A Phase 3, Randomized, Double-blind Study of Neoadjuvant Chemotherapy Plus Nivolumab Versus Neoadjuvant Chemotherapy Plus Placebo, Followed by Surgical Resection and Adjuvant Treatment With Nivolumab or Placebo for Participants With Resectable Stage II-IIIB Non-small Cell Lung Cancer
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Bristol-Myers Squibb

 
 
Official Title of Study: 
A Phase 3, Randomized, Double-blind Study of Neoadjuvant Chemotherapy plus Nivolumab  
versus Neoadjuvant Chemotherapy plus Placebo, followed by Surgical Resection and Adjuvant  
Treatment with Nivolumab or Placebo for Participants with Resectable Stage II-IIIB Non-small  
Cell Lung Cancer 
(CheckMate 77T, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 77T) 
 
Protocol: CA209-77T 
 
NCT Number: NCT04025879 
 
Document Date (Date in which document was last revised): 28-Feb-2024 

Page:
1
Protocol Number:
CA20977T
IND Number:
100,052
EU CT Number:
2022-502658-15
NCT Number
NCT04025879
Universal Trial Number
U1111-1226-5321
Date:
26-Mar-2019
Revised date
28-Feb-2024
CLINICAL PROTOCOL CA20977T
A Phase 3, Randomized, Double-blind Study of Neoadjuvant Chemotherapy plus Nivolumab 
versus Neoadjuvant Chemotherapy plus Placebo, followed by Surgical Resection and Adjuvant 
Treatment with Nivolumab or Placebo for Participants with Resectable Stage II-IIIB Non-small 
Cell Lung Cancer
(CheckMate 77T, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 77T)
Short title: A Study of Neoadjuvant Chemotherapy Plus Nivolumab Versus Neoadjuvant 
Chemotherapy plus Placebo, Followed by Surgical Removal and Adjuvant Treatment with 
Nivolumab or Placebo for Participants With Surgically Removable Early Stage Non-small Cell 
Lung Cancer
Protocol Amendment 04
Incorporates Administrative Letters 04 and 06
Medical Monitor
Route de Perreux 1, 2017
Switzerland
3401 Princeton Pike
Lawrenceville, NJ 08648
Phone: 
Email: 
Telephone (office): 
Email: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
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CA20977T
BMS-936558
nivolumab
Protocol Amendment No.: 04
Date: 28-Feb-2024
2
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
© 2024 Bristol-Myers Squibb Company
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Protocol Amendment No.: 04
Date: 28-Feb-2024
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 04
28-Feb-2024
The primary reasons for this amendment are to: 
•
Clarify the timing of the imaging requirements
•
Reduce the number of sample collections for circulating tumor 
deoxyribonucleic acid
•
Update the contraceptive requirements to align with the current 
approved product label.
Administrative 
Letter 06
01-Dec-2022
Updated study personnel information.
Administrative 
Letter 05
25-Aug-2021
Updated study personnel information.
Administrative 
Letter 04
10-May-2021
Corrected a typo found in Table 9.8.1-1 in protocol amendment 03.
Protocol 
Amendment 03
20-Apr-2021
•
Updated requirement for tumor tissue submission at screening, and upon 
progression or recurrence of disease
•
Language regarding event-free survival was aligned throughout the 
document
•
Imaging requirements and definitions were clarified for the neoadjuvant 
setting
•
SARS-CoV-2 serology samples added
•
AE/SAE collection added to collect SARS-CoV-2 related events. 
Revised 
Protocol 02
11-May-2020
•
Updated PD-L1 stratification 
•
Clarified language for inclusion criteria for tumor eligibility
•
Updated Table 2-4 survival status window and collection of EQ-5D-3L
outcomes by phone
•
Updated window for preoperative imaging assessment
•
Clarifies instructions when participants do not receive surgery
•
Removed carboplatin + docetaxel as a chemotherapy regimen for 
patients with squamous histology
•
Added CYP3A4 inhibitors as prohibited medications when treated with
docetaxel
•
Added docetaxel dose reduction for impaired renal function 
•
Added docetaxel treatment delay when total bilirubin > ULN
•
Added docetaxel discontinuation for cystoid macular edema 
Revised 
Protocol 01
20-Dec-2019
 the revised protocol:
•
modifies endpoints and definitions
•
adds additional chemotherapy regimens
•
instructs participants to follow local regulations for pregnancy testing 
and contraceptive use. 
•
incorporates Administrative Letter 01 
Additional updates were made to the imaging assessments and biomarker 
collections.
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Protocol Amendment No.: 04
Date: 28-Feb-2024
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Document
Date of Issue
Summary of Change
Original 
Protocol
26-Mar-2019
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 04:
The primary reasons for this amendment are to: 
•
Clarify the timing of the imaging requirements
•
Reduce the number of sample collections for circulating tumor deoxyribonucleic acid (ctDNA)
•
Update the contraceptive requirements to align with the current approved product label.
Additional revisions, including to the Synopsis, have been made to align the protocol with respect 
to these changes.
This amendment incorporates the changes from the approved Administrative Letters 04 and 06
which are detailed in the Document History but not listed in the Summary of Key changes below.
This protocol amendment applies to all participants.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
Updated EudraCT Number to European 
Union (EU) Clinical Trial (CT) Number.
The term "EudraCT" is obsolete, as 
it refers to the previous legislation 
shortening the number per clinical 
trial regulation minimum 
requirements.
Updated Clinical Scientist contact 
information.
To reflect current contact 
information.
Table 2-3: Post surgery/Pre-
adjuvant and Adjuvant 
Treatment Procedures and 
Assessments (CA20977T)
Table 2-4: Long-term Follow-
up Assessments (CA20977T)
Section 5.1.2.5: Post 
surgical/Preadjuvant 
Evaluation
Section 9.1.2.1: Neodadjuvant 
and Pre-Surgical Imaging
Section 9.1.2.2: Post Surgical 
/ Preadjuvant Restaging and 
Adjuvant Imaging
Section 9.1.2.4: BICR 
Assessment of Progression
Updated timing of body imaging.
Timing of imaging requirements 
was clarified throughout the 
protocol. There are no changes to 
how this data is collected, just 
clarifying previously unclear 
information.
Added that, in addition, scans will 
continue until investigator-assessed distant 
metastasis.
Clarified requirement of imaging 
assessments from the time of 
local/locoregional recurrence until 
distant metastasis.
Figure 5.1-1: CA20977T 
Schema
Removed “and follow-up” from 
Biomarker collection and added that 
Follow-up is for up to “and including” 
5 years from randomization.
For consistency with changes in 
the protocol.
Protocol Amendment No.: 04
Date: 28-Feb-2024
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & 
Title
Description of Change
Brief Rationale
Figure 5.1.2-1: CA20977T 
Flowchart for Efficacy and 
Safety Data Collection
Table 9.8.1-1: Biomarker 
Sample Schedule for All 
Participants
Removed ctDNA collections from Year 2 
and Year 3 and added a footnote “b” to 
Table 9.8.1-1. Plasma ctDNA samples 
should only be collected during Years 2 
through 5 at the time of recurrence or 
progression.
To clarify ctDNA sample 
collection timing and to reduce the 
number of collections to reduce 
patient burden. 
Section 9.2.5: Pregnancy
Appendix 4: Women of 
Childbearing Potential 
Definitions and Methods of 
Contraception
Updated contraception and reporting 
requirements.
To align with the current approved 
product label.
Table 9.4.4-1: Clinical 
Laboratory Assessments
Removed “pre” from “Hepatitis B/C, pre-
screening only” and “Follicle stimulating 
hormone pre-screening only.”
To align with current protocol 
requirement.
Table 9.8.1-1: Biomarker 
Sample Schedule for All 
Participants
Removed footnote from 
Surgery/Resection row regarding 
participants stopping treatment for reasons 
other than blinded independent central 
review confirmed disease progression or 
recurrence during Adjuvant Treatment 
Period.
Administrative change to reduce 
confusion.
Appendix 2: Study 
Governance Considerations
Added Dissemination of Clinical Study 
Data section.
Updated based on BMS policy for 
dissemination of study data.
Throughout
Editorial updates.
Minor; therefore, have not been 
summarized.
Protocol Amendment No.: 04
Date: 28-Feb-2024
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 04: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 Research Hypothesis ................................................................................ 
 
3.2 Background ....................................................................................................... 
 
3.2.1 Nivolumab Mechanism of Action ............................................................. 
 
3.2.2 Clinical Activity of Immuno-oncology Treatment Combined with 
Chemotherapy ............................................................................................. 
 
3.3 Benefit/Risk Assessment .................................................................................. 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Screening.................................................................................................. 
 
5.1.2 Treatment Period ..................................................................................... 
 
5.1.2.1 Neoadjuvant / Pre-surgical Treatment Period ............................... 
 
5.1.2.2 Surgery ............................................................................................ 
 
5.1.2.3 Participants not receiving surgery .................................................. 
 
5.1.2.4 Postoperative radiotherapy as Standard of Care (SOC) ................ 
 
5.1.2.5 Post surgical/Preadjuvant Evaluation ............................................ 
 
5.1.2.6 Adjuvant Treatment (Post surgical treatment) [Year 1] ................. 
 
5.1.3 Disease Surveillance Assessments from Year 2 to Year 5 and Safety 
Follow-up Visits .......................................................................................... 
 
5.1.4 Disease Progression/Recurrence ............................................................. 
 
5.1.5 Data Monitoring Committee and Other External Committees. ............... 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.4.1 Rationale for Study Design ...................................................................... 
 
5.5 Justification for Nivolumab Dose ..................................................................... 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening ..................................................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 Neoadjuvant Treatment ............................................................................ 
 
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BMS-936558
CA20977T
nivolumab
Protocol Amendment No.: 04
Date: 28-Feb-2024
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7.1.1.1 Nivolumab or Placebo during Neo-adjuvant Treatment ................ 
 
7.1.1.2 Platinum-based Doublet Chemotherapy Regimens ........................ 
 
7.1.1.3 Dosing Information for Platinum-based Doublet Chemotherapy .. 
 
7.1.2 Nivolumab or Placebo for Adjuvant Treatment ....................................... 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Dose Reductions for Platinum-based Doublet Chemotherapy ................ 
 
7.4.1.1 Platinum-based Doublet Chemotherapy - Dose Reductions for 
Hematologic Toxicity ............................................................................ 
 
7.4.1.2 Platinum-based Doublet Chemotherapy - Dose Reductions for Non-
Hematologic Toxicities ......................................................................... 
 
7.4.2 Dose Delay ............................................................................................... 
 
7.4.2.1 Nivolumab Dose Delay Criteria ..................................................... 
 
7.4.2.2 Dose Delay Criteria for Platinum-based Doublet Chemotherapy . 
 
7.4.3 Treatment of Nivolumab-related Infusion Reactions ............................... 
 
7.4.4 Criteria to Resume Dosing....................................................................... 
 
7.4.4.1 Criteria to Resume Nivolumab ........................................................ 
 
7.4.4.2 Criteria to Resume Treatment with Chemotherapy ........................ 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Nivolumab Discontinuation Criteria ....................................................... 
 
8.1.2 Platinum-based Doublet Chemotherapy Dose Discontinuation .............. 
 
8.1.3 Post Study Treatment Follow-up ............................................................. 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.3 Lost to Follow-Up ............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Definition of Events in EFS ...................................................................... 
 
9.1.1.1 Definition of Disease Recurrence ................................................... 
 
9.1.1.2 Definition of Disease Progression .................................................. 
 
9.1.1.3 Definition of pCR ............................................................................ 
 
9.1.1.4 Definition of MPR ........................................................................... 
 
9.1.2 Imaging Assessment for the Study............................................................ 
 
9.1.2.1 Neoadjuvant and Pre-Surgical Imaging ......................................... 
 
9.1.2.2 Post Surgical / Preadjuvant Restaging and Adjuvant Imaging ...... 
 
9.1.2.3 Methods of Measurement ................................................................ 
 
9.1.2.4 BICR Assessment of Progression .................................................... 
 
9.1.3 Blinded Independent Pathology Review .................................................. 
 
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CA20977T
nivolumab
Protocol Amendment No.: 04
Date: 28-Feb-2024
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9.1.4 Outcomes Research Assessments ............................................................. 
 
9.1.4.1 FACT-L ........................................................................................... 
 
9.1.4.2 Non-Small Cell Lung Cancer Symptom Assessment Questionnaire 
(NSCLC-SAQ) ....................................................................................... 
 
9.1.4.3 EQ-5D-3L ....................................................................................... 
 
9.1.4.4 PROMIS Physical Function ............................................................ 
 
9.1.4.5 Patient Global Impression of Severity (PGIS) ................................ 
 
9.2 Adverse Events ................................................................................................. 
 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
 
9.2.8 Other Safety Considerations .................................................................... 
 
9.2.9 Management Algorithms for Immuno-Oncology Agents ......................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Physical Examinations ............................................................................. 
 
9.4.2 Vital signs................................................................................................. 
 
9.4.3 ECG.......................................................................................................... 
 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.5 Imaging Safety Assessment ...................................................................... 
 
9.5 Pharmacokinetics .............................................................................................. 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.1 Tumor Tissue and Blood Tissue Collection ............................................. 
 
9.8.1.1 Diagnostic/Baseline Biopsy ............................................................ 
 
9.8.1.2 Whole Exome Sequencing of Tissue and Whole Blood DNA .......... 
 
9.8.1.3 Tissue Biopsy at Disease Progression or Recurrence .................... 
 
9.8.1.4 Circulating tumor DNA (ctDNA) .................................................... 
 
9.8.1.5 Serum Soluble Factors .................................................................... 
 
9.8.1.6 Tissue and Whole Blood Gene Expression ..................................... 
 
9.8.1.7 Peripheral blood mononuclear cells (PBMCs)............................... 
 
9.8.1.8 Myeloid Derived Suppressor Cells (MDSCs) ................................. 
 
9.8.1.9 Other Assessments .......................................................................... 
 
9.8.2 Additional Research Collection ............................................................... 
 
9.8.3 Immunogenicity Assessments ................................................................... 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.1.1 Sample Size Justification for EFS .......................................................... 
 
10.1.2 Power Calculation for OS ...................................................................... 
 
10.2 Populations for Analyses ................................................................................ 
 
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Clinical Protocol
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Protocol Amendment No.: 04
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10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.3 Other Analyses ....................................................................................... 
 
10.3.4 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 6 MANAGEMENT ALGORITHMS ....................................................... 
 
APPENDIX 7 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS FOR 
NEOADJUVANT LUNG STUDY ......................................................................... 
 
APPENDIX 8 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
 
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Clinical Protocol
BMS-936558
CA20977T
nivolumab
Protocol Amendment No.: 04
Date: 28-Feb-2024
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CA20977T
BMS-936558
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1
SYNOPSIS
Protocol Title: A Phase 3, Randomized, Double-blind Study of Neoadjuvant Chemotherapy 
plus Nivolumab versus Neoadjuvant Chemotherapy plus Placebo, followed by Surgical 
Resection and Adjuvant Treatment with Nivolumab or Placebo for Participants with 
Resectable Stage II-IIIB Non-small Cell Lung Cancer
(CheckMate 77T, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 77T)
Short title: A Study of Neoadjuvant Chemotherapy Plus Nivolumab Versus Neoadjuvant 
Chemotherapy plus Placebo, Followed by Surgical Removal and Adjuvant Treatment with 
Nivolumab or Placebo for Participants with Surgically Removable Early Stage Non-Small Cell 
Lung Cancer
Study Phase: 3
Rationale: Approximately 80% of lung cancer cases are NSCLC, with most patients presenting 
with late stage disease. Of these patients with NSCLC, 20% present with stage I or II disease, 
whereas 30% present with stage III disease and 50% with stage IV disease. Patients with pathologic 
stage I NSCLC have a 5-year survival of approximately 60%. Stage II to III NSCLC patients have 
a 5-year survival of approximately 25% to 40%.1 The early-stage (II-IIIB) NSCLC represents a 
population of high unmet need with poor 5-year survival. 
Surgical resection remains the mainstay of treatment for Stage I and II patients. Despite potential 
curative surgery, approximately 50% of stage IB and 60-75% of stage I-II NSCLC patients will 
relapse and eventually die of their disease.2,3 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. This periadjuvant phase 3 study (CA20977T) will evaluate the 
clinical efficacy and will establish the safety of neoadjuvant therapy of nivolumab plus platinum-
based doublet chemotherapy followed by adjuvant therapy of nivolumab in resectable lung cancer. 
Study Population: Participants with resectable Stage IIA >4 cm - IIIB (T3N2) non-small cell lung 
cancer
Objectives and Endpoints:
Table 1-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To compare the event-free survival (EFS) by blinded 
independent central review (BICR) in Arm A vs Arm 
B participants
•
EFS is defined as the length of time from
randomization to any of the following events:
progression of disease or worsening of disease 
precluding surgery, if surgery is attempted but 
gross resection is abandoned due to unresectable 
tumor or worsening of disease, progression or 
recurrence of disease after surgery, progression or 
recurrence of disease without surgery, or death due 
Protocol Amendment No.: 04
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Clinical Protocol
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Table 1-1:
Objectives and Endpoints
Objectives
Endpoints
to any cause. Progression/recurrence will be 
assessed by BICR per RECIST 1.1.
•
Participants who do not undergo surgery for reason 
other than progression will be considered to have 
an event at RECIST 1.1 progression or death.
Secondary
•
To compare the overall survival (OS) in Arm A vs 
Arm B participants
•
OS is defined as the time between the date of 
randomization and the date of death due to any 
cause. OS will be censored on the last date a 
subject was known to be alive.
•
To assess the pathologic complete response (pCR) 
rate by BIPR in Arm A vs Arm B participants
•
pCR rate is defined as the number of randomized 
participants with absence of residual viable tumor 
in lung and lymph nodes as evaluated by blinded 
independent pathology review (BIPR), divided by 
the number of randomized participants for each 
treatment group.
•
To assess the major pathological response (MPR)
rate by BIPR in Arm A vs Arm B participants
•
MPR rate is defined as number of randomized 
participants with ≤10% residual viable tumor in 
lung and lymph nodes as evaluated by BIPR, 
divided by the number of randomized participants 
for each treatment group.
•
To assess safety and tolerability in Arm A vs Arm B
participants
•
Incidence of AEs, SAEs, and select AEs
Overall Design:
This phase 3, double-blind, periadjuvant study (CA20977T) will evaluate the clinical efficacy and 
will establish the safety of neoadjuvant therapy of nivolumab plus platinum-based doublet 
chemotherapy followed by adjuvant therapy of nivolumab in resectable lung cancer. 
Number of Participants: Approximately 452 participants
Protocol Amendment No.: 04
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Schema for CA20977T 
Treatment Arms and Duration:
•
Arm A: nivolumab 360 mg Q3W + SOC platinum-based doublet chemotherapy Q3W x 4
cycles as neoadjuvant treatment followed by surgery; then post surgery, nivolumab 480 mg 
Q4W adjuvant therapy for up to 13 cycles (approximately 1 year)
•
Arm B: placebo Q3W + SOC platinum-based doublet chemotherapy Q3W x 4 cycles as 
neoadjuvant therapy followed by surgery, then post surgery, placebo Q4W up to 13 cycles
(approximately 1 year)
Study treatment: 
Study Drug for CA20977T
Medication 
Potency 
IP/Non-IP 
Protocol Amendment No.: 04
Date: 28-Feb-2024
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Clinical Protocol
CA20977T
BMS-936558
nivolumab
Nivolumab
100 mg/vial (10 mg/mL)
IP
Carboplatin
450 mg/vial (10 mg/mL)
IP
Cisplatin 
100 mg/vial (1 mg/mL)
IP
Docetaxel 
80 mg/vial (10 mg/mL)
IP
Paclitaxel Solution 
100mg/vial (6 mg/mL)
IP
Pemetrexed Powder 
500 mg/vial
IP
Data Monitoring Committee: Yes
References
1
Mountain CA and Dresler CM. Regional lymph node classification for lung cancer staging. 
Chest. 1997: 1718-23.
2
Goldstraw P, Crowley J, Chansky K, et al for the International Association for the Study of 
Lung Cancer International Staging Committee. The IASLC Lung Cancer Staging Project: 
proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of 
the TNM Classification of malignant tumours. J Thorac Onco. 2007; 2(8):706-14.
3
Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest. 2009; 136: 
260-71.
Protocol Amendment No.: 04
Date: 28-Feb-2024
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Clinical Protocol
CA20977T
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA20977T)
Procedure
Screening Visit
Notes
Eligibility Assessments
Informed Consent
X
Informed Consent Form prior to screening for study participation. 
Register in the Interactive Response system to obtain participant number.
If a participant is re-enrolled, the participant must be re-consented, re-registered in the 
Interactive Response system to obtain a new participant number and eligibility should be 
re-confirmed. 
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to 
randomization.
Participants must be evaluated by the multidisciplinary team (including surgeon, medical 
oncologist, radiation oncologist, etc) during screening.
Medical History
X
All medical history relevant to the disease under study, including the following: any serious 
organ system dysfunction; prior cancer therapy; Tumor; Node and Metastasis (TNM) stage 
II, IIIA, and IIIB (T3N2) and smoking history (including electronic cigarettes), 
documentation of prior COVID-19 vaccine or infection. Within 14 days prior to 
randomization.
Concomitant Medication Review
X
Within 14 days prior to randomization. Vaccine use within 30 days prior to randomization 
must be collected.
ECOG Performance Status
X
Within 14 days prior to randomization (Appendix 5)
Safety Assessments
Physical Examination
X
Includes assessment of symptoms, review of system (ROS), height, weight, BSA (for 
chemotherapy dosing), and full physical exam within 14 days prior to randomization.    
Vital Signs 
X
Includes body temperature, respiratory rate, blood pressure, heart rate. 
Serious Adverse Events Assessment
X
Serious Adverse Events from the time of consent
Clinical Laboratory Testing
X
All laboratory assessments to be performed within 14 days prior to randomization. 
Serology must completed within 28 days prior to randomization.
See Section 9.4.4 for a list of laboratory tests.
Protocol Amendment No.: 04
Date: 28-Feb-2024
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Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA20977T)
Procedure
Screening Visit
Notes
SARS-CoV-2 Serology 
X
Serum collected to be used for potential future measurements of anti-SARS-CoV-2 
serology (anti-SARS-CoV-2 total or IgG [see Section 9.8])
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 
must be performed at screening and within 24 prior to the start of treatment.
Serum or urine pregnancy must be performed for at least every 4 weeks on treatment, 
during pre-surgery period, and during post surgery recovery period. See Appendix 4
Pulmonary Function Test
X
Mandatory PFTs including FVC, FEV1, TLC, FRC, DLco, and oxygen saturation. It is 
recommended to use same machine and methods throughout study. To be performed within 
45 days prior to randomization.
ECG
X
ECG to be performed within 14 days prior to randomization 
Imaging Assessments 
Body Imaging
X
PET-CT with contrast is required at screening for all participants and should be acquired up 
to 45 days prior to randomization. If the CT component of a PET-CT is not of sufficient 
diagnostic quality for RECIST 1.1 assessment, a separate CT with contrast of the chest, 
abdomen, pelvis and other suspected areas (in addition to the PET-CT) is required. If CT 
with contrast of the abdomen, pelvis, and all other known and/or suspected sites of disease 
is contraindicated, then a MRI is acceptable. 
See Section 9.1.2 for further details.
Brain Imaging
X
MRI of the brain without and with contrast is required for ALL participants to rule out 
brain metastases. CT of the brain without and with contrast can be performed if MRI is 
contraindicated. To be performed within 45 days prior to randomization. See Section 9.1.2
for further details.
Staging mediastinal lymph node evaluation
X
Mandatory mediastinal lymph node evaluation, when clinically feasible. Acceptable 
method of evaluations include mediastinoscopy, mediastinotomy EBUS, EUS, and CT 
guided biopsy. An EBUS-TBNA negative for malignancy in a clinically positive 
mediastinum (PET and or /CT positive mediastinum) should undergo subsequent 
mediastinoscopy.
Note: When enlarged PET positive lymph nodes are visualized at subaortic lymph nodes 
(station 5) or the para-aortic lymph nodes (station 6), AND if these lymph node stations 
cannot be biopsied by routine mediastinoscopy due to difficult approach, THEN these 
participants can enroll without further invasive mediastinal LN evaluation.
Protocol Amendment No.: 04
Date: 28-Feb-2024
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Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA20977T)
Procedure
Screening Visit
Notes
Biomarkers
EGFR mutation status
X
EGFR mutation status required for all non-squamous participants. Historical results 
obtained as standard of care prior to screening period are acceptable. Use of a FDA-
approved or local Health Authority-approved test (tissue or blood) is strongly encouraged.
Tumor Tissue Sample collection
X
Tumor tissue submission prior to randomization is mandatory. If a recent/archived (within 
3 months from randomization) biopsy sample is not available at screening, a fresh biopsy 
will be taken. 
Sufficient tumor tissue obtained prior to randomization (FFPE block [preferred] or 5 to 10
unstained slides, obtained from core biopsy, excisional biopsy or surgical specimen). For 
participants for whom a fresh biopsy is not feasible, archival tumor material obtained 
within 3 months prior to randomization must be made available. Fine needle aspirate of 
draining lymph node is not acceptable. Core needle biopsies obtained by EBUS are 
acceptable. 
Tumor tissue and pathology report must be submitted to central laboratory and PD-L1 
status results available prior to randomization. 
Tissue requirements are outlined in the CA20977T Laboratory Manual. 
Study Treatment
Randomize
X
PD-L1 will be analyzed by a central laboratory, with results required in IRT prior to 
randomization
Randomize in the Interactive Response system
Treatment to be started within 3 calendar days from randomization
Protocol Amendment No.: 04
Date: 28-Feb-2024
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Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-2:
Neoadjuvant and Pre-surgery Procedures and Assessments (CA20977T)
Procedure
Cycle 1 to 4 
Each Cycle
Day 1 
Pre-surgery 
(Within 14 Days 
Before Surgery)
Notes: 1 cycle = 3 weeks
Safety Assessments
Targeted Physical Examination, Vital 
Signs, Performance Status 
X
X
Targeted physical examination as clinically indicated at each study visit; 
temperature, heart rate, blood pressure, respiratory rate; and weight. Confirm 
ECOG performance status (See Appendix 5).
Adverse Events Assessment
Continuously
Collect AEs and SAEs. See Section 9.2.
All AEs (SAEs or nonserious AEs), including those associated with SARS-
CoV-2 infection, must be collected continuously during the treatment period.
Review of Concomitant Medications
Continuously
Record at each visit during treatment.
Pulmonary Function Test
X
Mandatory PFTs to be re-evaluated prior to surgery only. It is recommended to 
use same machine and methods throughout study. Includes FVC, FEV1, TLC, 
FRC, DLco, and oxygen saturation. 
ECG
X
To be performed before surgery
Clinical Laboratory Testing
X
X
Hematology and chemistry assessments scheduled for the day of study drug(s) 
dosing must be available and assessed before dosing. Hematology and chemistry 
assessments can be drawn within 72 hours prior to dosing. See Section 9.4.4. for 
a list of laboratory tests
Pregnancy Test (WOCBP only)
See notes
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units 
of HCG) to be done within 24 hours prior to Day 1 of each cycle.
Serum or urine pregnancy must be performed for at least every 4 weeks on 
treatment, during pre-surgery period, and during post surgery recovery period. 
See Appendix 4
Protocol Amendment No.: 04
Date: 28-Feb-2024
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6.0
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v

Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-2:
Neoadjuvant and Pre-surgery Procedures and Assessments (CA20977T)
Procedure
Cycle 1 to 4 
Each Cycle
Day 1 
Pre-surgery 
(Within 14 Days 
Before Surgery)
Notes: 1 cycle = 3 weeks
Efficacy Assessments
Body Imaging
X
See notes
A preoperative PET-CT with contrast should be acquired  at least 14 days after 
last neoadjuvant dose and before surgery. If the CT component of a PET-CT is 
not of sufficient diagnostic quality for RECIST 1.1 assessment, a separate CT 
with contrast of the chest, abdomen, pelvis and other suspected areas (in 
addition to the PET-CT) is required. If CT with contrast of the abdomen, pelvis, 
and all other known and/or suspected sites of disease is contraindicated, then a 
MRI is acceptable. See Section 9.1.2 for further details. 
Brain Imaging
X
See notes
Participants should have a brain MRI at least 14 days after last neoadjuvant 
dose and before surgery, if clinically indicated. CT of the brain without and 
with contrast prior can be performed prior to surgery if MRI is contraindicated. 
See Section 9.1.2 for further details.
Pharmacokinetic/Immunogenicity Assessments
Pharmacokinetics samples
See notes
Refer to Section 9.5
Immunogenicity
See notes
Refer to Section 9.5
Biomarker Assessments
Biomarker sample collection
See notes
See notes
To be collected before dosing. See Section 9.8.
Collection of optional tumor tissue (if
disease progression/recurrence)
See notes
Excised tumor tissue submission (FFPE block [preferred] or 10 to 15 unstained 
slides) obtained from core biopsy, excisional biopsy, or surgical specimen is 
optional but strongly encouraged upon disease progression/recurrence and prior 
to subsequent systemic treatment. Fine needle aspirate of draining lymph node 
is not acceptable. Core needle biopsies obtained by EBUS are acceptable. See 
Section 9.8.
If a tumor tissue sample is collected, see CA20977T Laboratory Manual for 
tissue requirements
Protocol Amendment No.: 04
Date: 28-Feb-2024
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6.0
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1.0
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Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-2:
Neoadjuvant and Pre-surgery Procedures and Assessments (CA20977T)
Procedure
Cycle 1 to 4 
Each Cycle
Day 1 
Pre-surgery 
(Within 14 Days 
Before Surgery)
Notes: 1 cycle = 3 weeks
Collection of blood sample (if disease 
progression/recurrence)
See notes
Blood sample collection at the time of disease progression/recurrence is 
mandatory prior to subsequent systemic treatment. See Section 9.8 and refer to 
CA20977T Laboratory Manual for sample requirements.
Surgical tumor tissue and lymph node 
sample collection at time of surgery
See note
Tissue collection from definitive surgical resection is mandatory for 
•
Central review of pathologic response: the completed surgical and 
pathology reports, as well as any photograph or sketches noting the 
measurements of the primary tumor bed or location of tumor are required. 
H&E slides from any tumor, tumor bed, and lymph node specimens which 
were reviewed locally must be submitted for central pathology review. 
Additionally, all H&E slides (1 stained slide per block) from all of the 
blocks from surgery are submitted for central pathology review. 
•
Biomarker assessments: Submission of the following is required: 1 tumor 
block (Preferred, consisting of 2-3 pieces 3-5 mm in size) or 15 unstained 
slides obtained from a similar surgical specimen.
Tissue requirements are outlined in CA20977T Laboratory Manual.
Outcomes Assessments
NSCLC-SAQ
X
X
Completed prior to treatment at each cycle and pre-surgery visit. 
See Section 9.1.4 for further details.
PGIS
X
X
Completed prior to treatment at each cycle and pre-surgery visit. 
See Section 9.1.4 for further details.
PROMIS PF 8c
X
X
Completed prior to treatment at each cycle and pre-surgery visit. 
See Section 9.1.4 for further details.
FACT-L
X
X
Completed prior to treatment at each cycle and pre-surgery visit. 
See Section 9.1.4 for further details.
EQ-5D-3L
X
X
Completed prior to treatment at each cycle and pre-surgery visit. 
See Section 9.1.4 for further details.
Protocol Amendment No.: 04
Date: 28-Feb-2024
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6.0
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1.0
v

Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-2:
Neoadjuvant and Pre-surgery Procedures and Assessments (CA20977T)
Procedure
Cycle 1 to 4 
Each Cycle
Day 1 
Pre-surgery 
(Within 14 Days 
Before Surgery)
Notes: 1 cycle = 3 weeks
HCRU (Health Care Resource 
Utilization)
X
X
Health care resource utilization data will be collected at each visit by study site 
staff using the case report form (CRF)
Study Treatment
IRT Drug Vial Assignments
X
Register the visit in the Interactive Response system for drug allocation 
(performed by unblinded site staff)
Dispense Study treatment
X
See Section 7 for complete details. 
Protocol Amendment No.: 04
Date: 28-Feb-2024
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6.0
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v

Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-3:
Post surgery/Pre-adjuvant and Adjuvant Treatment Procedures and Assessments (CA20977T)
Procedure
Post surgery/Pre-
adjuvant Visita
(after post surgery 
recovery period of 
30-90 days)
Cycle 1 to Cycle 13b
Each Cycle Day 1
1 cycle = 4 weeks
1 year of treatment
Notes
Safety Assessments
Adverse Event and 
Serious Adverse Event 
Assessments
Continuously 
All AEs (SAEs or nonserious AEs), including those associated with SARS-CoV-
2 infection, must be collected continuously during the treatment period. See 
Section 9.2.
Concomitant
Medication Review
Continuously
Record at each visit during treatment.
Targeted Physical 
Examination
X
X
Vital Signs: temperature, heart rate, blood pressure, and respiratory rate; and 
weight. Confirm ECOG performance status (Appendix 5)
Laboratory Tests
Clinical Laboratory 
Testing
X
X
Hematology and chemistry assessments scheduled for the day of study drug(s) 
dosing must be available and assessed before dosing.
Hematology and chemistry assessments can be drawn within 72 hours prior to 
dosing.
See Section 9.4.4. for a list of laboratory tests to conduct
Pregnancy Test 
(WOCBP only) 
See notes
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units 
of HCG) to be done within 24 hours prior to Day 1 of each cycle.
Serum or urine pregnancy must be performed for at least every 4 weeks on 
treatment, during pre-surgery period, and during post surgery recovery period.
See Appendix 4
Biomarker Assessments
Biomarker Sample 
Collection
See notes
See notes
See section 9.8
Collection of optional
tumor tissue (if disease 
progression/recurrence)
See note
At time of disease progression or recurrence (see Section 9.8) 
Excised tumor tissue submission (FFPE block [preferred] or 10 to 15 unstained 
slides), obtained from core biopsy, excisional biopsy, or surgical specimen is 
Protocol Amendment No.: 04
Date: 28-Feb-2024
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6.0
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930137469
6.0
v
Approved
1.0
v

Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-3:
Post surgery/Pre-adjuvant and Adjuvant Treatment Procedures and Assessments (CA20977T)
Procedure
Post surgery/Pre-
adjuvant Visita
(after post surgery 
recovery period of 
30-90 days)
Cycle 1 to Cycle 13b
Each Cycle Day 1
1 cycle = 4 weeks
1 year of treatment
Notes
optional but strongly encouraged upon disease progression/recurrence and prior 
to subsequent systemic treatment. Fine needle aspirates of draining lymph node 
are not acceptable. Core needle biopsies obtained by EBUS are acceptable. 
If a sample is collected, see CA20977T Laboratory Manual for tissue 
requirements.
Collection of blood
sample (if disease 
progression/recurrence)
See note
Blood sample collection at the time of disease progression is mandatory prior to 
subsequent systemic treatment. See section 9.8 and refer to CA20977T 
Laboratory Manual for sample requirements.
Efficacy Assessments
Body Imaging
X
See notes
Contrast enhanced CT of the chest, abdomen, pelvis, and all other known and/or 
suspected sites of disease. If CT with contrast of the abdomen, pelvis, and all 
other known and/or suspected sites of disease is contraindicated, then a MRI is 
acceptable.
The first tumor assessment post surgery should occur within 1 week prior to 
initiation of study adjuvant treatment. 
Subsequent assessment should occur every 12 weeks (± 7 days) for up to and 
including 108 weeks (approximately 2 years) following first dose of adjuvant 
treatment, then every 24 weeks (±14 days) for up to and including Week 276 
(approximately 5 years) or until disease recurrence or disease progression is 
confirmed by blinded independent central review (BICR) and, in addition,
continue until investigator-assessed distant metastasis.
Participants that do not undergo surgery  will continue to have tumor assessments 
every 12 weeks (±7 days) for up to and including 108 weeks (approximately 2 
years), (following the pre-surgery PET-CT scan) then every 24 weeks (±14 days) 
for up to and including Week 276 (approximately 5 years) or until disease 
Protocol Amendment No.: 04
Date: 28-Feb-2024
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930137469
6.0
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1.0
v

Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-3:
Post surgery/Pre-adjuvant and Adjuvant Treatment Procedures and Assessments (CA20977T)
Procedure
Post surgery/Pre-
adjuvant Visita
(after post surgery 
recovery period of 
30-90 days)
Cycle 1 to Cycle 13b
Each Cycle Day 1
1 cycle = 4 weeks
1 year of treatment
Notes
recurrence or disease progression is confirmed by BICR and, in addition, 
continue until investigator-assessed distant metastasis.
See Section 9.1.2 for further details.
Body Brain Imaging
X
See notes
Participants should have a brain MRI, if clinically indicated. CT of the brain 
without and with contrast can be performed if MRI is contraindicated. 
See Section 9.1.2 for further details.
Pharmacokinetic/Immunogenicity Assessments 
Pharmacokinetics
See notes
See 9.5 for further details.
Immunogenicity
See notes
See 9.5 for further details.
Outcomes Assessments
NSCLC-SAQ
X
X
Completed at post surgery visit and prior to treatment at each cycle. See Section 
9.1.4 for further details.
PGIS
X
X
Completed at post surgery visit and prior to treatment at each cycle. See Section 
9.1.4 for further details.
PROMIS PF 8c
X
X
Completed at post surgery visit and prior to treatment at each cycle. See Section 
9.1.4 for further details.
FACT-L
X
X
Completed at post surgery visit and prior to treatment at each cycle. See Section 
9.1.4 for further details.
EQ-5D-3L
X
X
Completed at post surgery visit and prior to treatment at each cycle. See Section 
9.1.4 for further details.
Protocol Amendment No.: 04
Date: 28-Feb-2024
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930137469
6.0
v
Approved
1.0
v

Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-3:
Post surgery/Pre-adjuvant and Adjuvant Treatment Procedures and Assessments (CA20977T)
Procedure
Post surgery/Pre-
adjuvant Visita
(after post surgery 
recovery period of 
30-90 days)
Cycle 1 to Cycle 13b
Each Cycle Day 1
1 cycle = 4 weeks
1 year of treatment
Notes
Healthcare Resource 
Utilization
X
X
Healthcare resource utilization data will be collected at each visit by study site 
staff using the case report form (CRF).
Administer Study Drug
IRT Drug Vial 
Assignments
X
Register the visit in the Interactive Response system for drug allocation 
(performed by unblinded site staff)
Register the study drug discontinuation at the end of the study treatment period in 
the Interactive Response system
Dispense Study 
treatment
X
See Section 7 for complete details. 
Participants should be treated within 90 days from surgery.
a Participants who have not had definitive surgical resection, may continue onto adjuvant cycles 1-13 and follow the post surgery on study assessments (See 
Section 5.1.2.3)
b If a dose is delayed, the procedures scheduled for that same time point, except body/brain imaging and pregnancy testing, should also be delayed to coincide 
with when the time point’s dosing actually occurs
Note: Some assessments referred to in this section may not be captured as data in the CRF. These assessments are intended to be used as safety monitoring by the 
investigator. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations
Protocol Amendment No.: 04
Date: 28-Feb-2024
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v

Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-4:
Long-term Follow-up Assessments (CA20977T)
Procedure
Follow-up 
Visit 1a,b
Follow-up 
Visit 2a,b
Disease Surveillance and 
Survival Follow-upc
Notes
Survival status
X
X
X
Survival status should be obtained every 3 months (± 14 days) 
after Follow-up Visit 2.
Subsequent anti-cancer 
therapy 
X
X
X
The date of disease progression and response to anti-cancer 
subsequent therapy will be collected.
Safety Assessments
Targeted Physical 
Examination
X
X
Vital Signs: blood pressure, heart rate, temperature, respiratory 
rate; and weight. ECOG performance status (Appendix 5)
Serious Adverse Events 
Assessment
X
X
All SAEs must be collected within 100 days of the last dose of 
study treatment and followed until SAE is resolved.
Participants will be followed for all SAEs, nonserious AEs of 
special interest (as defined in Section 9.2.1), and all AEs (SAEs 
and nonserious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection until resolution, the condition stabilizes, 
the event is otherwise explained, the event is deemed irreversible, 
the participant is lost to follow-up (as defined in Section 8.3), or 
for suspected cases, until SARS-CoV-2 infection is ruled-out.
Adverse Events Assessment
X
X
All AEs must be collected within 100 days of the last dose of 
study treatment 
Concomitant Medications
X
X
Subsequent anti-cancer 
therapy 
X
X
X
Laboratory Tests
Clinical Laboratory Testing
X
X
See note
See Section 9.4.4 for a list of laboratory tests to conduct
Collect hematology and chemistry at FU1 and FU2 and until all 
previous toxicities have resolved. See Section 9.2.6.
Protocol Amendment No.: 04
Date: 28-Feb-2024
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v

Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-4:
Long-term Follow-up Assessments (CA20977T)
Procedure
Follow-up 
Visit 1a,b
Follow-up 
Visit 2a,b
Disease Surveillance and 
Survival Follow-upc
Notes
Pregnancy Test (WOCBP)
See notes
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) to be done every 4 weeks for 6 months 
or longer as per the local regulation and approved product label 
(for nivolumab and chemotherapy regimens specified as study 
treatment in the protocol) after the last dose of study treatment.
See Appendix 4
Serum or urine pregnancy test must be performed prior to 
imaging 
Efficacy Assessment,
Body imaging
Contrast enhanced CT of the chest, abdomen, pelvis, and all other known and/or suspected sites of disease. (Section 9.1.2 for 
further details). If CT with contrast of the abdomen, pelvis, and all other known and/or suspected sites of disease is 
contraindicated, then a MRI is acceptable.
For participants that undergo definitive surgery, the first tumor assessment should occur within 1 week prior to adjuvant 
treatment and will follow the outlined schedule for ongoing tumor assessments. Imaging should be continued for a maximum of 
5 years from the first dose of adjuvant treatment or until BICR confirmed disease progression or recurrence and, in addition, 
continue until investigator-assessed distant metastasis at intervals of:
•
Every 12 weeks (± 7 days)  during Year 1 and Year 2 (for up to and including 108 weeks from first dose of adjuvant 
treatment)
•
Every 24 weeks (± 14 days) during Year 3, Year 4 and Year 5 (for up to and including 276 weeks)
For participants that do not undergo surgery should align with ongoing tumor assessments. Imaging should be continued 
for a maximum of 5 years from the pre-surgery PET-CT scan or until BICR confirmed disease progression or recurrence and, 
in addition, continue until investigator-assessed distant metastasis at intervals of:
•
Every 12 weeks (± 7 days) during Year 1 and Year 2 (for up to and including 108 weeks from presurgery PET scan)
•
Every 24 weeks (± 14 days) during Year 3, Year 4 and Year 5 (for up to and including 276 weeks from presurgery PET 
scan)
See Section 9.1.2 for further details.
Protocol Amendment No.: 04
Date: 28-Feb-2024
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930137469
6.0
v
Approved
1.0
v

Clinical Protocol
CA20977T
BMS-936558
nivolumab
Table 2-4:
Long-term Follow-up Assessments (CA20977T)
Procedure
Follow-up 
Visit 1a,b
Follow-up 
Visit 2a,b
Disease Surveillance and 
Survival Follow-upc
Notes
Brain Imaging 
Only for participants without BICR-confirmed progression or recurrence and without investigator-assessed progression 
precluding surgery. Participants should have a brain MRI, if clinically indicated. CT of the brain without and with contrast 
can be performed if MRI is contraindicated. See Section 9.1.2 for further details.
Biomarkers
Biomarker sample collection
See notes
See Section 9.8.
Collection of optional tumor 
tissue upon disease 
progression/recurrence
See notes
At time of disease progression or recurrence (see Section 9.8) 
Excised tumor tissue submission (FFPE block [preferred] or 10 to 
15 unstained slides), obtained from core biopsy, excisional 
biopsy, or surgical specimen is optional but strongly encouraged 
upon disease progression/recurrence and prior to subsequent 
systemic treatment. Fine needle aspirates of draining lymph node 
are not acceptable. Core needle biopsies obtained by EBUS are 
acceptable. If a sample is collected, see CA20977T Laboratory 
Manual for tissue requirements
If disease is inaccessible at disease progression/recurrence, tumor 
tissue can be accessed later in the disease course (if available) 
with intervening therapy documented in the CRF. 
Collection of blood sample 
upon disease 
progression/recurrence
See notes
Blood sample collection at the time of disease progression is 
mandatory prior to subsequent systemic treatment. See section 
9.8 and refer to CA20977T Laboratory Manual for sample
requirements.
Outcomes Assessments
NSCLC-SAQ
X
X
X
To be administered during the Follow-up Visits 1 & 2 and at each 
study visit during disease surveillance. See Section 9.1.4 for 
PGIS
X
X
X
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Table 2-4:
Long-term Follow-up Assessments (CA20977T)
Procedure
Follow-up 
Visit 1a,b
Follow-up 
Visit 2a,b
Disease Surveillance and 
Survival Follow-upc
Notes
PROMIS PF 8c
X
X
X
further details. Survival visits may be conducted in person or by 
telephone (if by telephone, only EQ-5D-3L (phone) outcome 
assessments questionnaire should be collected).
FACT-L
X
X
X
EQ-5D-3L
X
X
X
Healthcare Resource 
Utilization
X
X
X
Healthcare resource utilization data will be collected at each visit 
by study site staff using the case report form (CRF).
a Participants must be followed for at least 100 days after the last dose of study treatment. Follow-up Visit 1 should occur 30 days from the last dose (± 7 days) 
or can be performed on the date of discontinuation if that date is greater than 42 days from the last dose. Follow-up Visit 2 occurs approximately 100 days 
(± 7 days) from the last dose of study treatment. Both follow-up visits should be conducted in person. For participant who did not undergo adjuvant treatment 
after surgery, FU1 should occur 30 days from post-surgery visit (± 7 days). FU2 should occur approximately 100 days (± 7 days) from post-surgery visit. Both 
follow-up visits should be conducted in person.
b Some assessments referred to in this section may not be captured as data in the CRF. These assessments are intended to be used as safety monitor by the 
investigator. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
c Survival follow-up visits to occur every 3 months (± 14 days) from Follow-up Visit 2. Survival visits may be conducted in person or by telephone. Bristol-Myers 
Squibb may request that survival data be collected on all treated participants outside of the 3-month specified window.
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3
INTRODUCTION
CA20977T is a phase 3, randomized, double-blinded Study of neoadjuvant chemotherapy plus 
nivolumab versus neoadjuvant chemotherapy plus placebo, followed by surgical resection and 
adjuvant treatment with nivolumab or placebo for participants with resectable stage IIA-IIIB non-
small cell lung cancer. 
Approximately 80% of lung cancer cases are NSCLC, with most patients presenting with late stage 
disease. Of patients with NSCLC, 20% present with stage I or II disease, whereas 30% present 
with stage III disease and 50% with stage IV disease. Patients with pathologic stage I NSCLC have 
a 5-year survival of approximately 60%. Stage II to III NSCLC patients have a 5-year survival of 
approximately 25% to 40%.1 Therefore, earlier diagnosis and treatment of NSCLC at stage II will 
provide better micrometastatic disease control, which may support greater survival.
CA20977T is a phase 3, randomized, double-blinded study of neoadjuvant chemotherapy plus 
nivolumab versus neoadjuvant chemotherapy plus placebo, followed by surgical resection and 
adjuvant treatment with nivolumab or placebo for participants with resectable stage IIA-IIIB non-
small cell lung cancer. The study will allow for direct comparison of nivolumab plus chemotherapy 
versus SOC chemotherapy alone in the periadjuvant setting. The study is designed with an analysis 
of event free survival (EFS) as the primary end point and pathologic complete response (pCR) rate 
as the key secondary endpoint.
3.1
Study Rationale
The early-stage (IIA-IIIB) NSCLC represents a population of high unmet need with a 5-year 
survival rate of 25-50%. A rational approach to improve survival in these patients is to eradicate 
micrometastatic disease and to minimize the risk of relapse with neoadjuvant and adjuvant
maintenance therapy. 
The SOC treatment comprises adjuvant or neoadjuvant platinum-based doublet chemotherapy for 
patients with operable stage IB-IIIA NSCLC or chemoradiation for patients with unresectable 
stage IIIA/B NSCLC. Preoperative or neoadjuvant chemotherapy has been assessed in a number 
of trials for patients with operable NSCLC. A meta-analysis based on 7 trials involving 
988 patients suggested that neoadjuvant chemotherapy improved OS when given preoperatively 
in a similar magnitude to those observed with adjuvant chemotherapy. Neoadjuvant 
immunotherapy in combination with chemotherapy offers the possibility achieving enhanced 
pathological complete response rate compared to SOC chemotherapy alone. In addition, it also 
allows for the identification of surrogate clinical and biological markers that may correlate with 
response to therapy and a potential long-term outcome. Randomized trials are currently ongoing 
to explore the potential benefit of nivolumab in the neoadjuvant, adjuvant, and locally advanced 
unresectable NSCLC setting. In addition, the safety and efficacy profile of neoadjuvant nivolumab 
monotherapy or combination therapy (nivolumab plus chemotherapy) are being evaluated in 
ongoing trials. 
Emerging phase 1/2 data provides the early encouraging signal of nivolumab or nivolumab in 
combination with chemotherapy as neoadjuvant therapy with increasing major pathological 
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response rate and pathological complete response rates, respectively, with no delay in surgery and 
tolerable safety profile. Data from NADIM trial (NCT03081689), a phase 1/2 study evaluating 
nivolumab given concomitantly with chemotherapy indicated this combination, was well tolerated 
thus far with no major increase in prohibitive toxicity, including pneumonitis. Data from this 
phase 2 study presented at the 19th World Conference on Lung Cancer showed 18 patients (75.0%) 
achieved complete response, while 24 patients (80.0%) had a major pathologic response. Overall, 
periadjuvant scheduling with combination of immunotherapy and chemotherapy in the 
neoadjuvant setting followed by immunotherapy maintenance in the adjuvant setting following 
definitive surgery may offer enhanced efficacy with improved survival with an acceptable toxicity 
profile.
This study of nivolumab and chemotherapy followed by continued adjuvant nivolumab after 
surgical resection, aims to demonstrate that treatment with nivolumab combined with 
chemotherapy in neoadjuvant phase and maintenance with nivolumab in the adjuvant phase will 
significantly prolong EFS and increase the rate of pCR in participants with resectable Stage IIA-
IIIB non-small cell lung cancer.
3.1.1
Research Hypothesis
The incorporation of nivolumab to neoadjuvant chemotherapy with adjuvant maintenance will 
prolong event-free survival (EFS) and increase overall survival (OS), as compared with 
neoadjuvant chemotherapy as SOC in participants with newly diagnosed, resectable NSCLC.
3.2
Background
Surgical resection remains the mainstay of treatment for stage I and II patients; however, despite 
potential curative surgery, approximately 27% of stage IB and 35-59% of stage II-IIA NSCLC 
patients will relapse and eventually die of their disease.2 With enhanced lung cancer screening 
techniques, the percentage of those diagnosed during the early stages may increase over the 
duration of the trial. The eighth edition of the TNM staging system is used to determine the staging 
for NSCLC.3 Patients with pathologic stage IA1 NSCLC have a 5-year survival of approximately 
90%. Stage II to III NSCLC patients have a 5-year survival of approximately 12% to 65%.4
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. Many adjuvant 
studies have been performed, and these trials are summarized in Table 3.2-1. Although there are 
some conflicting results, the overall evidence from these studies suggests that adjuvant platinum-
based doublet chemotherapy is beneficial for good Performance Status patients with stage 
≥II disease. The benefit to stage IB patients is less clear and may depend on the size of the primary 
tumor (eg, Stage Ib) and other risk factors. A 2010 meta-analysis including both older and more 
recent trials confirmed the survival benefit shown in the LACE meta-analysis and also suggested 
a benefit of adjuvant chemotherapy for stage IB disease.5
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Table 3.2-1:
Select Adjuvant NSCLC Studies
Trial
Stage
Treatment
# of Pts
5 Yr OS
HR
P Value
ECOG 1505
I-III
Cis-doublet
Cis-double+Bev
749
752
72 mo mOS in 
both arms
0.99
0.9
ALPI
I – III
Surg
MVP
603
601
45%
50%
0.96
0.59
IALT
I – III
Surg
Cis-based
935
932
40%
44.5%
0.86
<0.03
ANITA
IB - IIIA
Surg
Cis-Vin
433
407
43%
51%
0.80
0.017
BLT
I – IIIA
Surg
Cis-based
189
192
58%
60%
1.02
0.90
NCIC/JBR10
IB – II
Surg
Cis-Vin
240
242
54%
69%
0.69
0.03
CALGB
IB
Surg
Carb-pac
171
173
57%
59%
0.80
0.10
ALPI
I – III
Surg
MVP
603
601
45%
50%
0.96
0.59
ALPI, Adjuvant Lung Cancer Project Italy; OS, overall survival; HR, hazard ratio; ECOG, Eastern Cooperative 
Oncology Group, IALT, International Adjuvant Lung Cancer Trial; ANITA, Adjuvant Navelbine International Trialist 
Association; BLT, Big Lung Trial; NCI-C, National Cancer Institute-Canada; CALGB, Cancer and Leukemia Group 
B; MVP, mitomycin, vindesine, cisplatin; Cis-Vin, cisplatin-vinorelbine; Carb-pac, carboplatin-paclitaxel.
The early-stage (IB-III) NSCLC represents a population of high unmet need with a 5-year survival 
rate of 25-50%.6 The current available standard of care (SOC) only provides a 5% absolute 
improvement in 5-year overall survival (OS).2,7,8,9 The SOC comprises adjuvant or neoadjuvant 
platinum-based doublet chemotherapy for patients with operable stage IB-IIIA NSCLC or 
chemoradiation for patients with unresectable stage IIIA/B NSCLC. Follow-up of adjuvant trials 
are long and may require decades before a new treatment is introduced into clinical practice. 
Preoperative or neoadjuvant chemotherapy has been assessed in a number of trials for patients with 
operable NSCLC. A meta-analysis based on 7 trials involving 988 patients suggested that 
neoadjuvant chemotherapy improved OS when given preoperatively in a similar magnitude to 
those observed with adjuvant chemotherapy.10
Randomized trials are currently on-going to explore the potential benefit of nivolumab in the 
neoadjuvant, adjuvant, and locally advanced unresectable NSCLC setting. In addition, the safety 
and efficacy profile of neoadjuvant nivolumab monotherapy or combination therapy (nivolumab 
plus chemotherapy) are being evaluated in ongoing trials. 
Emerging phase 1/2 data provides the early encouraging signal of nivolumab or nivolumab in 
combination with chemotherapy as neoadjuvant therapy with increasing MPR or pCR rates, 
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respectively, with no delay in surgery and tolerable safety profile. Preliminary data from NADIM 
trial (NCT03081689) which is a phase 1/2 study to evaluate nivolumab given concomitantly with 
chemotherapy indicated this combination, was well tolerated thus far with no major increase in 
prohibitive toxicity, including pneumonitis.11 Overall, periadjuvant scheduling of immunotherapy 
with chemotherapy may offer enhanced efficacy with an acceptable toxicity profile.
This periadjuvant phase 3 study (CA20977T) will evaluate the clinical efficacy and will establish 
the safety of neoadjuvant therapy of nivolumab plus platinum-based doublet chemotherapy 
followed by adjuvant therapy of nivolumab in resectable lung cancer. Specifically, this study will 
compare EFS and OS and estimate pCR rate among participants treated with periadjuvant therapy.
3.2.1
Nivolumab Mechanism of Action 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.12,13,14
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor (TCR).15 Collectively, these signals govern 
the balance between T-cell activation and tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA 4, ICOS, and BTLA.16 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression also been 
noted to inhibit T cell activation, and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes.17 These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon various 
host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 
and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a 
cytomegalovirus (CMV) restimulation assay with human peripheral blood mononuclear cells 
(PBMC), the effect of nivolumab on antigen specific recall response indicates that nivolumab 
augmented IFN-γ secretion from CMV specific memory T cells in a dose-dependent manner versus 
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isotype-matched control. In vivo blockade of PD-1 by a murine analog of nivolumab enhances the 
anti-tumor immune response and result in tumor rejection in several immunocompetent mouse 
tumor models (MC38, SA1/N, and PAN02).18
A detailed description of the chemistry, pharmacology, efficacy, and safety of nivolumab is 
provided in the Nivolumab Investigators Brochure.
3.2.2
Clinical Activity of Immuno-oncology Treatment Combined with 
Chemotherapy 
The combination of immuno-oncology agents and traditional chemotherapy has been explored. In 
addition to the additive effects of combining drugs with different mechanisms of action, emerging 
evidence indicates that one of the mechanisms of actions of chemotherapy is via activation of the 
immune system through multiple pathways.8 The subsequent cytotoxic cell death from 
chemotherapies and subsequent antigen release may provide immune stimulation. Certain 
chemotherapy regimens have a broad effect on cell death and physiological response. As an 
example, cyclophosphamide reduces the number of circulating Treg cells, which are a key 
component in immunosuppression and gemcitabine has also been shown to reduce MDSCs and 
hence interferon-gamma, which have inhibitory roles in the immune response.19, 20 The dual role 
of cytotoxicity and immune activation from chemotherapy has provided the biological rationale 
for the development of combinations with immunotherapy.21
Nivolumab added to chemotherapy has been evaluated in several cohorts of chemotherapy-naive 
patients with advanced NSCLC in study Checkmate 012. Nivolumab 10 mg/kg was combined with 
gemcitabine and cisplatin or pemetrexed + cisplatin. Nivolumab 10 mg/kg and 5 mg/kg were
combined with paclitaxel and carboplatin.
The safety profile of nivolumab plus platinum-based doublet chemotherapy reflects additive 
toxicities of the individual agents, which were manageable using established safety guidelines. No 
dose-limiting toxicities were observed during first 6 weeks of treatment. The frequency of most 
immune-related select AEs was higher for the combination than what has been observed for 
nivolumab monotherapy. However, these treatment-related AEs, including pneumonitis, were 
effectively managed and did not lead to any deaths. Pneumonitis of any grade was reported in 
7 participants (13%): Grade 3-4 in 4 participants (7%). Twelve (21%) participants discontinued 
due to treatment-related AEs.
Table 3.2.2-1:
Safety in CA209012
Total (N=56)
All Grades
Grade 3
Grade 4
Participants with any treatment-related AE, % (n)
95 (53)
41 (23)
4 (2)a
Treatment-related AE in >15% of Patients, % (n)
Fatigue 
71(40)
5 (3)
0
Nausea
46 (26)
2 (1)
0
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Table 3.2.2-1:
Safety in CA209012
Total (N=56)
All Grades
Grade 3
Grade 4
Decrease Appetite
36 (20)
2 (1)
0
Alopecia
30 (17)
0
0
Anemia
27 (15)
4 (2)
0
Rash
27 (15)
2 (1)
0
Arthralgia
21 (12)
0
0
Diarrhea
21 (12)
2 (1)
0
Constipation
20 (11)
0
0
Peripheral Neuropathy
20 (11)
0
0
a Grade 4 events: neutrophil count decreased (n = 1), pneumonitis and neutropenia (n = 1 each; occurred in the same 
patient).
The overall response rate across all the nivolumab and chemotherapy cohorts ranged from 33-47% 
and median duration of response was 27.3 weeks (see Table 3.2.2-2). Activity was evaluated by 
PD-L1 expression and was observed in participants with both PD-L1 expressing and non-
expressing tumors. Overall, 79% (44/56) of participants had evaluable tumor samples. At the ≥1% 
expression level, the response rate was 48% and 43% for expressers and non-expressers, 
respectively. The 1-year OS was 70% and 76% for expressers and non-expressers, respectively. 
Table 3.2.2-2:
Efficacy of First-Line Treatment of Nivolumab/Chemotherapy 
Combination in CA209012
Nivolumab 10 mg/kg
Nivolumab 5 mg/kg
Gem/Cis
(n=12)
Pem/Cis
(n=15)
Pac/Carb
(n=15)
Pac/Carb
(n=14)
ORR, %
33
47
47
43
SD, %
58
47
27
43
Median Duration of Response, Weeks
45
24.4
2.3
27.3
12-mo OS rate, %
50
87
7
86
18-mo OS Rate, %
33
60
40
62
Median OS, Weeks
51
83
65
Not Reached
In the ongoing CheckMate 227 trial, in the setting of first line NSCLC with <1% tumor PD-L1 
expression, PFS was improved with nivolumab plus chemotherapy vs chemotherapy (mPFS: 5.6m 
vs 4.7m; HR=0.74 [95% CI: 0.58 to 0.94]), ORR was 36.7% in nivolumab plus chemotherapy arm, 
23.1% in chemotherapy arm, mDOR was 7.2 months in nivolumab plus chemotherapy arm, 
4.7 months in chemotherapy arm. The rate of grade 3 or 4 treatment-related adverse events was 
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52% with nivolumab plus chemotherapy, 35% with chemotherapy, Overall, the safety profile and 
efficacy are consistent with previously reported data for nivolumab plus chemotherapy, as well as 
data from other PD-(L)1 blockades in combination with chemotherapy.
The early clinical data is emerging to show the benefit of immunotherapy and chemotherapy 
combination in early NSCLC setting. The nivolumab in combination with paclitaxel and 
carboplatin has shown increased pathological response rate in IIIA NSCLC patients. Similarly, 
combination of atezolizumab in combination with carboplatin and nab-paclitaxel has demonstrated 
significant activity in neoadjuvant setting. In both trials, combination of immunotherapy with 
chemotherapy has been well tolerated in patients with early stage NSCLC. 
The clinical activity of nivolumab observed to date in NSCLC, including 2 positive phase 3 studies 
demonstrated prolonged survival with nivolumab monotherapy compared to docetaxel in 
squamous and non-squamous NSCLC after platinum failure. CA209057 (An Open-Label 
Randomized Phase III Trial of Nivolumab versus Docetaxel in Previously Treated Metastatic 
NSCLC) study demonstrated OS was superior for participants receiving nivolumab compared to 
those receiving docetaxel. Higher confirmed ORRs in PDL1 expressers were seen in the 
combination arm compare to the nivolumab monotherapy arm in CA209012 (A Multi-arm Phase I 
Safety Study of Nivolumab in Combination with Gemcitabine/Cisplatin, Pemetrexed/Cisplatin, 
Carboplatin/Paclitaxel, Bevacizumab Maintenance, Erlotinib, Ipilimumab or as Monotherapy in 
Subjects with Stage IIIB/IV NSCLC).
3.3
Benefit/Risk Assessment
Extensive details on the safety profile of nivolumab or in combination with chemotherapy are 
available in the Investigator Brochure, and will not be repeated herein.
Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical trials with no MTD reached at any dose tested up to 
10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 
to 4) AEs. There was no pattern in the incidence, severity, or causality of AEs with respect to 
nivolumab dose level.
A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed; these are provided in Appendix 06. Most high-grade events were 
manageable with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as 
instructed in these algorithms. Additional details on the safety profile of nivolumab, including 
results from other clinical studies, are also available in the nivolumab IB.
The early-stage (IIA-IIIB) NSCLC represents a population of high unmet need with a 5 year 
survival rate of 25-50%. The current available SOC, including adjuvant or neoadjuvant platinum-
based doublet chemotherapy, only provides a 5% absolute improvement in 5-year OS. Combining 
nivolumab with SOC has the potential for increased clinical benefit compared to SOC alone. 
Data is emerging to show the clinical benefit of nivolumab and chemotherapy combination in early 
NSCLC. Preliminary data from ongoing phase 2 trial of neoadjuvant nivolumab plus platinum-
based doublet chemotherapy showed striking pCR rate. Preliminary experience gained from these 
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ongoing phase 2 trials with neoadjuvant nivolumab and nivolumab-based combinations suggests 
these study treatments were well tolerated. The platinum-based doublet chemotherapy regimens 
have well described safety profiles, characterized by myelosuppression and other regimen-specific 
non-hematologic toxicities, such as peripheral
neuropathy, nausea/vomiting, and renal 
impairment. 
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
To compare the event-free survival (EFS) by blinded 
independent central review (BICR) in Arm A vs Arm B 
participants
EFS is defined as the length of time from 
randomization to any of the following events: 
progression of disease or worsening of disease 
precluding surgery, if surgery is attempted but gross 
resection is abandoned due to unresectable tumor or 
worsening of disease, progression or recurrence of 
disease after surgery, progression or recurrence of 
disease without surgery, or death due to any cause. 
Progression/recurrence will be assessed by BICR per 
RECIST 1.1.
Participants who do not undergo surgery for reason 
other than progression will be considered to have an 
event at RECIST 1.1 progression or death.
Secondary
To compare the overall survival (OS) in Arm A vs Arm 
B participants
OS is defined as the time between the date of 
randomization and the date of death due to any cause. 
OS will be censored on the last date a subject was 
known to be alive.
To assess the pathologic complete response (pCR) rate 
by BIPR in Arm A vs Arm B participants
pCR rate is defined as the number of randomized 
participants with absence of residual viable tumor in 
lung and lymph nodes as evaluated by blinded 
independent pathology review (BIPR), divided by the 
number of randomized participants for each treatment 
group.
To assess the major pathological response (MPR) rate 
by BIPR in Arm A vs Arm B participants
MPR rate is defined as number of randomized 
participants with ≤10% residual viable tumor in lung 
and lymph nodes as evaluated by BIPR, divided by 
the number of randomized participants for each 
treatment group.
To assess safety and tolerability in Arm A vs Arm B 
participants
Incidence of AEs, SAEs, and select AEs
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Exploratory
To assess objective response rate (ORR) by BICR in 
Arm A vs Arm B participants
ORR is defined as proportion of all randomized 
participants whose overall radiological response prior 
to definitive surgery (no confirmation required) is 
either a complete response or partial response per 
RECIST 1.1 criteria by BICR. For participants 
without surgery, the first scheduled tumor assessment 
per protocol will be used to assess ORR. Participants 
who received alternative anticancer therapy before the 
presurgery tumor assessment will be counted as 
nonresponders.
To assess time to death or distant metastasis (TTDM) as 
reported by investigator in Arm A vs Arm B participants
TTDM is defined as the time between the date of 
randomization and the first date of distant metastasis 
or the date of death in the absence of distant 
metastasis. Distant metastasis is defined as any new 
lesion that is outside of the thorax or in the 
contralateral lung using RECIST 1.1 as reported by 
investigator. Participants who have not developed 
distant metastasis or died at the time of analysis will 
be censored on the date of their last evaluable tumor 
assessment.
To assess the event-free survival (EFS) by blinded 
independent central review (BICR), overall survival 
(OS), MPR rate, and pCR rate in Arm A vs Arm B 
participants by PD-L1 status
EFS, OS, MPR rate, and pCR rate as previously 
defined
To assess the feasibility of surgery and rate of peri- and 
post operative complications (within 90 days of surgery) 
in Arm A vs Arm B participants
Proportion of delayed or canceled surgery, duration of 
surgery, length of hospital stay, surgical approach, 
incidence of AE/SAE associated with surgery 
including intraoperative complications (eg, 
pneumonitis, ARDS, PRBC, bronchopleural fistulas, 
airleaks, etc), re-admission to the Intensive Care Unit, 
atrial fibrillation. other supraventricular tachycardia 
(SVT), etc to 90 days post surgery
To assess changes in disease-related symptoms and 
impacts on health-related quality of life in Arm A vs 
Arm B participants
Time to symptom deterioration, proportion of 
participants without meaningful symptom 
deterioration, based on the NSCLC-SAQ and the LCS 
subscale of the FACT-L.  Mean change from baseline 
in FACT-L total and subscale scores and NSCLC-
SAQ total score
To assess changes in health status and health-related 
quality of life.
Mean change from baseline, time to deterioration, 
proportion of participants without meaningful 
deterioration in EQ-5D-3L VAS and Utility Index
To assess changes in physical function
Mean change from baseline in PROMIS T-score 
based on the PROMIS PF 8c
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
To characterize participant perceptions of the 
bothersomeness of symptomatic AEs.
GP5 item from the FACT-L
Assess the measurement properties of the NSCLC-SAQ.
Reliability, validity and responsiveness of the 
NSCLC-SAQ
To characterize the immunogenic potential of 
nivolumab 
Anti-nivolumab antibodies and their relationship with 
other outcome measures
To characterize PK of nivolumab 
PK measurements of nivolumab
To evaluate the efficacy after next line of treatment
PFS after next line of treatment (PFS2)
To evaluate candidate predictive biomarkers including, 
but not limited to, biomarkers within the tumor (e.g. 
tumor inflammatory gene expression signatures, driver 
mutations, immune cell infiltrates, etc) as well as within 
the periphery (eg, ctDNA, soluble inflammatory / 
immunosuppressive factors, as potential predictive 
biomarkers of efficacy) 
Gene expression signatures (eg. tumor inflammation, 
immune cell infiltration etc), driver mutations (e.g. 
STK11, KRAS) as well as peripheral markers and 
soluble factors within blood (eg, cytokines, solHLA) 
and other factors within blood (eg, MDSC)  and their 
association with clinical outcomes (EFS, pCR, 
mMPR, OS, cRR)
Circulating tumor DNA for blood TMB and/or MRD 
analysis.
5
STUDY DESIGN
5.1
Overall Design
This is a randomized, double blind, multicenter phase 3 study for participants with early stage 
(Stage IIA [> 4 cm] to IIIB [T3N2 only]) NSCLC evaluating Arm A with the comparator arm 
(Arm B). This study will examine if periadjuvant (neoadjuvant, then adjuvant) immunotherapy 
will prolong event free survival in participants with early stage (Stage IIA [> 4 cm] to IIIB [T3N2 
only]) NSCLC. 
Participants will be randomized (1:1 ratio) across 2 treatment arms:
•
Arm A: nivolumab 360 mg Q3W + SOC platinum-based doublet chemotherapy Q3W x 4
cycles as neoadjuvant treatment followed by surgery; then post surgery nivolumab 480 mg 
Q4W adjuvant treatment for up to 13 cycles (approximately 1 year)
•
Arm B: placebo Q3W + SOC platinum-based doublet chemotherapy Q3W x 4 cycles as 
neoadjuvant treatment followed by surgery, then post surgery placebo Q4W for up to 13 cycles 
(approximately 1 year)
The study is divided into screening period, neoadjuvant / pre-surgery treatment period, surgical 
period, adjuvant / post surgery treatment period, and disease surveillance/long-term follow-up 
period. 
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Randomization will be stratified by the following:
•
Tumor histology (squamous/non-squamous)
•
NSCLC Stage (II vs III)
•
PD-L1 status 
−
≥1% 
−
<1%
−
indeterminate or not evaluable 
•
PD-L1 status will be determined by immunohistochemical (IHC) staining of PD-L1 protein in 
the submitted tumor sample and categorized as follows:
−
PD-L1 positive is defined as ≥1% tumor cell membrane staining positive in a minimum
of 100 evaluable tumor cells
−
PD-L1 negative is defined as <1% tumor cell membrane staining positive in a minimum
of 100 evaluable tumor cells
−
PD-L1 indeterminate is defined as participants with indeterminate (<1% tumor cell 
membrane staining in a minimum of 100 evaluable tumor cells/tumor cell membrane 
scoring hampered by high cytoplasmic staining or melanin content) insufficient sample
quantity or quality to stain for PD-L1 status or those participants in whose samples
PD-L1 status could not be determined despite appropriate amounts of tissue sample. No
more than 10% of participants randomized in this trial will be PD-L1 indeterminate
and not evaluable category.
Total duration of the study from start of randomization to final analysis of EFS is expected to be 
approximately 38 months, assuming 23 months accrual duration. Final analysis of OS is expected 
to be 46 months after the start of randomization. 
The study design schematic is presented in Figure 5.1-1. 
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Figure 5.1-1:
CA20977T Schema
5.1.1
Screening
Participants will provide written informed consent to participate in the study before completing 
any protocol-specified procedures or evaluations not considered to be part of the participants’ 
standard care. After signing the informed consent form (ICF), participants will be evaluated for 
entry criteria during the Screening period before randomization. The screening assessments are 
shown in Table 2-1.
Participants must be evaluated by the multidisciplinary team (including surgeon, medical 
oncologist, radiation oncologist, etc) to confirm eligibility during screening. The multidisciplinary 
team review must be documented in medical record and CRF. Tumor tissue submission prior to 
randomization is mandatory. If a recent/archived (within 3 months from randomization) biopsy 
sample is not available at screening, a fresh biopsy will be taken. 
Sufficient tumor tissue obtained prior to randomization (FFPE block or 5 to 10 unstained slides, 
obtained from core biopsy, excisional biopsy or surgical specimen) is acceptable. 
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For participants for whom a fresh biopsy is not feasible, archival tumor material obtained within 
3 months prior to randomization must be made available. Fine needle aspirate of draining lymph 
node is not acceptable. Core needle biopsies obtained by EBUS are acceptable. 
Tumor tissue and pathology report must be submitted to central laboratory and PD-L1 status results 
available prior to randomization. Tissue requirements are outlined in CA20977T Laboratory 
Manual.
Screening phase ends with either confirmation of full eligibility and randomization or with the 
confirmation that the participant is a screen failure. This study permits the re-enrollment of a 
participant that has discontinued the study as a pretreatment failure prior to randomization. If 
re-enrolled, the participant must be re-consented.
5.1.2
Treatment Period
The treatment phase begins with randomization after confirming all eligibility criteria have been 
met. The treatment period further consists of Neoadjuvant Period, Surgical Period, and the 
Adjuvant period. 
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Figure 5.1.2-1 shows a flowchart for efficacy and safety data collection during the Neoadjuvant period, Surgical period, Adjuvant period, 
and disease surveillance period. 
Figure 5.1.2-1:
CA20977T Flowchart for Efficacy and Safety Data Collection
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5.1.2.1
Neoadjuvant / Pre-surgical Treatment Period
Following confirmation of eligibility, the participants will be randomized in a 1:1 ratio across the 
2 arms via IRT. Treatment should begin within 3 calendar days of randomization (Figure 5.1-1). 
Nivolumab 360 mg or placebo (administered IV over 30 minutes) will be combined with platinum-
based doublet chemotherapy administered every 3 weeks. Combination treatment will continue 
until disease progression, unacceptable toxicity or completion of the 4 cycles, whichever comes 
first. Choice of platinum-based doublet regimens is made by investigator and is dependent on 
NSCLC histology:
Histology-based chemotherapy:
•
Squamous histology: 
−
carboplatin (AUC 5 or AUC 6) + paclitaxel (175 mg/m2 or 200 mg/m2)
−
cisplatin (75 mg/m2) + docetaxel (75 mg/m2)
•
Non-squamous histology: 
−
carboplatin (AUC 5 or AUC 6) + paclitaxel (175 mg/m2 or 200 mg/m2)
−
carboplatin (AUC 5 or AUC 6) + pemetrexed 500 mg/m2
−
cisplatin 75 mg/m2 + pemetrexed 500 mg/m2
All chemotherapy agents’ preparation, premedication, administration, monitoring, and 
management of complications are to follow local prescription guideline permitted as per the 
approved product label and local regulation. The dose of chemotherapy may be capped per local 
standards.
After completing neoadjuvant treatment, participants must have a pre-surgical visit to assess status. 
The Neoadjuvant / Pre-surgical Treatment Period assessments are shown in Table 2-2.
5.1.2.2
Surgery 
Following the completion of neoadjuvant treatment, all participants who remain operative 
candidates will undergo definitive surgery for NSCLC within 6 weeks of the last neoadjuvant 
treatment administration. In specific cases, when definitive surgery does not occur within 6 weeks 
of the last neoadjuvant treatment administration, definitive surgery may be permitted at a later date 
after discussion with the Medical Monitor. The investigator must document reason for delay of 
surgery in the CRF and the medical record. Participants with progressive disease or worsening of 
disease that precludes definitive surgery will be discontinued from treatment and will enter follow 
up phase.
Prior to surgery, any treatment-related toxicity should have been resolved to ≤Grade 1 or returned 
to baseline (except for alopecia and fatigue). It is planned that all participants will undergo surgery 
following recovery from neoadjuvant therapy.
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Diagnostic/Pre-surgical Evaluation and Surgical Guidelines
A participant is considered functionally operable if the following criteria are met: 
•
ECOG Performance Status ≤1
•
Absence of major associated pathologies that increase the surgery risk to an unacceptable level
at the discretion of the investigator or surgeon
•
Pulmonary function capacity (eg, FVC, FEV1, TLC, FRC, DLco, and oxygen saturation) 
capable of tolerating the proposed lung resection according to the surgeon
•
Absence of locally advanced, unresectable, or metastatic disease (stage IV) in the pre-treatment 
assessment 
All participants enrolled on this study must be surgical candidates with clinical Stage IIA (> 4 cm), 
to resectable IIIB (T3N2 only) NSCLC. Participants will have undergone radiographic evaluation 
(PET/CT) indicating no evidence of distant disease and no evidence of unresectable loco-regional 
tumor extension (EBUS, mediastinoscopy, or thoracoscopy). Any further preoperative testing that 
is recommended by the surgeon or anesthesiologist will be performed as part of standard of care. 
Surgery for participants enrolled on this protocol will be according to generally accepted standards 
of care. Operative approach (VATS vs open) will be determined by the surgeon.
Accepted types of resection (with negative margins) will consist of lobectomy, sleeve lobectomy, 
bi-lobectomy, or pneumonectomy. Resections of primary tumor by segmentectomy or wedge 
resection will not be accepted. If PET-CT scan is positive after neoadjuvant therapy and before 
surgery, it is recommended that participants undergo a preoperative mediastinal evaluation by 
bronchoscopy/EBUS or by mediastinoscopy with pathological assessment of sites concerning for 
progression prior to surgery. The decision to proceed to surgery is per local guidelines and 
practices as long as there is no evidence of progressive disease precluding surgery. The decision 
to proceed with the surgery is at the discretion of treating surgeon after carefully considering the 
risk/benefit assessment and feasibility. For example, participants may experience an apparent 
radiographic progression in a solitary or in multiple nodes post treatment with the immune 
checkpoint inhibitor in the neoadjuvant treatment phase with pathology revealing granulomas 
without any evidence of tumor. The apparent radiographic progression in such cases could be 
attributed to nodal immune flare. Potentially curative surgery could be avoided due to failure to 
distinguish nodal immune flare from true disease progression. Nodal rebiopsy or restaging prior 
to final surgical resection is recommended if there is a high index of suspicion for true disease 
progression outside of the surgical field (ie, supraclavicular nodes or contralateral etc). Participants 
should not be denied complete resection based solely on imaging restaging following neoadjuvant 
therapy due to possible false positive results findings in this setting.  
Therefore, pre-surgical evaluation is recommended for the following conditions:
1) Pre surgical restaging PET- CT scan reveals a new PET positive solitary or multiple nodes 
2) Enlarging of preexisting, PET positive lymph node(s)
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It is recommended that participants have at least 3 mediastinal and hilar lymph node stations 
sampled and evaluated during surgery. Systematic sampling is defined as removal of at least 1 
representative lymph node at specified levels. MLND entails resection of all lymph nodes at those 
same levels. 
The following sampling for MLND locations are required, when clinically feasible:
•
For right-sided tumor: Levels 4, 7, 9R, 10R and 11R
•
For left-sided tumor: Levels 5 and/or 6; 7, 9L, 10L, and 11L
A clear documentation in the operative report or in a separately submitted addendum by the 
surgeon of exploration of the required lymph node areas is required. Pathologists must examine the
resected specimen according to SOC practices. To the extent feasible, all excised lymph nodes
should be identified, processed, and examined microscopically for the presence or absence of 
metastasis.
Pathology slides (comprehensive guidelines for specimen handling and identification of the
tumor/tumor bed and lymph nodes are described in the pathology manual) from the surgical 
resection must be submitted to blinded independent pathology review (BIPR) at a central site to 
confirm whether a pCR or major pathologic response (MPR) was achieved.
Tumor tissue from the surgical resection must also be submitted for exploratory biomarker 
analyses. Details will be found in the CA20977T Laboratory Manual.
Prior to surgery, participants with disease progression that precludes surgery must be discontinued
from study treatment and tumor assessments and will enter follow up phase. 
5.1.2.3
Participants not receiving surgery
Some participants who have completed neoadjuvant therapy (4 or fewer cycles) may develop
medical conditions due to adverse events or other causes that, in the opinion of the investigator,
precludes them from safely undergoing surgery. The reasons for not proceeding with surgery
should be clearly documented in the medical records and the CRF.
For participants not receiving surgery, the decision for subsequent adjuvant treatment or treatment 
discontinuation will be based on criteria for disease recurrence or disease progression, as defined in 
Section 9.1.1 and Section 9.1.2. 
•
If a participant does not receive surgery and meets the definition of an event, study treatment 
must be discontinued and participant should move to Follow-up care. This decision must be 
clearly documented in the medical records and i n  the CRF.
•
If a participant does not receive surgery and does not meet the definition of an event, 
adjuvant treatment may be initiated upon approval from Medical Monitor or designee. This 
decision must be clearly documented in the medical records and in the CRF.
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Participants who do not have surgery will be unable to submit tissue for pCR, but will be able to 
submit samples for biomarker analyses. See Section 9.8. 
5.1.2.4
Postoperative radiotherapy as Standard of Care (SOC)
Following surgery, participants in both treatment arms may receive post-operative radiation 
therapy (PORT) at the discretion of the investigator per SOC and local institutional standards under 
the following conditions:
•
Positive margins post-surgery
•
N 2 disease post-surgery
•
Macroscopic residual tumor
Investigators should document the reason for choosing radiation in the medical records and the 
CRF. 
Postoperative radiotherapy should not commence until post surgical adverse events or treatment-
related toxicity have returned to baseline or resolved to ≤Grade 1 (exceptions for fatigue and 
alopecia).
As radiation may interfere with imaging interpretation, efforts should be made to schedule 
radiotherapy so that scheduled tumor assessments do not cross over into the radiation period.
PORT must be completed before initiating adjuvant treatment in both arms. The rebaseline tumor 
assessment after surgery must be done after PORT has been completed and within 1 week before 
initiating adjuvant treatment.
5.1.2.5
Post surgical/Preadjuvant Evaluation 
Participants receiving Surgery: All AEs, serious adverse event (SAE), and drug-related AEs 
resulting in surgical delays and post surgical complications will be collected. Peri-operative 
complications, including a delay in planned surgery, pneumonitis, ARDS, re-admission to the 
Intensive Care Unit, atrial fibrillation or other SVTs, potential immune-related toxicities, and post 
operative complications will be collected. Surgical complications occurring within 90 days of 
surgery will be documented and followed until resolution. 
The first tumor assessment should occur within 1 week prior to adjuvant treatment. Subsequent 
assessments should occur every 12 weeks (± 7 days) for up to and including 108 weeks 
(approximately 2 years) following first dose of adjuvant treatment, then every 24 weeks (± 14 days) 
for up to and including Week 276 (approximately 5 years) until disease recurrence or disease 
progression is confirmed by blinded independent central review (BICR) and, in addition, continue 
until investigator-assessed distant metastasis.
All assessments should be collected as per Table 2-3 before receiving adjuvant treatment.  
Participants not receiving Surgery: All AEs and SAEs related to neoadjuvant treatment will be 
collected. Participants that do not undergo surgery  will continue to have tumor assessments every 
12 weeks (± 7 days) for up to and including 108 weeks (approximately 2 years) following on the 
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presurgery PET-CT scan, then every 24 weeks (± 14 days) for up to and including Week 276 
(approximately 5 years)  until disease progression or disease recurrence is confirmed by BICR and, 
in addition, continue until investigator-assessed distant metastasis.
5.1.2.6
Adjuvant Treatment (Post surgical treatment) [Year 1]
Adjuvant treatment (after surgery) should begin within 90 days from the date of definitive surgery. 
All participants should have a post surgery visit (30 to 90 days post definitive surgery) and re-
baseline restaging imaging prior to beginning adjuvant treatment (within 1 week prior to adjuvant 
treatment) to rule-out recurrence. 
All toxicities associated with neoadjuvant therapy must have been resolved prior to adjuvant 
treatment (exceptions for fatigue, alopecia, and neuropathy). All assessments (including post 
surgery/preadjuvant visit) must be performed prior t o  adjuvant treatment.
After the surgical phase, participants will continue to receive treatment in the assigned treatment 
arms. Each treatment cycle lasts for 28 days:
Arm A adjuvant treatment: Participants will receive nivolumab 480 mg flat dose IV Q4 weeks 
maximum treatment duration of 13 cycles (for approximately 1 year).
Arm B adjuvant treatment: Participants will receive placebo Q4 weeks IV for a maximum 
treatment duration for 13 cycles (for approximately 1 year).
Participants will complete 13 cycles (approximately 1 year) of adjuvant treatment except in the 
event of disease progression, disease recurrence, death, unacceptable toxicity, symptomatic 
deterioration, investigator’s decision to discontinue treatment, the participant’s decision to 
discontinue treatment or withdraw consent, the participant being lost to follow-up, end of the study, 
or BMS decision to terminate the study. All assessments should be collected as per Table 2-3.
5.1.3
Disease Surveillance Assessments from Year 2 to Year 5 and Safety 
Follow-up Visits
After completing treatment with protocol specified adjuvant study treatment, participants will have 
follow-up assessments (FU1 and FU2) and disease surveillance (Year 2 through year 5).
Participants who receive study treatment and discontinue treatment for unacceptable toxicity will 
be followed for drug-related toxicities until these toxicities resolve, return to baseline, or are 
deemed irreversible. All adverse events will be documented for a minimum of 100 days after the 
last dose of study medication. During the follow-up visit, participants will have assessments and 
continue disease surveillance as described in Table 2-4.
5.1.4
Disease Progression/Recurrence
If a participant received study treatment and has disease recurrence/progression precluding surgery 
in neoadjuvant phase or BICR-confirmed disease progression or worsening of disease after 
adjuvant treatment, the participant will complete the 2 safety Follow-up visits and then enter into 
the survival follow-up phase (Table 2-4). At BICR-confirmed disease progression, the investigator 
may request PD-L1 status from screening.
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5.1.5
Data Monitoring Committee and Other External Committees.
An independent Data Monitoring Committee (DMC) will be established to provide oversight of 
safety and efficacy considerations, study conduct, and risk-benefit ratio in protocol. Following 
review, the DMC will recommend continuation, modification, or discontinuation of this study 
based on reported safety data. Representatives of the Sponsor will serve only as coordinators of 
the committee, without having full member responsibilities or privileges. In addition, the Sponsor 
will independently review safety data in a blinded manner during the conduct of this trial to ensure 
that any safety issues are identified and addressed. Available efficacy data will also be reviewed 
by the DMC during the conduct of the study. Details of the DMC responsibilities and procedures 
will be specified in the DMC charter.
5.2
Number of Participants
Approximately 452 participants will be randomized in a 1:1 ratio to treatment with either Arm A 
or Arm B. Assuming a 40% screening failure rate, it is estimated that approximately 
750 participants will be enrolled in order to have approximately 452 participants randomized.
5.3
End of Study Definition
The start of the trial is defined as the first participant’s first visit. End of trial is defined as the last 
participant’s last study visit or last survival assessment. Study completion is defined as the final 
date on which data for the primary endpoint was or is expected to be collected, if this is not the 
same. 
5.4
Scientific Rationale for Study Design
The incorporation of nivolumab to neoadjuvant chemotherapy with adjuvant maintenance may 
increase the pathological complete response rate (pCR) and prolong event-free survival (EFS) and 
increase overall survival (OS) as compared with neoadjuvant chemotherapy in participants with 
newly diagnosed  resectable NSCLC.
The early-stage (II-IIIB) NSCLC represents a population of high unmet need with a 5-year survival 
rate of 25-50%. The current available standard of care (SOC) only provides a 5% absolute 
improvement in 5-year overall survival (OS). The SOC comprises adjuvant or neoadjuvant 
platinum-based doublet chemotherapy for patients with operable stage IB-IIIA NSCLC or 
chemoradiation for patients with unresectable stage IIIA/B NSCLC. Follow-up of adjuvant trials 
are long and may require decades before a new treatment is introduced into clinical practice. 
Preoperative or neoadjuvant chemotherapy has been assessed in a number of trials for patients with 
operable NSCLC. A meta-analysis based on 7 trials involving 988 patients suggested that 
neoadjuvant chemotherapy improved OS when given preoperatively in a similar magnitude to 
those observed with adjuvant chemotherapy. Neoadjuvant therapy offers the possibility for the 
identification of surrogate clinical and biological markers that may correlate with response to 
therapy and a potential long-term outcome. Studies that address the role of preoperative 
chemotherapy have found chemotherapy compliance to be favorable in the preoperative setting. 
Randomized trials are currently on-going to explore the potential benefit of nivolumab in the 
neoadjuvant, adjuvant and locally advanced unresectable NSCLC setting. In addition, the safety 
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and efficacy profile of neoadjuvant nivolumab monotherapy or in combination (nivolumab plus 
chemotherapy) are being evaluated in ongoing trials. 
5.4.1
Rationale for Study Design
Standard of care treatment using 3 different treatment modalities (surgery, systemic therapy, and 
radiotherapy) is used to treat participants with locally advanced NSCLC Stage II to IIIB. 
Depending on participant status and clinical outcomes from neoadjuvant treatment, participants 
may subsequently undergo surgical resection. The efficacy of periadjuvant immunotherapy has 
not been fully evaluated in participants with locally advanced NSCLC. Therefore, in addition to 
SOC platinum-based doublet chemotherapy with surgical resection, participants will receive 
nivolumab/ nivolumab placebo before surgery (neoadjuvant) and after surgery (adjuvant). The use 
of placebo as a control will allow for a more objective evaluation of the efficacy and safety of 
nivolumab. A double blinded, placebo controlled study is ethically justified as participants will 
receive SOC treatment and potentially, participants receiving immunotherapy may demonstrate 
clinical benefit by adding immunotherapy in this periadjuvant setting. 
5.5
Justification for Nivolumab Dose
Nivolumab monotherapy has been extensively studied in NSCLC patient population in studies 
CA209003, CA209063, CA209017, and CA209057 with body weight normalized dosing (mg/kg). 
Nivolumab pharmacokinetics (PK) and exposures of participants in these studies have been 
characterized by population pharmacokinetic (PPK) analysis of data collected from these studies, 
together with PK data from several Phase 1, 2, and 3 clinical studies of nivolumab monotherapy 
in solid tumors. Nivolumab PK was determined to be linear, with dose proportional exposures over 
a dose range of 0.1 to 10 mg/kg. Nivolumab clearance and volume of distribution was found to 
increase with increasing body weight, but the increase was less than proportional, indicating that 
a mg/kg dose represents an over-adjustment for the effect of body weight on nivolumab PK.
Flat dosing offers several advantages over body weight normalized dosing, including reduced 
potential for dosing errors and shortened dosage preparation time. A flat dose of 360 mg every 
3 weeks is expected to produce the equivalent average exposure to 3 mg/kg every 2 weeks at the 
median body weight of ~80 kg in nivolumab-treated participants.
A PPK model predicted overall nivolumab exposures across participants with a wide range of body 
weight (35-160 kg) for a 360 mg every 3 weeks flat dose to be similar to that from 3 mg/kg every 
2 weeks. Although the flat dose is expected to lead to higher exposure in lighter patients, relative 
to the exposure in heavier patients given the relationship between nivolumab PK and body weight, 
the predicted median and 95th percentile of exposures from these regimens are maintained well 
below those in 10 mg/kg every 2 weeks, which was established as a safe and well-tolerable dose.
Nivolumab 5 or 10 mg/kg every 3 weeks plus platinum-based chemotherapy was evaluated in 
CA209012 and deemed to be tolerable. In addition, nivolumab 360 mg every 3 weeks plus 
platinum-based chemotherapy is further being evaluated on several global randomized phase 3 
trials including CA209227 and has been safe and tolerable.
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After surgery, participants will receive nivolumab 480 mg every 4 weeks (Q4W), which provides 
a  more  convenient  dosing  regimen  for  participants.  Based  on  PK modeling  and  simulations, 
administration  of  nivolumab  480  mg  Q4W  will  be  started  after  steady  state  is  achieved  with 
240 mg Q2W and is predicted to provide Cavgss similar to 240 mg Q2W. While 480 mg Q4W is 
predicted to provide greater (approximately 20%) maximum steady state concentrations and lower 
(approximately 10%) steady state trough concentrations, these exposures are predicted to be within 
the  exposure  
ranges  observed  exposures  at  doses  up  
to  10  mg/kg Q2W  used  
in  
the  nivolumab 
clinical program,  and  are  not  considered  to  put  participants  at  increased  risk.  Similar  to  the 
nivolumab  240  mg  Q2W  dosing  
regimen,  
the  exposures  predicted  following  administration  of 
nivolumab  480  mg  Q4W,  are  on  the  flat  part  of  
the  exposure-response  curves  for  previously 
investigated tumors,  melanoma  and  NSCLC,  and are  not  predicted to  affect  efficacy.  Based  on 
these  data,  nivolumab  480  mg  Q4W  
is  expected  
to  have  similar  efficacy  and  safety  profiles  
to 
nivolumab 240 mg Q2W.
6 
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1 
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants or legal authorized representatives where  
locally allowed (see Appendix 2). 
Participants must have signed and dated an IRB/IEC approved written informed consent 
form  in  accordance  with  regulatory  and  institutional  guidelines.  This  must  be  obtained 
before  the  performance  of  any  protocol  related  procedures  
that are  not  part  of  normal 
participant care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
and laboratory testing. tumor biopsies, and other requirements of the study
2) Type of Participant and Target Disease Characteristics
a) Participants with suspected or histologically confirmed Stage IIA (> 4 cm) to IIIB (T3N2) 
NSCLC (per the  American Joint Committee on Cancer (AJCC) Cancer Staging Manual 
8th Edition22) with disease that is considered resectable. 
Note: Participants  must be evaluated by the  multidisciplinary team (including surgeon, 
medical oncologist, radiation oncologist, etc) during screening.
Note: Participants with N3 nodal disease are not eligible. Participants with resectable T4
tumor size with Stage IIIA or IIIB disease must be reviewed and approved for participation 
in the study by the multidisciplinary team (including surgeon, medical oncologist, radiation 
oncologist, etc). The review of the multidisciplinary team must be documented in CRF and 
medical record.
b) No brain metastasis 
c) Participant  must  be  deemed  eligible  for  complete  resection  and  must  agree  
to  undergo 
standard of care surgery for complete resection of NSCLC after neoadjuvant therapy
d) Treatment-naive for NSCLC (no prior systemic anti-cancer treatment)
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nivolumab
e) Ability to provide surgical or biopsy tumor tissue for biomarkers (eg, whole exome 
sequencing, PD-L1 testing, etc) See Section 9.8.
i)
All participants must have tissue submitted to a central laboratory during screening. 
Either FFPE (preferred) tissue block or 5-10 unstained tumor tissue slides, obtained 
within 3 months prior to enrollment, with an associated pathology report, must be 
submitted to the central laboratory for inclusion. Biopsy should be excisional, core 
needle, or surgical specimen. Fine needle aspiration is unacceptable for submission. 
The central laboratory must provide IRT with PD-L1 status prior to randomization.
f)
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1
3) Age and Reproductive Status
a) Males and Females, ≥18 years 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception (Appendix 4) for 
the duration of treatment with study treatments and after the last dose of study treatment 
(ie, 30 days [duration of ovulatory cycle] plus the time required for the study drug to 
undergo approximately 5 half-lives. WOCBP must agree to follow instructions for 
method(s) of contraception for 6 months or longer as per the local regulation and approved 
product label after the last dose of study treatment (for nivolumab and chemotherapy 
regimens specified as study treatment in the protocol).
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 4) for the duration of treatment with study 
treatments and after the last dose of study treatment (ie, 90 days [duration of sperm 
turnover] plus the time required for the study drug to undergo approximately 5 half-lives). 
Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for 7 months after the last dose of study treatment. In addition, 
male participants must be willing to refrain from sperm donation during this time.
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, (Appendix 4) 
which have a failure rate of < 1% when used consistently and correctly.
6.2
Exclusion Criteria
1) Medical Conditions
a) Participants with EGFR mutation regardless of mutation type are excluded. Non-squamous 
tumors with unknown EGFR mutation status must be tested for EGFR mutation. Use of a 
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FDA-approved or local Health Authority-approved test (tissue or blood) is strongly 
encouraged.
b) Participants with known ALK mutations 
c) Participants with Grade ≥ 2 peripheral neuropathy
d) Participants with an active, known or suspected autoimmune disease. Participants with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (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.
e) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
f)
Participants with interstitial lung disease
or active, non-infectious pneumonitis 
(symptomatic and/or requiring treatment) that may interfere with the detection or 
management of suspected drug-related pulmonary toxicity.
g) Participants with previous malignancies (except non-melanoma skin cancers, and in situ 
cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or 
breast) are excluded unless a complete remission was achieved at least 2 years prior to first 
treatment and no additional therapy is required or anticipated to be required during the 
study period.
h) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally.
i)
Known medical condition that, in the investigator’s opinion, would increase the risk 
associated with study participation or study drug administration or interfere with the 
interpretation of safety results. 
j)
Participants with serious or uncontrolled medical disorders.
2) Prior/Concomitant Therapy
a) Any previous anti-cancer treatment including cytotoxic, IO treatment, targeted agents, or 
radiotherapy for NSCLC
b) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to randomization/treatment. Use of marijuana and its derivatives for 
treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally.
c) Participants who have received a live/attenuated vaccine within 30 days of randomization 
d) Prior treatment with any anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways 
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL
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b) Neutrophils < 1500/μL
c) Platelets < 100 x 103/μL
d) Hemoglobin < 9.0 g/dL
e) Serum creatinine >1.5 x ULN or calculated creatinine clearance < 40 mL/min (using the 
Cockcroft-Gault formula)
f)
AST/ALT: > 3.0 x ULN
g) Total bilirubin >1.5 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0x ULN)
h) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to platinum-containing compounds, pemetrexed, 
paclitaxel, docetaxel, or other study drugs and their components
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
Note: The approved local Product Label requirements for the individual chemotherapy drugs in 
this trial must be followed when determining subject eligibility.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, as applicable, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any serious AEs.
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6.4.1
Retesting During Screening 
This study permits the re-enrollment of a participant that has discontinued the study as a pre-
treatment failure (ie, participant has not been randomized / has not been treated). If re-enrolled, 
the participant must be re-consented and re-registered in the IRT for new patient ID allocation.
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
•
Nivolumab 
•
Carboplatin
•
Cisplatin
•
Docetaxel
•
Paclitaxel
•
Pemetrexed
•
Normal saline or dextrose (eg, 5% dextrose in water) will be used as nivolumab-placebo and 
will not be provided by BMS/Sponsor.
An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
•
Refer to the pharmacy manual for instructions on handling and labeling to preserve the blind.
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Table 7-1:
Study treatments for CA20977T
Product Description / 
Class and Dosage 
Form
Potency
IP/
Non-IMP
Blinded or Open 
Label
Appearance
Storage Conditions
(per label)
BMS-936558-01
Solution for 
Injection/Nivolumaba
100 mg (10 mg/mL)
IP
Open-label
Clear to opalescent, 
colorless to pale yellow 
liquid. Few particulates 
may be present.
2 to 8° C. Protect from 
light and freezing
Carboplatin Solution 
for Injection b
450 mg/vial 
(10 mg/mL)
IP
Open-label
Clear, colorless or 
slightly yellow solution.
Product should be 
stored as per market 
product conditions.
Cisplatin Concentrate 
for Solution for 
Infusion b
100 mg/vial (1 mg/mL)
IP
Open-label
Clear, colorless solution
Product should be 
stored as per market 
product conditions.
Docetaxel Concentrate 
for Solution for 
Infusion b
80 mg (10 mg/ml) 
IP
Open label
Clear, colorless to pale 
yellow solution
Product should be 
stored as per market 
product conditions.
Paclitaxel Solution for 
Injection b
100 mg/vial
(6 mg/mL)
IP
Open-label
Clear, colorless or 
slightly yellow viscous 
solution.
Product should be 
stored as per market 
product conditions.
Pemetrexed Powder for 
Concentrate for 
Solution for Infusion b
500 mg/vial
IP
Open-label
White to either light 
yellow or green-yellow 
lyophilized powder
Product should be 
stored as per market 
product conditions.
a May be labeled as either “BMS-936558-01” or “nivolumab”
b These products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. In these cases, 
products may be a different pack size/potency than listed in the table. These products should be prepared/stored/administered in accordance with the package 
insert or summary of product characteristics (SmPC)
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7.1
Treatments Administered
Table 7.1-1 describes the selection and timing of dose for each participant. 
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose strength(s)/
Dosage level(s)
Dosage formulation
Frequency of Administration
Route of 
Administration
BMS-936558-01
Nivolumaba
10 mg/mL
360 mg on Day 1 of a 3-week cycle for up to 
4 cycles as neoadjuvant therapy
480 mg on Day 1 of a 4-week cycle for up to 
13 cycles (approximately 1 year) as adjuvant 
therapy
IV
Carboplatin23
10 mg/mL
AUC 5 or AUC 6 on Day 1 of a 3-week 
cycle for up to 4 cycles a,b
IV.
Cisplatin24
1 mg/mL
75 mg/m2 on Day 1 of a 3-week cycle for up 
to 4 cycles a
IV
Docetaxel25
10 mg/mL
75 mg/m2 on Day 1 of a 3-week cycle for up 
to 4 cycles a
IV
Paclitaxel 
(Taxol PI)26,27
6 mg/mL
175 mg/m2 or 200 mg/m2 on Day 1 of a 
3-week cycle for up to 4 cycles a
IV
Pemetrexed28
500 mg/vial
500 mg/m2 on Day 1 of a 3-week cycle for 
up to 4 cycles a
IV
a Participant in the nivolumab placebo arm will receive normal saline or dextrose following the same dosing schedule.
b Carboplatin is initiated at a dose of AUC 5 or 6 
7.1.1
Neoadjuvant Treatment
7.1.1.1
Nivolumab or Placebo during Neo-adjuvant Treatment
Participants will be randomized to receive nivolumab/nivolumab placebo as neoadjuvant 
treatment.
Participants are to begin study treatment within 3 calendar days of randomization. Participants will 
receive nivolumab at a dose of 360 mg as a 30-minute infusion or placebo on Day 1 of every 3 
weeks cycle (± 3 days) for 4 cycles. There will be no dose escalations or reductions of nivolumab 
allowed. Neoadjuvant treatment will be given for up to 4 cycles until progression, unacceptable 
toxicity, withdrawal of consent, or the study ends, whichever occurs first. Participants may be 
dosed no less than 18 days from the previous dose during Q3W cycles. 
Instructions for dilution and infusion of nivolumab injection may be provided in the clinical 
protocol, pharmacy binder, or pharmacy manual. Care must be taken to assure sterility of the 
prepared solution as the product does not contain any antimicrobial preservative or bacteriostatic 
agent. 
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Premedications are not recommended for the first dose of nivolumab.
Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.4.3.
Dose of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participants tolerates the treatment. Dose delay criteria can be found in Section 7.4.2.1 and 
discontinuation criteria can be found in Section 8.1.1. Criteria to resume treatment can be found 
in Section 7.4.4.1.
Refer to instructions below for instructions for doublet chemotherapy administration in Section
7.1.1.2 and Section 7.1.1.3.
7.1.1.2
Platinum-based Doublet Chemotherapy Regimens
Participants are to begin study treatment within 3 calendar days of randomization. Participants will 
receive nivolumab/nivolumab placebo, followed by chemotherapy on day 1 of every 3 weeks 
cycle. Treatment will continue until progression, unacceptable toxicity, withdrawal of consent, or 
the study ends, whichever occurs first. Participants are to receive nivolumab 360 mg IV (or 
nivolumab placebo) plus histology dependent platinum-based doublet chemotherapy in 3-week 
cycles for 4 cycles. 
Histology-based chemotherapy:
•
Squamous histology: 
−
carboplatin (AUC 5 or AUC 6) + paclitaxel (175 mg/m2 or 200 mg/m2)
−
cisplatin (75 mg/m2) + docetaxel (75 mg/m2) 
•
Non-squamous histology: 
−
carboplatin (AUC 5 or AUC 6) + pemetrexed (500 mg/m2)
−
cisplatin (75 mg/m2) + pemetrexed (500 mg/m2)
−
carboplatin (AUC 5 or AUC 6) + paclitaxel (175 mg/m2 or 200 mg/m2)
All chemotherapy agents’ preparation, premedication, administration, monitoring, and 
management of complications are to follow local prescription guideline as per approved product 
label and local regulation. The dose of chemotherapy may be capped per local standards.
Dosing calculations for chemotherapy should be based on the body surface area calculation 
assessed as per standard of care. The dose should remain the same if the participant’s weight is 
within 10% of the baseline weight or prior dose weight All doses should be rounded up or to the 
nearest milligram or per institutional standard. When study drugs (nivolumab and chemotherapy) 
are to be administered on the same day, nivolumab is to be administered first. Nivolumab infusion 
must be promptly followed by a saline flush to clear the line of nivolumab before starting the 
chemotherapy infusion. The time in between infusion of nivolumab and chemotherapy is expected 
to be approximately 30 minutes but may be more or less depending on the situation 
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If any adverse event meeting the dose delay criteria for chemotherapy is thought to be related to 
one individual chemotherapy agent only in the platinum-based doublet chemotherapy regimen, 
then that individual chemotherapy agent alone may be omitted for that cycle while the other agents 
(nivolumab and the other chemotherapy agent) are administered. If the dose delay criteria for 
nivolumab or both platinum-based doublet chemotherapy agents are met, dosing of nivolumab and 
both chemotherapy agents should be delayed.
7.1.1.3
Dosing Information for Platinum-based Doublet Chemotherapy 
Pemetrexed/Cisplatin: Pemetrexed will be administered at a dose of 500 mg/m2 as a 10 minute 
or per institutional standard IV infusion and cisplatin will be administered at a dose of 75 mg/m² 
as a 120-minute or per institutional standard IV infusion on Day 1 of a 3-week treatment cycle for 
up to 4 cycles. 
Dosing calculation for pemetrexed should be based on the body surface area calculation and may 
be capped per local standards. The dose may remain the same if the participant’s weight is within 
10% of the baseline weight or prior dose weight. All doses should be rounded up or to the nearest 
milligram per institutional standard. 
Cisplatin will be administered to participants at least 30 minutes following the end of the 
pemetrexed infusion or per institutional standard. Pretreatment hydration for cisplatin can follow 
local standard of care, or use 1 to 2 liters of fluid (per local standards) infused IV for 8 to 12 hours 
prior to cisplatin infusion is recommended. Adequate hydration and urinary output must be 
maintained for at least 24 hours following cisplatin administration. Administration and monitoring 
should be performed according to local standards. Use of mannitol following the cisplatin infusion 
should also follow local standards-of-care.
Doses of pemetrexed and/or cisplatin may be interrupted, delayed, or discontinued depending on 
how well the participant tolerates the treatment. Dose modifications for toxicity will be performed 
according to Section 7.4.1. Dose delay criteria can be found in Section 7.4.2.2, and discontinuation 
criteria can be found in Section 8.1.2. Criteria to resume treatment can be found in Section 7.4.4.2. 
Caution should be used when administering NSAIDs concurrently with pemetrexed to patients 
with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). 
Pemetrexed should not be administered if the calculated CrCl is < 45 mL/min. 
Participants with pre-existing hearing impairment should not receive cisplatin and should receive 
carboplatin-based regimen.
Premedications for use with pemetrexed: Oral corticosteroid should be given according to local 
standards at a dose equivalent to dexamethasone 4 mg twice daily on the day prior to, the day of, 
and the day after the administration of pemetrexed. Oral folic acid 350 to 1,000 mcg daily should 
be given starting approximately 1 week prior to the first dose of pemetrexed, with at least 5 doses 
of folic acid administered in the 7 days prior to the first dose. Oral folic acid should be continued 
daily throughout the treatment with pemetrexed and for 21 days after the last dose of pemetrexed. 
Intramuscular (IM) injection of vitamin B12 1000 mcg should be given approximately 1 week 
prior to the first dose of pemetrexed. See details below regarding administration of cisplatin.
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Antiemetic premedication will be administered according to local standards. Recommended 
antiemetic treatments are dexamethasone (dosing according to local standards; an equivalent dose 
of another corticosteroid may be substituted) and a 5-HT3 receptor antagonist (type per 
investigator discretion and local standards-of-care). Additional use of antiemetic premedications 
may be employed at the discretion of the Investigator.
Docetaxel /Cisplatin: Docetaxel will be administered at a dose of 75 mg/m2 as a 60 minute IV 
infusion on Day 1 of a treatment cycle every 3 weeks (21 days ) or per institutional standard IV 
infusion followed by cisplatin which will be administered at a dose of 75 mg/m² over  60 -minute 
IV infusion or per institutional standard on Day 1 of a 3-week treatment cycle for up to 4 cycles. 
Dosing calculation for docetaxel should be based on the body surface area calculation and may be 
capped per local standards. The dose may remain the same if the participant’s weight is within 
10% of the baseline weight or prior dose weight. All doses should be rounded up or to the nearest 
milligram per institutional standard. 
Cisplatin will be administered to participants at least 30 minutes following the end of the docetaxel 
infusion or per institutional standard. Pretreatment hydration for cisplatin can follow local standard 
of care, or use 1 to 2 liters of fluid (per local standards) infused IV for 8 to 12 hours prior to 
cisplatin infusion is recommended. Adequate hydration and urinary output must be maintained for 
at least 24 hours following cisplatin administration. Administration and monitoring should be 
performed according to local standards. Use of mannitol following the cisplatin infusion should 
also follow local standards-of-care.
Participants with pre-existing hearing impairment should not receive cisplatin and should receive 
carboplatin-based regimen. For participants with squamous histology who have preexisting 
hearing impairment, the carboplatin + paclitaxel regimen should be used.
Doses of docetaxel and/or cisplatin may be interrupted, delayed, or discontinued depending on 
how well the participant tolerates the treatment. Dose modifications for toxicity will be performed 
according to Section 7.4.1. Dose delay criteria can be found in Section 7.4.2.2, and discontinuation 
criteria can be found in Section 8.1.2. Criteria to resume treatment can be found in Section 7.4.4.2.
Paclitaxel/Carboplatin: Paclitaxel will be administered at a dose of 175 or 200 mg/m2 as a 
180 minute or per institutional standard IV infusion and carboplatin will be administered at a dose 
of AUC 5 or 6 as a 30-minute or per institutional standard IV infusion on Day 1 of a 3-week 
treatment cycle for up to 4 cycles. 
Dosing calculations for paclitaxel should be based on the body surface area calculation and may 
be capped per local standards. The dose may remain the same if the participant’s weight is within 
10% of the baseline weight or prior dose weight.
Carboplatin should be given following paclitaxel on Day 1 of each cycle, and the carboplatin dose 
will be calculated using the Calvert formula as follows:
Carboplatin dose (mg) = Target AUC x (CrCl [ml/min] + 25)
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nivolumab
Creatinine clearance (CrCl) calculation is based on the Cockcroft-Gault formula and should 
include the most recent serum creatinine and most recent weight. 
NOTE: If calculation of the CrCl by the Cockcroft-Gault formula yields a result of > 125 mL/min, 
then a CrCl should be calculated by an alternative formula per institutional standards or capped at 
125 mL/min.
The dose of carboplatin may be capped per local standards
Doses of paclitaxel and/or carboplatin may be modified, delayed, or discontinued depending on 
how well the participant tolerates the treatment. Dose modifications for toxicity will be performed 
according to Section 7.4.1. Dose delay criteria can be found in Section 7.4.2.2, and discontinuation 
criteria can be found in Section 8.1.2. Criteria to resume treatment can be found in Section 7.4.4.2.
Premedications for use with paclitaxel: Oral or IV corticosteroid should be given prior to 
paclitaxel according to local standard. Such premedication may consist of oral dexamethasone 20 
mg 12 hours and 6 hours prior to paclitaxel administration. Oral or IV diphenhydramine 50 mg (or 
its equivalent) and an H2-blocker (per local standard of care) should be administered 30 to 60 
minutes prior to paclitaxel infusion. Antiemetic premedication will be administered according to 
local standards. Recommended antiemetic treatments are dexamethasone (dosing according to 
local standards; an equivalent dose of another corticosteroid may be substituted) and a 5-HT3 
receptor antagonist (type per investigator discretion and local standards of care). Additional use of 
antiemetic premedications may be employed at the discretion of the investigator per local standards 
of care.
All participants should be carefully monitored for infusion reactions during the paclitaxel 
administration. Participants should be treated in a facility with the necessary medical-resuscitation 
equipment and medications on hand to manage serious acute infusion reactions.
See below for the details regarding administration of carboplatin. 
For participants who do not receive cisplatin-based regimen at C1D1, the investigator should 
document the reason for not choosing a cisplatin-based regimen in the CRF and medical records. 
For participants who are unable to tolerate cisplatin, the investigator should document the 
reasons for intolerability. If the investigator would like to use a carboplatin-based regimen as 
specified in the protocol, the investigator should document reasons in CRF and medical record. 
Pemetrexed/Carboplatin: Pemetrexed will be administered at a dose of 500 mg/m2 as a 10 
minute or per institutional standard IV infusion and carboplatin will be administered at a dose of 
AUC 5 or 6 as a 30-minute or per institutional standard IV infusion on Day 1 of a 3-week treatment 
cycle for up to 4 cycles. 
Dosing calculation for pemetrexed should be based on the body surface area calculation and may 
be capped per local standards. The dose may remain the same if the participant’s weight is within 
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10% of the baseline weight or prior dose weight. All doses should be rounded up or to the nearest 
milligram per institutional standard. 
Carboplatin should be given following pemetrexed per institutional standard on Day 1 of each 
cycle. The carboplatin dose will be calculated using the Calvert formula as follows:
Carboplatin dose (mg) = Target AUC x (CrCl [ml/min] + 25)
Creatinine clearance (CrCl) calculation is based on the Cockcroft-Gault formula and should 
include the most recent serum creatinine and most recent weight. 
NOTE: If calculation of the CrCl by the Cockcroft-Gault formula yields a result of > 125 mL/min, 
then a CrCl should be calculated by an alternative formula per institutional standards or capped at 
125 mL/min.
The dose of carboplatin may be capped per local standards
Doses of pemetrexed and/or carboplatin may be interrupted, delayed, or discontinued depending 
on how well the participant tolerates the treatment. Dose modifications for toxicity will be 
performed according to Section 7.4.1. Dose delay criteria can be found in Section 7.4.2.2, and 
discontinuation criteria can be found in Section 8.1.2. Criteria to resume treatment can be found 
in Section 7.4.4.2. Caution should be used when administering NSAIDs concurrently with 
pemetrexed to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 
79 mL/min). Pemetrexed should not be administered if the calculated CrCl is < 45 mL/min. 
Premedications for use with pemetrexed: Oral corticosteroid should be given according to local 
standards at a dose equivalent to dexamethasone 4 mg twice daily on the day prior to, the day of, 
and the day after the administration of pemetrexed. Oral folic acid 350 to 1,000 mcg daily should 
be given starting approximately 1 week prior to the first dose of pemetrexed, with at least 5 doses 
of folic acid administered in the 7 days prior to the first dose. Oral folic acid should be continued 
daily throughout the treatment with pemetrexed and for 21 days after the last dose of pemetrexed. 
Intramuscular (IM) injection of vitamin B12 1000 mcg should be given approximately 1 week 
prior to the first dose of pemetrexed. 
Antiemetic premedication will be administered according to local standards. Recommended 
antiemetic treatments are dexamethasone (dosing according to local standards; an equivalent dose 
of another corticosteroid may be substituted) and a 5-HT3 receptor antagonist (type per 
investigator discretion and local standards-of-care). Additional use of antiemetic premedications 
may be employed at the discretion of the Investigator.
For All Arms Containing Chemotherapy: Participants should begin study treatment within 3 
calendar days of randomization. Doses of chemotherapy may be interrupted, delayed, or 
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discontinued depending on how well the participants tolerates the treatment. If a dose is delayed 
for any reason, participants should be dosed no less than 18 days from the previous dose. 
Premedications: Antiemetic premedication will be administered according to local standards. 
Recommended antiemetic treatments are dexamethasone (dosing according to local standards; an 
equivalent dose of another corticosteroid may be substituted) and a 5-HT3 receptor antagonist 
(type per investigator discretion and local standards-of-care). Additional use of antiemetic 
premedications may be employed at the discretion of the Investigator.
All chemotherapy agents’ preparation, premedication, administration, monitoring, and 
management of complications are to follow local prescription guideline and regulation. The dose 
of chemotherapy may be capped per local standards.
7.1.2
Nivolumab or Placebo for Adjuvant Treatment
Participants will follow previous randomization and will receive nivolumab or placebo as adjuvant 
treatment.
After surgery, participants will receive nivolumab  at a dose of 480 mg as a 30-minute infusion or 
placebo on Day 1 of every 4 weeks cycle (± 3 days) for up to 13 cycles (approximately 1 year) 
until progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever 
occurs first. There will be no dose escalations or reductions of nivolumab allowed. Participants 
may be dosed no less than 25 days from the previous dose during Q4W cycles. 
7.2
Method of Treatment Assignment
Before the study is initiated, each user will receive log-in information and directions on how to 
access the IRT. Each participant will be assigned a unique participant number after signing the 
ICF. Participant numbers will be used on all participants’ study information. Participant numbers 
will not be reassigned. An IRT will be employed to manage participant randomization. The 
investigator or designee will register the participant for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:
•
Date that informed consent was obtained
•
Year of birth
•
Gender at birth
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be ready to be 
randomized through the IRT. The following information is required for participant randomization:
•
Participant number
•
Year of birth
•
Tumor histology (squamous vs non-squamous)
•
NSCLC stage (II vs III)
•
PD-L1 tumor expression status (PD-L1 positive vs PD-L1 negative vs PD-L1 
indeterminate/not evaluable), analyzed by the central laboratory vendor and transferred to the 
IRT
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The exact procedures for using the IRT will be detailed in the IRT manual. Study treatment will 
be administered at the study visits as listed in the Schedule of Activities (Section 2).
7.3
Blinding
This is a randomized, double blinded study. Access to treatment codes will be restricted from all 
participants, and site and BMS personnel prior to database lock with exceptions as specified below.
Treatment allocation (nivolumab versus placebo) will only be available through the IRT to an 
unblinded pharmacist or other individual(s) who will be responsible for the dispensing of blinded 
study drug. This (these) individual(s) will be unblinded to study drug identification but will not be 
involved in any other aspect of study conduct. 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of the 
investigational product is critical to the participant's management, the blind for that participant 
may be broken by the investigator. The participant’s safety takes priority over any other 
considerations in determining if a treatment assignment should be unblinded.
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, ie, that it will alter the participant's 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the investigational product, the problem may be properly managed by assuming that the participant 
is receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The actual TASK of unblinding can be delegated by the investigator to a 
designee assigned the task on the Delegation of Authority. The Principal Investigator or appointed 
designee should only call in for emergency unblinding AFTER the decision to unblind the 
participant has been documented.
For this study, the method of unblinding for emergency purposes is IRT (refer to the IRT manual 
for further instructions).
In cases of accidental unblinding, contact the BMS unblinded study team (as described in the 
Onsite Investigator File) and NOT the Medical Monitor) and ensure every attempt is made to 
preserve the blind.
Any request to unblind a participant for non-emergency purposes should be discussed with the 
Medical Monitor.
In case of an emergency, the investigator(s) has unrestricted access to randomization information 
via the Interactive Response Technology (IRT) and is capable of breaking the blind through the 
IRT system without prior approval from sponsor. Following the unblinding the Investigator shall 
notify the medical monitor and/or study director.
Additionally, designated staff in the Bristol-Myers Squibb Bioanalytical Sciences department 
(and/or a designee in the external bioanalytical laboratory) may receive the randomization 
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treatment assignments in order to minimize unnecessary bioanalytical analysis of PK and 
immunogenicity samples.
7.4
Dosage Modification
7.4.1
Dose Reductions for Platinum-based Doublet Chemotherapy
Dose reductions of platinum-based doublet chemotherapy may be required and will be performed 
according to Table 7.4.1-1. Chemotherapy dose reductions are permanent; once the dose of any 
chemotherapy agent is reduced, it may not be re-escalated in subsequent cycles. The dose 
reductions for each agent in the platinum-based doublet chemotherapy regimen are not linked and 
may be adjusted independently as summarized below. 
Table 7.4.1-1:
Dose Reductions for Platinum-based Doublet Chemotherapy
Dose Level
Pemetrexed
Cisplatin
Carboplatin
Paclitaxel
Docetaxel
Starting dose
500 mg/m²
75 mg/m²
AUC 5 or 6
175 or 
200 mg/m²
75 mg/m²
First dose 
reduction
75% of the 
starting dose
75% of the 
starting dose
AUC 4 or 5
150 mg/m²
75% of the 
starting dose
Second dose 
reduction
50% of the 
starting dose
50% of the 
starting dose
AUC 3 or 4
100 mg/m²
50% of the 
starting dose
Third dose 
reduction
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
NOTE: Follow local regulations if they are different than what appears in this table.
Any participant with 2 prior dose reductions for 1 agent who experiences a toxicity that would 
cause a third dose reduction must be discontinued from that agent.
7.4.1.1
Platinum-based Doublet Chemotherapy - Dose Reductions for 
Hematologic Toxicity
Dose modifications for hematologic toxicities (according to CTCAE version 4) are summarized in 
Table 7.4.1.1-1. Dose adjustments are based on nadir blood counts (assessed as per local standards) 
since the preceding drug administration. Dose level adjustments for platinum-based doublet 
chemotherapy are relative to that of the preceding administration. Generally, both chemotherapy 
agents in the platinum-based doublet chemotherapy regimen should be dose reduced together for 
hematologic toxicity. After the first cycle, growth factors may be used to assist hematologic 
recovery. Use local standards of care in the use of these supportive measures. Additionally, 
prophylactic antibiotics may be used according to local standards of care. Please report any 
antibiotic or growth factor use on the eCRF.
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Table 7.4.1.1-1:
Dose Modifications for Hematologic Toxicity (based on Nadir 
Counts)a
Toxicity
Pemetrexed
Cisplatin
Carboplatin
Paclixatel
Docetaxel
Neutrophil Count Decreased
Grade 4
(< 500/mm3 or
< 0.5 x 109/L)
Reduce one 
dose level 
and consider 
prophylactic 
GCSF in 
subsequent 
cycles
Reduce one 
dose level 
and consider 
prophylactic 
GCSF in 
subsequent 
cycles
Reduce one 
dose level 
and consider 
prophylactic 
GCSF in 
subsequent 
cycles
Reduce one 
dose level 
and consider 
prophylactic 
GCSF in 
subsequent 
cycles
Reduce one 
dose level 
and consider 
prophylactic 
GCSF in 
subsequent 
cycles
Platelet Count Decreased
Grade 3
(25,000 to < 50,000/mm3; 25.0 
to < 50.0 x 109/L)
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Grade 4
(< 25,000/mm3;
< 25.0 x 109/L)
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Hemoglobin
Grade 2
(< 10.0 to 8.0 g/dL; 
< 6.2 to 4.9 mmol/L;
< 100 - 80 g/L)
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Grade 3 (< 8.0 g/dL;
< 4.9 mmol/L, < 80 g/L)
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Grade 4
(Lifethreatening consequences)
Hold drug
Hold Drug
Hold Drug
Hold drug
Hold drug
a If local standard for dose adjustments differ from those outlined, please discuss with the Medical Monitor. 
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7.4.1.2
Platinum-based Doublet Chemotherapy - Dose Reductions for Non-
Hematologic Toxicities
Dose adjustments for platinum-based doublet chemotherapy for non-hematologic toxicities during 
treatment are summarized in Table 7.4.1.2-1. Participants experiencing any of the toxicities during 
the previous cycle should have their chemotherapy delayed until retreatment criteria are met (per 
Section 7.4.2.2) and then reduced for all subsequent cycles by 1 dose level or discontinued as 
appropriate. Dose levels for the 2 drugs in the platinum-based doublet chemotherapy regimen are 
not linked and may be reduced independently, as summarized in Table 7.4.1.2-1.
Table 7.4.1.2-1:
Dose Modifications for Non-hematologic Toxicity
Toxicity
Pemetrexed
Cisplatin
Carboplatin
Paclitaxel
Docetaxel
Febrile Neutropenia 
Grade ≥3
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Diarrhea Grade ≥3
Reduce one 
dose level
No change
No change
Reduce one 
dose level
Reduce one 
dose level
Allergic reactiona Grade 
≥3
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Neuropathy Grade 2
No change
Reduce one 
dose levelb
No change
Reduce one 
dose level
Reduce one 
dose level
Neuropathy Grade ≥3
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Calculated creatinine 
clearance < 50 mL/min
Discontinue if 
creatinine 
clearance < 45 
mL/min
Discontinue
Discontinue 
if creatinine 
clearance 
< 20 mL/min
No change
Reduce one 
dose level if 
creatinine 
clearance < 30 
mL/min
Other Grade ≥3 toxicity 
(except for fatigue and 
transient arthralgia and 
myalgia)
Adjust as 
medically 
indicated
Adjust as 
medically 
indicated
Adjust as 
medically 
indicated
Adjust as 
medically 
indicated
Adjust as 
medically 
indicated
Note: If local standard for dose adjustments differ from those outlined, please discuss with the Medical Monitor.
Please see local drug label for additional adjustments.
a Only the drug(s) causing the hypersensitivity reaction or acute infusion reaction (≥Grade 3) require(s) 
discontinuation. All other drugs may be continued.
b When given with pemetrexed, cisplatin should be reduced 2 dose levels (ie, by 50% for Grade 2 neuropathy).
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7.4.2
Dose Delay
7.4.2.1
Nivolumab Dose Delay Criteria
Nivolumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related AE
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section 8.1.1).
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
7.4.2.2
Dose Delay Criteria for Platinum-based Doublet Chemotherapy
Dosing of both drugs in the platinum-based doublet chemotherapy regimen selected should be 
delayed for any of the following on the Day 1 of each cycle: 
•
Absolute neutrophil count (ANC) ≤1500/μL 
•
Platelets < 100,000/mm3 
•
Any Grade ≥2 non-skin, non-hematologic, drug-related adverse event (excluding Grade 2 
alopecia, Grade 2 fatigue, and Grade 2 laboratory abnormalities) 
•
Any Grade ≥3 skin, drug-related adverse event 
•
Any Grade ≥3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, AST, ALT, or total bilirubin: 
−
Grade 3 lymphopenia does not require dose delay. 
−
If a participant has a baseline AST, ALT or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥2 toxicity. 
−
If a participant has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥3 toxicity. 
−
If total bilirubin is > ULN, delay docetaxel administration
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. Investigators should consult local 
labeling for the chemotherapy drugs being administered to any given participant for additional 
guidance on dose delays. 
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If any non-hematologic adverse event meeting the dose delay criteria above is felt to be related to 
only 1 particular agent in the platinum-based doublet chemotherapy regimen, then that agent alone
may be omitted for that cycle while the other agent is given. In order to maintain synchronized 
dosing of the regimen, the omitted agent should be resumed with the next scheduled cycle once 
the AE has improved and retreatment criteria are met. Please refer to Section 7.4.1 to determine if 
dose reduction of the resumed agent is required. 
If both drugs in the platinum-based doublet chemotherapy regimen are delayed, then the 
participant should be re-evaluated weekly or more frequently if clinically indicated until re-
treatment criteria are met (as per Section 7.4.4.2).
7.4.3
Treatment of Nivolumab-related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, they are unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the BMS Medical Monitor and reported as an SAE if criteria are met. 
Infusion reactions should be graded according to National Cancer Institute (NCI) common 
terminology criteria for adverse event (CTCAE, Version 4) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated)
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
≤24 hours)
•
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the participant 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor participant closely. If symptoms recur, 
then no further nivolumab will be administered at that visit. Administer diphenhydramine 
50 mg IV, and remain at bedside and monitor the participant until resolution of symptoms. The 
amount of study drug infused must be recorded on the case report form (CRF).
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•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab. If necessary, corticosteroids (up 
to 25 mg of SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae [eg, renal impairment, 
pulmonary infiltrates]. Grade 4: Life threatening; pressor or ventilatory support indicated).
•
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the participant t as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.4.4
Criteria to Resume Dosing
7.4.4.1
Criteria to Resume Nivolumab
Participants may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue.
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.
•
For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete. 
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor (or designee).
•
Participants who delay study treatment due to any Grade 3 amylase or lipase abnormality that 
is not associated with symptoms or clinical manifestations of pancreatitis, which is assessed 
by the investigator not to be related to nivolumab, may resume nivolumab when the amylase 
or lipase abnormality has resolved to Grade < 3. The Medical Monitor should be consulted 
prior to resuming nivolumab in such participants. 
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7.4.4.2
Criteria to Resume Treatment with Chemotherapy 
•
Participants may resume treatment with chemotherapy when the ANC returns to 1500/μl. the 
platelet count returns to 100,000/mm3, and all other drug-related toxicities have returned to 
baseline or Grade 1 (or Grade 2 for alopecia and fatigue).
•
If a participant fails to meet criteria for re-treatment, then re-treatment should be delayed, and 
the participant should be re-evaluated weekly or more frequently as clinically indicated. Any 
participant who fails to recover from toxicity attributable to chemotherapy to baseline or Grade 
1 (except Grade 2 alopecia and fatigue) within 8 weeks from the last dose given should 
discontinue the drug(s) that caused the delay.
When resuming chemotherapy treatment, follow the dose reduction recommendations in 
Section 7.4.1.
7.5
Preparation/Handling/Storage/Accountability
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The unblinded pharmacist and/or product storage manager should ensure that the study treatment 
is stored in accordance with the environmental conditions (temperature, light, and humidity) as 
determined by BMS. If concerns regarding the quality or appearance of the study treatment arise, 
the study treatment should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
The unblinded pharmacist will obtain treatment assignment by IRT and prepare blinded drug 
(nivolumab or placebo).
Please refer to the current version of the appropriate IB, Pharmacy Manual and Appendix 2, for 
complete storage, handling, dispensing and final disposition of unused study treatment. 
7.6
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and case report form (CRF). Drug accountability should be reviewed by the 
unblinded pharmacist at each visit to confirm treatment compliance.
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7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.2
•
Any additional, concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, extensive, non-palliative radiation therapy, or standard or investigational 
agents for treatment of NSCLC) outside of study treatment.
•
Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally.
•
Any live / attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella (MMR)) during treatment and until 100 days post last dose.
•
Strong
CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, etc) 
must not be administered with docetaxel. If strong CYP3A4 inhibitors cannot be discontinued, 
another chemotherapy regimen must be used.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. 
Participants may receive other medications that the investigator deems to be medically necessary.
The exclusion criteria (Section 6.2) describe other medications that are prohibited during this 
study. There are no prohibited therapies during the post treatment follow-up phase.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
7.7.2.1
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history and renal status), the appropriate imaging modality and 
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contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participant with renal insufficiency should be assessed as to whether 
or not they should receive contrast and if so, what type and dose of contrast is appropriate. Specific 
to MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis, therefore MRI 
contrast is contraindicated. In addition, participants may be excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc. This will be outlined in the image acquisition manual.
Gentle hydration before and after IV contrast should follow local standard of care. The ultimate 
decision to perform MRI in an individual participant in this study rests with the site radiologist, 
the investigator, and standards set by the local Ethics Committee.
7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of the nivolumab is 
terminated for other reasons, including but not limited to lack of efficacy and/or not meeting the 
study objectives; c) the participant can obtain medication from a government sponsored or private 
health program. In all cases BMS will follow local regulations.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)
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8.1.1
Nivolumab Discontinuation Criteria
Nivolumab treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm,
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, myocarditis,
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Grade ≥3 adrenal insufficiency 
requires discontinuation regardless of control with hormone replacement. 
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
♦Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
* In most cases of Grade 3 AST or ALT elevation, study treatment will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur.
•
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.
•
Any event that leads to delay in dosing lasting > 8 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 
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−
Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor (or designee). 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks, the BMS 
Medical Monitor (or designee) must be consulted. Tumor assessments should continue as per 
protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
should also continue every 6 weeks or more frequently if clinically indicated during such dosing 
delays.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab dosing.
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Refer to Section 9.2.5 Pregnancy. 
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.1.2
Platinum-based Doublet Chemotherapy Dose Discontinuation
Except where specified below, both chemotherapy drugs in the platinum-based doublet 
chemotherapy regimen should be discontinued for any of the following:
•
Any Grade ≥3 peripheral neuropathy
•
Grade ≥3 drug-related thrombocytopenia associated with clinically significant bleeding
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
−
AST or ALT > 5-10x ULN for > 2 weeks
−
AST or ALT > 10x ULN
−
Total bilirubin > 5 x ULN
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
Any cisplatin-related decrease in creatinine clearance to < 50 mL/min (using the Cockroft 
Gault formula) requires discontinuation of cisplatin. The other chemotherapeutic agent may be 
continued or the regimen may be switched to a carboplatin-based regimen as specified in the 
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protocol. The investigator should discuss this with and obtain approval from the Medical 
Monitor prior to switch.
•
Pemetrexed should be discontinued when creatinine clearance to < 45 mL/min (using the 
Cockroft Gault formula)
•
Any drug-related adverse event which recurs after 2 prior dose reductions for the same 
drug-related adverse event (as specified in Section 7.4.1.1 and Section 7.4.1.2) requires 
discontinuation of the drug(s) which was/were previously dose reduced.
•
Any Grade ≥3 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) felt to be causing the reaction. The drug not felt to be related to 
the hypersensitivity reaction or infusion reaction may be continued.
•
Any Grade 4 drug-related adverse event which the investigator deems is inappropriate to be 
managed by dose reduction(s) requires discontinuation of the drug(s) felt to be causing the 
event. The drug not felt to be related to the event may be continued.
•
Any event that leads to delay in dosing of any study drug(s) for > 8 weeks from the previous 
dose requires discontinuation of that drug(s) with the following exception:
−
Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. Prior to re-initiating 
treatment in a participant with a dosing delay lasting > 8 weeks, the BMS Medical Monitor 
must be consulted. Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such dosing 
delays.
•
Cystoid macular edema (CME) diagnosed by ophthalmologic examination requires 
discontinuation 
•
Note: CME has been reported in patients treated with docetaxel. Patients with impaired vision 
should undergo a prompt and complete ophthalmologic examination. If CME is diagnosed, 
docetaxel treatment should be discontinued and appropriate treatment initiated.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued platinum-
based doublet chemotherapy dosing. Investigators should consult local labeling for the 
chemotherapy drugs being administered to any given participant for additional guidance on 
dose discontinuation.
If the investigator is unable to determine whether an adverse event is due to nivolumab or to 
platinum-based doublet chemotherapy, then all drugs must be discontinued.
8.1.3
Post Study Treatment Follow-up
In this study, overall survival is a key endpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study treatment must continue to be followed for collection of 
outcome and/or survival follow-up data as required and in line with Table 2-4 until death or the 
conclusion of the study. 
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BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window. At the time of this request, each participant will be contacted to 
determine their survival status unless the participant has withdrawn consent for all contacts or is 
lost to follow-up.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified disease surveillance procedures. The only exception to this 
is when a participant specifically withdraws consent for any further contact with him/her or 
persons previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
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9
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and timing are summarized in the Schedule of Activities. 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline, or are deemed irreversible. 
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg. dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the investigator. Additional testing or assessments 
may be performed as clinically necessary or where required by institutional or local regulations.
9.1
Efficacy Assessments
Study evaluations will take place in accordance with the Schedule of Activities in Section 2.
Participants will be followed for survival every 3 months via in person or by telephone contact 
after the participants have discontinued study drug treatment. All randomized participants will be 
followed for survival.
9.1.1
Definition of Events in EFS
EFS is defined as the length o f time from randomization to any of the following events:
progression of disease or worsening of disease that precludes surgery, if surgery is attempted but 
gross resection is abandoned due to unresectable tumor or worsening of disease, progression or 
recurrence of disease without surgery, or death due to any cause. Details on EFS events are 
provided below:
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•
Disease progression or worsening of disease that precludes surgery (as determined by 
Investigator)
•
If surgery is possible but not performed for other reasons (participant refuses or worsening of 
medical condition), then the participant may continue on study treatment and will be considered 
to have an EFS event if and when there is RECIST v1.1 defined progression (requires BICR
confirmation)
•
If surgery is attempted but gross resection is abandoned, due to unresectable tumor or 
worsening of disease, then that will be considered an EFS event (Investigator assessment 
collected on the eCRF surgery page) [event date = surgery date]. If surgery is attempted but 
gross resection is abandoned for reasons other than unresectable tumor or worsening of disease, 
this will not be considered an EFS event. The participant may continue on study treatment and 
will be considered to have an EFS event if and when there is RECIST v1.1 defined progression 
(requires BICR confirmation).
•
If surgery is completed with unequivocal gross residual disease (visible on imaging), then the 
participant may continue on study treatment and will be considered to have an EFS event if and 
when there is RECIST v1.1 defined progression (requires BICR confirmation)
•
If surgery is completed with no or only microscopic residual disease (positive margins, not
visible on imaging), then the participant will continue on study and will be considered to have an
EFS event if and when radiographically visible recurrence occurs (requires confirmation by
BICR) or by biopsy.
•
Local or distant recurrence or new tumor confirmed by BICR or biopsy
•
Death due to any cause
9.1.1.1
Definition of Disease Recurrence
Disease recurrence will be defined as any unequivocal evidence of new lung cancer lesions that 
are detected after surgery. Biopsy should be employed where required to prove recurrence. In cases 
where recurrence is equivocal and biopsy cannot be performed or were not diagnostic, the 
participant may continue treatment and imaging of suspect lesions should be repeated in 4-8 weeks 
(Section 9.1.2.4).
The first post surgery assessment will occur within 90 days after surgery and prior to beginning 
post surgery IO therapy for Arms A and B. Participants who have new LNs of ≥10 mm in short 
axis or with growth of ≥5mm (eg, 9 mm LN grows to 14 mm) have findings of other new, 
unequivocal non-nodal lesions will be considered as having recurrence. Confirmation of 
recurrence must be attempted as described in Section 9.1.1.2
Tumor may recur in the following sites:
•
Local recurrence (ie, ipsilateral [disease in same lung])
•
Distant recurrence (any new non-local recurrence)
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9.1.1.2
Definition of Disease Progression
All participants will be followed by imaging for disease progression until BICR-confirmed 
unequivocal progression per RECIST 1.1.
9.1.1.3
Definition of pCR
The pCR rate is defined as the number of randomized participants with absence of residual viable 
tumor in lung and lymph nodes as evaluated by blinded independent pathology review (BIPR), 
divided by the number of randomized participants for each treatment group.
9.1.1.4
Definition of MPR
MPR is defined as number of randomized participants with ≤10% residual viable tumor in lung 
and lymph nodes as evaluated by BIPR, divided by the number of randomized participants for each 
treatment group.
9.1.2
Imaging Assessment for the Study
Images will be submitted to a central imaging vendor and may undergo blinded independent 
central review (BICR) at any time during the study. Prior to scanning first participant, sites should 
be qualified and understand the image acquisition guidelines and submission process as outlined 
in the CA20977T Imaging Manual provided by the central imaging vendor.
Imaging assessments will occur in accordance with the Schedule of Activities in Section 2.
9.1.2.1
Neoadjuvant and Pre-Surgical Imaging
PET-CT with contrast is required at Screening for all participants and should be acquired up to 
45 days prior to randomization. If the CT component of a PET-CT is not of sufficient diagnostic 
quality for RECIST 1.1 assessment, a separate CT with contrast of the chest, abdomen, pelvis and 
other suspected areas (in addition to the PET-CT) is required. If CT with contrast of the abdomen, 
pelvis, and all other known and/or suspected sites of disease is contraindicated, then a MRI is 
acceptable.
A preoperative PET-CT with contrast should be acquired at least 14 days after last neoadjuvant 
dose and before surgery. If the CT component of a PET-CT is not of sufficient diagnostic quality 
for RECIST 1.1 assessment, a separate CT with contrast of the chest, abdomen, pelvis and other 
suspected areas (in addition to the PET-CT) is required. If CT with contrast of the abdomen, pelvis 
and all other known and/or suspected sites of disease is contraindicated, then a MRI is acceptable.
Participants that do not undergo surgery  will continue to have tumor assessments every 12 weeks 
(± 7 days) for up to and including 108 weeks (approximately 2 years) following on the presurgery 
PET-CT scan, then every 24 weeks (± 14 days) for up to and including Week 276 (approximately 
5 years) or until BICR-confirmed disease progression or recurrence and, in addition, continue until 
investigator-assessed distant metastasis.
9.1.2.2
Post Surgical / Preadjuvant Restaging and Adjuvant Imaging
Post surgical and/or preadjuvant restaging using contrast-enhanced CT chest, as well as pre and 
post contrast-enhanced CT of abdomen, pelvis, and other suspected areas should occur within 7 
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days prior to first dose of adjuvant treatment. If CT with contrast of the abdomen, pelvis and all 
other known and/or suspected sites of disease is contraindicated, then a MRI is acceptable.
Radiographic assessments will continue every 12 weeks (± 7 days) for up to and including 108
weeks (approximately 2 years) following first dose of adjuvant treatment, then every 24 weeks (±
14 days) for up to and including Week 276 (approximately 5 years) until disease recurrence or 
disease progression is confirmed by blinded independent central review (BICR) and, in addition, 
continue until investigator-assessed distant metastasis.  
9.1.2.3
Methods of Measurement
Contrast-enhanced CT of the chest, abdomen, pelvis, and all other known and/or suspected sites 
of disease should be performed for tumor assessments. Images should be acquired with slice 
thickness of 5 mm or less with no intervening gap (contiguous). Every attempt should be made to 
image each participant using an identical acquisition protocol on the same scanner for all imaging 
timepoints. Tumor measurements should be made by the same investigator or radiologist for each 
assessment, whenever possible. Change in tumor measurements and tumor response to guide 
ongoing study treatment decisions will be assessed by the investigator.
If a participant has a contraindication for CT with intravenous contrast, then a non-contrast CT of 
the chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites 
of disease should be obtained.
If a participant has a contraindication for both MRI and CT with intravenous contrasts, then a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
If a participant has a contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT with intravenous contrast, then a non-contrast CT of the chest, abdomen, 
pelvis, and other known/suspected sites of disease is acceptable. Bone scans may be collected per 
local standards, as clinically indicated.
MRI of brain should be acquired as outlined in Section 2 (Schedule of Activities). CT of the Brain 
(without and with contrast) can be performed if MRI is contraindicated.
During the neoadjuvant therapy period, participants should have 2 PET-CT scans, ideally with IV 
contrast, of skull base through the mid-thigh performed: 
•
within 45 days of randomization, and then 
•
at least 14 days after last neoadjuvant dose and before planned surgery to assess for clinical 
response. 
A separate contrast enhanced CT of the chest, abdomen, pelvis, and other known/suspected areas 
is required if the CT component of a PET-CT is not of sufficient diagnostic quality of RECIST 1.1 
measurements. If CT with contrast of the abdomen, pelvis, and all other known and/or suspected 
sites of disease is contraindicated, then a MRI is acceptable.
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9.1.2.4
BICR Assessment of Progression
Sites should submit all scans to BICR as performed on a rolling basis, preferably within 5 days of 
scan acquisition, throughout the duration of the study. BICR of scans will occur on a rolling basis, 
blinded to treatment arm, clinical data, and investigator assessment of submitted scans. When 
progression or recurrence per RECIST 1.1 criteria is assessed by the investigator, the site will 
inform the central imaging vendor, in order for BICR assessment of progression to be performed. 
The BICR will be completed and the results provided to the site as specified in the imaging vendor 
documents, provided there are no pending imaging queries to the site. All details on the timelines 
and associated process requirements will be outlined in the Imaging Manual.  
Participants whose progression or recurrence is not confirmed by BICR will be required to 
continue tumor assessments (if clinically feasible) according to the protocol-specified schedule or 
sooner if clinically indicated until the BICR confirmed progression or recurrence and, in addition, 
continue until investigator-assessed distant metastasis. Also, if participants discontinue treatment 
without radiographic progression, tumor assessments will continue according to the protocol 
specified schedule, as noted in Section 5.1.4 until progression or recurrence is confirmed by BICR.
All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment.
9.1.3
Blinded Independent Pathology Review
Independent pathology review will be established for central review and confirmation of 
endpoints. Tumor and lymph node collection from definitive surgical resection and sampling of 
fresh tumor for biomarker studies is mandatory. Specimen sampling for histopathologic analysis 
should be performed within 72 hours of the surgical procedure. Sections will be used for central 
pathology review assessing pathologic response. All H&E slides prepared from the specimens that 
are reviewed locally must be sent for central pathology review. Diagnostic H&E slides are 
preferred, but recut sections from all the tissue blocks are acceptable. Sites will be trained prior to 
enrolling the first study participant. Pathology samples acquisition guidelines and submission 
process will be outlined in the study Laboratory Manual to be provided by the vendors. 
9.1.4
Outcomes Research Assessments
The evaluation of patient-reported outcomes is an increasingly important aspect of clinical efficacy 
in oncology trials. Such data provide an understanding of the impact of treatment from the 
participant’s perspective and offer insights into patient experience that may not be captured 
through physician reporting. Additionally, generic health-related quality of life measures provide 
data needed for calculating utility values to inform health economic models.
Participants will be asked to complete the Functional Assessment of Cancer Therapy – Lung 
Cancer (FACT-L) Module, the Non-Small Cell Lung Cancer – Symptom Assessment 
Questionnaire (NSCLC-SAQ), 3-level version of the EuroQol Group’s EQ-5D (EQ-5D-3L), 
PROMIS Physical Function - Short Form 8c (PROMIS PF 8c) and the Patient Global Impression 
of Severity (PGIS).
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The NSCLC-SAQ, FACT-L, EQ-5D-3L, PROMIS PF 8c and PGIS will be administered during 
specified clinic visits, and will be completed prior to any other assessments or study procedures 
when they are being administered during study visits. In addition, the PRO measures will be
completed at designated time points during the long-term follow-up period.
Section 2 provides information regarding the timing of patient-reported outcomes assessments 
during the study period. The baseline for outcome assessments must be performed prior to neo 
adjuvant C1D1 treatment. Additional information about the timing of each assessment is described 
below.
9.1.4.1
FACT-L
The Functional Assessment of Cancer Therapy – Lung (FACT-L) cancer module, is a widely-used, 
reliable, and valid measure of multidimensional health status among people who have lung cancer. 
The FACT-L scale is a 36-item self-report instrument that measures multidimensional QOL by 
asking patients to rate a series of statements on a 5-point Likert scale. The FACT-L, version 4, is 
a combination of the 27-item FACT-General (FACT-G) and the 9-item Lung Cancer Subscale 
(LCS). A subset of the 7 items (2 of the 9 items are not scored, and will not be administered) from 
the LCS will be used to calculate the FACT-Lung Cancer Subscale (FACT-LCS), which will be 
used to assess disease-specific symptom severity. 
A total FACT-G score is calculated by summing the physical well-being (PWB), social/family 
well-being (SWB), emotional well-being (EWB), and functional well-being (FWB) subscale 
scores. A total FACT-L score is obtained by summing the FACT-G score with the LCS, thereby 
augmenting the FACT-G with lung cancer–specific QOL information. The FACT-L also contains 
the GP5 item from the FACT-G, which is used to assess the bother associated with the side effects 
of treatment. Each of the items is scored on a five-point scale from zero (Not at all) to four 
(Very much). Higher scores indicate greater quality of life. The FACT-L uses a recall period of 
“the past 7 days.”
•
The FACT-L will be administered per Schedule of Assessment tables in Section 2.
9.1.4.2
Non-Small Cell Lung Cancer Symptom Assessment Questionnaire 
(NSCLC-SAQ)
The NSCLC-SAQ is a 7-item PRO measure intended for use in advanced NSCLC clinical trials to 
support medical product labelling.29 The NSCLC-SAQ uses a 7-day recall period and verbal rating 
scales. It was developed in accordance with the US Food and Drug Administration’s PRO 
Guidance and scientific best practices, and the resulting qualitative interview data provide 
evidence of content validity. The NSCLC-SAQ total score measures overall severity of the 
following NSCLC symptoms: cough, pain, dyspnea, fatigue, and appetite. The NSCLC-SAQ has 
been qualified for exploratory use to measure symptoms of non-small cell lung cancer in drug 
development programs. Further evaluation is needed on the instrument’s longitudinal 
measurement properties and the interpretation of clinically meaningful within-patient change in 
score.  After the NSCLC-SAQ’s longitudinal measurement properties and the interpretation of 
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clinically meaningful within-patient change have been evaluated, the NSCLC-SAQ total score is 
intended to support labeling claims related to change in overall symptoms of NSCLC. Data from 
this study will help to interpret the psychometric properties and threshold for clinically meaningful 
within-patient change in the NSCLC-SAQ total score within locally advanced unresectable 
NSCLC patients.
The NSCLC-SAQ will be administered per Schedule of Assessment tables in Section 2.
9.1.4.3
EQ-5D-3L
The EQ-5D-3L30,31is a standardized instrument used to measure self-reports of health status and 
functioning. The instrument’s descriptive system consists of 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting 
“no health problems,” “moderate health problems,” and “extreme health problems.” A dimension 
for which there are no problems is said to be at level 1, while a dimension for which there are 
extreme problems is said to be at level 3. Thus, the vectors 11111 and 33333 represent the best 
health state and the worst health state, respectively, as described by the EQ-5D-3L. Altogether, the 
instrument describes 35 = 243 health states.
Empirically-derived weights can be applied to an individual’s responses to the EQ-5D-3L 
descriptive system to generate an index measuring the value to society of his or her current health. 
Such preference-weighting systems have been developed for the UK, US, Spain, Germany, and 
numerous other populations. Utility index values range from a 1 (full health) to 0 (dead) with 
negative values indicating a state considered worse than being dead. In addition, the EQ-5D-3L 
includes a visual analog scale (VAS) that allows respondents to rate their own current health on a 
101-point scale ranging from “best imaginable” to “worst imaginable” health. The EQ-5D-3L uses 
a recall period of “today.” 
The EQ-5D-3L will be administered per Schedule of Assessment tables in Section 2.
9.1.4.4
PROMIS Physical Function
Physical function has been identified as a key domain for assessing symptom-related impacts and 
health-related quality of life (HRQoL) in patients with cancer in clinical trials. Physical function, 
along with symptoms of specific tumor types and symptomatic adverse events, can provide 
important data to support the safety and efficacy of a cancer treatment. The Patient-Reported 
Outcome Measurement Information System (PROMIS) is a set of self-report measurement tools 
that was developed by the US National Institutes for Health (NIH). PROMIS contains an item-
bank of physical function items that assess a range of physical abilities. The PROMIS Physical 
Function Short Form 8c (PROMIS PF 8c) contains a subset of 8 items selected from the PROMIS 
Physical Function item bank, which were determined to be relevant to cancer patients. Each items 
assesses the difficulty a respondent has in performing different activities using a 5 level verbal 
rating scale. The PROMIS PF 8c uses a recall period of the past 7 days.
The PROMIS PF 8c will be administered per Schedule of Assessment tables in Section 2.
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9.1.4.5
Patient Global Impression of Severity (PGIS)
Patient global impression of severity (PGIS) will be included as additional exploratory endpoint. 
The PGIS is a single item that assesses participant’s perceptions of overall severity of cancer 
symptoms for the last 7 days with response options ranging from “none” to “very severe.” Data 
collected via the PGIS will be used as anchor measures for use in assessing the psychometric 
measurement properties and the threshold for meaningful change for the NSCLC-SAQ. 
The PGIS will be administered per Schedule of Assessment tables in Section 2.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until 
100 days after last dose of study treatment at the timepoints specified in the Schedule of Activities 
(Section 2). Nonserious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the participants.
Refer to the Nivolumab IB for the Reference Safety Information to determine expectedness of 
serious adverse events for expedited reporting. For reference safety information on chemotherapy 
regimens, refer to the drug product labels. Following the participant’s written consent to participate 
in the study, all SAEs, whether related or not related to study drug, must be collected, including 
those thought to be associated with protocol-specified procedures.
The collection of nonserious AEs (with the exception of nonserious AEs related to SARS-CoV-2 
infection) should begin at initiation of study treatment.
All SAEs, and all AEs (SAEs and nonserious AEs) associated with confirmed or suspected SARS-
CoV-2 infection, must be collected from the date of the participant’s written consent until 100 days 
following discontinuation of dosing.
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All SAEs must be collected that occur during the pre-screening/screening period, during treatment, 
within 100 days of discontinuation of dosing. If applicable, SAEs must be collected that relate to 
any later protocol-specified procedure (eg, a follow-up skin biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the CRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
All SAEs, and all AEs (SAEs and nonserious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection, must be collected from the date of the participant’s written consent 
until 100 days following discontinuation of dosing.
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
All SAEs must be collected that occur during the screening period and treatment period and 100 
days after the last dose of study treatment. For participants randomized/assigned to treatment and 
never treated with study drug, SAEs should be collected for 30 days from the date of 
randomization.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in 
the context of known adverse events, when appropriate for the program or protocol.
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment. 
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
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9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
 All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and nonserious AEs of special interest (as defined in 
Section 9.2) and AEs (SAEs and nonserious AEs) associated with confirmed or suspected SARS-
CoV-2 infection, will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3) or for 
suspected cases, until SARS-CoV-2 infection is ruled out. Further information on follow-up 
procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
6 months or longer as per the local regulation and approved product label after product 
administration, the investigator must immediately notify the BMS Medical Monitor/designee of 
this event and complete and forward a Pregnancy Surveillance Form to BMS Designee within 24 
hours of awareness of the event and in accordance with SAE reporting procedures described in 
Appendix 3.
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If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. If, for whatever reason, the pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
greater than 6 weeks after the pregnancy has ended), following approvals of participant /sponsor 
/IRB/EC, as applicable.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant at the time of study 
intervention exposure, including at least 7 months after the study intervention administration, 
should be reported to Sponsor or designee. In order for Sponsor or designee to collect any 
pregnancy surveillance information from the female partner, the female partner must sign an 
informed consent form for disclosure of this information. Information on this pregnancy will be 
collected on the Pregnancy Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
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AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.2.9
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is an immuno-oncology agent in this 
protocol. Early recognition and management of AEs associated with immuno-oncology agents 
may mitigate severe toxicity. Management Algorithms have been developed to assist investigators 
in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
•
Myocarditis
The above algorithms are found in the nivolumab Investigator Brochure, as well as in Appendix 6.
9.3
Overdose
For this study, an overdose is defined as the accidental or intentional administration of any dose 
of a product that is considered both excessive and medically important. Overdoses that meet the 
regulatory definition of SAE will be reported as an SAE (see Appendix 3). 
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1
Physical Examinations
Refer to Section 2 Schedule of Activities.
9.4.2
Vital signs
Refer to Section 2 Schedule of Activities.
9.4.3
ECG
Refer to Section 2 Schedule of Activities.
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9.4.4
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report. A clinical safety 
laboratory assessment is required within 72 hours before each study drug treatment.
Table 9.4.4-1:
Clinical Laboratory Assessments
Hematology – CBC
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase (ALP)
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN) or serum UREA
Glucose
Albumin - screening only
Sodium
Potassium
Chloride
Calcium or ionized calcium
Phosphorus
TSH, free T3 and free T4 - screening 
TSH, with reflexive fT3 and fT4 if TSH is abnormal -
on treatment 
Serology
Hepatitis B/C, (HBV sAG or HBV DNA, and HCV antibody or HCV RNA) - screening only 
HIV testing where locally mandated. 
Pregnancy test (WOCBP only minimum sensitivity 25 IU/L or equivalent units of HCG).
Follicle stimulating hormone (FSH) screening only as required to confirm menopause in women < age 55) 
9.4.5
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.5
Pharmacokinetics
Samples for PK and immunogenicity assessments will be collected for all participants in the 
treatment arm receiving nivolumab or nivolumab placebo (± chemotherapy). All time points are 
relative to the start of study drug administration. All on-treatment time points are intended to align 
with days on which study drug is administered, if dosing occurs on a different day, the PK and 
immunogenicity sampling should be adjusted accordingly. Further details of sample collection, 
processing, and shipment will be provided in the laboratory procedures manual. 
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A detailed schedule of PK and immunogenicity evaluation is provided in Table 9.5-1. PK samples 
will be analyzed for nivolumab by a validated ligand binding assay. Immunogenicity samples will 
be analyzed for anti-nivolumab antibodies and neutralizing antibodies by a validated method. Only 
samples from participants in the nivolumab treatment arm will be analyzed. Serum samples may 
be analyzed by an exploratory method that measures nivolumab for technology exploration 
purposes, exploratory results will not be reported. Serum samples designated for PK or biomarker 
assessments may also be used for immunogenicity analysis if required (eg. insufficient volume for 
complete immunogenicity assessment or to follow upon suspected immunogenicity related AE).
Table 9.5-1:
Pharmacokinetic and ADA Sampling Schedule 
Study Day of Sample 
Collectiona
Event
Time Relative to 
nivolumab/placebo 
dose
Nivolumab 
PK Sample b
Nivolumab 
ADA Sampleb
Neoadjuvant treatment (1 Cycle = 3 weeks)
Cycle 1 Day 1
Predosec
0:00
X
X
End of infusiond
0:30
X
Cycle 2 Day 1
Predosec
0:00
X
X
Cycle 3 Day 1
Predosec
0:00
X
X
Adjuvant treatment (1 Cycle = 4 weeks)
Cycle 1 Day 1
Predosec
0:00
X
X
End of infusiond
0:30
X
Cycle 2 Day 1
Predosec
0:00
X
X
Cycle 3 Day 1
Predosec
0:00
X
X
Cycle 7 Day 1
Predosec
0:00
X
X
Cycle 11 Day 1
Predosec
0:00
X
X
a Part A1 indicates 4 cycles of neoadjuvant treatment of nivolumab/nivolumab placebo + chemotherapy prior to 
surgery. Part A2 indicates adjuvant treatment of nivolumab/nivolumab placebo monotherapy post surgery.
b If a subject discontinues nivolumab/nivolumab placebo treatment during the sampling period, PK and ADA samples 
should be only collected for the next 1 time point according to PK table.
c Predose samples should be collected just before the administration of nivolumab/nivolumab placebo (preferably 
within 30 minutes). If it is known that a dose is going to be delayed, then the predose sample should be collected 
just prior to the delayed dose. However, if a predose sample is collected but the dose is subsequently delayed, an 
additional predose sample should not be collected.
d EOI: End of Infusion. This sample should be taken immediately prior to stopping nivolumab/nivolumab placebo 
drug infusion (preferably within 2 minutes prior to the end of infusion). If the end of infusion is delayed to beyond 
the nominal infusion duration, the collection of this sample should also be delayed accordingly. EOI samples may 
not be collected from the same IV access as drug was administered.
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9.6
Pharmacodynamics
See Section 9.8.
9.7
Pharmacogenomics
See Section 9.8.
9.8
Biomarkers
9.8.1
Tumor Tissue and Blood Tissue Collection
Schedule for biomarker collection is found in Table 9.8.1-1.
Table 9.8.1-1:
Biomarker Sample Schedule for All Participants
Study Day of 
Sample 
Collection
Tumor 
Archiva
l or 
fresh 
biopsy 
in 
FFPE
Plasma 
for 
ctDNAa,
b
Whol
e 
Blood 
DNAa
Serum 
(Soluble 
Factors)
a
Whole 
Blood 
GEPa,
c
Myeloid 
Derived 
Suppressor 
cells 
(MDSCs)a,
c
PBMCa,
d
SARS-
CoV-2 
Serology
c
Diagnostic 
Biopsy
X
Screening
X
Approximately 4 
weeks after 
confirmed or 
suspected SARS-
CoV-2 infectione
X
6 months after 
C1D1
X
Neoadjuvant treatment (1 cycle = 3 weeks)
C1D1
X
X
X
X
X
X
C4D21 or End of 
the last 
Neoadjuvant 
Treatment cycle
X
X
X
X
X
Surgery prior to adjuvant treatment
Surgery/Resectio
nf
X
Xi
Adjuvant treatment during Year 1 (1 cycle = 4 weeks)
Cycle 1 Day 1
X
X
X
X
X
Cycle 2 Day 1
X
X
X
X
X
Cycle 3 Day 1
X
X
X
X
X
Every Cycle Day 
1, starting at 
X
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Table 9.8.1-1:
Biomarker Sample Schedule for All Participants
Study Day of 
Sample 
Collection
Tumor 
Archiva
l or 
fresh 
biopsy 
in 
FFPE
Plasma 
for 
ctDNAa,
b
Whol
e 
Blood 
DNAa
Serum 
(Soluble 
Factors)
a
Whole 
Blood 
GEPa,
c
Myeloid 
Derived 
Suppressor 
cells 
(MDSCs)a,
c
PBMCa,
d
SARS-
CoV-2 
Serology
c
Cycle 4 Day 1 
until Cycle 13
Disease surveillance
Recurrence or 
Disease 
Progressionh
Xg
Xi
X
X
X
X
a Prior to dosing (when applicable)
b Plasma ctDNA samples should only be collected during Years 2 through 5 at the time of recurrence or progression. 
If a participant does not have surgery and/or adjuvant therapy, plasma ctDNA samples should not be collected 
during adjuvant or disease surveillance/Follow-up. If a participant discontinues adjuvant treatment early, plasma 
ctDNA samples should not be collected during disease surveillance/Follow-up.
c SARS-Cov-2 serology, Whole Blood GEP and MDSCs are not collected in China.
d PBMCs are not collected in Australia and China.
e A sample is collected approximately 4 weeks after a suspected or confirmed SARS-CoV-2 infection to be used for 
potential future measurements of anti-SARS-CoV-2 serology (anti-SARS-CoV-2 total or IgG).
f Assessment of pathological response and additional biomarker analysis. Please refer to CA20977T laboratory 
manual.
g At the time of disease recurrence or progression, excised tumor tissue submission (FFPE block [preferred] or 10 to 
15 unstained slides), obtained from core biopsy, excisional biopsy, or surgical specimen is optional but strongly 
encouraged. Fine needle aspirates of draining lymph node are not acceptable. Core needle biopsies obtained by 
EBUS are acceptable. If a sample is collected, see CA20977T Laboratory Manual for tissue requirements.
h Samples collected upon recurrence or progression of the disease should be collected prior to subsequent therapy.
i ctDNA plasma collections at “Surgery/Resection” and “Recurrence or Disease Progression” should be obtained 
prior to surgery or tumor sample collection. 
9.8.1.1
Diagnostic/Baseline Biopsy 
Tumor tissue submission prior to randomization is mandatory. If a recent/archived (within 3 
months from randomization) biopsy sample is not available at screening, then a fresh biopsy will 
be taken. 
Sufficient tumor tissue obtained prior to randomization (FFPE block or 5 to 10 unstained slides, 
obtained from core biopsy, excisional biopsy or surgical specimen) is acceptable. For participants 
for whom a fresh biopsy is not feasible, archival tumor material obtained within 3 months prior to 
randomization must be made available. Fine needle aspirate of draining lymph node is not 
acceptable. Core needle biopsies obtained by EBUS are acceptable.
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9.8.1.2
Whole Exome Sequencing of Tissue and Whole Blood DNA
After the participant has enrolled in the study, the participant will undergo surgery and surgical 
tumor sample(s) will be submitted for GCLP approved whole exome sequencing. An assessment 
of biopsy quality by a pathologist/cytopathologist is encouraged at the time of procedure. Please 
refer to the lab manual for specific tumor collection instructions. Assessment of deep whole exome 
next-generation sequencing, that targets entire coding region (exome) within genome will be 
performed to allow evaluation of specific mutations and aggregate. The tissue signature mutations 
will define residual disease progression by following defined gene variants in the whole blood. 
Identification of target mutations in the tissue requires paired blood (whole blood DNA sample) 
for germline variation subtraction, exomes from both tumor and blood are sequenced and are 
compared to one another for germline variant correction. 
9.8.1.3
Tissue Biopsy at Disease Progression or Recurrence
Upon disease progression/recurrence, excised tumor tissue submission (FFPE block [preferred] or 
10 to 15 unstained slides), obtained from core biopsy, excisional biopsy, or surgical specimen is 
optional but strongly encouraged upon disease progression/recurrence and prior to subsequent 
systemic treatment. Fine needle aspirates of draining lymph node are not acceptable. Core needle 
biopsies obtained by EBUS are acceptable. Tissue upon disease progression/recurrence should be 
performed prior to subsequent systemic treatment. Biopsy samples collected at the time of disease 
progression or recurrence is to evaluate changes in exploratory biomarkers, which may provide 
critical insight into the tumor microenvironment (TME) at the time of acquired resistance. The 
procedure may be performed if deemed an acceptable clinical risk as judged by the investigator or 
in consultation with the radiology staff. Such analyses may inform future combination strategies 
designed to prevent/delay acquired resistance to nivolumab.
9.8.1.4
Circulating tumor DNA (ctDNA)
ctDNA analysis will be used to identify single nucleotide variants for disease monitoring or 
mimimal residual disease. Additional batched analyses of ctDNA isolated from on treatment 
patients can be utilized to perform non-invasive phylogenetic analyses of tumor evolution under 
the selective pressure of systemic treatment in a research setting. The longitudinal analyses of 
MRD+ status patient samples potentially allows tracking of adjuvant chemotherapy/IO resistance 
and identifies patients destined to experience recurrence of their lung cancer. This biomarker 
provides phylogenetic ctDNA profiling of subclonal nature of lung cancer relapse and metastases, 
providing a new approach for ctDNA driven therapeutic studies. 
Timepoints for ctDNA plasma collection pre and post treatment are in Table 9.8.1-1.
9.8.1.5
Serum Soluble Factors
Serum will be obtained from all participants prior to first dose of study drug and during the study. 
To understand the prevalence of circulating proteins and the impact they may have on the clinical 
activity of study treatment, panel of cytokines, chemokines, and other relevant 
immunomodulatory, serum-soluble factors will be investigated by ELISA, seromics, and/or other 
relevant multiplex-based protein assay methods. Circulating proteins of interest may include, but 
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are not limited to, factors induced by IFNγ signaling (eg, T cell chemoattractants CXCL9; 
CXCL10) antibodies to tumor-associated antigens, and soluble PD-L1 (sPD-L1).
9.8.1.6
Tissue and Whole Blood Gene Expression
Resected tumor specimen and peripheral blood will be collected (prior to- and during treatment) 
to evaluate baseline and changes from baseline in gene expression patterns. Signaling pathways, 
both immune-related and non-immune related, may be explored for association with response to 
treatment. Gene expression data will be generated from tissue and blood using RNAseq or similar 
methodology.
Note: Whole blood GEP will not be collected in countries where not logistically feasible.
9.8.1.7
Peripheral blood mononuclear cells (PBMCs) 
To assess the immunomodulatory properties of nivolumab over the course of treatment, peripheral 
blood samples will be collected from all participants according to the schedule provided in Table 
9.8.1-1 and will be used to prepare viable PBMCs. Cytometric analyses (such as, but not limited 
to flow, chip- and mass-spec-based) may be completed using these samples to quantify increases 
or decreases from baseline in various immune cell populations, including but not limited to 
activated (HLA-DR+), memory (CD45RO+), and regulatory (FoxP3+) T cells. Baseline levels and 
changes from baseline levels in candidate biomarkers, assessed by cytometry analyses will be 
evaluated for association with efficacy and/or safety. Additional analyses of PBMCs may include 
functional assessment using methods such as, but not limited to, tetramer analysis and/or EliSpot 
analysis, potentially using peptides derived from neoantigen prediction studies from whole exome 
sequencing in tumor samples.
Note: PBMCs will not be collected in countries where not logistically feasible.
9.8.1.8
Myeloid Derived Suppressor Cells (MDSCs)
Myeloid derived suppressor cells are an immune cell population capable of suppressing T cell 
activation and proliferation. Low pre-treatment MDSC levels in peripheral blood may be 
associated with better overall survival in NSCLC patients treated with the immunotherapeutic 
agent MDSCs will be measured at baseline and on-treatment to assess pharmacodynamic changes 
or associations with outcome.
Note: MDSCs will not be collected in countries where not logistically feasible.
9.8.1.9
Other Assessments
Serum will be collected for potential future measurements of anti-SARS-CoV-2 antibodies by serology 
(anti-SARS-CoV-2 total or IgG) to explore potential association with safety, efficacy, and/or immune 
biomarkers.
9.8.2
Additional Research Collection
This protocol will include residual sample storage for additional research (AR).
For All US sites: Additional research participation is required for all investigational sites in the 
U.S.
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For non-US Sites: Additional research is optional for all study participants, except where retention 
and/or collection is prohibited by local laws or regulations, ethics committees, or institutional 
requirements. 
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right patients. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment etc. 
Sample Collection and Storage
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development (or designee) to 
ensure the research supports appropriate and well-defined scientific research activities.
Residual whole blood, serum, plasma, and tumor biopsy/surgical collections (see Table 9.8.2-1) 
will be retained for additional research purposes.
Samples kept for future research will be stored at the BMS Biorepository or an independent, 
BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher
to connect a sample to a specific individual.
All samples from screened participants will be archived at the BMS Biorepository or an 
independent, BMS-approved storage vendor.
Table 9.8.2-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Timepoints for which residual samples will be retained
PK/Immunogenicity
All
Tumor Biopsy
All 
Surgical tissue
All
Blood samples for biomarkers
All
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9.8.3
Immunogenicity Assessments 
Immunogenicity samples will be analyzed for anti-nivolumab antibodies and neutralizing 
antibodies by a validated method. Only samples from participants in the nivolumab treatment arm 
will be analyzed. Serum samples may be analyzed by an exploratory method that measures anti-
drug antibodies for technology exploration purposes, exploratory results will not be reported. 
Serum samples designated for PK or biomarker assessments may also be used for immunogenicity 
analysis if required (eg. insufficient volume for complete immunogenicity assessment or to follow 
upon suspected immunogenicity related AE). Further details of blood collection and processing 
will be provided to the site in the procedure manual.
A detailed schedule of immunogenicity evaluation is provided in Table 9.5-1.
9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Healthcare resource utilization data will be collected for all randomized participants using an 
internal CRF developed for use in previous trials. The form, which is completed by study staff, 
records information about hospital admissions, including the number of days spent in various 
wards and discharge diagnosis, and non-protocol specified visits related to study therapy, including 
date of visit, reason for visit, and type of visit. The healthcare resource utilization data will be used 
to support subsequent economic evaluations.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The sample size is determined based on the primary endpoint of event-free survival (EFS) in 
nivolumab plus chemotherapy (Arm A) and placebo plus chemotherapy (Arm B). Initially, an 
alpha of 0.05 will be allocated to the EFS comparison of Arm A vs Arm B, and if that comparison 
is statistically significant, the full alpha will be reallocated to the overall survival comparison of 
Arm A vs Arm B.
10.1.1
Sample Size Justification for EFS
In this study, the sample size is calculated to compare EFS between Arm A and Arm B under a 
two-side 0.05 type I error with 90% power consideration. The number of events was estimated 
assuming an exponential distribution for EFS in each arm. 
Approximately 452 subjects will be randomized to the two treatment groups in a 1:1 ratio. 
Approximately 231 EFS events observed among the above described population provides 90%
power to detect a hazard ratio (HR) of 0.65 with a type 1 error of 0.05 (two-sided). The HR of 0.65 
corresponds to a 54% increase in the median EFS, assuming a median EFS of 21 months for Arm 
B and 32.3 for Arm A. The interim analyses is scheduled to take place after approximately 185 
events (80% of the total number of events), which corresponds to 32 months after the first subject 
is randomized. The stopping boundaries at the interim and final analyses will be based on the actual 
number of EFS events at the time of the analysis using Lan-DeMets alpha spending function with 
O’Brien-Fleming boundaries. If the interim analysis is performed exactly at 185 events, the study 
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could be stopped by the DMC for EFS superiority if the p-value is ≤0.025. The nominal 
significance level for the final look of EFS after 231 events would then be 0.043.
Assuming the accrual rate (number of randomized subjects per month: 20), it will approximately 
take 38 months (23 months for accrual and 15 months for follow-up) from the randomization of 
the first subject to observe the required number of events among subjects randomized for final EFS 
analysis.
Table 10.1.1-1 summarizes of the key parameters of the sample size justification for EFS Analyses. 
Table 10.1.1-1:
Sample Size Justification for EFS Analyses
Primary Endpoint
EFS
Primary analysis Comparison population
Arm A and Arm B
Power (interim analysis /final analysis)
90% (75% / 15% )
Alpha
0.05
Hypothesized Median nivolumab + chemotherapy (arm 
A) vs placebo + chemotherapy (arm B)  (months)
32.3 vs 21
Hypothesized Hazard ratio
0.65
Accrual Duration (months)
23
Timing of interim analysis(IA) from randomization of 
first subject (months)
32
Timing of final analysis(FA) from randomization of 
first subject (months)
38
Sample size for Arms A and B
452
Expected number of events for 
     EFS interim analysis 1 (80% events) 
     EFS final analysis 
185 
231 
10.1.2
Power Calculation for OS
If the superiority of EFS per BICR assessment for the comparison between nivolumab plus 
chemotherapy (Arm A) and placebo plus chemotherapy (Arm B) is demonstrated at a two sided 
type I error rate 0.05, OS will be tested hierarchically (Section 10.3.2) .
Approximately 174 events, among the 452 subjects randomized to Arms A and B provides 80% 
power to detect a hazard ratio of 0.65 with a type I error of 0.05. The HR of 0.65 corresponds to a 
54% increase in the median OS, assuming a median OS of 40 months for Arm B and 61.5 months 
for Arm A. One interim analysis are planned at the time of the EFS FA (where approximately 80% 
of the total number of events are projected to have occurred at 140 events). The stopping 
boundaries at the interim and final analyses will be based on the actual number of OS events at the 
time of the analysis using Lan-DeMets alpha spending function with O’Brien-Fleming boundaries. 
If the first interim analysis is performed exactly at 140 events, a p-value ≤0.025 would result in a 
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statistically significant improvement in OS. The nominal significance level for the final look of 
OS after 174 events would then be 0.043. 
Assuming an accrual rate of 20 participants per month, it will take approximately 46 months from 
the randomization of the first subject to observe the required number of events for the final OS 
analysis. The interim analysis will take place at the same time as the final EFS analysis, which is 
projected to be 38 months from the randomization of the first subject. Table 10.1.2-1 summarizes 
the key parameters of the power calculation for OS Analyses.
Table 10.1.2-1:
Power Calculation for OS Analyses
Secondary Endpoint
OS
Primary analysis Comparison population
Arm A and Arm B
Power (interim analysis /final analysis)
80% (60% / 20% )
Alpha
0.05
Hypothesized Median nivolumab + chemotherapy (arm A) 
vs placebo + chemotherapy (arm B)  (months)
61.5 vs 40
Hypothesized Hazard ratio
0.65
Accrual Duration (months)
23
Timing of interim analysis(IA) from randomization of first 
subject (months)
38
Timing of final analysis(FA) from randomization of first 
subject (months)
46
Sample size for Arms A and B
452
Expected number of events for 
     OS interim analysis 1 (80% events) 
     OS final analysis 
140 
174 
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled participants
All participants who sign informed consent and were registered 
into the IRT
Treated participants
All participants who received at least one dose of study medication 
in neoadjuvant or adjuvant setting.
This is the primary dataset for drug exposure and safety analysis.
PK participants
All treated subjects with available serum time-concentration data 
Randomized participants
All participants who were randomized to any treatment arm in the 
study. This population will be used for analyses of study conduct 
and study population. Analysis of demography, protocol 
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Population
Description
deviations, baseline characteristics and efficacy will be performed 
for this population
Biomarker participants
All treated subjects with biomarker data available.
Patient-Reported Outcome 
participants
All treated subjects who have a valid baseline assessment and at 
least one post baseline assessment
10.3
Statistical Analyses
The statistical analysis plan (SAP) will be developed and finalized before database lock. For the 
stratified test, stratum may be combined if stratum size is too small. Additional details will be 
outlined in the SAP. Below is a summary of planned statistical analyses of the primary and 
secondary endpoints.
A description of the participant population will be included in a statistical output report, including 
subgroups of age, gender and race.
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary 
Event-free Survival
EFS is defined as the length of time from randomization to any of the 
following events: progression of disease or worsening of disease 
precluding surgery, if surgery is attempted but gross resection is 
abandoned due to unresectable tumor or worsening of disease,
progression or recurrence of disease after surgery, progression of disease 
for participants without surgery, or
death due to any cause.
Progression/recurrence will be assessed by BICR per RECIST 1.1. 
Participants who do not undergo surgery for reason other than 
progression will be considered to have an event at RECIST 1.1 
progression or death. Participants who undergo surgery with incomplete 
resection (residual disease visible on imaging) will be considered to have 
an event at RECIST 1.1 progression or death. Participants who die 
without a reported progression/disease recurrence will be considered to 
have experienced an event on the date of their death. Participants who 
do not report progression/recurrence of disease or die will be censored 
on the date of their last evaluable tumor assessment. Participants who 
did not have any on-study tumor assessments and did not die will be 
censored on the date they were randomized. Participants who started any 
subsequent anti-cancer therapy outside of the protocol-specified 
adjuvant therapy without a prior reported progression/recurrence will be 
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Endpoint
Statistical Analysis Methods
censored at the last evaluable tumor assessment prior to initiation of the 
subsequent anticancer therapy.
There are two scheduled EFS analyses: one EFS interim analysis and 
one EFS final analysis. EFS primary hypothesis testing will be 
conducted between 2 randomized arms via a 2-sided, log rank test 
stratified by the stratification factor (ie, tumor histology, PD-L1 status 
and tumor stage). The alpha spending allocated to the testing is based on 
the number of events at the time of interim analyses based on Lan-
DeMets alpha spending function. 
The hazard ratio and the two sided 95% confidence interval will be 
estimated in a stratified Cox proportional hazards model using the 
randomized arm as a single covariate. In addition, EFS rates at 6, 12, 18 
and 24 months will be estimated using KM estimates on the EFS curve 
for each randomized arm provided a minimum follow-up is longer than 
the time point to generate the rate. Associated 2-sided 95% CIs will be 
calculated using the Greenwood formula (using log-log transformation). 
Sensitivity analysis on EFS will also be performed, and details will be 
included in statistical analysis plan.
Secondary
Overall survival
If the comparison of primary endpoint EFS is statistically significant, OS 
will be tested hierarchically and the full alpha (0.05) will be recycled to 
the OS comparison. There will be one interim analysis and one final 
analysis scheduled for the OS comparison and the alpha spending 
allocated to the testing is based on the number of events at the time of 
the interim analysis based on the Lan-DeMets alpha spending function. 
Hazard ratios (HR) of OS and corresponding two-sided 95% confidence 
intervals (CI) will be estimated using a stratified Cox proportional 
hazard model, with treatment group as a single covariate. OS curves, OS 
medians with 95% CIs, and OS rates at 6, 12, 18, 24 and 36 months with 
95% CIs will be estimated by treatment group using Kaplan Meier 
methodology if follow-up requirement is met.
Overall survival (OS) is defined as the time between the date of 
randomization and the date of death due to any cause. OS will be 
censored on the last date a subject was known to be alive. OS will be 
followed continuously while participants are on the study drug and every 
3 months via in-person or phone contact after participants discontinue 
the study drug.
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Endpoint
Statistical Analysis Methods
Pathologic Complete 
Response and Major 
Pathological 
Response
Pathological response will be summarized by category for each 
treatment group. MPR and pCR rate will be computed in each treatment 
group along with the exact 95% CI using Clopper-Pearson method. The 
stratified by tumor histology, PD-L1 status and tumor stage odds ratios 
(Mantel-Haenszel estimator) between the treatments will be provided 
along with the 95% CI. 
In addition, an estimate of the difference in MPR and pCR rates and 
corresponding 95% CI will be calculated using CMH methodology and 
adjusted by stratification factors.
Exploratory
Will be described in the statistical analysis plan finalized before database 
lock
10.3.2
Safety Analyses
Endpoint
Statistical Analysis Methods
Primary
Not applicable
Secondary
Safety
Safety analysis will be performed in all treated participants. Descriptive 
statistics of safety will be presented using National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 by 
treatment group. All on-study AEs, drug-related AEs, SAEs and drug-related 
SAEs will be tabulated using worst grade per NCI CTCAE v 4.0 criteria by 
system organ class and preferred term. On-study lab parameters including 
hematology, chemistry, liver function and renal function will be summarized 
using worst grade per NCI CTCAE v 4.0 criteria.
Frequency, management and resolution of IMAEs will be analyzed. A tabular 
summary and comparative analysis between treatment arms of the incidence 
of overall IMAEs (by preferred term) and serious IMAEs will be performed. 
A descriptive analysis of IMAEs including time-to-onset, severity, duration, 
action taken with the study drug, dosing delays of the study drug, 
corticosteroid details, re-challenge information and outcome of the AE will 
be individually characterized in the SAP.
Exploratory
Will be described in the statistical analysis plan finalized before database lock
10.3.3
Other Analyses 
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the statistical 
analysis plan finalized before database lock. The population pharmacokinetics analysis and 
pharmacodynamic analyses will be presented separately from the main clinical study report. 
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PFS2 is defined as the time from randomization to the date of investigator-defined documented 
disease progression after next line of treatment or death due to any cause, whichever comes first. 
Clinical deterioration will not be considered as progression. A participant who neither progresses 
after next line of treatment nor dies will be censored on the last known date alive. A participant 
who does not have any post baseline tumor assessments and who has not died will be censored on 
the date at which he/she was randomized. 
Methodology for exploratory immunogenicity analyses is described in the statistical analysis plan.
10.3.4
Interim Analyses 
One formal interim analysis for EFS is planned after approximately 185 events have been 
observed. This is projected to occur approximately 32 months after start of randomization. The 
formal comparisons of EFS will allow for early stopping for superiority, and the boundaries for 
declaring superiority will be derived based on the actual number of events using Lan-DeMets α 
spending function with O’Brien and Fleming type of boundary. If the analysis were performed 
exactly at 185 events, the boundary for declaring superiority would be 0.025. An independent 
statistician external to BMS will perform the analyses. 
If the study continues beyond this interim analyses, the nominal significance level for the final 
look after 231 EFS events would be 0.043. All events in the database at the time of the lock will 
be used. If number of final events exceeds the number specified per protocol, final boundary will 
not be recalculated using updated information fraction at interim.
If the EFS comparison is statistically significant, one formal interim analysis for OS is planned at 
the time of the EFS FA (corresponding to approximately 80% of the total number of events). The 
formal comparisons of OS will allow for early stopping for superiority. The stopping boundary 
will depend on the actual number of events at the time of the interim analysis
The Statistical Analysis Plan will further describe the planned interim analyses.
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REFERENCES
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15 Greenwald  RJ,  Freeman  GH,  Sharpe  AH.  The  B7  family  revisited.  Annu  Rev  Immunol. 
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31 Dolan P. Modeling valuations for EuroQol health states. Med Care 1997; 35(11):1095-1108.
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AR
Additional Research
AST
aspartate aminotransferase
BICR
Blinded independent central review
BID, bid
bis in die, twice daily
BIPR
Blinded independent pathological review
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
cm
centimeter
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form, paper or electronic
cRR
clinical response rate
CT
computed tomography
ctDNA
circulating tumor deoxyribonucleic acid
dL
deciliter
DLco
carbon monoxide diffusing capacity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
EBUS
endobronchial ultrasound
ECG
electrocardiogram
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Term
Definition
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EFS
event-free survival
eg
exempli gratia (for example)
EQ-5D-3L
European Quality of life 5 dimensions 3 level
EU
European Union
EWB
emotional well-being
FACT-G
FACT-General 
FACT-L
Functional Assessment of Cancer Therapy – Lung
FACT-LCS
FACT-Lung Cancer Subscale 
FDA
Food and Drug Administration
FEV1
forced expiratory volume in the first second of expiration
FFPE
formalin-fixed paraffin-embedded
FRC
functional residual capacity
FSH
follicle stimulating hormone
FVC
forced vital capacity
FWB
functional well-being 
g
gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GWAS
genome-wide association study
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HRQoL
health-related quality of life 
HR
heart rate
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
ie
id est (that is)
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Term
Definition
IEC
Independent Ethics Committee
IHC
Immunohistochemical
IMP
investigational medicinal products
IRB
Institutional Review Board
IRT
Interactive Response Technology
IU
International Unit
IV
intravenous
kg
kilogram
L
liter
LAM
lactation amenorrhea method
LCS
Lung Cancer Subscale
LDH
lactate dehydrogenase
mg
milligram
min
minute
mL
milliliter
mmHg
millimeters of mercury
MPR
major pathological response
MLND
mediastinal lymph node dissection
MRI
magnetic resonance imaging
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NIH
National Institutes of Health 
NSCLC
non-small cell lung carcinoma
NSCLC-SAQ
non-small cell lung cancer symptom assessment questionnaire 
NIMP
non-investigational medicinal products 
OS
overall survival 
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Term
Definition
PBMC
peripheral blood mononuclear cells
pCR
Pathologic complete response
PET
positron emission tomography
PGIS
Patient Global Impression of Severity 
PK
pharmacokinetics
PPK
Population pharmacokinetic 
PO
per os (by mouth route of administration)
PRO
patient-reported outcomes
PROMIS
Patient-Reported Outcome Measurement Information System 
PROMIS PF 8c
PROMIS Physical Function Short Form 8c 
PWB
physical well-being 
QOL
quality of life
R&D
Research and Development
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SCCHN
squamous cell carcinoma of the head and neck 
SD
standard deviation
SOC
Standard of care
SOP
Standard Operating Procedures
t
temperature
TAO
Trial Access Online, the BMS implementation of an EDC capability
TLC
total lung capacity
TME
tumor microenvironment 
VAS
visual analog scale
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical GuidelinesGood Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of Good Clinical Practice (GCP) (occurring in 
any country) in connection with that trial or the protocol related to the trial which is likely to affect 
to a significant degree the safety or physical or mental integrity of 1 or more subjects of the trial 
or the scientific value of the trial.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given by subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Subjects/participants unable to give their written consent (e.g., stroke or subjects/participants with 
or severe dementia) may only be enrolled in the study with the consent of a legally acceptable 
representative. The participant must also be informed about the nature of the study to the extent 
compatible with his or her understanding, and should this participant become capable, he or she 
should personally sign and date the consent form as soon as possible. The explicit wish of a 
participant who is unable to give his or her written consent, but who is capable of forming an 
opinion and assessing information to refuse participation in, or to be withdrawn from, the clinical 
study at any time should be considered by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
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SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
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If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage 
area
•
amount currently in storage area
•
label identification number or batch 
number
•
amount dispensed to and returned by each 
participant, including unique participant 
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (e.g., lost, wasted) 
•
amount destroyed at study site, if 
applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence, if 
applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study treatment integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
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understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee. 
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RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
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•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
Study Steering Committee chair or their designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Other criteria (as determined by the study team)
DISSEMINATION OF CLINICAL STUDY DATA
To benefit potential study participants, patients, health care providers, and researchers and to help 
BMS honor its commitments to study participants, BMS will make information about clinical 
research studies and a summary of their results available to the public per regulatory and BMS 
requirements. BMS will post study information on local, national, or regional databases in 
compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
In the European Union (EU), the summary of results and summary for laypersons will be submitted 
within 1 year of the end of trial in the EU/European Economic Area and third countries.
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
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Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors.  No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW
UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment 
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via email or 
confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
Local laws and regulations may require the use of alternative and/or additional contraceptive 
methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
•
Combined (estrogen- and progestogen-containing) hormonal contraception must begin at 
least 7 days prior to initiation of study therapy.
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
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Progestogen-only hormonal contraception must begin at least 7 days prior to initiation of 
study therapy.
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b
•
Intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
•
Periodic abstinence (including, but not limited to, calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactation amenorrhea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
•
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Unacceptable Methods of Contraception*
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 5
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUS a
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
a Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 6
MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 7 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS FOR NEOADJUVANT 
LUNG STUDY
HIGH LEVEL SUMMARY OF THE MODIFICATIONS
• Removal of fluid (ascites, pleural and pericardial effusions) from response assessment as non-
target or new lesion due to potential unconfirmed etiology and volume changes resulting from 
interventional procedures unrelated to treatment response (thoracentesis), 
• Best Overall Response of CR or PR does not require confirmation. 
1 
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.
1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1 
Measurable
Tumor lesions:Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or 2x slice thickness 
if greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph  nodes  merit special  mention since they  are normal anatomical structures which  may  be 
visible  by  imaging  even  if  not  involved  by  tumor.  Pathological nodes  which  are  defined  as 
measurable  and  may  be  identified  as  
target  lesions  must  meet  
the  criterion  of  a  short  axis  of 
≥15 mm by CT/MRI 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 two dimensions in the plane in which 
the  
image  
is  obtained  
(for  CT  scan  
this  
is  almost  always  
the  axial  plane;  
for  MRI the  plane  of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 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  non-target  
lesions.  Nodes  
that  have  a  short  axis  <  10  mm  are  considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan and 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 non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
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All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) 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).
•
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.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
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 complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
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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 
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
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’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target 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 non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
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2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) 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 non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described 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 non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). 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 the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
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. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
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possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment in the 
Neoadjuvant (Pre-surgery) phase.
For patients who undergo surgery, best overall response is assessed from start of the study 
treatment to tumor assessment prior to definitive surgery
For patients not undergoing definitive surgery, the best response is assessed from the start of study 
treatment until the first scheduled tumor assessment per protocol. 
The patient’s best overall response assignment will depend on the findings of both target and non-
target disease and will also take into consideration the appearance of new lesions. Assessments of 
partial response and complete response do not require confirmation. 
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
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Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response does not require confirmation. When 
SD is believed to be best response, it must meet the protocol specified minimum time from the 
date of first treatment or randomization date.
Best overall response is defined as:
•
For patients undergoing definitive surgery: the best response is recorded from the start of study 
treatment until the last tumor assessment performed prior to definitive surgery.
•
For patients not undergoing definitive surgery: the best response is recorded from the start of 
study treatment until the first scheduled tumor assessment per protocol.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
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2.3.4
Confirmation Scans
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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APPENDIX 8
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Amendment 03, 20-Apr-2021
The overall rationale for the amendment is to reduce the number of slides required at screening 
and change the requirement for biopsy at disease progression/recurrence from mandatory to 
optional in order to address potential barriers to enrollment, reduce burden on participants, and 
reduce trial complexity. In addition, the definition of Event-Free Survival was aligned throughout 
protocol sections, imaging requirements were clarified, and response evaluation criteria was 
clarified. Serology samples for SARS-CoV-2 were added. AE collection was updated to include 
collection of SARS-CoV-2-related adverse events. These changes apply to all patients. 
Summary of Key Changes for Amendment 03
Section Number & Title
Description of Change
Brief Rationale
Section 2, Schedule of 
Activities, Table 2-1 Screening 
Procedural Outline
•
Documentation of 
COVID-19 vaccine or 
infection history added
•
Added to specify that 
collection of COVID-19 
vaccination status will be 
collected as part of 
participants medical history 
Section 2, Schedule of 
Activities, Table 2-1 Screening 
Procedural Outline; Section 
9.8.1.1, Diagnostic/Baseline 
Biopsy
•
Required tissue 
amount updated to 5-
10 slides
•
Serology samples for 
SARS-CoV-2 
•
The number of tissue slides 
reduced from 15 to 5-10, to 
address potential 
enrollment barriers
•
Serum will be collected for 
potential future anti-SARS-
CoV-2 based analysis
Section 
2, 
Schedule 
of 
Activities, 
Table 
2-2: 
Neoadjuvant and Pre-Surgery 
Procedures and Assessments; 
Table 2-3: Post surgery/Pre-
adjuvant 
and 
Adjuvant 
Treatment 
Procedures 
and 
Assessments; Table 2-4: Long-
term Follow up Assessment;
Table 
9.8.1-1: 
Biomarker 
Sample 
Schedule 
for 
All 
Participants; Section 9.8.1.3, 
Tissue 
Biopsy 
at 
Disease 
Progression or Recurrence
•
Reduction in number 
of slides required at 
enrollment from 15 to 
5-10. 
•
Biopsy upon disease 
progression/recurrence 
changed from 
mandatory to optional
•
To reduce burden on 
participants and reduce 
trial complexity
Section 2, Schedule of 
Activities; Table 2-1 Screening 
Procedural Outline; Table 2-2: 
•
Updated note added to 
AE collection related 
•
SARS-CoV-2 AEs/SAEs 
will be collected
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Summary of Key Changes for Amendment 03
Section Number & Title
Description of Change
Brief Rationale
Neoadjuvant and Pre-Surgery 
Procedures and Assessments; 
Table 2-3: Post surgery/Pre-
adjuvant and Adjuvant 
Treatment Procedures and 
Assessments; Table 2-4: Long-
term Follow up Assessment;
to SARS-CoV-2 
infection
Section 2, Schedule of 
Activities, Table 2-4: Long-
term Follow-up Assessments 
•
Clarification of body 
imaging requirements 
to include participants 
who do not undergo 
surgery
•
To provide language clarity 
for schedule of activities 
Synopsis; Section 4, Objectives 
and Endpoints, Table 4-1
•
To specify 
abandonment of 
surgery due to disease 
progression
•
•
Language clarification 
to assess ORR
•
Align the definition of an 
event for Event Free 
Survival (EFS) to be 
consistent with Statistical 
Analysis Plan (SAP)  
•
Language updated to align 
with current protocol 
requirements 
Section 9.1.1.1, Definition of 
Disease Recurrence; Section
9.1.1.2, Definition of Disease 
Progression 
•
Clarified definition of 
disease 
progression/recurrence
•
Clarified language 
regarding disease 
progression/recurrence
Section 10.3, Statistical 
Analysis
•
Clarified that stratum 
may be combined if 
stratum size is too 
small
•
Clarification and alignment 
with statistical analysis 
plan 
Appendix 2, Study Governance 
Considerations, Monitoring
•
Information on remote 
monitoring added
•
Updated to include the 
latest BMS standard 
language regarding study 
monitoring
Appendix 7, Response 
Evaluation Criteria in Solid 
Tumors Guidelines (Version 
1.1) with BMS Modifications 
for Neoadjuvant Lung Study
•
Clarified evaluation of 
Best Overall Response
•
•
Confirmatory scan 
requirement for CR 
and PR deleted
•
The assessment of Best 
Overall Response 
assessment was clarified 
for participants within this 
trial
•
Response evaluation 
criteria guidelines modified 
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Summary of Key Changes for Amendment 03
Section Number & Title
Description of Change
Brief Rationale
to align with protocol 
requirements
Overall Rationale for Revised Protocol 02, 11-May-2020
This revised protocol updates the stratification for PD-L1 and provides clarity to the eligibility 
criteria and time windows for imaging assessment. These changes apply to all patients.  
Summary of Key Changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Synopsis, Schema
Section 5.1 Overall Design 
Section 7.2 Method of Treatment 
Assignment
Updated stratification 
categories for PD-L1 status
 
 
 
 
Table 2-1: Screening Procedural 
Outline
Table 2-2: Neoadjuvant and Pre-
surgery Procedures and 
Assessments
Table 2-3: Post surgery/Pre-
adjuvant and Adjuvant 
Treatment Procedures and 
Assessments 
Table 2-4: Long-term Follow-up 
Assessments
Section 9.1.2.1 Neoadjuvant and 
Pre-Surgical Imaging
Section 9.1.2.2 Post Surgical / 
Preadjuvant Restaging and 
Adjuvant Imaging
Section 9.1.2.3 Methods of 
Measurement
Updated language for 
contraindications for CT 
with contrast
This change provides the 
option to use MRI instead of
CT in all body regions 
except chest and allows 
compliance with  site-
specific radiation protection 
requirements.
Table 2-2: Neoadjuvant and Pre-
surgery Procedures and 
Assessments (CA20977T)
Section 9.1.2.3 Neoadjuvant and 
Pre-Surgical Imaging
Updated window for 
preoperative imaging 
assessment. 
Window expansion provides 
additional guidance. 
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Summary of Key Changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Table 2-4 Long-term Follow-up 
Assessments (CA2097TT)
Corrected survival status 
window and updated 
footnote 
This change clarifies data 
collection during follow-up
Synopsis
Section 5.1.2.1 Neoadjuvant / 
Pre-surgical Treatment Period
Section 7.1.1.2Platinum-based 
Doublet Chemotherapy 
Regimens
Removed carboplatin and 
docetaxel regimen
 
 
 
 
Section 5.1.2.3 Participants not 
receiving surgery
Updated section to clarify 
treatment instructions when 
participants do not receive 
surgery. 
This change clarifies 
decision for adjuvant 
treatment or discontinuation 
based occurrence of an 
event/non-event.
Section 6.1 Inclusion criteria 
2) Type of Participant and 
Target Disease Characteristics 
letter a)
Added requirement for 
multidisciplinary team 
evaluation and that 
participants with N3 nodal 
disease are not eligible
Provides clarity for 
eligibility requirements.
Exclusion Criteria 
2) Prior/Concomitant Therapy 
letter d)
Added exclusion criteria for 
prior treatment with drug 
specifically targeting T-cell 
co-stimulation or 
checkpoint pathways
Provides clarity for 
eligibility requirements.
Section 7.1.1.3 Dosing
Information for Platinum-based 
Doublet Chemotherapy
Added dosing information 
for Pemetrexed/Carboplatin:
Provides instructions for 
treatment
Table 7.4.1.2-1 Dose 
Modifications for Non-
hematologic Toxicity
Reduced dose level if 
creatinine clearance < 30 
mL/min
 
 
 
Section 7.4.2.2 Dose Delay 
Criteria for Platinum-based 
Doublet Chemotherapy
Updated dose delay criteria 
for docetaxel if total 
bilirubin is > ULN 
 
 
 
Section 7.7.1 Prohibited and/or 
Restricted Treatments
Prohibited administration of 
strong CYP3A4 inhibitors 
with docetaxel. 
 
 
 
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Summary of Key Changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 8.1.2 Platinum-based 
Doublet Chemotherapy Dose 
Discontinuation
•
Added 
discontinuation for cystoid 
macular edema 
 
 
 
9.8.1
Tumor Tissue and Blood 
Tissue Collection
Removed minimal residual 
disease, single nucleotide 
assessments, whole blood 
single nucleotide 
polymorphism, serum 
miRNA, T-cell repertoire 
assessments and analysis
Updated biomarker 
collection to align with 
program strategy
Overall Rationale for the Revised Protocol 01, 20-Dec-2019
The revised protocol updates the document 
 for modifying 
endpoints, adding additional chemotherapy treatment regimens, adhering to local regulations for 
pregnancy testing and contraceptive instructions. The revisions also updates the imaging 
assessments and biomarker collection. Minor edits and corrections were made in the document.
Revisions apply to all current participants and participants in the future. 
Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Title page and synopsis
Added short title
Aligns with disclosure title 
Synopsis
Section 4 Objectives and 
Endpoints
•
Added EFS and OS 
comparisons by PD-L1 
status as exploratory 
objective
•
Moved safety and 
tolerability as secondary 
objective
•
Updated endpoint 
definitions
•
Removed exploratory 
endpoints from synopsis
Endpoints were modified 
 
. Other 
changes were added for 
clarity. 
Synopsis
Section 5.1.2.1 Neoadjuvant / 
Pre-surgical Treatment Period
Added drug neoadjuvant 
regimens for 
Chemotherapy drug 
regimens were updated
 
 
 and 
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Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Table 7-1 Study Treatments for 
CA20977T
Table 7.1-1 Selection and 
Timing of Dose
Section 7.1.1.2 Platinum-based 
Doublet Chemotherapy 
Regimens
Section 7.1.1.3 Dosing 
Information for Platinum-based 
Doublet Chemotherapy
Section 7.4.1 Dose Reductions 
for Platinum-based Doublet 
Chemotherapy
•
carboplatin and docetaxel 
regimen for squamous 
histology
•
cisplatin and docetaxel 
regimen for squamous 
histology
•
carboplatin and paclitaxel 
regimen for nonsquamous 
histology
Updated study treatment
internal consistency in the 
document.
Table 2-1 Screening Procedural 
Outline
Added pregnancy test
Provides internal 
consistency in the 
document.
Table 2-1 Screening Procedural 
Outline 
Table 2-2: Neoadjuvant and 
Pre-surgery Procedures and 
Assessments
Table 2-3:Post-surgery/Pre-
adjuvant and Adjuvant 
Treatment Procedures and 
Assessments
Section 5.1.2.5 Post-
surgical/Pre-adjuvant 
Evaluation
Section 9.1.2.1 Neoadjuvant 
and Pre-Surgical Imaging
Section 9.1.2.2 Post Surgical / 
Preadjuvant Restaging and 
Adjuvant Imaging
Updated imaging language to 
require PET-CT for body 
imaging.
Updated Imaging frequency 
and baseline measurements 
Updated instructions for 
BICR assessments.
Imaging assessments were 
updated to align with study 
needs and to provide 
clarity. 
Table 2-1: Screening 
Procedural Outline 
•
Updated EGFR testing 
•
Updated staging 
mediastinal lymph node 
evaluation
EGFR testing and lymph 
node evaluation were 
updated for clarity. 
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Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Table 2-2: Neoadjuvant and 
Pre-surgery Procedures and 
Assessments
Table 2-3:Post-surgery/Pre-
adjuvant and Adjuvant 
Treatment Procedures and 
Assessments
Section 5.1.2.5 Post-
surgical/Pre-adjuvant 
Evaluation
Section 5.1.1 Screening
Section 9.8.1.1 
Diagnostic/Baseline Biopsy
Updated collection of tumor 
tissue and surgical tumor 
tissue. 
Instructions were expanded 
to collect tissue and 
information for central 
pathology review and 
biomarker assessments. 
Table 2-4 Long-term Follow-up 
Assessments 
Section 6.1 Inclusion Criteria
Pregnancy testing and 
contraception use should be 
performed as per local 
regulation and approved 
product label. 
Duration of pregnancy 
testing and contraception 
use was updated for safety. 
Table 2-3:Post-surgery/Pre-
adjuvant and Adjuvant 
Treatment Procedures and 
Assessments 
Instruction provided for 
staging mediastinal lymph 
node. 
Instructions provide clarity 
Figure 5.1.2-1 Flowchart for 
Efficacy and Safety Data 
Collection
Table 9.4.4-1 Clinical 
Laboratory Assessments
Table 9.8.1-1: Biomarker 
Sample Schedule for All 
Participants
Corrected errors in data 
collection timing, clinical 
laboratory assessments, and 
biomarker sample.
Corrected document.
Section 5.1.2.2 Surgery
Updated instructions for 
preoperative mediastinal 
evaluation by 
bronchoscopy/EBUS
Change made to provide 
clarity.
Section 5.1.2.4 Postoperative 
radiotherapy as SOC
Conditions for post-operative 
radiation therapy were added.
Change made to provide 
clarity.
Section 5.1.2.5 Post 
surgical/Preadjuvant Evaluation
Imaging frequency and 
baseline measurements were 
updated.
Imaging modality updated 
for internal consistency.
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Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Section 5.1.4 Disease 
Progression/Recurrence
Added the investigator may 
request PD-L1 status from 
screening at BICR-confirmed 
disease progression,
Providing the PD-L1 status 
will allow investigator to 
make treatment decisions.
Section 6.1 Inclusion Criteria
Legal authorized 
representatives will be 
allowed to sign Informed 
Consent where locally 
allowed
Language updated
 
 
.
Section 6.2 Exclusion Criteria
The approved local Product 
Label requirements for the 
individual chemotherapy 
drugs in this trial must be 
followed when determining 
participant eligibility.
Language updated  
 
.
Section 7.3 Blinding
Section 7.5 Preparation/ 
Handling/Storage/ 
Accountability
Section 7.6 Treatment 
Compliance
Instructions for accidental 
blinding was updated. 
Instructions for accidental 
blinding was updated.
Section 6.2 Exclusion Criteria 
Section 7.7.1 Prohibited and/or 
Restricted Treatments
Use of marijuana and its 
derivatives for treatment of 
symptoms related to cancer or 
cancer treatment, if obtained 
by medical prescription or if 
its use (even without a 
medical prescription) has 
been legalized locally.
Language updated to 
provide clarity. 
Table 7.4.1-1 Dose Reductions 
for Platinum-based Doublet 
Chemotherapy
Table 7.4.1.1-1:Dose 
Modifications for Hematologic 
Toxicity (based on Nadir 
Counts)
Dose modification for 
docetaxel was added.  
Language updated  
 
 
. 
Section 8.4.5 
Preparation/Handling/Storage
Duplicate sections removed.
Duplicate sections 
removed.
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Summary of key changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Section 8.5.6 Treatment 
Compliance
Section 9.1.1.1 Definition of 
Disease Recurrence
Section 9.1.1.4 Definition of 
MPR
Definition of disease 
recurrence was updated for 
local and distant recurrence.
Definition of MPR was 
updated.
Definition of MPR was 
added.
Changes were  made to 
provide clarity.
Section 9.1.2.2 Post-Surgical / 
Pre-adjuvant Restaging and 
Adjuvant Imaging
Timing of imaging 
assessments and baselines 
were updated.
Imaging modality updated 
to align with study needs 
and provide clarity. 
Section 9.1.2.4 BICR 
Assessment of Progression
Section updated
Change made to provide 
clarity.
Section 9.8.1 Tumor Tissue and 
Blood Tissue Collection
Section 9.8.1.1 Diagnostic/ 
Baseline Biopsy
Section 9.8.2.1 Circulating 
tumor DNA (ctDNA)
Updated for biomarker and 
tissue collection
Changes made to provide 
internal consistency for 
clarity.
Appendix 2 Study Governance 
Considerations
Appendix 6
Management 
Algorithms
Updated CSR and publication 
authoring process
Added algorithm for 
myocarditis
Aligned with BMS 
standards
All
Minor formatting and 
typographical corrections
Minor, therefore have not 
been summarized
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