on survival follow-up and new anticancer therapy 
(including targeted therapy and immunotherapy) will be collected via telephone calls, review of patient 
medical records, and/or clinic visits approximately every 6 months (± 4 weeks) (until the patient withdraws 
consent, or the sponsor terminates the study). If a patient requests to be withdrawn from follow-up, this 
request must be documented in the source documents and signed by the investigator. If a patient withdraws 
from the study, the study staff may use a public information source (eg, county records) in accordance with 
local regulations to obtain information about survival status only. 
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APPENDIX 2. CLINICAL LABORATORY ASSESSMENTS  
Serum chemistry 
Hematology 
Coagulation 
Urinalysis 
Thyroid 
function 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate 
aminotransferase 
Albumin 
Total bilirubin 
Direct bilirubin 
Blood urea nitrogen or 
urea 
Chloride 
Potassium 
Sodium 
Total calcium b 
Creatinine 
Glucose 
Lactate dehydrogenase 
Total protein 
CK c 
CK-MB c 
Hematocrit 
Hemoglobin 
Lymphocyte count 
Neutrophil count 
Platelet counts 
WBC count 
 
International 
normalized ratio 
(INR)  
Partial 
thromboplastin time 
or activated partial 
thromboplastin time 
Prothrombin time 
 
Blood 
Glucose 
Ketones 
Protein 
Random urine 
protein to 
creatinine ratio a 
24-hour protein a 
 
Free and total 
triiodothyronine 
Free thyroxine 
Thyroid-
stimulating 
hormone 
Abbreviations: CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; WBC, white blood cell. 
a. 
If during 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 should be obtained to determine a protein-
to-creatinine ratio. 
b. 
Total calcium values will be corrected for patients with hypoproteinemia. 
c. 
All patients will have creatine kinase and CK-MB testing at screening, which is to be repeated at all 
scheduled visits during the 2 to 4 cycles in the neoadjuvant phase, in the Presurgical Visit and at the 
EOT/Safety Follow-up Visits. If CK-MB fractionation is not available, assess troponin I and/or troponin T 
should be assessed instead. Refer to Section 8.3.6 for additional information regarding clinical assessment 
and management of clinical laboratory abnormalities. 
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APPENDIX 3. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS (ECOG PS)  
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 study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (v1.1). Changes in 
only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in 
RECIST. 
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 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 examination (when superficial) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered to indicate 
nonmeasurable disease. Leptomeningeal disease, ascites, pleural, or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques are all nonmeasurable. 
Bone lesions: 
• Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
• Blastic bone lesions are nonmeasurable. 
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Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) because they 
are, by definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
• The concept of cystic metastases also applies to metastatic lesions with a necrotic 
component. Hence, measurable lesions with a necrotic component may be selected as 
target lesions. However, if non-necrotic lesions are present, these are preferred for 
selection as target lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total should be 
identified as target lesions and recorded and measured at baseline. A maximum of 2 measurable 
lymph nodes, inclusive of all lymphatic chains involved, may be chosen as target lesions (ie, the 
lymphatic system is considered one organ). Target lesions should be selected based on size 
(lesions with the longest diameter), how representative they are of all involved organs, and 
whether they lend themselves to reproducible repeated measurements. 
Lymph nodes merit special mention because 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 perpendicular dimensions in the plane in 
which the image is obtained (for CT scan, this is almost always the axial plane; for MRI, the 
plane of acquisition may be axial, sagittal, or coronal, but the axial plane is recommended for 
measurements). The smaller of these measures is the short axis. For example, an abdominal node 
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 
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these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression” (more details to follow). In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”). If a nontarget lymph node normalizes 
(< 10 mm in short axis) after baseline, the respective evaluation should be “absent.” 
Guidelines for Evaluation of Measurable Disease  
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules). For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. As noted above, when lesions can be 
evaluated by both clinical examination and imaging, imaging evaluation should be 
undertaken because it is more objective and may also be reviewed at the end of the 
study. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, because CT is more sensitive than X-ray, particularly in 
identifying new lesions. However, lesions on chest X-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
• CT, MRI: Target lesion measurements should be performed in the axial plane. CT is 
the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. MRI is also acceptable in certain situations (eg, for body 
scans). If there is a change from CT to MRI or the reverse, target lesions should 
continue to be measured provided the imaging parameters do not render 
measurements incomparable. 
• Ultrasound: Ultrasound is not useful in the assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations cannot be reproduced 
in their entirety for independent review at a later date, and because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
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• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in studies 
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. However, if markers are initially above the upper normal limit, they must 
normalize for a patient to be considered to have 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 studies in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between partial 
response (PR) and CR in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain). When effusions are known to be a potential adverse effect of treatment 
(eg, with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met the criteria for response 
or stable disease  to differentiate between response (or stable disease) and PD. 
New or enlarging fluid collections in an otherwise stable or responding patient should 
not result in a conclusion of PD. However, if the fluid collection has malignant 
radiographic features, PD may be declared. 
An increase in the amount of accumulated fluid should not in isolation result in a 
conclusion of PD but rather be assessed in the context of other disease and evidence 
of PD. 
Response Criteria  
Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes must have reduction in short axis to < 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance 
of one or more new lesions is also considered progression.) 
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• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
• Both PR and PD: If the change in the sum of diameters is consistent with both PR and 
PD at a tumor assessment visit, PD should take precedence. 
• Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study. This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if CR criteria are met, because a normal lymph node is defined 
as having a short axis of < 10 mm. The case report form (CRF) may be designed to 
have target nodal lesions recorded in a separate section where, to qualify for CR, each 
node must achieve a short axis < 10 mm. For PR, SD, and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
• 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 a 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 CRF (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 because 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 conclusions of progressions based on measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that measurement should be recorded, even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion.” 
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Evaluation of Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the timepoints specified in the protocol. 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker level. 
All lymph nodes must be nonpathological in size (< 10 mm short axis). 
• Non-CR/non-PD: Persistence of 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 SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in the size of one or more nontarget 
lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in nontarget disease 
in the face of SD or PR of target disease will therefore be extremely rare. 
• When the patient has only nonmeasurable disease: This circumstance arises in some 
Phase 3 studies when it is not a criterion for study entry to have measurable disease. 
The same general concept applies here as noted above; however, in this instance, 
there is no measurable disease assessment to factor into the interpretation of an 
increase in nonmeasurable disease burden. Because worsening in nontarget disease 
cannot be easily quantified (by definition: if all lesions are truly nonmeasurable), a 
useful test that can be applied when assessing patients for unequivocal progression is 
to consider if the increase in overall disease burden based on the change in 
nonmeasurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease; ie, an increase in tumor burden 
representing an additional 73% increase in “volume” (which is equivalent to a 20% 
increase in 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 one that may be described in 
protocols as “sufficient to require a change in therapy.”  If “unequivocal progression” is 
seen, the patient should be considered to have had overall PD at that point. While it 
would be ideal to have objective criteria to apply to nonmeasurable disease, the very 
nature of that disease makes it impossible to do so; therefore, the increase must be 
substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on the 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 
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modality, or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or a flare-up of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up study 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 
in 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 
PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm that 
there is definitely a new lesion, then progression should be declared using the date of the initial 
scan. 
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in the assessment of progression (particularly possible “new” disease). New lesions can be 
identified on the basis of FDG-PET imaging according to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not found to be progressing on the basis of the anatomic 
images, this is not PD. 
• Timepoint Response 
− It is assumed that at each protocol-specified timepoint, a response assessment 
occurs. The following table provides a summary of the overall response status 
calculation at each timepoint for patients who have measurable disease at 
baseline: 
Target lesions 
Nontarget lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
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Target lesions 
Nontarget lesions 
New lesions 
Overall response 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; 
SD, stable disease. 
When patients have nonmeasurable (therefore nontarget) disease only, the following table is to 
be used: 
Nontarget lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
SD (Non-CR/non-PD) 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; SD, stable 
disease. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study drug treatment 
until the end of treatment considering any requirement for confirmation. On occasion, a response 
may not be documented until after the end of therapy, so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the findings 
of both target and nontarget disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in nonrandomized studies where response 
is the primary endpoint, confirmation of PR or CR is needed to deem either one the “best overall 
response.” 
The best overall response is determined once all the data for the patient is known. 
Best response determination in studies where confirmation of CR or PR  IS NOT required: Best 
response in these studies is defined as the best response across all timepoints (for example, a 
patient who has SD at first assessment, PR at second assessment, and PD on last assessment has 
a best overall response of PR). When SD is believed to be best response, it must also meet the 
protocol-specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best timepoint response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and does not 
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meet minimum duration for SD, will have a best response of PD. The same patient lost to 
follow-up after the first SD assessment would be considered inevaluable. 
Best response determination in studies 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 timepoint as specified in the 
protocol (generally 4 weeks later). 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on an increase in the size of the nodes. As noted earlier, this means that patients with CR 
may not have a total sum of “zero.” 
In studies where confirmation of response is required, repeated "NE" (not evaluable) timepoint 
assessments may complicate best response determination. The analysis plan for the study must 
address how missing data/assessments will be addressed in determination of response and 
progression. For example, in most studies, it is reasonable to consider a patient with timepoint 
responses of PR-NE-PR to have 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 having 
“symptomatic deterioration.”  Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. 
Conditions that define “early progression, early death, and inevaluability” are study specific and 
should be clearly described in each protocol (depending on treatment duration and treatment 
periodicity). 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on 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 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 a false-positive conclusion of CR due to the limitations of 
FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
progression is confirmed at the next scheduled assessment, the date of progression should be the 
earlier date when progression was suspected. 
Confirmation of Measurement/Duration of Response  
Confirmation 
In nonrandomized studies where response is the primary endpoint, confirmation of PR or 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 
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traditionally required confirmation in such studies. However, in all other circumstances such as 
in randomized studies (Phase 2 or 3) or studies where SD or progression are the primary 
endpoints, confirmation of response is not required because it will not add value to the 
interpretation of study results. However, elimination of the requirement for response 
confirmation may increase the importance of central review to protect against bias, in particular 
in studies that are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study 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 when recurrent disease or PD is 
objectively documented (taking as reference for PD the smallest measurements recorded on 
study). 
The duration of overall CR is measured from the time the measurement criteria are first met for 
CR until the first date when recurrent disease is objectively documented. 
Duration of Stable Disease 
SD is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of SD varies in different studies and diseases. If the 
proportion of patients achieving SD for a minimum period of time is an endpoint of importance 
in a particular study, the protocol should specify the minimal time interval required between 2 
measurements for determination of SD. 
Note: The duration of response and SD 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 studies 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. 
Contact the medical monitor regarding any uncertainty about immune deficiency/autoimmune 
disease exclusions. 
Acute disseminated encephalomyelitis 
Addison disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating 
polyneuropathy 
Chung-Strauss syndrome 
Crohn disease 
Dermatomyositis 
Dysautonomia 
Epidermolysis bullosa acquisita 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture syndrome 
Granulomatosis with polyangiitis 
Graves’ disease 
Guillain-Barré syndrome 
Hashimoto disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki disease 
Lambert-Eaton myasthenic syndrome 
Lupus erythematosus 
Lyme disease (chronic) 
Mooren ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus syndrome 
Optic neuritis 
Ord thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodosa 
Polyarthritis 
Polyglandular autoimmune syndrome 
Primary biliary cirrhosis 
Psoriasis 
Reiter syndrome 
Rheumatoid arthritis 
Sarcoidosis  
Sjögren syndrome 
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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, p 114. 
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APPENDIX 7. INFUSION-RELATED REACTIONS, 
HYPERSENSITIVITY REACTIONS AND 
IMMUNE-MEDIATED ADVERSE EVENTS: 
EVALUATION AND MANAGEMENT  
Management of Infusion-Related Reactions  
Patients should be closely monitored during and after study drug administration for 
infusion-related reactions and hypersensitivity reactions. See Appendix 11, Appendix 12, 
Appendix 13, and Appendix 14 for the monitoring periods required. Immediate access to an 
intensive care unit or equivalent environment and appropriate medical therapy (including 
epinephrine, corticosteroids, antihistamines, bronchodilators, and oxygen) must be available to 
treat infusion-related reactions. 
Management of infusion-related reactions are provided in the table below (Rosello et al 2017). 
NCI-CTCAE Grade v5.0 
Management 
Grade 1 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
• Decrease infusion rate by 50%.   
• Closely monitor for worsening signs or 
symptoms.   
• Medical management as needed. 
• Subsequent infusions should be given after 
appropriate premedication and at the reduced 
infusion rate. 
Grade 2  
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for ≤ 24 hours 
• Temporarily stop infusion.   
• Treatment includes but is not limited to H1/H2 
antagonists, corticosteroids.  
• Restart infusion at 50% rate once 
infusion-related reaction has resolved or 
decreased to Grade 1 in severity and titrate to 
tolerance. 
• Closely monitor for worsening signs or 
symptoms.   
• Appropriate medical management should be 
instituted. 
• Subsequent infusions should be given after 
premedication and at the reduced infusion rate. 
Grade 3  
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.   
• Treatment includes but is not limited to H1/H2 
antagonists, corticosteroids.  
• The patient should be withdrawn from study 
drug(s) treatment. 
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NCI-CTCAE Grade v5.0 
Management 
Grade 4  
Life-threatening consequences; urgent 
intervention indicated 
• Immediately stop the infusion.  
• Treatment includes but is not limited to H1/H2 
antagonists, corticosteroids.  
• Proper medical management should be 
instituted. 
• The patient should be withdrawn from study 
drug(s) treatment. 
• Hospitalization is recommended. 
Abbreviations: H1/H2, histamine H1 and H2 receptors; IV, intravenous; NCI-CTCAE, National Cancer 
Institute-Common Terminology Criteria for Adverse Event; NSAIDS; nonsteroidal anti-inflammatory drugs. 
For the prophylaxis of mild events (eg, nasal congestion or flu-like symptoms), a dose of 25 mg 
indomethacin or a comparable dose of nonsteroidal anti-inflammatory drugs (eg, 600 mg 
ibuprofen or 500 mg naproxen sodium) may be administered 2 hours before and 8 hours after the 
start of each dose of study drugs(s) infusion. Alternative treatments for fever (eg, paracetamol) 
may be given to patients at the discretion of the investigator. 
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 the treatment. 
Management of Anaphylaxis  
If anaphylaxis occurs, the patient must be managed according to the best available medical 
practice, as described in the guideline for emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) (Soar et al 
2008). Patients should be instructed to report any delayed reactions to the investigator 
immediately.  
The NCI-CTCAE grading of anaphylaxis starts from Grade 3.  
Management and treatment modifications for symptoms of anaphylaxis associated with study 
drug(s) administration are provided in the table below. 
NCI-CTCAE Grade v5.0 
Management 
Grade 3  
Symptomatic bronchospasm, with or without 
urticaria; parenteral intervention indicated; 
allergy-related edema/angioedema; hypotension 
 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
• Immediately stop the infusion. 
• Proper medical management should be 
instituted. 
• Treatment includes but is not limited to oral or 
intravenous antihistamines, antipyretics, 
glucocorticoids, epinephrine, bronchodilators, 
and oxygen. 
• The patient should be withdrawn from study 
drug(s) treatment. 
• Rechallenge is prohibited. 
Abbreviations: NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Event. 
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Evaluation of Immune-Mediated Adverse Events  
The recommendations below for the diagnosis and management of any imAE are intended as 
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. 
The recommendations for the diagnostic evaluation and management of  imAEs are based on 
European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology 
(ASCO) guidelines (Haanen et al 2017, Brahmer et al 2018). For any adverse events not included 
in the tables below, refer to the ASCO Clinical Practice Guideline (Brahmer et al 2018) for 
further guidance on the diagnostic evaluation and management of immune-mediated toxicities. 
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 diagnosing an imAE: 
• What was the temporal relationship between initiation of investigational agent(s) and 
the adverse event? 
• How did the patient respond to withdrawal of investigational agent(s)? 
• Did the event recur when of investigational agent(s) 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 adverse event in the eCRF should be checked. If further diagnostic 
evaluations change the assessment, the eCRF should be updated accordingly. 
Recommended Diagnostic Tests in the Management of Possible Immune-Mediated Adverse 
Events 
Immune-Mediated 
toxicity 
Diagnostic evaluation guideline 
Thyroid disorders 
Scheduled and repeated thyroid function tests (TSH and T4). 
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile. 
Perform pituitary and whole brain MRI in patients with headache, visual 
disturbance, unexplained fatigue, asthenia, weight loss, and unexplained 
constitutional symptoms. 
Consider consultation with an endocrinologist if an abnormality is 
detected. 
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Immune-Mediated 
toxicity 
Diagnostic evaluation guideline 
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.  
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, and 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 adverse event (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. 
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Immune-Mediated 
toxicity 
Diagnostic evaluation guideline 
Myocarditis 
Perform ECG, echocardiogram, CK/CK-MB, troponin (I and/or T), and 
refer to a cardiologist. 
Abbreviations: 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. 
Management of Immune-Mediated Adverse Events  
imAEs can escalate quickly. Study treatment interruption, close monitoring, timely diagnostic 
work-up, and treatment intervention, as appropriate, are required. imAEs 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. 
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 restarting treatment with the study drug should permanently 
discontinue treatment. 
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. 
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Management of Immune-Mediated Adverse Events 
Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
Thyroid 
disorders 
1 or 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 to 4 weeks. 
Monitor thyroid 
function regarding the 
need for hormone 
replacement. 
Continue study 
treatment or 
withhold 
treatment in cases 
with systemic 
symptoms. 
3 or 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 or 1.  
 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
Hypophysitis 
1 or 2 
Mild-moderate symptoms 
Refer patient to an 
endocrinologist for 
hormone replacement. 
Add oral prednisolone 
0.5-1 mg/kg/day for 
patients with pituitary 
inflammation. Taper 
corticosteroids over at 
least 1 month. 
If there is no 
improvement in 
48 hours, treat as 
Grade 3 or 4. 
Continue study 
treatment. 
3 or 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 to 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 (or 
its equivalent) 
≤ 10 mg/day. If 
the event recurs 
upon 
reintroduction of 
study treatment, 
the patient 
discontinues the 
study treatment. 
3 or 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. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
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 or 1. 
3 or 4 
Severe/life-threatening symptoms 
or Grade 3 or 4 encephalitis, or 
Guillain-Barré syndrome 
 
 
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. 
Guillain-Barré 
syndrome: Start 
intravenous 
immunoglobulin 0.4 
g/kg/day for 5 days or 
plasmapheresis. 
Consider 
corticosteroids 
(methylprednisolone 2 
to 4 mg/kg/day) 
followed by a slow 
taper. Monitor for 
concurrent autonomic 
dysfunction. 
Discontinue study 
treatment. 
Colitis/Diarrhea 
1 
Mild symptoms: ≤ 4 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. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
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 to 
4 weeks. 
Consider endoscopy if 
symptoms are 
recurring. 
Hold study 
treatment; resume 
when 
resolved/improved 
to baseline grade. 
3 
Severe symptoms: ≥ 7 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. 
Skin reactions 
1 
Skin rash, with or without 
symptoms, < 10% BSA 
Avoid skin irritants and 
sun exposure; topical 
emollients 
recommended. 
Continue study 
treatment. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
2 
Rash covers 10%-30% of BSA 
Avoid skin irritants and 
sun exposure; topical 
emollients 
recommended. 
Topical steroids 
(moderate strength 
cream once a day or 
potent cream twice a 
day) ± oral or topical 
antihistamines for itch. 
Consider a short course 
of oral steroids.  
Consider holding 
study treatment 
and monitor 
weekly for 
improvement. If 
not resolved, 
interrupt treatment 
until improved to 
Grade 1. 
3 
Rash covers > 30% BSA or Grade 
2 with substantial symptoms 
Avoid skin irritants and 
sun exposure; topical 
emollients, oral 
antihistamines, and 
high-potency topical 
corticosteroids 
recommended. 
Initiate 
(methyl)prednisolone 
(or equivalent) 1 to 2 
mg/kg, tapering for a 
period of ≥ 4 weeks. 
 
Hold study 
treatment. 
Re-treat after 
discussion with 
the study medical 
monitor, if 
adverse event has 
resolved or 
improved to mild 
rash (Grade 1 or 
2). 
Do not 
rechallenge cases 
of suspected SJS 
or TEN, unless 
SJS/TEN has been 
ruled out in 
consultation with 
appropriate 
specialists. 
4 
Skin sloughing > 30% BSA with 
associated symptoms 
(eg, erythema, purpura, epidermal 
detachment), including Stevens-
Johnson syndrome (all grades), and 
toxic epidermal necrolysis 
Initiate intravenous 
methylprednisolone 
1-2 mg/kg/day. 
Convert to oral 
prednisolone and taper 
over at least 4 weeks. 
Admit to a hospital and 
seek urgent 
dermatology 
consultation. 
Discontinue study 
treatment. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
Hepatitis 
1 
ALT or AST > ULN to 3 x ULN 
Check LFTs within 
1 week and before the 
next dose; check LFTs 
to verify that there has 
been no worsening. 
If LFTs are worsening, 
recheck every 
48-72 hours until 
improvement is seen. 
Continue study 
treatment if LFTs 
are unchanged or 
improving. 
Hold study 
treatment if LFTs 
are worsening 
until improvement 
is seen. 
2 
ALT or AST > 3 x to 5 x ULN 
Recheck LFTs every 
48-72 hours. 
Administer 
prednisolone at a dose 
of 0.5 to 2 mg/kg/day 
for ≥ Grade 2 liver 
enzyme elevations, 
with or without 
concomitant bilirubin 
elevations.  
For Grade 2 hepatitis, 
withhold tislelizumab 
until the event has 
resolved or improved 
to baseline and 
prednisolone has been 
tapered to ≤ 10 mg/day 
over 2 to 4 weeks. 
Hold study 
treatment; 
treatment may be 
resumed when 
resolved/improved 
to baseline grade 
and prednisolone 
tapered to 
≤ 10 mg. 
3 
ALT or AST > 5 x to 20 x ULN 
 
Immediately start 
methylprednisolone 1 
to 2 mg/kg (or 
equivalent). Monitor 
closely. If no 
improvement after 3 
days, consider 
additional treatment 
options 
(mycophenolate 
mofetil or azathioprine. 
If ALT and AST 
≤ 10 x ULN: Hold 
study treatment 
until improved to 
baseline grade; 
reintroduce only 
after discussion 
with the medical 
monitor. 
If ALT or 
AST > 10 x ULN: 
Discontinue study 
treatment. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
 
4 
ALT or AST > 20 x ULN 
Initiate intravenous 
methylprednisolone 
2 mg/kg/day. Convert 
to oral prednisolone 
and taper over at least 
6 weeks.  
Discontinue study 
treatment. 
 
Worsening LFTs despite steroids: 
 If on oral prednisolone, change to pulsed intravenous 
methylprednisolone. 
 If on intravenous methylprednisolone, add MMF 500 to 1000 mg 
twice a day. 
 If worsens on MMF, consider addition of tacrolimus. 
Duration and dose of steroid required will depend on severity of event. 
Nephritis 
1 
Creatinine 1.5 x baseline 
or > ULN to 1.5 x ULN 
Repeat creatinine test 
weekly. 
If symptoms worsen, 
manage as per criteria 
below. 
Continue study 
treatment. 
2 
Creatinine > 1.5-3 x baseline 
or > 1.5-3 x ULN 
Ensure hydration and 
review creatinine in 
48-72 hours; if not 
improving, consider 
creatinine clearance 
measurement by 
24-hour urine 
collection. 
Discuss with 
nephrologist the need 
for kidney biopsy. 
If attributed to study 
drug, initiate oral 
prednisolone 
0.5-1 mg/kg and taper 
over at least 2 weeks. 
Repeat creatinine/U&E 
every 48-72 hours. 
Hold study 
treatment. 
If not attributed to 
drug toxicity, 
restart treatment. 
If attributed to 
study drug and 
resolved/improved 
to baseline grade, 
restart study drug 
if tapered to 
< 10 mg 
prednisolone. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
3 
Creatinine > 3 x baseline 
or > 3-6 x ULN 
Hospitalize patient for 
monitoring and fluid 
balance; repeat 
creatinine test 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. 
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 free of 
hyperglycemia 
symptoms, and 
blood glucose has 
been stabilized at 
baseline or 
Grade 0 or 1. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
4 
Fasting glucose 
value > 500 mg/dL; > 27.8 mmol/L 
Admit patient to 
hospital and institute 
local emergency 
diabetes management. 
Refer the patient to a 
diabetologist for 
insulin maintenance 
and monitoring. 
Hold study 
treatment until 
patient is free of 
hyperglycemia 
symptoms, and 
blood glucose has 
been stabilized at 
baseline or 
Grade 0 or 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 or 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 or 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 or 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. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
2 
Moderate pain, reduced oral 
intake, limited instrumental 
activities 
As per local guidelines, 
treat with analgesics, 
topical treatments, and 
oral hygiene care. 
Ensure adequate 
hydration. 
If symptoms worsen or 
there is sepsis or 
bleeding, manage as a 
Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited food and fluid 
intake, daily living activity limited 
Admit to hospital for 
appropriate 
management. 
Initiate 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 or 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 to 1. 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
3 or 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 or 1. 
Discontinue upon 
any evidence of 
myocardial 
involvement. 
 
Myocarditis  a 
< 2 
Asymptomatic but significantly 
increased CK-MB or increased 
troponin or clinically significant 
intraventricular conduction delay 
Initiate cardiac 
evaluation under close 
monitoring with repeat 
serum testing and 
including ECG, cardiac 
echo/MUGA, and/or 
other interventions per 
institutional guidelines; 
consider referral to a 
cardiologist. 
If diagnosis of 
myocarditis is 
confirmed, treat as 
Grade 2. 
Hold study 
treatment. 
If a diagnosis of 
myocarditis is 
confirmed and 
considered 
immune-mediated, 
permanently 
discontinue study 
treatment in 
patients with 
moderate or 
severe symptoms. 
Patients with no 
symptoms or mild 
symptoms may 
not restart 
tislelizumab 
unless cardiac 
parameters have 
returned to 
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 
3 
Severe symptoms with mild 
exertion 
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Autoimmune 
toxicity 
Grade 
Treatment guidelines 
(subject to clinical 
judgement) 
Study drug 
management 
4 
Life-threatening 
cardiologist and 
manage symptoms of 
cardiac failure 
according to local 
guidelines. 
If no immediate 
response, change to 
pulsed doses of 
(methyl)prednisolone 
1 g/day and add MMF, 
infliximab, or anti-
thymocyte globulin. 
baseline and after 
discussion with 
the study medical 
monitor. 
Other 
immune-mediated 
adverse events 
Grade 3 (first occurrence) 
 
Grade 4 or recurrent Grade 3; 
persistent Grade 2 or 3 despite 
treatment modification; inability to 
reduce corticosteroid dose to 10 mg 
prednisone or equivalent per day 
NA 
Hold study 
treatment 
 
Discontinue study 
treatment.  
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body surface area; CHF, 
congestive heart failure; CK, creatine kinase; CK-MB, creatine kinase cardiac isoenzyme; ECG, electrocardiogram; 
INR, international normalized ratio; LFT, liver function test; MMF, mycophenolate mofetil; MUGA, multigated 
acquisition scan; NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; 
TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 
a If clinically significant cardiac enzyme abnormalities are detected during laboratory assessment and serial cardiac 
enzyme assessments pose logistical hardship for the patient, then patient hospitalization should strongly be 
considered until immune-mediated myocarditis has been ruled out. 
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APPENDIX 8. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION 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 women and 0.9 for men, 
α is -0.329 for women and -0.411 for men, 
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 studies include the use of highly effective forms of birth control (Clinical 
Trials Facilitation and Coordination Group 2020). These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation 
− Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
− Oral, injectable, implantable 
Note: Oral birth control pills are not considered a highly effective form of birth 
control, and if they are selected, they must be used with a second, barrier method 
of contraception such as condoms with or without spermicide. 
• An intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
Note: This is only considered a highly effective form of birth control when the 
vasectomized partner is the sole partner of the study participant and there has been a 
medical assessment confirming surgical success. 
− A sterile male is one for whom azoospermia, in a semen sample, has been 
demonstrated as definitive evidence of infertility. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatment) 
Note: Total sexual abstinence should only be used as a contraceptive method if it is in 
line with the patients’ usual and preferred lifestyle. Periodic abstinence (eg, calendar, 
ovulation, sympto-thermal, post-ovulation methods), declaration of abstinence for the 
duration of exposure to the 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 concentration > 30 mIU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months 
have been ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, 
etc. 
If a follicle-stimulating hormone measurement is required to confirm postmenopausal state, 
concomitant use of hormonal contraception or hormonal replacement therapy should be 
excluded. 
Adapted from Clinical Trials Facilitation and Coordination Group (CTFG) 2020. 
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APPENDIX 10. LIST OF RESTRICTED CHINESE HERBAL AND 
PATENT MEDICINES  
The following table provides examples of Chinese herbal and patent medications that may be 
used to treat cancer or that have immune-stimulating properties.  This list is not intended to be 
all-inclusive.  These medications require a 14-day washout period and should be restricted 
during the study. 
Drug Name (Chinese) 
Drug Name (English) 
Rg3 参一胶囊 
Ginsenoside-Rg3 capsule 
养正消积胶囊 
Yangzheng Xiaoji Jiaonang 
化癥回生口服液  
Huazheng Huisheng Koufuye 
十全大补汤  
Juzentaihoto 
华蟾素注射液  
Cinobufacini/Huachansu injection 
华蟾素片/胶囊 
Cinobufacini/Huachansu Pian/Capsules 
博尔宁胶囊  
Boerning capsule 
去甲斑蝥素片  
Norcantharidin Pian 
参丹散结胶囊  
Shendan Sanjie Jiaonang 
参芪扶正注射液  
Shengqi Fuzheng Zhusheye 
参莲胶囊/颗粒  
Shen Lian Jiao Nang/Ke Li 
吗特灵注射液  
Ma Te Ling injection 
回生口服液  
Hui Sheng Kou Fu Ye 
复方斑蝥胶囊  
Fufang Banmao Jiaonang 
复方红豆杉胶囊  
Fufang Hongdoushan Jiaonang 
复方苦参注射液  
Fufang Kushen Zhusheye 
天仙胶囊  
Tian Xian capsule 
奇宁注射液  
Qining injection 
威麦宁胶囊  
Weimaining Jiao Nang 
安尔欣注射液  
Anerxin/Ginseng polysaccharide injection 
安康欣胶囊  
Ankangxin Jiaonang 
安替可胶囊  
Antike capsule 
岩舒注射液  
Yanshu injection 
平消片/胶囊  
Ping Xiao Pian/Jiao Nang 
康力欣胶囊  
Kanglixin Jiaonang 
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Drug Name (Chinese) 
Drug Name (English) 
康艾注射液  
Kang’ai Zhusheye 
康莱特注射液  
Kanglaite Injection 
康莱特软胶囊  
Kanglaite Soft Capsules 
慈丹胶囊  
CIDAN Capsule 
槐耳颗粒  
Huaer Keli 
海生素注射液  
Haishengsu injection 
消癌平丸/片/胶囊/颗粒  
Xiaoaiping Wan/Pian/Jiao Nang/Ke Li 
消癌平注射液  
Xiaoaiping Zhusheye 
牛黄醒消丸  
Niuhuang Xingxiao pill 
猪苓多糖注射液  
Polyporus polysaccharide injection 
白花蛇舌草注射液  
Hedyotis Dissusa wild injection 
紫龙金片 
Zi Long jin pian 
肝复乐片/胶囊  
Ganfule Jiaonang/GFL tablet 
肿节风片 
Zhongjiefeng tablet 
胃复春片  
Weifuchun pill 
艾迪注射液  
Ai Di Zhu She Ye 
芪珍胶囊  
Qizhen Jiaonang 
莪术油注射液  
Zedoary turmeric oil injection 
金复康口服液  
Kanglixin Jiaonang 
金蒲胶囊  
Jinpu capsule 
金龙胶囊  
Jinlong Capsules 
香菇多糖  
Lentinan 
鸦胆子油乳注射液  
Yadanzi/Brucea javanica Youru Zhusheye 
鸦胆子油软胶囊/口服乳液  
Yadanziyou Ruan jiao nang/Kou Fu Ru Ye 
Terminology list: Gao, ointment; He Ji/Heji, mixture; Jiao Nang/Jiaonang, capsule; Ke Li/Keli, granules; Kou Fu 
Ye/koufuye, oral liquid; Pian, tablet; Wan, pill/bolus; Zhue She ye/Zhusheye, injections. 
 
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APPENDIX 11. TISLELIZUMAB  
1. INTRODUCTION - TISLELIZUMAB 
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 is being investigated either as monotherapy or in combination 
with other therapies. 
PD-1 is mainly expressed in activated T cells, including cluster of differentiation (CD)8+ 
cytotoxic T lymphocytes and CD4+ T-helper lymphocytes (McDermott and Atkins 2013). The 
PD-1 signaling cascade negatively regulates the T-cell and attenuates T-cell proliferation and 
functional activities, leading to T-cell exhaustion. PD-1 expression is markedly up-regulated on 
TILs, while the expression of PD-L1 is significantly increased on tumor cells and 
tumor-associated immune cells in the presence of stimulating cytokines such as 
interferon-gamma (IFN-γ) and interferon-alpha in the tumor microenvironment (Riley 2009), 
which is observed in many types of human solid tumors. This body of evidence provides the 
basis for cancer immunotherapeutic intervention via the approach of antagonizing PD-1. 
Refer to Tislelizumab Investigator’s Brochure for additional background. 
1.1 Background Information on Tislelizumab 
1.1.1. Pharmacology 
Tislelizumab binds to the extracellular domain (ECD) of human PD-1 with high specificity and 
affinity (dissociation constant = 0.15 nM), as demonstrated by receptor binding assays based on 
surface plasmon resonance. Tislelizumab competitively blocks the binding of both PD-L1 and 
programmed death ligand-2 (PD-L2). Robust antitumor activity of tislelizumab was also 
observed in human PD-1 transgenic mice transplanted with B16/F10 mouse melanoma cells 
overexpressing murine granulocyte-macrophage colony-stimulating factor. 
The IgG4-variant antibody has demonstrated very low binding to gamma fragment crystallizable 
region receptor (FcγR) RI, RIIIA, and complement 1q (C1q) by in vitro assays, suggesting low 
or no antibody-dependent cellular phagocytosis, antibody-dependent cellular cytotoxicity, and 
complement-dependent cytotoxicity (CDC) effects in humans. 
Tislelizumab binds to the PD-1 of cynomolgus monkey and human with a similar affinity but 
does not bind to mouse PD-1. The cynomolgus monkey is therefore considered the relevant 
animal species for nonclinical studies. In single-dose and 13-week repeated-dose toxicology 
studies in cynomolgus monkeys, no specific concerns were identified in vital organ systems, 
including the cardiovascular system, central nervous system, and respiratory system. 
Refer to the Tislelizumab Investigator’s Brochure for detailed information regarding 
pharmacology studies. 
1.1.2 Toxicology 
In single-dose toxicity studies in both mice and cynomolgus monkeys, no mortality or apparent 
toxicity was noted at single doses up to 100 mg/kg. 
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In a repeated-dose study in cynomolgus monkeys, no apparent toxicity was noted following 
intravenous infusion of tislelizumab at 3, 10, or 30 mg/kg once every 2 weeks for 13 weeks 
(7 doses). No test-article-related histopathologic changes were noted in any tissues. No specific 
concerns were identified for vital organ system functions, including the cardiovascular system, 
the central nervous system, and the respiratory system. ADAs with neutralization activity were 
noted but appeared to have no impact on systemic exposure except at the low dose of 3 mg/kg. 
Thus, with sustained systemic drug exposure, the efficacy of the drug would not be impacted. 
The no-observed-adverse-effect level (NOAEL) was 30 mg/kg in this study. 
Overall, the available toxicological data are considered adequate in support of the clinical 
development of tislelizumab in patients with advanced cancer. 
Refer to the Tislelizumab Investigator’s Brochure for detailed information regarding toxicology 
studies. 
1.1.3.  Clinical Pharmacology 
Based on pooled data from 2596 patients across 12 clinical studies, the PK of tislelizumab was 
best characterized using a 3-compartmental linear population PK model with linear clearance 
mechanisms. No time-varying clearance was observed in tislelizumab PK. The Cmax and AUC 
increased in a nearly dose-proportional manner from 0.5 mg/kg to 10 mg/kg. The terminal t1/2 
was estimated to be approximately 23.8 days, and the steady state is expected to be reached in 
12 weeks. Tislelizumab PK was generally similar between Chinese patients and patients of other 
ethnic groups and across tumor types. 
Refer to the Tislelizumab Investigator’s Brochure for detailed information regarding clinical 
pharmacology studies. 
1.1.4.  Prior Clinical Experience with Tislelizumab 
As of 20 July 2022, 18 studies with tislelizumab are ongoing, and 7 studies have been completed 
(Tislelizumab Investigator’s Brochure). Of the 18 ongoing studies, 10 studies have data 
available: 5 monotherapy studies and 5 chemotherapy combination therapy studies. 
For more detailed information on the safety and efficacy of tislelizumab when given as 
monotherapy or in combination with chemotherapy, refer to the most recent edition of the 
Tislelizumab Investigator’s Brochure. 
1.1.4.1.  Pooled Safety Assessment of Monotherapy Studies 
A pooled analysis of monotherapy studies was conducted to provide a comprehensive safety 
assessment separate from combination therapy. Data from patients with solid tumors were 
analyzed separately from patients with hematologic malignancies. 
As of 20 July 2022, data are available from patients treated in 7 pooled solid tumor monotherapy 
studies (Tislelizumab Investigator’s Brochure).  
For monotherapy, the safety profile of tislelizumab was considered adequate, and tislelizumab 
was well tolerated. In pooled solid tumor studies, the majority of AEs were Grade 1 or 2, and 
most ≥ Grade 3 TEAEs were assessed as unrelated to tislelizumab. AEs were generally 
reversible and manageable. The percentage of patients with ≥ Grade 3 immune-mediated AEs 
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(imAEs), ≥ Grade 3 infusion-related AEs, and TEAEs leading to tislelizumab discontinuation 
was small.  
The data collected shows that tislelizumab monotherapy has an adequate safety profile. The 
safety profile for single agent tislelizumab is similar to that observed with other PD-1 inhibitors 
in solid tumors. 
For more detailed information on the safety of tislelizumab when given as monotherapy or in 
combination with chemotherapy, refer to the most recent edition of the Tislelizumab 
Investigator’s Brochure. 
1.1.4.2.  Efficacy Assessment of Tislelizumab 
Efficacy data are available from 9 monotherapy studies and 6 combination therapy studies. 
Among these 15 studies, 13 studies were in patients with solid tumors, and 2 studies were in 
patients with hematologic malignancies.  
The data collected show that tislelizumab monotherapy can result in antitumor activity across a 
variety of tumor types, and the antitumor activity has been observed across the dose ranges 
evaluated in patients.  
Please refer to the Tislelizumab Investigator’s Brochure for detailed efficacy information. 
1.2. Tislelizumab Rationales 
1.2.1.  Rationale for Tislelizumab Monotherapy in the Neoadjuvant Treatment of Patients 
With Resectable NSCLC 
With the successful development of cancer immunotherapy in advanced NSCLC, several studies 
on neoadjuvant/adjuvant immunotherapy are being conducted in resectable NSCLC. Preclinical 
studies showed that the immune-suppressive PD-1 axis is activated early in NSCLC; induction of 
an immune response before surgery may lead to durable protection (Chiari et al 2018). After 
surgical resection, tumor antigens decrease dramatically and intact blood vessels and lymph 
nodes for drug delivery are removed, which may influence the effects of immunotherapy. Taking 
these data into consideration, immunotherapy was given in the neoadjuvant phase. In previous 
Phase 1b or 2 studies, drugs targeting PD-1 and its ligand, PD-L1, have shown a manageable 
safety profile and promising preliminary efficacy data, including increased pathological response 
rate when used for neoadjuvant treatment in patients with resectable NSCLC (Cascone et al 
2021, Forde et al 2018, Gao et al 2020, Lee et al 2021). 
Tislelizumab monotherapy and the combination of tislelizumab plus platinum-based doublet 
chemotherapy have demonstrated clinical benefit in advanced NSCLC in 3 Phase 3 studies 
(BGB-A317-303, BGB-A317-304, and BGB-A317-307) (Tislelizumab Investigator’s Brochure). 
Overall, above evidence could support sponsor’s opinion that tislelizumab neoadjuvant may 
benefit patients with PD-L1-expression-positive, early-stage, resectable NSCLC and have a 
tolerable safety profile.  
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1.2.2.  Rationale for Selection of Tislelizumab Dose 
The dosage of 200 mg intravenously once every 3 weeks was selected based on safety, efficacy, 
and PK assessments in the first-in-human study BGB-A317_Study_001. A wide range of 
dosages were investigated in this study, including 2 mg/kg or 5 mg/kg on schedules of once 
every 2 weeks or once every 3 weeks. For the once every 3 weeks schedule, a fixed dose of 
200 mg was also investigated, and was ultimately selected for the following reasons: 
• All dosages tested, including 200 mg once every 3 weeks, were tolerated. The 
maximum tolerated dose was not reached with dosages of up to 10 mg/kg once every 
2 weeks. The observed serum concentration after 200 mg dosing was within the range 
seen after 2 mg/kg and 5 mg/kg dosing. 
• Preliminary clinical activity was observed at this dosage. 
• Exposure-response relationships were flat for ORR and safety endpoints across a 
variety of tumor types (data from studies BGB-A317_Study_001, BGB-A317-102, 
and BGB-A317-203). In addition, population PK analysis based on 2596 cancer 
patients demonstrated that no covariates had clinically relevant effect on tislelizumab 
PK, suggesting no dose modification is needed based on patient demographics and 
characteristics. 
• Compared with doses based on patient weight, a fixed dose simplifies dose 
administration and reduces the chance of medical errors. 
• Compared with a once every 2 weeks schedule, a once every 3 weeks schedule allows 
for more convenient integration with common chemotherapeutic regimens and 
increases patient convenience. 
Additionally, tislelizumab is currently approved and marketed in China at the recommended 
dosage of 200 mg once every 3 weeks for multiple indications either alone or in combination 
with standard of care chemotherapy. Please refer to the Tislelizumab Investigator’s Brochure for 
additional details. 
1.2.3.  Biomarker Strategy Rationale 
As the most well-known immune checkpoint molecule, the PD-1 pathway has received 
considerable attention for its role in maintaining T cell exhaustion, a dysfunction state of T cell 
in the setting of chronic antigen stimulation including cancer. Blockade of the PD-1 pathway 
using monoclonal antibodies against either PD-1 or the ligand PD-L1 could at least partially 
restore functions to these T cells with enhanced proliferation, pro-inflammatory cytokine 
production and killing activity (Pauken et al 2021). However, emerging studies revealed that not 
all exhausted CD8+ T cells could respond to PD-1 blockade due to large heterogeneity or distinct 
epigenetic landscapes. Progenitor-like population, which retains the ability to proliferate in 
response to antigen and produce inflammatory cytokines, is preferentially responsive to PD-1 
pathway blockade with a stronger degree of reinvigoration, despite lower PD-1 expression level. 
Meanwhile, the other more terminally differentiated T cells may not (Miller et al 2019). Besides 
cytotoxic effector function, the PD-1 pathway may also regulate the differentiation of naive T 
cells into memory T cells and modulate the responses of existing memory T cell populations 
(Ahn et al 2018).  
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Treg cells play a critical role in immune suppression with elevated levels of the PD-1 receptor by 
at least a fraction of them, suggesting the potential role of PD-1 pathway in regulating this 
population. It has been reported that PD-1 signaling inhibits Treg cell activation and function, 
while improved suppressive capacity of Treg is observed after PD-1 blockade (Kamada et al 
2019). In tumors, PD-1 blockade leads to both increased PD-1+ CD8+ T cell function as well as 
enhanced PD-1+ Treg cell-mediated immunosuppression, with the ratio between them may direct 
the outcome of the final immune response (Kumagai et al 2020).  
Additionally, PD-1 expression has been described on NK cells in some types of cancer and 
modulating PD-1 can impact NK cell functions. However, other work suggests minimal 
expression of PD-1 on NK cells (Hsu et al 2018, Judge et al 2020). Consequently, the extent to 
which PD-1 on NK cells can contribute to regulating host immunity remains an active area of 
investigation. 
In summary, further exploration is needed to clarify the impact of PD-1 on the reinvigoration, 
formation and maintenance of different T-cell effector/memory subsets, as well as Treg cells and 
NK cells in this study. 
1.3.  Benefit-Risk Assessment of Tislelizumab 
Blockade of the PD-1 pathway has demonstrated strong antitumor efficacy either alone or in 
combination with standard of care chemotherapy in multiple cancer indications. As of 
20 July 2022, tislelizumab has been evaluated in 3220 patients (2173 patients treated with 
monotherapy and 1047 patients treated with combination therapy), 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. In 2 Phase 3 clinical studies (BGB-A317-304 and BGB-A317-307), 
tislelizumab in combination with doublet platinum chemotherapy showed statistical and clinical 
improvement in PFS as the primary endpoint in comparison with chemotherapy, regardless of 
PD-L1 expression, in treatment-naive metastatic NSCLC patients.  
Tislelizumab received approval from China NMPA based on these data for use in the first-line 
treatment of patients with unresectable, locally advanced, or metastatic squamous and 
nonsquamous NSCLC in 2021. 
The safety profile of tislelizumab is largely consistent with that of other anti-PD-1 antibodies and 
includes mostly mild or moderate AEs. Very few Grade 3 or Grade 4 imAEs have been 
observed, and they have been generally reversible and manageable with study drug interruption 
and/or steroid treatment. 
The benefit-risk assessment for tislelizumab monotherapy arm (Arm 1A), based on available 
tislelizumab data, is considered favorable. 
2.  STUDY TREATMENT – TISLELIZUMAB 
2.1.  Formulation, Packaging, Labeling, and Handling 
Tislelizumab is a monoclonal antibody formulated for intravenous infusion in a single-use vial 
(20R glass, 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 
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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 and light conditions as specified on the label and 
in the pharmacy manual. Refer to the pharmacy manual for details regarding reconstitution, 
intravenous administration, accountability, and disposal. Refer to the Tislelizumab Investigator’s 
Brochure for other details regarding tislelizumab. 
2.2. Dosage, Administration, and Compliance 
Dosing schedules for the treatment Arm 1A are provided in §Table 1. The first dose of the study 
drug is to be administered ≤ 2 days after randomization. All patients will be monitored for AEs 
throughout the study. Treatment modification (ie, dose delay or interruption) or discontinuation 
will be based on specific laboratory and AE criteria, as described in §Section 2.4. 
Refer to §Section 2.2.1 for details on monitoring time.  
§Table 1: Selection and Timing of Neoadjuvant Dose in Arm 1A 
Treatment 
arm 
Study drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Duration of 
treatment 
Arm 1A 
Tislelizumab 
200 mg 
Day 1 of each 3-week 
cycle  
Intravenously  2 to 4 Cycles 
2.2.1 Tislelizumab Treatment Administration 
Tislelizumab will be administered according to the dosing schedule provided in §Table 1. 
Assigned study drugs will be administered by intravenous infusion through an intravenous line 
containing a sterile, nonpyrogenic, low-protein-binding 0.2 or 0.22 μm in-line or add-on filter. 
Specific instructions for product preparation, storage, and administration are provided in the 
pharmacy manual. 
The delivery period of the initial infusion for tislelizumab (Day 1 of Cycle 1) will be 
over 60 minutes (± 5 minutes); if this is well tolerated, then the delivery period of subsequent 
infusions may be shortened to over 30 minutes (± 5 minutes), which is the shortest time period 
permissible for infusion. Tislelizumab must not be concurrently administered with any other 
drug (§Section 3). 
Use of a volumetric pump is recommended to control the infusion speed and to avoid potential 
infusion reactions associated with fast administration. The pump may not be needed if the 
infusion speed is controlled through alternative means and is consistent with approved 
institutional procedures. 
At the end of each study drug infusion period, the line will be flushed with enough normal saline 
to make sure the complete doses of the study drug are administered. 
As a routine precaution, after completion of study treatment on Day 1 of Cycle 1, patients must 
be monitored ≥ 60 minutes and ≥ 30 minutes from Cycle 2 afterward in an area with 
resuscitation equipment and emergency agents.  
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Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
§Section 2.4. Details for the management of imAEs, infusion-related reactions, and anaphylaxis 
reactions are provided in detail in Section 8.7 and Appendix 7. 
§Table 2: Administration of Tislelizumab and Monitoring Time  
Cycle 
Tislelizumab Monotherapy 
Cycle 1 Day 1 
 
Tislelizumab infusion ≥ 60 minutes followed by patient monitoring for 
≥ 60 minutes 
Cycle 2 Day 1 
onwards 
If well tolerated, tislelizumab infusion ≥ 30 minutes followed by patient 
monitoring for ≥ 30 minutes 
Note: The infusion rate of tislelizumab may be decreased or the infusion may be stopped in the event of an 
infusion-related reaction.  
2.3.  Overdose 
An overdose is defined as ≥ 600 mg of tislelizumab in a 24-hour period. Any overdose or 
incorrect administration of study drug should be noted in the patient’s source documents and in 
the appropriate eCRF.  
2.4.  Dose Modification for Tislelizumab 
Dose modification for tislelizumab is defined as any of the following: dose delay, dose 
interruption, and infusion rate decrease. A dose delay is a deviation from the prescribed dosing 
schedule (ie, the drug is withheld beyond the visit window). A dose interruption is an 
interruption of an infusion. An infusion rate decrease is a decrease of infusion rate. There will be 
no dose reduction for tislelizumab in this study.  
The dose modification guidelines in this section are not intended to be a substitute for clinical 
judgment. Investigators may delay doses for other reasons (eg, AEs or laboratory findings) as 
appropriate. 
If study treatment is delayed due to treatment-emergent adverse events, study treatment may 
resume only after the AEs have returned to baseline or ≤ Grade 1 severity except for alopecia or 
AEs that, in the opinion of the investigator, are not considered a safety risk to the patient. If a 
treatment delay is due to worsening of laboratory results, eg, hematologic or biochemical 
parameters, the frequency of relevant blood tests should be increased, as clinically indicated. 
When several toxicities with different grades of severity occur at the same time, the dose 
modifications should be according to the highest grade observed. 
In general, dose delays for reasons other than management of AEs are prohibited. Total duration 
of dose delay (ie, the delay duration from first dose of study treatment to actual last dose 
compared with prescribed dosing schedule) of ≤ 3 weeks is allowed under the following 
guidance and at the discretion of the investigator. Study treatment should resume as soon as 
possible after the AEs recover to baseline or Grade 1 (whichever is more severe) if the total 
delay duration is not more than 3 weeks.  
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If the patient is unable to resume study treatment ≤ 3 weeks of total delay duration, then the 
patient should be discontinued from treatment. If the patient is not able to resume study treatment 
≤ 3 weeks of total delay duration for unforeseen non-drug-related reasons, continued treatment 
may be allowed after consolation and approval by the medical monitor.  
If a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with the medical 
monitor. Specific treatment modifications to manage treatment-related toxicities, such as imAEs, 
infusion-related reactions, and anaphylaxis reactions, are described in Section 8.7 and 
Appendix 7. 
3. PRIOR AND CONCOMITANT THERAPY – TISLELIZUMAB 
3.1.  Potential Interactions Between the Study Drugs and Concomitant Medications 
The potential for drug-drug interaction between tislelizumab, standard chemotherapy, and small-
molecule drug products is very low, given tislelizumab is a therapeutic monoclonal antibody. 
Tislelizumab is unlikely to have an effect on drug metabolizing enzymes or transporters because 
it is expected to be degraded into amino acids and recycled into other proteins. 
4.  SAFETY MONITORING AND REPORTING -TISLELIZUMAB 
4.1.  Risks Associated With Tislelizumab 
Tislelizumab is an investigational agent that is currently in clinical development. The following 
recommendation is based on results from nonclinical and clinical studies with tislelizumab and 
published data on other molecules within the same biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, this type of 
therapy may increase the risk of imAEs, specifically the induction or exacerbation of 
autoimmune conditions. AEs observed with anti-PD-1 therapy are presented in Section 8.7.2. 
An imAE may occur at any time during or after treatment. Often, the etiology of imAEs is not 
clear, and other causes should be ruled out. This may require diagnostic testing and consultation 
with a specialist. Suggested evaluation and management guidelines for suspected imAEs are 
provided in Appendix 7. Refer to the Tislelizumab Investigator’s Brochure for additional details. 
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APPENDIX 12. OCIPERLIMAB  
1.  INTRODUCTION - OCIPERLIMAB 
Immune surveillance plays a critical role in cancer prevention. However, in situations in which 
tumors develop resistance mechanisms to suppress the host immune system, tumors eventually 
grow out of control (Schreiber et al 2011; Swann and Smyth 2007). One such resistance 
mechanism is up-regulation of immune checkpoint receptors, such as PD-1 and TIGIT (Johnston 
et al 2014; Chauvin et al 2015). 
Ociperlimab (also known as BGB-A1217) is a humanized immunoglobulin G (IgG) 1 
monoclonal antibody binding to TIGIT under clinical development for the treatment of human 
malignancies. TIGIT is an immune checkpoint receptor primarily expressed on immune cells, 
such as T cells and natural killer (NK) cells (Manieri et al 2017). A large body of literature 
suggests that TIGIT plays a key role in promoting T-cell exhaustion and maintaining immune 
tolerance, in both chronic viral infections and the tumor microenvironment (Yu et al 2009; Boles 
et al 2009; Stanietsky et al 2009; Levin et al 2011; Johnston et al 2014). 
When expressed on effector T cells, TIGIT competes with costimulatory receptor cluster of 
differentiation (CD) 226 (CD226) for binding to its ligands (such as poliovirus receptor [PVR] 
and poliovirus receptor–related 2 [PVRL2]) and reduces cytokine production, T-cell 
proliferation, and cytotoxicity (Bottino et al 2003; Stanietsky et al 2009). A similar phenomenon 
was also observed in NK cells of cancer patients. In addition, regulatory T cells (Tregs) 
expressing TIGIT demonstrated greater immunosuppressive functions compared with 
TIGIT-negative Tregs (Joller et al 2014). Some studies have also shown that the interaction 
between TIGIT and PVR suppresses immune responses mediated by dendritic cells (DCs), 
especially in the inhibition of type I interferon and IL-12 production and promotion of 
anti-inflammatory cytokine interleukin (IL) 10 (IL-10) (Yu et al 2009). 
Up-regulation of TIGIT expression on tumor-infiltrating lymphocytes (TILs) has been reported 
in many types of cancers, such as lung (Tassi et al 2017), stomach (He et al 2017), breast (Gil 
Del Alcazar et al 2017), esophageal (Xie et al 2016), brain (Hung et al 2018), acute myeloid 
leukemia (Kong et al 2016), and melanoma (Mahnke and Enk 2016). A higher TIGIT/CD226 
ratio was associated with poor prognosis in melanoma patients treated with anti-PD-1 and/or 
anticytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibodies (Fourcade et al 
2018). 
Refer to the most recent edition of the Ociperlimab Investigator’s Brochure for additional 
background on ociperlimab. 
1.1. Background Information on Ociperlimab 
Refer to the Ociperlimab Investigator’s Brochure for additional background on Ociperlimab.  
1.1.1 Pharmacology 
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 (SPR) characterization. In in vitro cell-based assays, ociperlimab 
consistently and dose-dependently enhances the functional activities of activated human 
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peripheral blood mononuclear cells (PBMCs). In the MC-38 mouse colon cancer model in 
TIGIT-humanized mice, ociperlimab in combination with anti–mouse PD-1 enhanced inhibition 
of tumor growth compared with either monotherapy.  
Refer to the Ociperlimab Investigator’s Brochure for detailed information regarding 
pharmacology studies. 
1.1.2. Toxicology 
The safety profile of ociperlimab was characterized in a 4-week repeat-dose toxicity study in 
humanized TIGIT knock-in mice and in a 13-week repeat-dose toxicity study in cynomolgus 
monkeys. Overall, no apparent toxicity was observed in the 13-week cynomolgus monkey or in 
the 4-week humanized TIGIT knock-in mouse studies. A dose-proportional increase in systemic 
exposure (AUC and Cmax) was noted in both species without apparent sex difference while 
excluding the impact of positive antidrug antibodies (ADAs) in individual animals with lower 
systemic exposure and/or faster clearance. No accumulation was observed in monkeys after 
once-every-2-week dosing for 13 weeks, but a trend of accumulation was shown in mice after 
weekly dosing for 4 weeks. The no-observed-adverse-effect level (NOAEL) of ociperlimab was 
50 mg/kg in mice and 100 mg/kg in monkeys, which were the tested high doses in both species. 
No specific tissue cross-reactivity was detected in normal human tissues.  
Refer to the Ociperlimab Investigator’s Brochure for detailed information regarding toxicology 
studies. 
1.1.3. Clinical Pharmacology 
Preliminary pharmacokinetics (PK) data are available from 52 patients in the Phase 1 (dose 
escalation and dose verification in China) portion of Study AdvanTIG-105. Ociperlimab 
exposures (AUC and Cmax) increased approximately dose proportionally from the 50 mg to the 
1800 mg dose. Across dose groups, serum concentrations of ociperlimab decreased in a 
biexponential manner after administration. The geometric mean terminal half-life estimate 
following the first dose ranged from approximately 7 days to 11 days. Postdose PK sampling 
duration may not be sufficient for robust characterization of elimination half-life using 
noncompartmental analysis (NCA); hence, the reported half-life values should be interpreted 
with caution.  
Peripheral TIGIT receptor occupancy data were available for 32 enrolled patients treated with 
ociperlimab at 50, 150, 450, 900, and 1800 mg dose levels in Study AdvanTIG-105. Complete 
TIGIT receptor occupancy (100%) was observed on CD8+ T cells, CD4+ T cells, and regulatory T 
cells in peripheral blood at all tested dose levels. 
Refer to the Ociperlimab Investigator’s Brochure for detailed information on ociperlimab clinical 
pharmacokinetics and pharmacodynamics. 
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1.1.4. Prior Clinical Experience With Ociperlimab 
1.1.4.1.  Safety Assessment of Ociperlimab monotherapy or in combination with 
tislelizumab 
As of July 2022, preliminary safety data are available from 4 studies (AdvanTIG-105, 
AdvanTIG-202, AdvanTIG-204, and AdvanTIG-206). Study AdvanTIG-105 is a Phase 1/1b 
study investigating the safety, tolerability, PK, and preliminary antitumor activity of the 
anti-TIGIT monoclonal antibody ociperlimab in combination with the anti-PD-1 monoclonal 
antibody tislelizumab with or without chemotherapy in patients with unresectable locally 
advanced or metastatic solid tumors. Study AdvanTIG-202 is a Phase 2 study investigating the 
efficacy and safety of tislelizumab with or without ociperlimab in patients with previously 
treated recurrent or metastatic cervical cancer. Study AdvanTIG-204 is a Phase 2 study 
investigating the preliminary efficacy and safety of ociperlimab plus tislelizumab plus concurrent 
chemoradiotherapy in patients with untreated limited-stage small cell lung cancer. A total of 126 
patients were enrolled in the study across 30 to 40 centers globally. Study AdvanTIG-206 is a 
Phase 2 study investigating the efficacy and safety of tislelizumab in combination with 
ociperlimab plus BAT1706 (a bevacizumab biosimilar, a vascular endothelial growth factor 
[VEGF] inhibitor) and of tislelizumab plus BAT1706 as first-line treatment in patients with 
advanced hepatocellular carcinoma. A total of 94 patients were enrolled in mainland China/ 
Taiwan. 
As of July 2022, a total of 592 patients had been treated with ociperlimab as monotherapy, in 
combination with tislelizumab only, in combination with tislelizumab plus chemotherapy, in 
combination with tislelizumab plus concurrent chemoradiotherapy, or in combination with 
tislelizumab plus BAT1706 across a variety of tumor types. 
Ociperlimab was well tolerated. A pooled analysis of monotherapy and combination therapies 
conducted to provide a comprehensive safety assessment showed that AEs were generally 
reversible and manageable. Of 592 patients in the pooled analysis, 65 patients (11.0%) reported 
≥ Grade 3 treatment-emergent adverse events assessed as related to ociperlimab, and 59 patients 
(10.0%) reported AEs leading to discontinuation of ociperlimab. Furthermore, 35 patients (5.9%) 
experienced a TEAE that led to death, and 5 (0.8%) of them were assessed as related to 
ociperlimab. Dose-limiting toxicities (DLTs) were assessed in the dose escalation and dose 
verification parts of AdvanTIG-105 and AdvanTIG-206, and no TEAEs were considered to be a 
DLT.   
Please refer to the Ociperlimab Investigator’s Brochure for detailed safety information. 
1.1.4.2.  Efficacy Assessment of Tislelizumab in Combination With Ociperlimab  
The ociperlimab dose of 900 mg once every 3 weeks combined with tislelizumab 200 mg once 
every 3 weeks was selected as the recommended Phase 2 dose (RP2D) for further investigation 
based on data from the ongoing Phase 1/1b Study AdvanTIG-105.  
Please refer to the Ociperlimab Investigator’s Brochure for detailed efficacy information.  
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1.2.  Ociperlimab Rationales 
1.2.1.  Rationale for Tislelizumab in Combination With Ociperlimab in the Treatment of 
Patients With Resectable Non-Small Cell Lung Cancer 
Upregulation of TIGIT expression in TILs has been reported in NSCLC (Tassi et al 2017). 
Blockade of TIGIT receptor alone or in combination with PD-1/PD-L1 blockade has been shown 
to rescue functionally “exhausted” T cells both in vitro and in vivo (Johnston et al 2014, Chauvin 
et al 2015). In mouse models, TIGIT blockade in combination with anti-PD-1/PD-L1 antibodies 
demonstrated significantly better antitumor efficacy than either monotherapy (Johnston et al 
2014, Dixon et al 2018).  
Clinically, treatment with anti-TIGIT antibody in combination with anti-PD-L1 therapy has the 
potential to be more efficacious than anti-PD-L1 therapy alone in metastatic NSCLC without 
prior checkpoint inhibitor therapy. Improvements in both overall response rate (ORR) and 
median PFS were reported with tiragolumab plus atezolizumab compared to placebo plus 
atezolizumab (ORR: 37.31% versus 20.6%; and median PFS: 5.6 months versus 3.9 months) in 
the first-line treatment of patients with Stage IV NSCLC with a PD-L1 tumor proportion score 
≥ 1% (Rodriguez-Abreu et al 2020). Similarly, the combination of vibostolimab, an anti-TIGIT 
antibody, and pembrolizumab showed unconfirmed and confirmed ORR of 29% and 24%, 
respectively, in patients who were untreated or had been treated with ≥ 1 line of 
platinum-containing chemotherapy who had not previously received anti-PD-(L)1 therapy (Ahn 
et al 2020, Niu et al 2020). 
The safety profiles of both the combinations of tiragolumab plus atezolizumab and vibostolimab 
plus pembrolizumab were found to be tolerable. The rate of imAEs with tiragolumab plus 
atezolizumab was higher than that with placebo plus atezolizumab (69% versus 47%), but most 
of the imAEs were manageable Grade 1 or 2 events of infusion-related reaction, including rash. 
The rate of treatment-related AEs of any grade with vibostolimab plus pembrolizumab was 
slightly higher than that with vibostolimab monotherapy (71% versus 59%); however, the 
≥ Grade 3 treatment-related AE rates were similar between the 2 arms (13% versus 15%), 
indicating that most of the treatment-related AEs in the combination arm were Grade 1 or 2 in 
severity (Ahn et al 2020, Niu et al 2020, Rodriguez-Abreu et al 2020).  
Study BGB-900-105 showed that the preliminary safety of ociperlimab plus tislelizumab was 
consistent with that of other anti-TIGIT plus anti-PD-L1 treatment combinations, with no 
maximum tolerated dose (MTD) reached and no DLT occurring during the treatment period at 
any dose level (Tislelizumab Investigator’s Brochure). Ociperlimab plus tislelizumab appeared 
to be well tolerated at all the administered doses. 
Ociperlimab plus tislelizumab is expected to be tolerable. Ociperlimab and tislelizumab have 
nonoverlapping anticancer mechanisms and are likely to have synergistic and/or added activity. 
Adding ociperlimab to tislelizumab will likely further enhance the overall clinical activity of 
tislelizumab and bring long-term benefits for patients with resectable Stage II to IIIA NSCLC. 
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1.2.2.  Rationale for Selection of Ociperlimab Dose in Combination With Tislelizumab 
The ociperlimab dose of 900 mg once every 3 weeks combined with tislelizumab 200 mg once 
every 3 weeks was selected as the RP2D for further investigation based on clinical safety, 
tolerability, PK, and pharmacodynamic data from the ongoing Phase 1/1b Study AdvanTIG-105.  
Complete TIGIT receptor occupancy was observed in circulating T cells in peripheral blood at 
all the tested doses of ociperlimab in Study AdvanTIG-105. However, the correlation between 
TIGIT receptor occupancy in the periphery and in tumor tissues is unknown. In a previous 
Phase 1 study of tiragolumab, another anti-TIGIT antibody, complete peripheral receptor 
occupancy was reached at the 30 mg dose level, but the clinical dose of 600 mg was determined 
as the RP2D, which was 20 times the 30 mg dose (Bendell et al 2020). Similarly, although 
complete peripheral receptor occupancy was observed at the 50 mg dose level of ociperlimab, 
the 900 mg dose level is approximately 20-fold higher than the dose of 50 mg.  
As of May 2021, a total of 3 patients were assessed to have a confirmed partial response (PR), 
1 patient each in 450 mg, 900 mg, and 1800 mg cohorts. Ociperlimab exposure in all 3 patients 
with a PR was consistent with that expected at the 900 mg dose level. The confirmed disease 
control rate (DCR) observed in the 450 mg, 900 mg, and 1800 mg cohorts was 60%, 64.3%, and 
60%, respectively. 
Although the best overall response and DCR were numerically comparable at the 450 mg and 
900 mg dose levels, the 900 mg dose was chosen for the following reasons: 
• 900 mg was well tolerated in AdvanTIG-105 
• Exposure in all 3 patients with PR was consistent with that expected at the 900 mg 
dose 
• Lack of sufficient information on the impact of immunogenicity on ociperlimab PK 
• An overall intent to minimize exposure overlap with doses < 450 mg 
1.2.3.  Biomarker Strategy Rationale 
Cell-surface expression of TIGIT is mainly restricted to lymphocytes including effector CD4+ 
and CD8+ T, NK cells and Treg cells. Thus, ociperlimab may modulate phenotypes and 
antitumor activities of these immune cells synergistically in combination with tislelizumab. 
Moreover, as a Fc-competent TIGIT blocking antibody, ociperlimab may also elicit immune 
response through Fc-medicated mechanisms of action. 
Considering that in patients with cancer, TIGIT is highly expressed by Tregs in peripheral blood 
mononuclear cells and further upregulated in the tumor microenvironment (TME), compared 
with other immune populations (Chauvin and Zarour 2020), it is hypothesized that anti-TIGIT 
mAbs with Fc-binding capability may preferentially induce Treg depletion through 
antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cell-mediated 
phagocytosis (ADCP). Supportively, it was observed that the higher TIGIT expression in Tregs 
is correlated with their depletion with an hIgG1 format in PBMCs from patients with cancer, as 
well as in TILs from mice (Preillon et al 2021). In contrast, no killing of activated TIGIT+ CD8+ 
T cells was observed (Lopez et al 2019). Accordingly, the ADCC/ADCP–enabling format of the 
anti-TIGIT mAb had superior antitumor activity, which was dependent upon Fcγ receptor 
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engagement (Preillon et al 2021). Consistently, in mouse models, the observed antitumor 
efficacy of ociperlimab is Fc effector function dependent and associated with a 
pharmacodynamic change of Treg reduction (Chen et al 2022). 
Target molecules can be removed from the cell surface through the FcγR-binding induced 
endocytosis (trogocytosis), thus impacting mAb-based therapies. Through co-culturing purified 
human T cells with FcγR+ monocytes or DCs, only ociperlimab with competent Fc, rather than 
the Fc mutant version, induced the trogocytosis of surface TIGIT. Besides, it was also observed 
in mouse models that ociperlimab treatment decreased the overall TIGIT expression on 
intra-tumoral T cells and NK cells, suggesting that FcγR trogocytosis may occur in vivo and 
contribute to the surface removal of TIGIT molecules (Chen et al 2022). 
Fc-FcγR interaction may modulate FcγR+ myeloid cells to create a proinflammatory tumor 
microenvironment (Dahan et al 2015). Supportively, ociperlimab treatment significantly 
increased the expression of CD86, a co-stimulatory ligand typically found on the surface of 
antigen-presenting cells (APC) and up-regulated during APC activation, while Fc mutant version 
showed no effect, suggesting TIGIT mAbs can induce an activation of APC via FcγRs (Chen et 
al 2022). 
Therefore, it is valuable to determine whether ociperlimab can induce Fc-mediated mechanisms 
including intratumoral Treg depletion, TIGIT downregulation and APC modulation in patients 
with cancer, as well as its association with clinical outcomes to facilitate drug development and 
identification of patients who are most likely to benefit from the therapeutic drugs.  
1.3.  Benefit-Risk Assessment of Tislelizumab in Combination With Ociperlimab 
There is extensive evidence supporting TIGIT’s role in regulating immune response. In addition, 
the interaction between the TIGIT and PD-1 pathways has been shown to promote tumor 
immune escape. The clinical efficacy demonstrated with tislelizumab and preliminary results 
from 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-naive 
setting. 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 those observed with tislelizumab 
alone. Preliminary data with ociperlimab plus tislelizumab showed that the combination was 
tolerated in patients with advanced solid tumors. The types and severity of AEs observed were 
also consistent with those observed with tislelizumab monotherapy. No DLTs were observed at 
dose levels from 50 mg to 1800 mg in dose escalation in combination with tislelizumab 200 mg 
(Study BGB-900-105).  
The risk of observing augmented safety signals, as has been shown for other anti-PD-1-based 
immuno-oncology combinations, still remains; therefore, a monitoring plan derived from the 
European Society for Medical Oncology and American Society for Clinical Oncology has been 
established to monitor, diagnose, and manage imAEs (Appendix 7). It is important to note that 
peripheral effector T cells typically do not express TIGIT, which is in contrast to TILs, 
stimulated by the antigens in the tumor microenvironment. Therefore, the combination of 
anti-TIGIT and anti-PD-L1 therapies provide an opportunity to specifically augment the activity 
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of effector T cells in the tumor rather than in the periphery and/or nontumor tissue (Johnston et al 
2014), from which the increased systemic toxicity should be limited. 
In summary, there is a strong scientific rationale that the combined blockade of the TIGIT 
pathway and PD-1 pathway may result in enhanced antitumor activity without a major increase 
in the risk of immune-mediated toxicities. The benefit-risk assessment for tislelizumab in 
combination with ociperlimab arm (Arm 1B), based on available data, is considered favorable. 
2.  STUDY TREATMENT – TISLELIZUMAB IN COMBINATION WITH 
OCIPERLIMAB 
2.1. Formulation, Packaging, Labeling, and Handling 
Ociperlimab is a monoclonal antibody formulated for intravenous infusion in a single-use vial 
(20 mL glass vial, United States Pharmacopeia [USP] Type I) containing a total of 300 mg 
antibody in 15 mL of buffered isotonic solution. 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 conditions 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 Investigator’s Brochure for other details regarding 
ociperlimab. 
2.2.  Dosage, Administration, and Compliance 
An overview on dosing schedules for the treatment Arm 1B is provided in §Table 1. The first 
dose of the study drugs is to be administered ≤ 2 days after randomization. All patients will be 
monitored continuously for AEs. Treatment modification (ie, dose delay or interruption) or 
discontinuation will be based on specific laboratory and AE criteria, as described in §Section 2.4. 
During the neoadjuvant phase, for each cycle, study drug administration in Arm 1B will follow 
this order: tislelizumab and then ociperlimab. Refer to §Section 2.2.1 for details on monitoring 
time.  
§Table 1: Selection and Timing of Neoadjuvant Dose in Arm 1B 
Treatment 
arm 
Study drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Duration of 
treatment 
Arm 1B 
Tislelizumab 
200 mg 
Day 1 of each 3-week 
cycle  
Intravenously  
  
2 to 4 Cycles 
Ociperlimab 
900 mg 
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2.2.1.  Tislelizumab and Ociperlimab Treatment Administration 
Ociperlimab and tislelizumab will be administered according to the dosing schedule provided in 
§Table 1. The assigned study drugs will be administered by intravenous infusion through an 
intravenous line containing a sterile, nonpyrogenic, low-protein-binding 0.2 or 0.22 μm in-line or 
add-on filter. Specific instructions for product preparation, storage, and administration are 
provided in the pharmacy manual. 
The delivery period of the initial tislelizumab and ociperlimab infusion for each study drug (Day 
1 of Cycle 1 and Cycle 2) will be over 60 minutes (± 5 minutes); if this is well tolerated, then the 
delivery period of subsequent infusions for each study drug may be shortened to over 30 minutes 
(± 5 minutes), which is the shortest time period permissible for infusion. Ociperlimab and 
tislelizumab must not be concurrently administered with any other drug (refer to §Section 3). 
Use of a volumetric pump is recommended to control the infusion speed and to avoid potential 
infusion reactions associated with fast administration. The pump may not be needed if the 
infusion speed is controlled through alternative means and is consistent with approved 
institutional procedures. 
At the end of each study drug infusion period, the line will be flushed with enough normal saline 
to make sure the complete doses of the study drugs are administered. 
As a routine precaution, after completion of study treatment on Day 1 of Cycle 1 and Cycle 2, 
patients must be monitored ≥ 120 minutes and ≥ 60 minutes from Cycle 3 afterward in an area 
with resuscitation equipment and emergency agents.  
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
§Section 2.4. Details for the management of imAEs, infusion-related reactions, and anaphylaxis 
reactions are provided in detail in Section 8.7 and Appendix 7. 
§Table 2: Administration of Tislelizumab and Ociperlimab and Monitoring Time 
Cycle 
Tislelizumab and Ociperlimab Combination 
Cycle 1-2 Day 1 
 
Tislelizumab infusion ≥ 60 minutes followed by ociperlimab infusion 
≥ 60 minutes 
Patient monitoring for ≥ 120 minutes after the last infusion 
Cycle 3 Day 1 
onwards 
 
If well tolerated, tislelizumab infusion ≥ 30 minutes followed by ociperlimab 
infusion ≥ 30 minutes 
Patient monitoring for ≥ 60 minutes after the last infusion 
Note: The infusion rate of tislelizumab or ociperlimab may be decreased or the infusion may be stopped in the event 
of an infusion-related reaction.  
2.3.  Overdose 
An overdose is defined as ≥ 600 mg of tislelizumab in a 24-hour period and as ≥ 1800 mg of 
ociperlimab in a 24-hour period. Any overdose or incorrect administration of study drug should 
be noted in the patient’s source documents and in the appropriate eCRF.  
 
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2.4.  Dose Modification for Ociperlimab and Tislelizumab 
Dose modification for ociperlimab is defined as any of the following: dose delay, dose 
interruption, and infusion rate decrease. A dose delay is a deviation from the prescribed dosing 
schedule (ie, the drug is withheld beyond the visit window). A dose interruption is an 
interruption of an infusion. An infusion rate decrease is a decrease of infusion rate. There will be 
no dose reduction for ociperlimab in this study. 
The dose modification guidelines in this section are not intended to be a substitute for clinical 
judgment. Investigators may delay doses for other reasons (eg, AEs or laboratory findings) as 
appropriate. 
If a dose delay is required, both ociperlimab and tislelizumab are to be delayed (ie, ociperlimab 
and tislelizumab must both be delayed and if applicable restarted at the same time). Exceptions 
may be considered following consultation between the investigator and the medical monitor. 
If study treatment is delayed due to TEAEs, study treatment may resume only after the AEs have 
returned to baseline or ≤ Grade 1 severity except for alopecia or AEs that, in the opinion of the 
investigator, are not considered a safety risk to the patient. If a treatment delay is due to 
worsening of laboratory results, eg, hematologic or biochemical parameters, the frequency of 
relevant blood tests should be increased, as clinically indicated. When several toxicities with 
different grades of severity occur at the same time, the dose modifications should be according to 
the highest grade observed. 
In general, dose delays for reasons other than management of AEs are prohibited. Total duration 
of dose delay (ie, the delay duration from first dose of study treatment to actual last dose 
compared with prescribed dosing schedule) of ≤ 3 weeks is allowed under the following 
guidance and at the discretion of the investigator. Study treatment should resume as soon as 
possible after the adverse events recover to baseline or Grade 1 (whichever is more severe) if the 
total delay duration is not more than 3 weeks.  
If the patient is unable to resume study treatment ≤ 3 weeks of total delay duration, then the 
patient should be discontinued from treatment. If the patient is not able to resume study treatment 
≤ 3 weeks of total delay duration for unforeseen non-drug-related reasons, continued treatment 
may be allowed after consolation and approval by the medical monitor  
If a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with the medical 
monitor. Specific treatment modifications to manage treatment-related toxicities, such as imAEs, 
infusion-related reactions, and anaphylaxis reactions, are described in Section 8.7 and 
Appendix 7. 
3.  PRIOR AND CONCOMITANT THERAPY – OCIPERLIMAB 
3.1.  Potential Interactions Between the Study Drugs and Concomitant Medications- 
OCIPERLIMAB 
The potential for drug-drug interactions between ociperlimab, standard chemotherapy, and 
small-molecule drug products is very low given that the ociperlimab is therapeutic monoclonal 
antibody. Ociperlimab is unlikely to have an effect on drug-metabolizing enzymes or 
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transporters because it is expected to be degraded into amino acids and recycled into other 
proteins. Based on the mechanism of action, any therapeutic protein drug-drug interaction is not 
expected between the investigational agents. 
4.  SAFETY MONITORING AND REPORTING – OCIPERLIMAB 
4.1.  Risks Associated With Ociperlimab 
Ociperlimab is investigational agent that is 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 
published data on other molecules within the same biologic class. 
Ociperlimab-mediated TIGIT inhibition may increase the risk of imAEs. However, no apparent 
immunotoxicity, or toxicity in general, has 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. An imAE may occur at any time during or after treatment. Often, the 
etiology of imAEs is not clear, and other causes should be ruled out. This may require diagnostic 
testing and consultation with a specialist. Suggested evaluation and management guidelines for 
suspected imAEs are provided in Appendix 7. 
Refer to the Ociperlimab Investigator’s Brochure for additional details. 
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APPENDIX 13. LBL-007  
1. Introduction of LBL-007 
LBL-007 is a fully human anti-lymphocyte activation gene-3 (LAG-3) monoclonal 
immunoglobulin (Ig) G4/κ isotype antibody codeveloped by Nanjing Leads Biolabs Co., Ltd. 
and BeiGene, Ltd. for the treatment of advanced solid tumors. Refer to the LBL-007 
Investigator’s Brochure for additional information.  
1.1.  Lymphocyte Activation Gene-3 
Lymphocyte Activation Gene-3 (LAG-3 or CD223) is an immune checkpoint protein 
predominantly expressed on the surface of activated T cells (Huard et al 1995), and natural killer 
(NK) cells (Triebel et al 1990). LAG-3 expression has also been reported in B cells (Kisielow et 
al 2005) and plasmacytoid dendritic cells (pDCs) (Workman et al 2009). The main ligand for 
LAG-3 is the major histocompatibility complex (MHC) Class II protein (Huard et al 1995), and 
engagement of LAG-3 by MHC II ligand leads to a state of T cell exhaustion, characterized by 
the attenuation of T-cell activation, inability to proliferate in response to antigen and reduced 
cytokine production (Huang et al 2004, Workman and Vignali 2003, Workman et al 2004). Liver 
sinusoidal endothelial cell lectin (LSECtin) (Xu et al 2014), galectin 3 (Kouo et al 2015), and 
fibrinogen-like protein 1 (FGL1) (Wang et al 2019) are other immune-inhibitory ligands that 
have been identified to interact with LAG-3 and mediate its inhibitory function in T cells. 
Consistent with its inhibitory function, LAG-3 expression is high in chronically exhausted or 
dysfunctional T cells in cancer, particularly in tumor infiltrated T cells (Matsuzaki et al 2010). In 
addition, LAG-3 is also expressed on regulatory T (Treg) cells and LAG-3+ Treg cells are highly 
suppressive compared to their LAG-3- counterparts (Camisaschi et al 2010, Huang et al 2004). A 
LAG-3 blockade has been shown to promote T cell proliferation and enhance cytotoxic T cells 
functions (Lichtenegger et al 2018). LAG-3 inhibition can also reduce the immunosuppressive 
activity of LAG-3+ Treg cells, resulting in enhanced activation of effector T cells (Huang et al 
2004).  
LAG-3 is frequently coexpressed with programmed cell death protein-1 (PD-1) on 
tumor-infiltrating T cells, LAG-3 and PD-1 double positive T cells are in a more severe 
dysfunctional state than T cells expressing either PD-1 or LAG-3 alone. Moreover, LAG-3 
expression is upregulated following anti-PD-1 treatment, and the frequency of LAG-3+ T cells is 
significantly upregulated in several solid tumors that are inherently resistant or that become 
refractory to PD-1 blockade including, non-small cell lung cancer (NSCLC), head and neck 
squamous cell carcinoma (HNSCC), melanoma, and bladder cancer (Datar et al 2019, Gettinger 
et al 2017, Hanna et al 2018, Johnson et al 2018, Kates et al 2021). Preclinical studies in mouse 
models have shown that a co-blockade of PD-1 and LAG-3 restores the function of exhausted 
T cells and synergizes to inhibit tumor growth by enhancing antitumor immunity (Mimura et al 
2021, Yang et al 2017, Ghosh et al 2019). Those results suggest that the combination of 
anti-LAG-3 and anti-PD-1 could further improve the clinical outcome of anti-PD-1, and the 
combination therapy may provide clinical benefit for those patients who are resistant to 
anti-PD-1 therapy. Indeed, the combination has been proven to be effective in clinic, in patients 
with previously untreated metastatic or unresectable melanoma in whom a combination of LAG-
3 and PD-1 inhibition provided greater benefit than PD-1 blockade alone (Tawbi et al 2022). 
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1.2.  Background Information on LBL-007 
1.2.1.  Pharmacology 
LBL-007 binds to the human LAG-3 extracellular domain with high specificity and affinity 
(KD = 4.39 x 10-10 M). LBL-007 effectively blocks the binding of LAG-3 to MHC II molecules, 
and thereby activates the immune system. An in vitro binding assay showed that LBL-007 also 
blocks the binding of LAG-3 with other ligands, including FGL-1, LSECtin, and galectin-3. In 
addition, in vivo studies in human LAG-3 knock-in mice showed LBL-007 significantly 
inhibiting the tumor growth used alone or in combination with an anti-PD-1 monoclonal 
antibody.  
In vitro studies showed that LBL-007 did not bind to either FcγRIIIA or C1q, indicating weak or 
no antibody-dependent cell-mediated cytotoxicity (ADCC) or CDC effect in humans. 
Additionally, in vitro experiments showed that LBL-007 with an S228P modification in the 
hinge region was more stable than wild-type LBL-007, and did not exchange Fab arms with a 
wild-type human IgG4 antibody. Therefore, it was predicted that the LBL-007 antibody would 
be stable in vivo. 
1.2.2.  Toxicology 
Cynomolgus monkey is considered to be the relevant species for nonclinical safety evaluation 
because it is the pharmacologically relevant species based on sequence homology of LAG-3 and 
binding affinity activity, and it is a commonly used species for biologic products with a 
substantial historical toxicology database. 
The nonclinical toxicity and toxicokinetic profile of LBL-007 was characterized in a single dose 
study in cynomolgus monkeys and in repeat-dose studies in rats and cynomolgus monkeys dosed 
weekly. These toxicity studies were conducted following Good Laboratory Practice regulations. 
At the single dose of 150 or 300 mg/kg (3 animals per group), the maximum tolerated dose 
(MTD) was 300 mg/kg; no mortality or moribundity was observed in cynomolgus monkeys. 
In the 3-week repeat dose study in rats, no LBL-007-related abnormal changes were observed in 
body weight, food consumption, ophthalmological examination, urinalysis, lymphocyte subsets, 
complement counts, or immunoglobulin counts (IgA, IgG, IgM, IgE) following intravenous 
infusion of LBL-007 at 20 mg/kg, 60 mg/kg, and 150 mg/kg once a week for 3 consecutive 
weeks (4 doses). Other abnormalities in hematology and blood chemistry recovered after 
4 weeks of dose interruption. The weight coefficient of the liver was increased in female rats in 
the 150 mg/kg group, and slight to mild hepatocellular necrosis or inflammatory cell infiltration 
was observed in the histopathological examination. Considering the lack of binding activity of 
LBL-007 to the LAG-3 in rats, the effects of LBL-007 on the liver were considered to be mostly 
likely off-target toxicities. Given that in vitro data indicated that cellular and tissue binding with 
LBL-007 was highly specific to monkey and human, and the absence of LBL-007 
pharmacological activity in the rats, the findings in the 3-week repeat-dose study are of uncertain 
clinical relevance.  
The 4-week repeat dose study in cynomolgus monkeys indicated that LBL-007 was well 
tolerated. Five consecutive weekly doses of LBL-007 at 10, 30, and 100 mg/kg in monkeys 
between 3 to 5 years old were not associated with any adverse effects. The no-observed-adverse-
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effect-level (NOAEL) was 100 mg/kg. LAG-3 receptor occupancy (RO) was increased in female 
and male cynomolgus monkeys at 1 to 2, 24 to 25, and 168 to 169 hours after the first dose as 
well as at 24 to 25 and 168 to 169 hours after the last dose. No significant dosage-related 
increase of LAG-3 RO was observed at all dose levels. At the dose levels of 10, 30, and 100 
mg/kg, after the first dose, the increased exposure of LBL-007 in the serum of monkeys in each 
LBL-007 group was correlated with the increase of the infusion dose. No sex differences in 
exposure were observed. After 5 consecutive doses, the accumulation factors of LBL-007 ranged 
from 2.02 to 0.61, indicating a slight accumulation. 
The in vitro studies to assess hemolytic potential were conducted in erythrocytes from Japanese 
white rabbits. There was no evidence of hemolysis or agglutination observed in vitro in rabbit 
erythrocytes with LBL-007 at a concentration of 5 mg/mL. 
The tissue cross-reactivity of LBL-007 was evaluated in healthy cynomolgus monkeys and 
healthy human frozen tissues using immunohistochemistry. LBL-007 specifically bound to 
human tissues of colon, ileum, pituitary gland, skeletal muscle, testis, lymph nodes, duodenum, 
and parathyroid gland, while LBL-007 specifically bound to cynomolgus monkey tissue of the 
cerebellum. 
The in vitro cytokine release study indicated that LBL-007 did not evoke cytokine release in 
human peripheral blood mononuclear cells. 
1.2.3.  Clinical Pharmacology 
Study WLZB-LBL-007-AST-001: 
LBL-007 exhibited dose-dependent increase in exposure over the dose range of 3.0 mg/kg to 
10 mg/kg after single intravenous infusion.  The time to peak concentration ranged from 1 to 
9 hours, and the mean elimination half-life ranged from 182 to 196 hours in the dose range of 
3 mg/kg to 10 mg/kg.  LBL-007 exhibited non-linear pharmacokinetics (PK) between the 
0.05 mg/kg and 1 mg/kg dose levels and linear PK between 3 mg/kg and 10 mg/kg.  
The PK characteristics of LBL-007 after multiple dose administration once every 2 weeks were 
similar to those of a single dose.  There was no significant accumulation in exposure of LBL-007 
in the lower dose groups (0.05 to 3 mg/kg once every 2 weeks). Little accumulation was 
observed in higher doses groups (6 and 10 mg/kg once every 2 weeks). 
Study LBL-007-CN-002: 
After a single intravenous infusion of 0.25 mg/kg, 1 mg/kg, 3 mg/kg, or 6 mg/kg LBL-007 in 
combination with toripalimab (3 mg/kg), the mean time to maximum LBL-007 concentration 
ranged from 1.0 to 2.0 hours; t1/2 was 43.63, 108.40, 165.89, and 192.30 hours, respectively, with 
a dose-dependent trend; the mean Cmax values were 3.350, 9.927, 36.707, and 73.050 μg/mL, 
respectively; the mean AUC0-336 values were 266.264, 1486.522, 5011.602, and 
11175.155 h•μg/mL, respectively. The exposure parameter Cmax increased dose proportionally, 
while AUC0-336 increased slightly more compared with the increase of dosage. Mean changes in 
Vss ranged from 4.785 to 6.829 L, and mean changes in CL ranged from 0.024 to 0.074 L/h, 
indicating that the drug was mainly distributed in plasma. 
The PK profile of LBL-007 after multiple doses was similar to that after a single dose. 
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The accumulation ratios for Cmax and AUC after multiple doses of LBL-007 ranged from 1.018 
to 1.553 and 1.019 to 1.543, respectively, suggesting a slight accumulation of LBL-007 in vivo. 
1.2.4.  Prior Clinical Experience With LBL-007 
As of 15 February 2023, the following 5 clinical studies (sponsored by Nanjing Leads Biolabs 
Co., Ltd.) have been conducted with LBL-007.  
Study WLZB-LBL-007-AST-001: 
Study WLZB-LBL-007-AST-001 is a recently completed single-arm Phase 1 dose-escalation 
study to evaluate the safety and tolerability of LBL-007 in patients with advanced solid tumors 
including lymphoma, and to explore MTD and dose-limiting toxicities (DLTs). The study had 
been completed with the last patient’s last visit on 28 December 2021. As of 15 January 2022, a 
total of 22 patients were enrolled and received once LBL-007 every 2 weeks at 0.05 mg/kg (n = 
2), 0.25 mg/kg (n = 4), 1 mg/kg (n = 3), 3 mg/kg (n = 3), 6 mg/kg (n = 3), or 10 mg/kg (n = 7); of 
these, 20 patients completed the DLT assessments.  
Preliminary safety results showed that the doses were well tolerated with no DLTs in any dose 
group. MTD was not reached with the maximum-administrated dose of 10 mg/kg in this study. 
Of the 22 patients, 21 (95.5%) experienced a total of 224 treatment-emergent adverse events 
(TEAEs); and TEAEs that occurred in ≥ 10% of the patients were anemia (59.1%); 
hyperglycemia (27.3%); neutrophil count increased, hypocalcemia, upper respiratory tract 
infection, hyponatremia, and pyrexia (22.7% each); gamma-glutamyltransferase increased 
(18.2%), white blood cell count increased (18.2%); and weight decreased, platelet count 
decreased, hypoalbuminemia, hypercalcemia, decreased appetite, asthenia, and sinus tachycardia 
(13.6% each). 
Two patients (9.1%) had TEAEs leading to permanent discontinuation of study treatment, 
including hypocalcemia (0.25 mg/kg dose group, possibly related to study drug) and 
gastrointestinal hemorrhage (3 mg/kg dose group, unlikely related to study drug) each in 
1 patient, with the outcomes of ongoing and unknown, respectively. No TEAEs leading to death 
were reported for either. 
During the treatment period, 8 patients (36.4%) experienced 13 serious adverse events (SAEs). 
Of them, 9 SAEs that occurred in 5 patients (22.7%) were considered to be related to the study 
drug. The 9 SAEs occurred in 1 patient each with an incidence of 4.5% each and included upper 
gastrointestinal hemorrhage (Grade 2, resolved without sequelae), gastrointestinal hemorrhage 
(Grade 3, ongoing), hypoalbuminemia (Grade 2, resolving to Grade 1), hypocalcemia (Grade 4, 
outcome unknown), bronchitis and bronchiectasis (reported by the investigator as one AE term, 
Grade 3, ongoing), deep vein thrombosis (Grade 3, outcome other: resolving to Grade 2), and 
anemia (2 events of Grade 3, resolving to Grade 2 and Grade 1, respectively; 1 event of Grade 2, 
upgraded to Grade 3). The remaining 4 SAEs were considered not to be related to the study drug. 
The events included enteritis (Grade 2, resolved without sequelae), abdominal pain upper (Grade 
3, ongoing), hyponatremia (Grade 3, outcome other: downgraded), and blindness unilateral 
(Grade 3, outcome unknown), and all occurred in 1 patient with an incidence of 4.5%. 
Efficacy results showed that of the 18 evaluable patients (2 patients in the 0.05 mg/kg group, 
1 patient in the 0.25 mg/kg group, 3 patients in the 1 mg/kg group, 3 patients in the 3 mg/kg 
group, 3 patients in the 6 mg/kg group, and 6 patients in the 10 mg/kg group), the objective 
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response rate (ORR) was 5.6% (1 patient with esophageal cancer in the 10 mg/kg group had 
partial response [PR]) and the disease control rate (DCR) was 55.6% (1 patient of PR and 9 
patients of stable disease [SD]).  
Study LBL-007-CN-002:  
Study LBL-007-CN-002 is an ongoing single-arm, multicenter Phase 1 dose-escalation and 
dose-expansion study to evaluate the safety, tolerability, and preliminary efficacy of LBL-007 
plus toripalimab or LBL-007 in combination with toripalimab and axitinib (tyrosine kinase 
inhibitor) for the treatment of unresectable or metastatic melanoma.  
As of 11 January 2023, a total of 68 patients were enrolled and treated with LBL-007 at different 
doses (0.25, 1, 3, 6, and 10 mg/kg, once every 2 weeks) in combination with toripalimab 
(3 mg/kg, once every 2 weeks). Four patients were enrolled in the 0.25 mg/kg dose group, 
3 patients in the 1 mg/kg dose group, 16 patients in the 3 mg/kg dose group, 42 patients in the 
6 mg/kg dose group, and 3 patients in the 10 mg/kg dose group. Twenty patients completed the 
DLT assessment, and no DLT events were observed. 
Of the 68 patients, 66 patients (97.1%) experienced ≥ 1 treatment-emergent adverse event. 
Common TEAEs (incidence ≥ 10%) were aspartate aminotransferase increased (27.9%); blood 
lactate dehydrogenase increased (27.9%); anemia (26.5%); alanine aminotransferase increased 
and hypothyroidism (25.0% each); blood creatine phosphokinase increased (20.6%); blood 
glucose increased, hypokalemia, hyperthyroidism, and COVID-19 (19.1% each); blood 
triglycerides increased (17.6%); blood bilirubin increased and asthenia (14.7% each); blood 
cholesterol increased (13.2%); pyrexia (11.8%); and white blood cell count decreased, bilirubin 
conjugated increased, decreased appetite, nausea, and cough (10.3% each). Most of the events 
were Grade 1 or 2. 
The incidences of TEAEs leading to dose delay and permanent discontinuation were 26.5% and 
2.9%, respectively. 
Nine SAEs were reported in 6 patients: obstructive jaundice (3.0 mg/kg, Grade 3, unlikely 
related), T2 bone destruction: melanoma metastasis (suspected; 3.0 mg/kg, Grade 3, definitely 
not related), hypopituitarism (0.25 mg/kg, Grade 3, possibly related), disease progression 
(6.0 mg/kg, Grade 5, unlikely related), nausea (3.0 mg/kg, Grade 2, unlikely related), vomiting 
(3.0 mg/kg, Grade 2, unlikely related), myocarditis (6.0 mg/kg, Grade 2, probably related), 
severe anemia (6.0 mg/kg, Grade 3, possibly related), and unknown death (3.0 mg/kg, Grade 5, 
to be evaluated). 
A total of 32 patients with melanoma were evaluable for response assessment: 21 had not 
received anti-PD-(L)-1 antibody therapy (abbreviated as immunotherapy-naive) and 11 had 
previously received prior anti-PD-(L)-1 antibody therapy (referred to as immunotherapy treated). 
Four patients achieved PR (3 with acral melanoma and 1 with skin non-acral melanoma; all were 
immunotherapy-naive patients); 13 patients achieved SD, including 11 immunotherapy-naive 
patients and 2 immunotherapy-treated patients (1 with mucosal melanoma and 1 with skin 
non-acral melanoma). 
As of 11 January 2023, 11 patients have been enrolled and treated with LBL-007 at 2 dose levels 
(3.0 mg/kg [n = 4] and 6.0 mg/kg [n = 7]) in combination with toripalimab (3 mg/kg, once every 
2 weeks) plus axitinib (5 mg, twice per day, oral). Ten patients (90.9%) experienced 
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≥ 1 treatment-emergent adverse event. Nine patients (81.8%) experienced LBL-007-related 
adverse events. Three patients (27.3%) had serious adverse events; 1 patient (9.1%) experienced 
LBL-007-related serious adverse events. Five patients (45.5%) experienced ≥ Grade 3 
treatment-emergent adverse events and none of the events were considered as related to 
LBL-007. imAEs occurred in 5 patients (45.5%) and none of the events of ≥ Grade 3 were 
considered as related to LBL-007. 
Study LBL-007-CN-003: 
Study LBL-007-CN-003 is an ongoing multicenter Phase 1b/2 clinical study to evaluate the 
safety, tolerability, and preliminary efficacy of LBL-007 in combination with toripalimab in the 
treatment of advanced malignancies, such as advanced esophageal squamous cell carcinoma 
(ESCC), HNSCC, cervical cancer, nasopharyngeal cancer, small cell lung cancer, and diffuse 
large B-cell lymphoma. 
As of 11 January 2023, a total of 80 patients received LBL-007 (200 or 400 mg, intravenously, 
once every 3 weeks) in combination with toripalimab (240 mg, once every 3 weeks). The 
tolerability evaluation for 400 mg was completed with no DLT events, and the MTD for this 
study was not reached with the maximum-administrated dose of 400 mg. A total of 12 TEAEs 
were reported in 7 patients, these AEs included pain in the left lower extremity and anemia 
(2 events each), and constipation, vomiting, oropharyngeal pain, rash, peripheral neuralgia, back 
pain, hyperuricemia, and lymphocyte count decreased (1 event for each term). There were no 
SAEs of any grade. Response assessment was performed in 4 patients, all of which were SD 
(2 patients with lung adenocarcinoma, 1 patient with nonkeratinizing pleomorphic 
nasopharyngeal carcinoma, and 1 patient with small cell lung cancer). 
Study LBL-007-CN-004: 
Study LBL-007-CN-004 is a multicenter, Phase 1b/2 study evaluating the safety, tolerability, and 
efficacy of LBL-007 in combination with tislelizumab in the treatment of ESCC, hepatocellular 
carcinoma (HCC), nasopharyngeal carcinoma, urothelial carcinoma, microsatellite 
instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors, HNSCC, and 
melanoma. 
As of 11 January 2023, 21 patients received LBL-007 (300 or 600mg, intravenously, once every 
3 weeks) in combination with tislelizumab (200 mg, intravenously, once every 3 weeks), 
including 10 patients in the LBL-007 dose group of 300 mg and 11 patients in the 600 mg dose 
group. All the 21 patients (100.0%) experienced treatment-emergent adverse events, 17 patients 
(80.95%) had LBL-007-related treatment-emergent adverse events, 4 patients (19.05%) 
experienced serious adverse events, and 2 patients (9.5%) had treatment-related serious adverse 
events. Three patients (14.29%) had ≥ Grade 3 treatment-emergent adverse events and 2 patients 
(9.52%) had ≥ Grade 3 treatment-emergent adverse events related to LBL-007. 
Treatment-emergent adverse events leading to dose hold of LBL-007 occurred in 12 patients 
(57.14%), and adverse event leading to dose hold of LBL-007 and related to LBL-007 occurred 
in 2 patients (9.52%). One patient (4.76%) experienced treatment-emergent adverse event 
leading to death. None of the patients experienced treatment-emergent adverse event leading to 
discontinuation of study drug. imAEs were reported in 6 patients (28.57%). None of the patients 
experienced infusion-related reactions. 
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Study BGB-900-102: 
Study BGB-900-102 is an open-label, multicenter, nonrandomized Phase 1/2 study evaluating 
various combinations of BGB-A425 (inhibitor of T-cell immunoglobulin and mucin-domain 
containing-3 [TIM-3]) and LBL-007 with tislelizumab in advanced solid tumors. This study will 
consist of 2 phases: Phase 1 dose escalation and Phase 2 with safety lead-in followed by dose 
expansion. LBL-007 will be initially evaluated in the safety lead-in portion of Phase 2 to confirm 
the recommended Phase 2 dose (RP2D) of LBL-007 when given in combination with 
tislelizumab or with tislelizumab plus BGB-A425, and then further evaluated in the 
dose expansion cohorts of the Phase 2 in various tumor types including HNSCC and NSCLC. 
As of 15 February 2023, 11 patients received treatment with LBL-007, including 5 patients who 
received LBL-007 in combination with tislelizumab (Safety Lead-in: LBL-007+A317), and 
6 patients who received LBL-007 in combination with tislelizumab and BGB-A425 (Safety 
Lead-in: LBL-007+A317+A425).  
In the Phase 2 (Safety Lead-in: LBL-007+A317) Cohort A, 5 patients received LBL-007 at 
2 dose levels of 300 mg (4 patients) or 600 mg (1 patient) in combination with 200 mg 
tislelizumab. All the 5 patients (100.0%) experienced ≥ 1 TEAE. Two patients (40.0%) had 
TEAEs that were assessed as related to the treatment. Three patients (60.0%) experienced 
≥ Grade 3 TEAEs; 1 patient (20.0%) had ≥ Grade 3 treatment-related TEAE. Three patients 
(60.0%) had serious TEAEs; 1 patient (20.0%) experienced serious treatment-related TEAEs. 
One patient (20.0%) experienced TEAE leading to treatment discontinuation and was considered 
as related to the treatment. None of the patients experienced fatal adverse events. 
In the Phase 2 (Safety Lead-in: LBL-007+A317+A425) Cohort B, 6 patients received LBL-007 
at 2 dose levels of 300 mg (3 patients) or 600 mg (3 patients) in combination with 200 mg 
tislelizumab and 600 mg BGB-A425. Five patients (83.3%) experienced ≥ 1 TEAE. Two patients 
(33.3%) had TEAEs that were assessed as related to the treatment. One patient (16.7%) 
experienced ≥ Grade 3 TEAEs; none of the events were considered as related to the treatment. 
One patient (16.7%) had serious TEAEs, none of the events were considered as related to the 
treatment. None of patients experienced TEAE leading to treatment discontinuation or fatal 
adverse events. 
1.3.  LBL-007 Rationales 
1.3.1.  Rationale for LBL-007 in Combination With Tislelizumab as Neoadjuvant 
Treatment In Patients With NSCLC 
Based on multiple preclinical and clinical studies, anti-LAG-3 and anti-PD-1 molecules have 
synergistic effects across several malignant tumors. Coordinated inhibition of LAG-3 and PD-1 
can further enhance the immune response and exert the best antitumor effect of the combination 
drugs. 
In a preclinical mouse study, LBL-007 in combination with anti-PD-1 significantly improved 
antitumor effect with a tumor growth inhibition (TGI) of 77.63%, superior to LBL-007 
(TGI = 56.10%) or anti-PD-1 (TGI = 58.99%) monotherapy in MC38-OVA (mouse colorectal 
cancer cell line stably expressing OVA protein) syngeneic model in a hLAG-3 knock-in mouse 
(§Figure 1). Refer to the LBL-007 Investigator’s Brochure for additional information.  
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§Figure 1: Tumor Growth Curve after Treatment With LBL-007, Anti-Mouse PD-1 and 
the Combination in MC38-OVA Model  
 
Abbreviations: MC38-OVA, mouse colorectal cancer cell line stably expressing OVA protein; PD-1, programmed 
cell death protein-1. 
The synergic antitumor efficacy for anti-LAG-3 antibody in combination with anti-PD-1 
antibody has been preliminarily validated in a clinical study. The first anti-LAG-3 antibody 
(relatlimab, Bristol Myer Squibb, Princeton, NJ) was recently approved by the FDA based on the 
significant clinical benefit of LAG-3/PD-1 combinational therapy compared to anti-PD-1 alone 
in unresectable metastatic melanoma (Tawbi et al 2022). In the study of LBL-007 in combination 
with anti-PD-1 antibody toripalimab in melanoma (LBL-007-CN-002), a total of 32 EE patients 
had an ORR of 12.5% and a DCR of 53.1% (4 PRs and 13 SDs). Of the 11 evaluable patients 
with cutaneous acral melanoma who had not received anti-PD-(L)-1 antibody treatment, the 
ORR was 27.3% and the DCR was 81.8%. In the study of LBL-007 in combination with 
toripalimab in the treatment of advanced malignancies (Study LBL-007-CN-003), efficacy was 
assessed in 4 patients, all of whom had SD. 
LAG-3 plays an important role in the immunosuppression of tumor-infiltrating lymphocytes 
(TILs) in NSCLC. Analysis from the TCGA database showed LAG-3 expression also ranked 
high in NSCLC, compared with all the indications. Multiplex quantitative immunofluorescence 
data from 730 clinically annotated NSCLC tissue analyses showed that LAG-3 was detected in 
TILs from 41.5% of NSCLC cases (Datar et al 2019), indicating high LAG-3 expression 
frequency in NSCLC. Besides, elevated LAG-3 ligands (FGL1 or galectin-3) are associated with 
resistance to anti-PD-(L)1 therapy (Wang et al 2019).  
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§Figure 2: 
Distribution and Frequency of T-cell PD-1 and LAG-3 Expression in NSCLC  
 
Source: Datar et al 2019 
Abbreviations: LAG-3, lymphocyte activation gene-3; NSCLC, non-small cell lung cancer; PD-1, programmed cell 
death protein-1.  
Note: Level of the markers measured using quantitative immunofluorescence (QIF) in 2 retrospective NSCLC 
cohorts- Cohort #1 (n=426) and #2 (n=304). The frequency of expression of each marker is indicated with white-
colored text within the charts. Detectable LAG-3 was seen in 33.34% and 49.67% in Cohorts 1 and 2 separately, and 
41.5% in the overall set. 
KEYNOTE-495 [NCT03516981] is a group-sequential, adaptively randomized, multisite, 
open-label, Phase 2 study, including a subgroup investigating first-line pembrolizumab plus 
LAG-3 inhibitor favezelimab (MK-4280) in patients with advanced NSCLC, with the primary 
endpoint of investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. At the data cutoff date of 11 January 2021, 30 patients were treated with 
pembrolizumab 200 mg + favezelimab 200 mg once every 3 weeks; and 34 patients were treated 
with pembrolizumab 200 mg + favezelimab 800 mg once every 3 weeks.  Although sample sizes 
were small, the TcellinfGEPhighTMBhigh subgroup demonstrated the best response among the 
biomarker subgroups for all pembrolizumab plus LAG-3 inhibitor favezelimab (MK-4280) 
therapies as demonstrated in §Table 1. which supports the benefit of LAG-3 combined with 
PD-1 as neoadjuvant in patients with early-stage, resectable NSCLC.  
§Table 1: Confirmed ORR by Therapy and Biomarker Status in KEYNOTE-495 
Arm  
Total 
% (n/N) 
(95% CI) 
TcellinfGEP high TMB high subgroup 
% (n/N) 
(95% CI) 
Pembrolizumab + 
Favezelimab  
200 mg Q3W 
23% (7/30) 
(95% CI: 10-42) 
60% (3/5) 
(95% CI: 15-95) 
Pembrolizumab + 
Favezelimab 
800 mg Q3W 
26% (9/34) 
(95% CI: 13-44) 
42% (5/12) 
(95% CI: 15-72) 
Source: Gutierrez et al 2021 
Abbreviations: ORR, overall response rate; Q3W, once every 3 weeks; TcellinfGEP, T-cell-inflamed gene expression 
profile; TMB, tumor mutational burden. 
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Moreover, PD-(L)1 combined with LAG-3 pathway targeting antibodies are under active 
investigation in the first-line treatment setting for NSCLC. CA224-104 (NCT04623775) is a 
Phase 2, randomized, double-blind study of relatlimab plus nivolumab in combination with 
chemotherapy versus nivolumab in combination with chemotherapy as first line treatment for 
participants with Stage IV or recurrent NSCLC, with estimated enrollment of 520 participants 
and projected primary completion date of February 2024. No data from this study has been 
released yet.  
In conclusion, as indicated by both nonclinical research and clinical studies as well as the high 
expression level of LAG-3 in NSCLC tumors along with supporting pharmacological toxicology 
and clinical PK data of LBL-007, the synergistic blockade effect of LAG-3 and PD-(L)1 
pathways provided a strong scientific rationale to expand the investigation of tislelizumab in 
combination with LBL-007 as neoadjuvant in patients with early-stage, resectable NSCLC.  
1.3.2.  Rationale for Selection of LBL-007 Dose in Combination With Tislelizumab 
In the single-agent dose escalation trial of WLZB-LBL-007-AST-001, the highest dose of 
10 mg/kg (once every 2 weeks) was tested in 7 patients with no DLT and was generally well 
tolerated. Limited drug accumulation was observed at steady-state due to its short half-life. The 
dose of 10 mg/kg (once every 2 weeks) provides exposure coverage up to 600 mg (for an 
average body weight of 60 kg) LBL-007 dosed once every 3 weeks. 
In Study BGB-900-102, Study LBL-007-CN-004, and BGB-A317-LBL-007-201, 300 and 
600 mg once every 3 weeks LBL-007 in combination with tislelizumab 200 mg once every 3 
weeks in patients with solid tumor will be evaluated for tolerability, PK, and clinical activity. 
The RP2D identified from these studies will be used as LBL-007 regimen in this study.  
The PK, safety, and efficacy data obtained from the first-in-human study AST-001, and from 
combination study with toripalimab (PD-1) CN-002, were analyzed in aggregate to determine the 
recommended dose for studies of LBL-007.  The dose of 300 and 600 mg intravenously once 
every 3 weeks was selected for further evaluation. 
In Study AST-001, doses of LBL-007 0.05, 0.25, 1, 3, 6, and 10 mg/kg once every 2 weeks were 
evaluated. Concentration-time profiles from 0.05 mg/kg up to 1 mg/kg exhibited a typical 
Target-mediated Drug Disposition (TMDD) pattern, suggesting lack of target saturation. Once 
doses reached 3 mg/kg and above, PK of LBL-007 became linear, indicating of target saturation. 
The observed mean trough concentration of 5.63 µg/mL at 3 mg/kg was selected as the at target 
concentration that overcomes TMDD. 
A preliminary population PK analysis was conducted pooling PK results from AST-001 and 
CN-002. The results of this analysis reveal that LBL-007 has a clearance of 0.022 L/hr with a 
half-life of approximately 12 days. Simulation suggests that at 600 mg once every 3 weeks, 
approximately 85% patients will achieve steady-state trough concentration of 5.63 µg/ml. 
1.3.3.  Biomarker Strategy Rationale 
Early studies suggested that LAG-3 was a negative regulator of T cells and blockade of LAG-3 
would boost human T-cell proliferation with elevated cytokine productions (Huard et al 1995). In 
multiple mouse tumor models, LAG-3 co-expresses with PD-1 on tumor-infiltrating CD4+ and 
CD8+ T cells, in which LAG-3 was shown to control T-cell proliferation and maintain 
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exhaustion. Although LAG-3 monotherapy in mice tumors was largely ineffective, interestingly, 
dual LAG-3/PD-1 co-blockade synergistically limited the tumor growth and resulted in tumor 
clearance better than anti-PD-1 monotherapy. Dual targeting increased CD4+ and CD8+ T-cell 
infiltration, as well as increased the frequency of single-and double-producing IFNγ+/TNFα+ 
CD8+ T cells in this model (Huang et al 2015, Woo et al 2012). 
Given that LAG-3 was predicted to be highly structurally homologous to CD4 with structure 
similarities, it is not surprising that MHC class II molecule is one of ligands for LAG-3. A recent 
study showed that MHC class II-expressing tumor cells (eg, melanoma cells) attracts 
tumor-specific CD4+ T cell infiltration, perhaps mediated by interaction with LAG-3, which in 
turn negatively influences CD8+ T-cell responses (Donia et al 2015). 
As LAG-3 impacts CD8+ T-cell function as well, it is speculated that there may be additional 
LAG-3 ligands for CD8+ T cells interacting with target cells that do not express MHC class II 
molecules. Several alternative ligands for LAG-3 are identified, including FGL-1, Gal-3, and 
LSECtin, which have each been shown to induce LAG-3-mediated inhibition of T-cell activation 
(Graydon et al 2021). 
In human cancer patients, LAG-3 has been found to be preferentially expressed on 
tumor-infiltrating Tregs in a number of tumor subtypes. LAG-3 has also been shown to be 
required for maximal activity of Tregs, whose blockade abrogates Treg suppressive function in 
vitro (Huang et al 2004). More recent study also showed that blockade or genetic deletion of 
LAG-3 skewed CD4+ T cells into a Th1 phenotype, with LAG-3 limiting IL-2 and STAT5 
signaling that modulates the ability to be suppressed by Tregs (Durham et al 2014). 
LAG-3 is constitutively expressed at a much greater level on pDCs than any other cell type, yet 
its functional role on these cells is not well understood. Lag3−/− pDCs show enhanced in vivo 
expansion without activation marker alteration or differential cytokine production compared with 
wildtype pDCs (Workman et al 2009). In humans, LAG-3+ pDCs were found to infiltrate the 
melanoma environment and interact with HLA-DR-expressing tumor cells in vivo (Camisaschi 
et al 2014). 
Additionally, LAG-3 was expressed in a subset of NK cells with high expression of activation 
and maturation markers, while its functional role is not well understood. LAG-3 blockade on NK 
cells resulted in enhanced secretion of pro-inflammatory cytokines, but not affecting the 
cytotoxic activity (Narayanan et al 2020).  
In summary, it is of great significance to explore whether LBL-007 could synergistically 
reinvigorate T cells with tislelizumab better in patients with cancer, as well as its impact on Treg, 
NK, and pDC cells. The association of pharmacodynamics induced by LBL-007 and LAG-3 
ligand expression with clinical outcomes will be assessed to identify the potential predictive or 
resistant biomarkers. 
1.4.  Benefit-Risk Assessment 
As described previously, both preclinical and clinical studies of LBL-007 or other anti-LAG-3 
antibodies combined with PD-1 inhibitors have shown the synergistic effect and improved 
antitumor activity along with a favorable safety profile. It is therefore expected that 
tislelizumab + LBL-007 will potentially have a favorable benefit- risk ratio and will demonstrate 
clinical efficacy in patients with NSCLC. 
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As of the cutoff date of 20 July 2022, tislelizumab has been evaluated in 3220 patients 
(2173 patients treated with monotherapy and 1047 patients treated with combination therapy, 
Tislelizumab Investigator’s Brochure) with a safety and efficacy profile similar to what has been 
reported for other anti-PD-1 therapies. However, based upon their mechanism(s) of action, 
preclinical, as well as clinical data, treatment with LBL-007 and tislelizumab is expected to 
increase the rate of immune-mediated toxicities as compared to treatment with tislelizumab 
monotherapy. A comprehensive practice guideline has been established to monitor, diagnose, 
and manage such immune-mediated toxicities (Appendix 7). This monitoring plan will be 
utilized to evaluate patient safety during the course of the study. The totality of the data in the 
study as well as external information including available data from the two Phase 1/2 studies of 
BGB-900-102 and Study LBL-007-CN-004 which will evaluate safety of LBL-007 in 
combination with tislelizumab in patients with solid tumors, may also be reviewed for the 
decision making.  
2. STUDY DESIGN 
2.1.  End of Treatment and Safety Follow-up Visit 
In addition to common requirements with respect to pregnancy testing after study treatment as 
described in Section 3.4, an additional pregnancy test should be performed at 6 months (± 14 
days) after the last dose of LBL-007 (in clinic or over the phone, as needed based on assessments 
required).  
3.  STUDY TREATMENT- LBL-007 in combination with tislelizumab 
3.1.  Formulation, Packaging, Labeling, and Handling 
LBL-007 is a recombinant monoclonal antibody formulated for intravenous infusion and is 
provided as a preservative-free, single-use vial, containing a minimum of 5 mL of a 17 mg/mL 
concentrated solution (85 mg) of antibody in a buffered isotonic solution. LBL-007 is aseptically 
filled in single-use vials (6 mL, United States Pharmacopeia [USP] Type I glass) with a coated 
butyl rubber stopper and sealed with an aluminum flip-off cap. 
Each vial is packaged into a single carton box. The contents of the label will be in accordance 
with all applicable local regulatory requirements.  
The study drug must be stored as specified on the label. Do not freeze. Shaking should be 
avoided. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal. Please also refer to the LBL-007 Investigator’s Brochure for additional 
information. 
3.2.  Dosage, Administration and Compliance 
Dosing schedules for Arm 1C are provided in §Table 2. The first dose of the study drug(s) is to 
be administered within 2 business days after randomization. All patients will be monitored 
throughout the study for AEs. Treatment modification (ie, dose delay or interruption) or 
discontinuation will be based on specific laboratory and AE criteria, as described in §Section 3.3. 
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During the neoadjuvant phase, for each cycle, study drug administration in Arm 1C will follow 
this order: LBL-007 and then tislelizumab. Refer to §Section 3.2.1 for details on monitoring 
time. 
§Table 2: Selection and Timing of Neoadjuvant Dose in Arm 1C 
Treatment 
arm 
Study Drug 
Dose 
Frequency of 
Administration 
Route of 
Administration 
Duration of 
Treatment 
Arm 1C 
LBL-007 
600 mg 
Day 1 of every 
3 weeks 
IV 
2 to 4 Cycles 
Tislelizumab 200 mg 
Abbreviation: IV, intravenous. 
3.2.1.  LBL-007 and Tislelizumab Treatment Administration 
Tislelizumab and LBL-007 will be administered separately by intravenous infusion, through an 
intravenous line containing a sterile, nonpyrogenic, low-protein-binding 0.2 micron in line or 
add-on filter. Tislelizumab and LBL-007 must be prepared and administered as separate 
infusions and may not be administered with any other drug (§Section 4). Refer to the Pharmacy 
Manual for detailed instructions on drug preparation, storage, and administration. 
Dosing administration and monitoring times are provided in §Table 3. For the first cycle, 
LBL-007 will be infused ≥ 60 minutes followed by patient monitoring for ≥ 60 minutes followed 
by tislelizumab infusion ≥ 60 minutes. After final infusion of the study drug, patients must be 
monitored for ≥ 60 minutes in an area with resuscitation equipment and emergency agents. 
If infusions of LBL-007 and tislelizumab are well tolerated in the first cycle, from Day 1 of 
Cycle 2, infusion of LBL-007 will remain ≥ 60 minutes followed by patient monitoring for 
≥ 30 minutes followed by the administration of tislelizumab ≥ 30 minutes. Thereafter, patients 
must be monitored for ≥ 30 minutes in an area with resuscitation equipment and emergency 
agents. 
Guidelines for dosage modification and treatment interruption or discontinuation are provided in 
§Section 3.3. Details for the management of imAEs, infusion-related reactions, and anaphylaxis 
reactions are provided in detail in Section 8.7 and Appendix 7. 
§Table 3: Administration of LBL-007 and Tislelizumab and Monitoring Time 
Cycle 
LBL-007 and Tislelizumab Combination 
Cycle 1 Day 1 
 
LBL-007 infusion ≥ 60 minutes followed by patient monitoring for ≥ 60 minutes 
followed by tislelizumab infusion ≥ 60 minutes 
Patient monitoring for ≥ 60 minutes after the last infusion 
Cycle 2 Day 1 
onwards 
 
If well tolerated, LBL-007 infusion ≥ 60 minutes followed by patient monitoring 
for ≥30 minutes followed by tislelizumab infusion ≥ 30 minutes  
Patient monitoring for ≥ 30 minutes after the last infusion 
Note: The infusion rate of tislelizumab or LBL-007 may be decreased or the infusion may be stopped in the event of 
an infusion-related reaction.  
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3.3.  Dose modification for LBL-007 and Tislelizumab 
Dose modification for LBL-007 is defined as any of the following: dose delay, dose interruption, 
and infusion rate decrease. A dose delay is a deviation from the prescribed dosing schedule (ie, 
the drug is withheld beyond the visit window). A dose interruption is an interruption of an 
infusion. An infusion rate decrease is a decrease of infusion rate. There will be no dose reduction 
for LBL-007 in this study. 
The dose modification guidelines in this section are not intended to be a substitute for clinical 
judgment. Investigators may delay doses for other reasons (eg, AEs or laboratory findings) as 
appropriate. 
If a dose delay is required, both LBL-007 and tislelizumab are to be delayed (ie, LBL-007 and 
tislelizumab must both be delayed and if applicable restarted at the same time). Exceptions may 
be considered following consultation between the investigator and the medical monitor. 
If study treatment is delayed due to TEAEs, study treatment may resume only after the AEs have 
returned to baseline or ≤ Grade 1 severity except for alopecia or AEs that, in the opinion of the 
investigator, are not considered a safety risk to the patient. If a treatment delay is due to 
worsening of laboratory results, eg, hematologic or biochemical parameters, the frequency of 
relevant blood tests should be increased, as clinically indicated. When several toxicities with 
different grades of severity occur at the same time, the dose modifications should be according to 
the highest grade observed. 
In general, dose delays for reasons other than management of AEs are prohibited. Total duration 
of dose delay (ie, the delay duration from first dose of study treatment to actual last dose 
compared with prescribed dosing schedule) of ≤ 3 weeks is allowed under the following 
guidance and at the discretion of the investigator. Study treatment should resume as soon as 
possible after the AEs recover to baseline or Grade 1 (whichever is more severe) if the total 
delay duration is not more than 3 weeks.  
If the patient is unable to resume study treatment ≤ 3 weeks of total delay duration, then the 
patient should be discontinued from treatment. If the patient is not able to resume study treatment 
≤ 3 weeks of total delay duration for unforeseen non-drug-related reasons, continued treatment 
may be allowed after consolation and approval by the medical monitor  
If a patient is benefiting from the study treatment while meeting the discontinuation criteria, 
resumption of study treatment may occur upon discussion and agreement with the medical 
monitor. Specific treatment modifications to manage treatment-related toxicities, such as imAEs, 
infusion-related reactions, and anaphylaxis reactions, are described in Section 8.7 and 
Appendix 7. 
4.  PRIOR AND CONCOMITANT THERAPY – LBL-007 
4.1.  Potential Interactions Between LBL-007 and Concomitant Medications 
A PK drug-drug interaction of LBL-007 with other therapeutics is not anticipated given that the 
primary elimination pathways are protein catabolism via the reticuloendothelial system or 
target-mediated disposition. LBL-007 is not expected to induce or inhibit the major drug 
metabolizing CYP pathways. Because LBL-007 is expected to be degraded into amino acids and 
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recycled into other proteins, it is unlikely to have an effect on drug metabolizing enzymes or 
transporters. Based on the mechanism of action, any therapeutic protein drug-drug interaction is 
not expected between the investigational agents. 
5.  SAFETY MONITORING AND REPORTING – LBL-007 
5.1.  Risks Associated With LBL-007 
LBL-007 is an investigational agent that is currently in clinical development. Limited clinical 
information is available for LBL-007 (§Section 1.4). Safety data is available from 22 patients 
treated with LBL-007 (§Section 1.4; LBL-007 Investigator’s Brochure). The following 
recommendation is based primarily upon results from clinical data of LBL-007. 
According to clinical studies for which safety results are currently available, the possible 
toxicities of LBL-007 include immune-mediated endocrine disorders (acute hypophysitis and 
thyroid disease), gastrointestinal disorders, anaemia, immune-mediated myocarditis (dyspnea, 
chest pain, palpitations, fatigue, decreased exercise tolerance, and syncope), and 
immune-mediated lung disease (pneumonia, cough, dyspnea, and respiratory failure). 
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. To assist with this, management guidelines for suspected imAEs are 
provided in Appendix 7. 
Refer to the LBL-007 Investigator’s Brochure for additional details. 
5.2.  Pregnancies 
In addition to common requirement with respect to pregnancy related SAE report stated in 
Section 8.6.6 , if a female patient or the female partner of a male patient becomes pregnant 
≤ 6 months after the last dose of LBL-007, a pregnancy report form must be submitted to the 
sponsor.  
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APPENDIX 14. CHEMOTHERAPY  
1. RATIONALE FOR CHOICE OF CHEMOTHERAPY 
Standard guidelines for the neoadjuvant and adjuvant treatment of resectable non-small cell lung 
cancer recommend platinum-based doublet chemotherapy with either cisplatin or carboplatin for 
patients with comorbidities or who are not able to tolerate cisplatin (NCCN 2023). Either 
platinum may be combined with a variety of chemotherapeutics, including vinorelbine, 
etoposide, gemcitabine, docetaxel, paclitaxel, and pemetrexed, with demonstrated comparable 
efficacy. In this study, neoadjuvant chemotherapy will consist of platinum in combination with 
either pemetrexed or paclitaxel for patients with nonsquamous and squamous histology, 
respectively.  
2. STUDY TREATMENT- CHEMOTHERAPY 
2.1.  Formulation, Packaging, Labeling, and Handling 
Management (ie, labeling, handling, storage, administration, and disposal) of these products will 
be in accordance with the relevant local guidelines and/or prescribing information. For further 
details, see the manufacturer’s prescribing information for the respective chemotherapy agents. 
2.2.  Dosage, Administration and Compliance 
Patients will receive treatment with platinum-based doublet chemotherapy in combination with 
tislelizumab (Arm 2A) or LBL-007 and tislelizumab (Arm 2C) during the neoadjuvant phase . 
An overview on dosing schedules for the treatment Arm 2A and 2C is provided in §Table 1. The 
first dose of the study drugs is to be administered ≤ 2 working days after randomization. All 
patients will be monitored continuously for AEs. Treatment modification (ie, dose delay or 
interruption) or discontinuation will be based on specific laboratory and AE criteria, as described 
in §Section 2.3 and §Section 2.4. For each cycle, tislelizumab and LBL-007 will be administered 
before chemotherapy drugs. The order of chemotherapy drugs administration will be conducted 
in accordance with the relevant local guidance and/or clinical practice. Refer to §Section 2.2.1 
for details on the administration of chemotherapy. 
§Table 1 Selection and Timing of Neoadjuvant Dose in Arm 2A and 2C 
Treatment 
Arm 
Study Drug 
Dose 
Frequency of 
Administration 
Route of 
Administration 
Duration of 
Treatment 
Arm 2A 
Tislelizumab 
200 mg 
Day 1 of every 
3 weeks 
 
IV 
2 to 4 
Cycles 
Cisplatin 
75 mg/m2 
Carboplatin* 
AUC of 
5 mg/mL/min  
Pemetrexed 
500 mg/m2 
Paclitaxel 
175 mg/m2  
Arm 2C 
LBL-007 
600 mg 
Day 1 of every 
3 weeks 
 
IV 
2 to 4 
Cycles 
Tislelizumab 
200 mg 
Cisplatin 
75 mg/m2 
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Abbreviations: AUC, area under the curve; IV, intravenous(ly).  
Chemotherapy options for Arm 2A and Arm 2C are: Cisplatin/Carboplatin + Pemetrexed (nonsquamous), 
Cisplatin/Carboplatin + Paclitaxel (squamous). For patients with tumors of mixed histology (squamous and 
non-squamous), appropriate chemotherapy regimen will be decided by investigators based on the major histological 
components assessed by pathologists.  
*Carboplatin can replace cisplatin per the investigator’s discretion in consideration of patient’s tolerability to 
cisplatin. The reasons for intolerability should be documented. 
2.2.1 Chemotherapy Treatment Administration 
Patients should receive antiemetics and intravenous hydration for chemotherapy according to the 
standard of care and manufacturer’s instruction. Due to their immunomodulatory effects, 
premedication with steroids should be limited when clinically feasible. In addition, in the event 
of chemotherapeutic agent-related skin rash, topical steroid use is recommended as treatment 
whenever it is clinically feasible.  
In special situations (eg, when the administration is delayed due to management of AEs or in the 
case of an infusion-related reaction), administration of the subsequent study drugs including 
chemotherapy might be delayed to the second day of each cycle. 
Cisplatin 75 mg/m2 will be administered as an intravenous infusion over 4 hours on Day 1 of 
each 3-week cycle for 2 to 4 cycles. All patients should receive adequate hydration (including 
pretreatment hydration) and diuretics. Urinary output > 2000 mL must be maintained in the 
following 24 hours of the infusion.  
Carboplatin area under the curve (AUC) of 5 mg/mL/min will be administered as an intravenous 
infusion over 1 hour on Day 1 of each 3- week cycle for 2 to 4 cycles. Carboplatin can replace 
cisplatin per the investigator’s discretion in consideration of patient’s tolerability to cisplatin. 
The reasons for intolerability should be documented. 
For nonsquamous: Pemetrexed 500 mg/m2 will be administered as an intravenous infusion over 
10 minutes on Day 1 of each 3-week cycle for 2 to 4 cycles. All patients should receive the 
appropriate supplementation of vitamin B12 and folic acid according to the approved product 
label and/or standard practice. In addition, all patients should receive the appropriate 
corticosteroid premedications as per the local approved label. Additional premedications should 
be administered as per standard practice. 
For squamous: Paclitaxel 175 mg/m2 will be administered as an intravenous infusion over 
3 hours on Day 1 of each 3-week cycle for 2 to 4 cycles. In addition, all patients should receive 
the appropriate premedications as per the local approved labels. Additional premedications 
should be administered as per standard practice. 
Patients will be monitored continuously for AEs and will be instructed to notify their physician 
immediately for any and all AEs. Management of suspected adverse drug reactions may require 
temporary interruption and/or dose reduction of each therapy. The infusion and monitoring of 
cisplatin, carboplatin, pemetrexed, and paclitaxel may also follow approved drug labels or 
Carboplatin* 
AUC of 
5 mg/mL/min  
Pemetrexed 
500 mg/m2 
Paclitaxel 
175 mg/m2  
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clinical practice. Please refer to Appendix 11 and Appendix 13 for the details of administration 
of tislelizumab and LBL-007. 
2.3 Dose Delay or Modification 
Effort should be made to administer the study drug(s) according to the planned dose and 
schedule. In the event of significant toxicities, dose modifications for chemotherapy agents are 
permitted according to the respective local prescribing information, guidelines, or clinical 
standard practice. 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 electronic case report 
form. 
There will be no dose reduction for tislelizumab or LBL-007 in Arms 2A and 2C. Dose 
modification or chemotherapy depends on the severity of toxicity and an assessment of the risk 
versus benefit for the patient, with the goal of maximizing the patient’s benefit. Dose 
modifications for chemotherapy should be performed per prescribing information and per local 
practice according to investigator’s clinical judgment. In a case of dose reduction of 
chemotherapy, all further chemotherapy doses will decrease by 25% for the next cycle. A 
maximum of 2 dose reductions for each chemotherapeutic agent is allowed, except that 
carboplatin is only permitted to decrease by 20% doses once. 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 should be discontinued. Study drug-related toxicities must be resolved to 
baseline level, or Grade 1 before administering the next dose of study drug, except for alopecia 
or Grade 2 fatigue. 
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%. 
Administration of chemotherapy should ideally remain synchronized with predefined cycles and 
tislelizumab and LBL-007 infusions. When a treatment cycle is delayed or interrupted because of 
toxicity resulting from either component of the chemotherapy regimen, other study drugs 
(tislelizumab and LBL-007) generally be withheld and resumed together to remain synchronized. 
At the subsequent cycle, if chemotherapy still cannot be given due to prolonged AE and 
toxicities, then tislelizumab and LBL-007 could be given as scheduled for that cycle alone, if 
clinically appropriate. If chemotherapy has been withheld for 42 days (delayed cycle + 
subsequent cycle), then it should permanently be discontinued. 
Risks Associated with Chemotherapy 
Cisplatin 
Cisplatin is known to cause myelosuppression, ototoxicity, and nephrotoxicity. 
Cisplatin-based chemotherapy is considered to be moderately emetogenic. Patients will be 
monitored for cisplatin-related AEs. 
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Carboplatin 
Carboplatin is known to cause bone marrow suppression including myelosuppression, anemia, 
and thrombocytopenia. Carboplatin-based chemotherapy is considered to be moderately 
emetogenic. Patients will be monitored for carboplatin-related AEs. 
Pemetrexed 
The most common side effects of pemetrexed include gastrointestinal symptoms (nausea, 
vomiting, diarrhea, or constipation), myelosuppression, infection, fatigue, stomatitis, loss of 
appetite, and rash. 
Paclitaxel 
Common side effects of paclitaxel include: hypotension, nausea, and vomiting, arthralgia, 
myalgia, alopecia, diarrhea, hypersensitivity condition, mucositis, skin rash, electrocardiogram 
abnormality, increased serum alkaline phosphatase, increased serum aspartate aminotransferase 
(AST), infusion site reaction, peripheral neuropathy, and flushing. 
For more details regarding the safety profiles of the respective chemotherapy agents, refer to the 
manufacturer’s prescribing information. 
Selected Precautions: 
• 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.  
• Ototoxicity and sensory neural damage should be assessed before each cycle. Cisplatin is 
contraindicated in patients with a pre-existing hearing deficit.  
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 that of the preceding administration. 
Recommended dose modifications for hematologic toxicity are provided in below table.  
Chemotherapy Dose Modification a for Hematological Toxicity 
Adverse Event 
Treatment  
Febrile neutropenia; documented 
infection 
The first episode of febrile neutropenia or documented infection will result 
in antibiotic treatment and reduction by 25% of both drugs doses. 
If there is a second episode despite dose reduction, the patient must receive 
prophylactic antibiotics during the subsequent cycles. 
If there is a third episode, the chemotherapy will be discontinued. 
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Adverse Event 
Treatment  
Neutropenia  
Grade 3 
(0.5-0.99 × 
109/L) 
Chemotherapy delay until ≤ Grade 1 (≥ 1.5 × 109/L); restart with the full 
dose 
Grade 4 
(< 0.5 × 
109/L) 
Chemotherapy delay until recovered to ≤ Grade 1; dose reduction of all 
further doses by 25% 
Thrombocytopenia 
Grade 1 
Chemotherapy delay until recovered to normal; restart with the full dose 
≥ Grade 2 
Chemotherapy delay until recovered to normal; dose reduction of all further 
doses by 25% 
Abbreviations: AUC, area under the curve. 
a If considered in the best interest of the patient and consistent with local practice, the 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. Carboplatin is only permitted to decrease by 
20% doses once (from AUC 5 to AUC 4). 
Recommended Dose Modifications for Non-Hematologic Toxicities 
The dose adjustments of chemotherapy for non-hematologic toxicity are described in §Table 2. 
All dose modifications should be made based on the worst grade toxicity. 
§Table 2. Chemotherapy Dose Modifications for Non-Hematological Toxicity 
Toxicity 
Grade 
Treatment  
Renal toxicity 
≥ Grade 1 
Delay chemotherapy until recovered to Grade 0 or baseline, change cisplatin to 
carboplatin, if possible; dose reduction by 25% for other drug; if recur, stop 
chemotherapy 
Ototoxicity  
Grade 2 
Dose reduction of all further doses of cisplatin by 25% 
Grade 3 or 4 
Delay chemotherapy until recovered to ≤ Grade 2, change cisplatin to carboplatin 
Sensory 
neuropathy 
Grade 2 
Dose reduction for all further doses of cisplatin by 25% 
Grade 3 
Stop cisplatin, change cisplatin to carboplatin 
Grade 4 
Stop cisplatin/carboplatin 
Total 
bilirubin 
Grade 2 
Two dose reduction level for all further doses of chemotherapy (each dose level 
requires a deduction by 25%) 
Grade 3 or 4 
Stop chemotherapy 
AST or ALT 
Elevation 
Grade 3 
Dose reduction for all further doses of by 25% 
Grade 4 
Stop chemotherapy 
Other organ 
toxicity 
Grade 2 
Delay chemotherapy until ≤ Grade 1 or baseline a 
Grade 3 or 4 
Delay chemotherapy until recovered to ≤ Grade 1 or baseline a, dose reduction of 
all further dose by 25% 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
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Note: If considered in the best interest of the patient and consistent with local practice, the 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.  
a Skin reactions, paronychia, alopecia, fatigue, nausea/vomiting which may have resolved to Grade 2 or baseline. 
2.4. 
Discontinuation of Chemotherapy Regimens 
Chemotherapy drugs could be discontinued for any of the following: 
• Any Grade 3 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 alanine aminotransferase (ALT) > 5 to 10 × upper limit of normal (ULN) 
for > 2 weeks  
− AST or ALT > 10 × ULN or 
− Total bilirubin > 5 × ULN or 
− Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN 
• Any cisplatin-related decrease in creatinine clearance to < 30 mL/min (using the 
Cockcroft-Gault formula) requires discontinuation of cisplatin.  
• Any drug-related AE that recurs after 2 prior dose reductions 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. If the drug is 
assessed as not related to the hypersensitivity reaction or infusion reaction, it may be 
continued. 
• Any Grade 4 AE that the investigator considers related to study drug(s) and 
inappropriate to be managed by dose reduction(s) requires discontinuation of drug(s). 
If the drug is not assessed to be related to the event it may be continued. 
• If any toxicity which led to treatment discontinuation does not resolve within 21 days, 
that component will be discontinued.  
For toxicities not listed above, the investigator’s medical judgment would determine whether 
chemotherapy regimen should be discontinued, in accordance with patient’s wellbeing and local 
standards. 
 
 
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APPENDIX 15. PREGNANCY REPORTING PERIOD  
If a female patient or the female partner of a male patient becomes pregnant during the following 
period for each arm, the pregnancy must be reported as specified in Section 8.6.6. 
Arm  
Treatment 
Pregnancy Reporting Period 
Experimental Arm 1A 
Tislelizumab  
On treatment or ≤ 180 days after the last 
dose of tislelizumab 
Experimental Arm 1B 
Tislelizumab + ociperlimab 
On treatment or ≤ 180 days after the last 
dose of tislelizumab or ociperlimab, 
whichever occurs later 
Experimental Arm 1C 
LBL-007 + Tislelizumab 
On treatment or ≤ 180 days after the last 
dose of LBL-007 or tislelizumab, whichever 
occurs later 
Experimental Arm 2A 
Tislelizumab + chemotherapy  
On treatment or ≤ 180 days after the last 
dose of tislelizumab or chemotherapy, 
whichever occurs later 
Experimental Arm 2C 
LBL-007 + Tislelizumab + 
chemotherapy  
On treatment or ≤ 180 days after the last 
dose of LBL-007 or tislelizumab or 
chemotherapy, whichever occurs later 
 
Approved Date
7/18/2023

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