Conditions: Non Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 505
Healthy volunteers: no

Brief summary:
The purpose of this neoadjuvant study is to compare nivolumab plus chemotherapy and chemotherapy alone in terms of safety and effectiveness, and to describe nivolumab plus ipilimumab's safety and effectiveness in treating resectable NSCLC.

This study has multiple primary endpoints.

Detailed description:

Arms:
arm 1: Specified dose on specified days arm 2: Specified dose on specified days arm 3: Specified dose on specified days

Interventions: intervention 1: Nivolumab intervention 2: Cisplatin intervention 3: Vinorelbine intervention 4: Gemcitabine intervention 5: Docetaxel intervention 6: Pemetrexed intervention 7: Carboplatin intervention 8: Paclitaxel intervention 9: Ipilimumab
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Specified dose on specified days intervention 4: Specified dose on specified days intervention 5: Specified dose on specified days intervention 6: Specified dose on specified days intervention 7: Specified dose on specified days intervention 8: Specified dose on specified days intervention 9: This arm is closed and no longer enrolling patients.

Protocol document:
Prot_000.pdf: 
Official Title of Study: 
Randomized, Open-Label, Phase 3 Trial of Nivolumab plus Ipilimumab or Nivolumab plus 
Platinum-Doublet Chemotherapy versus Platinum-Doublet Chemotherapy in Early Stage 
NSCLC 
(CheckMate 816: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 816) 
 
PROTOCOL(S) CA209-816 
 
NCT Number: NCT02998528 
  
Document Date (Date in which document was last revised): August 18, 2021 


Page:
1
Protocol Number:
CA209816
IND Number:
125,872
EUDRACT Number:
2016-003536-21
Date:
30-Sep-2016
Revised Date:
18-Aug-2021
CLINICAL PROTOCOL CA209816
Randomized, Open-Label, Phase 3 Trial of Nivolumab plus Ipilimumab or Nivolumab plus 
Platinum-Doublet Chemotherapy versus Platinum-Doublet Chemotherapy in Early Stage 
NSCLC
(CheckMate 816: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 816)
Protocol Amendment 07
24-hr Emergency Telephone Number
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
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 
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 (e.g., 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, e.g., a Contract Research 
Organization (CRO).
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BMS-936558
nivolumab
Protocol Amendment No.: 07
Date: 18-Aug-2021
2
DOCUMENT HISTORY
Document
Date of Issue
Summary of Changes
Protocol 
Amendment 07
18-Aug-2021
•
To account for a potential slowdown in EFS events accrual in long-term 
follow-up, the protocol was amended to:
−
Revise EFS modeling assumptions to a piecewise exponential 
distribution with lower events rate in the longer term.
−
Include one additional EFS interim analysis at 90% information 
fraction 
 
 
Revised 
Protocol 06
14-Jul-2020
•
Clarified EFS definition
•
Removed the first of 2 interim analyses of EFS and updated alpha 
spending on the remaining interim and final analyses of EFS
•
Clarified that the actual timing of analyses may differ from projected 
timing
•
Removed text about descriptive EFS analysis
Revised 
Protocol 05
18-Sep-2019
•
Modified pCR analysis population and projected timelines
•
Updated surgical approach endpoint 
•
Updated the censoring rule of TTDM
•
No optional biopsy at disease progression collected in China.
•
Updated Management Algorithms to include myocarditis
Revised 
Protocol 04
25-Jun-2019
•
Added the concomitant administration of substances that are also 
tubularly secreted (eg, probenecid) could potentially result in delayed 
clearance of pemetrexed. 
•
Added hypothesis testing for overall survival
•
Clarified the pCR analysis population
•
Added exploratory endpoint of Event Free Survival on next line of 
therapy
•
Added instructions for BICR
•
Updated Appendix 8 Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow Up and 
Reporting Adverse Events
Revised 
Protocol 03
21-Sep-2018
•
Enrollment in Arm A (nivolumab plus ipilimumab) was stopped
•
Randomization of participants (1:1 ratio) into Arm C and B will
continue to for a total of 350 participants
•
Definition of event free survival is clarified.
•
Participants with large-cell neuroendocrine carcinoma tumor histology 
are excluded
•
Additional platinum doublet chemotherapy regimen 
(paclitaxel/carboplatin) was added 
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CA209816
BMS-936558
nivolumab
Protocol Amendment No.: 07
Date: 18-Aug-2021
3
Document
Date of Issue
Summary of Changes
•
Dose modification for docetaxel was updated
•
Time to death or distant metastases (TTDM) was added to secondary 
endpoints.
•
Tumor assessments for participants who do not proceed to definitive 
surgery was clarified
•
Statistical analysis plan was updated
•
Rationale, background information, and trial schematic were updated
•
Pulmonary function parameters were clarified
•
Time relationship between adjuvant radiotherapy and tumor imaging 
assessments was clarified
•
Time window of Cycle 1 Day 1 end-of-infusion PK sampling for Arm A 
and C was clarified
Administrative 
Letter 03
31-Jan-2018
•
1.
Page 19, Table 2-1 Screening Procedural Outline (CA209816), 
Pulmonary Function Test notes
•
Previously written:
•
Should be performed within 6 weeks prior to randomization.
•
Changed to:
•
Should be performed within 6 weeks prior to randomization. PFTs 
should be evaluated at screening with the following parameters: FVC, 
FEV1, TLC, FRC, and DLco.
•
•
2.
Page 22, Table 2-2 Neoadjuvant Period Procedural Outline 
(CA209816), Pulmonary Function Test notes
• Previously written:
•
PFTs should be re-evaluated prior to surgery only.
•
Changed to:
•
PFTs should be re-evaluated prior to surgery with the following 
parameters: FVC, FEV1, TLC, FRC, and DLco.
•
3.
Page 28,  Section Table 2-4 Post-Neoadjuvant Period for 
Participants Receiving Adjuvant Chemotherapy (CA209816), Tumor 
Assessments
•
Previously written:
•
Tumor assessments using CT, with contrast, of the chest including 
adrenal glands and CT or MRI of other additional suspected/known sites 
of disease. The first tumor assessment should occur 12 weeks (±  7 days) 
after definitive surgery per RECIST 1.1 and then should occur every 12 
weeks (± 7 days) per RECIST 1.1 for 2 years (104 weeks), then every 6 
months (24 weeks ±  7 days) for 3 years, and every year (52 weeks ±  7 
days) for 5 years or until disease recurrence or progression is confirmed 
by BICR. Use same imaging methods and machine of the same quality as 
was used at screening/baseline.
•
Changed to:
•
Tumor assessments using CT, with contrast, of the chest including 
adrenal glands and CT or MRI of other additional suspected/known sites 
of disease. The first tumor assessment should occur 12 weeks (± 7 days) 
after definitive surgery per RECIST 1.1 and then should occur every 12 
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Protocol Amendment No.: 07
Date: 18-Aug-2021
4
Document
Date of Issue
Summary of Changes
weeks (± 7 days) per RECIST 1.1 for 2 years (104 weeks), then every 6 
months (24 weeks ±  7 days) for 3 years, and every year (52 weeks ±  7 
days) for 5 years or until disease recurrence or progression is confirmed 
by BICR. Use same imaging methods and machine of the same quality as 
was used at screening/baseline.
•
Adjuvant radiotherapy is allowed on study. As radiotherapy may 
interfere with imaging interpretation, efforts should be made to schedule 
radiotherapy so tumor assessments as scheduled per protocol do not 
cross over into the radiation period.
•
4.
Page 92, Table 9.5-1 Pharmacokinetic (PK) Sample Collections for 
Nivolumab and Ipilimumab - Arm A and Arm C  Footnote d
•
Previously written:
•
No text
•
Added footnote:
•
dAs per revised protocol 02, the Cycle 1 Day 1 end-of-infusion PK 
sampling of nivolumab/ipilimumab in Arm A and of nivolumab in Arm 
C should be taken immediately, ie within 5 minutes prior to stopping the 
infusion of nivolumab and ipilimumab, respectively. PK sampling 
greater than 5 minutes before the end of infusion will be reported as a 
deviation.
Revised 
Protocol 02
06-Jul-2017
•
Nivolumab plus platinum-doublet chemotherapy arm (Arm C) was 
added
•
The sample size was increased to 642 participants with the addition of 
the new treatment arm.
•
The primary objective was changed to multiple primary objectives of 
event free survival and pathological complete response; the secondary 
objective was changed to major pathology response.
•
Additional rationale and background information was provided. 
•
Pre-screening tissue requirement was increased from minimum of 10 
slides to 15 slides.
•
Contrast requirements for brain MRI scans were updated 
•
Time window for pulmonary function test window was expanded from 
with 28 days of randomization to within 6 weeks of randomization
•
Synopsis was updated with exploratory objectives, endpoints, and 
schema.
•
Language in treatments administered was deleted and reference to 
Investigator Brochure and Pharmacy Manual was included. 
Revised 
Protocol 01
03-Mar-2017
Incorporates Amendment 02 and Administrative Letters 01 and 02
Amendment 02
03-Mar-2017
•
To adjust the dosing details of the chemotherapy regimens to include the 
dose approved by the local prescribing information and the standard of 
care infusion time for each country included in this study. 
•
To expanded and to split the broad biomarker objective into 3 more 
detailed objectives 
•
Clarify lymph node samples at screening and at definitive surgery 
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Clinical Protocol
CA209816
BMS-936558
nivolumab
Protocol Amendment No.: 07
Date: 18-Aug-2021
5
Document
Date of Issue
Summary of Changes
•
Clarify requirements for PET/CT scans and broadening the window of 
scans prior to surgery
•
Clarify tissue sample process for calculation of the primary endpoint
•
Adjust Hepatitis B Virus criteria
•
Added live vaccines and strong CYP3A4 inhibitors to the Prohibited 
Treatments
•
Added caution for concomitant administration of NSAIDs with 
pemetrexed. 
•
Added unacceptable methods of contraception to Appendix 6
Administrative 
Letter 02
30-Nov-2017
•
Clarify the correct version of the TNM Staging System.
•
Clarify that a minimum of 228 PD-L1+ participants will be randomized.
•
Clarify that physical exams, vital signs, and physical measurements 
should be collected prior to each dose of neoadjuvant and adjuvant 
therapy.
•
Clarify that the first post-operative tumor assessment should be 
performed 12 weeks (± 7 days) after definitive surgery.
•
Remove the phrase “non-protocol regimen” in regards to a non-cisplatin 
regimen as the protocol includes a non-cisplatin regimen option.
•
Clarify that weight-based dosing should be rounded up to the nearest 
milligram or per institutional standards.
•
Clarify that the EQ-5D-3L should be collected prior to Day 1 only in 
cycles that have multiple dosing days in each cycle.
Administrative 
Letter 01
31-Oct-2017
•
To correct the IND number
Original 
Protocol
30-Sep-2016
Not Applicable
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Clinical Protocol
CA209816
BMS-936558
nivolumab
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07: 
Based on historical and emerging external data, event accrual for event-free survival (EFS) 
analysis is expected to slow down in long-term follow up after definitive surgery for resectable 
non-small-cell lung cancer (NSCLC). Recurrence dynamics after complete resection for stage I/II 
NSCLC show a constant recurrence rate of 6-7 events per 100 person-years of follow-up during 
the first 4 years, decreasing to 2 events per 100 person-year thereafter.1 A similar slowdown was 
seen with stage III NSCLC. In a randomized, Phase III trial comparing neoadjuvant 
chemoradiation and chemotherapy both followed by surgery in stage III NSCLC, no difference 
was seen in progression-free survival (PFS, primary endpoint), with the PFS curves dropping 
sharply during the first year indicating initial high hazard rates, then flattening thereafter 
suggesting a markedly decreasing and stabilizing hazard rate.2 Such pattern of recurrence 
dynamics was repeatedly seen in other neoadjuvant trials conducted in Stage I-III NSCLC.3,4
Furthermore, preliminary data from recently published Phase II trials incorporating nivolumab into 
neoadjuvant regimens suggest potentially further decreased hazard rates for recurrence after 
surgery by the flattened shape of Kaplan-Meier curves of EFS/PFS. For example, in the single-
arm NADIM trial of neoadjuvant nivolumab + chemotherapy followed by surgery and adjuvant 
nivolumab for Stage IIIA NSCLC, the 24-month PFS rate was 77.1% (95% CI 59.9-87.7), greatly 
exceeding historic standards.5,6
To account for the aforementioned event dynamics which may preclude the necessary EFS events 
from accruing in a reasonable timeframe or potentially never accruing, the statistical analyses plan 
has been updated to model the assumptions based on a piecewise exponential distribution and 
incorporate a calendar-based rule in addition to the existing event-driven approach to trigger 
analysis timing. Moreover, one additional EFS interim analysis (IA) has been added 
 
 at 90% of EFS events information fraction  
. No changes have been made to the target number of events for the existing 
interim and final analyses, and the overall type 1 error has been maintained. At the time of this 
amendment, EFS and overall survival (OS) remain blinded and have not been analyzed by the 
Sponsor or investigators.
Protocol Amendment No.: 07
Date: 18-Aug-2021
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Clinical Protocol
CA209816
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 07
Section Number and Name
Description of Change
Brief Rationale
Title Page
Updated title to “Clinical Trial Physician” and 
added Clinical Scientist contact information. 
Updated to align with study 
contacts and the role name 
for Medical Monitor at BMS. 
Section 5.3, End of Study 
Definition
Included additional interim analysis and 
calendar-based rule or the EFS final analysis.
To account for a potential 
slowdown in EFS event 
accrual in long-term follow-
up in this setting.
Section 9.2.1, Time Period and 
Frequency for Collecting AE 
and SAE Information
Removed obsolete cross-referenced sections 
to the Investigator Brochure (IB). 
To align with the updated IB. 
Section 10.1.2, Event Free 
Survival (EFS)
•
Updated power calculation.
•
Revised EFS assumptions for the control 
arm with piecewise exponential model.
•
Added an additional interim analysis at 
90% information fraction 
 
 
•
Updated the timing of analyses based on a 
piecewise exponential model. 
To account for a potential 
slowdown in EFS event 
accrual in long-term follow-
up in this setting.
Section 10.1.4, Analyses 
Timing Projections
Section 10.3.3, Interim 
Analyses
•
Revised timing projections based on 
updated EFS assumptions modeling and 
additional interim analysis included.
•
Removed Table 10.1.4-1,
Scheduled 
Analyses, 
Criteria, 
and 
Projected 
Timelines.
To align with Sections 10.1.2 
and 10.1.3 updates.
Appendix 2, Abbreviations and 
Trademarks 
Updated the following abbreviations:
•
final analysis
•
interim analysis 
Abbreviations were updated 
for clarity and completeness.
References
1
Luo F, Huang J, Sima CS et al. Patterns of recurrence and second primary lung cancer in early-stage lung cancer 
survivors followed with routine computed tomography surveillance. J Thorac Cardiovasc Surg. 2013; 145:75-81)
Protocol Amendment No.: 07
Date: 18-Aug-2021
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CA209816
BMS-936558
nivolumab
2
Thomas M, Rube C, Hoffknecht P et al. Effect of preoperative chemoradiation in addition to preoperative 
chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol 2008; 9:636-48.)
3 
Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 
3 randomised trial. Lancet 2015; 386:1049-56.
4
Felip E, Rosell R, Maestre JA, et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant 
chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. Clin Oncol 2010 Jul 1; 28(19): 
3138-45
5
Provencio M, Insa A, Casal-Rubio J et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-
cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2020; 21:1413-
22.
6
Cascone T, William WN, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in 
operable non-small cell lung cancer: the phase II randomized NEOSTAR trial. Nat Med 2021.27;504-14.)
Protocol Amendment No.: 07
Date: 18-Aug-2021
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TABLE OF CONTENT6 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 07: ............................ 
SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 07 .................. 
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 Indication Background ............................................................................. 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
3.2.3 Ipilimumab Mechanism of Action ............................................................ 
3.2.4 Nivolumab Combined with Ipilimumab Clinical Activity ........................ 
3.2.5 Immuno-oncology Treatment Combined with Chemotherapy Clinical 
Activity ........................................................................................................ 
3.3 Benefit/Risk Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 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 Open-Label Design ............................................................ 
5.4.2 Rationale for Preoperative Systemic Therapy in NSCLC ........................ 
5.4.3 Rationale for Immuno-oncology Treatment in Neoadjuvant NSCLC ...... 
5.4.3.1 Rationale for Combination of Nivolumab and Ipilimumab (Arm A):
............................................................................................................... 
5.4.3.2 Rationale for PD-1 Inhibitor with Chemotherapy (Arm C) ............ 
5.4.4 Rationale for Pathologic Response .......................................................... 
5.4.5 Rationale for Patient Population ............................................................. 
5.4.6 Rationale for Choices of Platinum-based Chemotherapy Doublet .......... 
5.5 Justification for Dose ........................................................................................ 
5.5.1 Rationale for Shorter Infusion Times for Nivolumab .............................. 
5.5.2 Rationale for Nivolumab 360 mg Flat 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 or Lead-In Period ....................................... 
7 TREATMENT ........................................................................................................... 
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Clinical Protocol
BMS-936558
CA209816
nivolumab
Protocol Amendment No.: 07
Date: 18-Aug-2021
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7.1 Treatments Administered .................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Dose Reductions for Platinum Doublet Chemotherapy ........................... 
7.4.1.1 Platinum Doublet Chemotherapy - Dose Reductions for 
Hematologic Toxicity ............................................................................ 
7.4.1.2 Platinum 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 Doublet Chemotherapy ............ 
7.4.2.3 Docetaxel Dose Delay Criteria ....................................................... 
7.4.3 Treatment of Nivolumab- and Ipilimumab-related Infusion Reactions ... 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.3 Permitted Therapy ................................................................................... 
7.8 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Study Treatment Discontinuation Criteria ............................................... 
8.1.1.1 Nivolumab Discontinuation Criteria .............................................. 
8.1.1.2 Platinum Doublet Chemotherapy Dose Discontinuation ............... 
8.1.1.3 Docetaxel Dose Discontinuation .................................................... 
8.1.2 Criteria to Resume Treatment .................................................................. 
8.1.2.1 Criteria to Resume Nivolumab Treatment ...................................... 
8.1.2.2 Criteria to Resume Platinum Doublet Chemotherapy Dosing ....... 
8.1.2.3 Criteria to Resume Treatment with Docetaxel ................................ 
8.1.3 Post Study 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 Imaging Assessment for the Study............................................................ 
9.1.2 Patient-reported Outcomes ...................................................................... 
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 ..................................................... 
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Clinical Protocol
BMS-936558
CA209816
nivolumab
Protocol Amendment No.: 07
Date: 18-Aug-2021
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9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
 
9.2.8 Other Safety Considerations .................................................................... 
 
9.2.9 Management Algorithms .......................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.2 Imaging Safety Assessment ...................................................................... 
 
9.5 Pharmacokinetics .............................................................................................. 
 
9.6 Pharmacodynamics ........................................................................................... 
 
9.7 Pharmacogenomics ........................................................................................... 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.1 Additional Research Collection ............................................................... 
 
9.8.1.1 Tumor Tissue Specimens ................................................................. 
 
 
9.8.2 Safety Analyses......................................................................................... 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
 
9.10 Other Assessments .......................................................................................... 
 
9.10.1 Diagnostic/Pre-surgical Evaluation and Surgical Guidelines: ............. 
 
9.10.2 Post-surgical Evaluation: ...................................................................... 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.1.1 Pathologic Complete Response (pCR) ................................................... 
 
10.1.2 Event Free Survival (EFS) ..................................................................... 
 
10.1.3 Power Consideration for Overall Survival (OS) ................................... 
 
10.1.4 Analyses Timing Projections .................................................................. 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Other Analyses ....................................................................................... 
 
10.3.3 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 TNM STAGING SYSTEM FOR LUNG CANCER (7TH EDITION)  
 
APPENDIX 2 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 3 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 4 NIVOLUMAB MANAGEMENT ALGORITHMS ............................. 
 
APPENDIX 5 RESPONSE CRITERIA (RECIST 1.1) ................................................ 
 
APPENDIX 6 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 7 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
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Clinical Protocol
BMS-936558
CA209816
nivolumab
Protocol Amendment No.: 07
Date: 18-Aug-2021
11
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APPENDIX 8 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ADVERSE EVENTS ..................................... 
 
APPENDIX 9 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
 
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Clinical Protocol
BMS-936558
CA209816
nivolumab
Protocol Amendment No.: 07
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Clinical Protocol
CA209816
BMS-936558
nivolumab
1
SYNOPSIS
Protocol Title: Randomized, Open-Label, Phase 3 Trial of Nivolumab plus Ipilimumab or 
Nivolumab plus Platinum-Doublet Chemotherapy versus Platinum-Doublet Chemotherapy in 
Early Stage NSCLC
Study Phase: 3
Rationale:
Approximately 80% of lung cancer cases are non-small cell lung cancer (NSCLC), with most 
patients presenting with late-stage disease. At initial diagnosis, 20% of patients present with stage 
I or II disease, whereas 30% present with stage III disease and 50% with stage IV disease. With 
enhanced lung cancer screening techniques, the percentage of patients diagnosed during the early 
stages may increase over the duration of the trial. A standard TNM staging system is used to 
determine the staging for NSCLC (Appendix 1). 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 Surgical resection remains the mainstay of treatment for stage I and 
II patients; however, despite potentially curative surgery, approximately 50% of stage IB and 
60-75% of stage 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 after adjuvant or neoadjuvant chemotherapy.
This phase 3 study, CA209816, will evaluate the clinical efficacy of nivolumab plus ipilimumab
or nivolumab plus platinum doublet chemotherapy in operable lung cancer. Specifically, this study 
will compare event free survival (EFS) and compare the pathologic complete response (pCR) rate
among participants with Stage IB-IIIa NSCLC treated with nivolumab plus platinum doublet 
chemotherapy to the EFS and pCR rates in participants treated with platinum-doublet 
chemotherapy.
Study Population:
1) Key Inclusion Criteria
a) Eastern Cooperative Group (ECOG) Performance Status 0-1
b) Participants with histologically confirmed Stage IB (≥ 4 cm), II, IIIA (N2) NSCLC (per 
the 7th International Association for the Study of Lung Cancer) who are considered 
resectable
c) Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1)
d) Participants must have tumor tissue sample available for PD-L1 immunohistochemical 
(IHC) testing performed by a third-party analyzing lab during the screening period:
i)
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor 
tissue sections, with an associated pathology report, must be submitted for biomarker 
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Clinical Protocol
CA209816
BMS-936558
nivolumab
evaluation prior to randomization. The tumor tissue sample may be fresh or archival if 
obtained within 3 months prior to enrollment. 
ii) Tissue must be a core needle biopsy, excisional or incisional biopsy. Fine needle 
biopsies obtained by EBUS is not considered adequate for biomarker review and 
randomization. Core needle biopsies obtained by EBUS are acceptable for 
randomization. 
e) All suspicious mediastinal lymph nodes including those that are pathologically enlarged or 
FDG avid on PET/CT require further sampling for pathological confirmation if accessible 
by EBUS, thoracoscopy, or mediastinoscopy. 
2) Key Exclusion Criteria:
a) Presence of locally advanced, unresectable or metastatic disease. 
b) Participants with known EGFR mutations or ALK translocation. If testing is done, testing 
will be done using an FDA-approved assay and will be performed locally.
Objectives and Endpoints:
Objective
Endpoint
Primary
•
To compare the event-free survival (EFS) by 
blinded independent central review (BICR) in 
participants receiving nivolumab plus platinum 
doublet chemotherapy vs  participants receiving 
platinum doublet chemotherapy in operable stage 
IB (≥4 cm), II, or resectable IIIA (N2) NSCLC.
•
EFS defined as the length of time from 
randomization to any of the following events: 
any progression of disease precluding surgery, 
progression or recurrence disease (based on 
BICR assessment per RECIST 1.1) after 
surgery, or death due to any cause. Participants 
who don’t undergo surgery for reason other 
than progression will be considered to have an 
event at RECIST 1.1 progression (based on 
BICR) or death.
•
To compare the pathologic complete response 
(pCR) rate in participants receiving nivolumab
plus 
platinum 
doublet 
chemotherapy 
vs 
participants 
receiving 
platinum 
doublet 
chemotherapy in operable stage IB (≥4 cm), II, or 
resectable IIIA (N2) NSCLC
•
pCR rate is defined as number of randomized 
participants with absence of residual 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. 
Secondary
•
To assess the major pathologic response (MPR) 
rate by BIPR of participants receiving nivolumab
plus 
platinum 
doublet 
chemotherapy 
vs  
participants 
receiving 
platinum 
doublet 
chemotherapy in operable stage IB (≥4 cm), II, or 
resectable IIIA (N2) NSCLC
•
MPR rate, defined as number of randomized 
participants with ≤ 10% residual tumor in lung 
and lymph nodes as evaluated by BIPR, 
divided by the number of randomized 
participants for each treatment group. Viable 
tumors in situ carcinoma should not be 
included in MPR calculation.
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CA209816
BMS-936558
nivolumab
Objective
Endpoint
•
To compare the OS of participants receiving 
nivolumab plus platinum doublet chemotherapy vs 
participants 
receiving 
platinum 
doublet 
chemotherapy in operable stage IB (≥4 cm), II, or 
resectable IIIA (N2) NSCLC
•
OS is defined as the time between the date of 
randomization and the date of death. OS will be 
censored on the last date a participant was 
known to be alive.
•
To assess the time to death or distant metastases 
(TTDM) of participants receiving nivolumab plus 
platinum doublet chemotherapy vs participants 
receiving platinum doublet chemotherapy in 
operable stage IB (≥4 cm), II, or resectable IIIA 
(N2) NSCLC
•
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
using BICR according to RECIST 1.1. Patients 
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.
•
Exploratory
•
To assess clinical response rate (cRR) by BICR of 
participants receiving nivolumab plus platinum 
doublet chemotherapy vs  participants receiving 
platinum doublet chemotherapy in operable stage 
IB (≥4 cm), II, or resectable IIIA (N2) NSCLC 
•
cRR is defined as proportion of all randomized 
participants 
whose 
overall 
radiological 
response prior to definitive surgery is either a 
complete response or partial response per 
RECIST 1.1 criteria by BICR
•
To assess the pCR rate, MPR rate , cRR, EFS, 
TTDM, and OS in early-stage NSCLC participants 
treated with nivolumab plus platinum doublet 
chemotherapy compared to those treated with 
platinum doublet chemotherapy by PDL1 status 
(PD-L1 
≥1% 
, 
PD-L1< 1%/not 
evaluable/indeterminate)   
•
pCR rate, MPR rate, cRR, EFS, TTDM, and OS 
as described above
•
To assess the feasibility of surgery and rate of peri-
and post-operative complications (within 90 days 
of surgery) in participants receiving nivolumab 
plus platinum doublet chemotherapy compared to 
participants receiving platinum doublet 
•
Proportion of delayed or canceled surgery, 
duration of surgery, length of hospital stay, 
surgical approach, including completeness of 
the resection, incidence of AE/SAE associated 
with surgery, including pneumonitis, ARDS, 
re-admission to the Intensive Care Unit, atrial 
fibrillation 
or 
other 
supraventricular 
tachycardia (SVT) to 90 days post-surgery 
•
To assess the safety and tolerability of nivolumab 
plus platinum doublet chemotherapy compared to 
platinum doublet chemotherapy in early stage 
NSCLC
•
Safety and tolerability will be measured by 
incidence of AE, SAE, immune-related AEs, 
deaths, and laboratory abnormalities
•
To describe the pCR rate, MPR rate , cRR, EFS, 
TTDM, OS, feasibility of surgery, rate of peri- and 
post-operative complications (within 90 days of 
surgery), safety and tolerability in early-stage 
NSCLC participants treated with nivolumab plus 
ipilimumab and by PDL1 status (PD-L1 ≥1% , 
PD-L1< 1%/not evaluable/indeterminate)
•
pCR rate, MPR rate, cRR, EFS, OS, TTDM, 
feasibility of surgery, rate of peri- and post-
operative complications, safety and tolerability 
Protocol Amendment No.: 07
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Clinical Protocol
CA209816
BMS-936558
nivolumab
Objective
Endpoint
•
To assess pharmacokinetics of the nivolumab plus 
ipilimumab or nivolumab plus platinum doublet 
chemotherapy in participants with early stage 
NSCLC 
•
Pharmacokinetic endpoints - See Table 9.5-1
•
To assess the participant’s overall health status and 
health utility using the 3-level version of the 
EQ-5D-3L visual analog scale (VAS) and utility 
index, respectively
•
Change in EQ-5D-3L scores
•
To assess Event Free survival on next line of 
therapy (EFS2) in early-stage NSCLC participants 
treated with nivolumab plus platinum doublet 
chemotherapy compared to those treated with 
platinum doublet
•
Event Free survival on next line of therapy 
(EFS2)
•
To evaluate tumor mutation burden as a potential 
predictive biomarker of efficacy (such as EFS and 
OS) of nivolumab plus platinum doublet 
chemotherapy
and 
of 
platinum-doublet 
chemotherapy, using data generated from tumor 
and blood (germ-line control) specimens.
•
To explore potential predictive biomarkers of  
nivolumab plus platinum doublet chemotherapy 
efficacy (such as EFS and OS) in peripheral blood 
and tumor specimens
 
 
 
 
 
 
•
Biomarker endpoints - See Section 9.8.
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Clinical Protocol
CA209816
BMS-936558
nivolumab
Overall Design:
This is an open-label, randomized clinical trial of up to 3 cycles of neoadjuvant nivolumab 
(3 mg/kg every 2 weeks) and a single dose of 1 mg/kg dose of ipilimumab, up to 3 cycles of 
nivolumab (360 mg) plus platinum doublet chemotherapy every 3 weeks, or neoadjuvant platinum 
doublet chemotherapy (up to 3 cycles) in participants with early stage (Stage IB [≥4 cm], II, and 
resectable IIIA [N2]) NSCLC. 
Revised protocol 03 withholds randomization into Arm A of neoadjuvant nivolumab plus 
ipilimumab but continues randomizing eligible participants into either neoadjuvant nivolumab plus 
platinum doublet chemotherapy arm or platinum doublet chemotherapy arm. Participants already 
randomized in the original 2-arm part (neoadjuvant nivolumab plus ipilimumab vs neoajduvant 
chemotherapy) and in the arm of neoadjuvant nivolumab plus ipilimumab in 3-arm part defined 
by revised protocol 02 will remain in trial and continue scheduled trial procedures.
Study Schema
Eligible participants will be randomized between 2 arms in a 1:1 ratio. Participants will be stratified 
by:
•
PD-L1 expression (≥1% or <1%/not evaluable/indeterminate)
•
Disease stage (IB/II vs IIIA)
•
Gender
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 -  defined as ≥ 1% tumor cell membrane staining positive in a minimum of 
100 evaluable tumor cells
•
PD-L1 negative – defined as < 1% tumor cell membrane staining positive in a minimum of 
100 evaluable tumor cells
•
PD-L1 not evaluable/indeterminate - defined as participants with insufficient sample quantity 
or quality to stain for PD-L1 status or those in whom PD-L1 status could not be determined 
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Clinical Protocol
CA209816
BMS-936558
nivolumab
despite appropriate amounts of tissue sample. For the purpose of stratification, this category 
will be grouped with PD-L1 negative participants. No more than 10% of participants will be 
randomized into this category.
Tumor tissue (archival [blocks/slides ≤3 months old] or recent tumor biopsy) must be submitted 
to a third-party vendor for determination of PD-L1 status testing prior to randomization. 
PET/CT including contrast from the base of the skull to upper thighs will be performed at baseline 
(within 28 days prior to randomization) and within 14 days prior to planned definitive surgery. A 
separate CT, with contrast, of the chest, abdomen, and all other suspected sites of disease (as well 
as the PET/CT) is required if the CT component of a PET/CT is not of sufficient diagnostic quality 
for RECIST 1.1 measurements. Subsequent assessments (CT, including contrast, of the chest
including adrenal glands and CT or MRI of other additional suspected/known sites of disease.) 
will be performed in accordance with the Schedule of Activities. Tumor assessments must continue 
per protocol until disease recurrence/progression is confirmed by BICR per RECIST 1.1. Details 
will be outlined in the radiology manual. OS will be followed continuously every 3 months via in-
person or phone contact after Post-neoadjuvant Follow-up Visit 2 or after completion of adjuvant 
therapy, when applicable. 
Following the completion of neoadjuvant treatment, all participants who remain operative
candidates will undergo definitive surgery for NSCLC. Surgery should be performed within 
6 weeks after completing neoadjuvant treatment for each treatment arm.
Following definitive surgery, participants in each arm may receive adjuvant chemotherapy with or 
without radiation per institutional standard at the discretion of the investigator. 
Number of Participants: 
Approximately 350 participants will be randomized in a 1:1 ratio (175 participants in each arm) to 
the 2 arms (neoadjuvant nivolumab plus platinum doublet chemotherapy and platinum doublet 
chemotherapy) from 1:1:1 randomization in revised protocol 02 and 1:1 randomization in revised 
protocol 03.
In addition, it is expected to have around 70 participants randomized in the original 2-arm study
(Arm A and Arm B) and approximately another 75 participants randomized in the arm of 
neoadjuvant nivolumab plus ipilimumab (Arm A) when the study had 3 arms. 
Treatment Arms and Duration:
Arm A: Participants randomized into Arm A received nivolumab 3 mg/kg IV over 30 minutes 
every 2 weeks for up to 3 doses (ie, 6 weeks of treatment; each cycle is 14 days). In Cycle 1 Day 1 
only, nivolumab will be followed by a single dose of ipilimumab 1 mg/kg IV over 30 minutes.
Arm B: Participants randomized to Arm B will receive investigator-choice of platinum doublet 
chemotherapy regimens in 3-week cycles up to a maximum of 3 cycles of IV chemotherapy 
(ie, 9 weeks of treatment; each cycle is 21 days). 
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Clinical Protocol
CA209816
BMS-936558
nivolumab
•
Regimen 1:
−
Vinorelbine 25 mg/m2 or 30 mg/m2 IV (per local prescribing information) push over 
10 minutes or per institutional standard, Days 1 and 8
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard Day 1, immediately 
following vinorelbine
•
Regimen 2:
−
Docetaxel 60 mg/m2 or 75 mg/m2 IV (per local prescribing information) over 60 minutes 
or per institutional standard on Day 1
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following docetaxel
•
Regimen 3: (squamous histology):
−
Gemcitabine 1000 mg/m2 or 1250 mg/m2 IV (per local prescribing information) over 
30 minutes or per institutional standard on Days 1 and 8
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following gemcitabine
•
Regimen 4: (non-squamous histology only):
−
Pemetrexed 500 mg/m2 IV over 10 minutes or per institutional standard on Day 1
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following pemetrexed
•
Regimen 5:
−
Paclitaxel 175 or 200 mg/m2 IV over 180 minutes or per institutional standard on Day 1
−
Carboplatin AUC 5 or 6 IV over 30 minutes or per institutional standard on Day 1, 
immediately following paclitaxel
Arm C: Participants randomized into Arm C will receive nivolumab 360 mg IV + platinum 
doublet chemotherapy in 3-week cycles up to a maximum of 3 cycles of IV chemotherapy 
(ie, 9 weeks of treatment; each cycle is 21 days)
•
Non-squamous NSCLC: nivolumab at a flat dose of 360 mg as 30-minute IV infusion on Day 
1, followed by pemetrexed at a dose of 500 mg/m2 IV over 10 minutes or per institutional 
standard with cisplatin at a dose of 75 mg/m² IV over 120 minutes or per institutional standard, 
of a 3-week treatment cycle, for up to 3 cycles.
•
Squamous NSCLC: nivolumab at a flat dose of 360 mg as 30 minute IV infusion on day 1, 
followed by gemcitabine at a dose of 1000 mg/m2 or 1250 mg/m2 (per local prescribing 
information) IV over 30 minutes or per institutional standard with cisplatin at a dose of 
75 mg/m2 IV over 120 minutes or per institutional standard, of a 3-week treatment cycle for 
up to 3 cycles. Gemcitabine will also be administered at a dose of 1000 mg/m2 or 1250 mg/m2
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CA209816
BMS-936558
nivolumab
as a 30 minute IV infusion or per institutional standard on day 8 of each 3-week treatment 
cycle.
•
Any histology: nivolumab at a flat dose of 360 mg as 30-minute IV infusion on Day 1, followed 
by paclitaxel 175 or 200 mg/m2 IV over 180 minutes or per institutional standard and 
carboplatin AUC 5 or 6 IV over 30 minutes or per institutional standard of a 3-week treatment 
cycle, for up to 3 cycles
Study treatment: 
Study Drug for CA209816
Medication 
Potency 
IP/Non-IP 
BMS-936558-01 Nivolumab
10 mg/mL
IP
Ipilimumab Solution for Injection
5 mg/mL
IP
Vinorelbine
10 mg/mL
IP
Gemcitabine
38 mg/mL
IP
Docetaxel
10 mg/mL
IP
Pemetrexed
500 mg/vial
IP
Cisplatin
1 mg/mL
IP
Carboplatin
10 mg/mL
IP
Paclitaxel
6 mg/mL
IP
Independent Data Monitoring Committee
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 CA209816. An 
interim DMC review will occur after 15 participants are enrolled in Arm A and after 15 participants 
are enrolled in Arm C and have completed surgery. 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.
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CA209816
BMS-936558
nivolumab
Independent Radiology/Pathology Review:
Independent pathology and radiology review will be established for central review and 
confirmation of endpoints. Images and tumor/lymph node samples will be submitted to these third-
party vendors for central review. Sites will be trained prior to enrolling the first study participant. 
Images and pathology samples acquisition guidelines and submission process will be outlined in 
the study Imaging/Laboratory Manuals to be provided by the vendors.
Tumor and lymph node collection from definitive surgical resection and sampling of fresh tumor 
sample in RNAlater for biomarker studies (as applicable dependent on the size of the residual 
tumor) is mandatory on the day of surgery. RNAlater sample will not be collected in China.
Processing the remainder of the specimen for histopathologic analysis should be performed within 
72 hours of the procedure. Sections will be used for central pathology review assessing pathologic
complete response (pCR) and major pathologic response (MPR). Any tumor, tumor bed or lymph 
node specimens that are reviewed locally must be submitted for central pathology review. Gross 
examination on the entire specimen should be performed which includes all tumor, and associated 
lymph node tissue and uninvolved parenchyma. The specimen should be sectioned at 0.5 cm 
intervals, and blocks should be submitted for the full cross section for every other 0.5 cm interval. 
For very large tumors with no gross evidence of response, a minimum of 1 slide/cm is required for 
assessment of pathologic response. When estimating viable tumor, in situ carcinoma should not be 
included. Pathology specimen collection and processing guidelines are outlined in the CA209816 
Laboratory Manual. A blinded pathology review process will be utilized to assess for confirmation 
of endpoints.
Radiologic tumor assessments should be submitted to the third-party radiology vendor as they are 
performed on an ongoing basis.
Tumor assessments will be sent to and reviewed by a Blinded Independent Central Review (BICR) 
from a third-party radiology vendor on an on-going basis. At the time of investigator assessed 
radiographic progression per RECIST 1.1, the site must request a BICR- for confirmation of 
progression or disease recurrence. However, BICR confirmation of progression should not be 
requested if investigator judges the progression will not preclude surgery. Participants should 
proceed to definitive surgery and tumor assessments post surgery should be continue per schedule 
of activities. Details of the BICR responsibilities and procedures will be specified in the BICR 
charter.
Participants whose disease progression or disease recurrence is not confirmed by central review 
will be required to continue tumor assessments (if clinically feasible) according to the protocol-
specified schedule, even after the initiation of subsequent anti-cancer therapies. Subsequent tumor 
assessments must be submitted to the third party radiology vendor for subsequent review and may 
be discontinued when the investigator and independent radiologists both assess the participant to 
have met RECIST 1.1 criteria for progression or disease recurrence.
Abbreviations are listed in Appendix 2.
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Clinical Protocol
CA209816
BMS-936558
nivolumab
REFERENCES
1
Mountain, CA.  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 Internatonal 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.
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Clinical Protocol
CA209816
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA209816) a
Procedure
Screening 
Visit
Notes
Eligibility Assessments
Informed Consent
X
Informed Consent Form prior to screening for study participation. If a participant is re-enrolled, the 
participant must be re-consented, and eligibility should be re-confirmed. Register in Interactive Response 
Technology to obtain participant number. 
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to first dose. 
Participants must also meet operative criteria (Section 9.10.1).
Medical History
X
Tumor Tissue Samples
X
Tumor tissue submission prior to randomization is mandatory. If a recent/archived (within 3 months) 
biopsy sample is not available at screening, a fresh biopsy will be taken. 
Sufficient tumor tissue obtained prior to randomization (block or minimum of 15 slides, obtained from 
core biopsy, punch biopsy, excisional biopsy or surgical specimen). If less than 15 slides are available, 
then the Medical Monitor should be contacted to advise on eligibility. 
For participants for whom a biopsy is not feasible, archival tumor material must be made available. Fine 
needle aspirate of draining lymph node is not acceptable. Core needle biopsies obtained by EBUS are 
acceptable. PD-L1 status must be determined prior to randomization.
Mediastinal lymph node sampling
X
All suspicious mediastinal lymph nodes including those that are pathologically enlarged or FDG avid on 
PET/CT require further sampling for pathological confirmation if accessible by EBUS, mediastinoscopy, 
or thoracoscopy.
Screening/Baseline Tumor 
Assessments
X
PET/CT including contrast from the base of the skull to the upper thighs, within 28 days prior to 
randomization. A separate CT with contrast of the chest, abdomen, and other suspected areas of disease (as 
well as the PET/CT) is required if the CT component of the PET/CT is not of sufficient diagnostic quality 
for RECIST 1.1 measurements.
Participants with stage II or higher disease and those with a suspicion of brain metastasis should have a 
MRI or CT of the brain pre- and post-contrast within 28 days of randomization. 
Tumor assessments should be performed following RECIST 1.1 criteria.
Prior Medication
X
ECOG Performance Status
X
Within 14 days prior to randomization (Appendix 3)
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CA209816
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA209816) a
Procedure
Screening 
Visit
Notes
Safety Assessments
History and Physical Examination
X
Includes assessment of symptoms, review of system (ROS), height, weight, BSA (for platinum dosing), 
and full physical exam within 14 days prior to randomization. 
Vital Signs and Oxygen Saturation
X
Includes body temperature, respiratory rate, and seated blood pressure, heart rate, and oxygen saturation by 
pulse oximetry (at rest). Obtained at the screening visit and within 72 hours prior to first dose. 
Pulmonary Function Test
X
Should be performed within 6 weeks prior to randomization. Includes FVC, FEV1, TLC, FRC, and DLco.
Concomitant Medication 
Collection 
X
Within 14 days of randomization.
Serious Adverse Events 
Assessment
X
Serious Adverse Events from the time of consent
Adverse Events Assessment
X
Laboratory Tests
X
CBC w/differential, chemistry panel including: Albumin, LDH, AST, ALT, ALP, T. Bili, BUN or serum 
urea level, creatinine, phosphate, Ca, Mg, Na, K, Cl, glucose, amylase, lipase, TSH, T4 (free), T3 (free or 
total) within 14 days prior to randomization.
Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), reflex HBV DNA, hepatitis C 
antibody (HCV Ab), and reflex hepatitis C RNA (HCV RNA). Within 28 days prior to randomization.
ECG
X
ECG to be performed prior to randomization and recorded after the participant has been supine for at least 
5 minutes.
Pregnancy Test  
X
Urine or serum test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 14 days prior to 
randomization. 
Study Treatment
Randomize
X
a
Screening assessments should occur within 28 days of randomization unless otherwise noted. 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CBC complete blood count; Cl, chloride; DLco, 
diffusing capacity; EBUS, endobronchial ultrasound; ECG, electrocardiogram; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; FRC,
functional residual capacity; FVC, forced vital capacity; HBcAb, Hepatitis B core antibody; HBsAg, Hepatitis B surface antigen; HCV Ab, Hepatitis C 
antibody; ICF, informed consent form; LDH, lactate dehydrogenase, K, potassium; Mg, magnesium; NA, sodium; RECIST, Response Evaluation Criteria in 
Solid Tumors; SOC, standard of care; T.Bili, total bilirubin; TLC, total lung capacity; TSH, thyroid stimulating hormone.
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Clinical Protocol
CA209816
BMS-936558
nivolumab
Table 2-2:
Neoadjuvant Period Procedural Outline (CA209816)
Procedure
During Treatment
Visitsa,b
Notes
Safety Assessments
Physical Examination
X
Includes assessment of signs, symptoms, and ROS prior to each dose. 
Vital Signs and Oxygen 
Saturation
X
Including BP, HR, temperature, respiratory rate, and oxygen saturation by pulse oximetry (at rest) 
prior to each dose. 
Physical Measurements
X
Weight, Body Surface Area (for cytotoxic dosing), and ECOG status. The dosing calculations for 
treatment arms should be based on the body weight, except for nivolumab on Arm C, which will be 
administered using a flat dose of 360 mg. If the participant’s weight on the day of dosing differs by 
> 10% from the weight used to calculate the previous dose, the dose must be recalculated for the dose 
of the day by using the participant’s weight of the day, and this updated value becomes the reference 
for subsequent dosing calculations. All doses should be rounded to the nearest milligram or as per 
institutional standard.
Serious Adverse Event 
Assessment
X
Adverse Events Assessment
X
Review of Concomitant 
Medications
X
Pulmonary Function Test
See notes
PFTs should be re-evaluated prior to surgery only. Includes FVC, FEV1, TLC, FRC, and DLco.
Laboratory test
X
On-study local laboratory assessments should be done within 72 hours prior to each dose, starting 
with Cycle 1 Day 1 (C1D1). C1D1 labs do not need to be repeated if they were performed within 14 
days of dosing.
CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum urea 
level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, albumin, and phosphate.
TSH with reflexive T4 (free), T3 (free or total) for Arm A and Arm C only. Repeat every 6 weeks 
while receiving nivolumab.
Pregnancy Test  
X
Serum or urine (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to 
first dose and then every 4 weeks for Arm A, every 3 weeks for Arm C, and Arm B while receiving 
study treatment. An extension of up to 72 hours prior to the start of study drug may be permissible in 
situations where results cannot be obtained within the standard 24 hours window, subject to Medical 
Monitor approval.
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CA209816
BMS-936558
nivolumab
Table 2-2:
Neoadjuvant Period Procedural Outline (CA209816)
Procedure
During Treatment
Visitsa,b
Notes
Efficacy Assessments
Tumor Assessments
X
PET/CT including contrast of the base of the skull through the upper thighs, within 14 days prior to 
surgery per RECIST 1.1. A separate CT with contrast of the chest, abdomen, and all other suspected 
areas of disease (as well as the PET/CT) is required if the CT component of a PET/CT is not of 
sufficient diagnostic quality for RECIST measurements. 
Pharmacokinetic Assessments
PK samplesc
X
Arm C only. Refer to Table 9.5-1
Biomarker Assessments
Exploratory Biomarker
X
Patient-reported Outcomes Assessment
EQ-5D-3L
X
For C1D1: performed after randomization PRIOR to first dose. On Day 1 of each cycle of study drug 
administration, the EQ-5D-3L will be administered PRIOR to treatment. 
Study Treatment
IRT Drug Vial Assignments
X
Dispense Study treatment
X
Within 7 calendar days after randomization, the participants must receive the first dose of study 
medication. Participants no less than 18 days between doses for nivolumab on Arm C.
If a dose is delayed for any reason, participants should be dosed no later than 7 days following a 
planned dose on any arm. 
If more than 7 days delay is needed for any reason, the intended dose should be skipped. If a 
participant receiving chemotherapy on a Day 1 and Day 8 schedule (ie, cisplatin/gemcitabine) is 
unable to receive Day 1 of chemotherapy but recovers in time to receive the Day 8 dose, the Day 8 
dose of chemotherapy may be administered.
Surgery per Standard of Care
See notes
Surgery should be performed within 6 weeks after completing up to 3 cycles of neoadjuvant therapy 
as indicated by the institutional standard of care (SOC). 
Doses skipped during pre-operative treatment should not be replaced.  
a Each cycle in Arm B and Arm C is 21 days.
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CA209816
BMS-936558
nivolumab
b Neoadjuvant period assessments should be performed within 72 hours prior to dosing, unless otherwise noted.
c Arm C only
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; BUN, blood urea nitrogen; Ca, calcium; CBC complete blood count; 
Cl, chloride; DLco, diffusing capacity; EBUS, endobronchial ultrasound; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; FEV1, 
forced expiratory volume in 1 second; FVC, forced vital capacity; FRC, functional residual capacity; FVC, forced vital capacity; HR, heart rate; HBcAb, 
Hepatitis B core antibody; HBsAg, Hepatitis B surface antigen; HCV Ab, Hepatitis C antibody; ICF, informed consent form; IRT, interactive response 
technology; LDH, lactate dehydrogenase, K, potassium; Mg, magnesium; NA, sodium; PFT, pulmonary function test; RECIST, Response Evaluation Criteria 
in Solid Tumors; SOC, standard of care; T.Bili, total bilirubin; TLC, total lung capacity; TSH, thyroid stimulating hormone.
Protocol Amendment No.: 07
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BMS-936558
nivolumab
Table 2-3:
Post-Neoadjuvant Period for Those Participants Not Receiving Adjuvant Therapy (CA209816)
Procedure
Post-Neoadjuvant 
Therapy 
Visits 1 and 2a
Survival 
Follow-Up 
Visits b,c
Notes
Safety Assessments
Physical Examination
X
Includes assessment of signs and symptoms and ROS.
Vital Signs and Oxygen Saturation
X
Include BP, HR, temperature, and oxygen saturation by pulse oximetry (at rest).
Serious Adverse Events Assessment
X
All AE/SAEs to be collected for up to 100 days after the last dose of 
neoadjuvant therapy or 90 days after surgery, whichever is longer. 
Adverse Events Assessment
X
All AE/SAEs to be collected for up to 100 days after the last dose of 
neoadjuvant therapy or 90 days after surgery, whichever is longer. 
Review of Concomitant 
Medications
X
X
Document subsequent cancer therapy
Laboratory Tests
X
CBC w/ differential, LFTs (ALTs, AST, total bilirubin, alkaline phosphatase), 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, 
amylase, lipase, albumin, and phosphate.
TSH with reflex T4 (free) and T3 (free or total) for Arm A and Arm C only. 
Laboratory tests should be done at Post-neoadjuvant Visit 1 and repeated at 
Post-neoadjuvant Visit 2 if study-related toxicity persists.
Pregnancy Test
X
Serum or urine (minimum sensitivity 25 IU/L or equivalent units of HCG)
Efficacy Assessments
Tumor Assessments
----See Notes---
Tumor assessments with CT, including contrast, of the chest including adrenal 
glands and CT or MRI of other additional suspected/known sites of disease. The 
first tumor assessment should occur 12 weeks (±7 days) after definitive surgery 
per RECIST 1.1 and then should occur every 12 weeks (± 7 days) per RECIST 
1.1 for 2 years (104 weeks), then every 6 months (24 weeks ±7 days) for 3 
years, and every year (52 weeks ± 7 days) for 5 years or until disease recurrence 
or progression is confirmed by blinded independent central review (BICR). 
For participants who did not receive definitive surgery AND without tumor 
progression confirmed by BICR, the first tumor assessments should be done 12 
weeks (± 7 days) following the tumor restaging, subsequent tumor assessments 
will be performed with the same frequency and methods as described for those 
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CA209816
BMS-936558
nivolumab
Table 2-3:
Post-Neoadjuvant Period for Those Participants Not Receiving Adjuvant Therapy (CA209816)
Procedure
Post-Neoadjuvant 
Therapy 
Visits 1 and 2a
Survival 
Follow-Up 
Visits b,c
Notes
having received definitive surgery; in case the planned initiation of subsequent 
anti-cancer therapy is within 12 weeks of restaging, every effort should be made 
to repeat tumor assessment prior to subsequent anti-cancer therapy.
Use same imaging method and a machine of the same quality as was used at 
screening/baseline
Pathology and Biomarker Assessments
Tissue and biomarker assessments
--See notes--
Tissue collection from definitive surgical resection is mandatory for pathologic 
response assessments and highly recommended for biomarker assessments on 
the day of surgery. Tumor biopsy collection is optional but highly 
recommended from participants at disease progression.
All tumor biopsy collection details will be provided in the lab manual. 
Patient-reported Outcomes Assessment
EQ-5D-3L
X
X
Every 3 months after Post-neoadjuvant Visit 2 for 1 year and then once every 
6 months thereafter. May be completed as a phone call if a clinic visit is not 
otherwise required. 
Participant Survival Status
Survival Status
X
X
Every 3 months after Post-neoadjuvant Follow-Up Visit 2. May be 
accomplished by visit, phone contact, or email to assess subsequent anti-cancer 
therapy
a Post-neoadjuvant Visit 1within 30 days from the last dose of neoadjuvant therapy ± 7 days and prior to surgery (this may lead to shortened interval between last 
dose of neoadjuvant treatment and post-neoadjuvant visit 1). If Post-neoadjuvant Visit 1 falls within 7 days of the scheduled surgery date, then the 
Post-neoadjuvant Visit 1 visit may coincide with the surgery admission. All Neoadjuvant Visit 1 assessment procedures should be completed prior to surgery. 
Post-adjuvant Visit 2 = 70 days (± 7 days) from Post-neoadjuvant Visit 1. Post-neoadjuvant visits may coincide with the date of post-surgical follow-up. Timing 
of Post-neoadjuvant Visits 1 and 2 are based on the pre-surgical neoadjuvant treatment timelines.
b Survival Follow-up Visits begin 3 months after Post-neoadjuvant Visit 2. Visits should occur every 3 months (± 7 days).
c For those participants who have progression confirmed by BICR, participants will continue to be followed for survival status every 3 months by visit, phone 
contact, or email.
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BMS-936558
nivolumab
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; CBC complete blood count; Cl, chloride; DLco, 
diffusing capacity; EBUS, endobronchial ultrasound; ECG, electrocardiogram; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; FRC, 
functional residual capacity; FVC, forced vital capacity; HBcAb, Hepatitis B core antibody; HBsAg, Hepatitis B surface antigen; HCV Ab, Hepatitis C 
antibody; ICF, informed consent form; LDH, lactate dehydrogenase, K, potassium; Mg, magnesium; NA, sodium; RECIST, Response Evaluation Criteria in 
Solid Tumors; SOC, standard of care; T.Bili, total bilirubin; TLC, total lung capacity; TSH, thyroid stimulating hormone.
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BMS-936558
nivolumab
Table 2-4:
Post-Neoadjuvant Period for Participants Receiving Adjuvant Chemotherapy (CA209816)
Procedure
During Adjuvant 
Treatment Visita
Post Neoadjuvant 
Therapy 
Visits 1 and 2b
Survival 
Follow-Up 
Visitsc,d
Notes
Safety Assessments
Physical 
Measurements
X
Weight, BSA (for cytotoxic dosing), and ECOG status prior to 
each dose. The dosing calculations for the platinum doublet 
chemotherapy arm should be based on the body weight. If the 
participant’s weight on the day of dosing differs by > 10% from 
the weight used to calculate the previous dose, the dose must be 
recalculated for the dose of the day using the participant’s weight 
of the day, and this updated value becomes the reference for 
subsequent dosing calculations. All doses should be rounded to 
the nearest milligram or per institutional standard.
Physical Examination
X
X
Includes assessment of signs, symptoms, and ROS prior to each 
dose.
Vital Signs and 
Oxygen Saturation
X
X
Include BP, HR, temperature, and oxygen saturation by pulse 
oximetry (at rest) prior to each dose
Serious Adverse 
Events Assessment
X
X
All AEs/SAEs to be collected for up to 30 days after the last dose 
of adjuvant therapy. 
Adverse Event 
Assessments
X
X
All AEs/SAEs to be collected for up to 30 days after the last dose 
of adjuvant therapy 
Review Concomitant 
Medication
X
X
X
Document subsequent cancer therapy.
Laboratory test
X
X
On-study local laboratory assessments should be done within 
72 hours prior to each dose and at Post-neoadjuvant Visit 1. To 
be repeated at Post-neoadjuvant Visit 2 if study-related toxicity 
persists.  
CBC w/ differential, albumin, LFTs (ALT, AST, total bilirubin, 
alkaline, phosphatase), BUN or serum urea level, creatinine, Ca, 
Mg, Na, K, Cl, LDH, glucose, amylase, lipase, phosphate.
TSH with reflex T4 (free) and T3 (free or total) for Arm A and 
Arm C only. To be conducted only at Post-neoadjuvant Therapy 
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BMS-936558
nivolumab
Table 2-4:
Post-Neoadjuvant Period for Participants Receiving Adjuvant Chemotherapy (CA209816)
Procedure
During Adjuvant 
Treatment Visita
Post Neoadjuvant 
Therapy 
Visits 1 and 2b
Survival 
Follow-Up 
Visitsc,d
Notes
Visit 1 and repeated at Post-Neoadjuvant Therapy Visit 2 if 
study-related toxicity persists.
Pregnancy test
X
X
Serum or urine (minimum sensitivity 25 IU/L or equivalent units 
of HCG) within 24 hours prior to first dose and then every 4 
weeks while receiving study treatment. 
An extension of up to 72 hours prior to the start of study drug 
may be permissible in situations where results cannot be obtained 
within the standard 24 hours window, subject to Medical Monitor 
approval.
Efficacy Assessments
Tumor Assessments
---See Notes---
Tumor assessments using CT, with contrast, of the chest 
including adrenal glands and CT or MRI of other additional 
suspected/known sites of disease. 
The first tumor assessment should occur 12 weeks (± 7 days) 
after definitive surgery per RECIST 1.1 and then should occur 
every 12 weeks (± 7 days) per RECIST 1.1 for 2 years (104 
weeks), then every 6 months (24 weeks ± 7 days) for 3 years, and 
every year (52 weeks ± 7 days) for 5 years or until disease 
recurrence or progression is confirmed by BICR. 
Use same imaging methods and machine of the same quality as 
was used at screening/baseline. 
Biomarker Assessment
Exploratory Biomarker
---See Notes---
Tumor biopsy collection is optional but highly recommended 
from participants at disease progression. 
All tumor biopsy collection details will be provided in the lab 
manual.
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BMS-936558
nivolumab
Table 2-4:
Post-Neoadjuvant Period for Participants Receiving Adjuvant Chemotherapy (CA209816)
Procedure
During Adjuvant 
Treatment Visita
Post Neoadjuvant 
Therapy 
Visits 1 and 2b
Survival 
Follow-Up 
Visitsc,d
Notes
Patient-reported Outcomes Assessment
EQ-5D-3L
X
X
X
Every 3 months after Post-neoadjuvant Visit 2 for 1 year and 
then once every 6 months thereafter. May be completed as a 
phone call if a clinical visit is not otherwise specified. 
Participant Survival Status
Survival Status
X
X
X
Every 3 months after Post-neoadjuvant Follow-Up Visit 2. May 
be accomplished by visit, phone contact, or email to assess 
subsequent anti-cancer therapy
Study Treatment
Administer Adjuvant 
Chemotherapy ±PORT
X
Post-operative radiation therapy (PORT) should be administered 
according to standard of care.
a Each cycle is 21 days. Assessments should be performed within 72 hours prior to dosing of adjuvant therapy. 
b Post-neoadjuvant Visit 1 within 30 days from the last dose of neoadjuvant therapy ± 7 days and prior to surgery (this may lead to shortened interval between 
last dose of neoadjuvant treatment and post-neoadjuvant visit 1).  If Post-neoadjuvant Visit 1 falls within 7 days of the scheduled surgery date, then the 
Post-neoadjuvant Visit may coincide with the surgery admission. All Post-neoadjuvant Visit 1 assessment procedures should be completed prior to surgery. 
Post-neoadjuvant Visit 2 = 70 days (± 7 days) from Post-neoadjuvant Visit 1. Post-neoadjuvant Visit 2 may coincide with the date of post-surgical follow-up. 
Timing of Post-neoadjuvant Visits 1 and 2 are based on the pre-surgical neoadjuvant therapy timelines.
c Survival Follow-up Visits begin 3 months after Post-neoadjuvant Visit 2 or after completion of adjuvant therapy, whichever occurs later. Visits should occur 
every 3 months (± 7 days).
d For those participants who have progression confirmed, participants will continued to be followed for survival status every 3 months by visit, phone contact, or 
email.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; BUN, blood urea nitrogen; Ca, calcium; CBC complete blood count; Cl, 
chloride; HR, heart rate; ECOG, Eastern Cooperative Oncology Group; DLco, diffusing capacity; EBUS, endobronchial ultrasound; ECG, electrocardiogram; 
FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; FRC, functional residual capacity; FVC, forced vital capacity; HBcAb, Hepatitis B 
core antibody; HBsAg, Hepatitis B surface antigen; HCV Ab, Hepatitis C antibody; ICF, informed consent form; LDH, lactate dehydrogenase, K, potassium; 
Mg, magnesium; NA, sodium; RECIST, Response Evaluation Criteria in Solid Tumors; SOC, standard of care; T.Bili, total bilirubin; PORT post-operative 
radiation therapyTLC, total lung capacity; TSH, thyroid stimulating hormone
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BMS-936558
nivolumab
3
INTRODUCTION
Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype mAb that binds PD-1 on 
activated immune cells and disrupts engagement of the receptor with its ligands PD-L1 
(B7 H1/CD274) and PD-L2 (B7-DC/CD273), thereby abrogating inhibitory signals and 
augmenting the host antitumor response. In early clinical trials, nivolumab has demonstrated 
activity in several tumor types, including melanoma, renal cell carcinoma (RCC), and non-small 
cell lung cancer (NSCLC).
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin superfamily that competes with CD28 for B7. The proposed mechanism of action 
for ipilimumab is interference of the interaction of CTLA-4 with B7 molecules on APCs, with 
subsequent blockade of the inhibitory modulation of T-cell activation promoted by the CTLA 4/B7 
interaction.
Nivolumab is in clinical development for the treatment of patients with NSCLC, RCC, melanoma, 
squamous cell carcinoma of the head and neck (SCCHN) and other tumors (eg, glioblastoma 
multiforme, mesothelioma, small cell lung cancer, gastric). The combination of nivolumab and 
ipilimumab is in clinical development for the treatment of NSCLC, RCC, and other tumors. 
Opdivo® is approved in the United States (US), European Union, and other countries for the 
treatment of patients with unresectable or metastatic melanoma, advanced NSCLC with
progression on or after platinum-based chemotherapy, advanced RCC whose disease progressed 
on an antiangiogenic therapy (US only), classical Hodgkin lymphoma that has relapsed or 
progressed after autologous hematopoietic stem cell transplantation and post-transplantation 
brentuximab vedotin treatment (US only), head and neck carcinoma (US only), and bladder cancer 
(US only). Opdivo is also approved in combination with Yervoy® in unresectable and metastatic 
melanoma. 
3.1
Study Rationale
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. With enhanced lung cancer screening 
techniques, the percentage of those diagnosed during the early stages may increase over the 
duration of the trial. A standard TNM staging system is used to determine the staging for NSCLC 
(Appendix 1). 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
Surgical resection remains the mainstay of treatment for stage I and II patients; however, 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. Many adjuvant studies have been performed, and these 
trials are summarized in Table 3.1-1. Although there are some conflicting results, the overall 
evidence from these studies suggests that adjuvant platinum doublet chemotherapy is beneficial 
for good Performance Status patients with stage ≥I disease. The benefit to stage IB patients is less 
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BMS-936558
nivolumab
clear and may depend on the size of the primary tumor and other risk factors. The LACE 
meta-analysis of modern adjuvant and neoadjuvant trials, all of which used cisplatin-based 
chemotherapy, suggested a 5% absolute survival advantage at 5 years from adjuvant chemotherapy 
with the benefit being greatest for stage II and IIIA patients. 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.4
Table 3.1-1:
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%.2,3,5 The current available standard of care (SOC) only provides a 5% absolute 
improvement in 5-year overall survival (OS).6,7,8,9 The SOC comprises adjuvant or neoadjuvant 
platinum 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 
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those observed with adjuvant chemotherapy.10 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.6,7,8 Randomized trials are currently on-going to explore the potential benefit of nivolumab 
in the adjuvant and locally advanced unresectable NSCLC setting. In addition, the safety and 
efficacy profile of neoadjuvant nivolumab monotherapy or in combination (nivolumab plus 
ipilimumab or nivolumab plus chemotherapy) are being evaluated in ongoing trials.   
The phase 3 study, CA209816, will evaluate the clinical efficacy and will establish the safety of 
nivolumab plus ipilimumab, especially nivolumab plus platinum doublet chemotherapy, in 
resectable lung cancer. Specifically, this study will compare EFS and pCR rate among participants 
treated with neoadjuvant nivolumab plus platinum doublet chemotherapy vs participants treated 
with platinum doublet chemotherapy, and will describe pCR rate and EFS for those treated with 
neoadjuvant nivolumab plus ipilimumab in Stage Ib-IIIa NSCLC.
3.1.1
Research Hypothesis
In participants with stage IB (≥4 cm), II or IIIA (N2) NSCLC considered resectable by the local 
multidisciplinary team, administration of neoadjuvant nivolumab plus platinum doublet 
chemotherapy (up to 3 cycles) has superior efficacy to neoadjuvant platinum doublet 
chemotherapy (up to 3 cycles).
3.2
Background
3.2.1
Indication Background
Approval of nivolumab in advanced NSCLC was based on 2 phase 3 trials (CheckMate 017 and 
CheckMate 057) which demonstrated survival benefit over docetaxel across histologies. The 
approval in squamous NSCLC was based on the results of CA209017, a randomized trial of 
nivolumab versus docetaxel. The median OS for patients in the nivolumab arm was 9.2 months 
versus 6 months for those in the docetaxel arm (HR = 0.59). Improvement in survival was observed 
for nivolumab regardless of PD-L1 expression, though there was a trend toward better efficacy for 
those with PD-L1 expressing tumors. A single-arm trial (CA209063) of 117 patients with 
metastatic squamous NSCLC with progression after platinum-based chemotherapy and at least 
1 additional systemic regimen showed a 15% objective response rate (ORR); 59% of participants 
with an ORR had response durations of 6 months or longer.11
The approval of nivolumab for the treatment of non-squamous NSCLC is based on a second phase 
3 study, CA209057, which met its primary endpoint of superior OS of nivolumab versus docetaxel 
in patients with previously treated non-squamous NSCLC at a preplanned interim analysis (IA). 
Patients in the nivolumab arm had a 27% reduction in risk of death (HR = 0.73; P = 0.0015). 
Interaction P values, reported for PD-L1 expression subgroups by each of the predefined 
expression levels, suggested a clinically important signal of a predictive association. Nivolumab 
also significantly improved ORR vs docetaxel (P=0.0246), with ORR as high as 36% in patients 
with PD-L1 expressing tumors. OS approximately doubled with nivolumab vs docetaxel at 1%, 
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5% and 10% PD-L1 expression level. In contrast, no statistically significant difference in OS was 
seen between nivolumab and docetaxel when PD-L1 was not expressed in the tumor, although 
these patients also experienced durable responses, and the safety profile was more favorable for 
nivolumab vs docetaxel.12
Although the first-line CA209026 trial did not demonstrate that single agent nivolumab provided 
superior efficacy over platinum doublet chemotherapy, the efficacy of nivolumab was similar to 
that of chemotherapy in this first line patient population. In the ongoing study CA209012, 
77 patients were treated with nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q12W or Q6W.
Overall response rates were observed in 43% of all treated patients and in 57% and 92% of patients 
with ≥1% and ≥50% tumor PD-L1 expression, respectively. Six investigator-assessed CRs (8%) 
and 3 pathologic responses were observed.  The median duration of response (DOR) was not 
reached in the overall population or subpopulations. Duration of response ranged from 1.4+ to 
27.9+ months.13 Recent 2-year OS data in CA209012 showed survival data in all treated patients 
and by PD-L1 expression. All treated patients (n = 77) showed a 1 years OS of 76% and 2 year OS 
of 49%. When analyzed by PD-L1 expression, patients with ≥1% PD-L1 (n = 47) had a 1 years 
OS of 87% and 2 year OS of 58%, which increased to 100% and 62%, respectively for ≥50% 
PD-L1 patients. Nivolumab plus ipilimumab remained tolerable, as most treatment-related AEs 
were manageable and no new safety concerns were identified in follow-up.14
The ongoing phase 3 CheckMate 227 study enrolled patients with stage IV or recurrent NSCLC 
that was not previously treated. Those with a level of tumor PD-L1 expression of at least 1% were 
randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab 
monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were 
randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus 
chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne 
CDx assay. Recently, in the pre-specified analysis of patients with high tumor mutational burden 
at a prospective cutoff of ≥10 mutations/MB, progression-free survival was significantly longer 
in the group treated by nivolumab plus ipilimumab compared to chemotherapy, demonstrating a 
median PFS of 7.2 months vs 5.5 months, respectively (HR 0.58; 97.5% CI 0.41, 0.81) (Nivolumab 
plus ipilimumab in lung cancer with a high tumor mutational burden.15 The treatment effect was 
consistent in a pre-specified multi-variate analysis when adjusted for PD-L1 expression, histology, 
and other clinical factors. The ORR was also significantly greater for the nivolumab plus 
ipilimumab group (45.3% vs 26.9%; treatment difference 18.4%; 95% CI (7.6, 28.8), and the 
responses appeared durable with 68% of responses ongoing after 1 year and the DOR not reached 
(95% CI 12.2, NR) compared to 5.4 months (95% CI 4.2,6.9) for chemotherapy. In patients with 
TMB <10 mut/Mb, ORR was 24.6% in nivolumab plus ipilimumab arm and 25.9% in 
chemotherapy arm, HR for PFS being 1.07 (95% CI: 0.84, 1.35). In all randomized patients 
(irrespective of TMB or PD-L1 status), 1-year PFS was also higher with nivolumab plus 
ipilimumab than with chemotherapy [30.9% vs 17%; HR 0.83 (95% CI, 0.72 to 0.96)]. The rate of 
grade 3 or 4 treatment-related adverse events in all treated population (regardless of TMB or 
PD-L1 status) was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy, it was 
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slightly higher with nivolumab plus ipilimumab in patients with high TMB tumor (37%), but the 
safety profile was overall consistent with previously reported data with no new safety signals.
Nivolumab added to chemotherapy has been evaluated in several cohorts of chemotherapy-naïve 
subjects with advanced NSCLC in CA209012.16 Nivolumab 10 mg/kg was combined with 
gemcitabine and cisplatin or pemetrexed and cisplatin. Nivolumab 10 mg/kg and 5 mg/kg was 
combined with paclitaxel and carboplatin. The safety profile of nivolumab plus platinum-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 overall response rate across all the nivolumab and chemotherapy cohorts range 
from 33-47% and median duration of response was 27.3 weeks. The 1-year survival rate for all 
cohorts combined is 71%. 
In the ongoing CheckMate 227 trial, data in patients with tumor of <1% PD-L1 expression became 
also available recently.17 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]), mPFS of nivolumab plus ipilimumab was 4.4 months (95%CI: 
3.1 to 6.0). ORR was 36.7% in nivolumab plus chemotherapy arm, 23.1% in chemotherapy arm, 
and 25.1% in nivolumab plus ipilimumab arm. mDOR was 7.2 months in nivolumab plus 
chemotherapy arm, 4.7 months in chemotherapy arm, and 18.0 months in nivolumab plus 
ipilimumab arm. The rate of grade 3 or 4 treatment-related adverse events was 52% with 
nivolumab plus chemotherapy, 35% with chemotherapy, and 25% with nivolumab plus 
ipilimumab, overall, for nivolumab plus chemotherapy, the safety profile and efficacy are 
consistent with previously reported data as well as data from other PD-(L)1 blockades in 
combination with chemotherapy.
Both nivolumab plus ipilimumab and nivolumab plus chemotherapy compare favorably in terms 
of the expected clinical benefit including response rate and overall survival observed with platinum 
doublet chemotherapy in first line NSCLC. These data suggest that nivolumab plus ipilimumab or 
nivolumab plus platinum doublet chemotherapy have the potential to provide superior pathologic 
response and event-free survival compared to platinum doublet chemotherapy as neoadjuvant 
therapy in early-stage NSCLC.18
In general, nivolumab plus ipilimumab or nivolumab plus platinum doublet chemotherapy is well 
tolerated, with a favorable safety profile relative to anticipated toxicities based on an 
immunostimulatory mechanism of action. Nivolumab plus ipilimumab and nivolumab plus 
platinum doublet chemotherapy are currently in phase 3 development in the first-line metastatic 
and as monotherapy in the early stage NSCLC settings.
As neoadjuvant therapy, in Stage I-III NSCLC, in ongoing phase 2 trial (Section 5.4.3) nivolumab 
as monotherapy showed promising anti-tumor activity in terms of depth of pathological response 
while the potential benefit of neoadjuvant nivolumab plus ipilimumab are still under study. On the 
other hand, preliminary data from ongoing phase 2 trial (NADIM, Section 5.4.3) of neoadjuvant 
nivolumab plus platinum doublet chemotherapy showed striking pCR rate. Preliminary experience 
gained from these ongoing phase 2 trials with neoadjuvant nivolumab and nivolumab-based 
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combinations suggests these study treatments were well tolerated with little adverse impact to the 
feasibility of surgery. The platinum 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. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of nivolumab is 
provided in the Investigator’s Brochure and local package insert.
3.2.2
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.19,20,21
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.22 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.23 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 has 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.24 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 CMV 
restimulation assay with human 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 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).25
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3.2.3
Ipilimumab Mechanism of Action
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin superfamily that competes with CD28 for B7. CTLA-4 mediated signals are 
inhibitory and turn off T cell-dependent immune responses.26 Ipilimumab is a fully human 
monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset of T cells from human 
and nonhuman primates. The proposed mechanism of action for ipilimumab is interference of the 
interaction of CTLA-4 with B7 molecules on APCs, with subsequent blockade of the inhibitory 
modulation of T-cell activation promoted by the CTLA 4/B7 interaction.
3.2.4
Nivolumab Combined with Ipilimumab Clinical Activity
CA209012 (Checkmate 012) is a multi-arm phase 1b trial evaluating the safety and tolerability of 
nivolumab in patients with chemotherapy-naïve advanced NSCLC, as either a monotherapy or in 
combination with other agents including ipilimumab, at different doses and schedules. The primary 
endpoint of the study was safety with secondary endpoints of objective response rates (ORR) and 
24-week PFS. Exploratory endpoints included OS and efficacy by PD-L1 expression. In the study, 
patients were tested for PD-L1 and 69% had evaluable PD-L1 expression. Participants were 
enrolled to receive nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q12W or Q6W (n = 77), and 
nivolumab 3 mg/kg Q2W (n = 52). ORR was 43% in all treated patients and 57% and 92% in 
patients with ≥ 1% and ≥ 50% tumor PD-L1 expression, respectively, 6 investigator-assessed CRs 
(8%); including 3 pathologic responses were achieved in the nivolumab 3 mg/kg Q2W + 
ipilimumab 1 mg/kg  Q12W/Q6W cohorts. The median duration of response (DOR) was not 
reached in the overall population or subpopulations.  Duration of response ranged from 1.4+ to 
27.9+ months. 
The rate of treatment-related adverse events in the Q12W/Q6W (79%) arms were comparable to 
monotherapy (73%). In the study, Grades 3 to 4 AEs were 36% and 19% for the Q12W/Q6W and 
nivolumab monotherapy arms, respectively. Treatment-related Grade 3-4 AEs led to 
discontinuation in 8% and 12% of patients in the Q12W/Q6W cohorts and nivolumab monotherapy 
arms, respectively. There were no treatment-related deaths. The treatment-related select AEs in 
patients across all treatment arms were skin-related (31%), gastrointestinal (19%), endocrine 
(18%), and pulmonary (6%). 
As described in Section 3.2.1, ongoing phase 3 CheckMate 227 study randomized patients with 
stage IV or recurrent NSCLC that was not previously treated in various study treatment arms by 
tumor PD-L1 status. Recently, in the pre-specified analysis of patients with high tumor mutational 
burden at a prospective cutoff of ≥ 10 mutations/MB, progression-free survival was significantly 
longer in the group treated by nivolumab plus ipilimumab compared to chemotherapy, HR of PFS 
being 0.58 (97.5% CI 0.41, 0.81). The treatment effect was consistent and independent of PD-L1 
expression, or histology. The ORR was also significantly greater for the nivolumab plus 
ipilimumab group (45.3% vs 26.9%) and the responses appeared more durable with median DoR 
not reached (95% CI 12.2, NR) compared to 5.4 months (95% CI 4.2, 6.9) for chemotherapy. In 
patients with TMB <10 mut/Mb, similar efficacy was seen in terms of PFS and ORR between 
nivolumab plus ipilimumab and chemotherapy. The safety profile was overall consistent with 
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previously reported data with no new safety signals. In another readout focusing on patients with 
tumor of <1% PD-L1 expression, nivolumab plus ipilimumab showed similar efficacy to 
chemotherapy in terms of PFS and ORR but with much longer DoR, with a consistent safety profile 
of previously reported data. 
As of revised protocol 03, the nivolumab plus ipilimumab has stopped enrollment.
3.2.5
Immuno-oncology Treatment Combined with Chemotherapy Clinical 
Activity
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.13 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 have also been shown to reduce MDSCs and 
hence interferon-gamma, which have inhibitory roles in the immune response.27,28 The dual role 
of cytotoxicity and immune activation from chemotherapy has provided the biological rationale 
for the development of combinations with immunotherapy.29
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 was 
combined with paclitaxel and carboplatin.
The safety profile of nivolumab plus platinum-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 subjects (13%): Grade 3-4 in 4 subjects (7%). Twelve (21%) subjects discontinued due to 
treatment-related AEs (Table 3.2.5-1).
Table 3.2.5-1:
Safety in CA209012
Total (N=56)
All Grades
Grade 3
Grade 4
Subjects 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
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Table 3.2.5-1:
Safety in CA209012
Total (N=56)
All Grades
Grade 3
Grade 4
Nausea
46 (26)
2 (1)
0
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 3.2.5-2). Activity was evaluated by 
PD-L1 expression and was observed in subjects with both PD-L1 expressing and non-expressing 
tumors. Overall, 79% (44/56) of subjects 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 3.2.5-2:
Efficacy of First-Line Treatment of Nivolumab/Chemotherapy 
Combination in CA209012
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
27.3
27.3
12-mo OS rate, %
50
87
72
86
18-mo OS Rate, %
33
60
40
62
Median OS, Weeks
51
83
65
Not Reached
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As described in Section 3.2.1 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]), mPFS of nivolumab plus 
ipilimumab was 4.4 months (95%CI: 3.1 to 6.0). ORR was 36.7% in nivolumab plus chemotherapy 
arm, 23.1% in chemotherapy arm, and 25.1% in nivolumab plus ipilimumab arm. mDOR was 
7.2 months in nivolumab plus chemotherapy arm, 4.7 months in chemotherapy arm, and 
18.0 months in nivolumab plus ipilimumab arm. The rate of grade 3 or 4 treatment-related adverse 
events was 52% with nivolumab plus chemotherapy, 35% with chemotherapy, and 25% with 
nivolumab plus ipilimumab. 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.
3.3
Benefit/Risk Assessment
The early-stage (IB-III) 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 doublet 
chemotherapy, only provides a 5% absolute improvement in 5-year OS.
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 participants with operable NSCLC. A meta-analysis based on 7 trials involving 
988 participants suggested that neoadjuvant chemotherapy improved OS when given 
preoperatively in a similar magnitude to those observed with adjuvant chemotherapy. Several 
studies have also shown preoperative cytotoxic chemotherapy to be safe prior to surgical resection 
of NSCLC with no difference in extent of surgical procedures performed, operative morbidity and 
mortality.
The clinical activity of nivolumab observed to date in NSCLC, including 2 positive phase 3 studies 
demonstrating prolonged survival with nivolumab monotherapy compared to docetaxel in 
squamous and non-squamous NSCLC after platinum failure, suggests the potential for improved 
clinical outcomes. CA209057 (non-squamous NSCLC) study demonstrated OS was superior for 
participants receiving nivolumab compared to those receiving docetaxel. In this study, interaction 
P values reported for PD-L1 expression subgroups by each of the pre-defined expression levels 
suggested a clinically important signal of a predictive association. Higher confirmed ORRs in 
PD-L1 expressors were seen in the combination arm compare to the nivolumab monotherapy arm 
in CA209012. Based on these data, CA209816 will stratify participants based on PD-L1 status, 
disease stage at randomization, and gender.  
In CA209012, nivolumab plus ipilimumab provides a higher ORR (43%) than nivolumab 
alone.27,30In first-line metastatic NSCLC, this regimen also provided encouraging overall survival, 
with an acceptable safety profile. Combination of anti-PD1 plus chemotherapy has also shown 
encouraging ORR and PFS with an acceptable safety profile compared to platinum doublet 
chemotherapy in first-line metastatic NSCLC. These data support our belief that combination of 
nivolumab with ipilimumab or platinum doublet chemotherapy will demonstrate superior benefit 
over platinum chemotherapy doublets in the neoadjuvant setting with an acceptable safety profile. 
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In general, nivolumab is well tolerated, with a favorable safety profile relative to anticipated 
toxicities based on an immunostimulatory mechanism of action. Overall, the safety profile of 
nivolumab monotherapy as well as combination therapy is manageable and generally consistent 
across completed and ongoing clinical trials with no maximum tolerated dose (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.
The ongoing phase 3 CheckMate 227 study randomized patients with stage IV or recurrent NSCLC 
not previously treated in various study treatment arms by tumor PD-L1 status. Recently, in the 
pre-specified analysis of patients with high tumor mutational burden at a prospective cutoff of ≥10 
mutations/MB, PFS was significantly longer in the group treated by nivolumab plus ipilimumab 
compared to chemotherapy, HR of PFS being 0.58 (97.5% CI 0.41, 0.81). The treatment effect 
was consistent and independent of PD-L1 expression, or histology. The ORR was also significantly 
greater for the nivolumab plus ipilimumab group (45.3% vs 26.9%) and the responses appeared 
more durable with median DoR not reached (95% CI 12.2, NR) compared to 5.4 months (95% CI 
4.2, 6.9) for chemotherapy. In patients with TMB <10 mut/Mb, similar efficacy was seen in terms 
of PFS and ORR between nivolumab plus ipilimumab and chemotherapy. The safety profile was 
overall consistent with previously reported data with no new safety signals. In another readout 
focusing on patients with tumor of <1% PD-L1 expression, nivolumab plus ipilimumab showed 
similar efficacy to chemotherapy in terms of PFS and ORR but with much longer DoR, the safety 
profile was consistent with previously reported data.
In the setting of first line NSCLC with <1% tumor PD-L1 expression in the ongoing CheckMate 
227 trial, 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]), mPFS of nivolumab plus ipilimumab was 4.4 months 
(95%CI: 3.1 to 6.0). ORR was 36.7% in nivolumab plus chemotherapy arm, 23.1% in 
chemotherapy arm, and 25.1% in nivolumab plus ipilimumab arm. mDOR was 7.2 months in 
nivolumab plus chemotherapy arm, 4.7 months in chemotherapy arm, and 18.0 months in 
nivolumab plus ipilimumab arm. The rate of grade 3 or 4 treatment-related adverse events was 
52% with nivolumab plus chemotherapy, 35% with chemotherapy, and 25% with nivolumab plus 
ipilimumab, overall, for nivolumab plus chemotherapy, the safety profile and efficacy are 
consistent with previously reported data as well as data from other PD-(L)1 blockades in 
combination with chemotherapy.
As described in Section 3.2.1, two ongoing phase 2 trials with nivolumab as monotherapy and 
nivolumab in combination with chemotherapy showed promising anti-tumor activity in terms of 
depth of pathological response without adverse impact on surgical results. Nivolumab and 
ipilimumab as neoadjuvant therapy remain under study, with data pending. 
A pattern of immune-related AEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 4. Most high-grade events were manageable with the 
use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in these 
algorithms. Extensive details on the safety profile of nivolumab and ipilimumab are available in 
the respective Investigator Brochures and will not be repeated herein.
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The potential benefit of nivolumab plus ipilimumab or nivolumab plus platinum doublet 
chemotherapy as neoadjuvant therapy in Stage I-III NSCLC are not yet known. The platinum 
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. 
In order to assess the potential benefit of nivolumab plus platinum doublet chemotherapy over 
platinum doublet chemotherapy as neoadjuvant therapy in Stage I-III resectable NSCLC, this trial 
will randomize participants to 2 arms: nivolumab plus platinum doublet chemotherapy, or platinum 
doublet chemotherapy alone. Under revised protocol 02, participants already enrolled in the 
original 2-arm part and in the arm of nivolumab plus ipilimumab in the 3-arm part per revised 
protocol 02 will continue scheduled trial procedures. To assure an ongoing favorable risk/benefit 
assessment for participants enrolled onto CA209816, an independent Data Monitoring Committee 
(DMC) will be utilized to monitor the safety and activity of the treatments throughout the conduct 
of the trial.
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 participants 
receiving 
nivolumab 
plus 
platinum 
doublet 
chemotherapy vs participants receiving platinum doublet 
chemotherapy in operable stage IB (≥4 cm), II, or 
resectable IIIA (N2) NSCLC
•
EFS defined as the length of time from 
randomization to any of the following events: 
any progression of disease precluding 
surgery, progression or recurrence disease 
(based on BICR assessment per RECIST 1.1) 
after surgery, or death due to any cause. 
Participants who don’t undergo surgery for 
reason other than progression will be 
considered to have an event at RECIST 1.1 
(based on BICR) progression or death. 
•
To compare the pathologic complete response (pCR) rate 
in participants receiving nivolumab plus platinum 
doublet chemotherapy vs participants receiving platinum 
doublet chemotherapy in operable stage IB (≥4 cm), II, 
or resectable IIIA (N2) NSCLC
•
pCR rate is defined as number of randomized 
participants with absence of residual tumor in 
lung and lymph nodes as evaluated by blinded 
independent pathological review (BIPR), 
divided by the number of randomized 
participants for each treatment group.
Secondary
•
To assess the major pathologic response (MPR) rate by 
BIPR of participants receiving nivolumab plus platinum 
doublet chemotherapy vs participants receiving platinum 
doublet chemotherapy in operable stage IB (≥4 cm), II, 
or resectable IIIA (N2) NSCLC
•
MPR rate, defined as number of randomized 
participants with ≤10% residual tumor in lung 
and lymph nodes as evaluated by BIPR, 
divided by the number of randomized 
participants for each treatment group. Viable 
tumors in situ carcinoma should not be 
included in MPR calculation.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
To compare the OS of participants receiving nivolumab 
plus platinum doublet chemotherapy vs participants 
receiving platinum doublet chemotherapy in operable 
stage IB (≥4 cm), II, or resectable IIIA (N2) NSCLC
•
OS is defined as the time between the date of 
randomization and the date of death. OS will 
be censored on the last date a participant was 
known to be alive.
•
To assess the time to death or distant metastases (TTDM) 
of participants receiving nivolumab plus platinum 
doublet chemotherapy vs participants receiving platinum 
doublet chemotherapy in operable stage IB (≥4 cm), II, 
or resectable IIIA (N2) NSCLC
•
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 using BICR according to RECIST 1.1. 
Patients 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.
Exploratory
•
To assess clinical response rate (cRR) by BICR of 
participants receiving nivolumab plus platinum doublet 
chemotherapy vs participants receiving platinum doublet 
chemotherapy in operable stage IB (≥4 cm), II, or 
resectable IIIA (N2) NSCLC 
•
cRR is defined as proportion of all 
randomized 
participants 
whose 
overall 
radiological response prior to definitive 
surgery is either a complete response or partial 
response per RECIST 1.1 criteria by BICR
•
To assess the pCR rate, MPR rate , cRR, EFS, TTDM 
and OS in early-stage NSCLC participants treated with 
nivolumab plus platinum doublet chemotherapy 
compared to those treated with platinum doublet 
chemotherapy by PDL1 status (PD-L1 ≥1% , 
PD-L1< 1% /not evaluable/ indeterminate)   
•
pCR rate, MPR rate, cRR, EFS, TTDM, and 
OS as described above
•
To assess the feasibility of surgery and rate of peri- and 
post-operative complications (within 90 days of surgery) 
in participants receiving  nivolumab plus platinum 
doublet chemotherapy compared to participants receiving 
platinum doublet 
•
Proportion of delayed or canceled surgery, 
duration of surgery, length of hospital stay, 
surgical approach including completeness of 
surgery, incidence of AE/SAE associated with 
surgery, including pneumonitis, ARDS, 
re-admission to the Intensive Care Unit, atrial 
fibrillation 
or 
other 
supraventricular 
tachycardia (SVT) to 90 days post-surgery 
•
To assess the safety and tolerability of nivolumab plus 
platinum doublet chemotherapy compared to platinum 
doublet chemotherapy in early stage NSCLC
•
Safety and tolerability will be measured by 
incidence of AE, SAE, immune-related AEs, 
deaths, and laboratory abnormalities
•
To describe the pCR rate, MPR rate , cRR, EFS, OS, 
TTDM, feasibility of surgery, rate of peri- and post-
operative complications (within 90 days of surgery), 
safety and tolerability in early-stage NSCLC participants 
treated with nivolumab plus ipilimumab and by PDL1 
status 
(PD-L1 
≥1% 
, 
PD-L1< 1%/not 
evaluable/indeterminate)
•
pCR rate, MPR rate, cRR, EFS, OS, TTDM, 
feasibility of surgery, rate of peri- and post-
operative 
complications, 
safety 
and 
tolerability as described above
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
To assess pharmacokinetics of the nivolumab plus 
ipilimumab or nivolumab plus platinum doublet 
chemotherapy in participants with early stage NSCLC
•
Pharmacokinetic endpoints (See Section 9.5) 
•
To assess the participant’s overall health status and health 
utility using the 3-level version of the EQ-5D-3L visual 
analog scale (VAS) and utility index, respectively
•
Change in EQ-5D-3L scores
•
To assess Event Free survival on next line of therapy 
(EFS2) in early-stage NSCLC participants treated with 
nivolumab 
plus 
platinum 
doublet 
chemotherapy 
compared to those treated with platinum doublet
•
Event Free survival on next line of therapy 
(EFS2)
•
To evaluate tumor mutation burden as a potential 
predictive biomarker of efficacy (such as EFS and OS) of 
nivolumab plus platinum doublet chemotherapy and of 
platinum-doublet chemotherapy, using data generated 
from tumor and blood (germ-line control) specimens.
•
To explore potential predictive biomarkers of  nivolumab 
plus platinum doublet chemotherapy efficacy (such as 
EFS and OS) in peripheral blood and tumor specimens  
 
 
•
Biomarker endpoints (See Section 9.8)
5
STUDY DESIGN
5.1
Overall Design
This is an open-label, randomized clinical trial of up to 3 cycles of neoadjuvant nivolumab 
(3 mg/kg every 2 weeks) and a single dose of 1 mg/kg dose of ipilimumab, nivolumab 360mg flat 
dose plus platinum doublet chemotherapy (up to 3 cycles), or platinum doublet chemotherapy (up 
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to 3 cycles) as neoadjuvant treatment in participants with early stage (Stage IB [≥4 cm], II, and 
resectable IIIA [N2]) NSCLC. 
The original study design (before revised protocol 02) had two arms. After signing the informed 
consent form and upon confirmation of the participant’s eligibility, participants were randomized 
in an open-label fashion (1:1 ratio) to either neoadjuvant nivolumab plus ipilimumab or platinum 
doublet chemotherapy.
Revised protocol 02 added a new, neoadjuvant nivolumab plus platinum doublet chemotherapy 
arm. When the third arm had opened and as each site had received IRB/EC approval of revised 
protocol 02, the IRT switched to a 1:1:1 randomization at the respective site.  Starting from that 
point on, the sites were only enrolling under revised protocol 02. 
Revised protocol 03 withholds randomization into the arm of neoadjuvant nivolumab plus 
ipilimumab but continues randomizing eligible participants into either neoadjuvant nivolumab plus 
platinum doublet chemotherapy arm or platinum doublet chemotherapy arm. Participants already 
randomized in the original 2-arm part (neoadjuvant nivolumab plus ipilimumab vs neoadjuvant 
chemotherapy) and in the arm of neoadjuvant nivolumab plus ipilimumab in 3-arm part defined 
by revised protocol 02 will remain in trial and continue scheduled trial procedures.
Participants will be randomized between 2 arms in a 1:1 ratio to neoadjuvant nivolumab plus 
platinum doublet chemotherapy or platinum doublet chemotherapy. Eligible participants will be 
stratified by:
•
PD-L1 expression (≥1% or <1%/not evaluable/indeterminate)
•
Disease stage (IB/II vs IIIA)
•
Gender
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 - defined as ≥1% tumor cell membrane staining positive in a minimum of 
100 evaluable tumor cells
•
PD-L1 negative – defined as < 1% tumor cell membrane staining positive in a minimum of 
100 evaluable tumor cells
•
PD-L1 not evaluable/indeterminate - defined as participants with 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. For the purpose of 
stratification, this category will be grouped with PD-L1 negative participants. No more than 
10% of participants enrolled in this trial will be PD-L1 not evaluable/indeterminate category.
Screening begins by establishing the participant’s initial eligibility and signing of the informed 
consent (ICF). Tumor tissue (archival [slides/block ≤3 month] or recent tumor biopsy) must be 
submitted to a third-party vendor for determination of PD-L1 status prior to randomization.
All screening assessments and procedures must be performed in accordance with Table 2-1.
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The Treatment Phase begins when the randomization call is made into the Interactive Response 
Technology (IRT). The participant will be randomly assigned to 1 of the 2 treatment arms: Arm B 
or Arm C. The first dose of study treatment must begin within 7 days of randomization.
•
Arm A treatment: Participants randomized into Arm A received nivolumab 3 mg/kg IV over 
30 minutes every 2 weeks for up to 3 doses (ie, 6 weeks of treatment; each cycle is 14 days). 
With Cycle 1 only, nivolumab was followed by a single dose ipilimumab 1 mg/kg IV over 30 
minutes.
•
Arm B treatment: Participants randomized into Arm B will receive investigator-choice 
platinum doublet chemotherapy in 3-week cycles up to a maximum of 3 cycles (ie, 9 weeks of 
treatment; each cycle is 21 days):
•
Regimen 1: 
−
Vinorelbine 25 mg/m2 or 30 mg/m2 IV (per local prescribing information) push over 
10 minutes or per institutional standard on Days 1 and 8
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following vinorelbine
•
Regimen 2:
−
Docetaxel 60 mg/m2 or 75 mg/m2  IV (per local prescribing information) over 60 minutes 
or per institutional standard on Day 1
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following docetaxel
•
Regimen 3 (squamous histology):
−
Gemcitabine 1000 mg/m2 or 1250 mg/m2 (per local prescribing information) IV over 
30 minutes or per  institutional standard on Days 1 and 8
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following gemcitabine
•
Regimen 4 (non-squamous histology only):
−
Pemetrexed 500 mg/m2 IV over 10 minutes or per institutional standard on Day 1
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following pemetrexed
•
Regimen 5:
−
Paclitaxel 175 or 200 mg/m2 IV over 180 minutes or per institutional standard on Day 1
−
Carboplatin AUC 5 or 6 IV over 30 minutes or per institutional standard on Day 1, 
immediately following paclitaxel
Arm C treatment: Participants randomized into Arm C will receive nivolumab 360 mg IV plus 
platinum doublet chemotherapy in 3-week cycles up to a maximum of 3 cycles of chemotherapy 
(ie, 9 weeks of treatment; each cycle is 21 days)
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•
Non-squamous NSCLC: nivolumab at a flat dose of 360 mg as 30-minute IV infusion on Day 
1, followed by pemetrexed at a dose of 500 mg/m2 IV over 10 minutes or per institutional 
standard and cisplatin at a dose of 75 mg/m² IV over 120 minutes or per institutional standard 
of a 3-week treatment cycle, for up to 3 cycles.
•
Squamous NSCLC: nivolumab at a dose of flat dose of 360 mg as 30 minute IV infusion on 
Day 1, followed by gemcitabine at a dose of 1000 mg/m2 or 1250 mg/m2 (per local prescribing 
information) for a 30 minute IV infusion or per institutional standard and cisplatin at a dose of 
75 mg/m2 as a 120-minute IV infusion or per institutional standard, of a 3-week treatment cycle 
for up to 3 cycles. Gemcitabine will also be administered at a dose of 1000 mg/m2 or 
1250 mg/m2 as a 30 minute IV infusion or per institutional standard on day 8 of each 3-week 
treatment cycle.
•
Any histology: nivolumab at a flat dose of 360 mg as 30-minute IV infusion on Day 1, followed 
by paclitaxel 175 or 200 mg/m2 IV over 180 minutes or per institutional standard and 
carboplatin AUC 5 or 6 IV over 30 minutes or per institutional standard of a 3-week treatment 
cycle, for up to 3 cycles.
Within 7 days of randomization, the participants must receive the first dose of study medication. 
Participants may be dosed no less than 12 days between nivolumab doses in Arm A and no less 
than 18 days between nivolumab doses in Arm C. If a dose is delayed for any reason, participants 
should be dosed no later than 7 days following a planned dose on any arm. If more than 7 days 
delay is needed for any reason, the intended dose should be skipped. If a participant receiving 
chemotherapy on a Day 1 and Day 8 schedule (ie, cisplatin/gemcitabine) is unable to receive Day 
1 of chemotherapy but recovers in time to receive the Day 8 dose, the Day 8 dose of chemotherapy 
may be administered. Doses that are skipped or missed will not be replaced. Surgery should be 
performed within 6 weeks after completing up to 3 cycles (last dose) of neodjuvant treatment as 
indicated by the institutional SOC.  
•
For participants who are unable to tolerate cisplatin, the reasons for intolerability should be 
documented. If the investigator would like to use a carboplatin-containing regimen, the 
investigator should discuss this with and obtain approval from the Medical Monitor prior to 
utilization, except for opting for carboplatin plus paclitaxel. 
•
Carboplatin will be administered at a dose of AUC 5 or 6 as a 30-minute IV infusion or per 
institutional standard, on Day 1 of each 3-week cycle.
•
Carboplatin should be given following gemcitabine, docetaxel, vinorelbine, pemetrexed, or 
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]
•
Creatinine clearance (CrCl) calculation is based on the Cockroft-Gault formula) and should 
include the most recent serum creatinine and most recent weight. NOTE: If calculation of the 
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CrCl by the Cockroft-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.
All Arms
PET/CT including contrast from the base of the skull to upper thighs will be performed at baseline 
(within 28 days prior to randomization) and within 14 days prior to planned definitive surgery. A 
separate CT, with contrast, of the chest, abdomen, and all other suspected sites of disease (as well 
as the PET/CT) is required if the CT component of a PET/CT is not of sufficient diagnostic quality 
for RECIST 1.1 measurements. Subsequent radiologic assessments CT, with contrast, of the chest 
including adrenal glands and CT or MRI of other additional suspected/known sites of disease will 
be performed in accordance with Table 2-3 and Table 2-4. Tumor assessments must continue per 
protocol until disease recurrence/progression is confirmed by BICR per RECIST 1.1 (Appendix 5),
even after the initiation of subsequent anti-cancer therapies. Exceptions are cases where disease 
progression does not preclude surgery, regardless of whether it has been confirmed by BICR, 
participants should proceed to definitive surgery and continue to get tumor assessments per Table 
2-3 and Table 2-4. Tumor assessments should be done as per Table 2-3 for those who did not get 
definitive surgery. Pharmacokinetics assessments are described in Section 9.5, and biomarker 
assessments are described in Section 9.8. OS will be followed continuously every 3 months via in-
person or phone contact after Post-neoadjuvant Follow-up Visit 2 or after completion of adjuvant 
therapy, when applicable.
Following the completion of neoadjuvant treatment, all participants who remain operative 
candidates will undergo definitive surgery for their NSCLC within 6 weeks after completing 
neoadjuvant treatment. 
Prior to surgery, any treatment-related toxicity should have resolved to ≤Grade 1 or returned to 
baseline (except for alopecia, fatigue, and neuropathy). Investigators should discuss residual 
endocrine toxicities or mild renal impairment with the Medical Monitor. 
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. Study drug dose omission or delays due to AEs will not be replaced for either arm, and 
participants should proceed to surgery within the predefined timeframe after standard preoperative
evaluation. Surgical complications occurring within 90 days of surgery will be documented and 
followed until resolution. 
All AEs and SAEs will be documented for a minimum of 100 days after the last dose of 
neoadjuvant therapy or 90 days post-surgery, whichever is longer, and for 30 days after the last 
dose of adjuvant therapy in participants who receive adjuvant therapy. 
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Following definitive surgery, participants in each arm may receive up to 4 cycles of adjuvant 
chemotherapy with or without radiation per institutional standard at the discretion of the 
investigator. Investigators may choose from the following post-operative regimens:
•
Regimen 1:
−
Vinorelbine 25 mg/m2 or 30 mg/m2 IV (per local prescribing information) push over 
10 minutes or per institutional standard on  Days 1 and 8
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following vinorelbine
•
Regimen 2:
−
Docetaxel 60 mg/m2 or 75 mg/m2 IV (per local prescribing information) over 60 minutes 
or per institutional standard on Day 1
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following docetaxel
•
Regimen 3 (squamous histology):
−
Gemcitabine 1000 mg/m2 or 1250 mg/m2 IV (per local prescribing information) over 
30 minutes or per institutional standard on Days 1 and 8
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following gemcitabine
•
Regimen 4 (non-squamous histology only):
−
Pemetrexed 500 mg/m2 IV over 10 minutes or per institutional standard on Day 1
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following pemetrexed
•
Regimen 5:
−
Paclitaxel 175 or 200 mg/m2 IV over 180 minutes or per institutional standard on Day 1
−
Carboplatin AUC5 or 6 IV over 30 minutes or per institutional standard on Day 1, 
immediately following paclitaxel
For participants who are unable to tolerate cisplatin, the reasons for intolerability should be
documented. If the investigator would like to use a carboplatin regimen, the investigator should 
discuss this with and obtain approval from the Medical Monitor prior to utilization, except for 
opting for carboplatin plus paclitaxel.
Postoperative chemotherapy should not commence until pre-operative, treatment-related toxicity 
has returned to baseline or resolved to ≤Grade 1 (exceptions for fatigue, alopecia, and neuropathy). 
Investigators should discuss residual endocrine toxicities or mild renal impairment with the 
Medical Monitor.
Assessments during adjuvant therapy are outlined in Table 2-4.
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Post-operative radiation should be administered per institutional standard of care. 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.
The Survival Follow-Up Phase begins 3 months after post-neoadjuvant Follow-up Visit 2 or after 
completion of adjuvant therapy, when applicable. Participants will be followed every 3 months for 
survival. Survival follow-up visits may be performed by phone contact or office visit.
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
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5.1.1
Data Monitoring Committee and Other External Committees
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
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 CA209816. An 
interim DMC review will occur after 15 participants have enrolled into Arm A and after 15 
participants have enrolled into Arm C and have completed surgery. 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.
Independent Radiology/Pathology Review
Independent pathology and radiology review will be established for central review and 
confirmation of endpoints. Images and tumor/lymph node samples will be submitted to these 
third-party vendors for central review. Sites will be trained prior to enrolling the first study 
participant. Images and pathology samples acquisition guidelines and submission process will be 
outlined in the study Imaging/Laboratory Manuals to be provided by the vendors. 
Independent Pathology Review: Tumor and lymph node collection from definitive surgical 
resection and sampling of fresh tumor sample in RNAlater for biomarker studies (as applicable 
dependent on size of residual tumor) is mandatory on the day of surgery. RNAlater sample will 
not be collected in China. Processing of the remainder of the specimens for histopathologic 
analysis should be performed within 72 hours of the procedure. Sections will be used for central 
pathology review assessing pathologic complete response (pCR) and major pathological response 
(MPR). Any tumor, tumor bed, or lymph node specimens that are reviewed locally must be 
submitted for central pathology review. Gross examination on the entire specimen should be 
performed which includes all tumor, associated lymph node tissue, and uninvolved parenchyma. 
The specimen should be sectioned at 0.5 cm intervals, and blocks should be submitted for the full 
cross section for every other 0.5 cm interval. For very large tumors with no gross evidence of 
response, a minimum of 1 slide/cm is required for assessment of pathologic response. When 
estimating viable tumor, in situ carcinoma should not be included. Pathology specimen collection 
and processing guidelines are outlined in the CA209816 Laboratory Manual. A blinded pathology 
review process will be utilized to assess for confirmation of endpoints.
Independent Radiology Review: Radiologic tumor assessments will be sent to and reviewed by a 
Blinded Independent Central Review (BICR) from a third-party radiology vendor on an on-going 
basis. At the time of investigator assessed radiographic progression per RECIST 1.1, the site must 
request a BICR- review confirmation of progression or recurrence. However, BICR confirmation 
of progression should not be requested if investigator judges the progression does not preclude 
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surgery. Participants should proceed to definitive surgery and tumor assessments post surgery 
should be continued per schedule of activities. Details of the Blinded Independent Central Review 
responsibilities and procedures will be specified in the Blinded Independent Central Review 
charter.
Participants whose disease progression or recurrence is not confirmed by central review will be 
required to continue tumor assessments (if clinically feasible) according to the protocol-specified 
schedule, even after the initiation of subsequent anti-cancer therapies. Subsequent tumor 
assessments must be submitted to the third party radiology vendor for subsequent review and may 
be discontinued when the investigator and independent radiologists both assess the participant to 
have met RECIST 1.1 criteria for progression or recurrence.
5.2
Number of Participants
Approximately 350 participants will be randomized in a 1:1 ratio (175 participants in each arm) to 
the 2 arms (neoadjuvant nivolumab plus platinum doublet chemotherapy and platinum doublet 
chemotherapy), from 1:1:1 randomization in revised protocol 02 and 1:1 randomization in revised 
protocol 03. 
In addition, it is expected to have around 70 participants randomized in the original 2-arm study 
(Arm A and Arm B) and approximately another 75 participants randomized in the arm of 
neoadjuvant nivolumab plus ipilimumab (Arm A) when the study had 3 arms. 
5.3
End of Study Definition
The start of the trial is defined as the first participant’s first visit. The analysis of pCR rate will 
take place after 350 participants on Arms B and C from 1:1:1 randomization defined by revised 
protocol 02, and 1:1 randomization by revised protocol 03 have the opportunity for surgery. After 
this analysis, participants will be followed for EFS and OS. Two formal interim analyses for EFS 
are planned after 148 events and 167 events have been observed in the participants on Arms B and 
C, which is projected to occur approximately 48 and 58 months after 1:1:1 randomization (the 
second interim analysis will take place when 167 events are observed 
 
). These formal comparisons of EFS will 
allow for determination of superiority. The final analysis (FA) of EFS will be conducted after 
approximately 185 participants in Arms B and C have experienced an event (approximately 73
months from 1:1:1 randomization), or 4 years after the last participant’s randomization.
 
 
5.4
Scientific Rationale for Study Design
5.4.1
Rationale for Open-Label Design
This study will use an open-label design. Due to the obvious difference in chemotherapy- and 
immunotherapy-related toxicities, histology-dependent chemotherapy options, different dose 
modification rules for safety management, including different dose delay rules per arm, and 
different premedication requirements according to chemotherapy, an open-label design is 
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appropriate. An open-label design will also help ensure that immune-related toxicities in 
participant receiving immunotherapy are promptly identified and managed.
Because this study will be open-label, independent pathology and radiology review will be used 
for central review and confirmation of pathologic and clinical responses in all randomized 
participants to determine all response-related endpoints.
5.4.2
Rationale for Preoperative Systemic Therapy in NSCLC
Follow-up of adjuvant trials may require decades until a new treatment can be introduced into the 
early treatment setting. Preoperative chemotherapy has been assessed in a number of trials for 
patients with resectable NSCLC, though most trials were closed early when the adjuvant 
chemotherapy data revealed a survival advantage. A meta-analysis based upon 7 trials involving 
988 participants suggested that neoadjuvant chemotherapy improved OS when given 
preoperatively (5-year survival 20% vs 14% without neoadjuvant chemotherapy). This 
improvement in survival is similar to that noted in the meta-analyses of predominantly adjuvant 
chemotherapy.31,32
Several studies have shown preoperative cytotoxic chemotherapy to be safe prior to surgical 
resection of NSCLC with no difference in extent of surgical procedures performed, operative 
morbidity, and mortality.6,33,34 Immune checkpoint inhibition has the potential to provide benefits 
in early-stage disease. Among these benefits are the opportunity to evaluate EFS in a 
moderate-sized population of early-stage NSCLC patients and the potential to demonstrate 
long-term, disease-free status in these patients.7,35,36,37
5.4.3
Rationale for Immuno-oncology Treatment in Neoadjuvant NSCLC
In contrast to the adjuvant setting in which only micrometastatic disease is present, one may 
hypothesize that the higher tumor burden present at the time of induction treatment may be 
necessary for abundant antigen release and presentation to the immune system, and consequently, 
development of a robust immune response to immune checkpoint inhibitors. 
In an ongoing feasibility trial with nivolumab monotherapy, a major pathologic response (MPR) 
rate was observed in 45% (9/20) of stage IB-IIIA NSCLC participants who were evaluable post-
surgery after 2 cycles of nivolumab. Two patients (10%, 2/20) achieved a pathologic complete
response. Major pathologic response was defined as ≤10% residual viable tumor at resection.38
Responses were observed across histology and regardless of PD-L1 expression. High tumor 
mutation burden and neoantigen density was associated with pathological response following 
neoadjuvant nivolumab treatment. With a median post-op follow-up of 12 months (range of 0.8 to 
19.7 months), 1 patient with MPR had a mediastinal lymph-node recurrence that was treated with 
concurrent chemoradiation and was free from further progression at more than 12 months of 
follow-up. Two patients without MPR have recurrence of lung cancer (1 solitary brain metastasis 
which was treated with radiotherapy and has no evidence of further recurrence at more than 16 
months of follow-up; 1 systemic recurrence 1 year after surgery and died from recurrent disease 4 
months later). Two additional deaths were reported including 1 disease progression in an 
unresected patient and 1 death not related to drug or disease).
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Nivolumab was well tolerated with a safety profile comparable to that observed in the phase 3 
program. Administration of nivolumab in the neoadjuvant setting was deemed to be feasible with 
no surgical delays or post-surgical complications (within 30 days post-surgery). This trial was 
recently expanded to include an additional 30 participants, who will be treated with nivolumab 
monotherapy (n=15) and nivolumab plus ipilimumab (n=15). In addition, nivolumab monotherapy 
will be extended to 3 cycles. It is hypothesized that the addition of a single dose of ipilimumab to 
3 doses of nivolumab and the addition of chemotherapy to nivolumab will result in the achievement 
of higher rate and deeper pathologic responses while maintaining an acceptable safety profile.
The 45% MPR rate from nivolumab in neoadjuvant NSCLC compares with a rate of approximately 
20% from platinum doublet chemotherapy in this context. The pCR of 10% also compares 
favorably to the historically observed pCR rate of approximately 4% with platinum doublet 
chemotherapy. 
In another ongoing phase 2 trial, patients with resectable stage IIIA N2 NSCLC receive 3 cycles 
of neoadjuvant therapy consisting of nivolumab 360mg IV plus paclitaxel/carboplatin IV Q3W 
then proceed to definitive surgery after which patients receive 1 year adjuvant nivolumab.39 In the 
first 22 patients in whom surgical resection was performed following neoadjuvant therapy, pCR 
was recorded in 13 patients (60%), MPR was noted in a further 4 patients (18%). Neoadjuvant 
nivolumab plus paclitaxel/carboplatin was well tolerated and surgery was not delayed. 
These findings, coupled with encouraging survival data from nivolumab plus ipilimumab and anti-
PD1 plus chemotherapy in first-line advanced NSCLC suggest that nivolumab plus ipilimumab, 
especially nivolumab plus platinum doublet chemotherapy, may improve both EFS and pathologic 
response relative to platinum doublet chemotherapy, while providing an acceptable safety profile 
in the neoadjuvant treatment of NSCLC.27
5.4.3.1
Rationale for Combination of Nivolumab and Ipilimumab (Arm A):
Combining immunotherapeutic agents with different mechanisms of action offers the possibility 
of synergistic response. PD-1 and CTLA-4 are both co-inhibitory molecules, but evidence suggests 
that they use distinct mechanisms, to limit T-cell activation. Preliminary indirect data from 
peripheral T-cell assessments suggests that a given T-cell checkpoint inhibitor may modulate host 
immune cell phenotype rendering them more susceptible to alternate checkpoint inhibitors and 
thereby enhancing anti-tumor activity.
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase IFN-γ 
production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased 
antitumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer models. 
In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased 
the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and 
dual blockade increased tumor infiltration of T effector cells and decreased intratumoral 
T regulatory cells, as compared to either agent alone.40
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The combination of nivolumab and ipilimumab was evaluated in CA209004 (MDX1106-04), a 
phase 1b, multiple ascending dose study in participants with treatment-naive and 
previously-treated advanced melanoma. Results showed promising activity with higher but 
tolerable toxicity than ipilimumab alone. Based on these data, CA209069, a phase 2 study, 
compared the combination to ipilimumab alone in treatment-naïve participants with advanced 
melanoma: nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by 
nivolumab 3 mg/kg every 2 weeks versus ipilimumab 3 mg/kg every 3 weeks for 4 doses.41 In 
participants with BRAF wild type tumors, the ORR was 61% (44/72), including 22% (16/72) CRs 
in the group treated with the combination, compared to 11% (4/37) with 0 CRs in those treated 
with ipilimumab alone. The median PFS was not reached in the combination versus 4.4 months 
for ipilimumab alone (HR = 0.4). Recently, a phase 3 study (CA209067, n = 945) reported 
significantly improved PFS and ORR with the combination of nivolumab and ipilimumab versus 
ipilimumab alone in previously untreated melanoma. The median PFS was 6.9 months (95% 
confidence interval [CI], 4.3 to 9.5) in the nivolumab group, 11.5 months (95% CI, 8.9 to 16.7) in 
the nivolumab plus ipilimumab group, and 2.9 months (95% CI, 2.8 to 3.4) in the ipilimumab 
group. Significantly longer PFS was observed in the nivolumab plus ipilimumab group than in the 
ipilimumab group (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; 
P < 0.001) and in the nivolumab group than in the ipilimumab group (hazard ratio, 0.57; 99.5% 
CI, 0.43 to 0.76; P < 0.001). The hazard ratio for the comparison between the nivolumab plus 
ipilimumab group and the nivolumab group was 0.74 (95% CI, 0.60 to 0.92).42
In addition, deep and durable responses were observed in previously treated, extensive stage small 
cell lung cancer (SCLC), with a response rate of 31.1% with the combination of nivolumab and 
ipilimumab.43
Based on the initial data in melanoma and the activity observed with nivolumab and ipilimumab 
in lung cancer, the nivolumab plus ipilimumab combination has been also evaluated as first-line 
therapy in participants with advanced NSCLC. In CA209012, early combination cohorts evaluated 
2 dosing schedules that were studied in the CA209004 study in melanoma.44
•
Nivolumab 1 mg/kg + ipilimumab 3 mg/kg, every 3 weeks for 4 doses, followed by nivolumab 
3 mg/kg q 2 weeks (Arms G and H, n=24);
•
Nivolumab 3 mg/kg + ipilimumab 1 mg/kg, every 3 weeks for 4 doses, followed by nivolumab 
3 mg/kg q 2 weeks (Arms I and J, n=25)
These regimens resulted in significant toxicity, with 39% of participants discontinuing treatment 
due to a treatment-related adverse event. Thus, additional combination cohorts were initiated 
(Arms N, O, P, Q), using lower doses of both nivolumab and ipilimumab, or the approved dose of 
nivolumab with less frequent dosing of ipilimumab. These new regimens were better tolerated, 
and the safety data are not dissimilar to what has been observed in the nivolumab monotherapy 
cohort (Arm F in CA209012) (Table 5.4.3.1-1).
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Table 5.4.3.1-1:
Treatment-related Adverse Events from Selected Cohorts in 
CA209012
Arma
No. 
Participa
nts/ arm
Follow-up 
time 
(median, 
wks)
No. 
Participants 
still on 
treatment
No. 
Participants 
with drug-
related AEs
No. 
Participants 
with grade 3-
4 drug-
related AEs
No. participants 
d/c due to drug-
related AEs 
(all grades)
Nb
31
72
6 (19%)
24 (77%)
9 (29%)
4 (13%)
Ob
40
27
14 (35%)
29 (73%)
14 (35%)
3 (8%)
Pb
38
37
20 (53%)
28 (74%)
11 (29%)
2 (5%)
Qb
39
34
15 (39%)
27 (69%)
11 (28%)
4 (10%)
Fc
52
62
5 (10%)
37 (71%)
10 (19%)
5 (10%)
a N:nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks x 4, followed by nivolumab 3 mg/kg every 2 weeks; 
O: nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks; P: nivolumab 3 mg/kg every 2 weeks 
plus ipilimumab every 12 weeks; Q: nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks; 
F: nivolumab 3 mg/kg every 2 weeks
b based on August 2015 database lock
c based on March 2015 database lock
Recently, the pooled results from the CA209012 (Checkmate 012) nivolumab 3 mg/kg Q2W and 
ipilimumab 1 mg/kg Q12W and Q6W cohorts showed continued clinical benefit (OS and PFS) 
with nivolumab plus ipilimumab in all patients and those with ≥1% and ≥50% tumor PD-L1 
expression.45 ORR was 43% in all treated patients and 57% and 92% in patients with ≥1% and 
≥50% tumor PD-L1 expression, respectively, consistent with the previous report. Additionally, 
6 investigator-assessed complete responses ([CRs] 8%; including 3 pathologic responses) were 
achieved in the Q12W/Q6W cohorts.46 Median duration of response had not yet been reached in 
the overall population or in subgroups with <1%, ≥1%, or ≥50% PD-L1 expression; duration of 
response ranged from 1.4+ to 27.9+ months. All treated patients (n = 77) showed a 1 year OS of 
76% and 2 year OS of 49%. When analyzed by PD-L1 expression, patients with ≥1% PD-L1 
(n = 47) had a 1 years OS of 87% and 2 year OS of 58%, which increased to 100% and 62%, 
respectively for ≥50% PD-L1 patients. Nivolumab plus ipilimumab remained tolerable, as most 
treatment-related AEs were manageable and no new safety concerns were identified in follow-up.
As described in Section 3.2.1, ongoing phase 3 CheckMate 227 study randomized patients with 
stage IV or recurrent NSCLC that was not previously treated in various study treatment arms by 
tumor PD-L1 status. Recently, in the pre-specified analysis of patients with high tumor mutational
burden at a prospective cutoff of ≥10 mutations/MB, progression-free survival was significantly 
longer in the group treated by nivolumab plus ipilimumab compared to chemotherapy, HR of PFS 
being 0.58 (97.5% CI 0.41, 0.81). The treatment effect was consistent and independent of PD-L1 
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expression or histology. The ORR was also significantly greater for the nivolumab plus 
ipilimumab group (45.3% vs 26.9%) and the responses appeared more durable with median DoR 
not reached (95% CI 12.2, NR) compared to 5.4 months (95% CI 4.2, 6.9) for chemotherapy. In 
patients with TMB < 10 mut/Mb, similar efficacy was seen in terms of PFS and ORR between 
nivolumab plus ipilimumab and chemotherapy. The safety profile was overall consistent with 
previously reported data with no new safety signals. In another readout focusing on patients with 
tumor of <1% PD-L1 expression, nivolumab plus ipilimumab showed similar efficacy to 
chemotherapy in terms of PFS and ORR but with much longer DoR, the safety profile was 
consistent with previously reported data.
5.4.3.2
Rationale for PD-1 Inhibitor with Chemotherapy (Arm C)
The interaction of a tumor with the immune system is complex. Tumors and the tumor 
microenvironment are known to express a variety of factors that impede a robust immune response 
from eliminating the tumor. Soluble and membrane-bound factors have been shown to inhibit the 
cytolytic activity of tumor infiltrating T-cells (eg, PD-L1 expression; TGF-beta). In addition, some 
tumor-derived factors are able to enhance the immune system counter-regulatory systems 
(eg, increased T-regulatory cells). Finally, suboptimal tumor antigen delivery and presentation has 
been postulated as another mechanism by which tumors can successfully evade immune system 
recognition. 
Cancer therapeutics such as chemotherapy may modulate tumor/immune-system interactions in 
favor of the immune system. Chemotherapy can result in tumor cell death with a resultant increase 
in tumor antigen delivery to antigen-presenting cells. Tumor cell death may also lead to a reduction 
in soluble and membrane-bound factors inhibiting tumor-infiltrating T-cells. Chemotherapy may 
also disrupt immune system regulatory networks by decreasing numbers of T-regulatory cells.
Nivolumab added to chemotherapy has been evaluated in several cohorts of chemotherapy-naive 
subjects with advanced NSCLC in study CA209012. Nivolumab 10 mg/kg was combined with 
gemcitabine and cisplatin and pemetrexed + cisplatin. Nivolumab 10 mg/kg and 5 mg/kg was 
combined with paclitaxel and carboplatin. 
The safety profile of nivolumab plus platinum-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 subjects (13%): Grade 3-4 in 4 subjects (7%). Twelve (21%) subjects discontinued due to 
treatment-related AEs (Table 5.4.3.2-1).
The overall response rate across all the nivolumab and chemotherapy cohorts ranged from 33-47% 
and median duration of response was 27.3 weeks. In the 15 participants that received nivolumab 
10 mg/kg plus pemetrexed and cisplatin, 47% achieved a PR or CR. In the 12 participants that 
received nivolumab 10 mg/kg plus gemcitabine and cisplatin, 33% achieved a CR or PR. The 
1-year survival rate was 87% (Table 5.4.3.2-2). 
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Activity was evaluated by PD-L1 expression and was observed in subjects with both PD-L1 
expressing and non-expressing tumors. Overall, 79% (44/56) of subjects 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 5.4.3.2-1:
Safety Evaluation in CA209012
Total (N=56)
All Grades
Grade 3
Grade 4
Subjects 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
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). 
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Table 5.4.3.2-2:
Efficacy of First-Line Treatment of Nivolumab/Chemotherapy 
Combination in CA209012
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
27.3
27.3
12-mo OS rate, %
50
87
72
86
18-mo OS Rate, %
33
60
40
62
Median OS, Weeks
51
83
65
Not Reached
As described in Section 3.2.1, 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]), mPFS 
of nivolumab plus ipilimumab was 4.4 months (95%CI: 3.1 to 6.0). ORR was 36.7% in nivolumab 
plus chemotherapy arm, 23.1% in chemotherapy arm, and 25.1% in nivolumab plus ipilimumab 
arm. mDOR was 7.2 months in nivolumab plus chemotherapy arm, 4.7 months in chemotherapy 
arm, and 18.0 months in nivolumab plus ipilimumab arm. The rate of grade 3 or 4 treatment-related 
adverse events was 52% with nivolumab plus chemotherapy, 35% with chemotherapy, and 25% 
with nivolumab plus ipilimumab, overall, for nivolumab plus chemotherapy, the safety profile and 
efficacy are consistent with previously reported data as well as data from other PD-(L)1 blockades 
in combination with chemotherapy.
5.4.4
Rationale for Pathologic Response
Pathologic complete response (pCR) has been long known to correlate with survival after tumor 
resection. Recently, the FDA approved pertuzumab based on pathologic response rate for the 
treatment of locally advanced breast cancer. In the ongoing feasibility trial with nivolumab 
monotherapy, 2 out of 20 (10%) patients achieved pCR. In another ongoing phase II trial (NADIM) 
to evaluate neoadjuvant nivolumab plus chemotherapy, 13 out of 22 (60%) patients achieved pCR. 
These compare favorably to the approximate 4% pCR in NSCLC observed historically with 
neoadjuvant chemotherapy. It is predicted that patients treated with the combination of nivolumab 
plus ipilimumab, especially nivolumab plus platinum doublet chemotherapy, will achieve a higher 
pCR rate than in patients treated with nivolumab monotherapy. Therefore, pCR will be one of 
primary objectives.
In a recent publication by Hellmann and colleagues, major pathologic response (MPR), defined as 
≤10% viable tumor, was proposed as a better surrogate for survival and is observed in 
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approximately 22% of NSCLC patients treated with neoadjuvant chemotherapy.47 This proposed 
surrogate for survival was supported by the data from a prospective study and retrospective 
study.48, 49 Pataer and colleagues used a score system that quantifies the percentage of viable tumor 
cells and demonstrated that there is a statistically significant correlation between higher percentage 
of viable cells and shorter disease-free and OS in patients who received induction treatment. This 
correlation was not evident in patients treated with upfront surgery alone. The 5-year recurrence-
free survival for patients with and without a pathologic response were 78% and 35%, respectively 
(P < 0.001). The 5-year overall survival for patients with and without a pathologic response were 
85% and 40%, respectively (P < 0.0001). In the on-going feasibility CA209159 trial with 
nivolumab monotherapy, a MPR rate of 45% (9/20) was observed in stage IB-IIIA NSCLC 
participants who were evaluable post-surgery after 2 cycles of nivolumab. In NADIM, further to 
60% pCR rate, MPR was also noted in 4 additional patients (18%). These results compare 
favorably to the MPR rate of approximately 22% observed with historical neoadjuvant 
chemotherapy. These results further support the exploration of MPR as a secondary objective for 
the CA209816 trial.
5.4.5
Rationale for Patient Population
The OS benefit of several adjuvant therapies in this population is presented in Table 3.1-1. The 
choice of stage II and resectable IIIA (N2) NSCLC was made because these participants have a 
high risk of tumor relapse and death with current standard therapy, including surgery with 
preoperative or postoperative chemotherapy. There is an urgent need for improved, novel therapies 
for this group of participants. Participants with stage IB NSCLC with primary tumors of ≥4 cm 
diameter have been included because these participants are also at a high risk of tumor relapse and 
may be considered candidates for standard adjuvant chemotherapy.2,50 It is anticipated that 
participants enrolled on this study may require adjuvant chemotherapy with or without radiation, 
and the administration of adjuvant chemotherapy will commence if considered clinically indicated 
in the postoperative period.
5.4.6
Rationale for Choices of Platinum-based Chemotherapy Doublet
The regimens selected for use in this study are commonly used adjuvant and neoadjuvant therapies 
in the clinical setting. A significant difference in outcome was not seen between participants using 
the regimens proposed in this trial.51 Cisplatin-based therapy has been shown to significantly 
improve survival.52 Several clinical trials have found a significant improvement in OS when using 
platinum-based chemotherapy regimens.53,54,55,56,57 In revised protocol 03, paclitaxel/carboplatin 
is added among available chemotherapy options based on the promising data of using this doublet 
as backbone to combine with nivolumab in neoadjuvant therapy. Besides, meta-analysis of 
individual participant data from neoadjuvant trials did not identify evidence of a difference in 
effect of chemotherapy by whether regimens were cisplatin or carboplatin-based (interaction 
p=0.48).58
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5.5
Justification for Dose
5.5.1
Rationale for Shorter Infusion Times for Nivolumab
Nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg safely 
over long treatment duration. In Study CA209010 (a phase 2, randomized, double-blinded, 
dose-ranging study of nivolumab in participants with advanced/metastatic clear cell RCC), a dose 
association was observed for infusion site reactions and hypersensitivity reactions (1.7% at 
0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1-2 and were 
manageable. An infusion duration of 30 minutes for 3 mg/kg of nivolumab and for a flat dose of 
360 mg (30% of the dose provided at 10 mg/kg and 45% of dose provided at 10 mg/kg assuming 
an average body weight of 80 kg, respectively) is not expected to present any safety concerns 
compared to the prior experience at 10 mg/kg nivolumab dose infused over a 60-minute duration.
Of note, CA209153, a phase 3b/4 safety study of nivolumab in participants with metastatic NSCLC 
who have progressed during or after at least 1 prior systemic regimen, used a 30-minute infusion 
in a cohort of participants with no safety issues. 
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across nivolumab. Overall, a change in safety profile is not anticipated with 30-minute infusion of 
nivolumab.
5.5.2
Rationale for Nivolumab 360 mg Flat 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 subjects 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 subjects.
A PPK model predicted overall nivolumab exposures across subjects 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.  
In addition, data from the Japanese Phase 1 study ONO-4538-01 did not demonstrate dose-limiting 
toxicity at nivolumab up to 20 mg/kg every 2 weeks in Japanese patients and showed similarity in 
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PK properties between Global and Japanese population. Therefore, the proposed 360 mg flat dose 
is expected to be safe and tolerable in an Asian population.
Nivolumab 5 or 10 mg 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 CA209722.
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 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.
2) Type of Participant and Target Disease Characteristics
a) Eastern Cooperative Group (ECOG) Performance Status 0-1 (Appendix 3)
b) Participants with histologically confirmed Stage IB (≥4 cm), II, IIIA (N2) NSCLC (per 
the 7th International Association for the Study of Lung Cancer) with disease that is 
considered resectable.59
c) Measurable disease according to RECIST version 1.1  
d) Participants must have a tumor tissue sample available for PD-L1 IHC testing performed 
by a third-party analyzing lab during the screening period:
i)
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor 
tissue sections, with an associated pathology report, must be submitted for biomarker 
evaluation prior to randomization. The tumor tissue sample may be fresh or archival if 
obtained within 3 months prior to enrollment. 
ii) Tissue must be a core needle biopsy, excisional or incisional biopsy. Fine needle 
biopsies obtained by EBUS is not considered adequate for biomarker review and 
randomization. Core needle biopsies obtained by EBUS are acceptable for 
randomization. 
e) Absence of major associated pathologies that increase the surgery risk to an unacceptable 
level 
f)
All suspicious mediastinal lymph nodes including those that are pathologically enlarged or 
FDG avid on PET/CT require further sampling for pathological confirmation if accessible 
by mediastinoscopy, thoracoscopy, or EBUS. 
g) Pulmonary function capacity (eg, FVC, FEV1, TLC, FRC, and DLco) capable of tolerating 
the proposed lung resection according to the surgeon. 
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3) Age and Reproductive Status
a) Males and Females, ages ≥18 or age of majority 
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) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception (Appendix 6) for the duration of treatment with nivolumab and 
5 months after the last dose of study treatment (ie, 30 days [duration of ovulatory cycle]) 
plus the time required for the investigational drug to undergo approximately 5 half-lives 
(for participants treated in Arm A and Arm C).
e) WOCBP must also agree to follow instructions for method(s) of contraception from the 
time of enrollment for the duration of treatment with chemotherapy plus 5 half-lives of 
chemotherapy plus 30 days (duration of ovulatory cycle) for a total of 30 days 
post-treatment completion or a duration specified by the local labels of the chemotherapy 
drugs received, whichever is longer (for participants treated in Arm B and Arm C). 
f)
Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 6) for the duration of treatment with nivolumab and 
7 months after the last dose of study treatment (ie, 90 days [duration of sperm turnover] 
plus the time required for the investigational drug to undergo approximately 5 half-lives) 
(for participants treated in Arm A and Arm C). In addition, male participants must be 
willing to refrain from sperm donation during this time. 
g) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s) with 
chemotherapy plus 5 half-lives of the study treatment plus 90 days (duration of sperm 
turnover) for a total of 90 days post-treatment completion or a duration specified by the 
local labels of the chemotherapy drugs received, whichever is longer (participants in Arm 
B and Arm C). In addition, male participants must be willing to refrain from sperm 
donation during this time. 
h) 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 6), 
which have a failure rate of < 1% when used consistently and correctly.
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6.2
Exclusion Criteria
1) Medical Conditions
a) Presence of locally advanced unresectable (regardless of stage) or metastatic disease 
(stage IV). 
b) Participants with known EGFR mutations or ALK translocation. If testing is done, an 
FDA-approved assay should be used, and testing will be performed locally.
c) Participants with brain metastases are excluded from this study, and all participants with 
stage II or higher disease and those with suspicion of brain metastases should have MRI or 
CT of the brain with pre- and post-contrast within 28 days prior to randomization.
d) Participants with ≥Grade 2 peripheral neuropathy 
e) 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.
f)
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
g) 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.
h) Participants with serious or uncontrolled medical disorders 
i)
Participants with large-cell neuroendocrine carcinoma tumor histology
2) Prior/Concomitant Therapy
a) Prior administration of chemotherapy or any other cancer therapy for early stage NSCLC.
b) Prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody or any 
other antibody targeting T cell co-regulatory pathways.
3) Physical and Laboratory Test Findings
a) Screening laboratory values must meet the following criteria (using CTCAE v4):
i)
WBC
< 2000/μL
ii) Neutrophils
< 1500/μL
iii) Platelets
< 100x103/μL
iv) Hemoglobin
< 9.0 g/dL
v) Serum creatinine > 1.5 x ULN or calculated creatinine clearance (CrCl) < 50 mL/min 
(using the Cockcroft-Gault formula)
Female CrCl = (140- age in years) x weight in kg x 0.85
72 x serum creatinine in mg/ dL
Male CrCl = (140- age in years) x weight in kg x 1.00
72 x serum creatinine in mg/ dL
vi) AST
> 3.0 x ULN 
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vii) ALT
> 3.0 x ULN 
viii) Total Bilirubin
> 1.5 x ULN (except participants with Gilbert Syndrome who must 
have a total bilirubin level of < 3.0 x ULN). 
b) Participants with active hepatitis B (positive hepatitis B surface antigen [HBsAg] or 
hepatitis C virus (HCV) (positive HCV RNA)
i)
Participants with past HBV infection or resolved HBV infection (defined as the 
presence of hepatitis B core antibody [HBcAb] and the absence of HBsAg) are eligible. 
HBV DNA must be obtained in these patients prior to randomization. HBV carriers or 
those participants requiring antiviral therapy are not eligible to participate. 
ii) Participants positive for HCV antibody are eligible only if PCR is negative for HCV 
RNA. 
c) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast.
d) Participants with serious or uncontrolled medical disorders
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug 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 Bristol-Myers Squibb Company 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.
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 are 
not subsequently randomized. 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, 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 or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant who 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. Participants are allowed to 
re-enroll twice. Eligibility will need to be confirmed if a participant is re-enrolled. 
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted up to 3 times (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.
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:
All products, active or placebo, being tested or used as a comparator in a clinical trial. 
An investigational product, also known as investigational medicinal product in some regions, is 
defined 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.
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Table 7-1:
Study treatments for CA209816
Product Description / 
Class and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
BMS-936558-01
Solution for 
Injection/Nivolumaba
10 mg/mL
IP
Open-label
5 or 10 (100 mg) vials per carton; Clear to 
opalescent, colorless to pale yellow liquid. Few 
particulates may be present.
2 to 8° C. Protect from light 
and freezing
Ipilimumab Solution for 
Injection
5 mg/mL
IP
Open-label
4 vials/carton. Clear to opalescent, colorless to 
pale yellow liquid. May contain particles
2 to 8° C. Protect from light 
and freezing
Vinorelbine NC Concentrate 
for Solution for Infusionb
10 mg/mL
IP
Open-label
1 vial/carton. Clear, colorless to pale yellow 
solution.
Product should be stored as 
per market product conditions.
Gemcitabine Concentrate 
for Solution for Infusionb
1000 
mg/vial
(38 mg/mL)
IP
Open-label
1 vial/carton. Clear, colorless or light straw-
colored solution
Product should be stored as 
per market product conditions.
Gemcitabine Powder for 
Solution for Infusionb
1000 
mg/vial
IP
Open label
1 vial per carton. White to off-white plug or 
powder
Product should be stored as 
per market product conditions.
Docetaxel Concentrate for 
Solution for Infusionb
10 mg/mL
IP
Open-label
1 vial/carton. Pale yellow to brownish yellow 
solution
Product should be stored as 
per market product conditions.
Pemetrexed Powder for 
Concentrate for Solution for 
Infusionb
500 mg/vial
IP
Open-label
1 vial/carton. White to either light yellow or 
green-yellow lyophilised powder
Product should be stored as 
per market product conditions.
Cisplatin Concentrate for 
Solution for Infusionb
100 mg/vial 
(1 mg/mL)
IP
Open-label
4 vials per carton. Clear, colorless solution
Product should be stored as 
per market product conditions.
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Table 7-1:
Study treatments for CA209816
Product Description / 
Class and Dosage Form
Potency
IP/
Non-IMP
Blinded or 
Open Label
Packaging / Appearance
Storage Conditions
(per label)
Carboplatin Solution for 
Injectionb
450 mg/vial 
(10 mg/mL)
IP
Open-label
4 vials/carton. Clear, colorless or slightly yellow 
solution.
Product should be stored as 
per market product conditions.
Paclitaxel Solution for 
Injectionb
100mg/vial
(6mg/mL)
IP
Open-label
4 vials/carton. Clear, colorless or slightly yellow 
viscous solution.
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 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, stored and administered with the Package Insert or Summary of Product 
Characteristics.
Note: As of revised protocol 03, enrollment in nivolumab + ipilimumab arm has stopped enrollment.
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7.1
Treatments Administered
The selection and timing of dose for each participant is presented in Table 7.1-1.
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
Nivolumab
10 mg/mL
3 mg/kg every 2 weeks for up to 
3 cycles (Arm A)
360 mg every 3 weeks for up to 
3 cycles (Arm C)
IV
Ipilimumab
5 mg/mL
1 mg/kg at Cycle 1 only
IV
Vinorelbine60
10 mg/mL
25 mg/m2 or 30 mg/m2 on Days 1 and 
8 of a 3-week cycle for up to 3 cyclesa
IV
Gemcitabine61
38 mg/mL
1000 mg/m2 or 1250 mg/m2 on Days 1 
and 8 of a 3-week cycle for up to 3 cyclesa
IV
Docetaxel62
10 mg/mL
60 mg/m2 or 75 mg/m2 on Day 1 of a 
3-week cycle for up to 3 cyclesa
IV
Pemetrexed63
500 mg/vial
500 mg/m2 on Day 1 of a 3-week cycle 
for up to 3 cyclesa
IV
Cisplatin64
1 mg/mL
75 mg/m2 on Day 1 of a 3-week cycle 
for up to 3 cyclesa
IV
Carboplatin65
10 mg/mL
AUC 5 or 6 on Day 1 of a 3-week 
cycle for up to 3 cyclesa,b
IV.
Paclitaxel 
(Taxol PI TBC)66,67
6 mg/mL
175 or 200 mg/m2 on Day 1 of a 
3-week cycle for up to 3 cyclesa
IV
a Following definitive surgery, participants may receive up to 4 cycles of adjuvant chemotherapy with or without 
radiation at the discretion of the investigator.
b Carboplatin is initiated at a dose of AUC 5 or 6 when combined with paclitaxel.
Note: As of revised protocol 03, enrollment in nivolumab + ipilimumab arm has stopped 
enrollment.
Nivolumab and Ipilimumab (Arm A)
NOTE: As of revised protocol 03, enrollment has stopped in Arm A. 
Participants are to receive nivolumab at a dose of 3 mg/kg as a 30-minute infusion on Day 1 of 
each treatment cycle every 2 weeks for a maximum of 3 doses. In Cycle 1, participants will also 
receive a single dose of ipilimumab 1 mg/kg as a 30-minute infusion on Day 1. Participants are to
begin study treatment within 7 calendar days of randomization. 
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Dosing calculations should be based on the body weight assessed at baseline. It is not necessary to 
re-calculate subsequent doses if the participant weight is within 10% of the weight used to calculate 
the previous dose. All doses should be rounded up or to the nearest milligram or per institutional 
standard.
When study drugs (nivolumab and ipilimumab) 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 ipilimumab infusion. The second infusion will 
always be the ipilimumab study drug and will start after the infusion line has been flushed, filters 
changed and participant has been observed to ensure no infusion reaction has occurred. The time 
in between infusions is expected to be approximately 30 minutes but may be more or less 
depending on the situation.
There will be no dose escalations or reductions of nivolumab or ipilimumab allowed. Participants 
may be dosed no less than 12 days from the previous dose. Premedications are not recommended 
for the first dose of nivolumab and ipilimumab.
Participants should be carefully monitored for infusion reactions during nivolumab and 
ipilimumab administration. If an acute infusion reaction is noted, participants should be managed 
according to Section 7.4.3.
Doses of nivolumab and ipilimumab may be interrupted, delayed, or discontinued depending on 
how well the participants tolerates the treatment. If a participant requires a dose delay of > 7 days, 
the dose should be skipped.  
Dose delay criteria can be found in Section 7.4.2.1, and discontinuation criteria can be found in 
Section 8.1.1.1. Criteria to resume treatment can be found in Section 8.1.2.1.
Please see the nivolumab IB, ipilimumab IB, and pharmacy manual for specific infusion 
preparation recommendations.
Nivolumab plus Platinum Doublet Chemotherapy (Arm C)
Participants are to begin study treatment within 7 calendar days of randomization. Participants are 
to receive nivolumab 360 mg IV plus histology dependent platinum doublet chemotherapy in 
3-week cycles up to a maximum of 3 cycles:
•
Non-squamous NSCLC: nivolumab at a flat dose of 360 mg as 30-minute IV infusion on Day 
1, followed by pemetrexed at a dose of 500 mg/m2 IV over 10 minutes or per institutional 
standard with cisplatin at a dose of 75 mg/m² IV over 120 minutes or per institutional standard, 
of a 3-week treatment cycle, for up to 3 cycles.
•
Squamous NSCLC: nivolumab at a flat dose of 360 mg as 30 minute IV infusion on day 1, 
followed by gemcitabine at a dose of 1000 mg/m2 or 1250 mg/m2 (per local prescribing 
information) IV over 30 minutes or per institutional standard with cisplatin at a dose of 75 
mg/m2 IV over 120 minutes or per institutional standard, of a 3-week treatment cycle for up to 
3 cycles.  Gemcitabine will also be administered at a dose of 1000 mg/m2 or 1250 mg/m2 for 
a 30 minute IV infusion or per institutional standard on day 8 of each 3-week treatment cycle.
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•
Any histology: nivolumab at a flat dose of 360 mg as 30-minute IV infusion on Day 1, followed 
by paclitaxel 175 or 200 mg/m2 IV over 180 minutes or per institutional standard and 
carboplatin AUC 5 or 6 IV over 30 minutes or per institutional standard of a 3-week treatment 
cycle, for up to 3 cycles.
•
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 
There will be no dose escalations or reductions of nivolumab allowed. Participants may be dosed 
no less than 18 days from the previous dose. 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. If a participant requires a dose delay of > 7 days, the dose 
should be skipped.  
Dose delay criteria can be found in Section 7.4.2.1, and discontinuation criteria can be found in 
Section 8.1.1.1. Criteria to resume treatment can be found in Section 8.1.2.1
Please see the nivolumab IB, ipilimumab IB, and pharmacy manual for specific infusion 
preparation recommendations.
Refer to instructions below for instructions for pemetrexed/cisplatin, gemcitabine/cisplatin, and 
paclitaxel/carboplatin administration. 
Doses of gemcitabine and/or cisplatin 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 8.1.1.2. Criteria to resume treatment can be found in 
Section 8.1.2.2.
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 8.1.1.2. Caution should be used when administering NSAIDs 
concurrently with pemetrexed to patients with mild to moderate renal insufficiency (creatinine 
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clearance from 45 to 79 mL/min). Pemetrexed should not be administered if the calculated CrCl 
is < 45 mL/min. 
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 8.1.1.2. Criteria to resume treatment can be found in 
Section 8.1.2.2.
Dosing of all drugs should be delayed if any criteria in Section 7.4.2.1 (nivolumab), 
Section 7.4.2.2, or Section 7.4.2.3 (platinum doublet chemotherapy) are met. That is, nivolumab 
should be delayed if criteria for delay of platinum doublet chemotherapy are met, and platinum 
doublet chemotherapy should be delayed if criteria for delay of nivolumab are met. 
Participants may resume dosing only when criteria for BOTH resumption of nivolumab 
(Section 8.1.2.1) AND platinum doublet chemotherapy (Section 8.1.2.2 and Section 8.1.2.3) are 
met. That is, nivolumab and platinum doublet chemotherapy must be administered together until 
treatment discontinuation criteria (Sections 8.1.1.1, 8.1.1.2, and 8.1.1.3) or up to 3 cycles of study 
treatment have been completed.
If a participant who is receiving nivolumab and platinum doublet chemotherapy experiences an 
adverse event and the investigator can attribute it to either nivolumab or chemotherapy, then either 
nivolumab or the chemotherapy agents can be discontinued, and the other agent(s) can be 
continued.
Platinum Doublet Chemotherapy (Arm B)
Vinorelbine/Cisplatin
Vinorelbine will be administered at a dose of 25 mg/m2 or 30 mg/m2 (per local prescribing 
information) over 10 minutes or per institutional standard as an IV infusion on Days 1 and 8 
followed by cisplatin at a dose of 75 mg/m² as a 120-minute or per institutional standard IV 
infusion on Day 1 only, of a 3-week treatment cycle for up to 3 cycles. 
Dosing calculations for vinorelbine 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. Doses of vinorelbine and/or cisplatin may be 
interrupted, delayed, reduced, 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 8.1.1.2. Criteria to resume treatment can be found in Section 8.1.2.2.
See below for the details regarding administration of cisplatin. 
Docetaxel/Cisplatin
Docetaxel will be administered at a dose of 60 mg/m2 or 75 mg/m2 (per local prescribing 
information) as a 60 minute or per institutional standard IV infusion on Day 1 followed by cisplatin 
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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 3 cycles. 
Dosing calculations for docetaxel 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. Dose modifications for toxicity will be performed 
according to Section 7.4.1. Dose delay criteria can be found in Section 7.4.2.3, and dose 
discontinuation criteria can be found in Section 8.1.1.3. Criteria to resume treatment can be found 
in Section 8.1.2.3.
See below for the details regarding administration of cisplatin. 
Premedications for use with docetaxel: Premedication with corticosteroids will be given to 
participants receiving docetaxel. The recommended premedication per the USPI and SmPC is 
dexamethasone 8 mg PO twice daily given one day before, on the day of, and one day after 
administration of chemotherapy. For institutions that have established an equivalent premedication 
regimen consistent with local docetaxel labeling, such premedication regimens will be permitted.
Gemcitabine/Cisplatin (Squamous histology only)
Participants will receive gemcitabine at a dose of 1000 mg/m2 or 1250 mg/m2 (per local prescribing 
information) as a 30 minute or per local institutional standard IV infusion on Days 1 and 8 followed 
by cisplatin 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 3 cycles. Prolonged gemcitabine infusions > 60 
minutes and/or administration more frequent than weekly has been associated with increased 
toxicity. 
Dosing calculations for gemcitabine 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.
Doses of gemcitabine and/or cisplatin 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 8.1.1.2. Criteria to resume treatment can be found in 
Section 8.1.2.2.
See below for the details regarding administration of cisplatin. 
Pemetrexed/Cisplatin (non-Squamous histology only)
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 3 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. 
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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 8.1.1.2. 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. 
See below for the details regarding administration of cisplatin. 
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 3 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.
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 8.1.1.2. Criteria to resume treatment can be found in 
Section 8.1.2.2.
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 diphenydramine 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.
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nivolumab
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. 
Cisplatin
Cisplatin 75 mg/m2 as a 120 minute or per institutional standard IV infusion will be administered 
to participants as the second infusion. Dosing calculations for cisplatin 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.
Pretreatment hydration for cisplatin can follow local standard of care or use 1 to 2 liters of fluid 
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. 
All participants who will be receiving cisplatin should have audiometric testing performed prior 
to initiation of therapy and prior to subsequent doses of cisplatin, as per local or institutional 
standards of care. Participants considered to be at higher risk for ototoxicity with cisplatin have 
the option to receive carboplatin-based chemotherapy regimen after discussion with the Medical 
Monitor. 
For participants who are unable to tolerate cisplatin, the reasons for intolerability should be 
documented. If the investigator would like to use a carboplatin-based regimen, the investigator 
should discuss this with and obtain approval from the Medical Monitor prior to utilization, except 
for opting for carboplatin plus paclitaxel. 
Carboplatin
Carboplatin will be administered at a dose of AUC 5 or 6 as a 30-minute or as per institutional 
standard IV infusion, on Day 1 of each 3-week cycle.
Carboplatin should be given following gemcitabine, docetaxel, vinorelbine or pemetrexed on Day 
1 of each cycle, and the carboplatin dose will be calculated using the Calvert formula as follows:
•
Carboplatin dose (mg) will be calculated using the Calvert formula as follows = Target AUC 
x [(CrCl (mL/min) + 25]
•
Creatinine clearance (CrCl) calculation is based on the Cockroft-Gault formula and should 
include the most recent serum creatinine and most recent weight. NOTE: If calculation of the 
CrCl by the Cockroft-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.
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For All Arms Containing Chemotherapy:  
Participants should begin study treatment within 7 calendar days of randomization. Doses of 
chemotherapy may be interrupted, delayed, or discontinued depending on how well the 
participants tolerates the treatment. If a dose is delayed for any reason, participants should be dosed 
no later than 7 days following a planned dose on any arm. 
If more than 7 days delay is needed for any reason, the intended dose should be skipped. If a 
participant receiving chemotherapy on a Day 1 and Day 8 schedule (ie, cisplatin/gemcitabine) is 
unable to receive Day 1 of chemotherapy but recovers in time to receive the Day 8 dose, the Day 8 
dose of chemotherapy may be administered.
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.
7.2
Method of Treatment Assignment
CA209816 is an open-label, randomized trial. Participants with Stage IB (≥4 cm), II and IIIA (N2) 
considered resectable will be eligible to participate. After the participant’s initial eligibility is 
established and informed consent has been obtained, the participant must be enrolled into the study 
by calling the IRT to obtain a participant number. Every participant that signs the informed consent 
form must be assigned a participant number in IRT. Specific instructions for using IRT will be 
provided to the investigational site in a separate document. 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
•
Date of birth, where applicable by local regulations
•
Gender at birth
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be ready to be 
randomized through IRT. PD-L1 expression data will be transferred directly from analyzing lab to 
IRT. The following information is required for participant randomization:
•
Participant number
•
Date of birth, where applicable per local regulations
•
Stage of disease (IB, IIA, IIB or IIIA)
•
PD-L1 status
•
Gender
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Participants meeting all eligibility criteria will be stratified according to PD-L1 status into 
2 categories (≥1% and < 1% or not evaluable/indeterminate). Enrollment of participants with not 
evaluable or indeterminate PD-L1 status will be capped at 10%. Participants will also be stratified 
based disease stage (IB/II vs IIIA) and gender.
The exact procedures for using the IRT will be detailed in the IRT manual.
7.3
Blinding
This is an open-label study; blinding procedures between participants and investigators are not 
applicable. The BIPR and BICR will be blinded.  
7.4
Dosage Modification
7.4.1
Dose Reductions for Platinum Doublet Chemotherapy 
Dose reductions of platinum 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 doublet chemotherapy regimen are not linked and may 
be adjusted independently as summarized below.
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Table 7.4.1-1:
Dose Modifications of Chemotherapeutic Agentsa
Dose Level
Vinorelbine
Docetaxel
Gemcitabine
Pemetrexed
Cisplatin
Carboplatin
Paclitaxel
Starting dose
25mg/m2 or 
30 mg/m2
60 mg/mg2 or 
75 mg/m2
1000 mg/m²  or 
1250 mg/m² 
500 mg/m²
75 mg/m²
AUC 5 or 6
175 or 200 mg/m²
First dose reduction
75% of 
starting dose
75% of starting 
dose
75% of starting 
dose
75% of starting 
dose
75% of 
starting dose
AUC 4 or 5
150 mg/m²
Second dose reduction
50% of the 
starting dose
50% of starting 
dose
50% of the 
starting dose
50% of the 
starting dose
50% of the 
starting dose
AUC 3 or 4
100 mg/m²
Third dose reduction
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
a Follow local regulations if they are different than what appears in this table. 
Any participants 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.
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7.4.1.1
Platinum 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 doublet 
chemotherapy are relative to that of the preceding administration. Generally, both chemotherapy 
agents in the platinum 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
Vinorelbine
Gemcitabine
Pemetrexed
Cisplatin
Carboplatin
Paclixatel
Neutrophil Count Decreased
Grade 4
(< 500/mm3 or
< 0.5 x 109/L)
Reduce one dose 
level and consider 
prophylactic 
G-CSF in 
subsequent cycles
Reduce one dose 
level and consider 
prophylactic 
G-CSF in 
subsequent cycles
Reduce one dose 
level and 
consider 
prophylactic 
G-CSF in 
subsequent 
cycles
Reduce one dose 
level and 
consider 
prophylactic 
G-CSF in 
subsequent 
cycles
Reduce one dose 
level and consider 
prophylactic 
G-CSF in 
subsequent cycles
Reduce one dose 
level and consider 
prophylactic G-CSF 
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
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
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
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
Reduce one dose 
level
Grade 4
(Life threatening 
consequences)
Hold drug
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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Dose Modifications for Hematologic Toxicity for Docetaxel: Doses of docetaxel will be 
modified for participants who experience docetaxel-related events of febrile neutropenia, 
neutrophils < 500 cell/mm³ for > 7 days during docetaxel treatment. Participants should have 
treatment delayed according to Section 7.4.2.3 and then resumed at 1 dose level reduction (75% 
of starting dose). Should these AEs occur after the first dose reduction, then a second dose 
reduction to (50% of starting dose) is permitted. If a third dose reduction is required, then the 
participants should discontinue docetaxel treatment. 
7.4.1.2
Platinum Doublet Chemotherapy - Dose Reductions for Non-
Hematologic Toxicities
Dose adjustments for platinum doublet chemotherapy for non-hematologic toxicities during 
treatment are described in Table 7.4.1.2-1. All dose reductions should be made based on the worst 
grade toxicity. Participants experiencing any of the toxicities detailed in Table 7.4.1.2-1 during the 
previous cycle should have their chemotherapy delayed until retreatment criteria are met (per 
Section 8.1.2.2) and then reduced for all subsequent cycles by 1 dose level or discontinued as 
appropriate. Dose levels for the 2 drugs in the platinum-doublet chemotherapy regimen are not 
linked and may be reduced independently, as summarized in Table 7.4.1.2-1.
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Table 7.4.1.2-1:
Dose Modifications for Non-hematologic Toxicitya,b
Toxicity
Vinorelbine
Gemcitabine
Pemetrexed
Cisplatin
Carboplatin
Paclitaxel
Febrile Neutropenia
Grade ≥3
Reduce one 
dose level
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
Reduce one dose 
level
Reduce one dose 
level
No change
No change
Reduce one dose 
level
Allergic reactionc
Grade ≥3
Reduce one 
dose level
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Neuropathy
Grade 2
No Change
No change
No change
Reduce one dose 
leveld
No change
Reduce one dose 
level
Neuropathy
Grade ≥3
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Discontinue
Calculated creatinine 
clearance
< 50 mL/min
No change
No change
Discontinue if 
creatinine 
clearance < 45 
mL/min
Discontinue
Discontinue if 
creatinine 
clearance 
< 20 mL/min
No change
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
Adjust as 
medically indicated
a If local standard for dose adjustments differ from those outlined, please discuss with the Medical Monitor.
b Please see local drug label for additional adjustments. 
c Only the drug(s) causing the hypersensitivity reaction or acute infusion reaction (≥Grade 3) require(s) discontinuation. All other drugs may be continued.
d When given with pemetrexed, cisplatin should be reduced 2 dose levels (ie, by 50% for Grade 2 neuropathy. 
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Participants receiving docetaxel who develop Grade ≥3 peripheral neuropathy, or who otherwise 
meet criteria specified in Section 8.1.1.3, should discontinue docetaxel treatment.
Dose Modifications for Non-hematologic Toxicity for Docetaxel: Doses of docetaxel will be 
modified for participants who experience docetaxel-related events of severe or cumulative 
cutaneous reactions or other Grade 3/4 non-hematological toxicities during docetaxel treatment. 
Participants should have treatment delayed according to Section 7.4.2.3 and then resumed at 1 dose 
level reduction (75% of starting dose). Should these AEs occur after the first dose reduction, then 
a second dose reduction to (50% of starting dose) is permitted. If a third dose reduction is required, 
then the participants should discontinue docetaxel treatment. 
7.4.2
Dose Delay
If any agent is delayed > 7 days, the dose should be skipped, and the participant should resume 
treatment at the next scheduled dose if criteria to resume treatment (Section 8.1.2) for the 
appropriate arm are met. If the last dose of study drug is delayed >7 but < 11 days, while it is 
recommended that this dose be skipped, if the investigator feels that it is appropriate to administer 
the last dose, discuss with the Medical Monitor before administering the last dose of study drug.
7.4.2.1
Nivolumab Dose Delay Criteria
Nivolumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related adverse event, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related adverse event
•
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 8.1.1.1)
•
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 Doublet Chemotherapy
Dosing of both drugs in the platinum 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 
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•
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. 
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. Participants receiving gemcitabine with cisplatin or carboplatin should 
omit the Day 8 gemcitabine dose for any of the following on Day 8 of any cycle:
•
ANC < 1,000/mm3
•
Platelets < 75,000/mm3
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 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 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 8.1.2.2 or Section 8.1.2.3).
7.4.2.3
Docetaxel Dose Delay Criteria
Docetaxel administration should be delayed for the following:
•
Any Grade ≥2 non-skin, drug-related adverse event, with the following exceptions:
−
Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay
•
Any Grade 3 skin, drug-related adverse event
•
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, neutrophil count, AST, ALT, or total bilirubin:
−
Grade 3 lymphopenia does not require dose delay
−
Should not be given if neutrophil counts are < 1500 cells/mm3
−
Should not be given if total bilirubin > upper limit of normal (ULN), or if AST and/or ALT 
> 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN
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•
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication
Subsequent dose reductions may be required as per Section 7.4.1.
Participants receiving docetaxel may receive growth factors (including G-CSF and erythropoietin) 
at the discretion of the investigator.
7.4.3
Treatment of Nivolumab- and Ipilimumab-related Infusion Reactions
Since nivolumab and ipilimumab contain 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, hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 
or 4 infusion reactions should be reported within 24 hours to the study Medical Monitor and 
reported as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI 
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 required 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/ipilimumab 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.
•
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 infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
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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/ipilimumab. Begin an IV infusion of normal 
saline and treat the participant 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).
7.5
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 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).
Handling of chemotherapy should be according to local prescribing information.  
Please refer to the current version of the Investigator Brochures (IBs) and/or the Pharmacy Manual 
for complete storage, handling, and preparation information. Further guidance and information for 
final disposition of unused study treatment are provided in Appendix 7 and the Pharmacy Manual. 
7.5.1
Retained Samples for Bioavailability / Bioequivalence
At the time of receipt of the investigational product by the investigator or designee’s, BMS will 
specify the appropriate number of containers or units to select for retention, the conditions of 
sample storage, required duration of sample retention, and provisions for returning or disposing of 
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the investigational product. When samples are selected, containers or units should be placed in 
packaging with a tamper evident seal provided by BMS. Package labeling should clearly identify 
the contents as bioavailability/bioequivalence (BA/BE) samples and state that the investigational 
product should be stored in the restricted area with limited access.
7.6
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and eCRF.
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 7.7.3)
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of NSCLC)
•
Investigators should refer to the local product labeling for the chemotherapy drugs selected for 
use in Arm B and Arm C and for additional prohibited and restricted concomitant medications.
•
Caution should be used regarding the use of herbal medication, as there may be as yet unknown 
interactions with nivolumab and ipilimumab. Discontinuation of the use of herbal medications 
prior to the study enrollment is encouraged.  
•
Live vaccines (eg, yellow fever, MMR, nasal flu vaccine, chicken pox [varicella]) should be 
avoided while receiving neoadjuvant or adjuvant study drug
•
Avoid using concomitant strong CYP3A4 inhibitors or inducers with docetaxel, vinorelbine, 
or paclitaxel. Avoid using concomitant strong CYP2C8 inhibitors or inducers with paclitaxel.  
Consult the local prescribing information for further guidance. 
•
Avoid the concomitant administration of substances that are also tubularly secreted (eg, 
probenecid) which could potentially result in delayed clearance of pemetrexed.
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.
It is the local imaging facility’s responsibility to determine, based on participants attributes 
(eg, allergy history, diabetic history and renal status), the appropriate imaging modality and 
contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participants 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. 
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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. MRI 
contrast should not be given to this population. In addition, participants are excluded from MRI if 
they have tattoos, metallic implants, pacemakers, etc. The ultimate decision to perform MRI in an 
individual participant in this study rests with the site radiologist, the investigator, and the standard 
set by the local Ethics Committee.
7.7.3
Permitted Therapy
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.
7.8
Treatment After the End of the Study
At the end of the study period, 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 lung cancer treatment.
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. Participant should notify the investigator of the decision to withdraw 
from future follow-up in writing, whenever possible, and this should be documented in the 
medical records.
•
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 Company (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
Refer to the Schedule of Activities for data to be collected at the time of neoadjuvant treatment 
discontinuation and subsequent study procedures and for any further evaluations that can be 
completed.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes pregnant 
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during a clinical trial, the study treatment must be discontinued immediately. In most cases, the 
study treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Please call the BMS Medical Monitor within 24 hours of 
awareness of the pregnancy. 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.
All participants who discontinue study treatment should comply with protocol specified 
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.
8.1.1
Study Treatment Discontinuation Criteria
Doses that are missed or delayed by > 7 days will not be replaced, and participants should proceed 
to surgery within the indicated timelines. Participants who discontinue their assigned study 
treatment prematurely will not be allowed to receive subsequent neoadjuvant therapy, and 
participants should proceed to surgery within the indicated timelines.
In Arm C, nivolumab and platinum doublet chemotherapy can be discontinued independently 
based on their discontinuation criteria.  
8.1.1.1
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 adverse event lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-related 
uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, 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. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
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−
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
♦Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:
o
Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
•
* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study drug(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
o
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
•
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 of any study drug for > 6 weeks from the previous dose 
requires discontinuation of that drug(s) with the following exception:
−
Dosing delays lasting > 6 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 > 6 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.
•
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.
8.1.1.2
Platinum Doublet Chemotherapy Dose Discontinuation
Except where specified below, both chemotherapy drugs in the platinum doublet chemotherapy 
regimen should be discontinued for any of the following:
•
Any Grade ≥3 peripheral neuropathy
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•
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, and the platinum agent may be switched to carboplatin, 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 > 6 weeks from the previous 
dose requires discontinuation of that drug(s) with the following exception:
−
Dosing delays lasting > 6 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 > 6 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.
•
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 
doublet chemotherapy dosing. Investigators should consult local labeling for the chemotherapy 
drugs being administered to any given participant for additional guidance on dose 
discontinuation.
For participants in Arms C, if the investigator is unable to determine whether an adverse event is 
due to nivolumab or to platinum doublet chemotherapy, then all drugs must be discontinued.
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8.1.1.3
Docetaxel Dose Discontinuation
Docetaxel treatment should be permanently discontinued for the following:
•
Any ≥Grade 3 peripheral neuropathy
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for laboratory abnormalities:
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except
♦Grade 3 drug-related thrombocytopenia associated with bleeding requires 
discontinuation.
♦Any drug-related liver function test (LFT) abnormalities that meets the following 
criteria require discontinuation: 
o
AST or ALT > 5 - 10x ULN for > 2 weeks
o
AST or ALT > 10x ULN
o
Total bilirubin > 5x ULN
o
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN
•
Any Grade 4 drug-related adverse event including laboratory abnormalities except for the 
following events which do not require discontinuation:
−
Grade 4 neutropenia >7 days despite 2 prior docetaxel reductions requires discontinuation
−
Grade 4 lymphopenia or leukopenia does not require discontinuation
−
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 does not require discontinuation.
•
Any dosing interruption lasting > 6 weeks with the following exceptions:
−
Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS Medical Monitor/Study Director. Prior to re-initiating treatment in 
a participant with a dosing interruption lasting > 6 weeks, the BMS Medical Monitor/Study 
Director must be consulted. Tumor assessments should continue as per protocol even if 
dosing is interrupted. 
8.1.2
Criteria to Resume Treatment
8.1.2.1
Criteria to Resume Nivolumab Treatment
Participants may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, 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.
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•
Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 8.1.1.1) should have treatment permanently discontinued. 
•
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.
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor. 
Please refer to the Management Algorithms in Appendix 4. 
8.1.2.2
Criteria to Resume Platinum Doublet Chemotherapy Dosing
•
Participants may resume treatment with platinum doublet 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 reinitiating treatment, then treatment should be delayed, 
and the participant should be re-evaluated weekly or more frequently as clinically indicated
•
When resuming platinum doublet chemotherapy treatment, please follow the dose reduction 
recommendations in Section 7.4.1
8.1.2.3
Criteria to Resume Treatment with Docetaxel
Participants may resume treatment with docetaxel 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 
•
Participants with decreased neutrophil counts, or with elevations in total bilirubin, AST or ALT 
must meet criteria for resuming treatment according to the boxed warning contained within the 
docetaxel Prescribing Information
•
Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 8.1.1.3) should have treatment permanently discontinued
When resuming docetaxel treatment, please follow the dose reduction recommendations noted in 
Section 7.4.1.
8.1.3
Post Study Follow-up
In this study, EFS and pCR are multiple primary endpoints. 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 
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outcome and/or survival follow-up data as required and in line with Section 2 until death or the 
conclusion of the study.
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window (Table 2-3 and Table 2-4). 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 participation 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. 
•
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.
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•
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.
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 treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
The primary efficacy assessments will be EFS and pCR, and a key secondary endpoint is MPR 
rate (defined as number of randomized participants with ≤10% residual tumor in lung and lymph 
nodes as evaluated by BIPR, divided by the number of randomized participants for each treatment 
group), which will be assessed by BIPR at the time of definitive surgery. Surgery should be 
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performed within 6 weeks after completing up to 3 cycles (last dose) of neoadjuvant treatment. 
The following lymph node levels should be sampled at the time of definitive surgery:
•
For right-sided tumor: Levels 4, 7, 9R, 10R and 11 R
•
For left-sided tumor: Levels 5 and/or 6; 7, 9L, 10L, and 11L 
Tumor and lymph node collection from definitive surgical resection and sampling of fresh tumor 
sample in RNAlater for biomarker studies (as applicable dependent on the size of residual tumor) 
is mandatory on the day of surgery. Processing of the remainder of the specimens for 
histopathologic analysis should be performed within 72 hours of the procedure. Sections will be 
used for central pathology review assessing pCR and MPR. Any tumor, tumor bed, or lymph 
node specimens that are reviewed locally must be submitted for central pathology review.
Gross examination on the entire specimen should be performed which includes all tumor, 
associated lymph node tissue, and uninvolved parenchyma. The specimen should be sectioned at 
0.5 cm intervals, and blocks should be submitted for the full cross section for every other 0.5 cm 
interval. When estimating viable tumors, in situ carcinoma should not be included. For very large 
tumors with no gross evidence of response, a minimum of 1 slide/cm is required for assessment of 
major pathologic response. Sites are strongly encouraged to submit the diagnostic H&E stained 
slides assessed by the local pathologist for central pathology review. The final diagnostic 
pathology report must be submitted with the slides and blocks for review. Tumor sample 
acquisition guidelines and submission process will be outlined in the study Laboratory Manual to 
be provided by the central lab.
Radiographic assessments will be performed with the Schedule Activities in Table 2-2.
Disease recurrence, change in tumor measurements, and tumor response will be assessed by the 
BICR using the RECIST 1.1 criteria. 
9.1.1
Imaging Assessment for the Study
Study evaluations will take place in accordance with the Schedule of Activities. 
Screening (baseline) assessments are to be performed within 28 days prior to randomization. 
PET/CT with contrast should be assessed at baseline. A separate CT with contrast of the chest, 
abdomen, and other suspected areas (as well as the PET/CT) is required if the CT component of a 
PET/CT is not of sufficient diagnostic quality for RECIST 1.1 measurements. Participants with 
suspected brain metastases and all those with stage II disease or higher should be evaluated with 
MRI/CT of the brain pre- and post-contrast. Tumor assessments should be performed following 
RECIST 1.1 criteria.  
A preoperative PET/CT with contrast should be acquired within 14 days of surgery. A separate 
CT with contrast of the chest, abdomen, and other suspected areas (as well as the PET/CT) is 
required if the CT component of a PET/CT is not sufficient diagnostic quality for RECIST 1.1 
measurements. 
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Postoperative assessments with CT with contrast of the chest including the adrenal glands and CT 
or MRI of other additional suspected/known sites of disease. The first tumor assessment should 
occur 12 weeks (± 7 days) after definitive surgery per RECIST 1.1 and then should occur every 
12 weeks (± 7 days) for 2 years (104 weeks), then every 6 months (24 weeks ± 7 days) for 3 years, 
and then every year (52 weeks ± 7 days) for 5 years or until disease recurrence or progression 
confirmed by BICR. The same imaging method should be used as the screening/baseline. For 
participants who did not receive definitive surgery AND without tumor progression confirmed by 
BICR, the first tumor assessments should be done 12 weeks (± 7 days) following the tumor 
restaging, subsequent tumor assessments will be performed with the same frequency and methods 
as described for those having received definitive surgery; in case the planned initiation of 
subsequent anti-cancer therapy is within 12 weeks of restaging, every effort should be made to 
repeat tumor assessment prior to subsequent anti-cancer therapy.
Images will be submitted to the third-party radiology vendor for central review as they are 
performed on an ongoing basis. Sites will be trained prior to scanning the first study participant. 
Image acquisition guidelines and submission process will be outlined in the study Imaging Manual 
to be provided by the radiology vendor. 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 judgement. 
9.1.2
Patient-reported Outcomes
The evaluation of health-related quality of life (QoL) is an increasingly important aspect of a 
clinical efficacy in oncology trials. Such data provides an understanding of the impact of treatment 
from the participants’ perspective and offers insights into the patient experience that may not be 
captured through physician reporting. Generic health-related QoL scales additionally provide data 
necessary in calculating utility values for health economic models. 
Participants will be asked to complete the 3-level version of the EQ-5D before any clinical 
activities are performed during on-treatment clinic visits, at Post-neoadjuvant Visits 1 and 2, and 
at designated visits or during phone calls during the Survival Follow-up Phase. The questionnaire 
will be provided in the participants preferred language and may be administered by telephone 
during the Survival Follow-up Phase. A standardized script will be used to facilitate telephone 
administration of the EQ-5D-3L. Table 2-2, Table 2-3, and Table 2-4 provide information 
regarding the timing of participant-reported outcomes assessments.
The EQ-5D-3L is 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, 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 
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value to society of his or her current health. Such preference-weighting systems have been 
developed for Japan, UK, US, Spain, Germany, and numerous other populations. In addition, the 
EQ-5D-3L includes a visual analog scale 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 is 
available for use in over 150 languages.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 8.
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. 
Contacts for SAE reporting specified in Appendix 8.
Immune-mediated adverse events (IMAEs) 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.
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 the last dose of neoadjuvant therapy or 90 days after surgery, whichever is longer, 
and 30 days after the last dose of adjuvant therapy, at the time points 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.
The Investigator Brochure (IB) represents the Reference Safety Information to determine 
expectedness of serious adverse events for expedited reporting. 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.
All SAEs must be collected that occur during the screening period and 100 days after the last dose 
of neoadjuvant therapy or 90 days after surgery, whichever is longer, and 30 days after the last 
dose of adjuvant therapy. 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 eCRF section.
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•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 8. 
•
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.
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 8.
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. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
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 8)
•
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 non-serious AEs of special interest (as defined in 
Section 9.2 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).
Further information on follow-up procedures is given in Appendix 8.
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.
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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.
All SAEs must be collected that occur during the screening period and 100 days after the last dose
of last dose of neoadjuvant therapy or 90 days after surgery, whichever is longer, and 30 days after 
the last dose of adjuvant therapy. For participants randomized/assigned to treatment and never 
treated with study drug, SAEs should be collected for 30 days from the date of randomization. 
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 
5 half-lives 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 8.
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.
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 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
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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 8 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),
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.
Definition of immune-mediated adverse events (IMAEs) 
Immune-mediated AEs are specific events (that include pneumonitis, diarrhea/colitis, hepatitis, 
nephritis/renal 
dysfunction, 
rash, 
and 
endocrine 
[adrenal 
insufficiency, 
hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis]) for which 
participants received immunosuppressive medication for treatment of the event, with the exception 
of endocrine events (hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, diabetes mellitus, 
adrenal insufficiency), which are included regardless of treatment since these events are often 
managed without immunosuppression. 
Immune-mediated AEs are specific events (or groups of PTs describing specific events) that 
include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, endocrine 
(adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and 
hypophysitis), and other specific events, considered as potential immune-mediated events by 
investigator, that meet the definition summarized below: 
•
those occurring within 100 days of the last dose 
•
regardless of causality
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•
with no clear alternate etiology based on investigator assessment, or with an immune-mediated 
component 
•
treated 
with 
immune-modulating 
medication 
(Of 
note, 
adrenal 
insufficiency, 
hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis are 
considered IMAEs regardless of immune-modulating medication use, since endocrine drug 
reactions are often managed without immune-modulating medication). 
•
Table 9.2.8-1 below provides a summary of the IMAEs category and their respective preferred 
terms.
Table 9.2.8-1:
Preferred Terms Included in Analysis of IMAEs to Support 
Warnings and Precautions
IMAE Category
Preferred terms included under IMAE Category
Pneumonitis
Pneumonitis, interstitial lung disease
Diarrhea/Colitis
Diarrhea, colitis, enterocolitis
Hepatitis
Hepatotoxicity, hepatitis, hepatitis acute, autoimmune hepatitis, AST 
increased, ALT increased, bilirubin increased, ALP increased
Adrenal insufficiency
Adrenal insufficiency
Hypothyroidism/Thyroiditis
Hypothyroidism, thyroiditis
Thyroiditis acute (collapsed with thyroiditis for frequency), Autoimmune 
thyroiditis (collapsed with thyroiditis for frequency)
Hyperthyroidism
Hyperthyroidism
Hypophysitis
Hypophysitis
Diabetes mellitus
Diabetes mellitus, diabetic ketoacidosis
Nephritis and renal dysfunction
Nephritis, nephritis allergic, tubulointerstitial nephritis, acute renal failure, 
renal failure, increased creatinine
Rash
Rash, rash maculopapular
9.2.9
Management Algorithms
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered 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
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•
Skin
•
Neurological
•
Myocardial
The above algorithms are found in the Nivolumab Investigator Brochure and Appendix 4. 
9.3
Overdose
All occurrences of overdose must be reported as SAEs (see Section 9.2).
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
At screening, a medical history will be obtained to capture relevant underlying conditions. The 
screening examinations should include weight, height, ECOG Performance Status, blood pressure 
(BP), heart rate (HR), temperature, and oxygen saturation by pulse oximetry (at rest). Screening 
assessments and screening laboratory assessments should be performed in accordance with Table
2-1.
Pregnancy tests for WOCBP must be performed within 24 hours prior to the initial administration 
of study drug. 
Participants will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase as well as during the first 2 safety (neo-adjuvant) 
follow-up visits, for 90 days after surgery, and for 30 days after adjuvant therapy. Once participants 
reach the Survival Follow-up Phase, either in-person visits or documented telephone calls/email 
correspondence to assess the participant’s status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.
The start and stop time of the study therapy infusions and any interruptions or infusion rate 
reductions should be documented. 
Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate 
non-serious or serious adverse event page.
On treatment local laboratory assessments are to be completed within 3 calendar days prior to 
dosing in accordance with Table 2-2.
On treatment pregnancy tests should be performed as per the schedule in the Schedule of Activity 
Table.
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 
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induced liver enzyme evaluations) will be monitored during the Neoadjuvant and Adjuvant 
Follow-up Phases 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 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 treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.4.1
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
Please refer to the Schedule of Activities in Section 2 for details related to the required laboratory 
assessment. 
9.4.2
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 ipilimumab PK assessment will be collected from participants in Arm A only. Samples 
for nivolumab PK assessments will be collected from participants in Arm A and Arm C described 
in Table 9.5-1. Treatment assignments will be released to the bioanalytical laboratory in order to 
minimize unnecessary analysis of samples. 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 sampling should be adjusted 
accordingly. Further details of sample collection, processing, and shipment will be provided in the 
laboratory procedures manual. PK samples will be analyzed for nivolumab and ipilimumab by a 
validated ligand binding assay. 
Table 9.5-1:
Pharmacokinetic (PK) Sample Collections for Nivolumab and 
Ipilimumab - Arm A and Arm C
Study Day 
1 Cycle = 2 weeks
for Arm A
and
1 Cycle = 3 weeks
for Arm C
Event
(Relative to Dosing)
Hour
Time
(Relative to Dosing)
Hour: Min
Pharmacokinetic 
Blood Sample for 
Nivolumab
Pharmacokinetic 
Blood Sample for 
Ipilimumaba
C1D1
0.5 (EOI) b
00:30
X
X
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Table 9.5-1:
Pharmacokinetic (PK) Sample Collections for Nivolumab and 
Ipilimumab - Arm A and Arm C
Study Day 
1 Cycle = 2 weeks
for Arm A
and
1 Cycle = 3 weeks
for Arm C
Event
(Relative to Dosing)
Hour
Time
(Relative to Dosing)
Hour: Min
Pharmacokinetic 
Blood Sample for 
Nivolumab
Pharmacokinetic 
Blood Sample for 
Ipilimumaba
C2D1
Predosec
00:00
X
X
C3D1
Predosec
00:00
X
X
a PK blood samples for ipilimumab were be collected from Arm A participants only.
b EOI: End of Infusion. This sample should be taken immediately (ie, within 5 minutes) prior to stopping ipilimumab 
infusion in Arm A or nivolumab infusion in Arm C. 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.
c Predose sample should be collected just before the administration of nivolumab (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.
9.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7
Pharmacogenomics
Not applicable.
9.8
Biomarkers
9.8.1
Additional Research Collection
Additional research retention are mandatory for all study participants, except where prohibited by 
local laws or regulations, ethics committees, institutional requirements, or where a waiver is 
provided by BMS or their designee. Where one or more of these exceptions occurs, participation 
in the additional research should be encouraged, but will not be a condition of overall study 
participation. Study participants may opt out of the additional research. 
This protocol will include residual sample storage for additional research (AR).
This retention for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb Company 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 participants. This may also include genetic/genomic exploration aimed at 
exploring disease pathways, progression and response to treatment etc. 
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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 to ensure the 
research supports appropriate and well-defined scientific research activities.
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; no researcher will have access to the key, which is 
securely held by the Investigator at the clinical site, so that there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided to the site in the procedure 
manual.
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9.8.1.1
Tumor Tissue Specimens
Archival (slides [blocks/slides] ≤3 months) FFPE tumor tissue collected at initial diagnosis is 
required for study entry. Samples will be sent to a third party to stain and score for PD-L1 
expression using the PD-L1 IHC 28-8 pharmDx kit (Dako). Stained tissue samples will be assessed 
by a pathologist at a central lab identified by the Sponsor and scored as PD-L1 expressing if 
membrane staining is observed in ≥1% tumor cells among a minimum of 100 evaluable tumor 
cells. If an archived specimen is not available, a fresh tumor biopsy will be collected. Additional 
tumor will be collected during surgical resection, which will be after 3 cycles of treatment in each 
arm. A third (optional) biopsy will be collected at the time of disease progression. The third biopsy 
will not be collected in China.
Collected tumors may be further analyzed by additional modalities
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9.8.2
Safety Analyses
Endpoint
Statistical Analysis Methods
Exploratory
Proportion of delayed or canceled surgery, duration of surgery, length of hospital stay, surgical 
approach, incidence of AE/SAE associated with surgery, including pneumonitis, ARDS, re-
admission to the Intensive Care Unity, atrial fibrillation or other supraventricular tachycardia up to 
90 days after surgery will be summarized by treatment group using descriptive statistics.
The safety and tolerability objective will be measured by the incidence of adverse events, serious 
adverse events, deaths, and laboratory abnormalities.
The safety analysis will be performed in all treated participants. The rate of treatment-related 
selected AEs and SAEs in each treatment arm will be summarized. Descriptive statistics of safety 
will be presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 by treatment arm. All treatment-emergent 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, thyroid function and renal function will be summarized using worst grade per NCI 
CTCAE v 4.0 criteria.
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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
9.10
Other Assessments
9.10.1
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
•
Pulmonary function capacity (eg, FVC, FEV1, TLC, FRC, and DLco) 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 IB (≥4 cm), 
II or resectable IIIA (N2) 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) prior to randomization. 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 by segmentectomy or wedge resection will not be 
accepted. If mediastinoscopy was not performed preoperatively, it is expected that, at a minimum, 
mediastinal lymph node systematic sampling and evaluation will have occurred, though complete 
mediastinal lymph node dissection (MLND) is preferred. 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 or MLND locations are required:
•
For right-sided tumor: Levels 4, 7, 9R, 10R and 11 R
•
For left-sided tumor: Levels 5 and/or 6; 7, 9L, 10L, and 11L 
If there is clear documentation in the operative report or in a separately submitted addendum by 
the surgeon of exploration of the required lymph node areas, the participant will be considered 
eligible if no lymph nodes are found in those areas. 
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Participants should have a PET/CT scan with contrast of the base of the skull through the upper 
thigh performed within the 14 days prior to planned surgery to assess for clinical response. A 
separate CT with contrast of the chest, abdomen, and other suspected areas (as well as the PET/CT) 
is required if the CT component of a PET/CT is not of sufficient diagnostic quality of RECIST 1.1 
measurements. Surgery should be performed within 6 weeks of completing up to 3 cycles (last 
dose) of neoadjuvant treatment.
9.10.2
Post-surgical Evaluation:
The first tumor assessment should occur 12 weeks (±7 days) after definitive surgery per RECIST 
1.1. Afterwards, radiographic assessment will be performed every 12 weeks (± 7 days) for 2 years) 
following surgery, every 6 months (± 7 days) for 3 years, and then every year ( ±7 days) for 5 years 
or until recurrence or progression of disease is documented.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
The original study design (before Revised protocol 01) had two arms, with participants randomized 
in a 1:1 ratio to either neoadjuvant nivolumab plus ipilimumab or platinum doublet chemotherapy 
arm. Revised protocol 02 added a new, neoadjuvant nivolumab plus platinum doublet 
chemotherapy arm. When the third arm opens and as each site receives IRB/EC approval of revised 
protocol 02, the IRT will switch to a 1:1:1 randomization at the respective site.  Starting from that 
point on, the site will only enroll under revised protocol 02.
Revised protocol 03 withholds randomization into the arm of neoadjuvant nivolumab plus 
ipilimumab but continues randomizing eligible participants into either neoadjuvant nivolumab plus 
platinum doublet chemotherapy arm or platinum doublet chemotherapy arm in a 1:1 ratio. 
Approximately 350 participants (175 participants per arm) will be randomized between 2 arms 
neoadjuvant nivolumab plus platinum doublet chemotherapy or platinum doublet chemotherapy 
from 1:1:1 randomization in revised protocol 02 and 1:1 randomization in revised protocol 03. 
Participants already randomized in the original 2-arm part (neoadjuvant nivolumab plus 
ipilimumab vs neoadjuvant chemotherapy) and in the arm of neoadjuvant nivolumab plus 
ipilimumab in 3-arm part defined by revised protocol 02 will remain in trial and continue scheduled 
trial procedures. It is expected to have around 70 participants randomized in the original 2-arm 
part and approximately another 75 participants randomized in the arm of neoadjuvant nivolumab 
plus ipilimumab in the 3-arm part. It is estimated that there will be a total of approximately 
500 participants on the study.
Starting from 1:1:1 randomization, approximately 350 participants will be randomized to the 
2 arms neoadjuvant nivolumab plus platinum doublet chemotherapy or platinum doublet 
chemotherapy in a 1:1 ratio. The sample size of the study is calculated based on the primary 
endpoint of EFS and accounts for the multiple primary endpoints comparisons: pCR (per BIPR) 
and EFS (per BICR) with an initial alpha allocation of 0.01 and 0.04 respectively. Formal analyses 
of pCR and EFS may be conducted at different timepoints. The fallback method will be used, ie, 
if the pCR comparison between Arm C and Arm B is statistically significant, then 0.01 alpha 
allocated to pCR will be passed to the EFS comparison for Arm C vs Arm B and the EFS 
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comparison will be conducted at the alpha = 0.05 level. If the pCR comparison between Arm C 
and Arm B is not statistically significant, then the EFS comparison for Arm C vs Arm B will be 
conducted at the alpha = 0.04 level. In addition, if EFS is significant, OS will be tested 
hierarchically at the same level as EFS.
10.1.1
Pathologic Complete Response (pCR)
The primary analysis of pCR will be performed after 350 randomized participants in neoadjuvant 
nivolumab plus platinum doublet chemotherapy and platinum doublet chemotherapy (from start 
of 1:1:1 randomization) have an opportunity for surgery. 
Assuming an accrual rate of 10 participants (all comers) a month between Arms B and C during 
1:1:1 randomization (about 10 months), and 15 participants per month during 1:1 randomization, 
it is anticipated that the 350 participants will be randomized in approximately 27 months. The pCR 
endpoint is expected to be analyzed after about 30 months from start of 1:1:1 randomization.
The sample size of 350 participants is based on the EFS endpoint. With this sample size, assuming 
pCR rate of 10% on Arm B chemotherapy and 30% on Arm C nivolumab plus chemotherapy, 
respectively, the 350 participants will provide more than 90% power to detect an odds ratio of 
3.857 with a 2-sided type I error of 1%.
It is estimated that there will be about 110 subjects randomized to Arm A neoadjuvant nivolumab 
plus ipilimumab before revised protocol 03 is implemented. Assuming true pCR rate is 15% on 
this arm, there is 95% probability that the lower bound of 95% exact confidence interval of pCR 
is above 5%.
10.1.2
Event Free Survival (EFS)
For the formal comparison of EFS as assessed by BICR for nivolumab plus platinum doublet 
chemotherapy (Arm C) vs platinum doublet chemotherapy (Arm B), only participants randomized 
from 1:1:1 randomization in revised protocol 02 and 1:1 randomization in revised protocol 03 will 
be counted. 
The power details are provided below using alpha = 0.05 (0.01 alpha from the pCR endpoint 
fallback to the EFS comparison), considering this protocol amendment (protamend07) occurs after 
the statistically significant pCR final analysis but before any analysis of EFS or OS. In addition, 
the accrual reflects 358 participants who were actually concurrently randomized in Arms B and C. 
A total of 185 events ensure that an overall 2-sided 5% significance level sequential test procedure 
with 2 interim analyses occurring after 148 events (80% of events required for final analysis) and 
167 events (90% of events required for final analysis) in 358 randomized participants will have 
82% power assuming an HR of 0.65 between the 2 arms. Considering a piecewise exponential 
distribution with control hazard rates of 0.028 before 20 months, 0.017 between 20 months and 40 
months, 0.014 between 40 and 60 months, and 0.008 after 60 months, and a dropout rate of 
approximately 20%, it is anticipated the EFS analyses will take place at approximately 48, 58, and 
73 months from the start of 1:1:1 randomization. The trigger of the first interim analysis is event 
driven. The second interim analysis will take place when 167 events are observed 
 
. The final analysis will take place 
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when approximately 185 events are observed 
 
. The stopping boundaries at the interim and final EFS 
analyses will be derived based on the exact number of events using Lan-DeMets alpha spending 
function with O’Brien-Fleming boundaries. If the interim analyses of EFS are performed at exactly 
148 and 167 events, the nominal significance level for EFS superiority will be 0.024 and 0.030,
respectively. The nominal significance level for the final look of EFS after 185 events would then 
be 0.038. 
Table 10.1.3-1 summarizes the key parameters of the sample size justification in the randomized 
participants.
10.1.3
Power Consideration for Overall Survival (OS)
The secondary endpoint OS will be tested hierarchically after EFS with the same overall alpha as 
for the EFS comparison (two-sided 4% if the pCR comparison is not significant or 5% if the pCR 
comparison is significant).
For the formal comparison of OS for nivolumab plus platinum doublet chemotherapy (Arm C) vs 
platinum doublet chemotherapy (Arm B), only participants concurrently randomized from 1:1:1 
randomization in revised protocol 02 and 1:1 randomization in revised protocol 03 will be 
included. Three interim analyses for OS are planned to occur at the time of EFS interim and final 
analyses, only if EFS is significant. 
The power details are provided below using alpha = 0.05 (0.01 alpha from the pCR endpoint 
fallback to the EFS comparison, then hierarchically on the OS comparison), considering this 
protocol amendment (protamend07) occurs after the readout of the statistically significant pCR 
final analysis but before any analysis of EFS or OS. In addition, they reflect the 358 participants 
that were actually concurrently randomized in Arms B and C:  
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Table 10.1.3-1:
Power Calculation for EFS and OS
EFS
Arm C vs Arm B
OS
Arm C vs Arm B
Accrual
Actual accrual
25 months
Actual accrual
25 months
Power
82%
Two-sided alpha
0.05
0.05
Hypothesized median control 
vs exp (months)
28 vs 52*
Hypothesized hazard ratio
0.65
Sample size for concurrent 
comparison
358
358
First interim analysis for EFS 
(EFS IA1) and OS (OS IA1)
148 events
Alpha boundary: 0.024
Triggered by EFS IA1
Second interim analysis for 
EFS (EFS IA2) and OS (OS 
IA2)
167 events
 
Alpha boundary: 0.030
•
If EFS IA1 not significant: triggered by 
EFS IA2.
Final EFS (EFS FA) and third 
OS (OS IA3) interim analysis
185 events 
Alpha boundary: 0.038
•
If EFS IA2 not significant: triggered by 
EFS FA.
Final OS analysis (OS FA)
-
*Calculated from piecewise exponential distribution
EFS, event free survival; FA, final analysis; IA, interim analysis; OS, overall survival
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10.1.4
Analyses Timing Projections
The pCR analysis occurred with a database lock on 16-Sep-2020.
Considering the actual enrollment, it will take:
•
Approximately 48 months when 148 events on Arms B and C (after start of 1:1:1
randomization) are observed for the first interim analysis (EFS IA1, OS IA1). This is about 54
months from first patient first visit (FPFV) of the study. This analysis will be triggered by the 
number of EFS events.
•
Approximately 58 months when 167 EFS events on Arms B and C (after start of 1:1:1
randomization) are observed for the second interim analysis (EFS IA2, OS IA2). This is 
approximately 64 months from FPFV. 
 
 
•
Approximately 73 months when 185 EFS events on Arms B and C (after start of 1:1:1
randomization) are observed for the final EFS analysis (EFS FA, OS IA3). This is about 79
months from FPFV of the study.
 
 
 
 
10.2
Populations for Analyses
Population
Description
All enrolled 
participants
All participants who signed an informed consent form and were registered into the IRT
All randomized 
participants
All participants who were randomized to any treatment arm in the study. This is the 
primary dataset for analyses of study conduct, study population and efficacy.
All concurrently 
randomized participants 
in Arms B and C
All randomized participants on Arms B and C after 1:1:1 randomization. Analysis of 
demography, protocol deviations, baseline characteristics, and primary efficacy 
analyses will be performed for this population.
All treated participants
All participants who received any dose of study medication in neoadjuvant setting. 
This is the primary dataset for drug exposure and safety analysis.
PK participants
All participants with available serum time-concentration data from randomized 
participants dosed in Arm A and Arm C
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10.3
Statistical Analyses
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The fallback method will be used for the hypothesis testing of the two primary endpoints pCR and 
EFS. Initially, the type 1 error of 0.05 will be allocated as follows: 0.01 will be allocated to the 
pCR comparison between Arm C and Arm B, and 0.04 will be allocated to the EFS comparison 
between Arm C and Arm B. If the pCR comparison between Arm C and Arm B is statistically 
significant, then 0.01 alpha will be passed to the EFS comparison for Arm C vs Arm B and the test 
comparison will be conducted at the alpha = 0.05 level.
pCR analysis will be based on all concurrently randomized participants in Arms B and C analysis 
population. pCR rate will be computed in each treatment group along with the exact 95% CI using 
Clopper-Pearson method. For pCR rate comparison between arms C vs B, the difference will be 
tested via the Cochran Mantel-Haenszel (CMH) test using a 2-sided, 1% alpha level. the odds 
ratios stratified by PD-L1, disease stage (IB/II vs IIIA) and gender (Mantel-Haenszel estimator) 
between Arms C and B will be provided along with the 99% CI. In addition, an estimate of the 
difference in pCR rates and corresponding 99% CI will be calculated using CMH methodology 
and adjusted by stratification factors (PD-L1, disease stage (IB/II vs IIIA) and gender). 
pCR rate will also be computed for subjects randomized to Arm A neoadjuvant nivolumab plus 
ipilimumab along with the exact 95% CI using Clopper-Pearson method.
EFS is defined as time from randomization to any of the following events: any documented 
progression of disease precluding surgery, progression or recurrence disease (based on BICR 
assessment per RECIST 1.1) after surgery, or death due to any cause. Participants who don’t 
undergo surgery for reason other than progression will be considered to have an event at RECIST 
1.1 progression (based on BICR) 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 did 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 censored at the last evaluable tumor 
assessment prior to initiation of the subsequent anti-cancer therapy.
If the pCR analysis comparing Arms C vs B is statistically significant, a two-sided alpha of 0.05 
will be used for the comparison of EFS in Arms C vs B. If the pCR analysis comparing Arms C 
vs B is not statistically significant, a two-sided alpha of 0.04 will be used for the comparison of 
EFS in Arms C vs B. EFS among the all concurrently randomized participants in Arms B and C
analysis population will be tested. The distribution of EFS will be compared between Arm C vs 
Arm B via a 2-sided, log rank test stratified by the randomization stratification factor (ie, PD-L1, 
disease stage [IB/II vs IIIA] and gender).The hazard ratio and the corresponding (1-adjusted alpha) 
confidence interval will be estimated for Arm C vs Arm B in a stratified Cox proportional hazards 
model using the randomized arm as a single covariate. The EFS curves for each randomized arm 
will be estimated using the Kaplan-Meier (KM) product-limit method using a log-log 
transformation. In addition, EFS rates at 1, 2, 3, and 4 years 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
At the time of pCR analysis, MPR rate will be computed in each treatment group along with the 
exact 95% CI using Clopper-Pearson method. An estimate of the difference in MPR rates between 
Arm C and Arm B and corresponding 95% CI will be calculated using CMH methodology and 
adjusted by stratification factors (PD-L1, disease stage (IB/II vs IIIA) and gender).
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Endpoint
Statistical Analysis Methods
OS curves, OS medians with 95% CIs, and OS rates at 1, 2, 3, and 4 years with 95% CIs will be 
estimated using Kaplan-Meier methodology. HR and corresponding 2-sided 95% CI will be 
estimated for Arm C vs Arm B using a Cox proportional hazards model with treatment group as a 
single covariate, stratified by randomization stratification factors. If tested, the distribution of OS 
will be compared between Arm C vs Arm B in the all concurrently randomized participants in 
Arms B and C population via a 2-sided, log rank test stratified by the randomization stratification 
factors.
Time to death or distant metastases (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 using BICR 
according to RECIST 1.1. Participants who die without a reported distant metastasis will be 
considered to have experienced an event on the date of their death. Patients 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. Participants who did not have baseline scan, or participants who 
did not have any on-study tumor assessments and did not die, will be censored on the date they 
were randomized. 
TTDM curves, TTDM medians with 95% CIs, and TTDM rates at 1, 2, 3, and 4 years with 95% 
CIs will be estimated using Kaplan-Meier methodology. HR and corresponding 2-sided 95% CI 
will be estimated for Arm C vs Arm B using a Cox proportional hazards model with treatment 
group as a single covariate, stratified by randomization stratification factors. There will be no 
formal comparison of TTDM.
Exploratory
Will be described in the statistical analysis plan finalized before database lock
10.3.2
Other Analyses
Biomarker exploratory analyses will be described in the statistical analysis plan finalized before 
database lock. The population pharmacokinetics analysis will be presented separately from the 
main clinical study report. 
The EQ-5D-3L questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number, will be calculated and summarized at each assessment point. 
Summary statistics (ie, N, mean with SD and 95% CI, median, first and third quartiles, minimum, 
maximum) for the EQ-5D-3L utility index and VAS scores, as well as their corresponding changes 
from baseline, will be tabulated by treatment and planned time point. In the base case, index scores 
will be derived using the UK weighting algorithm. In addition, the proportion of participants 
reporting no, moderate, or severe problems in each of the 5 EQ-5D-3L dimensions will be 
summarized by treatment group at each time point. Proportions will be based on the number of 
participants assessed at assessment time point. A by-participant listing of the level of problems in 
each dimension, corresponding EQ-5D-3L health state (ie, 5-digit vector), EQ-5D-3L index score, 
and EQ-5D VAS score will be provided.
10.3.3
Interim Analyses
There is no interim analysis for the pCR endpoint.
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Two formal interim analyses for EFS are planned after approximately 148 and 167 events have 
been observed on Arms B and C, after the start of 1:1:1 randomization, which is projected to occur 
approximately 48 and 58 months after start of 1:1:1 randomization.
 
 
 The formal comparisons of EFS will allow for early stopping for superiority. An 
independent statistician external to BMS will perform the analysis. If the study continues beyond 
the second interim analysis, the final analysis will be conducted after 185 EFS events have been 
observed on Arms B and C from the start of 1:1:1 randomization. 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.
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42 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or 
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55 Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected 
non-small-cell lung cancer. N Engl J Med. 2005; 352:2589-2597. 
56 Butts CA, Ding K, Seymour L, et al: Randomized, phase III trial of vinorelbine plus cisplatin 
compared with observation in completely resected stage IB and II non-small-cell lung cancer: 
Updated survival analysis of JBR-10. J Clin Oncol. 2010; 28:29-34.  
57 Douillard JY, Rosell R, De Lena M, et al: Adjuvant vinorelbine plus cisplatin versus 
observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer 
(Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled 
trial. Lancet Oncol. 2006; 7:719-727.  
58 NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell 
lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 
2014;383:1561-71.
59 Rami-Porta, R. Bolejack, V. Crowley, J. et al. The IASLC Cancer Staging Project: Proposals 
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Classification for Lung Cancer. J Thorac Oncol. 2015 Jul;10(7):990-1003.
60 NAVELBINE® (vinorelbine tartrate). Prescribing Information. 2002. GlaxoSmithKline. 
Research Triangle Park, NC.
61 GEMZAR (gemcitabine for injection), for intravenous use. Revised June 2014. Lilly, USA, 
Inc. Indianapolis, IN.
62 TAXOTERE® (docetaxel) Injection Concentrate, Intravenous Infusion (IV). Prescribing 
Information. Revised December 2015. sanofi-aventis, US, LLC, Bridgewater, NJ. 
63 ALIMTA (pemetrexed for injection), for Intravenous Use. Update September 2013. Lilly, 
USA, Inc. Indianapolis, IN.
64 Platinol (cisplatin for injection). Prescribing information. Revised May 2010. Bristol-Myers 
Squibb Company, Princeton, NJ. 
65 PARAPLATIN (carboplatin aqueous solution) INJECTION. Updated July 2010. Bristol-
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66 Paclitaxel Aurobindo 6 mg/ml Concentrate for solution for infusion. Summary of Product 
Characteristics. Puren Pharma. 
67 Taxol (paclitaxel) Injection. Corden Pharma Latina. January 2011
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APPENDICES
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APPENDIX 1
TNM STAGING SYSTEM FOR LUNG CANCER (7TH EDITION)
Table -1:
International Association for the Study of Lung Cancer Definitions 
for T, N, and M Descriptors
T (Primary Tumor)
T1
Tumor ≤ 3 cm in greatest dimension, surrounded by lung or visceral pleura, without invasion more 
proximal than the lobar bronchus 
T1a
Tumor ≤ 2 cm in diameter
T1b
Tumor > 2 cm but ≤ 3 cm in diameter
T2
Tumor > 3 cm but ≤ 7 cm or tumor with any of the following features 
Involves main bronchus, ≥ 2 cm distal to carina
Invades visceral pleura
Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not 
involve the entire lung
T2a 
Tumor > 3 cm but _5 cm 
T2b 
Tumor > 5 cm but  ≤ 7 cm 
T3 
Tumor > 7 cm or any of the following: 
Directly invades any of the following: chest wall, diaphragm, phrenic nerve, mediastinal pleura, 
parietal pericardium; main bronchus < 2 cm distal to the carina (without involvement of the carina)
Atlelectasis or obstructive pneumonitis of the entire lung
Separate tumor nodule in same lobe
T4
Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, 
recurrent laryngeal nerve, esophagus, vertebral body, carina; or without separate tumor nodules in a 
different ipsilateral lobe
N (Regional Lymph Nodes)
N0
No regional lymph node metastasis
N1
Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary 
nodes, including involvement by direct extension
N2
Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or 
supraclavicular lymph node(s)
M (Distant Metastasis)
M0
No distant metastasis
M1
Distant metastasis
M1a
Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural or 
pericardial effusion
M1b
Distant metastasis (in extrathoracic organs)
Stage Groupings
Stage IA
T1a-T1b
N0
M0
Stage IB
T2a
N0
M0
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Table -1:
International Association for the Study of Lung Cancer Definitions 
for T, N, and M Descriptors
Stage IIA
T1a, T1b, T2a
N1
M0
T2b
N0
M0
Stage IIB
T2b
N1
M0
T3
N0
M0
Stage IIIA
T1a, T1b, T2a, T2b
N2
M0
T3
N1, N2
M0
T4
N0, N1
M0
Stage IIIB
T4
N3
M0
Any T
N3
M0
Stage IV
Any T
Any N
M1a or M1b
Adapted from Goldstraw P, Crowley J, Chansky K, et al. 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 Oncol. 2007 Aug;2(8):706-14. 
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APPENDIX 2
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 Company
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
dL
deciliter
DMC
Data Monitoring Committee
EBUS
endobronchial ultrasound
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EFS
event-free survival
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Term
Definition
eg
exempli gratia (for example)
FA
final analysis 
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
IA
Interim analysis 
IB
Investigator’s brochure 
ICH
International Conference on Harmonisation 
ie
id est (that is)
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
LC
liquid chromatography
LDH
lactate dehydrogenase
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Term
Definition
mg
milligram
min
minute
mL
milliliter
mmHg
millimeters of mercury
MPR
major pathological response
MLND
mediastinal lymph node dissection
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
NSCLC
non-small cell lung carcinoma
NIMP
non-investigational medicinal products 
OS
overall survival 
PBMC
peripheral blood mononuclear cells
pCR
Pathologic complete response
PFS
progression-free survival
PK
pharmacokinetics
PPK
Population pharmacokinetic 
PO
per os (by mouth route of administration)
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
SNP
single nucleotide polymorphisms
SOC
Standard of care
SOP
Standard Operating Procedures
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Term
Definition
t
temperature
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 3
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, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 4
NIVOLUMAB 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 5
RESPONSE CRITERIA (RECIST 1.1)
1
EVALUATION OF LESIONS
At baseline, tumor lesions/lymph nodes will be categorized 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:
1) 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
2) 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)
3) 20 mm by chest x-ray
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).
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 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, saggital 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.
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, ascites, pleural or pericardial effusion, 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.
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2
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).
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.
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 nontarget lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
3
RESPONSE CRITERIA
3.1
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.
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3.1.1
Special Notes on the Assessment of Target Lesions
3.1.1.1
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.
3.1.1.2
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 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived from 
the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially 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.
3.1.1.3
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’.
3.2
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.
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Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. 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) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also considered progression).
3.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
3.2.1.1
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 (see further details below). A modest ‘increase’ in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression status. 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.
3.2.1.2
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 a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as ‘sufficient 
to require a change in therapy’. If ‘unequivocal progression’ is seen, the patient should be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore the increase must be substantial.
3.2.2
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 
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lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up 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.
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. While FDG-
PET response assessments need additional study, it is sometimes reasonable to incorporate the use 
of FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
4) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
5) 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.
3.3
Response Assessment
3.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. 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. Furthermore, depending on the 
nature of the study and the protocol requirements, it may also require confirmatory measurement.
3.3.2
Time Point Response
It is assumed that at each protocol specified time point, a response assessment occurs. Table 3.3.2-
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 3.3.2-2 is to be used. 
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Table 3.3.2-1:
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
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 3.3.2-2:
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.
3.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks later. In this circumstance, the best overall response can be interpreted as in Table 3.3.3-
1.
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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Table 3.3.3-1:
Best Overall Response (Confirmation of CR&PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BEST Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD durationb met, 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD durationb met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration bmet, 
otherwise, NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
b Minimum criteria for SD duration is 6 weeks.
3.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no less than 
28 days after the criteria for response are first met. For this study, the next scheduled tumor 
assessment can meet this requirement.
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.
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APPENDIX 6
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
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment.
Local laws and regulations may require use of alternative and/or additional contraception 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
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
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−
oral 
−
injectable
Highly Effective Methods That Are User Independent 
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b
•
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and
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 
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
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal(coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
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 the end of relevant 
systemic exposure defined as 7 months after the end of treatment in the male participant.
•
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 treatment.
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of 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 7
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:
•
Good 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 GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
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 (e.g., 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 (e.g., 
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 (e.g., 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 for 
•
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 to 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 (i.e., 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 unable to give their written consent (e.g., stroke or subjects 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.
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 drug integrity in 
accordance with requirements applicable under law and 
the SOPs/standards of the sourcing pharmacy.   
These records should include:
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If
Then
•
label identification number or batch number 
•
amount dispensed to and returned by each 
participant, including unique participant identifiers
•
dates and initials of person responsible for 
Investigational Product dispensing/accountability, 
as per the Delegation of Authority Form.
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 
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. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
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
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. 
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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.
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.
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 (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., 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 (e.g., 
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 
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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.
•
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, i.e., 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 this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (e.g., among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (e.g., among top quartile of enrollers from a specified region or 
country)
•
Other criteria (as determined by the study team)
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 (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA.
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APPENDIX 8
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.
Protocol Amendment No.: 07
Date: 18-Aug-2021
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CA209816
BMS-936558
nivolumab
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
Protocol Amendment No.: 07
Date: 18-Aug-2021
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Clinical Protocol
CA209816
BMS-936558
nivolumab
APPENDIX 9
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
OVERALL RATIONALE FOR REVISED PROTOCOL 06, 14-Jul-2020
During recent interactions with health authorities (2020), they indicated that the early event-free 
survival (EFS) interim analysis (IA) may lack robustness due to immature data. Accordingly, the 
EFS IA plan was changed in protocol revision 06 to remove the first planned IA.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 06
Section Number and Name
Description of Change
Brief Rationale
Synopsis, Objectives and Endpoints
Table 4-1 Objectives and Endpoints
Table 10.3.1 Efficacy Analyses
Clarified that any progression precluding 
surgery is an EFS event and that 
RECIST 1.1 progression/recurrence per 
blinded independent central review 
(BICR) applies post surgery or for 
participants without surgery
Clarified EFS definition
Synopsis, Number of Participants
5.2 Number of Participants
Corrected the number of participants
To align with 10.1 Sample 
Size Determination
5.3 End of Study Definition
10.1.2 Event Free Survival
10.1.3 Power Consideration for 
Overall Survival (OS)
Table 10.1.3-1 Power Calculation for 
EFS and OS
10.1.4 Analyses Timing Projections
Table 10.1.4-1 Scheduled Analyses, 
Criteria, and Projected Timelines
10.3.3 Interim Analyses
Removed the first of 2 IA of EFS and 
updated alpha spending on the remaining 
single interim and final analyses of EFS
Health authorities suggested 
that the early EFS IA may 
lack robustness at that level 
of data maturity
10.1.2 Event Free Survival
10.1.4 Analyses Timing Projections
Table 10.1.4-1 Scheduled Analyses, 
Criteria, and Projected Timelines
Clarified that actual timing of analyses 
may differ from projected timing
Clarified potential variation 
in analyses timing 
10.1.2 Event Free Survival
Removed text about descriptive EFS 
analysis
Descriptive analyses for the 
DMC will be described in the 
DMC Charter
All
Corrected typographical errors
Minor, so not specified
Protocol Amendment No.: 07
Date: 18-Aug-2021
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CA209816
BMS-936558
nivolumab
OVERALL RATIONALE FOR REVISED PROTOCOL 05, 18-Sep-2019
The revised protocol updates analyses projections for pCR and EFS and clarifications of surgery 
exploratory endpoints, instruction for biomarker collection and pathology review, and rules for 
PD-L1 stratification. Additionally, management algorithms were updated for myocarditis.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 05
Section Number and Name
Description of Change
Brief Rationale
Synopsis 
Section 4 Objectives and Endpoints
Updated exploratory endpoint to include 
completeness of resection in surgical 
approach
Update provides clarity 
on collection of surgical 
outcomes
Synopsis 
Section 5.1 Overall Design
Updated stratification of participants with 
PD-L1 not evaluable/ indeterminate status 
to PD-L1 negative participants
Update provides clarity 
for stratification of  
participants with PD-L1 
not evaluable/ 
indeterminate status
Synopsis
Language updated to identify the 
CA209816 Laboratory Manual as a source 
for pathology specimen collection and 
processing. Additionally, blinded 
pathology review process will assess for 
confirmation of endpoints.
Updates provide 
instruction for guidelines 
for collection and 
processing of pathology 
specimens and 
confirmation of 
endpoints
Section 5.3 End of Study Definitions
Updated the timing of pCR rate
Provides updated 
projection of analysis for 
pCR rate. 
Section 9.8.1.1 Tumor Tissue 
Specimens
Clarified tumor biopsy collection will not 
be collected in China
Sites are unable to 
collect optional tumor 
biopsy in China. 
Section 10.1 Sample Size 
Determination
Section 10.1.1 Pathologic Complete 
Response (pCR)
Sections 10.1.4 Analyses Timing 
Projections
Section 10.2 Populations for Analyses
Section 10.3.1 Efficacy Analyses
Section 10.3.3 Interim Analyses
Updates anticipated sample size and 
projected timing of analyses for pCR and 
EFS
Provides updated 
information for analysis 
for pCR and EFS..
Section 10.3.1 Efficacy Analyses
Updated statistical analysis methods for 
TTDM 
Statistical analysis 
methods for TTDM were 
updated.
Appendix 4 Management Algorithms
Updated management algorithms to 
include myocarditis
Aligns management 
algorithms with updated 
Investigator Brochure
Protocol Amendment No.: 07
Date: 18-Aug-2021
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CA209816
BMS-936558
nivolumab
OVERALL RATIONALE FOR REVISED PROTOCOL 04, 25-Jun-2019
The CA209816 revised protocol 04 adds EFS on next line of therapy as an exploratory objective. 
Statistical analyses, power calculations, projected timelines
 
. Additional changes were added for clarity.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 04
Section Number and Name
Description of Change
Brief Rationale
Synopsis
Table 4-1: Objectives and Endpoints
Added exploratory endpoint of Event Free 
Survival on next line of therapy
Added EFS on next line 
of therapy, as provides 
additional follow-up 
information for efficacy 
and survival 
Section 7.7.1 Prohibited and/or 
Restricted Treatments
Added the concomitant administration of 
substances that are also tubularly secreted 
(eg, probenecid) could potentially result in 
delayed clearance of pemetrexed.
Added to comply with 
HA request
Section 10.2.1 Populations for 
Analysis at Pathologic Complete 
Response Analysis Timepoint
Clarified the pCR analysis population
Updated section for 
clarity
Synopsis
Section 5.1 Overall Design
Section 5.1.1 Data Monitoring 
Committee and Other External 
Committees
•
BICR confirmation of progression 
should not be requested if investigator 
judges the progression will not 
preclude surgery.
•
Tumor assessments (if clinically 
feasible) and BICR should continue
even after the initiation of subsequent 
anti-cancer therapies.
Updated parameters for 
BICR confirmation for 
clarity
Section 10.1.3 Power Consideration 
for Overall Survival (OS)
Table 10.1.3-1:
Power Calculation 
for EFS and OS
Section 10.3.3 Interim Analyses
Added power consideration for OS testing
In case of significant 
EFS, OS will be tested.
Section 10.1.4 Analyses Timing 
Projections
Table 10.1.3-1 Scheduled Analyses, 
Criteria, and Projected Timelines
Updated the analysis timing projections
Updated the analysis 
timing projections
Appendix 8 Adverse Events and 
Serious Adverse Events: Definitions 
and Procedures for Recording, 
Evaluating, Follow Up and Reporting 
Adverse Events
Updated AE template language
Updated appendix to 
align with program 
standards
Protocol Amendment No.: 07
Date: 18-Aug-2021
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Clinical Protocol
CA209816
BMS-936558
nivolumab
OVERALL RATIONALE FOR REVISED PROTOCOL 03, 21-Sep-2018
The CA209816 revised protocol closes enrollment in Arm A (nivolumab plus ipilimumab) and 
expands the sample size in Arm B (chemotherapy) and Arm C (nivolumab plus chemotherapy). 
Subsequently, the study rationale and statistical section was updated to support the new analyses. 
Additional changes were made to provide clarity in study conduct.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number and Name
Description of Change
Brief Rationale
Synopsis, Objectives, Overall Design, 
Schema, Number of Participants 
Section 4 Objectives and Endpoints
Section 5.1 Overall Design
Section 5.2 Number of Participants
Enrollment in Arm A (nivolumab 
plus ipilimumab) was stopped and 
randomization of participants (1:1 
ratio) into Arm B and C will continue 
enrolling for a total of 350 
participants
Study design was changed 
to support nivolumab plus 
chemotherapy as 
neoadjuvant therapy in 
NSCLC based on emerging 
data.
Synopsis, Objectives
Section 4 Objectives and Endpoints
•
Updated objectives for 
assessments of Arm B to Arm C
•
Added time to death or distant 
metastases (TTDM) as 
secondary objective
•
Updated tertiary objectives for 
Arm A (nivolumab and 
ipilimumab)
Objectives were updated to 
align with change in study 
design
Synopsis Overall Design
Participants with large-cell 
neuroendocrine carcinoma tumor 
histology are excluded
Eligibility criteria was 
updated as protocol’s 
chemotherapy regimens are 
not optimal for treating this 
specific subtype of NSCLC
Synopsis Treatment Arms and Duration, 
Study Treatment 
Section 5.1 Overall Design
Section 5.4.6 Rationale for Choices of 
Platinum-based Chemotherapy Doublet
Table 7-1 Study Treatments for CA209816
Section 7.1 Treatments Administered
Table 7.1-1 Selection and Timing of Doses
Section 7.4 Dose Modifications
Additional platinum doublet 
chemotherapy regimen 
(paclitaxel/carboplatin) was added
Additional platinum 
doublet chemotherapy 
regimens 
(paclitaxel/carboplatin) 
added to reflect knowledge 
gained from emerging data.
Section 7.4.1.1 Platinum Doublet 
Chemotherapy - Dose Reductions for 
Hematologic Toxicity
Section 7.4.1.2 Platinum Doublet 
Chemotherapy - Dose Reductions for Non-
Hematologic Toxicities
Updated and moved dose 
modification for docetaxel into 
hematologic toxicity and non-
hematologic toxicity sections.
Updated dose modification 
for docetaxel into correct 
sections of protocol.
Section 7.4.2.2 Dose Delay Criteria for 
Platinum Doublet Chemotherapy
Provided updated dose delay criteria 
for chemotherapy 
Provided updated dose 
delay criteria for safety
Protocol Amendment No.: 07
Date: 18-Aug-2021
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Clinical Protocol
CA209816
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 03
Section Number and Name
Description of Change
Brief Rationale
Table 2-3 Post Neoadjuvant Period for 
Those Participants Not Receiving 
Adjuvant Therapy
Section 9.1.1 Imaging Assessment for the 
Study
•
Updated time relationship 
between adjuvant radiotherapy 
and tumor imaging assessments
•
Clarified imaging for tumor 
assessments for participants who 
do not proceed to definitive 
surgery 
Updated imaging 
assessment requirements 
for clarity
Section 5.3 End of Study Definition
Section 10.1 Sample Size Determination 
Section 10.1.1 Pathologic Complete 
Response (pCR)
Section 10.1.2 Event Free Survival (EFS)
Section 10.1.3 Analyses Timing 
Projections
Section 10.3.1 Efficacy Analyses
Section 10.3.3 Interim Analyses
Statistical analysis plan was updated
Statistical analyses were 
updated to align with 
change in study design.
Section 3.2.1 Indication Background
Section 3.2.4 Nivolumab Combined with 
Ipilimumab Clinical Activity
Section 3.2.5 Immuno-oncology Treatment 
Combined with Chemotherapy Clinical 
Activity
Section 3.3 Benefit/Risk Assessment 
Section 5.4.3 Rationale for Immuno-
oncology Treatment in Neoadjuvant 
NSCLC
Section 5.4.3.1 Rationale for Combination 
of Nivolumab and Ipilimumab (Arm A)
Section 5.4.3.2 Rationale for PD-1 
Inhibitor with Chemotherapy (Arm C)
Section 5.4.4 Rationale for Pathologic 
Response
Rationale, background information, 
and trial schematic were updated 
Rationale, background 
information, and trial 
schematic were updated to 
align with changes in study 
design and current data. 
Table 2-1 Screening Procedural Outline 
Table 2-2 Neoadjuvant Period Procedural 
Outline
Updated to include FVC, FEV1, 
TLC, FRC, and DLco.
Parameters of pulmonary 
function tests to be 
collected were clarified.
Section 9.5 Pharmacokinetics
Time window of Cycle 1 Day 1 end-
of-infusion PK sampling for Arm A
and C was clarified
Time window for certain 
PK sample collection was 
provided.
Appendix 4 Hepatic Adverse Event 
Management Algorithm
Footnote stating I-O therapy may be 
delayed rather than discontinued if 
AST/ALT ≤ 8 x ULN or T.bili ≤ 5 x 
ULN was removed.
Language was modified to 
align protocol with current 
Nivolumab Investigator 
Brochure and nivolumab 
program safety 
management principals.
Protocol Amendment No.: 07
Date: 18-Aug-2021
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CA209816
BMS-936558
nivolumab
OVERALL RATIONALE FOR REVISED PROTOCOL 02, 06-JUL-2017
The CA209816 study has been revised in response to a health authority request to add the primary 
objective of event-free survival for the study population. In addition, a new treatment arm was 
added to the study as a new comparison for the current treatment landscape.
This revised protocol applies to all current and future participants.
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 02
Section Number and Name
Description of Change
Brief Rationale
Title; Section 1 Synopsis, Objective and Endpoints, Study 
Design, Number of Participants, Treatment Arms and Duration; 
Section 2 Schedule of Activities; Section 3.1 Study Rationale, 
Research Hypothesis; Section 4 Objectives and Endpoints; 
Section 5 Study Design; Section 5.2 Number of Participants; 
Section 5.3 End of Study Definition; Section 6 Study 
Population; Section 7 Treatment; Section 9.5 Pharmacokinetics; 
Section 10 Statistical Considerations (Sections 10.1.1, 10.1.2,  
10.1.3, 10.2, 10.3, 10.3.3)
A new treatment arm of 
nivolumab plus 
platinum doublet 
chemotherapy (Arm C) 
was added to the study. 
The sample size was 
increased to 642 with 
the addition of the new 
treatment arm.
New treatment arm 
was added for 
current treatment 
landscape.
Title, Section 1 Synopsis, Objective and Endpoints, Study 
Design, Number of Participants, Treatment Arms and Duration; 
Section 2 Schedule of Activities’ Section 3.1 Study Rationale; 
Section 3.2; Section 4 Objectives and Endpoints; Section 5 
Study Design (Section 5.1, Schema, Section 5.2, Number of 
participants, Section 5.3 End of Study Definition; Section 9.1 
Efficacy Assessments; Section 10 Statistical Considerations 
(Sections 10.1.1, 10.1.2, 10.1.3, 10.2 Populations for Analyses, 
10.3 Statistical Analyses, 10.3.3)
Primary objectives were 
modified to event free 
survival and 
pathological response.
New multiple 
primary objective 
was added in 
response to health 
authority request.
Synopsis, Background Section 3.2 (Sections 3.2.4, 3.2.5); 
Section 3.3 Benefit/Risk Assessment, Background, Section 5.4 
Scientific Rationale for Study Design (Sections 5.4.3, 5.4.4, 
5.5.2)
With the addition of 
new treatment arm and 
new primary endpoints, 
the background and 
rationale were updated 
with current safety and 
efficacy data.
Study sections 
were updated to 
reflect current 
study design and 
available data on 
safety and efficacy 
of study treatments.
Protocol Amendment No.: 07
Date: 18-Aug-2021
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SAP_001.pdf: 
Official Title of Study: 
Randomized, Open-Label, Phase 3 Trial of Nivolumab plus Ipilimumab or Nivolumab plus 
Platinum-Doublet Chemotherapy versus Platinum-Doublet Chemotherapy in Early Stage 
NSCLC 
(CheckMate 816: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 816) 
 
PROTOCOL(S) CA209-816 
 
NCT Number: NCT02998528 
  
Document Date (Date in which document was last revised): August 11, 2021 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
RANDOMIZED, OPEN-LABEL, PHASE 3 TRIAL OF NIVOLUMAB PLUS 
IPILIMUMAB OR NIVOLUMAB PLUS PLATINUM-DOUBLET CHEMOTHERAPY 
VERSUS PLATINUM-DOUBLET CHEMOTHERAPY IN EARLY STAGE NSCLC
PROTOCOL(S) CA209816
VERSION # 3.0
DATE: 11-AUG-2021
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Statistical Analysis Plan
CA209816
BMS-936558
nivolumab
2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................6
LIST OF FIGURES ....................................................................................................................7
1
BACKGROUND AND RATIONALE......................................................................8
2
STUDY DESCRIPTION ..........................................................................................9
2.1
Study Design ............................................................................................................9
2.2
Treatment Assignment............................................................................................12
2.3
Blinding and Unblinding.........................................................................................13
2.4
Protocol Amendments.............................................................................................13
2.5
Data Monitoring and Other External Committees ...................................................17
3
OBJECTIVES ........................................................................................................17
3.1
Primary...................................................................................................................17
3.2
Secondary...............................................................................................................17
3.3
Exploratory Objectives ...........................................................................................17
4
ENDPOINTS..........................................................................................................18
4.1
Primary Endpoint(s) ...............................................................................................18
4.1.1
Event-Free Survival................................................................................................19
4.1.1.1
Primary Definition of Event-Free Survival..............................................................19
4.1.1.2
Secondary Definition of Event-Free Survival ..........................................................20
4.1.2
Pathologic Complete Response Rate.......................................................................22
4.2
Secondary Endpoint(s)............................................................................................22
4.2.1
Overall Survival .....................................................................................................22
4.2.2
Major Pathological Response Rate.........................................................................22
4.2.3
Time to Death or Distant Metastases ......................................................................23
4.3
Exploratory Endpoint(s)..........................................................................................23
4.3.1
Clinical Response Rate by BICR.............................................................................23
4.3.2
Event Free Survival on Next Line of Therapy (EFS2)..............................................23
4.3.3
Surgery Related Endpoints......................................................................................24
4.3.4
Safety and Tolerability............................................................................................24
4.3.5
Pharmacokinetics ...................................................................................................24
4.3.6
Biomarkers .............................................................................................................24
4.3.6.1
Tumor Mutational Burden ......................................................................................24
4.3.6.2
PD-L1 Protein Expression......................................................................................25
4.3.7
Outcomes Research ................................................................................................25
4.3.7.1
EQ-5D-3L...............................................................................................................25
5
SAMPLE SIZE AND POWER...............................................................................27
5.1
Pathologic Complete Response (pCR) ....................................................................28
5.2
Event Free Survival (EFS) ......................................................................................29
5.3
Power Considerations for Overall Survival .............................................................30
5.4
Analyses Timing Projections ..................................................................................31
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................33
6.1
Study Periods..........................................................................................................33
6.2
Treatment Regimens...............................................................................................34
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CA209816
BMS-936558
nivolumab
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6.3
Populations for Analyses ........................................................................................34
7
STATISTICAL ANALYSES..................................................................................35
7.1
General Methods ....................................................................................................35
7.1.1
Adverse Events, Serious Adverse Events, Multiple Events, Select Adverse 
Events, Other Events of Special Interest and Immune-Mediated Adverse 
Events.....................................................................................................................36
7.1.1.1
Select Adverse Events .............................................................................................37
7.1.1.2
Other Events of Special Interest..............................................................................38
7.1.1.3
Immune-Mediated Adverse Events ..........................................................................38
7.1.2
Laboratory Tests.....................................................................................................38
7.2
Study Conduct........................................................................................................39
7.2.1
Accrual...................................................................................................................39
7.2.2
Relevant Protocol Deviations..................................................................................39
7.3
Study Population ....................................................................................................39
7.3.1
Subject Disposition.................................................................................................39
7.3.2
Demographics and Other Baseline Characteristics.................................................40
7.3.3
Medical History......................................................................................................41
7.3.4
Prior Therapy.........................................................................................................41
7.3.5
Physical Examinations............................................................................................41
7.3.6
Baseline Physical Measurements ............................................................................41
7.3.7
Consistency of Demographics and Baseline Characteristics by 
Randomization Period ............................................................................................41
7.4
Extent of Exposure .................................................................................................42
7.4.1
Administration of Study Therapy.............................................................................42
7.4.2
Modifications of Study Therapy ..............................................................................46
7.4.2.1
Dose Delay/Omission .............................................................................................46
7.4.2.2
Infusion Interruptions and Rate Changes................................................................46
7.4.2.3
Dose Reductions.....................................................................................................46
7.4.3
Concomitant Medications.......................................................................................48
7.4.3.1
Immune Modulating Medication .............................................................................48
7.4.3.2
Subsequent Cancer Therapy ...................................................................................49
7.5
Definitive Surgery ..................................................................................................49
7.6
Efficacy..................................................................................................................50
7.6.1
Type I Error Control...............................................................................................50
7.6.2
Analysis of Pathological Complete Response..........................................................51
7.6.2.1
Primary pCR Analysis ............................................................................................51
7.6.2.2
Supportive Analyses of pCR....................................................................................51
7.6.2.3
Subset Analyses of pCR...........................................................................................52
7.6.2.4
Major Pathological Response Rate.........................................................................53
7.6.2.5
Additional Pathological Related Analyses...............................................................53
7.6.2.6
Clinical Response Rate...........................................................................................53
7.6.3
Analysis of Event Free Survival ..............................................................................53
7.6.3.1
Primary Event Free Survival ..................................................................................53
7.6.3.2
Supportive Analyses of Event-Free Survival............................................................54
7.6.3.3
Subset Analyses of EFS...........................................................................................57
7.6.3.4
EFS Analyses by pCR and MPR Status ...................................................................57
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CA209816
BMS-936558
nivolumab
4
7.6.3.5
Current Status of EFS.............................................................................................57
7.6.4
Analysis of Overall Survival....................................................................................57
7.6.4.1
OS Analyses............................................................................................................57
7.6.4.2
Supportive Analyses for OS.....................................................................................58
7.6.4.3
Subset Analyses of OS.............................................................................................59
7.6.4.4
OS Landmark Analyses by pCR and MPR Status.....................................................60
7.6.4.5
Subject Follow-Up..................................................................................................60
7.6.5
Interim Analyses of EFS and OS.............................................................................60
7.6.6
Analysis of TTDM...................................................................................................61
7.6.7
Event Free Survival on Next Line of Therapy..........................................................61
7.6.8
Consistency of Efficacy by Randomization Period...................................................61
7.7
Safety.....................................................................................................................61
7.7.1
Definitive Surgery Related Safety............................................................................62
7.7.2
Deaths ....................................................................................................................62
7.7.3
Serious Adverse Events...........................................................................................62
7.7.4
Adverse Events Leading to Discontinuation of Study Therapy.................................63
7.7.5
Adverse Events Leading to Dose Modification........................................................63
7.7.6
Adverse Events .......................................................................................................63
7.7.7
Select Adverse Events .............................................................................................64
7.7.7.1
Incidence of Select AE ............................................................................................64
7.7.7.2
Time-to Onset of Select AE .....................................................................................64
7.7.7.3
Time-to Resolution of Select AE..............................................................................65
7.7.8
Immune-Mediated Adverse Events ..........................................................................65
7.7.9
Other Events of Special Interest..............................................................................66
7.7.10
Multiple Events.......................................................................................................66
7.7.11
New Primary Cancers.............................................................................................66
7.7.12
Laboratory Parameters...........................................................................................66
7.7.12.1
Hematology ............................................................................................................66
7.7.12.2
Serum Chemistry ....................................................................................................67
7.7.12.3
Electrolytes.............................................................................................................67
7.7.12.4
Additional Analyses................................................................................................67
7.7.13
Vital Signs and Pulse Oximetry...............................................................................68
7.7.14
Physical Measurements ..........................................................................................68
7.7.15
Non-Protocol Medical Procedures..........................................................................68
7.7.16
Immunogenicity Analysis ........................................................................................68
7.7.17
Pregnancy ..............................................................................................................68
7.7.18
Adverse Events By Subgroup ..................................................................................68
7.7.19
Consistency of Safety by Randomization Period......................................................69
7.7.20
Covid-19.................................................................................................................69
7.8
Pharmacokinetics....................................................................................................69
7.9
Biomarkers .............................................................................................................69
7.9.1
PD-L1 Expression ..................................................................................................69
7.9.2
Tumor Mutational Burden (TMB) ...........................................................................71
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Statistical Analysis Plan
CA209816
BMS-936558
nivolumab
5
7.10
Outcomes Research Analyses .................................................................................74
7.11
Country Specific Analyses......................................................................................74
8
CONVENTIONS....................................................................................................75
9
CONTENT OF REPORTS .....................................................................................76
10
DOCUMENT HISTORY........................................................................................76
11
PREVIOUS ANALYSES .......................................................................................79
APPENDIX 1
TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION 
AND CONVENTIONS FOR SELECT ADVERSE EVENTS, 
IMMUNE-MEDIATED ADVERSE EVENTS AND EVENTS OF 
SPECIAL INTEREST............................................................................80
APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS ...............................................82
12
REFERENCES.......................................................................................................84
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LIST OF TABLES
Protocol Amendments ............................................................................13
Time Windows for EQ-5D-3L Assessments ...........................................26
Power Calculation for EFS and OS.........................................................31
Study Therapy Parameter Definitions- Nivolumab and Ipilimumab ........42
Study Therapy Parameter Definitions - Regimen 1: 
Vinorelbine/Cisplatin..............................................................................43
Study Therapy Parameter Definitions - Regimen 2: 
Docetaxel/Cisplatin ................................................................................43
Study Therapy Parameter Definitions - Regimen 3: 
Gemcitabine/Cisplatin ............................................................................44
Study Therapy Parameter Definitions - Regimen 4: 
Pemetrexed/Cisplatin..............................................................................44
Study Therapy Parameter Definitions - Regimen 5: 
Paclitaxel/Carboplatin ............................................................................45
Dose Modifications of Chemotherapeutic Agents (Arms B and C)..........47
Calculated Dose Ranges and Related Dose Levels..................................47
Document History ..................................................................................76
Table 2.4-1:
Table 4.3.7.1-1:
Table 5.3-1:
Table 7.4.1-1:
Table 7.4.1-2:
Table 7.4.1-3:
Table 7.4.1-4:
Table 7.4.1-5:
Table 7.4.1-6:
Table 7.4.2.3-1:
Table 7.4.2.3-2:
Table 10-1:
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LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic.........................................................................12
Figure 4.1.1.1-1:
EFS Primary Definition..........................................................................20
Figure 4.1.1.2-1:
EFS Secondary Definition ......................................................................22
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1
BACKGROUND AND RATIONALE
Approximately 80% of lung cancer cases are non-small cell lung cancer (NSCLC), with most 
patients presenting with late-stage disease. At initial diagnosis, 20% of patients present with stage 
I or II disease, whereas 30% present with stage III disease and 50% with stage IV disease. With 
enhanced lung cancer screening techniques, the percentage of patients diagnosed during the early 
stages may increase over the duration of the trial. A standard TNM staging system is used to 
determine the staging for NSCLC. 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 Surgical resection remains the mainstay of treatment for stage I and II patients; 
however, despite potentially curative surgery, approximately 50% of stage IB and 60-75% of stage 
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 after adjuvant or neoadjuvant chemotherapy.
The phase 3 study, CA209816, will evaluate the clinical efficacy and will establish the safety of 
nivolumab plus platinum doublet chemotherapy and nivolumab plus ipilimumab, in resectable 
lung cancer. Specifically, this study will compare EFS and pCR rate among participants treated 
with neoadjuvant nivolumab plus platinum doublet chemotherapy vs participants treated with 
platinum doublet chemotherapy, and will describe pCR rate and EFS for those treated with 
neoadjuvant nivolumab plus ipilimumab in Stage Ib-IIIa NSCLC.
This document contains description of the statistical analyses that will be conducted for the clinical 
study report (CSR) of study CA209816. 
Research Hypothesis:  
In participants with stage IB (≥4 cm), II or IIIA (N2) NSCLC considered resectable by the local 
multidisciplinary team, administration of neoadjuvant nivolumab plus platinum doublet 
chemotherapy (up to 3 cycles) has superior efficacy to neoadjuvant platinum doublet 
chemotherapy (up to 3 cycles).
Schedule of Analyses:
Formal analysis of Pathological Complete Response (pCR) will occur after the 350 randomized 
participants on Arms B and C from start of 1:1:1 randomization have an opportunity for surgery 
and is projected to occur approximately 30 months after 1:1:1 randomization.
Two formal interim analyses for Event Free Survival (EFS) are planned after 148 and 167 events 
have been observed on Arms B and C after start of 1:1:1 randomization, respectively. The second 
interim analysis may take place one year after the first interim analysis in case the required number 
of events is not yet reached at that time. This is projected to occur approximately 48 and 58 (or 
max 60) months after start of 1:1:1 randomization. The formal interim comparisons of EFS will 
allow for determination of superiority. If the study continues beyond these interim analyses, the 
final analysis will be conducted after approximately 185 EFS events have been observed on Arms 
B and C from start of 1:1:1 randomization, or at a maximum 4 years after the last subject’s 
randomization (December 2023). 
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2
STUDY DESCRIPTION
2.1
Study Design
This is an open-label, randomized clinical trial of up to 3 cycles of neoadjuvant nivolumab 
(3 mg/kg every 2 weeks) and a single dose of 1 mg/kg dose of ipilimumab, nivolumab 360mg flat 
dose plus platinum doublet chemotherapy (up to 3 cycles), or platinum doublet chemotherapy (up
to 3 cycles) as neoadjuvant treatment in participants with early stage (Stage IB [≥4 cm], II, and 
resectable IIIA [N2]) NSCLC. 
The original study design (before revised protocol 02) had two arms. After signing the informed 
consent form and upon confirmation of the participant’s eligibility, participants were randomized 
in an open-label fashion (1:1 ratio) to either neoadjuvant nivolumab plus ipilimumab or platinum 
doublet chemotherapy.
Revised protocol 02 added a new, neoadjuvant nivolumab plus platinum doublet chemotherapy 
arm. When the third arm had opened and as each site had received IRB/EC approval of revised 
protocol 02, the interactive response technology IRT switched to a 1:1:1 randomization at the 
respective site.  Starting from that point on, the sites were only enrolling under revised protocol 
02. 
Revised protocol 03 withholds randomization into the arm of neoadjuvant nivolumab plus 
ipilimumab but continues randomizing eligible participants into either neoadjuvant nivolumab plus 
platinum doublet chemotherapy arm or platinum doublet chemotherapy arm. Participants already 
randomized in the original 2-arm part (neoadjuvant nivolumab plus ipilimumab vs neoadjuvant 
chemotherapy) and in the arm of neoadjuvant nivolumab plus ipilimumab in 3-arm part defined 
by revised protocol 02 will remain in trial and continue scheduled trial procedures. The primary 
population for comparisons of the primary endpoints is the subjects concurrently randomized in 
arms B and C (as of revised protocol 02).
As of Revised protocol 03, participants will be randomized between 2 arms in a 1:1 ratio to 
neoadjuvant nivolumab plus platinum doublet chemotherapy or platinum doublet chemotherapy. 
Eligible participants will be stratified by:
•
PD-L1 expression (≥1% or <1%/not evaluable/indeterminate)
•
Disease stage (IB/II vs IIIA)
•
Gender
The treatment arms are as follows:
Arm A treatment: Participants randomized into Arm A received nivolumab 3 mg/kg IV over 30 
minutes every 2 weeks for up to 3 doses (ie, 6 weeks of treatment; each cycle is 14 days). With 
Cycle 1 only, nivolumab was followed by a single dose ipilimumab 1 mg/kg IV over 30 minutes.
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Arm B treatment: Participants randomized into Arm B will receive investigator-choice platinum 
doublet chemotherapy in 3-week cycles up to a maximum of 3 cycles (ie, 9 weeks of treatment; 
each cycle is 21 days):
•
Regimen 1: 
−
Vinorelbine 25 mg/m2 or 30 mg/m2 IV (per local prescribing information) push over 
10 minutes or per institutional standard on Days 1 and 8
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following vinorelbine
•
Regimen 2:
−
Docetaxel 60 mg/m2 or 75 mg/m2  IV (per local prescribing information) over 60 minutes 
or per institutional standard on Day 1
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following docetaxel
•
Regimen 3 (squamous histology):
−
Gemcitabine 1000 mg/m2 or 1250 mg/m2 (per local prescribing information) IV over 
30 minutes or per  institutional standard on Days 1 and 8
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following gemcitabine
•
Regimen 4 (non-squamous histology only):
−
Pemetrexed 500 mg/m2 IV over 10 minutes or per institutional standard on Day 1
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following pemetrexed
•
Regimen 5:
−
Paclitaxel 175 or 200 mg/m2 IV over 180 minutes or per institutional standard on Day 1
−
Carboplatin AUC 5 or 6 IV over 30 minutes or per institutional standard on Day 1, 
immediately following paclitaxel
Arm C treatment: Participants randomized into Arm C will receive nivolumab 360 mg IV plus 
platinum doublet chemotherapy in 3-week cycles up to a maximum of 3 cycles of chemotherapy 
(ie, 9 weeks of treatment; each cycle is 21 days)
•
Non-squamous NSCLC: nivolumab at a flat dose of 360 mg as 30-minute IV infusion on Day 
1, followed by pemetrexed at a dose of 500 mg/m2 IV over 10 minutes or per institutional 
standard and cisplatin at a dose of 75 mg/m² IV over 120 minutes or per institutional standard 
of a 3-week treatment cycle, for up to 3 cycles.
•
Squamous NSCLC: nivolumab at a dose of flat dose of 360 mg as 30 minute IV infusion on 
Day 1, followed by gemcitabine at a dose of 1000 mg/m2 or 1250 mg/m2 (per local prescribing 
information) for a 30 minute IV infusion or per institutional standard and cisplatin at a dose of 
75 mg/m2 as a 120-minute IV infusion or per institutional standard, of a 3-week treatment cycle 
for up to 3 cycles. Gemcitabine will also be administered at a dose of 1000 mg/m2 or 
1250 mg/m2 as a 30 minute IV infusion or per institutional standard on day 8 of each 3-week 
treatment cycle.
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•
Any histology: nivolumab at a flat dose of 360 mg as 30-minute IV infusion on Day 1, followed 
by paclitaxel 175 or 200 mg/m2 IV over 180 minutes or per institutional standard and 
carboplatin AUC 5 or 6 IV over 30 minutes or per institutional standard of a 3-week treatment 
cycle, for up to 3 cycles.
Following the completion of neoadjuvant treatment, all participants who remain operative 
candidates will undergo definitive surgery for their NSCLC within 6 weeks after completing 
neoadjuvant treatment. 
Following definitive surgery, participants in each arm may receive up to 4 cycles of adjuvant 
chemotherapy with or without radiation per institutional standard at the discretion of the 
investigator. Investigators may choose from the following post-operative regimens:
•
Regimen 1:
−
Vinorelbine 25 mg/m2 or 30 mg/m2 IV (per local prescribing information) push over 
10 minutes or per institutional standard on  Days 1 and 8
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following vinorelbine
•
Regimen 2:
−
Docetaxel 60 mg/m2 or 75 mg/m2 IV (per local prescribing information) over 60 minutes 
or per institutional standard on Day 1
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following docetaxel
•
Regimen 3 (squamous histology):
−
Gemcitabine 1000 mg/m2 or 1250 mg/m2 IV (per local prescribing information) over 
30 minutes or per institutional standard on Days 1 and 8
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following gemcitabine
•
Regimen 4 (non-squamous histology only):
−
Pemetrexed 500 mg/m2 IV over 10 minutes or per institutional standard on Day 1
−
Cisplatin 75 mg/m2 IV over 120 minutes or per institutional standard on Day 1, 
immediately following pemetrexed
•
Regimen 5:
−
Paclitaxel 175 or 200 mg/m2 IV over 180 minutes or per institutional standard on Day 1
−
Carboplatin AUC5 or 6 IV over 30 minutes or per institutional standard on Day 1, 
immediately following paclitaxel
The study design schematic is presented in Figure 2.1-1.
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Figure 2.1-1:
Study Design Schematic
A Data Monitoring Committee (DMC) will be established to provide oversight of safety and 
efficacy and overall risk/benefit monitoring of the study.
Note that in this document the words “participant” and “subject” are used intercheangeably. 
2.2
Treatment Assignment
CA209816 is an open-label, randomized trial. Participants with Stage IB (≥4 cm), II and IIIA (N2) 
considered resectable will be eligible to participate. After the participant’s initial eligibility is 
established and informed consent has been obtained, the participant must be enrolled into the study 
by calling the IRT to obtain a participant number. Every participant that signs the informed consent 
form must be assigned a participant number in IRT. 
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be ready to be 
randomized through IRT to treatment Arm A, Arm B or Arm C.
In the original study design (before revised protocol 02) subjects were randomized to in a 1:1 ratio 
to arms A or B.
Following revised protocol 02, subjects were randomized to in a 1:1:1 ratio to arms A, B or C.
As of revised protocol 03, subjects were randomized to in a 1:1 ratio to arms B or C.
•
Arm A: nivolumab 3 mg/kg plus ipilimumab 1 mg/kg.
•
Arm B: platinum doublet chemotherapy.
•
Arm C: nivolumab 360mg flat dose plus platinum doublet chemotherapy
The randomization uses permuted blocks stratified by the following factors:
•
PD-L1 expression (≥1% or <1%/not evaluable/indeterminate)
•
Disease stage (IB/II vs IIIA)
•
Gender
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2.3
Blinding and Unblinding
This is an open-label study; blinding procedures between participants and investigators are not 
applicable. The specific treatment to be taken by a participant will be assigned using an IRT. No 
aggregate summary data by treatment group are disclosed to the study team at any time of the 
study conduct until achievement of primary endpoint significance (pCR). 
As described in the DMC charter, at the time of the first EFS interim analysis, in case EFS is not 
significant, the closed DMC report (unblinded) will still be shared with a BMS executive restricted 
team (3 persons named in DMC charter) to possibly engage in conversation with health authorities 
based on a trend in EFS (even if not significant), in the context of a statistically significant result 
in the pCR primary endpoint. 
After discussion with health authorities, the BMS Executive restricted team may decide to share 
the DMC closed report with limited additional BMS members in order to prepare a broader health 
authority interaction. These additional BMS members will be outside of the CA209816 study team 
in addition to a small number of oncology leaders who would remain firewalled to the study in 
case the decision following health authorities interaction would be not to proceed to application. 
The members of this health authority interaction preparation team will be documented in a BMS 
internal document prior to the DMC meeting.
After formal discussion with FDA, should BMS proceed with an application for registration, the 
BMS study team will be unblinded to the study results and data.
Treatment assignments will be released to the bioanalytical laboratory in order to minimize 
unnecessary analysis of samples. 
The blinded independent pathology review (BIPR) and blinded independent central review (BICR)
will be blinded to treatment arms.
2.4
Protocol Amendments
Table 2.4-1:
Protocol Amendments
Document/Date of Issue
Summary of Change
Revised Protocol 07
Under finalization
To account for potential slowdown in event-free 
survival (EFS) events accrual in long-term follow-up 
the revised protocol was updated to:
•
Revise EFS modeling assumptions to a piecewise 
exponential with lower events rate in the longer 
term.
•
Include one additional EFS interim analysis at 90% 
information fraction 
 
Revised Protocol 06
•
Clarified EFS definition
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Table 2.4-1:
Protocol Amendments
Document/Date of Issue
Summary of Change
14-Jul-2020
•
Removed the 1st interim analysis of EFS and 
updated alpha spending of interim and final 
analyses of EFS
•
Clarified that actual timing of analyses may differ 
from projected timin
•
Removed text about descriptive EFS analysis
Revised Protocol 05
18-Sep-2019
•
Modified pCR analysis population and projected 
timelines.
−
Rationale: based on FDA feedback indicating 
that the subset of 260 patients might not yield
adequate numbers of patients with a pCR upon 
which to base reasonable assumptions of 
clinical meaningfulness. 
•
Updated surgical approach endpoint
•
Updated the censoring rule of TTDM
•
No optional biopsy at disease progression collected 
in China.
•
Updated Management Algorithms to include 
myocarditis
Revised Protocol 04
25-Jun-2019
•
Added 
the 
concomitant 
administration 
of 
substances that are also tubularly secreted (eg, 
probenecid) could potentially result in delayed 
clearance of pemetrexed.
•
Added hypothesis testing for overall survival
•
Clarified the pCR analysis population
•
Added exploratory endpoint of Event Free Survival 
on next line of therapy
•
Added instructions for BICR
•
Updated Appendix 8 Adverse Events and Serious 
Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow Up and Reporting 
Adverse Events
Revised Protocol 03
21-Sep-2018
•
Enrollment in Arm A (nivolumab plus ipilimumab) 
was stopped. Based on external data from a neo-
adjuvant phase 
II 
trial 
(NADIM4) which 
suggested anti-PD-1 + chemotherapy to be more 
promising, clinical development of nivolumab + 
chemotherapy was prioritized.
•
Randomization of participants (1:1 ratio) into Arm 
C and B will continue to for a total of 350 
participants
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Table 2.4-1:
Protocol Amendments
Document/Date of Issue
Summary of Change
•
Definition of event free survival is clarified.
•
Participants 
with 
large-cell 
neuroendocrine 
carcinoma tumor histology are excluded
•
Additional 
platinum 
doublet 
chemotherapy 
regimen (paclitaxel/carboplatin) was added
•
Dose modification for docetaxel was updated
•
Time to death or distant metastases (TTDM) was 
added to secondary endpoints.
•
Tumor assessments for participants who do not 
proceed to definitive surgery was clarified
•
Endpoints 
and 
statistical 
analyses 
adapted 
consequently to Arm A discontinuation.
•
Rationale, background information, and trial 
schematic were updated
•
Pulmonary function parameters were clarified
•
Time relationship between adjuvant radiotherapy 
and tumor imaging assessments was clarified
•
Time window of Cycle 1 Day 1 end-of-infusion PK 
sampling for Arm A and C was clarified
Revised Protocol 02
06-Jul-2017
•
Nivolumab plus platinum-doublet chemotherapy 
arm (Arm C) was added.
•
The sample size was increased to 642 participants 
consequently to the addition of Arm C and change 
of primary endpoint.
•
The primary objective was changed to multiple 
primary objectives of event free survival and 
pathological complete response; major pathological 
response was changed to the secondary objective.
•
Additional rationale and background information 
was provided.
•
Pre-screening tissue requirement was increased 
from minimum of 10 slides to 15 slides.
•
Contrast requirements for brain MRI scans were 
updated.
•
Time window for pulmonary function test window 
was 
expanded 
from 
within 
28 
days 
of 
randomization to within 6 weeks of randomization.
•
Synopsis was updated with exploratory objectives, 
endpoints and schema.
•
Language in treatment administered was deleted 
and reference to Investigator Brochure and 
Pharmacy Manual was included.
Revised Protocol 01
•
Incorporates Amendment 02 and Administrative 
Letters 01 and 02
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Table 2.4-1:
Protocol Amendments
Document/Date of Issue
Summary of Change
03-Mar-2017
Amendment 02
03-Mar-2017 
•
To adjust the dosing details of the chemotherapy 
regimens to include the dose approved by the local 
prescribing information and the standard of care 
infusion time for each country included in this 
study.
•
To expand and to split the broad biomarker 
objective into 3 more detailed objectives.
•
Clarify lymph node samples at screening and at 
definitive surgery.
•
Clarify requirements for PET/CT scans and 
broadening the window of scans prior to surgery.
•
Clarify tissue sample process for calculation of the 
primary endpoint.
•
Adjust Hepatitis B Virus criteria.
•
Added live vaccines and strong CYP3A4 inhibitors 
to the Prohibited Treatments.
•
added caution for concomitant administration of 
NSAIDs with pemetrexed
•
added unacceptable methods of contraception to 
Appendix 6.
Administrative Letter 02
30-Nov-2017
•
Clarify the correct version of the TNM Staging 
System.
•
Clarify that a minimum of 228 PD-L1+ participants 
will be randomized.
•
Clarify that physical exams, vital signs, and 
physical measurements should be collected prior to 
each dose of neoadjuvant and adjuvant therapy.
•
Clarify that the first post-operative tumor 
assessment should be performed 12 weeks (± 7 
days) after definitive surgery.
•
Remove the phrase “non-protocol regimen” in 
regards to a noncisplatin
•
Regimen as the protocol includes a non-cisplatin 
regimen option.
•
Clarify that weight-based dosing should be rounded 
up to the nearest milligram or per institutional 
standards.
•
Clarify that the EQ-5D-3L should be collected prior 
to Day 1 only in cycles that have multiple dosing 
days in each cycle.
Administrative Letter 01
31-Oct-2017
•
To correct the IND number
Original Protocol
•
Not Applicable
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Table 2.4-1:
Protocol Amendments
Document/Date of Issue
Summary of Change
30-Sep-2016
2.5
Data Monitoring and Other External Committees
A Data Monitoring Committee (DMC) is established to provide oversight of safety and efficacy 
considerations in protocol CA209816. Additionally, the DMC will provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of participants 
enrolled in the study. The DMC will be charged with assessing such actions in light of an 
acceptable benefit/risk profile for nivolumab in combination with ipilimumab or chemotherapy. 
The DMC will act in an advisory capacity to BMS and will monitor participant safety and evaluate 
the available efficacy data for the study. The oncology therapeutic area of BMS has primary 
responsibility for design and conduct of the study.
Independent pathology (BIPR) and radiology review (BICR) will be established for central review 
and confirmation of efficacy endpoints.
3
OBJECTIVES
3.1
Primary
•
To compare the event-free survival (EFS) by BICR in participants receiving nivolumab plus 
platinum doublet chemotherapy vs participants receiving platinum doublet chemotherapy in 
operable stage IB (≥4 cm), II, or resectable IIIA (N2) NSCLC
•
To compare the pathologic complete response (pCR) rate in participants receiving nivolumab 
plus platinum doublet chemotherapy vs participants receiving platinum doublet chemotherapy 
in operable stage IB (≥4 cm), II, or resectable IIIA (N2) NSCLC
3.2
Secondary
•
To assess the major pathologic response (MPR) rate by BIPR of participants receiving 
nivolumab plus platinum doublet chemotherapy vs participants receiving platinum doublet 
chemotherapy in operable stage IB (≥4 cm), II, or resectable IIIA (N2) NSCLC
•
To assess the OS of participants receiving nivolumab plus platinum doublet chemotherapy vs 
participants receiving platinum doublet chemotherapy in operable stage IB (≥4 cm), II, or 
resectable IIIA (N2) NSCLC
•
To assess the time to death or distant metastases (TTDM) of participants receiving nivolumab 
plus platinum doublet chemotherapy vs participants receiving platinum doublet chemotherapy 
in operable stage IB (≥4 cm), II, or resectable IIIA (N2) NSCLC
3.3
Exploratory Objectives
•
To assess clinical response rate (cRR) by BICR of participants receiving nivolumab plus 
platinum doublet chemotherapy vs participants receiving platinum doublet chemotherapy in 
operable stage IB (≥4 cm), II, or resectable IIIA (N2) NSCLC
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•
To assess the pCR rate, MPR rate , cRR, EFS, TTDM and OS in early-stage NSCLC 
participants treated with nivolumab plus platinum doublet chemotherapy compared to those 
treated with platinum doublet chemotherapy by PDL1 status (PD-L1 ≥1% , PD L1< 1% /not 
evaluable/ indeterminate)
•
To assess the feasibility of surgery and rate of peri- and post-operative complications (within 
90 days of surgery) in participants receiving  nivolumab plus platinum doublet chemotherapy 
compared to participants receiving platinum doublet
•
To assess the safety and tolerability of nivolumab plus platinum doublet chemotherapy 
compared to platinum doublet chemotherapy in early stage NSCLC
•
To describe the pCR rate, MPR rate, cRR, EFS, OS, TTDM, feasibility of surgery, rate of peri-
and post-operative complications (within 90 days of surgery), safety and tolerability in early-
stage NSCLC participants treated with nivolumab plus ipilimumab and by PDL1 status (PD-
L1 ≥1% , PD L1< 1%/not evaluable/indeterminate)
•
To assess pharmacokinetics of the nivolumab plus ipilimumab or nivolumab plus platinum 
doublet chemotherapy in participants with early stage NSCLC
•
To assess the participant’s overall health status and health utility using the 3-level version of 
the EQ-5D-3L visual analog scale (VAS) and utility index, respectively
•
To evaluate tumor mutational burden as a potential predictive biomarker of efficacy (such as 
EFS and OS) of nivolumab plus platinum doublet chemotherapy and of platinum-doublet 
chemotherapy, using data generated from tumor and blood (germ-line control) specimens.
•
To explore potential predictive biomarkers of  nivolumab plus platinum doublet chemotherapy 
efficacy (such as EFS and OS) in peripheral blood and tumor specimens
 
 
 
 
4
ENDPOINTS
4.1
Primary Endpoint(s)
The primary objectives in the study will be evaluated by the multiple primary endpoints of EFS 
and pCR.
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4.1.1
Event-Free Survival
Two definitions are used for analysis of EFS. The primary definition accounts for subsequent 
therapy by censoring at the last evaluable tumor assessment on or prior to the date of subsequent 
therapy (outside of the protocol specified adjuvant therapy). The secondary definition does not 
incorporate censoring due to subsequent therapy. 
EFS rate at time T is defined as the probability that a subject has not progressed/recurred and is 
alive at time T following randomization. EFS rates at fixed time points (e.g. 12 months, depending 
on the minimum follow-up) are defined as the probability that a subject has not progressed and is 
alive at time T following randomization.
4.1.1.1
Primary Definition of Event-Free Survival
Event free survival is defined as the length of time from randomization to any of the following 
events: any progression of disease precluding surgery, progression or recurrence disease after 
surgery (based on BICR assessment per RECIST 1.1), or death due to any cause. 
•
A pre-surgical progression (even if reaching the RECIST 1.1 criteria) which does not preclude 
surgery is not considered as an event. 
•
A progression not reaching the RECIST 1.1 criteria (e.g. clinical progression) but which still 
precludes surgery (i.e. reason for no surgery is disease progression) is considered as an event
(event at the investigator reported earliest clinical or radiographic progression date, or at the 
date of randomization if no progression date reported). 
•
For participants with surgery, any new lesions identified by BICR on the first post-surgical 
baseline imaging compared with the pre-surgical scans will be identified as new lesion and 
will be counted as an event. For those without new lesion on the first post-surgical scan, the 
first tumor assessment post surgery will be used as re-baseline and recurrence/progression per 
RECIST 1.1 by BICR will be evaluated based on that re-baseline.
•
Participants who do not undergo surgery for reason other than progression will be considered 
to have an event at RECIST 1.1 progression (based on BICR) or death.
•
Participants who died without a reported progression/disease recurrence will be considered to 
have experienced an event on the date of their death. 
The following censoring rules will be applied for the primary definition of EFS:
•
Participants who did 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.
•
Subjects who receive subsequent anti-cancer therapy, outside of the protocol-specified 
adjuvant therapy, prior to documented progression/recurrence/death will be censored at the 
date of the last evaluable tumor assessment conducted on or prior to the date of initiation of 
the subsequent anti-cancer therapy.
•
Subjects who did not have a documented progression/recurrence/death and received 
subsequent anti-cancer therapy outside of the protocol-specified adjuvant therapy will be 
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censored at the date of the last evaluable tumor assessment conducted on or prior to the 
initiation of the subsequent anti-cancer therapy.
•
Participants without baseline scan and without surgery will be censored on the date of 
randomization (regardless of death).
•
Censoring rules for the primary definition of EFS (EFS truncated at subsequent therapy) are
presented as follows and depicted in Figure 4.1.1.1-1.
•
It is to be noted that in case of new primary cancer, if such lesions are present on tumor 
assessment at the BICR, they will be considered as new lesions, since the BICR does not have 
access to biopsy results.
Figure 4.1.1.1-1:
EFS Primary Definition
•
4.1.1.2
Secondary Definition of Event-Free Survival
The secondary definition of EFS (ITT definition) is defined as the length of time from 
randomization to any of the following events: any progression of disease precluding surgery, 
progression or recurrence disease after surgery (based on BICR assessment per RECIST 1.1), or 
death due to any cause. 
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•
Progression/recurrence will be based on BICR assessment per RECIST 1.1. 
•
A progression (even if reaching the RECIST 1.1 criteria) which does not preclude surgery is 
not considered as an event. 
•
A progression not reaching the RECIST 1.1 criteria but which still precludes surgery (i.e. 
reason for no surgery is disease progression) is considered as an event (event at the investigator 
reported earliest clinical or radiographic progression date, or at the date of randomization if no 
progression date reported). 
•
For participants with surgery, the first tumor assessment post surgery will be used as re-
baseline and recurrence/progression per RECIST 1.1 will be evaluated based on that re-
baseline. Any new lesions on the post-surgical baseline imaging compared with the pre-
surgical scans will be identified as new lesion and will be counted as an event.
•
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 died without a reported progression/disease recurrence will be considered to 
have experienced an event on the date of their death. 
The following censoring rules will be applied for the secondary definition of EFS:
•
Participants who did 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 without baseline scan and without surgery will be censored on the date of 
randomization (regardless of death).
•
Censoring rules for the secondary definition of EFS (ITT definition) are presented as follows 
and depicted in Figure 4.1.1.2-1
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Figure 4.1.1.2-1:
EFS Secondary Definition
4.1.2
Pathologic Complete Response Rate
Pathological complete response (pCR) rate is defined as number of randomized participants with 
absence of residual tumor in lung and lymph nodes at surgery as evaluated by blinded independent 
pathological review (BIPR), divided by the number of randomized participants for each treatment 
group. Randomized subjects who are no longer eligible for surgery, or who are on alternative anti-
cancer therapy before surgery, or who discontinue the study (e.g. withdraw consent) before 
surgery, or who otherwise do not have an evaluable BIPR result available are all counted as non-
responders.
4.2
Secondary Endpoint(s)
4.2.1
Overall Survival
Overall survival (OS) is defined as the time between the date of randomization and the date of 
death due to any cause. For a subject without documentation of death, OS will be censored on the 
last date the subject was known to be alive.
4.2.2
Major Pathological Response Rate
Major pathological response (MPR) rate, defined as number of randomized participants with ≤
10% residual tumor in lung and lymph nodes at surgery as evaluated by BIPR, divided by the 
number of randomized participants for each treatment group. Viable tumors in situ carcinoma 
should not be included in MPR calculation. Randomized subjects who are no longer eligible for 
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surgery, or who are on alternative anti-cancer therapy, or who discontinue the study (e.g. withdraw 
consent) before surgery, or who otherwise do not have an evaluable BIPR result available are all 
counted as non-responders.
4.2.3
Time to Death or Distant Metastases
Time to Death or Distant Metastates (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 using BICR 
according to RECIST 1.1. It will be derived based on the location of lesions outside the thorax. 
Participants who died without reported distant metastasis will be considered to have experienced 
an event on the date of their death. 
The following censoring rules will be applied TTDM:
•
Participants who have not developed distant metastasis nor died 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.
4.3
Exploratory Endpoint(s)
4.3.1
Clinical Response Rate by BICR
Clinical response rate (cRR) is defined as proportion of randomized participants whose overall 
radiological response prior to definitive surgery (or best overall radiological response (BOR) at
the first protocol planned tumor assessment if a subject has no surgery) is either a complete 
response (CR) or partial response (PR) per RECIST 1.1 criteria by BICR. Participants who 
received alternative anti-cancer therapy before the pre-surgery tumor assessment will be counted 
as non-responders.
4.3.2
Event Free Survival on Next Line of Therapy (EFS2)
EFS on next line therapy (EFS2) is defined as the time from randomization to objectively 
documented progression, per investigator assessment, after the next line of therapy or to death 
from any cause, whichever occurs first. Subjects who were alive and without progression after the 
next line of therapy will be censored at last known alive date. 
The following censoring rules will be applied for EFS2:
•
Subjects who did not receive subsequent next line systemic anti-cancer therapy:
−
Subjects who died, the death date is the event date;
−
Else the subject’s EFS2 is censored at the last known alive date.
•
Subjects who received subsequent next line anti-cancer therapy:
−
Subjects who had a disease recurrence/progression after the start of subsequent anti-cancer 
therapy, this disease progression date is the event date;
−
Else if a subject died or start of second next line therapy, the date of min (death, start date 
of second next line therapy) is the event date;
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−
Else the subject’s EFS2 is censored at the last known alive date.
Subsequent next line of therapy will include subsequent systemic regimen given in one of the 
following settings Unresectable, Locally Advanced or lines of therapy in metastatic setting.
4.3.3
Surgery Related Endpoints
The endpoints related to surgery include proportion of subjects with delayed (including duration 
of delay) or canceled surgery, duration of surgery, length of hospital stay, surgical approach, 
including completeness of surgery (R0/R1/R2 resection), incidence of AE/SAE associated with 
surgery up to 90 days after surgery.
4.3.4
Safety and Tolerability
The assessment of safety will be based on the incidence of adverse events (AEs), serious adverse 
events (SAEs), adverse events leading to discontinuation, adverse events leading to dose 
modification, select adverse events (select AEs) for EU/ROW Submissions, immune-mediated 
AEs (IMAEs) for US Submission, other events of special interest (OEOSI), and deaths. The use 
of immune modulating concomitant medication will be also summarized. In addition clinical 
laboratory tests will be analyzed.
4.3.5
Pharmacokinetics
Pharmacokinetics will be measured by the serum concentration of nivolumab and ipilimumab. 
Samples will be collected to characterize pharmacokinetics of nivolumab and ipilimumab and to 
explore exposure-safety and exposure-efficacy relationships. The population pharmacokinetics 
analysis will be presented separately from the main clinical study report.
4.3.6
Biomarkers
Biomarkers potentially associated with clinical endpoints will be measured by analyzing tumor 
and blood samples.
Biomarker endpoints include, but not limited to, tumor mutational burden (TMB) using data 
generated from tumor specimens., tumor inflammatory gene expression signatures using data 
generated from tumor specimen
 
 
 
 Results for biomarkers analyses (other than PD-L1, TMB
) will be 
summarized outside of CSR.
4.3.6.1
Tumor Mutational Burden
TMB is measured in CA209816 using the 
 assay. 
 is a next-generation sequencing (NGS) assay targeting the full coding regions of 523 
genes implicated in the pathogenesis of solid tumors. Using enrichment-based library preparation 
techniques for use with formalin-fixed, paraffin-embedded (FFPE) samples, 
 can analyze 
DNA and RNA from the same sample, detecting single nucleotide variants (SNVs), insertions and 
deletions (indels), amplifications, splice variants, and fusions, in a single sequencing run. TMB, is 
derived by summing the total of all synonymous and non-synonymous detected small DNA 
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variants (SNVs and indels) across the entire coding region (~1.3Mb are in coding regions) with 
sophisticated variant calling and germline filtering algorithms for enhanced accuracy. The 
resulting number is communicated as mutations per Mb unit (mut/Mb). The cutoff used for 
analysis will be ≥12.3 mut/Mb, <12.3 mut/Mb5.
4.3.6.2
PD-L1 Protein Expression
PD-L1 expression is defined as the percent of tumor cells membrane staining in a minimum of 100 
evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is 
referred to as quantifiable PD-L1 expression. If the PD-L1 staining could not be quantified, it is 
further classified as:
1) Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology 
of the tumor tissue sample and not because of improper sample preparation or handling.
2) Not evaluable: Tumor tissue sample was not optimally collected or prepared and PD-L1 
expression is neither quantifiable nor indeterminate. Not evaluable can be determined from 
H&E process before the tumor biopsy specimen is sent for PD-L1 evaluation or from the H&E 
process during PD-L1 evaluation.
Subjects with missing PD-L1 expression are subjects with no tumor tissue sample available for 
evaluation.
PD-L1 expression will be collected in the IRT as well as in the clinical database. Statistical analysis 
using PD-L1 expression will be solely based on PD-L1 expression data from clinical database.
Stratified analyses will use stratification from IRT, unless otherwise specified.
4.3.7
Outcomes Research
4.3.7.1
EQ-5D-3L
Subjects’ reports of general health status will be assessed using the EuroQoL Group’s EQ-5D-3L. 
EQ-5D-3L essentially has 2 components: the descriptive system and the visual analogue scale 
(VAS).
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, 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. For this study, EQ-5D-3L utility index 
values will be computed using a scoring algorithm based on the United Kingdom Time-Trade-Off 
(UK TTO) value set6
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In addition, the EQ-5D-3L includes a VAS, which allows respondents to rate their own current 
health on a 101-point scale ranging from 0=”worst imaginable” health to 100=“best imaginable” 
health state 7.
All questionnaires completed at baseline and on-study will be assigned to a time-point according 
to the windowing criteria in Table 4.3.7.1-1 and included in the analysis. In case a subject has two 
on-study assessments within the same window, the assessment closest to the time-point will be 
used and, in the case of two assessments at a similar distance to the time-point, the latest one will 
be chosen. In the event where the subject has no assessment at all in a specific window, the 
observation will be treated as missing for that time-point.
Table 4.3.7.1-1:
Time Windows for EQ-5D-3L Assessments
Time Point
Nominal Day
Time Window
Baseline
D1
Prior to first dose on Day 1
Week 3 (Arm A)
D15
Day 2 thru day 22 inclusive
Week 4 (Arms B and C)
D22
Day 2 thru day 32 inclusive
Week 5 (Arm A)
D29
Day 23 thru day 36 inclusive
Week 7 (Arms B and C)
D43
Day 33 thru day 53 inclusive
Post-neoadjuvant visit 1
Last neodajuvant dose + 30 
days
Assessment post last neoadjuvant dose and 
within 65 days of last neo dose
Post-neoadjuvant visit 2
Last neodajuvant dose + 100 
days
Assessment post 65 days of last neoadjuvant
dose and within 145 days of last neo dose
Subjects without 
adjuvant:
Survival Follow-up 1
Last neodajuvant dose + 190 
days
Assessment post 145 days of last neoadjuvant
dose and within 235 days of last neo dose
Survival Follow-up 2
Last neodajuvant dose + 280 
days
Assessment post 235 days of last neoadjuvant
dose and within 325 days of last neo dose
Survival Follow-up 3
Last neodajuvant dose + 370 
days
Assessment post 325 days of last neoadjuvant
dose and within 415 days of last neo dose
Survival Follow-up 4
Last neodajuvant dose + 460 
days
Assessment post 415 days of last neoadjuvant
dose and within 550 days of last neo dose
Survival Follow-up 5
Last neodajuvant dose + 640 
days
Assessment post 550 days of last neoadjuvant
dose and within 730 days of last neo dose
Survival Follow-up 6
Last neodajuvant dose + 820 
days
Assessment post 730 days of last neoadjuvant
dose and within 910 days of last neo dose
Then Survival Follow-up i
Last neodajuvant dose + 460 + 
(i-4)*180 days
Assessment post (nominal day - 90) days of last 
neoadjuvant dose and within (nominal day + 90) 
days of last neo dose
Subjects with systemic 
adjuvant:
Adjuvant Cycle 1
-
Assessment reported in the F01 (adjuvant cycle 
1) visit
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Table 4.3.7.1-1:
Time Windows for EQ-5D-3L Assessments
Time Point
Nominal Day
Time Window
Adjuvant Cycle 2
-
Assessment reported in the F02 (adjuvant cycle 
2) visit
Adjuvant Cycle 3
-
Assessment reported in the F03 (adjuvant cycle 
3) visit
Adjuvant Cycle 4
-
Assessment reported in the F04 (adjuvant cycle 
4) visit
Survival Follow-up 1
Max (Last adjuvant systemic 
dose or Post-neoadjuvant visit) 
+ 90 days
Assessment post 45 days of Max (Last adjuvant 
dose or Post-neoadjuvant visit) and within 135 
days of Max (Last adjuvant dose or Post-
neoadjuvant visit)
Survival Follow-up 2
Max (Last adjuvant systemic 
dose or Post-neoadjuvant visit) 
+ 180 days
Assessment post 135 days of Max (Last 
adjuvant dose or Post-neoadjuvant visit) and 
within 225 days of Max (Last adjuvant dose or 
Post-neoadjuvant visit)
Survival Follow-up 3
Max (Last adjuvant systemic 
dose or Post-neoadjuvant visit) 
+ 270 days
Assessment post 225 days of Max (Last 
adjuvant dose or Post-neoadjuvant visit) and 
within 315 days of Max (Last adjuvant dose or 
Post-neoadjuvant visit)
Survival Follow-up 4
Max (Last adjuvant systemic 
dose or Post-neoadjuvant visit) 
+ 360 days
Assessment post 315 days of Max (Last 
adjuvant dose or Post-neoadjuvant visit) and 
within 450 days of Max (Last adjuvant dose or 
Post-neoadjuvant visit)
Survival Follow-up 5
Max (Last adjuvant systemic 
dose or Post-neoadjuvant visit) 
+ 540 days
Assessment post 450 days of Max (Last 
adjuvant dose or Post-neoadjuvant visit) and 
within 630 days of Max (Last adjuvant dose or 
Post-neoadjuvant visit)
Survival Follow-up 6
Max (Last adjuvant systemic 
dose or Post-neoadjuvant visit) 
+ 720 days
Assessment post 630 days of Max (Last 
adjuvant dose or Post-neoadjuvant visit) and 
within 810 days of Max (Last adjuvant dose or 
Post-neoadjuvant visit)
Then Survival Follow-up i
Max (Last adjuvant systemic 
dose or Post-neoadjuvant visit) 
+ 360 + (i-4)*180 days
Assessment post (nominal day - 90) days of last 
neo dose and within (nominal day + 90) days of 
last neo dose
5
SAMPLE SIZE AND POWER
The original study design (before Revised protocol 02) had two arms, with participants randomized 
in a 1:1 ratio to either neoadjuvant nivolumab plus ipilimumab or platinum doublet chemotherapy 
arm. Revised protocol 02 added a new, neoadjuvant nivolumab plus platinum doublet 
chemotherapy arm. When the third arm opens and as each site receives IRB/EC approval of revised 
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protocol 02, the IRT will switch to a 1:1:1 randomization at the respective site.  Starting from that 
point on, the site will only enroll under revised protocol 02. 
Revised protocol 03 withholds randomization into the arm of neoadjuvant nivolumab plus 
ipilimumab but continues randomizing eligible participants into either neoadjuvant nivolumab plus 
platinum doublet chemotherapy arm or platinum doublet chemotherapy arm in a 1:1 ratio. 
Approximately 350 participants (175 participants per arm) will be randomized between 2 arms 
neoadjuvant nivolumab plus platinum doublet chemotherapy or platinum doublet chemotherapy 
from 1:1:1 randomization in revised protocol 02 and 1:1 randomization in revised protocol 03. 
Participants already randomized in the original 2-arm part (neoadjuvant nivolumab plus 
ipilimumab vs neoadjuvant chemotherapy) and in the arm of neoadjuvant nivolumab plus 
ipilimumab in 3-arm part defined by revised protocol 02 will remain in trial and continue scheduled 
trial procedures. It is expected to have around 70 participants randomized in the original 2-arm 
part and approximately other 75 participants randomized in the arm of neoadjuvant nivolumab 
plus ipilimumab in the 3-arm part. It is estimated that there will be a total of approximately 
500 participants on the study.
Starting from 1:1:1 randomization, approximately 350 participants will be randomized to the 
2 arms neoadjuvant nivolumab plus platinum doublet chemotherapy or platinum doublet 
chemotherapy in a 1:1 ratio (concurrently randomized). 
The sample size of the study is calculated based on the primary endpoint of EFS and accounts for 
the multiple primary endpoints comparisons: pCR (per BIPR) and EFS (per BICR) with an initial 
alpha allocation of 0.01 and 0.04 respectively. Formal analyses of pCR and EFS may be conducted 
at different timepoints. The fallback method will be used, ie, if the pCR comparison between Arm 
C and Arm B is statistically significant, then 0.01 alpha allocated to pCR will be passed to the EFS 
comparison for Arm C vs Arm B and the EFS comparison will be conducted at the alpha = 0.05 
level. If the pCR comparison between Arm C and Arm B is not statistically significant, then the 
EFS comparison for Arm C vs Arm B will be conducted at the alpha = 0.04 level.
 
 
5.1
Pathologic Complete Response (pCR)
The primary analysis of pCR will be performed after the 350 randomized participants in 
neoadjuvant nivolumab plus platinum doublet chemotherapy and platinum doublet chemotherapy 
(from start of 1:1:1 randomization) have an opportunity for surgery. 
Assuming an accrual rate of 10 participants (all comers) a month between Arms B and C during 
1:1:1 randomization (about 10 months), and 15 participants per month during 1:1 randomization, 
it is anticipated that the 350 participants will be randomized in approximately 27 months. The pCR 
endpoint is expected to be analyzed after about 30 months from start of 1:1:1 randomization.
Assuming pCR rate of 10% on Arm B chemotherapy and 30% on Arm C nivolumab plus 
chemotherapy, respectively, the 350 participants will provide more than 90% power to detect an 
odds ratio of 3.857 with a 2-sided type I error of 1%.
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It is estimated that there will be about 110 subjects randomized to Arm A neoadjuvant nivolumab 
plus ipilimumab before revised protocol 03 is implemented. Assuming true pCR rate is 15% on 
this arm, there is 95% probability that the lower bound of 95% exact confidence interval of pCR 
is above 5%.
5.2
Event Free Survival (EFS)
For the formal comparison of EFS as assessed by BICR for nivolumab plus platinum doublet 
chemotherapy (Arm C) vs platinum doublet chemotherapy (Arm B), only participants randomized 
from 1:1:1 randomization in revised protocol 02 and 1:1 randomization in revised protocol 03 will 
be counted (participants concurrently randomized in arms B and C). 
Considering this SAP revision (v3) occurs after the readout of the pCR primary endpoint which 
was statistically significant, the power details are provided below using alpha=0.05 (0.01 alpha 
from the pCR endpoint fallback to the EFS comparison. In addition, it reflects the number of 
subjects that were actually concurrently randomized in Arms B and C: 358 subjects.
A total of 185 events ensure that an overall 2-sided 5% significance level sequential test procedure 
with two interim analyses after 148 events (80% of events required for final analysis) and 167 
events (90% of events required for final analysis) in 358 randomized participants will have 
82% power assuming an HR of 0.65 between the 2 Arms. Considering a piecewise exponential 
distribution with control hazard rates of 0.028 before 20 months, 0.017 between 20 months and 40 
months, 0.014 between 40 and 60 months and 0.008 after 60 months, and a dropout rate of 
approximately 20%, it is anticipated that the EFS analyses will take place at about 48, 58, and 73
months from start of 1:1:1 randomization. The trigger of the first interim analysis is event driven.
The second interim analysis will take place when 167 events are observed 
 
. The final analysis will take place when 
approximately 185 events are observed 
 
. The stopping boundaries at the interim and final EFS analyses will be derived 
based on the exact number of events using Lan-DeMets alpha spending function with O’Brien-
Fleming boundaries. If the interim analyses of EFS are performed at exactly 148 and 167 events, 
the nominal significance level for EFS superiority will be 0.024 and 0.030, respectively. The 
nominal significance level for the final look of EFS after 185 events would then be 0.038.
 
 
 
 
Table 5.3-1 summarizes the key parameters of the sample size justification in the concurrently 
randomized participants from Arms B and C.
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5.3
Power Considerations for Overall Survival
The secondary endpoint Overall survival will be tested hierarchically after EFS with the same 
overall alpha as for the EFS comparison (two-sided 4% if the pCR comparison is not significant 
or 5% if the pCR comparison is significant).  
For the formal comparison of OS for nivolumab plus platinum doublet chemotherapy (Arm C) vs 
platinum doublet chemotherapy (Arm B), only participants concurrently randomized from 1:1:1 
randomization in revised protocol 02 and 1:1 randomization in revised protocol 03 will be 
included. 
 
Considering this SAP revision (v3) occurs after the readout of the pCR primary endpoint which 
was statistically significant, the power details are provided below using alpha=0.05 (0.01 alpha 
from the pCR endpoint fallback to the EFS comparison, then hierarchically on the OS comparison). 
In addition, it reflects the number of subjects that were actually concurrently randomized in Arms 
B and C: 358 subjects. 
 
 
 
 
 
 
 
 
 
 
  The stopping boundaries at the interim and final OS
analyses will be derived based on the exact number of events using Lan-DeMets alpha spending 
function with O’Brien-Fleming boundaries. This spending function is specific to OS and accounts 
for potential interim OS analyses even if they did not actually take place because of EFS non-
significance8. 
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Table 5.3-1 summarizes the key parameters of the power calculation for EFS and OS in the 
concurrently randomized participants from Arms B and C.
Table 5.3-1:
Power Calculation for EFS and OS
EFS
Arm C vs Arm B
OS
Arm C vs Arm B
Accrual
Actual accural
25 months
Actual accural
25 months
Power
82%
Two-sided alpha
0.05
0.05
Hypothesized Median Control vs 
exp (months)
28 vs 52*
Piecewise exponential model
Hypothesized Hazard ratio
0.65
0.65
Sample size for concurrent 
comparison
358
358
First interim analysis for EFS (EFS 
IA1) and OS (OS IA1)
148 events
Alpha boundary: 0.024
Triggered by EFS IA1
Second interim analysis for EFS 
(EFS IA2) and OS (OS IA2)
167 events
 
Alpha boundary: 0.030
•
If EFS IA1 not significant: 
triggered by EFS IA2.
Final EFS (EFS FA) and third OS 
(OS IA3) interim analysis
185 events
 
Alpha boundary: 0.038
•
If EFS IA2 not significant: 
triggered by EFS FA.
Final OS analysis (OS FA)
-
* Estimated from the piecewise model described in Section 5.2
5.4
Analyses Timing Projections
The pCR analysis occured with a database lock on 16-Sep-2020.
Considering the actual enrollment, it will take
•
Approximately 48
months when 148 events on Arms B and C (after start of 
1:1:1 randomization) are observed for the first interim analysis (EFS IA1, OS IA1). This is 
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about 54 months from FPFV of the study.  This analysis is triggered by the number of EFS 
events. In case of significant EFS, OS will also be tested at that time (OS IA1).
•
Approximately 58 months when 167 EFS events on Arms B and C (after start of 
1:1:1 randomization) are observed for the second interim analysis (EFS IA2, OS IA2). This is 
about 64 months from FPFV of the study.
 
 
 
•
Approximately 73 months when 185 EFS events on Arms B and C (after start of 
1:1:1 randomization) are observed for the final EFS analysis (EFS FA, OSIA3). This is about 
79 months from FPFV of the study.
 
 
 
 
 
 
 
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6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
•
Baseline period:
−
Baseline evaluations or events will be defined as evaluations or events that occur before 
the date and time of the first dose of study treatment. Evaluations (laboratory tests, pulse 
oximetry and vital signs) on the same date and time of the first dose of study treatment will 
be considered as baseline evaluations. Events (AEs) on the same date and time of the first 
dose of study treatment will not be considered as pre-treatment events.
−
In cases where the time (onset time of event or evaluation time and dosing time) is missing 
or not collected, the following definitions will apply:
♦Pre-treatment AEs will be defined as AEs with an onset date prior to but not including 
the day of the first dose of study treatment;
♦Baseline evaluations (laboratory tests, pulse oximetry and vital signs) will be defined 
as evaluations with a date on or prior to the day of first dose of study treatment.
−
If there are multiple valid observations in the baseline period, then the latest non missing 
observation will be used as the baseline in the analyses. If multiple observations exist on 
the latest collection date (and time if collected), the record with the latest data entry date 
and time will be used. If multiple observations exist on the latest collection date (and time 
if collected) and data entry date and time, then the first observation is used as baseline, 
unless otherwise specified. 
♦For PD-L1, non-missing is identified as those with quantifiable test result. After 
applying the rule above, if there are no records with a quantifiable test result, then select 
those with indeterminate result (“INDETERMINATE”). If there are no records with 
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indeterminate test result, then select those with unavailable result (“NOT 
EVALUABLE”). If there are no records with unavailable test result, then select those 
which are not reported or not available result (all other records). 
•
Post baseline period:
−
Neoadjuvant on-treatment AEs will be defined as AEs with an onset date and time on or 
after the date and time of the first dose of neoadjuvant study treatment (or with an onset 
date on or after the day of first dose of neoadjuvant study treatment if time is not collected 
or is missing). For participants who are off neoadjuvant study treatment, AEs will be 
included if event occurred within a safety window of 30 days (or 100 days depending on 
the analysis) after the last dose of neoadjuvant study treatment. No “subtracting rule” will 
be applied when an AE occurs both pre-treatment and post-treatment with the same 
preferred term and grade.
−
Neoadjuvant on-treatment evaluations (laboratory tests, pulse oximetry and vital signs) 
will be defined as evaluations taken after the day (and time, if collected and not missing) 
of first dose of neoadjuvant study treatment. For participants who are off neoadjuvant study 
treatment, evaluations should be either within a safety window of 30 days (or 100 days 
depending on the analysis) after the last dose of neoadjuvant study treatment.
−
Adjuvant on-treatment AEs will be defined as AEs with an onset date and time on or after 
the date and time of the first dose of adjuvant systemic study treatment (or with an onset 
date on or after the day of first dose of adjuvant systemic study treatment if time is not 
collected or is missing). For participants who are off adjuvant study treatment, AEs will be 
included if event occurred within a safety window of 30 days after the last dose of adjuvant
study treatment.
6.2
Treatment Regimens
The treatment group “as randomized” corresponds to the treatment group assigned by the 
Interactive Response Technology (IRT) system.
The treatment group “as treated” will be same as the treatment group “as randomized” by IRT 
unless a subject received the incorrect study treatment for the entire period of treatment, in which 
case the subject’s treatment group “as treated” will be defined as the incorrect study treatment.
Unless otherwise specified, the safety analysis will be based on the treatment group “as treated”.
Unless otherwise specified, the efficacy analysis will be based on the treatment group “as 
randomized”.
The treatment arms are as follows:
•
Arm A: nivolumab 3 mg/kg plus ipilimumab 1 mg/kg.
•
Arm B: platinum doublet chemotherapy 
•
Arm C: nivolumab 360 mg plus platinum doublet chemotherapy
6.3
Populations for Analyses
•
All Enrolled Participants: All participants who signed an informed consent form and were 
registered into the IRT.
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•
All Randomized Participants: All participants who were randomized to any treatment group in 
the study.
•
All Treated Participants: All participants who received at least one dose of any study 
medication in neoadjuvant setting. This is the primary dataset for drug exposure and safety 
analysis for arm A.
•
All Concurrently Randomized Participants in Arms B and C: All participants concurrently 
randomized on Arms B and C as of the 1:1:1 randomization. This will be the primary analysis 
population for efficacy.
•
All Concurrently Randomized Participants in Arms A and B: All participants concurrently 
randomized on Arms A and B.
•
All Treated Participants from the Concurrently Randomized Arms B and C: All participants 
concurrently randomized on Arms B and C as of the 1:1:1 randomization who received at least 
one dose of any study medication in the neoadjuvant setting. This will be the primary analysis 
population for drug exposure and safety for arms B and C.
•
Tumor Tissue TMB evaluable subjects: All randomized subjects from the global study 
population with baseline evaluable tumor tissue TMB (non-missing numeric).
Concurrently randomized subjects from arms B and C (as of the 1:1:1 randomization) is considered 
at the site level basis, when the site switched to the revised protocol. In practice, this includes 
subjects randomized on the randomization lists from the 1:1:1 randomization (revised protocol 02) 
and the subsequent 1:1 randomization between B and C only (revised protocol 03). 
Unless otherwise specified, all analyses will be performed using the treatment arm as randomized 
(intent to treat), with the exception of dosing and safety, for which the treatment arm as received 
will be used.
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise specified, analyses will be performed by treatment group (as randomized or as 
treated, depending on the analysis) for all concurrently randomized participants from Arms B and 
C. Descriptive analyses will also be produced for Arm A. Participants in Arm B randomized in the 
initial protocol will only be reported in listings and in the consistency by randomization period 
analyses (Sections 7.3.7, 7.6.8 and 7.7.19).
Unless otherwise noted, discrete variables will be tabulated by the frequency and proportion of 
subjects falling into each category, grouped by treatment. Percentages given in these tables will be 
rounded to the first decimal and, therefore, may not always sum to 100%. Percentages less than 
0.1 will be indicated as ‘< 0.1’. If a missing category is not being presented in the data display, 
only those subjects with non-missing values for the parameter being assessed are included in the 
percentage calculation. Confidence intervals for binomial proportions will be derived using the 
Clopper-Pearson method9.
Continuous variables will be summarized by treatment group using the mean, standard deviation, 
median, minimum, and maximum values and quartiles.
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Time-to-event variables (e.g. time-to resolution, EFS) will be analyzed using the Kaplan-Meier 
technique. When specified, the median will be reported along with 95% CI using Brookmeyer and 
Crowley method10 (using log-log transformation for constructing the confidence intervals11).
Rates at fixed timepoints (e.g., OS at 12 months) will be derived from the Kaplan Meier estimate 
along with their corresponding log-log transformed confidence intervals12.
Unless otherwise specified, the stratified hazard ratio between 2 treatment groups along with CI 
will be obtained by fitting a stratified Cox model with the treatment group variable as unique 
covariate. 
Stratification 
factors 
per 
IRT 
(PD-L1 
expression 
(≥1% 
or 
<1%/not 
evaluable/indeterminate), disease stage (IB/II vs IIIA) and gender).
Unless otherwise specified, the stratified log-rank test will be performed to test the comparison 
between time to event distributions (OS and EFS). Stratification factors will be as described above.
The p-values from sensitivity analyses for efficacy endpoints, if presented, are for descriptive 
purpose only and not adjusted for multiplicity.
The conventions to be used for imputing missing and partial dates for analyses requiring dates are 
described in Section 8.
Note that in this document the terms “participant” and “subject” are used interchangeably. 
Terminology used in CSR will follow the BMS standard at the time of CSR.
Additional analyses by country or region may be conducted separately for country specific 
submissions.
7.1.1
Adverse Events, Serious Adverse Events, Multiple Events, Select 
Adverse Events, Other Events of Special Interest and Immune-Mediated 
Adverse Events
Drug-related AEs are those events with relationship to study drug “Related”, as recorded on the 
CRF. If the relationship to study drug is missing, the AE will be considered as drug-related. 
Serious adverse events consist of AEs deemed serious by the Investigator and flagged accordingly 
in the CRF and clinical database.
Adverse events leading to study drug discontinuation are AEs with action taken regarding study 
drug(s) = “Drug was discontinued”. This option is selected when at least one agent from the 
regimen is discontinued. 
Adverse events leading to dose delay are AEs with action taken regarding study drug(s) = “Drug
was delayed”.
Adverse events leading to dose reduction are AEs with action taken regarding study drug(s) = 
“Dose was reduced”.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and the most recent version of the dictionary at the time of the database lock will be used. Adverse 
events results will be graded for severity using NCI Common Terminology Criteria for Adverse 
Events (CTCAE) and the version of the criteria specified in the protocol will be used (version 4).
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In the AE summary tables, unless otherwise specified, subjects will be counted only once at the 
Preferred Term (PT), only once at the System Organ Class (SOC), and only once at subject level 
for the counting of total number of subjects with an AE. The AE tables will be sorted by the SOCs 
and then PTs. SOC will be ordered by descending frequency overall and then alphabetically. PTs 
will be ordered within SOC by descending frequency overall and then alphabetically. The sorting 
will be done based on the ‘Any Grade’ column of the experimental arm when arms are presented 
side-by-side.
Unless otherwise specified, the AE summary tables will be restricted to on-treatment events 
regardless of the causality.
Analyses that take into account the multiple occurrences of a given adverse event will be conducted 
(see Section 7.7.10). To prepare these analyses, the CRF data will be processed according to 
standard BMS algorithms13 in order to collapse adverse event records into unique records based 
on the preferred term. These data will be presented as the rate per 100 person-years of exposure. 
These analyses will take into account all on-treatment events (allowing more than 1 event per 
subject) and the total exposure time. The person-year exposure will be computed as the sum over 
the subjects’ neoadjuvant exposure expressed in years where the exposure time is defined as 
•
(Date of last dose of study treatment - date of first dose of study treatment + 31 days (or 
101 days, depending on the analysis))/365.25, for subject who are off study treatment and were 
followed for at least 30 days (or 100 days, depending on the analysis) after last dose of study 
treatment.
•
(Last known alive date - date of first dose of study treatment +1)/365.25, for subjects who are 
still on-treatment or who are off study treatment and were followed less than 30 days (or 
100 days depending on the analysis) after last dose of study treatment.
7.1.1.1
Select Adverse Events
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category (e.g. pulmonary events, gastrointestinal events categories, etc.). AEs that may differ from 
or be more severe than AEs caused by non-immunotherapies and AEs whose early recognition and 
management may mitigate severe toxicity are included as select AEs. Categories of select AEs 
may include subcategories (e.g. adrenal disorders, diabetes, pituitary disorders, and thyroid 
disorders are subcategories of the endocrine event category). 
The list of MedDRA preferred terms used to identify select adverse events is revisited quarterly 
and updated accordingly. The preferred terms used for the selection at the time of the database 
lock will be provided by categories/subcategories.
In addition to the frequency and worst severity of select AEs, time-to onset, time-to resolution,
and time-to resolution where immune modulating medication was initiated will be analyzed for 
each specific category/subcategory of drug-related select AEs when applicable.
Further details on the definitions time-to onset and time-to resolution are described in APPENDIX 
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7.1.1.2
Other Events of Special Interest
Other events of special interest (OEOSI) consist of a list of preferred terms grouped by specific 
category (e.g. Myositis Event, Myocarditis Event, Demyelination Event, Guillain-Barre 
Syndrome, Pancreatitis Event, Uveitis Event, Encephalitis Event, Myasthenic Syndrome, 
Rhabdomyolysis Event, Graft Versus Host Disease). The list of MedDRA preferred terms used to
identify OEOSI is revisited quarterly and updated accordingly. The preferred terms used for the 
selection at the time of the database lock by categories will be provided.
7.1.1.3
Immune-Mediated Adverse Events
In order to further characterize AEs of special clinical interest, analysis of immune-mediated AEs 
(IMAE) will be conducted. IMAEs are specific events (or groups of PTs describing specific events) 
that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, endocrine 
(adrenal insufficiency, hypothyroidism/thyroiditis, hypothyroidism, thyroiditis, hyperthyroidism, 
diabetes mellitus, and hypophysitis), and other specific events, considered as potential immune-
mediated events by investigator that meet the definition summarized below: 
•
those occurring within 100 days of the last dose, 
•
regardless of causality,
•
treated with immune-modulating medication (of note, endocrine AEs such as adrenal 
insufficiency, hypothyroidism/thyroiditis, hypothyroidism, thyroiditis, hyperthyroidism, 
diabetes mellitus, and hypophysitis are considered IMAEs regardless of immune-modulating
medication use, since endocrine drug reactions are often managed without immune-modulating 
medication).
•
with no clear alternate etiology based on investigator assessment, or with an immune-mediated 
component 
The list of MedDRA preferred terms used to identify IMAEs is revisited quarterly and updated 
accordingly. The preferred terms used for the selection at the time of the database lock by 
categories will be provided.
7.1.2
Laboratory Tests
Clinical laboratory parameters (hematology, serum chemistry and electrolytes) will be evaluated.
Laboratory tests will be graded using the NCI Common Terminology Criteria, and the most recent 
version of the criteria at the time of the database lock will be used.
Clinical laboratory data will be analyzed using International System of Units (SI). Analyses will 
be repeated using US conventional units.
In the laboratory summary tables, unless otherwise specified, subjects will be counted only once 
for each lab parameter according to their worst on treatment CTC grade (worst being the highest 
CTC grade). The laboratory tables and listings will be sorted by laboratory category, laboratory 
subcategory and laboratory test code sequence number.
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7.2
Study Conduct
Unless otherwise specified, analyses will be performed by treatment group as randomized for all 
concurrently randomized participants from Arms B and C. Descriptive analyses will also be 
produced for Arm A. Participants in Arm B randomized in the initial protocol will only be reported 
in listings.
For analysis based on enrolled subjects, the analysis population will consist of the all enrolled 
population.
7.2.1
Accrual
Enrollment and randomization by country and site, and enrollment and randomization by month 
will be summarized and listed for all enrolled and randomized subjects.
7.2.2
Relevant Protocol Deviations
Unless otherwise specified, analyses will be performed by treatment group as randomized for all 
concurrently randomized participants from Arms B and C. Descriptive analyses will also be 
produced for Arm A. Participants in Arm B randomized in the initial protocol will only be reported 
in listings.
Eligibility:
•
Inadequate disease stage: presence of locally advanced unresectable (regardless of stage), stage 
IIIB or metastatic disease (stage IV) or stage IA disease.
•
Subjects without measurable disease at baseline as per investigator.
•
Subject with baseline ECOG performance status > 1.
On-study:
•
Subjects receiving any concurrent anti-cancer therapy (chemotherapy, hormonal therapy, 
immunotherapy, radiation therapy, cancer related surgery (except definitive surgery), standard 
or investigational agents for treatment of cancer) outside of the protocol-specified neoadjuvant 
and adjuvant therapy (systemic and randiotherapy) while on study therapy (i.e. neoadjuvant or 
protocol adjuvant systemic treatment).
•
Subjects whose “as treated” arm different than their as randomized arm (subjects who received 
the wrong treatment for the entire neoadjuvant treatment period, excluding the never treated)
7.3
Study Population
Unless otherwise specified, analyses will be performed by treatment group as randomized for all 
concurrently randomized participants from Arms B and C. Descriptive analyses will also be 
produced for Arm A. Participants in Arm B randomized in the initial protocol will only be reported 
in listings.
7.3.1
Subject Disposition
The total number of subjects enrolled (randomized or not randomized) will be presented along 
with the reason for not being randomized. This analysis will be performed on the all enrolled 
subjects population.
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Number of subjects randomized but not treated along with the reason will be tabulated by treatment 
group as randomized. 
Number of subjects who discontinued study treatment along with corresponding reason will be 
tabulated by treatment group as treated. Reason for discontinuation will be derived from subject 
status CRF page (including covid-19 reason). This analysis will be restricted to the all treated 
subjects population.
A by-subject listing for all treated subjects will be provided showing the subject’s off treatment 
date along with the reason for going off treatment period. A by-subject listing for all enrolled 
subjects will also be provided, showing whether the subject was randomized/treated along with 
the reason for not being randomized/treated.
7.3.2
Demographics and Other Baseline Characteristics
The following demographic and baseline characteristics will be summarized and listed by 
treatment group as randomized:Age (descriptive statistics) 
•
Age (continuous)
•
Age categorization (< 65, ≥65 and < 75, ≥75 and < 85, ≥85, ≥75, ≥65)
•
Sex (male vs. female, CRF)
•
Sex (male vs. female, IRT)
•
Race (white, black , asian [asian Indian, Chinese, Japanese, asian other], American Indian or 
Alaska Native, Native Hawaiian or Other Pacific Islander, Other)
•
Ethnicity (Hispanic/Latino, Not Hispanic/Latino, Unknown) - Required for US subjects only, 
but any available data will be presented
•
Country by geographic region (North America, Europe, Asia, Rest of World)
The following baseline disease characteristics will be summarized by treatment group as 
randomized. 
•
Baseline ECOG performance status
•
Baseline weight
•
Tobacco use (Never Smoker, Current/Former, Unknown).
•
Electronic Cigarette Use  (Never Smoker, Current/Former, Unknown).
•
Disease stage at study entry (CRF)
•
Disease stage at study entry (IRT)
•
Cell type (histology) at study entry
(squamous cell carcinoma, non-squamous: 
adenocarcinoma, large cell carcinoma, broncho-alveolar carcinoma, other)
•
Time from current NSCLC diagnosis to randomization
•
Sites of diseases (all lesions) per BICR, 
•
Number of disease sites per subject (all lesions) per BICR
•
Number of target lesions, non-target lesions and disease sites at baseline as per BICR
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•
Sum of the diameters of target lesions as baseline per BICR
•
PD-L1 expression subgroups (clinical database, (<1%, >=1%, 1-49%, >=50%, inderterminate, 
not evaluable))
•
PD-L1 expression subgroups (IRT, (<1%, >=1%/indeterminate/not evaluable)
•
Tumor Tissue TMB subgroups (≥12.3 mut/MB, < 12.3 mut/MB, not evaluable)
Summary table (cross-tabulation) by treatment group for stratification factor  will be provided to 
show any discrepancies between what was reported through IRT vs. CRF/Clinical database at 
baseline. This summary will be performed based on all randomized subjects.
•
PD-L1 status (IRT vs. clinical database)
•
Disease stage (IRT vs CRF data)
•
Gender (IRT vs CRF data)
•
A listing of randomization scheme presenting randomized treatment group and as treated treatment 
group will be provided for all randomized subjects.
7.3.3
Medical History
A by-subject listing of general medical history for all randomized subjects will be provided.
7.3.4
Prior Therapy
•
Prior/current non-study medication classified by anatomic and therapeutic classes.
Agents and medication will be reported using the generic name. A listing by subject will also be 
provided.
7.3.5
Physical Examinations
Subjects with abnormal baseline physical examination will be listed by subject.
7.3.6
Baseline Physical Measurements
Baseline physical measurements will be listed by subject.
7.3.7
Consistency of Demographics and Baseline Characteristics by 
Randomization Period
Consistency of population amongs the different randomization periods will be examined by 
summarizing the characteristics listed in Section 7.3.2 by treatment arm as randomized in the the 
different randomization period: before revised protocol 02 (1:1 A vs B), under revised protocol 02 
(1:1:1 A vs B vs C) and after revised protocol 03 (1:1 B vs C). 
Concurrent randomization is considered at the site level basis, when the site switched to the revised 
protcol. In practice, this includes subjects randomized on the randomization lists from the 1:1:1 
randomization (revised protocol 02) and the subsequent 1:1 randomization between B and C only 
(revised protocol 03).
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7.4
Extent of Exposure
Listings will include all available exposure data. Analyses will be performed by treatment group 
“as treated” in all treated subjects and for all treated participants from concurrently randomized 
Arms B and C, unless otherwise specified. Descriptive analyses will also be produced for Arm A. 
Participants in Arm B randomized in the initial protocol will only be reported in listings.
7.4.1
Administration of Study Therapy
The following parameters will be summarized (descriptive statistics) by treatment group:
•
Number of neoadjuvant doses received by drug
•
Cumulative dose by drug in neoadjuvant
•
Relative dose intensity (%) by drug in neoadjuvant using the following categories: < 50%; 50 
- < 70%; 70 - < 90%; 90 - < 110%; ≥110%
•
Number of subjects who received protocol specified adjuvant systemic therapy number of 
adjuvant doses received by drug for subjects who received adjuvant therapy.
•
The frequency of subjects receiving carboplatin instead of cisplatin in the regimens other than 
carboplatin-paclitaxel will be reported and the reason for not using cisplatin for regimens other 
that carboplatin-paclitaxel will be summarized.
A by-subject listing of dosing of study medication (record of study medication, infusion details, 
and dose changes) and a listing of batch numbers will be also provided.
•
Number of subjects who received adjuvant radiotherapy, including radiotherapy type, number 
of doses and total cumulative dose.
Table 7.4.1-1 to Table 7.4.1-6 summarize the key parameters used to calculate dosing data.
Table 7.4.1-1:
Study Therapy Parameter Definitions- Nivolumab and Ipilimumab
Nivolumab
Nivolumab
Ipilimumab
Dosing schedule per 
protocol
3 mg/kg every 2 weeks
360 mg every 3 weeks
1 mg/kg on first cycle
Dose
Dose (mg/kg) is defined 
as Total Dose 
administered (mg)/Most 
recent weight (kg). Dose 
administered in mg at 
each dosing date and 
weight are collected on 
the CRF.
Dose (mg) is defined as 
Total Dose administered 
(mg) at each dosing date 
as collected on the CRF.
Dose (mg/kg) is defined 
as Total Dose 
administered (mg)/Most 
recent weight (kg). Dose 
administered in mg at 
each dosing date and 
weight are collected on 
the CRF.
Cumulative Dose
Cum dose (mg/kg) is sum 
of the doses (mg/kg) 
administered to a subject.
Cum dose (mg) is the sum 
of the doses (mg) 
administered to a subject.
Cum dose (mg/kg) is sum 
of the doses (mg/kg) 
administered to a subject.
Relative dose intensity 
(%)
Cum dose (mg/kg)/[(Last 
Nivolumab dose date -
Nivolumab start dose date 
+ 14) x 3/14] x 100
Cum dose (mg)/[(Last 
Nivolumab dose date -
Nivolumab start dose date 
+ 21) x 360/21] x 100
Cum dose (mg/kg) x 100
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Table 7.4.1-2:
Study Therapy Parameter Definitions - Regimen 1: 
Vinorelbine/Cisplatin
Vinorelbine
Cisplatin
Dosing schedule per protocol
25 mg/m2 or 30 mg/m2 on Day1 and 
Day8 of a 3 week cycle.
75mg/ m² on Day 1 of a 3 week 
cycle
Dose
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most 
recent BSA. Dose administered in 
mg at each dosing date is collected 
on the CRF and BSA is derived 
from most recent weight and 
baseline height also collected on the 
CRF.
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most 
recent BSA. Dose administered in 
mg at each dosing date is collected 
on the CRF and BSA is derived 
from most recent weight and 
baseline height also collected on the 
CRF.
Cumulative Dose
Cum dose (mg/ m²) is sum of the 
doses (mg/ m2) administered to a 
subject.
Cum dose (mg/m²) is sum of the 
doses (mg/m²) administered to a 
subject.
Relative dose intensity (%)
Cum dose (mg/m²)/[(First 
Vinorelbine dose date in the last 
cycle - Vinorelbine Start dose date 
+ 21) x 50/21] x 100 or Cum dose 
(mg/m²)/[(First Vinorelbine dose 
date in the last cycle - Vinorelbine
Start dose date + 21) x 60/21] x 100
Cum dose (mg/m²)/[(Last Cisplatin 
dose date - Start Cisplatin dose date 
+ 21) x 75/21] x 100
Table 7.4.1-3:
Study Therapy Parameter Definitions - Regimen 2: 
Docetaxel/Cisplatin
Docetaxel
Cisplatin
Dosing schedule per protocol
60 mg/m2 or 75 mg/m2 on Day1 of 
a 3 week cycle.
75mg/ m² on Day 1 of a 3 week 
cycle
Dose
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most 
recent BSA. Dose administered in 
mg at each dosing date is collected 
on the CRF and BSA is derived 
from most recent weight and 
baseline height also collected on the 
CRF.
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most 
recent BSA. Dose administered in 
mg at each dosing date is collected 
on the CRF and BSA is derived 
from most recent weight and 
baseline height also collected on the 
CRF.
Cumulative Dose
Cum dose (mg/ m²) is sum of the 
doses (mg/ m2) administered to a 
subject.
Cum dose (mg/m²) is sum of the 
doses (mg/m²) administered to a 
subject.
Relative dose intensity (%)
Cum dose (mg/m²)/[(First 
Docetaxel dose date in the last 
cycle - Docetaxel Start dose date + 
21) x 60/21] x 100 or Cum dose 
Cum dose (mg/m²)/[(Last Cisplatin 
dose date - Start Cisplatin dose date 
+ 21) x 75/21] x 100
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Table 7.4.1-3:
Study Therapy Parameter Definitions - Regimen 2: 
Docetaxel/Cisplatin
Docetaxel
Cisplatin
(mg/m²)/[(First Docetaxel dose date 
in the last cycle - Docetaxel Start 
dose date + 21) x 75/21] x 100
Table 7.4.1-4:
Study Therapy Parameter Definitions - Regimen 3: 
Gemcitabine/Cisplatin
Gemcitabine
Cisplatin
Dosing schedule per protocol
1250 mg/m2 or 1000 mg/m2 on 
Day1 and Day8 of a 3 week cycle.
75mg/ m² on Day 1 of a 3 week 
cycle
Dose
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most 
recent BSA. Dose administered in 
mg at each dosing date is collected 
on the CRF and BSA is derived 
from most recent weight and 
baseline height also collected on the 
CRF.
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most 
recent BSA. Dose administered in 
mg at each dosing date is collected 
on the CRF and BSA is derived 
from most recent weight and 
baseline height also collected on the 
CRF.
Cumulative Dose
Cum dose (mg/ m²) is sum of the 
doses (mg/ m2) administered to a 
subject.
Cum dose (mg/m²) is sum of the 
doses (mg/m²) administered to a 
subject.
Relative dose intensity (%)
Cum dose (mg/m²)/[(First 
Gemcitabine dose date in the last 
cycle - Gemcitabine Start dose date 
+ 21) x 2500/21] x 100 or Cum 
dose (mg/m²)/[(First Gemcitabine 
dose date in the last cycle -
Gemcitabine Start dose date + 21) x 
2000/21] x 100
Cum dose (mg/m²)/[(Last Cisplatin 
dose date - Start Cisplatin dose date 
+ 21) x 75/21] x 100
Table 7.4.1-5:
Study Therapy Parameter Definitions - Regimen 4: 
Pemetrexed/Cisplatin
Pemetrexed
Cisplatin
Dosing schedule per protocol
500 mg/ m² every 3 weeks 
75mg/ m² every 3 weeks 
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Table 7.4.1-5:
Study Therapy Parameter Definitions - Regimen 4: 
Pemetrexed/Cisplatin
Pemetrexed
Cisplatin
Dose
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most recent 
BSA. Dose administered in mg at 
each dosing date is collected on the 
CRF and BSA is derived from most 
recent weight and baseline height 
also collected on the CRF.
Dose (mg/m²) is defined as Total 
Dose administered (mg)/Most 
recent BSA. Dose administered in 
mg at each dosing date is collected 
on the CRF and BSA is derived 
from most recent weight and 
baseline height also collected on the 
CRF.
Cumulative Dose
Cum dose (mg/m²) is sum of the 
doses (mg/m²) administered to a 
subject.
Cum dose (mg/m²) is sum of the 
doses (mg/m²) administered to a 
subject.
Relative dose intensity (%)
Cum dose (mg/m²)/[(Last 
Pemetrexed dose date - Pemetrexed 
Start dose date + 21) x 500/21] x 
100
Cum dose (mg/m²)/[(Last Cisplatin
dose date - Cisplatin Start dose date 
+ 21) x 75/21] x 100
Table 7.4.1-6:
Study Therapy Parameter Definitions - Regimen 5: 
Paclitaxel/Carboplatin
Paclitaxel
Carboplatin
Dosing schedule per protocol
200 mg/ m2 or 175 mg/ m2 every 3 
weeks
AUC 5 or 6 every 3 weeks
Dose
Dose (mg/m²) is defined as Total 
Dose administered in mg at each 
dosing date is collected on the CRF 
and BSA is derived from most 
recent weight and baseline height 
also collected on the CRF.
Dose (AUC) is defined as Total 
Dose administered (mg)/(creatinine 
clearance +25). Dose administered 
in mg at each dosing date is 
collected on the CRF and creatinine 
clearance derived from the CRF 
data and capped at 125 mL/min
Cumulative Dose
Cum dose (mg/m²) is sum of the 
doses (mg/m²) administered to a 
subject.
Cum dose (AUC) is sum of the 
doses (AUC) administered to a 
subject.
Relative dose intensity (%)
Cum dose (mg/m²)/[(Last paclitaxel 
dose date - paclitaxel Start dose 
date + 21) x 200/21] x 100 or Cum 
dose (mg/m²)/[(Last paclitaxel dose 
date - paclitaxel Start dose date + 
21) x 175/21] x 100
Cum dose (AUC)/[(Last dose date 
of Carbo - Start dose date of Carbo 
+ 21) x 6/21] x 100 or Cum dose 
(AUC)/[(Last dose date of Carbo -
Start dose date of Carbo + 21) x 
5/21] x 100
Where the creatinine clearance will be calculated using Cockroft-Gault formula, defined as:  
mg/dL)
(in 
creatinine
serum
*
72
kg)
(in 
weight 
*
years))
(in 
age
-
(140
n)
CrCL(ml/mi =
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for males and 
85
.0
*
mg/dL)
(in 
creatinine
serum
*
72
kg)
(in 
weight 
*
years))
(in 
age
-
(140
n)
CrCL(ml/mi =
for females. The most recent weight will be used. If the computed creatinine clearance is more 
than 125 ml/min, then the creatinine clearance value should be capped at 125ml/min for dose 
exposure computations.
7.4.2
Modifications of Study Therapy
7.4.2.1
Dose Delay/Omission
Each study medication infusion may be delayed. A dose will be considered as actually delayed if 
the delay is exceeding 3 days (i.e., greater than or equal to 4 days from scheduled dosing date) for 
study medication. In case of reported omission of a dose between 2 doses, this will be taken into 
account in the derivation and will not count as a delay unless there is a delay in addition to the 
omission.Reason for dose delay/omission will be retrieved from CRF dosing pages.
The following parameters will be summarized by treatment group and by drug.
•
Number of subjects with at least one dose delayed, the number of dose delays per subject, the 
reason for dose delay (including covid related reason) and the length of dose delay.
•
Number of subjects with reported dose omission, reason for omission.
•
The listing of dosing will include the dose modifications, including dose modifications for 
adjuvant systemic therapy. Dose modifications for adjuvant therapy will only include the 
reported modifications, there will be no derivation.
7.4.2.2
Infusion Interruptions and Rate Changes
Each study drug infusion can be interrupted and/or the IV infusion rate can be reduced. This 
information will be retrieved from CRF dosing pages
The following parameters will be summarized by treatment group and study drug:
•
Number of subjects with at least one dose infusion interruption, the reason for interruption, 
and the number of infusion interruptions per subject.
•
Number of subjects with at least one IV infusion rate reduction, the reason for reduction and 
the number of infusion with IV rate reduction per subject.
7.4.2.3
Dose Reductions
There will be no dose reductions of nivolumab and ipilimumab allowed. Dose of platinum doublet 
chemotherapy (Arms B and C) may be modified for toxicity. Dose levels of platinum doublet 
chemotherapy (Arms B and C) are defined in the protocol as follows:
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Table 7.4.2.3-1:
Dose Modifications of Chemotherapeutic Agents (Arms B and C)
Dose Level
Vinorelbine
Docetaxel
Gemcitabine
Pemetrexed
Cisplatin
Carboplatin
Paclitaxel
Starting
dose
25 mg/m²
or 30
mg/m²
60 mg/m²
or 75 
mg/m²
1000 
mg/m² or 
1250 
mg/m²
500 mg/m²
75 mg/m²
AUC 5 or 6
175 or 200 
mg/mt
First dose
reduction
75% of 
strating 
dose 
75% of 
starting 
dose
75% of 
starting 
dose
75% of 
starting 
dose
75% of 
starting 
dose
AUC 4 or 5
150 mg/mt
Second
dose
reduction
50% of 
starting 
dose
50% of 
starting 
dose
50% of 
starting 
dose
50% of 
starting 
dose
50% of 
starting 
dose
AUC 3 or 4
100 mg/mt
Third dose
reduction
Discontinu
e
Discontinu
e
Discontinu
e
Discontinu
e
Discontinu
e
Discontinu
e
Discontinu
e
For any cycle, it will be defined as a dose reduction if the observed dose level (based on calculated 
administered dose) is below protocol specified dose level. Dose ranges for dose levels of platinum 
doublet chemotherapy are defined in Table 7.4.2.3-2.
Table 7.4.2.3-2:
Calculated Dose Ranges and Related Dose Levels 
Dose 
Level
Dose Range
Vinorelbine 
(mg/m²)
Docetaxel 
(mg/m²)
Gemcitabine 
(mg/m²)
Pemetrexed 
(mg/m²)
Cisplatin 
(mg/m²)
Carboplatin 
(AUC)
Paclitaxel 
(mg/m²)
Level 
0
≥21.875 or 
≥26.25
≥52.5 or 
≥65.625
≥875 or 
≥1093.75
≥437.5
≥65.625
≥4.5 or ≥5.5
≥153.125
or ≥175
Level 
-1
<21,875 
and ≥
15.625 or 
<26.25 and 
≥18.75
<52.5 and 
≥37.5 or 
< 65.625 
and 
≥46.875
<875 and 
≥625 or 
<1093.75 
and ≥781.25
<437.5 and 
≥312.5
<65.625
and 
≥46.875
<5.5 and ≥4.5 
or <4.5 and 
≥3.5
<175 and 
≥125
Level 
-2
<15.625 or 
<18.75
<37.5 or 
< 46.875
<625 or < 
781.25
<312.5
<46.875
<4.5 or <3.5
<125
The reason for dose reduction as reported by the investigator will be tabulated for all instances of 
dose reduction based on the Dose Change CRF page. A category ‘Unknown’ will be defined for 
all reductions with no reason reported by the investigator.
Chemotherapy dose reductions are permanent; once the dose of any chemotherapy agent is 
reduced, it may not be re-escalated in subsequent cycles.
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The following will be summarized for chemotherapeutic agent arm only:
Number and percentage of subjects with at least one dose reduction and reason of the dose 
reduction, number and percentage of subjects with a dose reduction to dose level -1, number and 
percentage of subjects with a dose reduction to dose level -2.
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of neoadjuvant study therapy or within 30 days following the last dose of adjuvant 
therapy, whichever is longest), will be coded using the WHO Drug Dictionary.
The following summary tables by treatment group will be provided: 
•
Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term).
Prior medications, defined as non-study medications with a start date before consent date, and 
current medications, defined as non-study medications with a start date before the first date of 
study medication and stop date after consent date, will be coded using the WHO Drug Dictionary. 
The following summary table will be provided: 
•
Prior/current medications (subjects with any prior/current medication, subjects by medication 
class and generic term) 
By-subject listings will accompany the tables.
7.4.3.1
Immune Modulating Medication
Immune modulating concomitant medications are medications entered on an immune modulating 
medication form or available from the most current pre-defined list of immune modulating 
medications. The list of anatomic class, therapeutic class and generic name used for the selection 
at the time of the database lock will be provided.
The percentage of subjects who received immune modulating concomitant medication for
•
management of adverse event 
•
premedication 
•
other use
•
any use
•
management of drug-related select adverse event (any grade, grade 3-5) by select AE category/ 
subcategory
•
management of IMAEs (any grade, grade 3-5) by IMAE category
will be reported separately for each treatment group (percentages of treated subjects by medication 
class and generic term).
For each category/subcategory of drug-related select AEs (any grade, grade 3-5) and IMAEs (any 
grade, grade 3-5), the following will be reported for each treatment group:
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•
The total immune modulating medication treatment duration (excluding overlaps), duration of 
high dose of corticosteroid, initial dose of corticosteroid, and tapering duration (summary 
statistics)
Duration represents the total duration the subject received the concomitant medication of interest. 
If the subject took the medication periodically, then DURATION in the summation of all use. 
Initial dose represents the dose of the concomitant medication of interest received at the start of 
the event. In the case multiple medications started on the same date, the highest equivalent dose is 
chosen and converted to mg/kg by dividing by the subject’s recent weight.
These analyses, except the ones related to IMAEs will be conducted using the 30-day safety 
window. The analyses related to IMAEs will be conducted using the 100-day safety window.
7.4.3.2
Subsequent Cancer Therapy
Subsequent therapies are defined as Cancer therapies started on or after the first study drug dose 
or date of randomization if the subject is no treated, outside of the protocol defined adjuvant 
therapy (systemic and radiotherapy).
The following information pertaining to subsequent therapies will be summarized by treatment 
arm, as randomized: 
•
Number and percentage of subjects receiving subsequent therapies including: 
•
Subsequent systemic therapy by drug name
•
Subsequent disease related surgery
•
Subsequent radiotherapy for treatment of tumors
A by-subject listing of subsequent cancer therapy will also be produced for randomized subjects.
7.5
Definitive Surgery
Unless otherwise specified, analyses will be performed by treatment group as randomized for all 
concurrently randomized participants from Arms B and C. Descriptive analyses will also be 
produced for Arm A. Participants in Arm B randomized in the initial protocol will only be reported 
in listings.
The following parameters will be summarized:
•
Disease Stage Prior to Surgery
•
Subjects with clinical downstaging (lower stage prior to surgery vs baseline)
•
Subjects with surgery
•
Subjects without surgery:
•
Reason for cancelled surgery
Subjects with surgery:
•
Delayed surgery (>6 weeks post last neoadjuvant dose), reason for delay as reported in CRF
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•
Duration of delay (number of weeks between last neoadjuvant dose and surgery date exceeding 
6 weeks), descriptive statistics and categories: 1-2 weeks, 3-4 weeks, 5-6 weeks, >6 weeks 
delay)
•
Duration of surgery
•
Length of hospitalization for definitive surgery
•
Method of surgery (Minimally invasive-thoracoscopic/robotic, Thoracotomy, Minimally 
innvasive to thoracotomy)
•
Type of Surgery (Pneumonectomy, Lobectomy, Sleeve Lobectomy, Bilobectomy, Other)
•
Surgery Outcome (R0, R1, R2, unknown)
Safety related to surgery analyses are described in section 7.7.1
7.6
Efficacy
Unless otherwise specified, analyses will be performed by treatment group as randomized for all 
concurrently randomized participants from Arms B and C. Descriptive analyses will also be 
produced for Arm A. Participants in Arm B randomized in the initial protocol will only be reported 
in listings and in analyses based on the All Concurrently Randomized Participants in Arms A and 
B population.
Unless stated otherwise, whenever a stratified analysis is specified, the following stratifications 
factors (recorded at randomization as per IRT) will be used:
•
PD-L1 expression (≥1% or <1%/not evaluable/indeterminate)
•
Disease stage (IB/II vs IIIA)
•
Gender
Alpha (ߙሻfor the confidence intervals (CIs) for hazard ratios, odds ratios or difference of rates 
will be the same as nominal significance level for hypothesis testing. CIs for endpoints not tested 
will be at the two-sided 95% level. All p-values reported will be two-sided. P-values will be 
rounded to the fourth decimal place. Point estimates and confidence bounds for efficacy variables 
will be rounded to the second decimal place.
7.6.1
Type I Error Control
The overall alpha will be controlled using the following procedure. The overall alpha is primarily 
allocated to the two primary endpoints: 1% for pCR and 4% for EFS.
•
The primary endpoint pCR will be tested at 1% alpha.
•
If pCR is not significant, the primary endpoint EFS will be tested at 4%
•
If pCR is significant, the 1% alpha will be re-allocated to the EFS primary endpoint which will 
be tested at 5% alpha level
•
If EFS is significant, OS will be tested at  the same level as EFS
EFS and OS (if EFS is significant) will be tested at planned interim and final analyses. Stopping 
boundaries will be calculated for each endpoint according to the observed number of events by 
Lan-DeMets alpha spending function with O’Brien-Fleming boundaries corresponding to an 
overall alpha of 4% or 5%. Given EFS and OS endpoints are tested using group sequential 
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approach, overall hierarchical testing approach will be used where each endpoint will have its own 
specific Lan-DeMets alpha spending function with O’Brien-Fleming boundaries8. Also refer to 
Sections 5.2 and 5.3.
If the p-value crosses the boundary at the interim analysis (EFS or OS), the p-value from the 
interim stratified log-rank test will be considered the final analysis result for the study.
The secondary endpoints of Major Pathologic Response and Time to Death or Distant Metastases 
will be analyzed descriptively without hypothesis testing.
7.6.2
Analysis of Pathological Complete Response
7.6.2.1
Primary pCR Analysis
Formal analysis of pCR will occur after the 350 randomized participants in arms B and C from 
start of 1:1:1 randomization have an opportunity for surgery.
At pCR analysis, the primary analysis population is the concurrently randomization participants in 
arms B and C. PCR rate will be computed in each treatment group along with the exact 95% CI 
using Clopper-Pearson method.
The numerator is based on randomized participants achieving pCR in both tumor and lymph nodes, 
as assessed by independent pathological review (BIPR). The denominator is based on All 
Concurrently Randomized Participants in Arms B and C. Subjects who are no longer eligible for 
surgery, or who are on alternative anti-cancer therapy before surgery, or who discontinue before 
surgery or for whom pCR results are not available are all counted as non-responders.
pCR will be compared between concurrent arms B and C by the stratified Cochran Mantel-
Haenszel (CMH) test using a 2-sided, 1% alpha level.
An estimate of the difference in pCR rates between the treatment groups along with the 
corresponding two sided 99% CI will also be computed using the following Cochran-Mantel-
Haenszel (CMH) method of weighting, adjusting for stratification factors14. A two sided 99% CI 
for odds ratio of pCR between the treatment groups will also be computed.
Estimate of the difference in pCR between arms A and B (in the All Concurrently Randomized 
Participants in Arms A and B population) and odds ratio will also be provided together with 
corresponding 95% CI using the same methodology.
The analysis will be conducted by an independant statistician external to BMS and reviewed by 
the DMC. At the time of pCR analysis, EFS descriptive analyses (by investigator and by BICR) 
will be produced in the DMC closed report and might be shared with regulatory authorities. The 
communication of results will be tightly controlled and pre-specified in the DMC charter to 
maintain trial integrity.
7.6.2.2
Supportive Analyses of pCR
pCR sensitivity analyses will be performed with the following consideration:
•
pCR analysis will be repeated for response evaluable subjects, where response evaluable 
subjects are subjects who had definitive surgery, and didn’t start alternative anti-cancer therapy 
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before surgery and pathologic samples results at surgery are evaluable. No p-value will be 
generated.
•
pCR using stratification factors as obtained from the baseline CRF pages or database (instead 
of IRT). This analysis will be performed only if the stratification variable/factor at 
randomization (as per IRT) and baseline are discordant for at least 10% of randomized subjects.
Stratified Cochran Mantel-Haenszel (CMH) p-value will be generated.
•
Considering the small number of subjects that may be impacted by the Covid-19 situation in 
terms of pathology assessment, no sensitivity analysis is currently planned. The potential 
surgeries delays or cancellation due to Covid-19 related issues will be reported based on the 
surgery listing. 
•
7.6.2.3
Subset Analyses of pCR
The influence of baseline and demographic characteristics on the treatment effect will be explored 
via exploratory subset analysis. BIPR assessment of pCR will be summarized for the following 
subgroups:
•
Age category 
a) <65, 
b) >=65 and <75
c) >=75 and <85
d) >=85
e) >=75
f)
>=65
•
Sex (male, female), per IRT and per CRF
•
Race (white, black, Asian, other)
•
Region (North America, Europe, Asia, Rest of World)
•
Baseline ECOG Performance Status (0, 1, >1)
•
Tobacco use (current/former, never smoked, unknown)
•
Disease stage (IB/II vs IIIA) per IRT and per CRF
•
Baseline histology (squamous, non-squamous)
•
PD-L1 subgroups (<1%, ≥1%, 1-49%, ≥50%, indeterminate, not evaluable)
•
Tumor Tissue TMB Evaluable (≥12.3 mut/MB, < 12.3 mut/MB, Overall)
•
Tumor Tissue TMB Not Evaluable
•
Type of platinum therapy (cisplatin, carboplatin, subjects switching from cisplatin to 
carboplatin). 
•
Type of chemotherapy regimen in arm B (available in arm C (Gemcitabine-Cisplatin, 
Pemetrexed-Cisplatin, Paclitaxel-Carboplatin, not available in arm C (Vinorelbine-Cisplatin, 
Docetaxel-Cisplatin)) , based on first neoadjuvant cycle.
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A forest plot of treatment effect on pCR per BIPR in the above subgroups will be produced. The 
un-weighted differences in pCR between concurrent arms B and C and corresponding 95% two-
sided CI using the method of Newcombe, will be provided. 
The analysis comparing treatment (i.e., pCR difference) will be conducted if the number of 
subjects in the subgroup category is more than 10.
7.6.2.4
Major Pathological Response Rate
MPR rate in concurrently randomized participants in arms B and C will be computed in each 
treatment group along with the exact 95% CI using Clopper-Pearson method. An estimate of the 
difference and odds ratio in MPR rates between concurrent arms B and C and corresponding 95% 
CI will be calculated using CMH methodology and adjusted by stratification factors.
Estimate of the difference in MPR between arms A and B (in the All Concurrently Randomized 
Participants in Arms A and B population) and odds ratio will also be provided together with 
corresponding 95% CI.
Subset analyses by PDL1 status will be performed (PD-L1<1% PD-L1 ≥1%, PD-L1 1-49%, PD-
L1 ≥50%, not evaluable/indeterminate) and by Tumor TMB (≥12.3 mut/MB, < 12.3 mut/MB, 
Overall, not evaluable).
7.6.2.5
Additional Pathological Related Analyses
Descriptive analyses of pCR and MPR, % tumor area with viable tumor cells in the tumor region 
and in lymph nodes separately will be provided.
7.6.2.6
Clinical Response Rate
Clinical response rate (cRR) by BICR will be summarized by treatment arm. cRR is defined as 
proportion of randomized participants whose radiologic response at the last scan prior to definitive 
surgery is either a complete response or partial response per RECIST 1.1 criteria by BICR. The 
response does not require confirmation. Response rates and their corresponding 95% exact CI will 
be calculated by Clopper-Pearson method presented for each randomized arm.
Clinical response rate by investigator will be reported similarly.
Subset analyses of cRR by BICR by PDL1 status will be performed (PD-L1<1% PD-L1 ≥1%, 
PD-L1 1-49%, PD-L1 ≥50%, not evaluable/indeterminate) and by Tumor TMB (≥12.3 mut/MB, 
< 12.3 mut/MB, Overall, not evaluable).
7.6.3
Analysis of Event Free Survival
7.6.3.1
Primary Event Free Survival
One of the primary objectives of the study is to compare the event-free survival (based on BICR 
assessments) between treatment groups in all concurrently randomized participants in Arms B and 
C. 
The primary definition of EFS, censoring for subsequent anticancer therapy, will be used in this 
analysis.
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EFS will be compared between the treatment groups (concurrent B and C) at the interim and final 
analyses, using stratified log-rank test, with stratification factors as per IRT, two-sided p-value 
will also be reported. A Lan DeMets α-spending function with O’Brien and Fleming type of 
boundary will be employed to determine the nominal significance levels for the interim and final 
analyses. The stratified hazard ratio between the treatment groups will be presented along with 
100*(1- α)% CI (adjusted for interim).
EFS will be estimated using the Kaplan Meier techniques and will be displayed graphically. A 
two-sided 95% CI for median EFS in each treatment group will be computed via the log-log 
transformation method. EFS rates at fixed time points (e.g. 6, 12 months, depending on the 
minimum follow-up) will be presented along with their associated 95% CIs. These estimates will 
be derived from the Kaplan Meier estimate and corresponding CIs will be derived based on 
Greenwood15 formula for variance derivation and on log-log transformation applied on the 
survivor function16.
These EFS analyses will also be conducted for Arm A, including Kaplan Meier curve, median and 
EFS rates with 95% CI and stratified HR between Arm A and Arm B (in the All Concurrently 
Randomized Participants in Arms A and B population) with 95% HR.
Analyses of EFS will also be conducted based on the secondary definition of EFS (not censoring 
for subsequent therapies). These analyses will be the same as those specified above.
The source of EFS event (progression precluding surgery, progression, recurrence (locoregional, 
distant) or death) will be summarized by treatment group. The status of subjects who are censored 
(as per primary definition of EFS) in the EFS KM analysis will be tabulated for each treatment 
group including the following categories:
•
On-study (on-neoadjuvant treatment, on-adjuvant treatment, in follow-up)
•
Off-study (lost to follow-up, withdraw consent, never treated)
•
No baseline tumor assessment
•
No on-study tumor assessment and no death
•
Received subsequent anticancer therapy
•
A by-subject listing will be presented including treatment group, EFS duration under the 
primary definition, EFS duration on the secondary definition, whether the subject was censored 
under the primary definition, and if censored, the reason, and whether the subject was censored 
under the secondary definition, and if censored, the reason.
A by-subject listing of lesion evaluations per BICR will be presented.
7.6.3.2
Supportive Analyses of Event-Free Survival
The following sensitivity analyses will be conducted in the concurrently randomized subjects in 
arms B and C for the primary definition. The p-values from sensitivity analyses for efficacy 
endpoints, are for descriptive purpose only and not adjusted for multiplicity.
•
Delayed effect of immunotherapy interventions may cause a late separation in the OS KM 
curves and non-proportional hazards.
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−
EFS will be compared between treatment groups via a 2-sided max-combo test. The max-
combo test statistic is the maximum of 4 diffrerent Fleming-Harrington family weighted 
log-rank test statistics. Zm = max (FH (0, 0), FH (0,1), FH (1,0), F(1,1)), where FH(ρ,γ)
are the test statistics from the Fleming-Harrington family of test statistics. FH (0, 0) 
corresponds to the log-rank test, while FH (0, 1) is more sensitive to late-difference 
alternatives, FH(1,0) is more sensitive to early difference with decreasing treatment effect 
and FH(1,1) uses weigths at the median.
−
To examine the assumption of proportional hazards in the Cox regression model, in 
addition to treatment, a time-dependent variable defined by treatment by time interaction 
will be added into the model. A two-sided Wald Chi-square p-value of less than 0.1 may 
indicate a potential non constant treatment effect. In such case, the following analysis will 
be conducted: 
♦The estimates of the EFS hazard ratios will be estimated in 2 periods. The periods will 
be defined by a cut off point. The cut off point will be calculated using a stratified time-
dependent Cox model with effects for treatment and period-by-treatment interaction. 
The cut off point will be estimated using a grid of possible cut off points and obtained 
by maximizing the partial log likelihood. Ties will be handled using the exact method. 
A two-sided 95% CI for the hazard ratio’s will also be presented. Visual interpretation 
of the curves may lead to additional analyses with several cut off points.
•
A multivariate Cox regression model will be used in order to estimate the treatment effect after 
adjustment for possible imbalances in known or potential prognostic factors. The factors used 
in the randomization, will be included in the model as stratification factors. However, all 
additional factors will be incorporated as covariates. The additional factors, which are all 
measured at baseline, will include:
−
Histology (Squamous, Non-squamous)
−
Age categorization (< 65, ≥ 65)
−
ECOG (0, ≥1)
−
Race (White, Black, Asian, Other)
•
The level of the covariate normally associated with the worst prognosis will be coded as the 
reference level.  The hazard ratio associated with treatment and with each of the baseline 
covariates will be presented along with associated 95% CIs and p-value. 
•
The primary EFS based on BICR assessments analysis will be repeated using secondary EFS 
definition which accounts for the tumor scans post subsequent therapies for  the primary 
efficacy population. Stratified log-rank test p-value will be generated.
•
EFS based on BICR assessments, using stratification factors as obtained from the baseline CRF 
pages or database (instead of IRT). This analysis will be performed only if the stratification 
variable/factor at randomization (as per IRT) and baseline are discordant for at least 10% of 
randomized subjects. Stratified log-rank test p-value will be generated.
•
EFS based on BICR assessments accounting for missing tumor assessment prior to EFS event 
(progression/recurrence or death). This analysis will be performed only if at least 10% of 
events have missing prior tumor assessment within the primary efficacy population. It will 
apply the following restriction to the primary definition: If the elapsed time between the EFS 
event and the last assessment immediately prior to the event is two or more missed visits, the 
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subject’s EFS will be censored at his/her last tumor assessment prior to the EFS event.
Stratified log-rank test p-value will be generated. This analyses may account for potential
missed assessments due to the Covid-19 situation.
•
EFS based on BICR assessments accounting for site reported pathology results. In case of site 
reported pathology recurrence on the CRF at an earlier date than the BICR event date, an event 
will be assigned at the pathology site reported date. No p-value will be generated.
•
EFS based on BICR assessments accounting for BICR assessed progressions occuring before 
surgery but not precluding surgery. This analysis will use the primary definition of EFS but 
will in addition count an event for BICR assessed RECIST 1.1 progression before surgery, that 
would not preclude surgery.
•
EFS based on investigator assessments. The hazard ratio associated with treatment and median 
EFS will be presented along with the associated two-sided 95% CIs. Kaplan-Meier plot will 
be produced. It is to be noted that per CRF instruction, the investigator will not consider a 
second primary cancer as a recurrence/progression. While if such lesions are present on tumor 
assessment at the BICR, they will be considered as new lesions, since the BICR does not have 
access to biopsy results. EFS by investigator is defined the same way as for EFS by BICR, 
except that both pathology and imaging recurrences reported in the CRF are taken into account 
as event and censoring will occur at the time of last tumor assessment prior to (or at the date 
of) second primary cancer. No p-value will be generated.
•
EFS based on BICR assessments using an un-stratified Cox model. Un-stratified log-rank test 
p-value will be generated
•
EFS in treated subjects from concurrently randomized arms B and C using treatment group “as 
treated” if more than 10% randomized subjects in any treatment group were never treated or 
treated differently than randomized among corresponding analysis population. Stratified log-
rank test p-value will be generated.
•
EFS analysis for participants with no relevant deviation. This analysis will be conducted only 
if there are more than 10% participants with relevant protocol deviations. Stratified log-rank
test p-value will be generated.
•
In order to assess the potential impact of the change in tumor assessment scheduled on the 
longer term and potential missing assessments, EFS (by BICR) will also be analyzed based on 
interval censoring method. The SAS PROC ICPHREG will be used to fit the proportional 
hazards regression models using interval censoring approach, with treatment arm as the only 
covariate in the model. Hazard ratio with 2-sided 95% and 100-alpha confidence intervals will 
be produced. The time period between time1 and time2 will be the interval during which the 
EFS event occurred. Time1 and time2 will be setup as follows: 
−
For subjects who had EFS event per EFS primary definition, time1 is the time from 
randomization date to the last tumor assessment date prior to EFS event date, and time2 is 
time to EFS event (EFS duration).
−
For subjects who are censored for EFS, time1 is time to EFS event (EFS duration), and 
time2 is infinite time (missing in SAS).
•
In order to assess the potential variability introduced by the optional adjuvant chemotherapy:
−
Baseline demographics and disease characterictics, characteristics at the time of surgery 
will be tabulated by adjuvant therapy status.
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−
A Cox regression model with treatment and an additional time-dependant covariate as 
indicator of the start of adjuvant therapy will used.
−
Additional sensitivity analyses may be performed
•
Given the small number of subjects expected to be impacted by a death due to Covid-19 
infection, no specifc sensitivity analysis is currently planned. Subjects with death (potentially) 
associated with Covid-19 infection will be reported based on the reason for death in the death 
listing.
7.6.3.3
Subset Analyses of EFS
The influence of baseline and demographic characteristics on the treatment effect will be explored 
via subset analyses for the factors specified in section 7.6.2.3.
A forest plot of the EFS based on BICR assessments, unstratified hazard ratios (HR) along with 
two-sided 95% CIs will be produced for each level of the subgroups listed in section 7.6.2.3. If 
subset category has less than 10 subjects per treatment group, HR will not be computed/displayed.
Median and 95% CI will be provided.
In addition, for gender, baseline disease stage, histology, PD-L1 and tumor TMB subsets, Kaplan 
Meier Curves will be generated.
Kaplan Meier curves, medians and 95% confidence interval will be generated for EFS based on 
BICR assessments by PD-L1 (≥  1%, <1%, 1%-49%, ≥ 50%) for Arm A.
7.6.3.4
EFS Analyses by pCR and MPR Status
EFS (based on BICR assessments, primary definition) Kaplan-Meier curves will be generated by 
pCR and by MPR status. These analyses will be landmarked at the time of surgery and will be 
limited to subjects with pCR or MPR status available. Median and 95% CI will be provided. HR 
and 95% CI for concurrently randomized subjects in arms B and C will be provided by pCR and 
by MPR status, as well as HR of pCR/MPR vs no pCR/MPR by treatment arm. If subset category 
has less than 10 subjects per treatment group, HR will not be computed/displayed.
In addition, EFS (based on BICR assessments, primary definition) Kaplan-Meier curves will be 
generated by pCR and by MPR status, without landmark. These analyses will include all 
randomized subjects concurrently ranomdized to Arms B and C. Median and 95% CI will be 
provided. HR and 95% CI for concurrently randomized subjects in arms B and C will be provided 
by pCR and by MPR status, as well as HR of pCR/MPR vs no pCR/MPR by treatment arm. If 
subset category has less than 10 subjects per treatment group, HR will not be computed/displayed.
7.6.3.5
Current Status of EFS
Time from last censoring point to cutoff date in months will be summarized by treatment group 
and overall for randomized subjects. Subjects who have a EFS event will be considered as current 
for this analysis. The secondary definition of EFS (by BICR) will be used for this summary.
7.6.4
Analysis of Overall Survival
7.6.4.1
OS Analyses
OS will be hierarchically tested if EFS is significant. Details are provided in section 5.3.
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OS will be compared between the treatment groups (concurrent B and C) at the interim and final 
analyses, using stratified log-rank test, with stratification factors as per IRT, two-sided p-value 
will also be reported. A Lan DeMets α-spending function with O’Brien and Fleming type of 
boundary will be employed to determine the nominal significance levels for the interim and final 
analyses. The stratified hazard ratio between the treatment groups will be presented along with 
100*(1- α)% CI (adjusted for interim).
OS will be estimated using the Kaplan Meier techniques and will be displayed graphically. A two-
sided 95% CI for median EFS in each treatment group will be computed via the log-log 
transformation method. EFS rates at fixed time points (e.g. 6, 12 months, depending on the 
minimum follow-up) will be presented along with their associated 95% CIs. These estimates will 
be derived from the Kaplan Meier estimate and corresponding CIs will be derived based on 
Greenwood  formula for variance derivation and on log-log transformation applied on the survivor 
function.
These analyses OS analyses will also be conducted for Arm A, including Kaplan Meier curve, 
median and OS rates with 95% CI and stratified HR between Arm A and Arm B (in the All 
Concurrently Randomized Participants in Arms A and B population) with 95% HR.
The number of participants who are censored in the OS KM analysis and their status will be 
tabulated using following categories:
•
Still on treatment (No recurrence/progression, recurrence/progression)
•
In follow-up 
•
Off study
−
lost to follow-up 
−
participant withdrew consent 
−
other 
7.6.4.2
Supportive Analyses for OS
The following sensitivity analyses will be conducted in the concurrently randomized subjects in 
arms B and C. The p-values from sensitivity analyses for efficacy endpoints, if presented, are for 
descriptive purpose only and not adjusted for multiplicity.
•
A multivariate Cox regression model will be used in order to estimate the treatment effect after 
adjustment for possible imbalances in known or potential prognostic factors. The factors used 
in the randomization, will be included in the model as stratification factors. However, all 
additional factors will be incorporated as covariates. The additional factors, which are all
measured at baseline, will include: 
−
Histology (Squamous, Non-squamous)
−
Age categorization (< 65, ≥ 65)
−
ECOG (0, ≥1)
−
Race (White, Black, Asian, Other)
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The level of the covariate normally associated with the worst prognosis will be coded as the 
reference level.  The hazard ratio associated with treatment and with each of the baseline covariates 
will be presented along with associated 95% CIs and p-value.
•
OS analysis using stratification factors as obtained from the baseline CRF pages or database 
(instead of IRT). This analysis will be performed only if the stratification variable/factor at 
randomization (as per IRT) and baseline are discordant for at least 10% of randomized subjects.
Stratified log-rank test p-value will be generated.
•
OS analysis using an un-stratified Cox model. Unstratified log-rank test p-value will be 
generated.
•
OS analysis for participants with no relevant deviation. This analysis will be conducted only if 
there are more than 10% participants with relevant protocol deviations. Stratified log-rank test
p-value will be generated.
•
OS in treated subjects from concurrently randomized arms B and C using treatment group “as 
treated” if more than 10% randomized subjects in any treatment group were never treated or 
treated differently than randomized among corresponding analysis population. Stratified log-
rank test p-value will be generated.
•
In order to assess the potential variability introduced by the optional adjuvant chemotherapy:
−
Baseline demographics and disease characteristics, characteristics at the time of surgery 
will be tabulated by adjuvant therapy status.
−
A Cox regression model with treatment and an additional time-dependant covariate as 
indicator of the start of adjuvant therapy will used.
−
Additional sensitivity analyses may be performed
•
Given the small number of subjects expected to be impacted by a death due to Covid-19 
infection, no specifc sensitivity analysis is currently planned. Subjects with death (potentially) 
associated with Covid-19 infection will be reported based on the reason for death in the death 
listing.
7.6.4.3
Subset Analyses of OS
The influence of baseline and demographic characteristics on the treatment effect will be explored 
via subset analyses for the factors specified in section 7.6.2.3.
A forest plot of the OS unstratified hazard ratios (HR) along with two-sided 95% CIs will be 
produced for each level of the subgroups listed in section 7.6.2.3. If subset category has less than 
10 subjects per treatment group, HR will not be computed/displayed. Median and 95% CI will be 
provided.
In addition, for gender, baseline disease stage, histology, PD-L1 and tumor TMB subsets, Kaplan 
Meier Curves will be generated.
Kaplan Meier curves, medians and 95% confidence interval will be generated for EFS based on 
BICR assessments by PD-L1 (≥  1%, <1%, 1%-49%, ≥ 50%), for Arm A.
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7.6.4.4
OS Landmark Analyses by pCR and MPR Status
OS Kaplan-Meier curves will be generated by pCR and by MPR status. These analyses will be 
landmarked at the time of surgery and will be limited to subjects with pCR or MPR status available. 
Median and 95% CI will be provided. HR and 95% CI for concurrently randomized subjects in 
arms B and C will be provided by pCR and by MPR status, as well as HR of pCR vs no pCR by 
treatment arm.
In addition, OS Kaplan-Meier curves will be generated by pCR and by MPR status, without 
landmark. These analyses will include all randomized subjects concurrently ranomdized to Arms 
B and C. Median and 95% CI will be provided. HR and 95% CI for concurrently randomized 
subjects in arms B and C will be provided by pCR and by MPR status, as well as HR of pCR/MPR 
vs no pCR/MPR by treatment arm.
If subset category has less than 10 subjects per treatment group, HR will not be 
computed/displayed.
7.6.4.5
Subject Follow-Up
The extent of follow-up defined as the time between randomization date and last known date alive 
(for subjects who are alive) or death date (for subjects who died). It will be summarized 
descriptively (median, min, max, etc) in months. 
The currentness of follow-up for survival, defined as the time between last OS contact (i.e., last 
known date alive or death date) and cut-off date (defined by last patient last visit date), will be 
summarized in months by treatment group. Subjects who died and subjects with a Last Known 
Date Alive on or after data cut-off date will have a zero value for currentness of follow-up.
7.6.5
Interim Analyses of EFS and OS
An independent statistician external to BMS will perform the interim analyses. In addition to the 
formal planned interim analyses for EFS and OS, the Data Monitoring Committee (DMC) will 
have access to periodic un-blinded interim reports of efficacy and safety to allow a risk/benefit 
assessment. Details are included in the DMC charter.
Details of interim analyses timing and significance boundaries are provided in sections 5.2 and 
5.3.
The DMC will review the safety and available efficacy data as planned in the DMC charter and 
will determine if the study should continue with or without changes or if accrual should be stopped. 
Subject enrollment will continue while waiting for the DMC’s decisions.
The chair of the DMC and the sponsor can call an unscheduled review of the safety data.
At the time of the interim analysis for of EFS and OS, the DMC may recommend continuing or 
declare superiority. If the trial continues beyond the formal interim analyses, the nominal critical 
point for the final analysis will be determined using the recalculated information fraction at the 
time of the interim analysis, as described above. The final hazard ratio and corresponding 
confidence interval will be reported whereby the confidence interval will be adjusted accordingly 
(i.e. using the recalculated nominal α level at the final analysis). 
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If the EFS is significant but not OS, the trial is successful but will continue for further OS evalution.
If the p-value crosses the boundary at the interim analysis (EFS or OS), the p-value from the 
interim stratified log-rank test will be considered the final analysis result.
7.6.6
Analysis of TTDM
Time to death or distant matastases is a secondary endpoint.
TTDM, based on BICR assessments, will be estimated using the Kaplan Meier techniques and will 
be displayed graphically. A two-sided 95% CI for median TTDM in each treatment group will be 
computed via the log-log transformation method. TTDM rates at fixed time points (e.g. 6, 12 
months, depending on the minimum follow-up) will be presented along with their associated 95% 
CIs. These estimates will be derived from the Kaplan Meier estimate and corresponding CIs will 
be derived based on Greenwood  formula for variance derivation and on log-log transformation 
applied on the survivor function.
7.6.7
Event Free Survival on Next Line of Therapy
Event Free survival on next line of therapy is an exploratory endpoint. 
Event free survival will be estimated using the Kaplan Meier techniques and will be displayed 
graphically. A two-sided 95% CI for median in each treatment group will be computed via the log-
log transformation method. Events rates at fixed time points (e.g. 6, 12 months, depending on the 
minimum follow-up) will be presented along with their associated 95% CIs. These estimates will 
be derived from the Kaplan Meier estimate and corresponding CIs will be derived based on 
Greenwood  formula for variance derivation and on log-log transformation applied on the survivor 
function.
7.6.8
Consistency of Efficacy by Randomization Period
Consistency of population amongs the different randomization periods will be examined by 
summarizing the primary endpoints by treatment arm as randomized in the the different 
randomization period: before revised protocol 02 (1:1 A vs B), under revised protocol 02 (1:1:1 A 
vs B vs C) and after revised protocol 03 (1:1 B vs C). Descriptive statistics will be provided 
including pCR rates, EFS medians, 95% CI and Kaplan-Meier plots. HR and 95% CI will be 
provided for arms C vs B during the 1:1:1 randomization (under revised protocol 02) and during 
the 1:1 randomization (under revised protocol 03).
Concurrent randomization is considered at the site level basis, when the site switched to the revised 
protcol. In practice, this includes subjects randomized on the randomization lists from the 1:1:1 
randomization (revised protocol 02) and the subsequent 1:1 randomization between B and C only 
(revised protocol 03).
7.7
Safety
Analyses in this section will be tabulated for all treated subjects by treatment group as treated, 
unless otherwise specified.
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Analyses will be performed on the treated subjects from arm A and from the concurrently 
randomized arms B and C. Participants in Arm B randomized in the initial protocol will only be 
reported in listings.
7.7.1
Definitive Surgery Related Safety
Incidence of AE/SAE indicated as surgical complication in the CRF, up to 90 days after surgery 
will be summarized by worst CTC grade, by treatment group.
Adverse events leading to cancellation of surgery and leading to  surgery delay  will be summarized
by worst CTC grade, by treatment group.
7.7.2
Deaths
Deaths will be summarized by treatment group:
•
All deaths, reasons for death.
•
Deaths within 30 days of last neoadjuvant dose received (30-day safety window), reasons for 
death.
•
Deaths within 100 days of last neoadjuvant dose received (100-day safety window), reasons 
for death.
•
Deaths within 30 days and 90 days from surgery
•
Overall summary of AEs leading to death within 100 days of last neoadjuvant dose received
•
Overall summary of drug-related AEs leading to death within 100 days of last neoadjuvant 
dose received
•
Overall summary of SAEs leading to death within 100 days of last dose received
•
For subjects with systemic adjuvant therapy: deaths from start of systemic adjuvant to last 
systemic adjuvant dose received + 30 days
A by-subject listing of deaths will be provided for the all enrolled subjects population.
7.7.3
Serious Adverse Events
Serious adverse events will be summarized by treatment group:
•
Overall summary of SAEs by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
SOC/PT.
•
Overall summary of drug-related SAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT.
•
For subjects with systemic adjuvant treatment: Overall summary of SAEs by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by SOC/PT from start of systemic adjuvant to last 
systemic adjuvant dose received + 30 days
•
All analyses will be conducted using the 30-day safety window. 
A by-subject SAE listing will be provided for the “enrolled subjects” population.
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7.7.4
Adverse Events Leading to Discontinuation of Study Therapy
AEs are indicated as leading to discontinuation, when they lead to discontinuation of at least one 
agent of the regimen. Reporting is done based on AE CRF form.
AEs leading to discontinuation (of neoadjuvant treatment) will be summarized by treatment group:
•
Overall summary of AEs leading to discontinuation by worst CTC grade (any grade, grade 
3-4, grade 5) presented by SOC/PT.
•
Overall summary of drug-related AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT.
•
For subjects with systemic adjuvant treatment: Overall summary of AEs leading to 
discontinuation by worst CTC grade (any grade, grade 3-4, grade 5) presented by SOC/PT
from start of systemic adjuvant to last systemic adjuvant dose received + 30 days
The analyses will be conducted using the 30-day safety window.
A by-subject AEs leading to discontinuation listing will be provided.
7.7.5
Adverse Events Leading to Dose Modification
AEs leading to dose delay/reduction will be summarized by treatment group:
•
Overall summary of AEs leading to dose delay/reduction by worst CTC grade (any grade, 
grade 3-4, grade 5) presented by SOC/PT.
•
Overall summary of related AEs leading to dose delay/reduction by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT.
The analysis will be conducted using the 30-day safety window.
A by-subject AEs leading to dose delay/reduction listing will be provided.
7.7.6
Adverse Events
Adverse events will be summarized by treatment group.
The following analyses will be conducted using the 30 days safety window only:
•
Overall summary of any AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) presented 
by SOC/PT. 
•
Overall summary of any AEs presented by worst CTC grade (any grade, grade 3-4, grade 5) 
by SOC/PT. This table will be restricted to events with an incidence greater or equal to 5% in 
any treatment group.
•
for subjects with systemic adjuvant: Overall summary of any AEs presented by worst CTC 
grade (any grade, grade 3-4, grade 5) by SOC/PT, from start of systemic adjuvant to last 
systemic adjuvant dose received + 30 days
•
Overall summary of any non-serious AEs presented by SOC/PT. This table will be restricted 
to events with an incidence greater or equal to 5% in any treatment group.
•
Overall summary of any AEs that required immune modulating medication by worst CTC 
grade (any grade, grade 3-4, grade 5) presented by SOC/PT.
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•
Overall summary of drug-related AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total)
presented by SOC/PT. 
•
For subjects with systemic adjuvant treatment: Overall summary of Drug-Related AEs by 
worst CTC grade (any grade, grade 3-4, grade 5) presented by SOC/PT from start of systemic 
adjuvant to last systemic adjuvant dose received + 30 days
The following analyses will be conducted using the 30 days safety window and repeated using the 
100 days safety window:
•
Overall summary of drug-related AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT
A by-subject AE listing will be provided. A by-subject listing of any AE requiring immune 
modulating medications will also be provided.
7.7.7
Select Adverse Events
Unless otherwise specified, analyses will be performed by select AE category. Analyses will also 
be repeated by subcategory of endocrine events.
7.7.7.1
Incidence of Select AE
Select AEs will be summarized by treatment group for each category/subcategory. 
The following analyses will be conducted using the 30-day safety window only:
•
Overall summaries of any select AEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category or Subcategory/PT.
•
Overall summaries of any drug-related select AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by Category or Subcategory/PT.
•
Overall summaries of any serious select AEs by worst CTC grade (any grade, grade 3-4, grade 
5) presented by Category or Subcategory /PT.
•
Overall summaries of drug-related serious select AEs by worst CTC grade (any grade, grade 
3-4, grade 5) presented by Category or Subcategory /PT.
•
Overall summaries of any select AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category or Subcategory /PT.
•
Overall summaries of drug-related select AEs leading to discontinuation by worst CTC grade
(any grade, grade 3-4, grade 5) presented by Category or Subcategory /PT.
•
Summary of frequency of unique select AEs by Category.
A by-subject select AE listing will be provided.
7.7.7.2
Time-to Onset of Select AE
Time-to onset of drug-related select AEs (any grade, grade 3-5) will be summarized for each 
category/subcategory by treatment group.
Time-to onset analyses are restricted to treated subjects who experienced at least one drug-related 
select AE in the category/subcategory. The analyses will be conducted using the 30-day safety 
window.
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Additional details regarding the time-to onset definition are described in time-to onset definition 
subsection of APPENDIX 1.
7.7.7.3
Time-to Resolution of Select AE
Time-to resolution of the following specific events will be summarized separately for each 
category/subcategory.
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) by treatment group
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) where immune modulating 
medication was initiated, by treatment group
Time-to resolution analyses are restricted to treated subjects who experienced the specific events. 
Time-to resolution where immune modulating medication was initiated analyses are restricted to 
treated subjects who experienced the specific events and who received immune modulating 
medication during the longest select AE.
The analyses will be conducted using the 30-day safety window.
The following summary statistics will be reported: percentage of subjects with resolution of the 
longest select AE, median time-to resolution along with 95% CI (derived from Kaplan-Meier 
estimation) and ranges.
See time-to resolution definition subsection of APPENDIX 1 for additional details.
7.7.8
Immune-Mediated Adverse Events
IMAEs will be summarized by treatment group for each immune-mediated category / PT using the 
100-day safety window:
•
Overall summary of non-endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 
5) where immune modulating medication was initiated presented by Category / PT.
•
Overall summary of endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT.
•
Overall summary of non-endocrine IMAEs leading to discontinuation by worst CTC grade 
(any grade, grade 3-4, grade 5) where immune modulating medication was initiated presented 
by Category / PT.
•
Overall summary of endocrine IMAEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category / PT.
•
Overall summary of non-endocrine IMAEs leading to dose delay or reduction by worst CTC 
grade (any grade, grade 3-4, grade 5) where immune modulating medication was initiated 
presented by Category / PT
•
Overall summary of endocrine IMAEs leading to dose delay or reduction by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by Category / PT.
•
Summaries of time-to onset and time-to resolution of non-endocrine IMAEs where immune 
modulating medication was initiated presented by Category.
•
Summaries of time-to onset and time-to resolution of endocrine IMAEs presented by Category.
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A by-subject listing of IMAEs will be provided. By-subject listings of time-to resolution for 
longest IMAEs cluster (any grade and grade 3-5 in separate summaries) will also be provided. For 
new studies which collect investigator assessment of potential IMAE data, a by-subject listing of 
AEs considered as immune-mediated events per investigator but not qualified for IMAEs 
definition will also be provided.
7.7.9
Other Events of Special Interest
OEOSI will be summarized by treatment group for each category.
The following analyses will be conducted using the 100-day safety window:
•
Overall summary of OEOSI by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
Category / PT
•
Overall summary of drug-related OEOSI by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT
A by-subject listing of OEOSI will be provided.
7.7.10
Multiple Events
The following summary tables will be provided:
•
A table showing the total number and rate (exposure adjusted) of occurrences for all AEs. 
•
A table showing the total number and rate (exposure adjusted) of occurrences for AEs
occurring in at least 5% of subjects in any treatment group.
Exposure adjustement will be based on the exposure in neoadjuvant treatment only.
A listing displaying the unique instances of all AEs, i.e., after duplicates have been eliminated and 
overlapping and contiguous occurrences of the same event (i.e. same PT) have been collapsed will 
be provided. No formal comparisons will be made between treatment groups.
7.7.11
New Primary Cancers
Occurence of new primary cancer reported on the new primary cancer CRF form will be listed
based on the all treated population.
7.7.12
Laboratory Parameters
The analysis population for each laboratory test is restricted to treated subjects who underwent that 
laboratory test.
A by-subject listing of differences in categorization of SI and US laboratory test results will be 
provided.
7.7.12.1
Hematology
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: hemoglobin (HB), platelets, white blood counts (WBC), absolute neutrophils count (ANC) 
and lymphocyte count (LYMPH). 
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The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.7.12.2
Serum Chemistry
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: ALT, AST, alkaline phosphatase (ALP), total bilirubin, creatinine, amylase, lipase.
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.7.12.3
Electrolytes
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: sodium (high and low), potassium (high and low), calcium (high and low), magnesium 
(high and low), and Glucose Serum (fasting hyperglycemia and hypoglycemia regardless of fasting 
status).
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.7.12.4
Additional Analyses
In addition, further analyses on specific laboratory parameters will be performed by treatment 
group:
Abnormal Hepatic Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
•
ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN
•
Total bilirubin > 2 x ULN
•
ALP > 1.5 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these specific abnormalities will be provided.
Abnormal Thyroid Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
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TSH value > ULN and
−
with baseline TSH value ≤ULN
−
with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal TSH 
test
−
with all FT3/FT4 test values ≥ LLN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test.
•
TSH < LLN and
−
with baseline TSH value ≥LLN
−
with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal 
TSH test
−
with all FT3/FT4 test values ≤ ULN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these specific abnormalities will be provided.
7.7.13
Vital Signs and Pulse Oximetry
Vital signs and pulse oximetry (i.e. % oxygen saturation) collected on the CRF will be provided 
in separate listings.
7.7.14
Physical Measurements
Physical measurements will be listed by subject.
7.7.15
Non-Protocol Medical Procedures
Non-protocol medical procedures will be listed by subject.
7.7.16
Immunogenicity Analysis
Not applicable in this protocol.
7.7.17
Pregnancy
A by-subject listing of pregnancy tests results will be provided for randomized female subjects.
7.7.18
Adverse Events By Subgroup
Overall summary of any AEs and drug-related AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by SOC/PT and for each treatment group for the following subgroups:
•
Sex (Male vs. Female)
•
Race
•
Age (< 65 vs. 65 - < 75 vs. 75 - < 85 vs. ≥85 vs. ≥75 vs. ≥65)
•
Region (North America, Europe, Asia, Rest of World)
•
Type of platinum therapy (cisplatin, carboplatin, subjects switching from cisplatin to 
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•
Type of chemotherapy regimen in arm B (available in arm C (Gemcitabine-Cisplatin, 
Pemetrexed-Cisplatin, Paclitaxel-Carboplatin, not available in arm C (Vinorelbine-Cisplatin, 
Docetaxel-Cisplatin)) , based on first neoadjuvant cycle.
These analyses will be conducted using the 30-day safety window only.
7.7.19
Consistency of Safety by Randomization Period
Consistency of population amongs the different randomization periods will be examined by 
summarizing key safety by treatment arm as randomized in the the different randomization period: 
before revised protocol 02 (1:1 A vs B), under revised protocol 02 (1:1:1 A vs B vs C) and after 
revised protocol 03 (1:1 B vs C). 
•
Overall summary of any AEs presented by worst CTC grade (any grade, grade 3-4, grade 5) 
by SOC/PT with 30-day safety window.
•
Overall summary of AEs leading to discontinuation (of neoadjuvant treatment) by worst CTC 
grade(any grade, grade 3-4, grade 5) presented by SOC/PT with 30-day safety window.
•
Overall summary of non-endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 
5) where immune modulating medication was initiated presented by Category / PT with 100-
day safety window.
•
Overall summary of endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT with 100-day safety window.
•
Concurrent randomization is considered at the site level basis, when the site switched to the 
revised protcol. In practice, this includes subjects randomized on the randomization lists from 
the 1:1:1 randomization (revised protocol 02) and the subsequent 1:1 randomization between 
B and C only (revised protocol 03).
7.7.20
Covid-19
•
COVID-19 related adverse events will be summarized (100 days window) and listed.
7.8
Pharmacokinetics
The nivolumab and ipilimumab concentration data obtained in this study will be combined with 
data from other studies in the clinical development program to develop a population PK model. 
This model will be used to evaluate the effects of intrinsic and extrinsic covariates on the PK of 
nivolumab and ipilimumab. In addition, exposure-response analyses with selected efficacy and 
safety endpoints will be conducted. Results of population PK and exposure response-analyses will 
be reported separately.
7.9
Biomarkers
Analyses for PD-L1 and TMB (tumor tissue) are described below.
Methodology for biomarkers other than PD-L1,Tumor TMB
will be reported 
separately.
7.9.1
PD-L1 Expression
Descriptive statistics of PD-L1 expression:
•
Listing of all PD-L1 IHC data, all randomized subjects.
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Summary of tumor specimen acquisition and characteristics, all randomized subjects.
•
Summary statistics of PD-L1 expression in all randomized subjects with quantifiable PD-L1 
expression.
•
Cumulative distribution plot of baseline PD-L1 expression versus population percentile in all 
randomized subjects with quantifiable PD-L1 expression.
•
Box plots of PD-L1 expression versus pCR in all randomized subjects with quantifiable PD-
L1 expression. 
•
Waterfall plot of Individual PD-L1 expression in all randomized subjects with quantifiable 
PD-L1 expression.
•
Subgroups analyses of efficacy (pCR, MPR, EFS, OS) by PD-L1 status (PD-L1<1% PD-L1 ≥
1%, PD-L1 1-49%, PD-L1 ≥50%, not evaluable/indeterminate) are described in Section 7.6.
•
In addition the following analyses will be conducted in the concurrently randomized subjects 
in arms B and C.
•
An exploratory Cox proportional hazards model, in order to assess the association of EFS 
(based on BICR assessments) with PD-L1, will be fitted for EFS with PD-L1, treatment arm 
and PD-L1* treatment arm interaction, among all PD-L1 evaluable subjects. An appropriate 
transformation of PD-L1 expression may be considered depending on an assessment of fit of 
the model. The following summaries will be presented by treatment arm
−
A plot of estimated loge(hazard ratio) with 95% confidence band vs PD-L1 expression(X-
axis) 
•
An exploratory Cox proportional hazards model, in order to assess the association of OS with 
PD-L1, will be fitted for OS with PD-L1, treatment arm and PD-L1* treatment arm interaction, 
among all PD-L1 evaluable subjects. An appropriate transformation of PD-L1 expression may 
be considered depending on an assessment of fit of the model. The following summaries will 
be presented by treatment arm
−
A plot of estimated loge(hazard ratio) with 95% confidence band vs PD-L1 expression (X-
axis). 
•
A logistic regression model will be fitted for pCR with PD-L1, treatment arm and PD-L1* 
treatment arm interaction, among all PD-L1 evaluable subjects. The following summaries will 
be reported:
−
A plot of estimated odds ratio with 95% confidence band vs PD-L1 expression (X-axis)
•
For both EFS (using primary definition, per BICR) and OS, a Cox proportional hazards 
regression model will be fitted with treatment, PD-L1 status (using 1%, 5%, 50% cut offs), and 
treatment by PD-L1 status interaction. Although the study is not designed to have appropriate 
power to formally test the interaction of the model, an interaction test at significance level of 
0.2 will warrant further exploration and the following statistics will be reported:
−
Interaction p-value
−
HR of treatment vs. control and its associated 95% CI for each of the PD-L1 status 
subgroup
−
HR PD-L1 ≥ cutoff vs. < cutoff and its associated 95% CI within each treatment group
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7.9.2
Tumor Mutational Burden (TMB)
The analyses are based on tumor tissue TMB evaluable subjects, defined as subjects with tissue 
TMB data available. It is known that not all subjects will provide tumor tissue TMB data, due to 
factors such as available remaining tissue and inherent failure rates of the TMB process.
The descriptive analyses of tumor tissue TMB at baseline will be conducted:
•
Listing of all tumor tissue TMB data.
•
Summary of tumor specimen characteristics
•
Cumulative distribution plot of TMB at baseline versus population percentile in all subjects 
with evaluable tumor tissue TMB.
In addition, the joint distribution of PD-L1 and tumor tissue TMB among both PD-L1 and tumor 
tissue TMB-evaluable subjects will be examined.
Subgroups analyses of efficacy (pCR, MPR, EFS, OS) by TMB status (≥12.3 mut/MB, < 12.3 
mut/MB, TMB evaluable, TMB not evaluable) are described in Section 7.6.
•
In addition the following analyses will be conducted in the concurrently randomized subjects 
in arms B and C.
•
An exploratory Cox proportional hazards model, in order to assess the association of EFS 
(based on BICR assessments) with TMB, will be fitted for EFS with TMB, treatment arm and 
TMB* treatment arm interaction, among all TMB evaluable subjects. An appropriate 
transformation of TMB may be considered depending on an assessment of fit of the model. 
The following summaries will be presented by treatment arm
−
A plot of estimated loge(hazard ratio) with 95% confidence band vs PD-L1 expression(X-
axis) 
•
An exploratory Cox proportional hazards model, in order to assess the association of OS with 
TMB, will be fitted for OS with TMB, treatment arm and TMB* treatment arm interaction, 
among all TMB evaluable subjects. An appropriate transformation of TMB may be considered 
depending on an assessment of fit of the model. The following summaries will be presented by 
treatment arm
−
A plot of estimated loge(hazard ratio) with 95% confidence band vs TMB (X-axis). 
•
A logistic regression model will be fitted for pCR with TMB, treatment arm and TMB* 
treatment arm interaction, among all TMB evaluable subjects. The following summaries will 
be reported:
−
A plot of estimated odds ratio with 95% confidence band vs TMB (X-axis)
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7.10
Outcomes Research Analyses
The analysis of EQ-5D-3L will be restricted to randomized subjects who have an assessment at 
baseline and at least one post-baseline assessment.
The following descriptive analyses will be conducted: 
•
EQ-5D-3L questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number (i.e. number of subjects on treatment or in follow up), will 
be calculated and summarized for each assessment time point by treatment group. 
•
A by-subject listing of the level of problems in each dimension, corresponding to EQ-5D-3L 
health state (i.e., 5-digit vector), EQ-5D-3L utility index score, and EQ-5D-3L VAS score will 
be provided.
•
Proportion of subjects reporting problems for the 5 EQ-5D-3L dimensions at each assessment 
time point will be summarized by level of problem and by treatment group. Percentages will 
be based on number of subjects assessed at assessment time point.
•
For the EQ-5D-3L utility index and VAS scores, separately:
−
Mean score and mean change from baseline at each assessment time point will be 
summarized by treatment group using descriptive statistics (N, mean with SD and 95% CI, 
median, first and third quartiles, minimum, maximum).
−
A line graph summarizing the mean changes from baseline will be produced.
7.11
Country Specific Analyses
Country or region specific analyses may take place to support regional health authorities 
submissions. In general these would consist of repeating a subset of the analyses described in this 
SAP for a subjects from a specific country or region, which would potentially be used for
evaluation of consistency between the country/region and the overall population. Unless otherwise 
noted, no formal hypothesis testing will be performed to evaluate consistency of the subpopulation. 
Instead, descriptive statistics will be provided to assess the consistency.
These analyses provided for regional submission needs would only performed when at least one 
of the primary endpoints is statistically significant (based on data from the global population), for 
regional submission needs. The analysis methods for the subpopulation will be the same as for the 
global population unless otherwise noted.
For China, the the following analysis sets will be used:
China subpopulation 
Chinese subpopulation is defined as Great China subgroup. It should contain subjects that are 
Chinese by race and enrolled from China, Hong-Kong or Taiwan sites.
Asian subpopulation
Asian subpopulation is defined as Asian subgroup. It should contain subjects that are Asian by 
race and enrolled from Asian countries, as per this SAP geographic region derivation.
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8
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates: 
•
For missing and partial adverse event onset dates, imputation will be performed using the 
Adverse Event Domain Requirements Specification17
•
For missing and partial adverse event resolution dates, imputation will be performed as 
follows:
−
If only the day of the month is missing, the last day of the month will be used to replace 
the missing day. If the imputed date is after the death date or the last known alive date, then 
the latest known alive date or death date is considered as the resolution date. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
•
Missing and partial non-study medication domain dates will be imputed using the derivation 
algorithm described in 4.1.3 of BMS Non-Study Medication Domain Requirements 
Specification18.
•
Missing and partial radiotherapy and surgery dates will be imputed using algorithm described 
in APPENDIX 2.
•
Missing of partial definitive surgery date
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. In case of the date of death is present and complete, the imputed definitive 
surgery date will be compared to the date of death. The minimum of the imputed definitive 
surgery date and date of death will be considered as the date of definitive surgery. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing. 
•
For death dates, the following conventions will be used for imputing partial dates:
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known alive date and the 
maximum will be considered as the death date. 
−
If the month or the year is missing, the death date will be imputed as the last known alive 
date. 
−
If the date is completely missing but the reason for death is present, the death date will be 
imputed as the last known date alive. 
•
For date of progression/recurrence after start of study therapy, the following conventions will 
be used for imputing partial dates: 
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. In case of the date of death is present and complete, the imputed 
progression/recurrence date will be compared to the date of death. The minimum of the 
imputed progression/recurrence date and date of death will be considered as the date of 
progression/recurrence. 
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−
If the day and month are missing or a date is completely missing, it will be considered as 
missing. 
•
For date of progression to prior therapies, the following conventions will be used for imputing 
partial dates: 
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing. 
•
For other partial/missing dates, the following conventions were used: 
−
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day. 
−
If both the day and the month are missing, “July 1” will be used to replace the missing 
information. 
−
If a date is completely missing, it will be considered as missing. 
The following conversion factors will be used to convert days to months or years: 
1 month = 30.4375 days and 1 year = 365.25 days.
Duration (e.g. time-to onset, time-to resolution) will be calculated as follows:
Duration = (Last date - first date + 1)
Last known alive date will be defined based on all appropriate dates collected on the CRF.
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
9
CONTENT OF REPORTS
All analyses described in this SAP will be included in the Clinical Study Report(s) except where 
otherwise noted. Additional exploratory analyses may be performed. Refer to the Data 
Presentation Plan for mock-ups of all tables and listings.
10
DOCUMENT HISTORY
Table 10-1:
Document History
Version Number
Author(s)
Description
1.0
Initial version dated 17-Apr-2020
2.0
29-Jul-2020
Revised Protocol 06 related changes:
•
Clarified EFS definition
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Table 10-1:
Document History
Version Number
Author(s)
Description
•
Removed the 1st interim analysis of EFS and updated alpha 
spending of interim and final analyses of EFS, based on health 
authorities feedback
•
Clarified that actual timing of analyses may differ from projected 
timing
Other changes:
•
Removed immunogenicity analyses as immunogenicity is not 
described in the protocol.
•
Sections 4.1.2 and 4.2.2, clarified that subjects with pCR/MPR 
not evaluable/no avaialble are considered as non-responders
•
Section 4.3.3: specified that the length of surgery delay will be 
reported
•
Section 4.3.7: EQ-5D analyses: clarify that the windowing for 
adjuvant is based on systemic adjuvant only
•
Section 5.3: removed OS analyses methodology which is repeated 
in section 7
•
Section 5.4: Refer to the DMC charter for handling of EFS 
descriptive analysis at the time of pCR
•
Section 7.2.2: Relevant deviations: clarify that the concurrent 
therapies are limited to neoadjuvant and adjuvant systemic 
treatment
•
Section 7.3.2: corrected the PDL1 should be per clinical database
•
Section 7.3.4: removed reporting of prior systemic therapies, 
radiotherapy and surgeries since the study is in neoadjuvant 
setting
•
Section 7.4.2.1: Dose delay/omission: describe the derivation of 
delay, when there is an omission between two doses. and the fact 
that delays during the adjuvant treatment are limited to reported 
delays on the CRF.
•
Section 7.5: added duration of surgery delay
•
Section 7.6: Added Covid-19 related consideration in the efficacy 
supportive analysis sections
•
Section 7.6.2.2: added pCR sensitivity analysis using CRF 
stratification factors
•
Section 7.6.3.2: added sensitivity analysis considering 
progressions before surgery as events, even if not precluding 
surgery
•
Section 7.6.3.4 and 7.6.4.4: added calculation of HR for pCR vs 
no pCR.
•
Section 7.6.4.2: remove extra paragraph on analysis on 
concurrently randomized arms B and C.
•
Section 7.6.5: clarified that the DMC may declare superiority but 
not stop the trial for superiority as the trial will continue for 
further endpoints
•
Section 7.7: clarified that the window for reporting AEs during 
the adjuvant period is  based on systemic aduvant theratpy (not 
radiotherapy)
•
Added section 7.11 for country/region specific analyses
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Table 10-1:
Document History
Version Number
Author(s)
Description
3.0
•
The main reason for amendment is to reflect the changes to Revised 
Proocol 07: add an interim analysis for EFS/OS
 
 
The rationale for change is the potential for a slow down of EFS 
events with a plateau towards the end of the curve.
•
 as well as some additional 
sensitivity, subgroup analyses and clarifications. 
•
Detailed changes are provided below:
•
Section 1: removed reference to the Core SAP which is outdated
•
Section 1: updated the schedule of analyses with an additional 
EFS/OS interim analysis at 90% EFS information fraction
 
 
•
Section 2.3: updates: In case of non-significant EFS at interim 
analysis, the DMC unblinded closed report will be shared with 
BMS executive restricted team. Further details on data 
communication are provided in section 2.3 and DMC charter.
•
Section 2.4: updated the Revised Protocol 07 and added rationale 
for revised protocol 05 (in response to internal audit finding)
•
Section 5.2: Updated with revised EFS assumptions assuming 
piecewise exponential distribution and added EFS interim analysis 
 
•
Section 5.3: updated to add one OS interim analysis at the time of 
newly added EFS interim analysis
•
Section 5.4: updated analyses timing following changes in section 
5.2 and indicated that the the DMC closed report, including OS will 
be shared with the BMS restricted team. removed table 5.4-1 which 
was repeating information from Table 5.3-1 and section 5.4
•
Section 7.3.1: clarified that covid-19 related reason will be 
provided
•
Section 7.4.2: clarified that covid-19 related reason will be 
provided
•
Section 7.6.3.2: Clarified that for EFS per investigator the 
censoring for new primary cancer is at the time of last tumor 
assessment prior or at the time of new primary cancer, instead of 
the date of new primary cancer
•
Section 7.6.3.2: added sensitivity analysis with interval censoring 
method
•
Section 7.6.3.3: added EFS analysis by PD-L1 for Arm A
•
Section 7.6.3.4: clarified that no HR will be generated for subsets 
with less than 10 subjects, added HR by MPR
•
Section 7.6.3.4: added EFS analysis by pCR and MPR without 
landmark to inform surrogacy
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Table 10-1:
Document History
Version Number
Author(s)
Description
•
Section 7.6.4.3: added OS analysis by PD-L1 for Arm A
•
Section 7.6.4.4: clarified that no HR will be generated for subsets 
with less than 10 subjects, added HR by MPR
•
Section 7.6.4.4: added OS analysis by pCR and MPR without 
landmark to inform surrogacy
•
Section 7.7.2: added Death within 30 days and 90 days from
surgery and added AE/SAE/related AE leading to death
•
Section 7.7.20: added section on Covid-19 AEs
•
Section 7.9.1: added predictive analysis between EFS/OS and PD-
L1
•
Section 11: updated the list of prior analysis including the pCR 
analysis
11
PREVIOUS ANALYSES
The following DMC safety meetings occured before approval of this SAP. Analyses were 
generated for these meetings according to the DMC charter.
•
1st interim safety review for Arms A and B after approximately 15 subjects in each 
arm completed surgery (14-Mar-2018)
•
2nd interim safety review after approximately 15 subjects in arm C completed 
surgery (03-Oct-2018)
•
Additional safety reviews approximately every 6 months until the primary endpoint 
of pathological complete response is analyzed (24-May-2019, 04-Dec-2019)
No by treatment data have been share with BMS for these meetings.
The analysis of the pCR primary endpoint was performed with a database lock of 16-Sep-2020. 
The DMC reviewed the data and BMS was unblinded to treatment arm.  A Clinical Study Report 
was written reporting the demographics, baseline characteristics, surgery related data, pathological 
response results,  clinical response and safety. No EFS/OS data by treatment arm was shared with 
BMS.
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APPENDIX 1
TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION AND 
CONVENTIONS FOR SELECT ADVERSE EVENTS, IMMUNE-
MEDIATED ADVERSE EVENTS AND EVENTS OF SPECIAL 
INTEREST
Time-to onset definition
Time-to onset of AE (any grade) for a specific category is defined as the time between the day of 
the first dose of study treatment and the onset date of the earliest AE (of any grade) in this category.
The time-to onset of AE (grade 3-5) for a specific category is defined similarly with an onset date 
corresponding to a grade 3-5 AE.
Time-to onset of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
Time-to onset for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Time-to resolution definition
In order to derive the time-to resolution, overlapping or contiguous AEs within a specific category
or subcategory will be collapsed into what will be termed “clustered” AEs. For example, if a 
subject (without pre-treatment AE) experienced an AE from 1st to 5th January, another AE (with 
different PT but within same category) from 6th to 11th January and same AE from 10th to 
12th January, these will be collapsed into one clustered AE from 1st to 12th January. Table 1 is 
summarizing key derivation steps for each type of clustered AEs.
Time-to resolution of AE (any grade) for a specific category is defined as the longest time from 
onset to complete resolution or improvement to the grade at baseline among all clustered AEs
experienced by the subject in this category per adverse event criteria category. Events which 
worsened into grade 5 events (death) or have a resolution date equal to the date of death are 
considered unresolved. If a clustered AE is considered as unresolved, the resolution date will be 
censored to the last known alive date. Improvement to the grade at baseline implies that all 
different events in the clustered adverse event should at least have improved to the corresponding 
(i.e. with same preferred term) baseline grade. This measure is defined only for subjects who 
experienced at least one AE in the specific category.
The time-to resolution of AE (grade 3-5) for a specific category is defined similarly with an onset 
date corresponding to a grade 3-5 AE.
Time-to resolution of drug-related AE (any grade or grade 3-5) for a specific category is defined 
similarly but restricted to drug-related AE.
The time-to resolution of AE (any grade or grade 3-5, drug-related or all) where immune 
modulating medication was initiated is defined similarly. For data presentation not restricted to 
IMAE, the additional condition that the subject started an immune modulating medication during 
the longest AE resolution period will be applied.
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Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Table 1:
Derivation of Clustered AE
Type of clustered AE
Derivation
Any grade
Collapse any on-treatment AE from the same category
Drug-related of any grade
Collapse any on-treatment drug-related
AE from the same category
Grade 3-5
Collapse any on-treatment AE from the same category.
Resolution will be based on the onset date of the earliest grade 3-
5 records (if no grade 3-5 record, clustered AE is excluded)
Drug-related of Grade 3-5
Collapse any on-treatment drug-related AE from the same 
category
Resolution will be based on the onset date of  the earliest grade 3-
5 record (if no Grade 3-5 record, clustered AE is excluded)
The algorithm for collapsing adverse event records is using the following conventions:
For each subject and specified category, the corresponding adverse event records will be collapsed 
when:
3) Multiple adverse event records have the same onset date.
4) The onset date of an event record is either the same day or 1 day later than the resolution date 
of a preceding event record (contiguous events).
5) The onset date of an event record is after the onset date and prior to or on the resolution date 
of a preceding event record (overlapping events).
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APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS
Procedures – Imputation Rules. 
If reported procedure start date is a full valid date then set start date equal to the date part of 
procedure start date. 
In case of partial date use imputation rules described below: 
•
If only day is missing then 
−
If month and year of procedure match month and year of first dose date then impute as date 
of first dose; 
−
If month and year of procedure don't match month and year of first dose date then impute 
as first day of that month and year. 
•
If both day and month are missing, then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing. 
Note: Imputation is not applicable to data where start date is not collected (for example "PRIOR 
RADIOTHERAPY" CRF). Set start date to missing in this case. 
If reported end date is a full valid date then set end date equal to the date part of the reported end 
date. 
In case of partial date use imputation rules described below: 
•
If reported end date is partial then set end date equal to the last possible reported end date based 
on the partial entered reported end date. 
•
If reported end date is missing, continuing, unknown or invalid then set end date equal to the 
most recent database extraction date. 
If end date was imputed then compare end date to the death date or last known alive date if subject 
is not dead. If posterior then end date should be imputed to death date (or last known alive date if 
subject not dead). 
Note: Imputation of partial dates only applies to data entered on "RADIOTHERAPY” CRF page. 
For other CRF pages in case of partial dates set end date to missing.  
Surgeries – Imputation Rules. 
If reported surgery date is a full valid date then set start date equal to the date part of surgery date. 
In case of partial date, use one of the two imputation rules described below: 
A. For data collected on "PRIOR SURGERY RELATED TO CANCER" CRF page: 
•
If only day is missing then impute as the first day of the month; 
•
If both day and month are missing then then impute as 01JAN of the year; 
•
If date is completely missing or invalid then leave missing. 
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B. For data collected on “SUBSEQUENT SURGERY” CRF page: 
•
If only day is missing then 
−
If month and year of surgery match month and year of first dose date then impute the 
missing date as the date of first dose; 
−
If month and year of surgery don't match month and year of first dose date then impute as 
first day of that month and year; 
•
If both day and month are missing then impute as maximum between 01JAN of the year and 
date of the first dose; 
•
If date is completely missing or invalid then leave missing. 
•
•
C. For DEFINITIVE SURGERY CRF page :
•
If only day is missing then 
−
if month and year of surgery match month and year of first dose date then impute the 
missing date as the date of first dose; 
−
if month and year of surgery match month and year of last neoadjuvant dose date then 
impute the missing date as the date of last Neoadjuvant dose
−
if month and year of surgery don't match month and year of first dose or last Neoadjuvant 
dose date then impute as first day of that month and year; 
•
If both day and month are missing then impute as maximum between 01JAN of the year and 
date of last Neoadjuvant dose date; 
•
If date is completely missing or invalid then leave missing. 
•
For incomplete definitive surgery end date: set to definitive surgery start date
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18 Non-Study Medication Domain Requirements Specification Bristol Myers Squibb Co. PRI. 
Version 2.10.0 April 23, 2018
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