Conditions: Gastric Cancer Gastroesophageal Junction Cancer Esophageal Adenocarcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2031
Healthy volunteers: no

Brief summary:
The main purpose of this study is to compare how long patients with gastric or gastroesophageal junction cancer live after receiving nivolumab and ipilimumab or nivolumab and chemotherapy compared with patients receiving chemotherapy alone.

Detailed description:

Arms:
arm 1: Nivolumab + Ipilimumab for 4 doses, followed by Nivolumab monotherapy

Enrollment is closed for this arm arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab intervention 3: Oxaliplatin intervention 4: Capecitabine intervention 5: Leucovorin intervention 6: Fluorouracil
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

Protocol document:
Prot_000.pdf: 
Official Title of Study: 
A Randomized, Multicenter, Open-Label, Phase 3 Study of Nivolumab plus Ipilimumab or 
Nivolumab in Combination with Oxaliplatin plus Fluoropyrimidine versus Oxaliplatin plus 
Fluoropyrimidine in Subjects with Previously Untreated Advanced or Metastatic Gastric or 
Gastroesophageal Junction Cancer 
(CheckMate 649: CHECKpoint pathway and nivoluMab clinical Trial Evaluation 649) 
 
NCT Number: NCT02872116 
Document Date (Date in which document was last revised): 16-Sep-2019 


Page:
1
Protocol Number:
CA209649
IND Number:
126,406
Ex-US
Non-IND
EUDRACT Number
2016-001018-76
Date:
04-May-2016
Revised Date
16-Sep-2019
CLINICAL PROTOCOL CA209649
A Randomized, Multicenter, Open-Label, Phase 3 Study of Nivolumab plus Ipilimumab or 
Nivolumab in Combination with Oxaliplatin plus Fluoropyrimidine versus Oxaliplatin plus 
Fluoropyrimidine in Subjects with Previously Untreated Advanced or Metastatic Gastric or 
Gastroesophageal Junction Cancer
(CheckMate 649: CHECKpoint pathway and nivoluMab clinical Trial Evaluation 649)
Revised Protocol Number: 09
Incorporates Amendment 29 and Administrative Letter 08
24-hr Emergency Telephone Number
USA:
International: 
BRISTOL-MYERS SQUIBB RESEARCH AND DEVELOPMENT
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
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BMS-936558
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Date: 16-Sep-2019
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be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions.
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Date: 16-Sep-2019
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 09
16-Sep-2019

Incorporates Amendment 29 and Administrative Letter 08.
Amendment 29
16-Sep-2019

Based on the data from the Keynote 062 study, PFS and OS Kaplan-Meier 
curves separation observed delay, the timing of PFS and OS analyses are 
updated with minimum follow up 12 and 24 months. In addition, to 
reduce variability of efficacy results, PFS population was expanded to all 
randomized subjects with PD-L1 CPS 5.

Per Amendment 29, a 480 mg Q4W nivolumab dosing option for subjects 
who receive nivolumab alone after treatment with nivolumab in 
combination with ipilimumab or FOLFOX/XELOX is allowed. 
Administrative 
Letter 08
13-Feb-2019

Updates address, telephone and fax numbers of the Medical Monitor 
.
Revised 
Protocol 08
15-Nov-2018

Incorporates Amendment 26
Amendment 26
15-Nov-2018

Based on recent internal data, added approximately 356 subjects into 
randomization, in total of approximately 2005 subjects will be 
randomized to keep sample size for primary analyses of PFS and OS in 
PD-L1 CPS
≥5 subjects for nivolumab in combination with 
chemotherapy vs chemotherapy. 
Revised 
Protocol 07
14-Sep-2018
Incorporates Amendment 23 and Administrative Letter 04.
Amendment 23
14-Sep-2018
Major Changes
Incorporates the combined positive score (CPS) for PD-L1 expression 
into CA209649; the primary population is now subjects with 
PD-L1expression ≥5 by CPS rather than by the tumor proportion score 
(TPS) for subjects with nivolumab in combination with oxaliplatin and 
fluoropyrimidine compared to oxaliplatin and fluoropyrimidine.
The planned analysis of overall survival (OS) for nivolumab plus 
ipilimumab arm is changed to a secondary objective. 
Objective response rate (ORR) has been changed to a secondary 
endpoint.
The primary, secondary, and exploratory objectives have been updated to 
reflect changes in subject population definition.
Second disease progression (PFS2) and time to secondary subsequent 
therapy (TSST) have been added as exploratory analyses. Information on 
subsequent treatment will be collected during follow-up period. 
Statistical assumptions and considerations revised to reflect changes in 
study population and revised objectives.
Biomarker sampling has been adjusted based on new knowledge in this 
area of clinical research. 
Administrative 
Letter 04
18-Jun-2018
Corrects approximate number of total randomized subjects to 1649.
Revised 
Protocol 06
11-Jun-2018
Incorporates Amendment 20
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Document
Date of Issue
Summary of Change
Amendment 20
11-Jun-2018
Per recommendation of the Data Monitoring Committee (DMC), as of 
05-June-2018, the nivolumab plus ipilimumab arm is now closed. 
Subjects randomized to this arm prior to or on 05-June-2018 will 
continue to receive treatment with study drugs per protocol, and the study 
data will remain blinded until planned primary analysis.  
Revised 
Protocol 05
29-May-2018
Incorporates Amendment 19
Amendment 19
29-May-2018
Added that randomization of an additional 300 subjects beyond the 
originally planned 1349 subjects across the 3 study arms will allow for 
more robust analysis of the treatment effect of nivolumab in combination 
with ipilimumab or chemotherapy across different PD-L1 cutoffs in 1L 
GC/GEJ cancer.
Revised 
Protocol 04
05-Jan-2018
Incorporates Amendment 17
Amendment 17
05-Jan-2018
Change the primary population to all comers in nivolumab in 
combination with oxaliplatin and fluoropyrimidine, 
Add ORR by Blinded Independent Central Review (BICR) and PFS by 
BICR as primary endpoints in the nivolumab in combination with 
oxaliplatin and fluoropyrimidine and oxaliplatin plus fluoropyrimidine 
arms.
Clarify distal esophageal adenocarcinoma is eligible in the inclusion 
criteria. 
Removal of the 28 day screening window, amylase and lipase removal 
from mandatory tests, clarification of procedures
Correction of minor formatting and typographical errors
Revised 
Protocol 03
10-May-2017
Incorporates Amendment 13
Amendment 13
10-May-2017
Modified inclusion value for albumin to 3.0 g/dL.
Added clarification for traditional Chinese medicines.
Clarified that PDL1 result must be evaluable in order to be randomized 
and that tumor sample must be submitted on positively charged slides if 
not sent as a tumor block.
Added instructions for the administration of nivolumab and 
chemotherapy when administered on the same day.
Specified that capecitabine should be taken with food.
Clarified that outcome research assessments schedule is independent of 
dosing schedule, and removed some wording that was leading to 
confusion regarding the safety visits schedule and treatment beyond 
disease progression.
Revised 
Protocol 02
07-Dec-2016
Incorporates Amendment(s) 08
Amendment 08
07-Dec-2016
Added a new randomization arm, nivolumab-plus-chemotherapy (XELOX 
or FOLFOX) to the study
Added Blinded Independent Central Review (BICR) of tumor images
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Revised Protocol No.: 09
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Document
Date of Issue
Summary of Change
Clarified some study procedures, including limiting the treatment period 
with nivolumab to 2 years
Added safety recommendations for subjects receiving capecitabine
Revised 
Protocol 01
20-Oct-2016
Incorporates Amendment(s) 07 and Administrative Letter 01
Amendment 07
20-Oct-2016
Provided reference to the newly-updated Nivolumab Investigator 
Brochure Version 15 in order to ensure the latest safety information is 
available, including updated algorithms for the management of side 
effects and contraception language
Clarified some study inclusion/exclusion criteria and procedures
Provided additional guidance on the implementation of RECIST 1.1 
criteria
Administrative 
Letter 01
02-Aug-2016
Clarified the protocol instructions regarding the administration of 
chemotherapy and biomarker sampling
Original 
Protocol
04-May-2016
Not applicable
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nivolumab
SYNOPSIS
Clinical Protocol CA209649
Protocol Title: A Randomized, Multicenter, Open-Label, Phase 3 Study of Nivolumab plus Ipilimumab or Nivolumab 
in Combination with Oxaliplatin plus Fluoropyrimidine versus Oxaliplatin plus Fluoropyrimidine in Subjects with 
Previously Untreated Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): 

Nivolumab+ipilimumab: nivolumab 1 mg/kg administered IV over 30 minutes followed by ipilimumab 3 mg/kg 
administered IV over 30 minutes on Day 1 of each treatment cycle every 3 weeks for 4 doses (Cycles 1 to 4), 
followed by nivolumab 240 mg administered IV over 30 minutes on Day 1 of each treatment cycle every 2 weeks 
(Cycle 5 and beyond). Closed to enrollment as of 05-June-2018.

Nivolumab+XELOX: nivolumab 360 mg administered IV over 30 minutes on Day 1 of each treatment cycle, 
oxaliplatin 130 mg/m2 administered IV on Day 1 of each treatment cycle and capecitabine 1000 mg/m2
administered orally twice daily on Days 1 to 14 of each treatment cycle, every 3 weeks, or

Nivolumab+FOLFOX: nivolumab 240 mg administered IV over 30 minutes on Day 1 of each treatment cycle, 
oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and fluorouracil 400 mg/m2 administered IV on Day 1 of each 
treatment cycle, and fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours (or per local standard) daily
on Days 1 and 2 of each treatment cycle, every 2 weeks, or

XELOX: oxaliplatin 130 mg/m2 administered IV on Day 1 of each treatment cycle and capecitabine 1000 mg/m2
administered orally twice daily on Days 1 to 14 of each treatment cycle, every 3 weeks, or 

FOLFOX: oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and fluorouracil 400 mg/m2 administered IV on Day 1 of 
each treatment cycle, and fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours (or per local standard) 
daily on Days 1 and 2 of each treatment cycle, every 2 weeks.
Study drugs will be administered until disease progression (PD) (unless treatment beyond PD is permitted, in 
nivolumab-plus-ipilimumab and nivolumab-plus-chemotherapy arms; see Section 4.5.1.6 of the protocol), 
unacceptable toxicity, withdrawal of consent, or other reasons of discontinuation specified in the protocol.
The treatment with nivolumab will be given for up to 24 months in the absence of disease progression or unacceptable 
toxicity. Chemotherapy will be given as per the study dosing schedule.
Study Phase: Phase 3
Research Hypotheses: In subjects with advanced or metastatic GC or GEJ cancer with PD-L1 combined positive
score (CPS) ≥5, the administration of nivolumab plus ipilimumab will improve OS compared to oxaliplatin plus 
fluoropyrimidine.
In subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS ≥ 5, the administration of nivolumab in 
combination with oxaliplatin plus fluoropyrimidine will improve PFS, or OS compared to oxaliplatin plus 
fluoropyrimidine.
Objectives: 
Primary Objectives
Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs oxaliplatin plus fluoropyrimidine:

To compare OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS 

To compare PFS, as assessed by BICR in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS 
Revised Protocol No.: 09
Date: 16-Sep-2019
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Secondary Objectives
Nivolumab plus ipilimumab vs oxaliplatin plus fluoropyrimidine:

To compare OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS ≥5 or in all 
randomized

To evaluate OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS ≥10 or 1 

To evaluate PFS, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS 1 or all randomized subjects

To evaluate ORR, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS 10, 5, 1 or all randomized subjects

To compare the time to symptom deterioration (TTSD) as assessed using the Gastric Cancer Subscale (GaCS) of 
the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) in subjects with advanced or metastatic GC or 
GEJ cancer with PD-L1 CPS ≥ 5 or all randomized subjects.
Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs oxaliplatin plus fluoropyrimidine:

To compare OS in subjects with advanced or metastatic GC or GEJ cancer with  PD-L1 CPS ≥1 or all randomized 
subjects

To evaluate OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS 10 

To evaluate PFS, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS ≥10, 1, or all randomized subjects 

To evaluate ORR, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS ≥10, 5, 1, or all randomized subjects 
Key Exploratory Objectives
Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs oxaliplatin plus fluoropyrimidine:

To assess TTSD using GaCS of FACT-Ga in subjects with advanced or metastatic GC or GEJ cancer 
with PD-L1 CPS ≥ 5 or all randomized subjects
For both comparisons: Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs oxaliplatin plus 
fluoropyrimidine and Nivolumab plus ipilimumab vs oxaliplatin plus fluoropyrimidine : 

To assess PFS and ORR, as assessed by the investigator in subjects with advanced or metastatic GC or GEJ cancer
across PD-L1 CPS cut-offs

To evaluate Duration of Response (DOR) as assessed by BICR and by investigator, in subjects with advanced or 
metastatic GC or GEJ 

To evaluate the durable response rate (objective response lasting continuously > 6 months) as assessed by BICR 
and by investigator, in subjects with advanced or metastatic GC or GEJ cancer.

To evaluate at 18, 24, and 36 months survival rates in subjects with advanced or metastatic GC or GEJ cancer 

To evaluate second disease progression (PFS2) or time to second subsequent line therapy (TSST) in subjects 
with advanced or metastatic GC or GEJ cancers 

To assess PFS, ORR as assessed by either BICR or investigator, OS in subjects with advanced or metastatic GC 
or GEJ cancer across TPS cut-offs.

To assess the overall safety and tolerability of nivolumab plus ipilimumab or nivolumab in combination with 
oxaliplatin plus fluoropyrimidine and oxaliplatin plus fluoropyrimidine in subjects with advanced or metastatic 
GC or GEJ cancer

To explore potential biomarkers predictive of or associated with clinical efficacy (OS, PFS and ORR) and/or 
incidence of AEs of nivolumab plus ipilimumab or nivolumab in combination with oxaliplatin plus 
fluoropyrimidine including but not limited to microsatellite instability (MSI) status, tumor mutational burden 
Revised Protocol No.: 09
Date: 16-Sep-2019
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nivolumab
(TMB) 
 and inflammatory signatures in subjects 
with advanced or metastatic GC or GEJ cancer. 

To compare TTSD as assessed using GaCS of FACT-Ga in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS ≥ 10, or 1.
More exploratory objectives are listed in the protocol.
Study Design: 
This is a Phase 3, randomized, open-label, three-arm study of nivolumab plus ipilimumab or nivolumab in combination 
with oxaliplatin plus fluoropyrimidine versus oxaliplatin plus fluoropyrimidine in subjects with previously untreated 
advanced or metastatic GC or GEJ cancer. As of 05-June-2018, the nivolumab plus ipilimumab arm is closed to 
enrollment. Subjects randomized to this arm prior to or on 05-June-2018 will continue to receive treatment with study 
drugs per protocol and the study data will remain blinded for the planned primary analysis.
The original study design (before Amendment 08) had two arms. After signing the informed consent form, and upon 
confirmation of the subject’s eligibility, subjects were randomized in an open-label fashion (1:1 ratio) to either the 
nivolumab-plus-ipilimumab arm or the chemotherapy (XELOX or FOLFOX) arm.
Amendment 08 added a new, nivolumab-plus-chemotherapy (XELOX or FOLFOX) arm. Approximately 
1266 subjects were to be randomized in an open-label fashion (1:1:1 ratio) to nivolumab plus ipilimumab, nivolumab 
in combination with chemotherapy (XELOX or FOLFOX), or chemotherapy (XELOX or FOLFOX). Randomization 
will be stratified by TPS PD-L1 status (1% vs < 1% or indeterminate), region (Asia vs US vs Rest of World), ECOG 
performance status (0 vs 1), and chemotherapy regimen (XELOX vs FOLFOX). The study enroll subjects regardless 
PDL1 tumor expressing. During enrollment, the proportion of subjects with or without PD-L1 tumor expression will 
be monitored in pooled fashion, and may be re-assessed in case it does not reflect study assumptions (ie, subjects with 
PD-L1 tumor expression 1% is approximately 40% of all comers).
Amendment 19 added approximately 300 subjects to the study, in total approximately 1649 subjects will be 
randomized. The nivolumab plus ipilimumab arm was closed to enrollment as of 05-June-2018. Subjects randomized 
to treatment in this arm prior to or on 05-June-2018 will continue to receive treatment with study drugs per protocol, 
and the study data will remain blinded for the planned analysis. Per Amendment 20, subjects will be randomized in 
an open-label fashion (1:1) to either the nivolumab-plus-chemotherapy (XELOX or FOLFOX) or the chemotherapy 
arm (XELOX or FOLFOX).
Per Amendment 23, PD-L1 expression has incorporated CPS scoring for study analyses as described in detail in 
Section 1.1.13. However, the stratification factor of tumor proportion score (TPS) remains unchanged for consistency. 
Amendment 26 is adding approximately 356 subjects to the study, and in total approximately 2005 subjects will be 
randomized.
 
 
 Given the uncertainty about the CPS 5 prevalence, the sample size may 
need to be further adjusted based on the monitoring of the prevalence to keep sample size for the primary population.
The treatment will be given until PD (unless treatment beyond PD is permitted, in nivolumab-plus-ipilimumab and 
nivolumab-plus chemotherapy arms; see Section 4.5.1.6 of the protocol), unacceptable toxicity, or subject withdrawal 
of consent, whichever comes first.
The treatment with nivolumab will be given for up to 24 months in the absence of disease progression or unacceptable 
toxicity. Chemotherapy will be given as per the study dosing schedule.
Per Amendment 29, a 480 mg Q4W nivolumab dosing option for subjects who receive nivolumab alone after treatment 
with nivolumab in combination with ipilimumab or FOLFOX/XELOX is allowed. 
Revised Protocol No.: 09
Date: 16-Sep-2019
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BMS-936558
nivolumab
Study Schematic:
Study Population: 
Subjects must meet all eligibility criteria. The key inclusion and exclusion criteria are as follows:
Key Inclusion Criteria:
a)
All subjects must have inoperable, advanced, locally advanced or metastatic GC or GEJ or distal esophageal 
carcinoma and have histologically confirmed predominant adenocarcinoma.
b)
Subject must be previously untreated with systemic treatment including HER 2 inhibitors given as primary 
therapy for advanced or metastatic disease.
c)
Allowed Prior Therapies: Prior adjuvant or neoadjuvant chemotherapy, radiotherapy and/or chemoradiotherapy 
for GC or GEJ cancer are permitted as long as the last administration of the prior regimen (whichever was given 
last) occurred at least 6 months prior to randomization. Palliative radiotherapy is allowed and must be completed 
2 weeks prior to randomization. 
d)
Subject must have at least one measurable lesion or evaluable disease by CT or MRI per RECIST 1.1 criteria.
e)
ECOG performance status score of 0 or 1.
f)
Tumor tissue must be provided for PD-L1 biomarker analyses prior to randomization.
Key Exclusion Criteria:
a)
Known Her2 positive status 
b)
Subjects with untreated CNS metastases.
c)
Subjects with ascites which cannot be controlled with appropriate interventions.
d)
Subjects with > Grade 1 peripheral neuropathy. 
e)
Treatment with botanical preparations (eg herbal supplements or traditional Chinese medicines) intended to treat 
the disease under study within 2 weeks prior to randomization/treatment.
f)
Participants who have received a live/attenuated vaccine within 30 days of first treatment.
Revised Protocol No.: 09
Date: 16-Sep-2019
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BMS-936558
nivolumab
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drugs for CA209649
Medication 
Potency 
IP/Non-IP 
Nivolumab
10 mg/mL
IP
Ipilimumab
5 mg/mL
IP
Oxaliplatin
5 mg/mL
IP
Fluorouracil
50 mg/mL
IP
Leucovorin
50 mg/mL
IP
Capecitabine
150 mg and 500 mg tablets
IP
Study Assessments: 
The primary endpoints of this study are OS and PFS (by BICR) in subjects with PD-L1 CPS 5 (nivolumab with 
oxaliplatin plus fluoropyrimidine vs oxaliplatin plus fluoropyrimidine). 
Key secondary endpoints include: OS in subjects with PD-L1 CPS and in all randomized subjects and TTSD 
in subjects with PD-L1 CPS 5 or all randomized subjects (nivolumab plus ipilimumab vs oxaliplatin plus 
fluoropyrimidine ) and OS with PD-L1 CPS 1 or all randomized subjects (nivolumab in combination with oxaliplatin 
plus fluoropyrimidine vs oxaliplatin plus fluoropyrimidine). Other secondary and exploratory endpoints include ORR, 
DOR and DRR.
Subjects will be assessed for response by CT or MRI. Radiologic assessments will be performed at baseline (within 
28 days prior to randomization), then every 6 weeks (± 7 days) from first dose up to and including Week 48, and then 
every 12 weeks (± 7 days) thereafter, regardless of treatment schedule, until PD or the subject discontinues the study, 
whichever comes first. Subjects who discontinue study drug for reasons other than PD and who continue in the 
follow-up phase of the study will continue to have tumor assessments as indicated above.
Statistical Considerations: 
Sample Size Determination
Randomization Schema
The original study design (before Amendment 08) had 2 arms, with subjects being randomized in a 1:1 ratio to the 
nivolumab plus ipilimumab or to the oxaliplatin plus fluoropyrimidine arm (XELOX or FOLFOX; arm will be further 
referred to as chemotherapy arm). Amendment 08 added a new arm: nivolumab in combination with oxaliplatin plus 
fluoropyrimidine (XELOX or FOLFOX; arm will be further referred to as nivolumab plus chemotherapy arm). The 
IRT switched to a 1:1:1 randomization at all the participating sites when this third arm was ready to be opened on 
27-Mar-2017. Up until that point, there were 83 subjects randomized in the 1:1 randomization to nivolumab plus 
ipilimumab and chemotherapy arm. In Amendment 08, it was planned to randomize 1266 subjects at 1:1:1 ratio to 
nivolumab plus ipilimumab, chemotherapy and nivolumab plus chemotherapy arms. The total number of subjects to 
be randomized was planned to be 1349.
Newly available internal and external data suggested a stronger predictability of PD-L1 CPS than TPS of 
immunotherapy treatment effects. However, uncertainty still exists of CPS at different cutoffs when extrapolated to 
Revised Protocol No.: 09
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CA209649
BMS-936558
nivolumab
first line (1L) metastatic setting in GC and GEJ. To ensure sufficient sample size for evaluating the correlation of 
efficacy and different CPS cutoffs and to keep continuity of enrollment of the study, on 29-May-2018, Amendment 
19 was approved to allow additional 300 subjects to be randomized under 1:1:1 ratio for a total sample size of 1566 
to the 3 treatment arms.
Per DMC recommendation, randomization to the nivolumab plus ipilimumab arm was stopped on 05-June-2018. The 
subjects who were already randomized to treatment in this arm prior to or on 05-June-2018 continued to receive study 
treatment per protocol, and the study data remained blinded for the planned analysis. As such, the 1:1:1 randomization 
was carried through on 05-Jun-2018. These changes were implemented in Amendment 20. At this point, a total of 
1098 subjects were randomized under 1:1:1 ratio. In addition there were 83 subjects randomized to nivolumab plus 
ipilimumab and to chemotherapy arms (prior to Amendment 08). Following Amendment 20, subjects were to be 
randomized in 1:1 ratio to either the nivolumab plus chemotherapy or the chemotherapy arm.
 
Therefore, the enrollment was extended to ensure that the study was 
appropriately powered for PFS and OS primary endpoints in the CPS population. To allow for this, Amendment 
26 increased the total sample size from 1649 to approximately 2005. This resizing of the total population was to ensure 
that the sample size of the enriched population for the primary analyses (subjects with CPS was the same as was 
specified in Amendment 23 to maintain the same power under the statistical assumptions as stated in Amendment 23.
The accrual was completed in May 2019 and in total 2032 subjects were randomized. It is estimated that 1582 subjects 
were concurrently randomized to nivolumab plus chemotherapy and to chemotherapy and that 815 subjects were 
concurrently randomized to nivolumab + ipilimumab and chemotherapy.
General Assumptions of Sample Size Determinations:
Primary Endpoints Family:
For the comparison of nivolumab plus chemotherapy vs chemotherapy both PFS and OS are primary endpoints. 
Type I Error Splitting for Primary Endpoints Family:
For the purpose of sample size calculation, the family-wise error rate of 5% will be split as follows:
1.
Comparison of PFS between nivolumab plus chemotherapy and chemotherapy in subjects with PD-L1 
CPS with alpha of 2
2.
Comparison of OS between nivolumab plus chemotherapy and chemotherapy in subjects with PD-L1 
CPS with alpha of 
Population for Primary Endpoints:
As mentioned in Section 1.1.13, the population for the primary endpoints will be all randomized subjects with PD-L1 
CPS . For the design purpose, the prevalence was assumed to be 35% of all randomized subjects.
Sample Size: Nivolumab plus Chemotherapy vs Chemotherapy
Progression Free Survival
All concurrently randomized subjects to N+CT and CT arms with PD-L1 CPS 5 will be used for the PFS analysis. 
Given the delayed separation in the PFS distributions between pembrolizumab + chemotherapy and chemotherapy, 
the PFS analysis will be conducted after a minimum of 12 months follow-up after the last patient is randomized.
As such, the PFS analysis will be conducted after the following criteria are all met: 

CPS scoring by central laboratories is complete

a minimum follow-up of 12 months 
The HR is modelled as a 2-piece hazard ratio with a delayed effect between 3 and 6 months (a HR of 1 versus 
chemotherapy for the first 3 or 6 months) followed by a constant HR of 0.56. With 12 months minimum follow-up it 
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is expected that the number of events will range between 497 and 506 respectively and the power will range 
approximately between 99% and 60% with a Type I error of 2% (two-sided) (see Table 1 below). 
The primary PFS analysis will be based on all the events observed at time of database lock.
Table 1:
Summary of Sample Size Parameters and Schedule of Analyses for PFS 
(Nivolumab plus Chemotherapy vs Chemotherapy)
3 months Delay
6 months Delay
# subjects with PD-L1 CPS 5a
554
554
Hypothesized delayed period
3
6
Hypothesized HR after delayed 
period
0.56
0.56
Hypothesized median in control arm
5.5 months
5.5 months
Significance level (2-sided)
0.02
0.02
Enrollment Period (from start of 
1:1:1) 
25.4 months
25.4 months
Minimum follow-up / Expected 
number of eventsa,b,c
12 months / 497
12 months / 506
Time of Analysis 
37.4 months
37.4 months
Powerb
99%
60%
Average HRb
0.66
0.8
a Based on 35% prevalence of PD-L1 CPS 5
b Results based on simulations.
c Number of events for the nivolumab plus chemotherapy vs. chemotherapy comparison in total.
Overall Survival 
The interim analysis will be conducted after at least 12 months minimum follow-up, and the final analysis will be 
conducted after at least 24 months minimum follow-up. 
With 24 months minimum follow-up at final analysis it is expected that 466 events will be observed. With an average 
HR of 0.74 modelled as a 2-piece hazard ratio, a delayed effect with a HR of 1 versus chemotherapy for the first 6 
months followed by a constant HR of 0.65  the power will be approximately 85% with a Type I error of 3% (two-
sided) (See Table 2).
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Table 2:
Summary of Sample Size Parameters and Schedule of Analyses for OS 
(Nivolumab plus Chemotherapy vs Chemotherapy)
# with PD-L1 CPS a
554
Hypothesized delayed period
6 months
Hypothesized HR after delayed period
0.65
Hypothesized median in control arm
11.1 months
Significance level (2-sided)
0.03
Enrollment Period (from start of 1:1:1) 
25.4 months
INTERIM ANALYSIS #1 for OS
Minimum follow-up/Expected number of eventsa,b,c
12 months/395
Time of analysisd
37.4 months
Significance levele
0.0164
Power
64%
FINAL ANALYSIS
Minimum follow-up/Expected number of eventsa,b,c
24 months/466
Time of analysisd
49.4 months
Significance level
0.0252
Powerb
85%
Average HR
0.74
a Based on a 35% prevalence of PD-L1 CPS 
b Results based on simulations
c Number of events for the nivolumab plus chemotherapy vs. chemotherapy comparison in total.
d After first patient randomized to nivolumab + chemotherapy or chemotherapy in 1:1:1 randomization.
e Significance levels will be calculated based on the actual number of deaths at each interim analysis
For the OS interim and final analyses, all the events reported in the database at time of database lock will be used for 
the primary analyses.
Primary Efficacy Measures
Overall survival (OS). OS is defined as the time between the date of randomization and the date of death. For subjects 
without documentation of death, OS will be censored on the last date the subject was known to be alive. 
Progression-free Survival (PFS) as assessed by BICR is defined as the time from randomization to the date of the first 
documented PD per BICR or death due to any cause. Subjects who die without a reported prior PD per BICR (and die 
without start of subsequent therapy) will be considered to have progressed on the date of death. Subjects who did not 
have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last 
evaluable tumor assessment on or prior to initiation of subsequent anti-cancer therapy. Subjects who did not have any 
on-study tumor assessments and did not die (or died after initiation of subsequent anti-cancer therapy) will be censored 
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at the randomization date. Subjects who started any subsequent anti-cancer therapy without a prior reported PD per 
BICR will be censored at the last tumor assessment prior to or on the initiation of the subsequent anti-cancer therapy.
Secondary Efficacy Measures
Time to Symptom Deterioration (TTSD) is defined as the time from randomization until a clinically meaningful 
decline from baseline in GaCS score. A clinically meaningful deterioration is defined as a reduction of 8.2 points in 
the GaCS score. Subjects who do not deteriorate will be censored at the time of their last GACS assessment. Subjects 
without baseline GaCS assessment will be censored on the randomization date. Those with baseline GaCS, who do 
not have any GaCS assessments after randomization will be censored on the day after randomization.
Objective Response Rate (ORR) as assessed by BICR is defined as the number of subjects with a best overall response 
(BOR) of CR or PR divided by the number of measurable subjects with target lesion at baseline. BOR is defined as 
the best response designation as determined by the BICR, recorded between the date of randomization and the date of 
objectively documented progression (per RECIST 1.1 as determined by the BICR) or the date of subsequent 
anti-cancer therapy, whichever occurs first. For subjects without documented progression or subsequent anti-cancer 
therapy, all available response designations will contribute to the BOR determination.
Efficacy Analyses
Strong Control Of Type I Error for Primary and Secondary endpoints
For design purposes, the alpha was split using Bonferroni method between the 2 primary endpoints: 
1)
Comparison of PFS between nivolumab plus chemotherapy and chemotherapy in subjects with PD-L1 CPS 
with alpha of 2
2)
Comparison of OS between nivolumab plus chemotherapy and chemotherapy in subjects with PD-L1 
CPS with alpha of 
For analyses purposes of primary and key secondary endpoints the Bonferroni-based graphical approach. will be used 
and full details will be provided in the statistical analysis plan.
The alpha from the PFS of N+CT vs CT in PD-L1 CPS testing will be carried to the testing of OS of N+I vs CT 
in PD-L1 CPS analysis, should the PFS analysis be statistically significant. If OS of N+CT vs CT is significantly 
superior in subjects with PD-L1 CPS then the inherited alpha will be shared equally to secondary endpoints of OS 
of N+CT vs CT in PD-L1 CPS subjects and OS of N+I vs CT in PD-L1 CPS . The comparison of OS for N+I 
vs CT in PD-L1 CPS may inherit alpha independently from the two primary endpoints and will be tested only 
once after 36 months of minimum follow-up. The alpha that will be allocated to the comparison of OS for N+I vs CT 
in PD-L1 CPS 5 will be 1.5%, 2% or 3.5% depending on the outcome of the primary endpoints for N+CT vs CT.
The SAP will document the details of the actual alpha allocation to the secondary endpoints. 
The timing of the efficacy analyses is described in Table 3.
Table 3:
Timing of Analyses
Endpoints
Timing of Analysis
PFS N+CT vs CT
in all randomized 
subjects with PD-L1 
CPS 5
OS N+CT vs CT
in all randomized 
subjects with PD-L1 
CPS 5
OS N+I vs CT
in all randomized 
subjects with PD-L1 
CPS 5
12-month minimum FU
X
X (IA)
24-month minimum FUa
X (FA)
X
a FU: follow-up. Twenty-four months minimum follow-up from last patient randomized to N+CT or CT, corresponds 
to approximately 36-month minimum follow-up for N+I vs CT.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Rationale for Investigating Advanced or Metastatic GC/GEJ in the First 
Line Setting ................................................................................................. 
1.1.2 Rationale for the Combined Targeting of PD-1 and CTLA-4 in Advanced 
or Metastatic GC/GEJ Cancer .................................................................... 
1.1.2.1 Previous Studies of Nivolumab and Ipilimumab in GC .................. 
1.1.3 Rationale for Nivolumab-plus-Ipilimumab Treatment in 1L GC/GEJ 
Cancer Treatment ....................................................................................... 
1.1.4 Rationale for Dose Selection of Nivolumab-plus-Ipilimumab Treatment 
1.1.5 Rationale for Nivolumab in Combination with Chemotherapy ............... 
1.1.5.1 Rationale for Primary Population in the Nivolumab in Combination 
with Chemotherapy ............................................................................... 
1.1.5.2 Rationale for PFS as the Primary Endpoint in the Nivolumab in 
Combination with Chemotherapy Arm ................................................. 
1.1.6 Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab .... 
1.1.7 Rationale for 2-year Nivolumab Treatment ............................................. 
1.1.8 Rationale for Including Both Subjects with PD-L1 and Non-PD-L1 
Expressing Tumors in 1L GC/GEJ and Stratification by PD-L1 Expression
..................................................................................................................... 
1.1.9 Rationale for Choice of Comparator ....................................................... 
1.1.10 Rationale for Adding Chemotherapy Regimen as Stratification Factor 
1.1.11 Rationale for Open-Label Design .......................................................... 
1.1.12 Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease for Subjects in the Nivolumab Plus Ipilimumab and 
Nivolumab in Combination with Chemotherapy Arms ............................... 
1.1.13 Rationale for incorporation of CPS for PD-L1 expression evaluation 
and changing primary population to subjects with PD-L1 CPS  5 .......... 
1.1.14 Rationale for Statistical Analyses Update in Amendment 29 ................ 
1.2 Research Hypotheses ........................................................................................ 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.3.3 Exploratory Objectives ............................................................................ 
1.4 Product Development Background ................................................................... 
1.4.1 Mechanism of Action ................................................................................ 
1.4.1.1 Nivolumab ....................................................................................... 
1.4.1.2 Ipilimumab ...................................................................................... 
1.4.2 Summary of Clinical Pharmacology ........................................................ 
1.4.2.1 Nivolumab ....................................................................................... 
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1.4.2.2 Ipilimumab ...................................................................................... 
1.4.3 Safety Summary ........................................................................................ 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.1.1 Screening Phase ....................................................................................... 
3.1.2 Treatment Phase ...................................................................................... 
3.1.3 Follow-up Phase ...................................................................................... 
3.2 Post-Study Access to Therapy .......................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.4.3 Permitted Therapy ................................................................................... 
3.5 Discontinuation of Subjects following any Treatment with Study Drug .......... 
3.6 Post-Study Drug Study Follow up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-Up .................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage of Study Drug ...................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Nivolumab and Ipilimumab Dosing ......................................................... 
4.5.1.1 Nivolumab and Ipilimumab Dose and Schedule ............................. 
4.5.1.2 Dose Delay Criteria for Nivolumab and/or Ipilimumab Therapy .. 
4.5.1.3 Dose Reductions for Nivolumab or Ipilimumab Therapy ............... 
4.5.1.4 Criteria for Resuming Treatment for Nivolumab or Ipilimumab.... 
4.5.1.5 Criteria for Nivolumab and/or Ipilimumab Treatment 
Discontinuation ..................................................................................... 
4.5.1.6 Treatment Beyond Disease Progression ......................................... 
4.5.1.7 Management Algorithms for Immuno-oncology Agents ................. 
4.5.1.8 Treatment of Nivolumab- or Ipilimumab-Related Infusion Reactions
............................................................................................................... 
4.5.2 Nivolumab plus Chemotherapy Arm ........................................................ 
4.5.2.1 Nivolumab plus Chemotherapy Arm Dosing Schedule ................... 
4.5.2.2 Dose Modification Criteria for Nivolumab-plus-Chemotherapy .... 
4.6 Chemotherapy Arm Dosing .............................................................................. 
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4.6.1 Oxaliplatin-Plus-Fluoropyrimidine Dose and Schedule ......................... 
4.6.2 Dose Modification Criteria for Oxaliplatin-Plus-Fluoropyrimidine 
Treatment .................................................................................................... 
4.6.2.1 General Guidance for Dose Modification for Chemotherapy ........ 
4.6.2.2 Dose Modification Criteria for XELOX .......................................... 
4.6.2.3 Dose Modification Criteria for FOLFOX ....................................... 
4.7 Criteria for Oxaliplatin-plus-Fluoropyrimidine Discontinuation ...................... 
4.8 Blinding/Unblinding ......................................................................................... 
4.9 Treatment Compliance ...................................................................................... 
4.10 Destruction or Return of Investigational Product ........................................... 
4.11 Retained Samples for Bioavailability/Bioequivalence/Biocomparability ...... 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening or Lead-in Period ....................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Screening Safety Assessments .................................................................. 
5.3.2 On-Treatment Safety Assessments ........................................................... 
5.3.3 Follow-up Safety Assessments ................................................................. 
5.3.4 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.4.1 Independent Review of Progression ......................................................... 
5.5 Pharmacokinetic Assessments .......................................................................... 
5.5.1 Pharmacokinetic and Immunogenicity Collection and Processing ......... 
5.6 Biomarker Assessments .................................................................................... 
5.6.1 Tumor Samples......................................................................................... 
5.6.1.1 Tumor Sample Collection Details ................................................... 
5.6.1.7 Microsatellite Instability Testing .................................................... 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Other Assessments ............................................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
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6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
6.7.1 Adverse Events of Interest ........................................................................ 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.1.1 Randomization Schema ............................................................................ 
8.1.2 Changes of Statistical Analyses and Timing of Analyses in Amendment 29
..................................................................................................................... 
8.1.3 General Assumptions of Sample Size Determinations ............................. 
8.1.4 Sample Size: Nivolumab plus Chemotherapy vs Chemotherapy ............. 
8.1.5 Power Considerations for Nivolumab Plus Ipilimumab vs Chemotherapy
..................................................................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Efficacy Measures...................................................................... 
8.3.2 Secondary Efficacy Measures .................................................................. 
8.3.3 Exploratory Measures .............................................................................. 
8.4 Analyses ............................................................................................................ 
8.4.1 Demographics and Baseline Characteristic ............................................ 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.2.1 Strong Control Of Type I Error for Primary and Secondary 
endpoints ............................................................................................... 
8.4.2.2 Analyses for Primary Objectives .................................................... 
8.4.2.3 Analyses for Secondary Objectives in Hierarchy ........................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.5 Biomarker Analyses ................................................................................. 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report ........................................................................................ 
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9.4 Scientific Publications ...................................................................................... 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 MANAGEMENT ALGORITHMS ....................................................... 
APPENDIX 2 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 3 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 4 RADIOLOGIC EVALUATION CRITERIA IN SOLID TUMOURS 
VERSION 1.1 (RECIST CRITERIA 1.1) .............................................................. 
 
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1
INTRODUCTION AND STUDY RATIONALE
CA209649 is a Phase 3, randomized, open-label study of nivolumab plus ipilimumab or nivolumab 
in combination with oxaliplatin plus fluoropyrimidine vs oxaliplatin plus fluoropyrimidine in 
subjects with previously untreated advanced or metastatic gastroesophageal junction (GEJ) or 
gastric cancer (GC). This study will determine if nivolumab plus ipilimumab improves overall 
survival (OS) vs the standard of care, oxaliplatin plus fluoropyrimidine, in subjects with GC/GEJ 
cancer with enriched PD-L1 expression by combined positive score (CPS); or whether nivolumab 
in combination with oxaliplatin plus fluoropyrimidine improves OS or PFS vs the standard of care, 
oxaliplatin plus fluoropyrimidine, in subjects with GC/GEJ cancer with enriched PD-LI expressing 
by CPS. Additional objectives include further characterization of efficacy, safety and tolerability, 
pharmacokinetics (PK), patient-reported outcomes, and potential predictive biomarkers of 
nivolumab in combination with ipilimumab or nivolumab in combination with oxaliplatin plus 
fluoropyrimidine in subjects with GC/GEJ whose tumors do or do not express PD-L1.
1.1
Study Rationale
1.1.1
Rationale for Investigating Advanced or Metastatic GC/GEJ in the First 
Line Setting
Gastric cancer is the 5th leading cancer and the 3rd leading cause of cancer-related deaths 
worldwide. The incidence of GC varies with different geographic regions, with over 70% of GCs 
occurring in developing countries. 1 Gastric cancer often presents as advanced disease upon 
diagnosis, comprising approximately 40% of newly diagnosed cases in the United States (US) and 
Europe, and approximately 20% in Japan and Korea, where early detection is common.2
Gastric cancer, including GEJ carcinoma, is a heterogeneous disease with several established risk 
factors, including environmental, genetic and behavioral risks. There has been a steady decline in 
GC mortality attributable to dietary and lifestyle changes worldwide3 and to decreasing infection 
with Helicobacter pylori, which is considered the main cause in Asian countries.4 However, the 
incidence of GEJ tumors and esophageal adenocarcinoma (EAC) has increased considerably due 
to increases in risk factors such as obesity and gastroesophageal reflux disease.1
Gastroesophageal junction cancer anatomically straddles the distal esophagus and proximal 
stomach; due to its location and given that, like GC, the majority of GEJ tumors are 
adenocarcinomas, GEJ tumors are frequently grouped together with GC. Adenocarcinoma is 
further classified into 2 distinct types: intestinal (well-differentiated) or diffuse (undifferentiated).5
Until optimal, tumor-specific treatment strategies are defined, advanced and metastatic GEJ cancer 
is treated and managed in a similar fashion to GC.6,7 As current understanding of EAC’s, are that 
they share similar disease and molecular characteristics8 as GEJ and GC adenocarcinomas, EACs 
are managed and treated similar to those tumors per treatment guidelines and clinical practice.9,10
Platinum
compounds (oxaliplatin and cisplatin) and fluoropyrimidines (5-fluorouracil, 
capecitabine, and tegafur/gimeracil/oteracil potassium [S1]) are generally considered as first-line 
(1L), standard-of-care treatment options in metastatic GC and GEJ cancer across geographic 
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regions.11,12,13 These platinum/fluoropyrimidine combinations are also generally accepted as 
active comparators in Phase 2 or Phase 3 randomized studies by health authorities worldwide. The
different biological characteristics and treatment approaches among regions result in different 
survival outcomes, with median overall survival (mOS) durations of 12 to 14 months in Asian 
countries and 8 to 11 months in the US and Europe.14,15,16. While these cytotoxic agents are 
clinically active, with a 30% to 50% objective response rate (ORR) in the 1L GC treatment setting, 
this clinical activity is accompanied by high toxicity.14,15,16,17 Grade 3/4 toxicities up to 77% have 
been reported for platinum doublets and > 80% for triplet regimens.14,15,17,18 Hematological 
toxicity is the major problem; Grade 3/4 neutropenia has been reported in approximately 40% of 
patients treated with platinum doublets, and has increased to 82% when docetaxel was added 
on.14,17,18 Renal toxicity and neuropathy are the main reasons for discontinuation of platinum 
treatment. Gastrointestinal complaints are also common.14,15,17,18 In addition, despite ORRs of 
30% to 50%, chemotherapy has resulted in few patients achieving complete response (CR); 
therefore, new treatment options are needed to improve survival and response as well as decrease 
toxicity in 1L GC/GEJ cancer.
In the past decade, multiple new investigational drugs with mainly molecular targets have been 
investigated in the 1L setting as add-ons to backbone platinum and fluoropyrimidine treatment. 
These agents, with the exception of trastuzumab, which targets the Her2-positive population,19
have failed to show a survival benefit in randomized trials. The reasons include regional 
differences in efficacy, with the highest survival rate but smallest benefit noted in Asia and the 
shortest mOS but greatest benefit in Western countries.14,18,19 Thus, a regional approach might be 
appropriate in 1L GC/GEJ treatment development, and this study will mainly focus on Western 
countries where great unmet medical needs are present. 
1.1.2
Rationale for the Combined Targeting of PD-1 and CTLA-4 in Advanced
or Metastatic GC/GEJ Cancer
Immunotherapeutic approaches have demonstrated clinical efficacy in several advanced cancer 
types, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and 
gastric cancer (GC).20,21,22,23 Nivolumab (BMS-936558), a programmed cell death protein-1 (PD-
1) antibody, and ipilimumab (BMS-734016), a cytotoxic T-cell lymphoma-4 (CTLA-4) antibody, 
are such immunotherapies that have been approved in the US, Europe, Japan and other 
countries.24,25,26,27
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may 
improve antitumor activity.28 In vitro combinations of nivolumab plus ipilimumab have increased 
IFN-production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. 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.28 In the Phase 1 dose escalation study 
CA209004, the combination of nivolumab and ipilimumab has been studied in subjects with 
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unresectable or metastatic melanoma. In this study, a safe dose level for the combination of 
ipilimumab and nivolumab was established for the treatment of advanced melanoma. At this dose 
level, 3 mg/kg ipilimumab plus 1 mg/kg nivolumab, an objective response rate of 53% was 
observed. This dose level has been approved in subjects with advanced melanoma in the US based 
on the Phase 3 study CA209067. In this study, the combination of nivolumab and ipilimumab has 
demonstrated increased benefit compared to either ipilimumab or nivolumab monotherapies in 
subjects with advanced melanoma.29
In GC patients, tumors with PD-L1 expression have been reported to be associated with depth of 
muscle invasion, tumor size, and lymph node metastasis. The survival of patients with PD-L1 or 
PD-L2 expressing tumors is significantly worse than for those patients without PD-L1/PD-L2 
expressing tumors. PD-L1 or PD-L2 expressing tumors have been reported in approximately 22% 
to 40% of GC and PD-L1 has been suggested as a prognostic marker.30,31 More and more data of 
PD-L1 expression in GC has become available since this study was originally designed. These 
data suggest that PD-L1 is an independent prognosis factor while other data suggest that its use as 
prognosis factor may not be proven.32,33,34,35,36
The blockage of PD-1/PD-L1/PD-L2 might improve the survival of GC patients. Anti PD-1 and 
PD-L1 inhibitors (eg, nivolumab, pembrolizumab, and avelumab) have been investigated in GC 
treatment and have demonstrated anti-tumor activity.37,38 39
Treatment with pembrolizumab achieved a 33% ORR by investigator assessment and 22% by 
central data review in GC subjects with PD-L1 expressing tumors.38 The 6-month progression-free 
survival (PFS) rate was 26% and median PFS was 1.9 months (95% CI: 1.8, 3.5). The 6-month OS 
rate was 66% and mOS was 11.4 months (95% CI: 5.7, NR). PD-L1 expressing tumors (cutoff 
1%) were reported in 40% of GC patients in this study, which is consistent with previous reports.38
Preliminary data for second line (2L) and switching maintenance use of avelumab, an anti-PD-L1 
IgG1 antibody, in advanced GC have been recently reported. The ORRs were 15% and 7.3%, the 
6-month PFS rates were 19% and 34%, and the median PFS were 2.9 months and 3.5 months in 
avelumab as 2L and switching maintenance therapy, respectively.39
1.1.2.1
Previous Studies of Nivolumab and Ipilimumab in GC
In addition to studies performed in subjects with melanoma treated with nivolumab and/or 
ipilimumab, BMS has conducted two studies in the treatment of GC/GEJ cancer: CA184162 
(ipilimumab alone) and CA209032 (nivolumab alone and in combination with ipilimumab).
CA184162 compared ipilimumab monotherapy 10 mg/kg (IV every 3 weeks x 4 doses, followed 
by ipilimumab 10 mg/kg IV every 12 weeks) to best supportive care (BSC) in subjects with 
unresectable locally advanced or metastatic GC/GEJ cancer who did not show evidence of disease 
progression following 1L or lead-in chemotherapy. A majority (88%) of subjects in the BSC arm 
continued to receive the fluoropyrimidine therapy that they had received during the lead-in period, 
ie, they were on active concomitant chemotherapy during the study. 
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A total of 114 subjects were randomized, 57 subjects to each group. The primary endpoint of the 
study was immune-related progression-free survival (irPFS) as per assessment of an Independent 
Review Committee (IRC). The endpoint was achieved at the time of interim analysis. At the 
interim analysis, the median irPFS in the ipilimumab and BSC groups were 2.92 months and 
4.90 months, respectively. The rates of irPFS at 6 months in the ipilimumab and BSC groups were 
22.3% and 38.5%, respectively. In the final analysis, the median OS (mOS) in the ipilimumab 
10 mg/kg group and in the BSC group were 12.7 months [95% CI: 10.5, 18.9] and 12.1 months 
[95% CI: 9.3, Not Estimable], respectively. Hence, ipilimumab did not improve irPFS and OS 
compared to placebo in the 1L maintenance setting.40
CA209032 is an ongoing, open-label, multi-center Phase 1/2 study to investigate the safety and 
efficacy of nivolumab monotherapy or nivolumab plus ipilimumab combination therapy in 
multiple tumor types including GC/GEJ, and esophageal adenocarcinoma. The following dose 
cohorts enrolled subjects with GC/GEJ cancer who had previously received at least one prior 
therapy, and more than 80% of subjects received more than 2 prior therapies:

N3 monotherapy cohort: nivolumab 3 mg/kg IV every 2 weeks (n = 59)

N1+I3 cohort: nivolumab 1 mg/kg + ipilimumab 3 mg/kg, IV every 3 weeks x 4 doses, 
followed by nivolumab 3 mg/kg IV every 2 weeks (n = 49);

N3+I1 cohort: nivolumab 3 mg/kg + ipilimumab 1 mg/kg, IV every 3 weeks x 4 doses, 
followed by nivolumab 3 mg/kg IV every 2 weeks (n = 52).
Table 1.1.2.1-1 summarizes the preliminary efficacy data obtained in CA209032.
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Table 1.1.2.1-1:
Clinical Activity of Nivolumab Monotherapy, and Nivolumab plus 
Ipilimumab Combination Therapy in Subjects with GC/GEJ 
Cancer (CA209032)
N3 monotherapy
N = 59
N3+I1
N = 52
N1+I3
N = 49 
Population
> 1L Prior therapy
Confirmed ORR, % 
(95% CI)
13.6 
(6.0 - 25.0)
10.2 
(3.4 - 22.2)
26.1 
(14.3 - 41.1)
Duration of Response, 
mos. (95% CI)
7.1 
(3.0 - 13.2)
NA 
(2.5 - NA)
5.6 
(2.8 - NA)
PFS rate at 24 wks, % 
(95% CI)
17.7 
(9.0 - 28.7)
8.8 
(2.8 - 19.1)
23.9 
(12.4 - 37.5)
Median PFS, mos
(95% CI)
1.36 
(1.25 - 1.51)
1.58 
(1.38 - 2.6)
1.45 
(1.25 - 3.94)
1-year OS rate, %  
(95% CI)
36 
(21 - 51)
NA
34 
(19 - 50)
Median OS, mos 
(95% CI)
5.03 
(3.35 - 12.42)
4.83 
(3.02 - 9.07)
6.87 
(3.61 - NA)
Median length of follow-
up, mos (range)
16.78 
(1.86 - 24.79)
6.26 
(1.07 - 13.28)
8.54 
(0.93 - 12.40)
N3: nivolumab; 3 mg/kg; I1: ipilimumab, 1mg/kg; N1: nivolumab, 1 mg/kg: I3: ipilimumab, 3 mg/kg; ORR: objective 
response rate; PFS: progression-free survival; mOS: median overall survival; CI: confidence interval; 1L: first line.
Data base lock: Nov 2015
Table 1.1.2.1-2 presents preliminary data from CA209032 describing the clinical activity of 
nivolumab monotherapy and nivolumab-plus-ipilimumab combination therapy in subjects with 
GC/GEJ cancer by PD-L1 status at a 1% cutoff. 
Clinical activity was observed in subjects with both PD-L1 expressing and non-expressing tumors, 
although there was a greater magnitude of efficacy in the subjects with PD-L1 expressing tumors 
with both nivolumab alone and in combination with ipilimumab. 
Table 1.1.2.1-2:
Clinical Activity of Nivolumab Monotherapy and in Combination 
with Ipilimumab in GC/GEJ Cancer by PD-L1 Status, Using 1% 
Cut Off, CA209032
PD-L1
ORR,
% (n/N) 
mDOR
Mon
(95% CI)
DCR
% (n/N)
CR/PR/SD 
mPFS 
(mon)
mOS
(mon)
N3 Q2W
1% 
26.7
(4/15)
7.1
(6.8 - 7.1)
33.3
(5/15)
1.33
(1.15 - 2.63)
3.35
(1.5 - 13)
N3 Q2W
< 1%
12
(3/25)
13.2
(3 - 13.2)
40
(10/25)
1.54
(1.22 - 2.79)
7.72
(3.3 - 16.1)
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Table 1.1.2.1-2:
Clinical Activity of Nivolumab Monotherapy and in Combination 
with Ipilimumab in GC/GEJ Cancer by PD-L1 Status, Using 1% 
Cut Off, CA209032
PD-L1
ORR,
% (n/N) 
mDOR
Mon
(95% CI)
DCR
% (n/N)
CR/PR/SD 
mPFS 
(mon)
mOS
(mon)
N1+I3 
1% 
44.4
(4/9)
NA
(2.8 - NA)
55.5
(5/9)
4.37
(0.99 - NA)
NA
(2.5 - NA)
N1+I3 
< 1%
20.7
(6/29)
5.6 
(2.7 - NA)
41.4 
(12/29)
1.45
(1.18 - 3.94)
6.47 
(3.09 - 9.79)
N3+I1
1% 
27.3
(3/11)
NA
(2.5 - NA)
36.4 
(4/11)
1.38
(1.22 - 5.26)
7.23 
(1.9 - NA)
N3+I1
< 1%
0 
(0/27)
NA
37
(10/27)
1.58
(1.25 - 2.66)
4.37 
(2.07 - 9.07)
ORR: Objective Response Rate; mDOR: median Duration of Response; DCR: Disease Control Rate; mPFS: median 
The preliminary safety data from CA209032 indicates that 70% of subjects treated with nivolumab 
and 84% of those treated with N1+I3 had at least 1 AE. A total of 17% of subjects in the nivolumab 
group and 45% in the N1+I3 group had Grade 3/4 AEs. Serious AEs (SAEs) were reported in 
69.5% of subjects in the nivolumab group and 87.8% in the N1+I3 group; SAEs in 45.8% of 
subjects in the nivolumab group and 34.7% in N1+I3 group were malignant neoplasm 
progressions. A total of 5% of subjects in the nivolumab group and 22% of subjects in the N1+I3 
treatment group discontinued study drug due to AEs. In N1+I3 arm, Grade 3/4 AEs reported in 
> 5% of subjects were ALT increased (14%), diarrhea (12%), AST increased (10%), and adrenal 
insufficiency (8%). Those SAEs (except malignant neoplasm progression) of any grade of intensity 
reported in > 5% of subjects were diarrhoea (10%), ALT increased (10%), AST increased (8%), 
adrenal insufficiency (8%), pyrexia (8%), nausea (6%), colitis (6%), hyperglycaemia (6%), and 
fatigue (6%). These data are consistent with those of the Phase 3 melanoma study CA209067 
where the same N1+I3 regimen was used.37
1.1.3
Rationale for Nivolumab-plus-Ipilimumab Treatment in 1L GC/GEJ 
Cancer Treatment 
In evaluating trials targeting PD-1 or PD-L1 in GC/GEJ cancer, the following observations from 
CA209032 can be made regarding the potential of combination nivolumab-plus-ipilimumab 
therapy in 1L GC/GEJ treatment development: 

For nivolumab-plus-ipilimumab treatment, the N1+I3 cohort demonstrated a doubling of ORR 
compared to nivolumab monotherapy or the N3+I1 cohort and had an estimated ORR of 26% 
in all comers and 44% in subjects with PD-L1 expressing tumors. These results compare 
favorably to 1L SOC chemotherapy. The N1+I3 regimen was efficacious in both PD-L1 1% 
and < 1% tumors, indicating a potential dose combination suitable for 1L evaluation in all 
comers.
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
The safety profiles of nivolumab monotherapy and N1+I3 (Grade 3/4 AEs: 45%) were 
generally more favorable than that for platinum doublet chemotherapy (Grade 3/4 AEs: 
approximately 77%), with a different characteristic toxicity profile. 

For nivolumab monotherapy (3 mg/kg), the low ORR (12%) and mPFS (< 2 months) in heavily 
pre-treated GC/GEJ cancer did not compare favorably to standard 1L chemotherapy, where the 
ORR was 30% to 50% and mPFS was 4 to 6 months. Analysis by PD-L1 (1% vs < 1%) 
suggests that monotherapy development in a biomarker-selected population in the 1L setting 
may bring a limited survival benefit due to the low mOS (3.55 months) estimate even with a 
doubling of ORR (26%) in the subjects with PD-L1 1% tumors.

The activities of other monotherapy drugs targeting PD-1 or PD-L1 in subjects with 
PD-L1-expressing tumors or in an unselected population are consistent with nivolumab 
monotherapy results.38,39 PD-L1 selected patients (ie, with PD-L1 expressing tumors) were 
reported with a mOS estimate of 11 months. However the single arm nature of the monotherapy 
trials and the mixing of regions (Asia and US/Europe) make these mOS estimates difficult to 
interpret when extrapolating to the 1L setting, even in a PD-L1 selected population.

For ipilimumab monotherapy, the inferior ORR and mPFS compared to BSC (with 88% of 
subjects in BSC also receiving fluoropyrimidine) do not compare favorably to the ORR and 
mPFS with 1L platinum doublet chemotherapy and do not support monotherapy development 
in the 1L setting. 
Thus, based on the aforementioned data, nivolumab 1 mg/kg with ipilimumab 3 mg/kg 
administered Q3W for a total of 4 doses followed by nivolumab 240 mg every 2 weeks (the 
rationale of nivolumab 240 mg is described in Section 1.1.4 below) will be used in this study as 
this combination regimen approach might bring greater clinical benefits than the SOC approach. 
Due to the early closure of enrollment into the nivolumab plus ipilimumab arm per DMC 
recommendation (see Section 1.5) as specified in Amendment 19, the number of enrolled subjects 
in this treatment group is lower than the original planned sample size. As a result, the planned 
analysis of overall survival for this regimen is underpowered and is therefore changed to a 
secondary objective of the study per Amendment 23. 
1.1.4
Rationale for Dose Selection of Nivolumab-plus-Ipilimumab Treatment
The nivolumab-plus-ipilimumab combination dosing regimen selected for evaluation in this study 
is N1+I3 administered every 3 weeks (Q3W) for 4 doses followed by nivolumab 240 mg 
administered every 2 weeks (Q2W) until end of treatment (EOT). 
The combination dosing of N1+I3 was selected based on its better clinical activity vs N3+I1 
demonstrated in the CA209032 study (Table 1.1.2.1-2). Similar to CA209032, following the 
administration of 4 doses of the combination with ipilimumab, nivolumab will be administered 
alone at a flat dose of 240 mg Q2W starting at Week 13 until EOT. 
Nivolumab 240 mg Q2W was selected based on clinical data as well as modeling and simulation 
approaches using population pharmacokinetics (PPK) and exposure-response analyses of data 
from studies in melanoma, NSCLC, and RCC, where body-weight normalized dosing (mg/kg) has 
been used. 
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PPK analyses have shown that the PK of nivolumab is linear with proportional exposure over a 
dose range of 0.1 to 10 mg/kg, and no differences in PK across ethnicities or tumor types were 
observed. Nivolumab clearance and volume of distribution were found to increase as the body 
weight increases, but less than proportionally with increasing weight, indicating that mg/kg dosing 
represents an over-adjustment for the effect of body weight on nivolumab PK. The PPK model 
previously developed using data from NSCLC subjects has recently been updated, using data from 
1,544 subjects from 7 studies investigating nivolumab in the treatment of melanoma, NSCLC, and 
RCC. In this dataset, the median (minimum - maximum) weight was 77 kg (35 160 kg) and thus, 
an approximately equivalent dose of 3 mg/kg for an 80 kg subject, nivolumab 240 mg Q2W, was 
selected for future studies. To predict relevant summary exposures of nivolumab 240 mg Q2W, 
the PPK model was used to simulate nivolumab 3 mg/kg Q2W and 240 mg Q2W. The simulated 
patient populations consisted of 1000 subjects per treatment arm randomly sampled from the 
aforementioned pooled database of cancer subjects. Because no differences in PK were noted 
across ethnicities and tumor types, these simulated melanoma and NSCLC data will be applicable 
to subjects with other tumor types. The simulated measures of exposure of interest, time-averaged 
concentrations (Cavgss) for 240 mg Q2W, are predicted to be similar for all subjects in reference 
to 80 kg subjects receiving 3 mg/kg Q2W.
Nivolumab is safe and well tolerated up to the 10 mg/kg Q2W dose level. Adverse events have 
been broadly consistent across tumor types following monotherapy and have not demonstrated 
clear dose-response or exposure-response relationships. Additionally, the simulated median and 
95th percentile interval of nivolumab summary exposures across body weight range (35 - 160 kg) 
are predicted to be maintained below the corresponding observed highest exposure experienced in 
nivolumab, ie, 95th percentile following nivolumab 10 mg/kg Q2W from clinical study 
CA209003. Thus, while subjects in the lower body weight ranges would have greater exposures 
than 80 kg subjects, the exposures are predicted to be within the range of observed exposures at 
doses (up to 10 mg/kg Q2W) used in the nivolumab clinical program, and are not considered to 
put subjects at increased risk. For subjects with greater body weights, the simulated ranges of 
exposures are also not expected to affect efficacy, because the exposures predicted following 
administration of a 240 mg Q2W are on the flat part of the exposure-response curves for previously 
investigated tumors, melanoma and NSCLC. Given the similarity of nivolumab PK across tumor 
types and the similar exposures predicted following administration of a 240 mg flat dose compared 
to 3 mg/kg, it is expected that the safety and efficacy profile of 240 mg nivolumab will be similar 
to that of 3 mg/kg nivolumab. Collectively, these data support the use of the N1+I3 Q3W 
combination for 4 doses followed by nivolumab 240 mg Q2W until end of EOT in this study.
Per Amendment 29, a 480 mg Q4W nivolumab dosing option for subjects who receive nivolumab 
alone after treatment with nivolumab in combination with ipilimumab or FOLFOX/XELOX is
allowed. As a treatment option, a 480 mg IV over 30-minutes Q4W nivolumab dosing regimen 
has been approved in US in subjects with advanced melanoma, SQ NSCLC, NSQ NSCLC, RCC, 
SCCHN, cHL and UC.41 This option will benefit patients and treatment providers by increasing 
the time between clinic visits and reducing the scheduling burden on cancer treatment institutions, 
without compromising the established efficacy or safety of the currently approved regimens. In 
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comparing nivolumab 480 mg Q4W to 3 mg/kg Q2W, the geometric mean time-averaged 
concentration over the first 28 days (Cavgd28) was approximately 27% higher with 480 mg Q4W, 
whereas the geometric mean steady-state time-averaged concentration (Cavgss) for both dosing 
regimens was similar. Nivolumab geometric mean trough concentrations at Day 28 (Cmind28) and 
at steady-state (Cminss) were 22% and 16% lower, respectively, with 480 mg Q4W dosing. 
Conversely, geometric mean peak nivolumab concentrations after the first dose (Cmax1) and at 
steady-state (Cmaxss) were 111% and 43.4% higher, respectively, with 480 mg Q4W dosing, 
however these exposures are predicted to be lower than the exposure ranges observed at doses up 
to nivolumab 10 mg/kg Q2W used in the nivolumab clinical program. Extensive E-R analyses 
were conducted for OS, OR, and tumor growth dynamics to bridge efficacy of nivolumab 240 mg 
Q2W and 480 mg Q4W with the clinically evaluated 3 mg/kg Q2W dosing regimen. The primary 
exposure measure used in the analyses was Cavgd28 because it represents the relevant drug 
concentration over the entire duration of earlier dosing intervals from Q2W and Q4W regimens. 
The hazard ratios with nivolumab 240 mg Q2W or 480 mg Q4W were predicted to be similar to 
3 mg/kg Q2W across multiple tumor types (melanoma, RCC, SQ and NSQ NSCLC). There were 
no differences in predicted response rate with nivolumab 240 mg Q2W or 480 mg Q4W compared 
to 3 mg/kg Q2W. There was also no apparent relationship between Cavgd28 and individual 
estimates of tumor growth rate. Key safety results from the interim safety population of CA209511 
demonstrated that the safety profile of nivolumab 480 mg IV over 30 minutes Q4W is consistent 
with the established safety profile of nivolumab (3 mg/kg Q2W administered IV over 60 minutes) 
across multiple indications.42 No new safety concerns were identified. Note that before 480 mg 
Q4W nivolumab flat dose in the CA209511 study, subjects had received 4 doses of nivolumab + 
ipilimumab (either 3 mg/kg of nivolumab + 1 mg/kg of ipilimumab or 1 mg/kg of nivolumab + 
3 mg/kg of ipilimumab). These data support nivolumab 480 mg Q4W can be safely administrated 
in 1L GC/GEJ subjects. 
1.1.5
Rationale for Nivolumab in Combination with Chemotherapy
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. 
Immunogenic chemotherapy such as oxaliplatin combination with immune checkpoint can trigger 
T-cell infiltration to tumor and provide additive or synergistic anti-tumor activity in-vivo, and 
expects to contribute for the durable anti-tumor responses.43
Nivolumab added to platinum doublet has been evaluated in chemotherapy-naive subjects with 
advanced NSCLC in a Phase 1/2 study CA209012.44 Nivolumab 10 mg/kg was combined with 
gemcitabine + cisplatin and pemetrexed + cisplatin. Nivolumab 10 mg/kg, and 5 mg/kg, were 
combined with paclitaxel and carboplatin. The safety profile of nivolumab plus platinum-doublet 
chemotherapy reflected additive toxicities of the individual agents, which were manageable using 
established safety guidelines. The ORR of nivolumab and chemotherapy (33 - 47%) compared 
favorably to previously reported rates for the platinum-doublet chemotherapy alone (15 - 32%), 
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though the duration of responses was longer. Despite the small sample sizes of each cohort, the 
median survival (11.6 - 19.2 months) is promising compared to the histological platinum doublet 
therapy (8.1 - 10.3 months).45,46,47,48,49 A confirmation Phase 3 study of nivolumab 360 mg flat 
dose plus platinum doublet chemotherapy in chemotherapy-naive NSCLC subjects is ongoing 
(CheckMate 227). 
A Phase 2/3 study of nivolumab in combination with oxaliplatin and fluoropyrimidine in patients
with chemotherapy-naive GC or GEJ in metastatic setting in Asia is ongoing. Part 1 includes 
21 subjects who received nivolumab 360 mg in combination with S1 and oxaliplatin (SOX) every 
3 weeks, and 19 subjects who received nivolumab 360 mg in combination with capecitabine and 
oxaliplatin (XELOX).50 At a median of 8.3 months follow up, the ORR (by the investigator 
assessment) was 67% and 71% in nivolumab + SOX and nivolumab + XELOX, respectively. The 
disease control rate (DCR) was 86% and 82% in nivolumab + SOX and nivolumab + XELOX, 
respectively. The median duration of response (DOR) was not reached in subjects treated with 
nivolumab + SOX, and 5.8 months in subjects treated with nivolumab + XELOX. The median PFS 
by the investigator assessment is 9.9 months in subjects treated with nivolumab + SOX, and 7.1 
months in subjects treated with nivolumab + XELOX. A total of 18/20 (90%) and 16/16 (100%) 
subjects evaluable for response in nivolumab + SOX and nivolumab + XELOX, respectively, 
experienced some tumor burden reduction, and the response were observed regardless of PDL1 
expression status. There were no large differences between the central vs investigator assessment 
of responses and PFS. As of the date of data cut-off on Feb 2017, 11/21 (52%) and 7/18 (39%) 
subjects are still under treatment with nivolumab + SOX, or nivolumab + XELOX, respectively. 
The safety profile reflects the cumulative profiles of nivolumab and chemotherapy. All patients 
experienced at least 1 treatment-related AE of any grade. A total of 11/21 (52%) and 12/18 (67%) 
were Grade 3/4 AEs. The most common treatment-related AEs occurring in >10% were decreased 
neutrophil count (14%) in nivolumab + SOX, and peripheral sensory neuropathy (11%), decreased 
appetite (11%) and nausea (11%) in nivolumab + XELOX. No treatment-related deaths occurred 
in either treatment arm. 
The preliminary safety data of pembrolizumab plus 5-FU and cisplatin in chemotherapy 
treatment-naive patients with advanced GC have been reported recently.51 The safety profile also 
reflected additive toxicity of the individual agents with 72% experiencing Grade 3/4 
treatment-related AE, and was also manageable. No treatment-related discontinuation attributed 
to pembrolizumab nor treatment-related deaths were reported. 
Thus, these pre-clinical and clinical data suggest that nivolumab in combination with oxaliplatin 
and fluoropyrimidine is also expected to bring clinical benefits to advanced GC/GEJ patients with 
manageable safety. 
In this nivolumab-plus-chemotherapy arm of the study, nivolumab 360 mg (for subjects assigned 
to nivolumab + XELOX) or nivolumab 240 mg (for subjects assigned to nivolumab + FOLFOX) 
will be administered as an IV infusion over 30 minutes every 3 weeks (Q3W) or every 2 weeks 
(Q2W), respectively. Nivolumab has been shown to be safe and well tolerated up to a dose level 
of nivolumab 10 mg/kg Q2W. As PPK analyses have shown that the PK of nivolumab are linear 
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over a dose range of 0.1 to 10 mg/kg with no differences observed in PK across ethnicities and 
tumor types, the PPK model was used to simulate exposures at different dosing regimens, 
including nivolumab 360 mg Q3W. The simulated steady-state average concentration (Cavgss) 
following administration of nivolumab 360 mg Q3W are expected to be similar to those following 
administration of nivolumab 240 mg Q2W and nivolumab 3 mg/kg Q2W administered to subjects 
weighing 80 kg. It should be noted that the steady-state peak concentrations (Cmaxss) following 
nivolumab 360 mg Q3W are predicted to be less than those following the administration of 
nivolumab 10 mg/kg Q2W providing sufficient safety margins. Finally, nivolumab 360 mg Q3W 
in combination with platinum-doublet chemotherapy dosing is currently being studied for the 
treatment of NSCLC in a Phase 3 study. 
See Section 1.1.4, for the rationale for the 480 mg Q4W nivolumab dosing option for subjects who 
receive nivolumab alone after treatment with nivolumab in combination with chemotherapy.
1.1.5.1
Rationale for Primary Population in the Nivolumab in Combination with 
Chemotherapy
As described in Section 1.1.5, the ORRs of nivolumab in combination with oxaliplatin and 
fluoropyrimidines were 60-70%, comparing to historical data (30-50%) in the treatment naive 
GC/GEJ patients, a favorable clinical benefit can be expected in this combination. In addition, only 
5 out of 38 PDL1 evaluable subjects was reported with PDL1 expressing tumors (PDL1 ≥1%). 
Although difficult to draw conclusion based on a small sample size, it is observed that the 
responses were independent from the PDL1 expressing status. Thus, considering all subjects are 
expected to benefit in the nivolumab in combination with chemotherapy, the primary population 
will be all comers. 
Per Amendment 23, the primary population is changed to subjects with PDL1 CPS as 
discussed in detail in Section 
1.1.5.2
Rationale for PFS as the Primary Endpoint in the Nivolumab in 
Combination with Chemotherapy Arm
PFS is a common efficacy endpoint, which helps to interpret the treatment effects when potential 
confounding effects are introduced by the subsequent therapies. As described in Section 1.1.5, 
both the ORR and PFS rates of nivolumab in combination with oxaliplatin and fluoropyrimidines
are larger than the previously reported rates for chemotherapy treatment alone (ORR: 60-70% 
compared to 30-50%; PFS: 7-10 months compared to the previously reported 4-6 
months).14,15,16,17,18 As a high unmet medical need remains for patients with advanced and 
metastatic GC/GEJ, an effective new treatment option is urgently needed. The addition of PFS as 
surrogate survival-marker enables an earlier assessment of treatment effects than OS, which may 
allow early access for this significantly ill population. 
Per Amendment 23, ORR has been changed to a secondary objective.
1.1.6
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab
Long infusion times place a burden on patients and treatment centers. Establishing that nivolumab 
and ipilimumab can be safely administered using shorter infusion times of 30 minutes’ duration 
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will diminish the burden, provided that there is no change in the safety profile. Previous clinical 
studies of nivolumab and ipilimumab monotherapies and the combination of nivolumab and 
ipilimumab have used a 60-minute infusion duration for nivolumab and a 90-minute infusion 
duration for ipilimumab (1 - 3 mg/kg dosing for both). However, both nivolumab and ipilimumab 
have been administered at up to 10 mg/kg with the same infusion duration (ie, 60 minutes).
Nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg over a 
long treatment duration. In subjects with advanced/metastatic clear cell RCC (CA209010 study), 
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 nivolumab (30% of the dose provided 
at 10 mg/kg), 240 mg or 360 mg are not expected to present any safety concerns compared to the 
prior experience at 10 mg/kg nivolumab dose infused over a 60-minute duration.
The safety of nivolumab 3 mg/kg administered as a 30-min infusion was assessed in CA209153 in 
patients (n = 322) with previously treated advanced NSCLC. Overall, there were no clinically 
meaningful differences in the frequency of hypersensitivity/infusion-related reactions (of any 
cause or treatment-related) in patients administered nivolumab over a 30-min infusion compared 
with that reported for patients with the 60-min infusion. Thus, it was shown that nivolumab can be 
safely infused over 30 minutes as a 3 mg/kg dose.
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In subjects with 
advanced Stage II or Stage IV melanoma (CA184022 study), where ipilimumab was administered 
up to a dose of 10 mg/kg, on-study drug related hypersensitivity events (Grade 1/2) were reported 
in 1 subject (1.4%) in the 0.3 mg/kg and in 2 subjects (2.8%) in the 10 mg/kg group. There were 
no drug-related hypersensitivity events reported in the 3 mg/kg group. Across the 3 treatment 
groups, no Grade 3/4 drug-related hypersensitivity events were reported and there were no reports 
of infusion reactions. Ipilimumab 10 mg/kg monotherapy has also been safely administered as a 
90-minute infusion in a large Phase 3 study in prostate cancer (CA184043) and as adjuvant therapy 
for Stage III melanoma (CA184029), with infusion reactions occurring in subjects. Administering 
3 mg/kg of ipilimumab represents approximately one-third of the 10 mg/kg dose.
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across clinical studies of nivolumab, ipilimumab, and nivolumab/ipilimumab combinations. 
Furthermore, a 30-minute break after the first infusion for the combination cohort will ensure the 
appropriate safety monitoring before the start of the second infusion. Overall, a change in safety 
profile is not anticipated with 30-minute infusions of nivolumab, ipilimumab or combination.
1.1.7
Rationale for 2-year Nivolumab Treatment 
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumors types in the nivolumab and ipilimumab development 
program indicate that most of the responses occur early, with a median time to response of 
2-4 months, and emerging data suggests that benefit can be maintained in the absence of continued 
treatment. A recent analysis in a melanoma study suggests the majority of patients who discontinue 
nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of further 
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treatment.52 Furthermore, a limited duration of ipilimumab, including only 4 induction doses, 
resulted in long term survival in patients with metastatic melanoma, with a sustained plateau in 
survival starting around 2 years after the start of treatment.53
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 subjects with NSCLC), specified a maximum treatment duration of 2 years. Among 
16 subjects with non-small cell lung cancer (NSCLC) who discontinued nivolumab after 
completing 2 years of treatment, 12 subjects were alive >5 years and remained progression-free 
without any subsequent therapy (2) In the CA209003 NSCLC cohort, the overall survival (OS) 
curve begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.54
These survival outcomes are similar to phase 3 studies in previously treated NSCLC, in which 
nivolumab treatment was continued until progression or unacceptable toxicity (2 year OS rates of 
23% and 29%, and 3 year OS rates of 16%-18% for squamous and non-squamous NSCLC 
respectively).55
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in subjects with previously treated, PD-L1-positive, advanced 
NSCLC which specified a  maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR 0.72, P = 0.00017) and 
pembrolizumab 10 mg/kg (HR 0.60, P < 0.00001) compared to docetaxel, with an OS plateau 
developing beyond 2 years in both pembrolizumab arms. Among 690 patients who received 
pembrolizumab, 47 patients completed 2 years of pembrolizumab and stopped treatment. Most 
were able to maintain their response, including those with stable disease, with only 2 patients (4%) 
having confirmed progression after stopping at 2 years.56
Keynote-006 was a randomized Phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2 year duration of pembrolizumab 
treatment. 104 (19%) of 556 patients randomized to pembrolizumab completed 2 years of 
treatment. With a median follow-up of 9 months after completion of pembrolizumab, the estimated 
risk of progression or death was 9% in these patients.57
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed 
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
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progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 10.3 months, respectively; HR=0.42 (95% CI, 
0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, there also was a trend 
for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note, 
the PFS curves in both groups plateau approximately 1 year after randomization (i.e., 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.58
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond two years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore, in 
this study, treatment will be given for a maximum of 2 years from the start of study treatment.
1.1.8
Rationale for Including Both Subjects with PD-L1 and Non-PD-L1 
Expressing Tumors in 1L GC/GEJ and Stratification by PD-L1 
Expression
Single-agent nivolumab in previously treated tumors, including squamous and non-squamous 
NSCLC, RCC and GC has demonstrated improved survival in subjects without preselection by 
PD-L1 tumor expression. 20,21,22,59 In GC/GEJ cancer, PD-L1 has been suggested as a prognostic 
marker.30,31 however, recent data suggested PD-L1 expression might not be an independent poor 
prognostic factor. 32,33,34,35,36,80 Clinical data for the N1+I3 combination in Table 1.1.2.1-2
suggests that PD-L1 may also be predictive (eg, numerically higher ORR) as a therapy targeting 
PD-1 alone or in combination with CTLA-4, but also having activity in subjects whose tumors did 
not express PD-L1. In addition, in the CA209067 study, nivolumab combination with ipilimumab 
demonstrated clinical activity in subjects with advanced melanoma tumors which did not express 
PD-L1.29 For these reasons, CA209649 will enroll subjects regardless of PD-L1 tumor expression, 
but stratify at the PD-L1 expression level of 1%, ie, subjects whose tumors express PD-L1 and 
those whose tumors do not, and have the primary analysis of OS in subjects with PD-L1 expressing 
tumors in N1+I3 versus chemotherapy.
In Study CA209012, 44 subjects with known PD-L1 expression received nivolumab combined 
with platinum doublet; the confirmed ORRs were 48% (11 of 23 subjects) and 43% (9 of 
21 subjects) for subjects with 1% and < 1% PD-L1 expressing tumors, respectively.44
 
 
 
 
 
 
 
Like non-squamous NSCLC, nivolumab in combination with 
chemotherapy is expected to have anti-tumor activity in chemotherapy-naive adenocarcinoma 
GC/GEJ subjects both with PD-L1 and non-PD-L1 expressing tumors, and might be higher in 
PD-L1 expressing tumors. In Study Ono-4538-37, 5 out 38 subjects with 1% PD-L1 expressing 
tumors received nivolumab combined with oxaliplatin and fluoropyrimidines, 4 of these 5 subjects 
achieved PR which is numerically higher than all comers (68%) in treatment naive GC/GEJ 
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subjects.50 As descripted in Section 1.1.5.2, the anti-tumor response observed regardless the PDL1 
expressing status subjects will be enrolled regardless of PD-L1 tumor expression in the nivolumab 
in combination with chemotherapy arm, with stratification by PD-L1 expression level of 1%.
As described above, PD-L1 is considered a potential predictive biomarker for immunotherapy in 
multiple tumor types, and the optimal cut-off and testing methods to determine PD-L1 expression 
are still evolving and under investigation. However, a significantly higher treatment effect was 
observed with immunotherapy in high PD-L1 expressing population of treatment naïve NSCLC60
A similar finding of improved efficacy with immunotherapy using a higher PD-L1 cut-off was 
also reported in GC.61,62 The most recent data in 2L advanced GC/GEJ cancer from Keynote 61 
suggested a higher treatment effect in patients with higher PD-L1 expression (CPS 10) vs lower 
PD-L1 expression (CPS1), with HR 0.64 vs HR 0.82.62  
The CPS scoring has been incorporated for the PD-L1 expression evaluation in CA209649 study 
in Amendment 23, as discussed in detail in Section 1.1.13.
1.1.9
Rationale for Choice of Comparator
Platinum compounds (oxaliplatin and cisplatin) and fluoropyrimidines (fluorouracil, capecitabine, 
and S1) are generally considered as the standard-of-care, 1L treatment options of choice across 
geographic regions.11,12,13, 63
Concerning fluoropyrimidines, Asian investigators prefer S1 
because of its better survival rates, tolerability, and convenience of oral administration. However, 
S1 is not approved in the US. Thus, this study will not include S1, but, rather, capecitabine or 
fluorouracil, which are the most frequently administered fluoropyrimidines in the US and Europe, 
and also available in Asia. The investigator can choose either capecitabine or fluorouracil, based 
on local standards.
The NCCN guideline suggests the 2-drug chemotherapy as the preferred regimen in the 1L setting; 
the 3-drug regimen, due to its toxicity profile, should be considered only for use in patients with 
good performance statuses.11 In addition, the triplet regimen is not common in Asia due to its high 
toxicity profile.13 Thus the comparator selected in this study is only the platinum doublet regimen.
Cisplatin has been the most frequently administered platinum in GC treatment. Since the REAL-2 
study demonstrated an oxaliplatin-based regimen to be non-inferior to cisplatin with a favorable 
safety profile,15 oxaliplatin combinations with fluoropyrimidines have been studied in multiple 
Phase 2 and 3 trials, and showed similar efficacy trends across regions.16,64,65,66 A meta-analysis 
comparing oxaliplatin-based and cisplatin-based regimens showed that oxaliplatin was associated 
with significant improvements in PFS (HR 0.88, 95% CI: 0.80 - 0.98) and OS (HR 0.88, 
95% CI: 0.78 - 0.99), with fewer AEs of neutropenia, anemia, alopecia and thromboembolic 
events, but more neurotoxicity and diarrhea.67 As a result, oxaliplatin has become one of the major 
backbone platinum compounds in the 1L setting.
A Phase 3 trial in esophageal/gastric/GEJ cancers comparing the FOLFOX regimen (5-fluorouracil 
plus leucovorin and oxaliplatin) vs FLP (5-fluorouracil plus leucovorin and cisplatin) showed no 
statistically significant differences between the 2 treatments, but favored the FOLFOX arm vs the 
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FLP arm in terms of median PFS (the primary endpoint, 5.7 months vs 3.9 months), response rate 
(35% versus 25%), and median survival (10.7 months vs 8.8 months). FOLFOX was associated 
with significantly less nausea and vomiting, fatigue, renal toxicity and alopecia, but more 
Grade 3/4 sensory neuropathy than FLP.64
A similar survival outcome with XELOX (capecitabine plus oxaliplatin) was demonstrated in 
Phase 2 studies;68 in addition, the convenience of the XELOX regimen (oral capecitabine every 
2 weeks plus an oxaliplatin IV infusion in a 3-week cycle) has favored increased implementation 
of this regimen in clinical practice globally. 
Based on these observations, the oxaliplatin-based regimens FOLFOX and XELOX are considered 
to be reasonable comparators in this Phase 3 study, and the investigators can choose either regimen 
per their local standard. 
1.1.10
Rationale for Adding Chemotherapy Regimen as Stratification Factor
In this study, the stratification factors are PD-L1 status, region and ECOG performance status. As 
described in Section 1.1.8, the antitumor activity has been observed in subjects with and without 
PD-L1 expressing tumors, and a greater response observed in the GC/GEJ and non-squamous 
NSCLC with nivolumab in combination with ipilimumab or chemotherapy. In Section 1.1.1, the 
different regional survival outcomes have been reported in GC/GEJ multi-Phase 3 studies, and 
performance status is known as an important parameter for predicting the survival in advanced 
GC.69 Thus, these 3 factors have been selected as stratification factors. 
Chemotherapy effectively treats cancer in part by facilitating an immune response to the tumor 
when given at the standard dose and schedule. This immunomodulatory effect is dependent on the 
drug itself, its dose and its schedule in relation to an immune-based intervention.70 The antitumor 
activity differs depending on the cytotoxic agents given in combination with the 
immunocheckpoint agents.43 Thus, the chemotherapy regimen has newly been added as a 
stratification factor in this study, to avoid a potential imbalance of different treatment effects of 
nivolumab when combined with XELOX or FOLFOX.
1.1.11
Rationale for Open-Label Design
The treatment schedule for administering the nivolumab combination with ipilimumab will be 
every 3 weeks for 4 doses followed by nivolumab monotherapy every 2 weeks. Administration of 
the control arm FOLFOX will be every 2 weeks and XELOX will be every 3 weeks. 
Administration of the nivolumab in combination with FOLFOX will be every 2 weeks, and 
XELOX will be every 3 weeks, to align with the schedule of the backbone therapies. These 
different dosing schedules and unique and characteristic drug-related AEs (eg, neuropathy with 
platinum doublets and immune AEs with nivolumab combined with ipilimumab) make blinding 
impractical. In addition, the correct management of frequent AEs such as diarrhea might require 
a process of unblinding which may delay appropriate supportive care for management of AEs 
(anti-diarrheals for chemotherapy-induced diarrhea and immune suppression for diarrhea 
associated with immune-mediated agents). Thus, this study is designed as an open-label trial.
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1.1.12
Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease for Subjects in the Nivolumab Plus Ipilimumab and 
Nivolumab in Combination with Chemotherapy Arms
Accumulating clinical evidence indicates some subjects treated with immune system stimulating 
agents may develop progression of disease (by conventional response criteria) before 
demonstrating clinical objective responses and/or stable disease. This phenomenon was observed 
in approximately 10% of subjects in the Phase 1 study of nivolumab and also with ipilimumab 
monotherapy.71 Two hypotheses have been put forth to explain this phenomenon. First, enhanced 
inflammation within tumors could lead to an increase in tumor size which would appear as 
enlarged index lesions and as newly visible small non-index lesions. Over time, both the malignant 
and inflammatory portions of the mass may then decrease, leading to overt signs of clinical 
improvement. Alternatively, in some individuals, the kinetics of tumor growth may initially 
outpace anti-tumor immune activity. With sufficient time, the anti-tumor activity will dominate 
and become clinically apparent. Therefore subjects will be allowed to continue study therapy after 
initial investigator-assessed RECIST 1.1-defined progression if they are assessed to be deriving 
clinical benefit and tolerating study drug (Section 4.5.1.6). Such subjects must discontinue study 
therapy upon evidence of further progression.
1.1.13
Rationale for incorporation of CPS for PD-L1 expression evaluation and 
changing primary population to subjects with PD-L1 CPS 5 
Combined positive score (CPS) is defined as the number of PD-L1 staining cells (tumor cells, 
lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.72
CPS is a composite score that incorporates both tumor and tumor-associated immune cell (TAIC) 
PD-L1 expression, whereas tumor proportion score (TPS) or tumor PD-L1 only reflects the 
percentage of tumor cells that are positive for PD-L1 expression. 
CPS appears to be a good predictor for response in gastric cancer with checkpoint inhibitors. In 
Keynote-059 Cohort 1, patients with advanced gastric cancer who had received ≥2 lines of prior 
chemotherapy were treated with pembrolizumab monotherapy (n=257). Pembrolizumab showed 
promising clinical activity with antitumor response significantly associated with CPS (P= 0.002) 
but not TPS (P= 0.224) at CPS/TPS 1 cut-off. The odds ratio between the PD-L1 positive and 
negative populations had increased from 1.4 for TPS 1 to 2.8 for CPS 1, indicating the better 
predictive value of CPS compared to TPS.73 In Keynote-061, which evaluated pembrolizumab vs. 
paclitaxel in 2L GC/GEJC, pembrolizumab did not improve overall survival or progression free 
survival in patients whose CPS 1; however the HRs of OS were 1.20, 0.82 and 0.64 in the CPS<1, 
CPS≥1 and CPS≥10 populations respectively, demonstrating a trend of increased efficacy with 
increasing CPS cutoffs.74
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The prevalence of CPS decreases with increasing CPS cut-offs.  In the KEYNOTE 61 study, the 
prevalence was up to 67% at CPS≥1, and up to 18% at CPS ≥10.74 In KEYNOTE 59 study, the
prevalence of CPS ≥1 was 58% in 3L GC/GEJ( N=259) and 64% in 1L GC/GEJ(N=25)73.75
While TPS was originally used to define the PD-L1 expressing population in the original protocol, 
the observed prevalence of PD-L1 1% by TPS based on aggregate data is much lower than the 
original assumption of 40% used in this study impacting the study power and current study sample 
size. More importantly, based on accumulating clinical data, CPS seems to better predict response 
than TPS and able to better select patients for treatment with checkpoint inhibitors in gastric 
cancer. Thus, CPS 5 will now be used to define the primary population for this study in order to 
achieve promising clinical benefit in a relatively biomarker enriched population. 
 
 
Therefore, 
a conservative prevalence of 35% prevalence will be assumed for CPS 5 in this study in order to 
ensure sufficient sample size for the primary analysis. In addition, the study will also evaluate the 
efficacy across different CPS cut-offs eg, CPS10, CPS1 as well as all randomized population in 
secondary and exploratory objectives.
 
 Therefore, the enrolment will be extended to ensure 
that the study is appropriately powered for PFS and OS primary endpoints in the CPS 
population. To allow for this, the total sample size will be increased from 1649 to approximately 
2005. This resizing of the total population will ensure that the sample size of the enriched 
population for the primary analyses (subjects with CPS is the same as is specified in 
Amendment 23, and will maintain the same power under the statistical assumptions as stated in 
Amendment 23.
The current estimation of 27% prevalence of CPS 5 may still change when more data are 
available. Close monitoring of the prevalence in a blinded fashion is ongoing and the final sample 
size of all randomized subjects may be adjusted accordingly to ensure sufficient power for the 
primary analyses.
1.1.14
Rationale for Statistical Analyses Update in Amendment 29
Per amendment 23, the primary population changed to subjects with PD-L1 expression by CPS 
5, and the PD-L1 CPS scoring process started for all randomized subjects. In March 2019, it was 
determined that additional scoring of a significant number of samples was needed. The expected 
completion of PD-L1 CPS scoring was delayed and is now projected to be completed
approximately 6 months or later after the completion of enrollment. Amendment 29 documents 
the corresponding changes to the statistical analysis timing and power estimation of PFS and OS 
(see Section 8).
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Early in June 2019, the final analyses of the 1L GC phase 3 Keynote-062 study were disclosed at 
the ASCO meeting. 76 The study included 3 arms: pembrolizumab monotherapy (Pem), 
pembrolizumab plus chemotherapy (Pem+CT) and chemotherapy (CT). Chemotherapy backbone 
used fluoropyrimidine and cisplatin. The study primary objectives to demonstrate non-inferiority 
for Pem vs CT and superiority for Pem+CT vs CT. For the comparison of Pem vs CT, the study 
met the non-inferiority of OS in CPS 1 with HR 0.91. In the subgroup analysis among subjects 
with CPS 10, OS improvement has been seen with HR 0.69, however it did not meet the pre-
specified statistical significance. A detriment of OS Kaplan-Meier (KM) curves has been observed 
for approximately the first 12 months and 9 months in subjects with CPS 1 and CPS 10, 
respectively. For the comparison of Pem+CT vs CT, the study did not meet the primary endpoints 
of PFS and OS in Pem+CT vs CT, at either CPS 1 or CPS 10. The HR for OS was 0.85 in both
subjects with CPS 1 and CPS 10. Approximately 6-month delayed separation of KM curves 
was also observed for both CPS 1 and CPS 10. The observed HR for PFS in CPS 1 vs 
CPS 10 were 0.84 and 0.73, respectively, demonstrating an enrichment by higher cutoff of CPS. 
Similar to the OS KM curves, a delayed separation of PFS KM curves also observed in subjects 
with CPS 1 vs CPS 10. In the summary, the Keynote-062 data suggested that sufficient 
follow-up for I-O alone or in combination with chemotherapy will be needed in order to fully 
capture long-term treatment effect.
1.2
Research Hypotheses
In subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS , the administration 
of nivolumab plus ipilimumab will improve OS compared to oxaliplatin plus fluoropyrimidine.
In subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS , the administration 
of nivolumab in combination with oxaliplatin plus fluoropyrimidine will improve PFS or OS 
compared to oxaliplatin plus fluoropyrimidine.
1.3
Objectives
1.3.1
Primary Objectives
Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs oxaliplatin plus 
fluoropyrimidine:

To compare OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS 

To compare PFS, as assessed by BICR in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS 
1.3.2
Secondary Objectives
Nivolumab plus ipilimumab vs oxaliplatin plus fluoropyrimidine:

To compare OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS ≥5
or in all randomized

To evaluate OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS ≥10 or 1
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
To evaluate PFS, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS 1 or all randomized subjects

To evaluate ORR, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS 10, 5, 1 or all randomized subjects

To compare the time to symptom deterioration (TTSD) as assessed using the Gastric Cancer 
Subscale (GaCS) of the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) in 
subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS ≥ 5 or all randomized 
subjects.
Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs oxaliplatin plus 
fluoropyrimidine:

To compare OS in subjects with advanced or metastatic GC or GEJ cancer with  PD-L1 
CPS ≥1 or all randomized subjects

To evaluate OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS 10 

To evaluate PFS, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS ≥10, 1 or all randomized subjects

To evaluate ORR, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS ≥10, 5, 1, or all randomized subjects 
1.3.3
Exploratory Objectives
Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs oxaliplatin plus 
fluoropyrimidine:

To assess TTSD as assessed using GaCS of FACT-Ga in subjects with advanced or metastatic 
GC or GEJ cancer with PD-L1 CPS ≥ 5 or all randomized subjects
For both comparisons: Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs 
oxaliplatin plus fluoropyrimidine and Nivolumab plus ipilimumab vs oxaliplatin plus 
fluoropyrimidine: 

To assess PFS and ORR, as assessed by the investigator in subjects with advanced or metastatic 
GC or GEJ cancer across CPS cut-offs

To evaluate Duration of Response (DOR) as assessed by BICR and by investigator, in subjects 
with advanced or metastatic GC or GEJ cancer 

To evaluate the durable response rate (objective response lasting continuously > 6 months) as 
assessed by BICR and by investigator, in subjects with advanced or metastatic GC or GEJ 
cancer  

To evaluate at 18-month, 24-month, and 36-month survival rates in subjects with advanced or 
metastatic GC or GEJ cancer

To evaluate second disease progression (PFS2) or time to second subsequent line therapy 
(TSST) in subjects with advanced or metastatic GC or GEJ cancers 
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
To assess PFS, ORR as assessed by either BICR or investigator, OS in subjects with 
advanced or metastatic GC or GEJ cancer across TPS cut-offs.

To assess the overall safety and tolerability of nivolumab plus ipilimumab or nivolumab in 
combination with oxaliplatin plus fluoropyrimidine and oxaliplatin plus fluoropyrimidine in 
subjects with advanced or metastatic GC or GEJ cancer

To explore potential biomarkers predictive of or associated with clinical efficacy (OS, PFS and 
ORR) and/or incidence of AEs of nivolumab plus ipilimumab or nivolumab in combination 
with oxaliplatin plus fluoropyrimidine including but not limited to microsatellite instability 
(MSI) 
status, 
tumor 
mutational 
burden 
(TMB) 
 
 
 
 
 and inflammatory signatures in subjects with advanced 
or metastatic GC or GEJ cancer. 

To characterize the pharmacokinetics (PK) of nivolumab and ipilimumab and nivolumab in 
combination with oxaliplatin plus fluoropyrimidine and explore exposure-response 
relationships with respect to safety and efficacy

To characterize the immunogenicity (IMG) of nivolumab and ipilimumab and nivolumab in 
combination with oxaliplatin plus fluoropyrimidine when administered in combination to 
subjects with advanced or metastatic GC or GEJ cancer

To assess TTSD as assessed using GaCS of FACT-Ga in subjects with advanced or metastatic 
GC or GEJ cancer with PD-L1 CPS ≥ 10 or 1

To assess changes from baseline in the subject’s overall health status using the 3-level version 
of the EQ-5D (EQ-5D-3L) index and visual analog scale (EQ-VAS) of nivolumab plus 
ipilimumab or nivolumab in combination with oxaliplatin plus fluoropyrimidine vs oxaliplatin 
plus fluoropyrimidine in subjects with advanced or metastatic GC or GEJ cancer 

To assess the subject’s cancer-related quality of life using the FACT-Ga questionnaire and 
selected components, including the GaCS and 7-item version of the FACT-General 
(FACT-G7) of nivolumab plus ipilimumab or nivolumab in combination with oxaliplatin plus 
fluoropyrimidine vs oxaliplatin plus fluoropyrimidine in subjects with advanced or metastatic 
GC or GEJ cancer.
1.4
Product Development Background
1.4.1
Mechanism of Action
1.4.1.1
Nivolumab 
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.77,78,79
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 
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involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor.80 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. 81 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression also been 
noted to inhibit T-cell activation and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes.82 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 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 cytotoxic T-cell lymphocyte 
associated protein 4 (CTLA-4). Blockade of the PD-1 pathway by nivolumab results in a 
reproducible enhancement of both proliferation and IFN-γ release in the mixed lymphocyte 
reaction (MLR). Using a cytomegalovirus (CMV) re-stimulation assay with human peripheral 
blood mononuclear cells (PBMCs), the effect of nivolumab on antigen-specific recall response 
indicates that nivolumab augments 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 results in tumor rejection in several 
immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).83
1.4.1.2
Ipilimumab 
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.84,85
Ipilimumab (BMS-734016) is a fully human monoclonal IgG1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 
antigen-presenting cells (APCs), with subsequent blockade of the inhibitory modulation of T-cell 
activation promoted by the CTLA-4/B7 interaction.
1.4.2
Summary of Clinical Pharmacology 
1.4.2.1
Nivolumab
The PK of nivolumab were studied in subjects over a dose range of 0.1 to 10 mg/kg administered 
as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. The geometric mean 
(% CV%) clearance (CL) was 9.5 mL/h (49.7%), geometric mean volume of distribution at steady 
state (Vss) was 8.0 L (30.4%), and geometric mean elimination half-life (t1/2) was 26.7 days 
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(101%). Steady-state concentrations of nivolumab were reached by 12 weeks when administered 
at 3 mg/kg Q2W, and systemic accumulation was approximately 3-fold. The exposure to 
nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered 
every 2 weeks. 
The clearance of nivolumab increased with increasing body weight. The PPK analysis suggested 
that the following factors had no clinically important effect on the CL of nivolumab: age (29 to 
87 years), gender, race, baseline LDH, PD-L1. Although ECOG status, baseline glomerular 
filtration rate (GFR), albumin and body weight had an effect on nivolumab CL, the effect was not 
clinically meaningful. When nivolumab is administered in combination with ipilimumab, the 
CL of nivolumab was increased by 24%, whereas there was no effect on the CL of ipilimumab. 
Additionally, PPK and exposure response analyses have been performed to support use of 240 mg 
Q2W dosing in addition to the 3 mg/kg Q2W regimen. Using the PPK model, exposure of 
nivolumab at 240 mg flat dose was identical to a dose of 3 mg/kg for subjects weighing 80 kg, 
which was the approximate median body weight in nivolumab clinical trials (see Section 1.1.4). 
Additional details are provided in the nivolumab investigator brochure (IB).86
1.4.2.2
Ipilimumab 
The PPK of ipilimumab was studied in 785 subjects (3200 serum concentrations) with advanced 
melanoma in 4 Phase 2 studies (CA184004, CA184007, CA184008, and CA184022),87 1 Phase 3 
study (CA184024), and 1 Phase 1 study (CA184078). The PPK analysis demonstrated that the PK 
of ipilimumab is linear, the exposures are dose proportional across the tested dose range of 0.3 to 
10 mg/kg, and the model parameters are time-invariant, similar to those determined by 
noncompartmental analyses.
Upon repeated dosing of ipilimumab, administered Q3W, minimal systemic accumulation was 
observed by an accumulation index of 1.5-fold or less, and ipilimumab steady-state concentrations 
were achieved by the third dose. The ipilimumab CL of 16.8 mL/h from PPK analysis is consistent 
with that determined by noncompartmental PK analysis. The terminal t1/2 and Vss of ipilimumab 
calculated from the model were 15.4 days and 7.47 L, respectively, which are consistent with those 
determined by noncompartmental analysis. Volume of the central compartment (Vc) and 
peripheral compartment were found to be 4.35 L and 3.28 L, respectively, suggesting that 
ipilimumab first distributes into the plasma volume and, subsequently, into extracellular fluid 
space. The CL and Vc of ipilimumab were found to increase with increase in body weight. 
However, there was no significant increase in exposure with increase in body weight when dosed 
on a mg/kg basis, supporting dosing of ipilimumab based on a weight-normalized regimen. The 
PK of ipilimumab is not affected by age, gender, race, immunogenicity (anti-drug antibody [ADA] 
status), concomitant use of chemotherapy, prior therapy, body weight, performance status, or 
tumor type. Other covariates had effects that were either not statistically significant or were of 
minimal clinical relevance.
In subjects with mild or moderate renal impairment, the CLs of ipilimumab were similar to that of 
subjects with normal renal function. No specific dose adjustment is necessary in subjects with mild 
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to moderate renal impairment. Likewise, the CLs of ipilimumab in subjects with mild or moderate 
hepatic impairment was similar to those of subjects with normal hepatic function. 
Additional details are provided in the ipilimumab IB.88
1.4.3
Safety Summary 
The overall safety experience with nivolumab, as monotherapy or in combination with other 
therapeutics, is based on experience in approximately 12,300 subjects treated to date. Extensive 
details on the safety profile of nivolumab, including results from other clinical studies, are 
available in the nivolumab IB, and will not be repeated herein. 
Overall, the safety profile of nivolumab alone or in combination with other therapeutic agents such 
as ipilimumab or chemotherapy is manageable and generally consistent across completed and 
ongoing clinical trials, with no MTD reached at any dose tested up to 10 mg/kg. Most AEs were 
low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There was no 
pattern in the incidence, severity, or causality of AEs with respect to nivolumab dose level. Results 
to date suggest that the safety profile of nivolumab/ipilimumab combination therapy and 
nivolumab in combination with chemotherapy is consistent with the mechanisms of action of 
nivolumab and ipilimumab. The nature of the AEs is similar to that observed with either agent 
used as monotherapy; however, both frequency and severity of most AEs are increased with the 
combination.
A pattern of immune-related AEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 1. Most high-grade events were manageable with the 
use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in these 
algorithms. For additional material, see the nivolumab IB.
Additional details on the safety profiles of nivolumab and ipilimumab, including results from other 
clinical studies, are also available in the respective nivolumab and ipilimumab IBs.
1.5
Overall Risk/Benefit Assessment
Subjects with advanced or metastatic GC and GEJ cancer present a great unmet need. Preliminary 
results from CA209032, in which nivolumab monotherapy and nivolumab-plus-ipilimumab 
treatments were administered to heavily pretreated subjects with advanced/metastatic GC and GEJ 
cancers, demonstrated clinical activity in subjects whose tumors did or did not express PD-L1; 
better results were obtained in subjects with PD-L1 expressing (PD-L1+) tumors. In addition, in 
various other tumor types, nivolumab alone and in combination with ipilimumab demonstrated 
clinical benefits independent or dependent of PD-L1 expressing status.20,21,22,39 Preliminary data 
from NSCLC study suggests that nivolumab in combination with platinum doublet has additive 
anti-tumor activity in subjects regardless of PD-L1 expression, but numerically higher ORR 
observed in non-squamous NSCLC.44 Based on this clinical experience, CA209649 will enroll 
patients regardless of PD-L1 status, but the efficacy analyses will be conducted first in the 
population with PD-L1 expressing tumors and then in the population of all comers in N1+I3 
comparison. Preliminary data from ONO-4538-37 suggested that nivolumab in combination with 
oxaliplatin and fluoropyrimidine had the promising clinical activity (60-70% ORR) in treatment-
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naive advanced/metastatic GC/GEJ subject regardless PDL1 expressing status. As the majority of 
all comer subjects are expected to benefit from nivolumab in combination with chemotherapy, the 
primary efficacy analysis will focus on all comers in this comparison.
The safety profile of nivolumab combined with ipilimumab in GC/GEJ cancer from CA209032, 
as measured by total and Grade 3/4 AEs, is comparable to that of a 1L platinum doublet. In the 
Ono-4538-37 study, the safety profile of nivolumab combined with oxaliplatin and 
fluoropyrimidine reflects the additive toxicity of nivolumab monotherapy and chemotherapy, and 
no new safety signal identified. The safety profile of this nivolumab-plus-ipilimumab combination 
or nivolumab is characterized by immune-related toxicities, such as diarrhea, rash, pneumonitis, 
liver toxicity, and endocrinopathies. These events were mostly low grade and manageable with the 
use of corticosteroids. The ongoing external studies of PD-L1 inhibitors in combination with 
chemotherapy in treatment-naive advanced GC/GEJ subjects suggest that this combination is 
tolerable and manageable, no new safety signals being detected. The safety profile of the 
combination used in CA209649 in GC and GEJ cancer is consistent with that reported in subjects 
with previously untreated melanoma. 
To ensure an ongoing favorable risk/benefit assessment for subjects enrolled in CA209649, a DMC 
will be utilized to monitor the safety and clinical activity of the treatments throughout the conduct 
of the trial.
At a regularly scheduled DMC meeting 
, the DMC recommended stopping further 
enrollment to the nivolumab plus ipilimumab treatment arm due to an observed increased early 
death rate in this arm as well as increased toxicity rate. The DMC also recommended that current 
subjects who are already in the nivolumab plus ipilimumab arm should continue as planned per 
protocol, as should enrollment to the other two arms (nivolumab combined with chemotherapy 
and chemotherapy alone).
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Council on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50) and applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent form will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following: (1) the physical, safety or mental 
integrity of one or more subjects/participants: (2) the scientific value of the trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or 
Trial protocol(s).
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Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
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, subject/participants 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/participants and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects/participants 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/participants, 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 subject 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.
Investigators must:

Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 

Allow time necessary for subject or subject's legally acceptable representative to inquire about 
the details of the study.

Obtain an informed consent signed and personally dated by the subject or the subject'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/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.

If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
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
Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects'/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects/participants unable to give their written consent (e.g., stroke or subjects/participants with 
or severe dementia) may only be enrolled in the study with the consent of a legally acceptable 
representative. The subject must also be informed about the nature of the study to the extent 
compatible with his or her understanding, and should this subject become capable, he or she should 
personally sign and date the consent form as soon as possible. The explicit wish of a subject 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/participants are the most important 
considerations and should prevail over interests of science and society.
After DMC recommendation 
, any subject enrolled and awaiting randomization 
before 05-June-2018 must be verbally re-consented to indicate their awareness of the closure of 
the nivolumab and ipilimumab arm with randomization now 1:1 to nivolumab plus chemotherapy 
versus chemotherapy only. These subjects will need to be re-consented once the revised IRB-
approved ICF is available. Subjects currently on study will need to be re-consented with the 
updated IRB-approved ICF at their next scheduled visit.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is a Phase 3, randomized, open-label, three-arm study of nivolumab plus ipilimumab or 
nivolumab in combination with oxaliplatin plus fluoropyrimidine vs oxaliplatin plus 
fluoropyrimidine in subjects with previously untreated advanced or metastatic GC or GEJ cancer. 
The nivolumab plus ipilimumab arm is closed to enrollment as of 05-June-2018. Subjects enrolled 
in this arm prior to 05-June-2018 will continue to receive treatment with study drugs per protocol 
and the study data will remain blinded for the planned primary analysis.
The study will enroll subjects regardless the PD L1 expressing tumors. 
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The original study design (before Amendment 08) had two arms. After signing the informed 
consent form, and upon confirmation of the subject’s eligibility, subjects were randomized in an 
open-label fashion (1:1 ratio) to either the nivolumab-plus-ipilimumab arm or the chemotherapy 
(XELOX or FOLFOX) arm.
Amendment 08 added a new, nivolumab-plus-chemotherapy (XELOX or FOLFOX) arm. The IRT 
switched to a 1:1:1 randomization at all the study participating sites. 
Amendment 19 added approximately 300 subjects to the study; in total approximately 1649
subjects will be randomized. The nivolumab plus ipilimumab arm was closed to enrollment as of 
05-June-2018. Subjects randomized to treatment in this arm prior to 05-June-2018 will continue 
to receive treatment with study drugs per protocol, and the study data will remain blinded for the 
planned primary analysis. Per Amendment 20, subjects will be randomized in an open-label 
fashion (1:1) to either the nivolumab-plus-chemotherapy (XELOX or FOLFOX) or the 
chemotherapy arm (XELOX or FOLFOX):

Nivolumab-plus-Ipilimumab Arm: nivolumab 1 mg/kg administered IV over 30 minutes 
followed by ipilimumab 3 mg/kg administered IV over 30 minutes on Day 1 of each treatment 
cycle every 3 weeks for 4 doses (Cycles 1 to 4), followed by nivolumab 240 mg administered 
IV over 30 minutes on Day 1 of each treatment cycle every 2 weeks (Cycle 5 and beyond). 
Arm is closed to enrollment as of 05-June-2018.

Nivolumab-plus-Chemotherapy Arm (XELOX or FOLFOX):
Nivolumab plus XELOX
Nivolumab plus FOLFOX
Nivolumab 360 mg IV over 30 minutes on 
Day 1 of each treatment cycle, every 3 weeks
+
Oxaliplatin 130 mg/m2 IV on Day 1 of each 
treatment cycle + capecitabine 1000 mg/m2 
orally twice daily (ie, 1000 mg/m2 in the 
morning and 1000 mg/m2 in the evening) on 
Days 1 to 14 of each treatment cycle, every 3 
weeks
Nivolumab 240 mg IV over 30 minutes on 
Day 1 of each treatment cycle, every 2 weeks
+
Oxaliplatin 85 mg/m2 + leucovorin 
400 mg/m2 + fluorouracil 400 mg/m2 IV on 
Day 1 of each treatment cycle, and 
fluorouracil 1200 mg/m2 IV continuous 
infusion over 24 hours (or per local 
standard) daily on Days 1 and 2 of each 
treatment cycle, every 2 weeks
or

Chemotherapy Arm (XELOX or FOLFOX) :
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XELOX
FOLFOX
Oxaliplatin 130 mg/m2 IV on Day 1 of each 
treatment cycle + capecitabine 1000 mg/m2 
orally twice daily (ie, 1000 mg/m2 in the 
morning and 1000 mg/m2 in the evening) on 
Days 1 to 14 of each treatment cycle, every 3 
weeks
Oxaliplatin 85 mg/m2 + leucovorin 
400 mg/m2 + fluorouracil 400 mg/m2 IV on 
Day 1 of each treatment cycle, and 
fluorouracil 1200 mg/m2 IV continuous 
infusion over 24 hours (or per local
standard) daily on Days 1 and 2 of each 
treatment cycle, every 2 weeks
Amendment 26 added approximately 356 subjects to the study; in total approximately 2005
subjects will be randomized. However, given the uncertainty about the CPS prevalence, the 
sample size may need to be further adjusted based on the monitoring of the prevalence to keep 
sample size for the primary population.
The treatment will be given until disease progression (PD) (unless treatment beyond progression 
is permitted, in nivolumab-plus-ipilimumab and nivolumab-plus-chemotherapy arms; see 
Section 4.5.1.6), unacceptable toxicity, maximum 24 months treatment duration or subject
withdrawal of consent, whichever comes first.
Based on investigator judgment of benefit/risk, nivolumab 480 mg flat dose Q4W (IV over 
30 minutes on Day 1 of each treatment cycle, Q4W) can be used as an option for those subjects 
who receive nivolumab treatment alone. For subjects in nivolumab-plus-chemotherapy arm, a 
480 mg Q4W nivolumab treatment regimen will be permitted when all chemotherapy is
discontinued and nivolumab is continued alone. Subjects must be in the study for a minimum of 
6 months from Cycle 1, Day 1 before switching to 480 mg Q4W nivolumab. 
Chemotherapy will be given as per the study dosing schedule. 
Stratification factors: 
1) PD-L1 status (1% vs < 1% [including indeterminate])*
2) Region (Asia vs US vs Rest of world [ROW])
3) ECOG performance status (0 vs 1).
4) Chemotherapy (XELOX vs FOLFOX)
* During enrollment, the proportion of subjects with or without PD-L1 tumor expression will be 
monitored in pooled fashion, and may be re-assessed in case it does not reflect study assumptions 
(ie, subjects with PD-L1 tumor expression 1% is approximately 40% of all comers).
Per Amendment 23, PD-L1 expression has incorporated CPS scoring for the analysis. However, 
the stratification factor of tumor proportion score (TPS) remains unchanged for consistency.
The study design schematic is presented in Figure 3.1-1.
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Figure 3.1-1:
Study Design Schematic
This study will consist of 3 phases: screening, treatment, and follow-up.
3.1.1
Screening Phase

Begins by establishing the subject’s initial eligibility and signing of the informed consent form 
(ICF).

Subject is enrolled using the Interactive Response Technology (IRT) system. 

The choice of chemotherapy regimen XELOX or FOLFOX must be decided before contacting 
the IRT system for randomization.

Subjects must have PD-L1 immunohistochemistry (IHC) testing, with evaluable results, 
performed by the central lab during the Screening period. 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 6 months prior to randomization, and there 
can have been no systemic therapy (eg, adjuvant) given after the sample was obtained. Tissue 
must be a core needle biopsy, excisional or incisional biopsy. Fine needle biopsies are not 
considered adequate for biomarker review and randomization. Biopsies of bone lesions that do 
not have a soft tissue component or decalcified bone tumor samples are also not acceptable. If 
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insufficient tumor tissue is provided for analysis, acquisition of additional tumor tissue (block 
and/or slides) for the biomarker analysis is required.
Subject is assessed for study eligibility according to the inclusion (Section 3.3.1) and exclusion 
(Section 3.3.2) criteria. The detailed procedures are described in Table 5.1-1. 
3.1.2
Treatment Phase

Begins after contacting the IRT system for randomization. 

Per Amendment 20, subjects will be randomized in an open-label fashion (1:1) to either the 
nivolumab-plus-chemotherapy (XELOX or FOLFOX) or the chemotherapy arm (XELOX or 
FOLFOX).

Administration of study treatment is to begin within 3 calendar days of randomization. 

The treatment phase ends when the subject is discontinued from study therapy (ie, PD, 
unacceptable toxicity, maximum 2 year treatment of nivolumab, or subject withdrawal of 
consent). 

Adverse event assessments should be documented at each clinic visit and Women of 
Child-bearing Potential (WOCBP) must have a pregnancy test every 4 weeks (7 days).

Treated subjects will be evaluated for tumor assessments every 6 weeks (7 days) up to and 
including Week 48, then every 12 weeks (7 days) thereafter.

Biomarker sampling will follow the protocol-defined schedule 
.

Patient-reported questionnaires EQ-5D-3L and FACT-Ga will be collected every 6 weeks.
Nivolumab-plus-Ipilimumab Arm: Closed to enrollment as of 05-June-2018.

On the day of infusion, nivolumab is to be administered first. The second infusion will always 
be ipilimumab, and will start at least 30 minutes after completion of the nivolumab infusion.

Treatment beyond initial, investigator-assessed, RECIST 1.1-defined progression is permitted 
if the subject has investigator-assessed clinical benefit and is tolerating treatment, as specified 
in Section 4.5.1.6.

PK and IMG sampling data will be collected as indicated in Table 5.5-1.
Nivolumab-plus-Chemotherapy (XELOX or FOLFOX) Arm:

On the day of infusion, nivolumab is to be administered first. The administration procedures 
of chemotherapy will follow local standards.

Nivolumab is allowed to be administrated alone in case the chemotherapy has to be 
discontinued due to toxicity. Chemotherapy alone is also allowed to be administered in doublet 
or monotherapy in case nivolumab has to be discontinued due to unacceptable toxicity.

Nivolumab treatment beyond initial, investigator-assessed, RECIST 1.1-defined progression 
is permitted if the subject has investigator-assessed clinical benefit and is tolerating treatment, 
as specified in Section 4.5.1.6. Chemotherapy alone is not allowed to treat beyond progression.

PK and IMG sampling data will be collected as indicated in Table 5.5-2 (Nivolumab with 
XELOX) and Table 5.5-3 (Nivolumab with FOLFOX).

No cross-over is allowed between XELOX and FOLFOX.
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Chemotherapy Arm (XELOX or FOLFOX)

The administration procedures will follow the local standards. 

No cross-over is allowed between XELOX and FOLFOX.
Study assessment data are to be collected as outlined in Table 5.1-2 (on-treatment assessments, 
nivolumab-plus-ipilimumab), 
Table 
5.1-3
(on-treatment 
assessments, 
nivolumab-plus-
chemotherapy), and Table 5.1-4 (on-treatment assessments, chemotherapy).
3.1.3
Follow-up Phase 

Begins when the decision is made to discontinue a subject from study therapy.

After completion of the first 2 follow-up (FU) visits (30 days [± 7 days] from last dose and 
84 days [± 7 days] from FU1), subjects will be followed by clinic visit or phone contact every 
3 months (14 days) or more frequently as needed for survival status and subsequent 
anti-cancer therapy.

Subjects who discontinue treatment for reasons other than PD will continue to have tumor 
assessments (until PD) every 6 weeks (± 7 days) up to and including Week 48, then every 
12 weeks (7 days) thereafter.

Subjects will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline or are deemed irreversible. All toxicities will be documented for a minimum of 
100 days after the last dose of study drug.

Patient-reported questionnaires EQ-5D-3L, GaCS from the FACT-Ga, and the FACT-G7 will 
be collected every 3 months (± 14 days) via phone contact or in-person visit.

The biomarker sampling will continue as per protocol defined schedule 
.
Study follow-up assessment data are to be collected as outlined in Table 5.1-5.
The start of the trial is defined as the first visit for the first subject screened. End of trial is defined 
as the last visit or scheduled procedure shown in the Time & Events schedule for the last subject. 
Study completion is defined as the final date on which data for the primary endpoint was or is 
expected to be collected, if this is not the same.
3.2
Post-Study Access to Therapy
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment for the maximum treatment duration allowed by 
the study protocol. Study treatment will be provided via an extension of the study, a rollover study 
requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of BMS. BMS reserves the right to terminate access to BMS supplied 
study drug if any of the following occur: a) the study is terminated due to safety concerns, b) 
development is terminated for other reasons, including but not limited to lack of efficacy and/or 
not meeting the study objectives, c) the subject can obtain medication from a government 
sponsored or private health program.
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3.3
Study Population
For entry into the study, the following criteria must be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Subjects 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 subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests and other requirements of the study.
2. Target Population
a) All subjects must have inoperable, advanced or metastatic GC or GEJ or distal esophageal 
carcinoma and have histologically confirmed predominant adenocarcinoma. The 
documentation of GEJ involvement can include biopsy, endoscopy, or imaging.
b) Subject must be previously untreated with systemic treatment (including HER 2 inhibitors) 
given as primary therapy for advanced or metastatic disease.
c) Allowed Prior Therapies: Prior adjuvant or neoadjuvant chemotherapy, radiotherapy 
and/or chemoradiotherapy for GC or GEJ cancer are permitted as long as the last 
administration of the last regimen (whichever was given last) occurred at least 6 months 
prior to randomization. Palliative radiotherapy is allowed and must be completed 2 weeks 
prior to randomization.
d) Subject must have at least one measurable lesion or evaluable disease by CT or MRI per 
RECIST 1.1 criteria; radiographic tumor assessment should be performed within 28 days 
prior to randomization.
e) ECOG performance status score of 0 or 1 (Appendix 3).
f)
Tumor tissue must be provided for biomarker analyses. In order to be randomized, a subject 
must have an evaluable PD-L1 expression classification (1% or < 1%, or indeterminate) 
as determined by the central lab. Subjects with non-evaluable results will not be allowed 
to be randomized. 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 6 months prior to randomization, and there can have been no 
systemic therapy (eg, adjuvant) given after the sample was obtained. Tissue must be a core 
needle biopsy, excisional or incisional biopsy.
g) Subject re-enrollment: this study permits the re-enrollment of a subject who has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized). If 
re-enrolled, the subject must be re-consented.
h) Screening laboratory values must meet the following criteria:
i)
WBC
2000/uL
ii) Neutrophils
1500/uL
iii) Platelets
100 x 103/uL
iv) Hemoglobin
9.0 g/dL
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v) Serum albumin      3.0 g/dL
vi) Serum creatinine 1.5 x ULN or calculated creatinine clearance > 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
vii)
AST
3.0 x ULN (or 5.0 x ULN if liver metastases are present)
viii)
ALT
3.0 x ULN (or 5.0 x ULN if liver metastases are present)
ix) Total Bilirubin 1.5 x ULN (except subjects with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 x ULN)
Note: For subjects with hemoglobin 8.0 g/dL, blood transfusion is allowed and must be 
completed at least 72 hours prior to randomization. The repeated hemoglobin value 9.0 g/dL 
must be verified prior to randomization.
3. Age and Reproductive Status
a) Males and Females, 18 years of age
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 drug.
c) WOCBP randomized to the nivolumab-plus-ipilimumab arm or the nivolumab-plus-
chemotherapy arm must agree to follow instructions for method(s) of contraception for the 
duration of study treatment and 5 months after the last dose of study treatment (i.e., 30 days 
[duration of ovulatory cycle] plus the time required for the investigational drug to undergo 
approximately five half-lives).
d) Males randomized to the nivolumab plus ipilimumab arm or the nivolumab-plus-
chemotherapy arm and who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception and fetal protection for the duration of study 
treatment and 7 months after the last dose of study treatment (i.e., 90 days [duration of 
sperm turnover] plus the time required for the investigational drug to undergo 
approximately five half-lives). In addition, male subjects must be willing to refrain from 
sperm donation during this time.
e) WOCBP randomized to the chemotherapy arm must agree to follow instructions for 
method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the 
time required for the investigational drug to undergo at least 5 half-lives. WOCBP 
randomized to the chemotherapy arm should use an adequate method to avoid pregnancy 
for approximately 4.5 months (ie, 30 days plus 98 days) after the last dose of investigational 
drug.
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f)
Males randomized to the chemotherapy arm and who are sexually active with WOCBP 
must agree to follow instructions for methods of contraception for a period of 90 days 
(duration of sperm turnover) plus the time required for the investigational drug to undergo 
at least 5 half-lives. Males randomized to the chemotherapy arm and who are sexually 
active with WOCBP should use an adequate method to avoid pregnancy for approximately 
6 months (ie, 90 days plus 98 days) after the last dose of investigational drug. In addition, 
male subjects must be willing to refrain from sperm donation during this time.
g) Azoospermic males are exempt from contraceptive requirements unless the potential exists 
for fetal toxicity due to study drug being present in seminal fluid, even if the subject has 
undergone a successful vasectomy or if the partner is pregnant. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
but still must undergo pregnancy testing as described in this section.
h) Women must not be breastfeeding.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy and 
when applicable, the potential of fetal toxicity occurring due to transmission of study drug, present 
in seminal fluid, to a developing fetus, even if the subject has undergone a successful vasectomy 
or if the partner is pregnant. Investigators shall advise on the use of highly effective methods of 
contraception (Appendix 2), which have a failure rate of < 1% when used consistently and 
correctly.
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Known Her2 positive status 
b) Subjects with untreated known CNS metastases. Subjects are eligible if CNS metastases 
are adequately treated and subjects are neurologically returned to baseline (except for 
residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to 
randomization. In addition, subjects must be either off corticosteroids, or on a stable or 
decreasing dose of 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to 
randomization.
c) Subjects with ascites which cannot be controlled with appropriate interventions.
2. Medical History and Concurrent Diseases
a) 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.
b) Subjects with active, known, or suspected autoimmune disease. Subjects with Type I 
diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring 
hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not 
requiring systemic treatment are permitted to enroll. For any cases of uncertainty, it is 
recommended that a BMS medical monitor be consulted prior to signing informed consent.
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c) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalents) or other immunosuppressive medications within 14 days of 
study drug administration. Inhaled or topical steroids, and adrenal replacement doses 
> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune 
disease.
d) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways.
e) All toxicities attributed to prior anti-cancer therapy other than hearing loss, alopecia and 
fatigue must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before 
administration of study drug.
f)
Subjects with > Grade 1 peripheral neuropathy. 
g) Any serious or uncontrolled medical disorder or active infection that, in the opinion of the 
investigator, may increase the risk associated with study participation, study drug 
administration, or would impair the ability of the subject to receive study drug.
h) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally.
i)
Treatment with botanical preparations (eg herbal supplements or traditional Chinese 
medicines) intended to treat the disease under study within 2 weeks prior to 
randomization/treatment. Refer to Section 3.4.1 for prohibited therapies.
j)
Subjects who have received a live/attenuated vaccine within 30 days of first treatment (eg, 
varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella [MMR]).
3. Physical and Laboratory Test Findings
a) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C 
antibody (anti-HCV) positive (except if HCV RNA negative).
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
b) Any contraindications to any of the study drugs of the chemotherapy regimen (XELOX or 
FOLFOX) selected by the investigator. Investigators should refer to local package insert 
of the chemotherapy drugs.
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific 
circumstances and only in countries where local regulations permit, a person who has been 
imprisoned may be included or permitted to continue as a subject). Strict conditions apply 
and Bristol-Myers Squibb approval is required.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness
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Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause 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.
*Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The duration 
of the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH level 
is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
3.4
Concomitant Treatments
3.4.1
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 3.4.2)

Any concurrent anti-neoplastic therapy (ie, surgery, chemotherapy, hormonal therapy, 
immunotherapy, extensive, non-palliative radiation therapy, or standard or investigational 
agents for treatment of GC/GEJ).

Any botanical preparation (eg herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study. Use of marijuana and its derivatives for treatment of symptoms 
related to cancer or cancer treatment are permitted if obtained by medical prescription or if its 
use (even without a medical prescription) has been legalized locally.  

Any live/attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella (MMR)) during treatment and until 100 days post last dose.
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3.4.2
Other Restrictions and Precautions
Subjects 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.
Subjects who need anticoagulation treatment due to concomitant cardiovascular disease should be 
monitored closely, a maintenance of INR > 2 is recommended.
Subjects who are administered concomitantly capecitabine and oral coumarin-derivative 
anticoagulant therapy such as warfarin should have their anticoagulant response (INR or 
prothrombin time) monitored frequently in order to adjust the anticoagulant dose. Subjects who 
are administered capecitabine and other sensitive CYP2C9 substrate or a CYP2C9 substrate with 
narrow therapeutic index should be closely monitored for toxicity.
3.4.3
Permitted Therapy
Subjects 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.
3.5
Discontinuation of Subjects following any Treatment with Study Drug 
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

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 subject

Termination of the study by Bristol-Myers Squibb (BMS)

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness. (Note: Under 
specific circumstances and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.)

Toxicity as specified in Sections 4.5.1.5 and 4.7

Disease progression assessed by RECIST 1.1 criteria, unless the subject meets criteria for 
treatment beyond progression.
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of this 
event. In most cases, the study drug will be permanently discontinued in an appropriate manner 
(e.g., dose tapering if necessary for subject safety). Please contact the Sponsor or designee within 
24 hours of awareness of the pregnancy. If the investigator determines a possible favorable 
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benefit/risk ratio that warrants continuation of study drug, a discussion between the investigator 
and the Sponsor or designee must occur, if local regulations allow. If, for whatever reason, the 
pregnancy has ended, confirmed by negative serum pregnancy test, treatment may be resumed (at 
least 3 weeks and not greater than 6 weeks after the pregnancy has ended), following approvals of 
participant /sponsor /IRB/EC, as applicable.
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
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 drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
All subjects must be followed for safety for at least 100 days after the last dose of study therapy. 
Follow-up (FU1) occurs approximately 30 days (7 days) after last dose or coinciding with the 
date of discontinuation (7 days) if the date of discontinuation is greater than 35 days after the 
last dose. Follow up visit #2 (FU2) occurs approximately 84 days (7 days) after FU1. These 
follow-up visits 1 and 2 should occur in person. Survival visits are every 3 months from FU2 until 
the end of the study and may be conducted during a clinic visit or via the phone. 
3.6
Post-Study Drug Study Follow up
In this study, OS is the primary endpoint of the study. Post study follow-up is of critical importance 
and is essential to preserving subject safety and the integrity of the study. Subjects who discontinue 
study drug must continue to be followed for collection of outcome and/or survival follow-up data 
as required and in line with Section 5 until death or the conclusion of the study.
BMS may request that survival data be collected on all treated/randomized subjects outside of the 
protocol defined window (see Section 5). At the time of this request, each subject will be contacted 
to determine their survival status unless the subject has withdrawn consent for all contacts or is 
lost to follow-up.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug 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 subject 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, if 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 drug 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 subject is alive or dead) is being measured, publicly available information 
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should be used to determine vital status only as appropriately directed in accordance with local 
law.
3.6.2
Lost to Follow-Up
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up 
is defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by subject to one registered mail letter. All attempts 
should be documented in the subject’s medical records. If it is determined that the subject has died, 
the site will use permissible local methods to obtain the 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 subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the subject remains 
lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes Investigational [Medicinal] Products (IPs/IMPs) consisting of the following:

Nivolumab Solution for Injection

Ipilimumab Solution for Injection

Oxaliplatin Concentrate for Solution for Infusion 

Fluorouracil Solution for Injection

Leucovorin (Folinic Acid) Solution for Injection

Capecitabine tablets 
The study drugs are described in Table 4-1.
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Table 4-1:
Study Drugs for CA209649
Product Description / 
Class and Dose Form
Potency
IP/Non-
IMP
Blinded or Open 
Label
Packaging / Appearance
Storage Conditions
(per label)
Nivolumab 
(BMS-936558-01)
Solution for Injectiona
100 mg 
(10 mg/mL)
IP
Open label
10 mL vial. Clear to opalescent, 
colorless to pale yellow liquid. 
May contain particles.
2to 8C. Protect from light and 
freezing.
Ipilimumab Solution 
for Injection
200 mg 
(5 mg/mL)
IP
Open label
40 mL vial/4 vials per carton. 
Clear to opalescent, colorless to 
pale yellow liquid. May contain 
particles.
2to 8C. Protect from light and 
freezing.
Oxaliplatin 
Concentrate for 
Solution for 
Infusionb,c
100 mg 
(5 mg/mL)
IP
Open label
Clear, colorless solution 
(20 mL/ vial), 1 vial/carton
Do not store above 25C. Do not 
refrigerate or freeze. Store vial 
in outer carton. Protect from 
light.
Capecitabineb,c
150 mg and 
500 mg tablets
IP
Open label
Wallet/blister card containing 
10, 20, or 30 tablets
Do not store above 30C.
Fluorouracil Solution 
for Injectionb,c
2500 mg 
(50 mg/ mL)
IP
Open label
Clear, colorless or almost 
colorless solution. 50 mL/vial 
(1 vial/carton)
Do not store above 25C. Do not 
refrigerate or freeze. Store in 
outer carton. Protect from light.
Leucovorin (folinic 
acid) 
Solution for 
Injectionb,c
400 mg 
(50 mg/mL)
IP
Open label
8 mL/vial (1 or 4 vials/carton)
2to 8C. Store in original 
container. Protect from light.
a May be labeled as either “BMS-936558-01” or “Nivolumab”
b These products may be obtained by the investigational sites as local commercial products in certain countries if allowed by local regulations. In these cases, 
products may be in a different pack size/potency/pharmaceutical form than listed in the table. These products should be prepared/stored/administered in 
accordance with the package inserts or summaries of product characteristics (SmPCs).
c Potency, packaging and storage conditions may vary for China. Storage conditions will be indicated on the clinical labels.
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4.1
Investigational Product
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.
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 subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
In this protocol, the investigational products are Nivolumab solution for injection, Ipilimumab 
solution for injection, Oxaliplatin solution for injection, Capecitabine tablets, Fluorouracil solution 
for injection, and Leucovorin solution for injection (Table 4-1).
4.2
Non-investigational Product
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. 
4.3
Storage of Study Drug
The product storage manager should ensure that the study drug 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 drug arise, the study drug should not be dispensed 
and BMS should be contacted immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Please refer to Section 9.2.2 for guidance on IP records and documentation.
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).
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCL solution, or pump) will not be 
supplied by the sponsor and should be purchased locally if permitted by local regulations.
Please refer to the current versions of the IBs, SPC or package inserts, and/or pharmacy manual 
for complete storage, handling, dispensing, and infusion/dosing information for nivolumab, 
ipilimumab, oxaliplatin, fluorouracil, leucovorin, and capecitabine.
4.4
Method of Assigning Subject Identification
After the subject’s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by entering information into the IRT system to obtain the 
subject number. Every subject that signs the ICF must be assigned a subject number in the IRT. 
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Specific instructions for using the IRT will be provided to the investigational site in a separate 
document. The investigator or designee will register the subject 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

Gender at birth.
Once enrolled in the IRT, subjects that have met all eligibility criteria (the required tumor tissue 
received and evaluable result obtained by the central laboratory) will be ready to be randomized 
through the IRT. The following information is required for subject randomization:

Subject number

Date of birth

Gender: male vs female

Region: Asia vs US vs rest of world

ECOG performance status: 0 vs 1 

PD-L1 evaluable status (the result of PD-L1 expression [1% or < 1% or indeterminate] is 
entered by the central laboratory vendor into the IRT and both the site and the BMS study team 
remain blinded to the result)

Chemotherapy regimen: XELOX vs FOLFOX.
The original study design (before Amendment 08) had 2 arms. Subjects meeting all eligibility 
criteria were randomized in an open-label fashion (1:1 ratio) to either the nivolumab-plus-
ipilimumab arm or the chemotherapy (XELOX or FOLFOX) arm.
Starting with Amendment 08, subjects meeting all eligibility criteria will be randomized in a 1:1:1 
ratio to either the nivolumab-plus-ipilimumab arm, the nivolumab-plus-chemotherapy (XELOX 
or FOLFOX) arm, or the chemotherapy (XELOX or FOLFOX) arm. The nivolumab plus 
ipilimumab arm was closed to enrollment as of 05-June-2018. Subjects randomized to treatment 
in this arm prior to or on 05-June-2018 will continue to receive treatment with study drugs per 
protocol, and the study data will remain blinded for the planned primary analysis. Per Amendment 
20, subjects will be randomized in an open-label fashion (1:1) to either the nivolumab-plus-
chemotherapy (XELOX or FOLFOX) or the chemotherapy arm (XELOX or FOLFOX).
Randomization will be stratified by the following factors:

PD-L1 expression level (1% vs < 1% or indeterminate)*

Region: Asia vs US vs rest of world

ECOG performance status: 0 vs 1 

Chemotherapy regimen (XELOX vs FOLFOX)
*During enrollment, the proportion of subjects with or without PD-L1 tumor expression will be 
monitored in pooled fashion, and may be re-assessed in case it does not reflect study assumptions 
(ie, subjects with PD-L1 tumor expression 1% is approximately 40% of all comers).
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The exact procedures for using the IRT will be detailed in the IRT manual.
4.5
Selection and Timing of Dose for Each Subject
4.5.1
Nivolumab and Ipilimumab Dosing
The nivolumab plus ipilimumab arm was closed to enrollment as of 05-June-2018. Subjects 
randomized to treatment in this arm prior to or on 05-June-2018 will continue to receive treatment 
with study drugs per protocol, and the study data will remain blinded until planned primary 
analysis.
4.5.1.1
Nivolumab and Ipilimumab Dose and Schedule
Subjects randomized to the nivolumab-plus-ipilimumab arm should receive nivolumab 1 mg/kg 
administered IV over 30 minutes followed by ipilimumab 3 mg/kg administered IV over 
30 minutes on Day 1 of each treatment cycle every 3 weeks for 4 doses (Cycles 1 to 4), followed 
by nivolumab 240 mg administered IV over 30 minutes on Day 1 of each treatment cycle every 
2 weeks (Cycle 5 and beyond) until PD (unless treatment beyond PD is permitted; see 
Section 4.5.1.6), unacceptable toxicity, withdrawal of consent, or the study ends, whichever 
occurs first. Subjects should begin study treatment within 3 calendar days of randomization. See 
Table 4.5.1.1-1 for details on the dosing schedule of nivolumab and ipilimumab. From Amendment 
29, subjects treated in the nivolumab 240 mg Q2W have an option to switch nivolumab 480 mg 
Q4W, the nivolumab 480 mg should be given 2 weeks following the last administration of 
nivolumab 240 mg dose.
Table 4.5.1.1-1:
Dose Schedule of Nivolumab and Ipilimumab
Treatment 
Group
Drug Name
Cycle 1 
(Week 1)
Cycle 2 
(Week 4)a
Cycle 3 
(Week 7)a
Cycle 4 
(Week 10)a
Cycle 5 
(Week13) till 
EOT
(Q2 weeks)b
Nivolumab 
+Ipilimumab
Nivolumab 
1 mg/kg
Day 1
Day 1
Day 1
Day 1
-
Ipilimumab
3 mg/kg
Day 1
Day 1
Day 1
Day 1
-
Nivolumab
Nivolumab 
240 mg
-
-
-
-
Day 1
a Cycles 2 to 4: Subsequent nivolumab and ipilimumab doses may be administered within 3 days before or after the 
scheduled date if necessary. Subjects may be dosed no less than 18 days between doses.
b Cycle 5 till EOT: Nivolumab may be administered up to 2 days before or 3 days after the scheduled date if 
necessary. Subjects may be dosed no less than 12 days between doses.
Dosing calculations should be based on the body weight assessed at baseline. It is not necessary to 
re-calculate subsequent doses if the subject weight is within 10% of the weight used to calculate 
the previous dose. All doses should be rounded to the nearest milligram per institutional standard.
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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 flush of diluent 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 the patient has been observed to ensure no infusion reaction has occurred. The time 
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 and ipilimumab allowed. Subjects 
may be dosed no less than 18 days from the previous dose during Q3W cycles (Cycles 1 to 4) and 
no less than 12 days from the previous dose during Q2W cycles (Cycles 5 and beyond). 
Pre-medications are not recommended for the first dose of nivolumab.
The treatment with nivolumab will be given for up to 24 months in the absence of disease 
progression or unacceptable toxicity.
Subjects should be carefully monitored for infusion reactions during nivolumab administration. If 
an acute infusion reaction is noted, subjects should be managed according to Section 4.5.1.8.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates the treatment. Dosing visits are not skipped, only delayed.
For further information related to nivolumab and ipilimumab preparation and dosing, please refer 
to the pharmacy manual.
4.5.1.2
Dose Delay Criteria for Nivolumab and/or Ipilimumab Therapy
Nivolumab and/or ipilimumab administration should be delayed for the following: 

Any Grade 2 non-skin, drug-related AE, with the following exception:

Grade 2 drug-related fatigue does not require a treatment delay.

Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities 

Any Grade 3 skin, drug-related AE

Any Grade 3 drug-related laboratory abnormality (excluding AST, ALT or Total Bilirubin), 
with the following exceptions for lymphopenia, and asymptomatic amylase or lipase 
abnormalities:

Grade 3 lymphopenia does not require dose delay

Any Grade 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay.

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Subjects receiving ipilimumab in combination with nivolumab who have drug-related toxicities 
that meet the criteria for dose delay should have both drugs (ipilimumab and nivolumab) delayed 
until retreatment criteria are met (exceptions apply to the retreatment criteria after dose delay of 
ipilimumab and nivolumab for Grade 3 amylase and lipase abnormalities that are not associated 
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with symptoms or clinical manifestations of pancreatitis and that are attributed to ipilimumab 
and/or nivolumab).
Subjects who require delay of nivolumab and ipilimumab should be re-evaluated weekly or more 
frequently if clinically indicated and resume nivolumab and/or ipilimumab dosing when 
re-treatment criteria are met.
4.5.1.3
Dose Reductions for Nivolumab or Ipilimumab Therapy
There will be no dose reductions for nivolumab or ipilimumab.
4.5.1.4
Criteria for Resuming Treatment for Nivolumab or Ipilimumab
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade 1 
or baseline value, with the following exceptions:

Subjects may resume treatment in the presence of Grade 2 fatigue.

Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity.

For subjects with Grade 2 AST, ALT, or total bilirubin elevations, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete.

Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 4.5.1.5) should have treatment permanently discontinued.

Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects 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.

Subjects with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor.

Participants who received systemic corticosteroids for the management of any drug-related 
toxicity must be off corticosteroids or have tapered down to an equivalent dose of prednisone 
≤ 10 mg/day.
If the criteria to resume treatment are met, the subject should restart treatment at the next scheduled 
timepoint per protocol. However, if the treatment is delayed past the scheduled timepoint per 
protocol, the scheduled study treatment administration will be delayed, but not skipped, until 
dosing resumes. In particular, this is to ensure that subjects will receive 4 administrations of 
combined nivolumab and ipilimumab treatment if toxicity allows.
If dose delay is necessary for subjects during Week 1 - 12, both nivolumab and ipilimumab must 
be delayed until treatment can resume. However, if a nivolumab-related infusion reaction prevents 
subsequent infusion of ipilimumab on the same day, the dose of ipilimumab should be replaced as 
soon as possible. In such instances, at least 19 days must elapse between the replacement dose of 
ipilimumab and the administration of the next dose of nivolumab combined with ipilimumab.
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in Section 4.5.1.5.
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4.5.1.5
Criteria for Nivolumab and/or Ipilimumab Treatment Discontinuation
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, neurologic toxicity, hypersensitivity reactions, infusion 
reactions, and endocrinopathies:

Grade 3 drug-related
diarrhea,
colitis, neurologic toxicity, myocarditis, 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. Grade ≥ 3 adrenal insufficiency
requires discontinuation regardless of control with hormone replacement (note:
Hospitalization for diagnostic workup of adrenal insufficiency without severe symptoms
should not be considered a Grade 3 event)

Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
Grade 3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN

*In most cases of Grade 3 AST or ALT elevation, study 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.

Any Grade 4 drug-related AE 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

Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis. 

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 AEs, such as hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor.

Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
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
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed.

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. 

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing.
Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 weeks from the previous 
dose, the BMS medical monitor must be consulted. Tumor assessments should continue as per 
protocol even if dosing is delayed.
The assessment for discontinuation of ipilimumab should be made separately from the assessment 
made for discontinuation of nivolumab. Although there is overlap among the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued.
If a subject meets the criteria for discontinuation of ipilimumab but not nivolumab, treatment with 
nivolumab may not resume until the AE has fully resolved and the subject has discontinued 
steroids, if they were required for treatment of the AE. The relationship to ipilimumab should be 
well documented in the source documents. Nivolumab should be resumed at 240 mg every 
2 weeks.
If a subject in any of the nivolumab/ipilimumab combination arms meets criteria for 
discontinuation and investigator is unable to determine whether the event is related to both or one 
study drug, the subject should discontinue both nivolumab and ipilimumab and be taken off the 
treatment phase of the study.
4.5.1.6
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD.89
Subjects treated with nivolumab alone or in combination with ipilimumab or chemotherapy will 
be permitted to continue their treatment beyond initial RECIST 1.1-defined PD, assessed by the 
investigator, up to a maximum of 24 months from date of first dose, as long as they meet the 
following criteria:

Investigator-assessed clinical benefit.

Tolerance of study drug

Stable performance status

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)

Subject provides written informed consent prior to receiving additional nivolumab treatment 
(alone or in combination with ipilimumab or chemotherapy). All other elements of the main 
consent including description of reasonably foreseeable risks or discomforts, or other 
alternative treatment options will still apply.
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A radiographic assessment/scan should be performed within 6 weeks of 
initial 
investigator-assessed progression to determine whether there has been a decrease in the tumor size 
or continued PD. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the subject is clinically deteriorating and unlikely to receive any benefit from continued 
treatment with nivolumab plus ipilimumab or nivolumab.
If the investigator feels that the subject treated with nivolumab (alone or in combination with 
ipilimumab or chemotherapy) continues to achieve clinical benefit by continuing treatment, the 
subject should remain on the trial and continue to receive monitoring according to Table 5.1-2.
For the subjects who continue treatment beyond progression, further progression is defined as an 
additional 10% increase in tumor burden with a minimum 5 mm absolute increase from time of 
initial PD. This includes an increase in the sum of diameters of all target lesions and/ or the 
diameters of new measurable lesions compared to the time of initial PD. Nivolumab treatment 
(alone or in combination with ipilimumab or chemotherapy) should be discontinued permanently 
upon documentation of further progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
4.5.1.7
Management Algorithms for Immuno-oncology Agents
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered I-O 
agents in this protocol. Early recognition and management of AEs associated with I-O agents may 
mitigate severe toxicity. Management algorithms have been developed to assist investigators in 
assessing and managing the following groups of AEs:

Gastrointestinal

Renal

Pulmonary

Hepatic

Endocrinopathy

Skin

Neurological

Myocarditis
The above algorithms are found in the nivolumab IB and Appendix 1 of this protocol.
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4.5.1.8
Treatment of Nivolumab- or 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 subject 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 or ipilimumab 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 or ipilimumab infusion, begin an IV infusion of normal saline, and treat 
the subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg; remain at bedside and monitor subject 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 subject closely. If symptoms recur, 
then no further nivolumab or ipilimumab 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 or ipilimumab infusions. If 
necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grades 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 or ipilimumab. Begin an IV infusion of normal 
saline and treat the subject 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 
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injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until 
the Investigator is comfortable that the symptoms will not recur. Nivolumab or ipilimumab 
will be permanently discontinued. Investigators should follow their institutional guidelines for 
the treatment of anaphylaxis. Remain at bedside and monitor subject 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.
4.5.2
Nivolumab plus Chemotherapy Arm 
4.5.2.1
Nivolumab plus Chemotherapy Arm Dosing Schedule
Subjects randomized to the nivolumab-plus-chemotherapy arm should receive either nivolumab 
360 mg plus XELOX or nivolumab 240 mg plus FOLFOX. 

Subjects assigned to nivolumab plus-XELOX will receive nivolumab 360 mg administered IV 
over 30 minutes and oxaliplatin 130 mg/m2 administered IV on Day 1 of each treatment cycle 
every 3 weeks, and capecitabine 1000 mg/m2 administered orally twice daily (ie, 1000 mg/m2
in the morning and 1000 mg/m2 in the evening) on Days 1 to 14 of each treatment cycle every 
3 weeks (see Table 4.5.2.1-1). Dosing windows for subsequent XELOX doses should adhere 
to recommendations in the prescribing information or local standards, where indicated.

Premedication is not usually required in the first cycle. For subsequent cycles, adequate 
premedication may be administrated per local standard.

Capecitabine should be taken with food.
Table 4.5.2.1-1:
Dose Schedule of Nivolumab-plus-XELOX
Treatment 
group
Drug name
Cycle 1 
(Week 1)
Cycle 2 
(Week 4)
Cycle 3 
(Week 7)
Cycle 4 
(Week 10)
Cycle 5 
(Week 13) till 
EOT
(Q3 weeks)
Nivolumab-
plus-XELOX
Nivolumab 
360 mg
Day 1
Day 1
Day 1
Day 1
Day 1
Oxaliplatin 
130 mg/m2
Day 1
Day 1
Day 1
Day 1
Day 1
Capecitabine 
1000 mg/m2
twice daily
Days 1 to 14
Days 1 to 14
Days 1 to 14
Days 1 to 14
Days 1 to 14

Subjects assigned to nivolumab-plus-FOLFOX will receive nivolumab 240 mg administered 
IV over 30 minutes and oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and fluorouracil 
400 mg/m2 administered IV on Day 1 of each treatment cycle every 2 weeks, and fluorouracil 
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nivolumab
1200 mg/m2 IV continuous infusion over 24 hours daily or per local standard on Days 1 and 2 
of each treatment cycle every 2 weeks (see Table 4.5.2.1-2). Dosing windows for subsequent 
FOLFOX doses should adhere to recommendations in the prescribing information or local 
standards, where indicated.
Premedication is not usually required in the first cycle. For subsequent cycles, adequate 
premedication may be administrated per local standard. 
Table 4.5.2.1-2:
Dose Schedule of Nivolumab-plus-FOLFOX
Treatment 
group
Drug name
Cycle 1 
(Week 1)
Cycle 2 
(Week 3)
Cycle 3 
(Week 5)
Cycle 4 
(Week 7)
Cycle 5 
(Week 9) till 
EOT
(Q2 weeks)
Nivolumab-
plus-FOLFOX
Nivolumab 
240 mg
Day 1
Day 1
Day 1
Day 1
Day 1
Oxaliplatin 
85 mg/m2
Day 1
Day 1
Day 1
Day 1
Day 1
Leucovorin
400 mg/m2
Day 1
Day 1
Day 1
Day 1
Day 1
Fluorouracil 
400 mg/m2
Day 1
Day 1
Day 1
Day 1
Day 1
Fluorouracil 
1200 mg/m2
Days 1 & 2
Days 1 & 2
Days 1 & 2
Days 1 & 2
Days 1 & 2

No cross-over will be allowed between XELOX and FOLFOX in this study.
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 flush 
of diluent to clear the line of nivolumab before starting the chemotherapy infusion(s). The second 
infusion will always be the chemotherapy study drug(s) and will start after the infusion line has 
been flushed, filters changed and the patient has been observed to ensure no infusion reaction has 
occurred. The time between infusions is expected to be approximately 30 minutes but may be more 
or less depending on the situation.
The treatment with nivolumab will be given for up to 24 months in the absence of disease 
progression or unacceptable toxicity. Chemotherapy will be given as per the study dosing schedule. 
4.5.2.2
Dose Modification Criteria for Nivolumab-plus-Chemotherapy
Dose modification criteria for the combination regimen should follow the respective individual 
dose modification criteria of each component. For chemotherapy, it is allowed to follow local 
standard or local package insert recommendations.
Dosing for all drugs should be delayed/interrupted if any criteria in Sections 4.5.1.2 (for 
nivolumab) or Sections 4.6.2.2 (for XELOX) and 4.6.2.3 (for FOLFOX.) are met.
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nivolumab
Dose reduction of nivolumab are not permitted. Dose reduction for chemotherapy is permitted 
according to local standard or local package insert. See also Sections 4.6.2.2 for XELOX and 
4.6.2.3 for FOLFOX. 
Subjects may resume dosing when resuming criteria for BOTH nivolumab (Section 4.5.1.4) and 
chemotherapy (Section 4.6.2.2 for XELOX and Section 4.6.2.3 for FOLFOX) are met. That is, 
nivolumab and chemotherapy must be administered together until treatment discontinuation. It is 
allowed to administer either nivolumab or chemotherapy doublet or single drug alone if the 
other(s) are delayed or discontinued due to toxicity which is not overlapping for nivolumab and 
chemotherapy, judging by the treating investigator if it is the best interest in the subjects.
The assessments for discontinuation of nivolumab and/or chemotherapy should be made 
separately. Nivolumab discontinuation criteria are detailed in Section 4.5.1.5, and chemotherapy 
discontinuation criteria are detailed in Sections 4.6.2.2 (for XELOX) and 4.6.2.3 (for FOLFOX). 
Continuation of nivolumab alone when chemotherapy has been discontinued due to toxicity is 
permitted. Chemotherapy doublet or single drug is allowed to continue if the discontinuation 
criteria for nivolumab is met. 
From Amendment 29, nivolumab 480 mg Q4W is permitted when all chemotherapy components
are discontinued and nivolumab is continued alone. Subjects must be in the study for a minimum 
of 6 months from Cycle 1, Day 1 before switching to 480 mg Q4W nivolumab. Nivolumab 480 mg 
should be given 2 weeks or 3 weeks following the last administration of nivolumab 240 mg Q2W 
or 360 mg Q3W, respectively. 
Subjects treated with nivolumab-plus-chemotherapy will be permitted to continue nivolumab 
treatment beyond initial RECIST 1.1-defined PD, assessed by the investigator, as long as they 
meet the criteria described in Section 4.5.1.6. The management of nivolumab-related adverse 
events and infusion reactions should follow instructions listed in Section4.5.1.7 and 4.5.1.8. 
4.6
Chemotherapy Arm Dosing
4.6.1
Oxaliplatin-Plus-Fluoropyrimidine Dose and Schedule 
Subjects randomized to the chemotherapy arm should receive either XELOX or FOLFOX:

Subjects assigned to XELOX will receive oxaliplatin 130 mg/m2 administered IV on Day 1 of 
each treatment cycle and capecitabine 1000 mg/m2 administered orally twice daily (ie, 1000 
mg/m2 in the morning and 1000 mg/m2 in the evening) on Days 1 to 14 of each treatment cycle, 
every 3 weeks (see Table 4.6.1-1). Dosing windows for subsequent XELOX doses should 
adhere to recommendations in the current prescribing information or local standards, where 
indicated.
Premedication is not usually required in the first cycle. For subsequent cycles, adequate 
premedication may be administrated per local standard. 
Capecitabine should be taken with food.
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BMS-936558
nivolumab
Table 4.6.1-1:
Dose Schedule of XELOX
Treatment 
group
Drug name
Cycle 1 
(Week 1)
Cycle 2 
(Week 4)
Cycle 3 
(Week 7)
Cycle 4 
(Week 10)
Cycle 5 
(Week 13) till 
EOT
(Q3 weeks)
XELOX
Capecitabine 
1000 mg/m2
twice daily
Days 1 to 14
Days 1 to 14
Days 1 to 14
Days 1 to 14
Days 1 to 14
Oxaliplatin 
130 mg/m2
Day 1
Day 1
Day 1
Day 1
Day 1

Subjects assigned to FOLFOX will receive oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and 
fluorouracil 400 mg/m2 administered IV on Day 1 of each treatment cycle, and fluorouracil 
1200 mg/m2 IV continuous infusion over 24 hours daily or per local standard on Days 1 and 2 
of each treatment cycle, every 2 weeks (see Table 4.6.1-2). Dosing windows for subsequent 
FOLFOX doses should adhere to recommendations in the prescribing information or local 
standards, where indicated. 
Premedication is not usually required in the first cycle. For subsequent cycles, adequate 
premedication may be administrated per local standard. 
Table 4.6.1-2:
Dose Schedule of FOLFOX
Treatment 
group
Drug name
Cycle 1 
(Week 1)
Cycle 2 
(Week 3)
Cycle 3 
(Week 5)
Cycle 4 
(Week 7)
Cycle 5 
(Week 9) till 
EOT
(Q2 weeks)
FOLFOX
Oxaliplatin 
85 mg/m2
Day 1
Day 1
Day 1
Day 1
Day 1
Leucovorin
400 mg/m2
Day 1
Day 1
Day 1
Day 1
Day 1
Fluorouracil 
400 mg/m2
Day 1
Day 1
Day 1
Day 1
Day 1
Fluorouracil 
1200 mg/m2
Days 1 & 2
Days 1 & 2
Days 1 & 2
Days 1 & 2
Days 1 & 2

No cross-over will be allowed between XELOX and FOLFOX in this study.
4.6.2
Dose Modification Criteria for Oxaliplatin-Plus-Fluoropyrimidine 
Treatment
Dose modifications of oxaliplatin, capecitabine, leucovorin, and fluorouracil are permitted 
according to local standards or local package inserts.
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4.6.2.1
General Guidance for Dose Modification for Chemotherapy 

Treatment for the first cycle should only commence if all the inclusion criteria are met and the 
subject has been enrolled. For subsequent cycles, dose delay/modification is permitted per 
local standard or as described in Section 4.6.2.2 and Section 4.6.2.3.  

Doses of any study drug omitted for toxicity are not replaced or restored; instead, the patient 
should resume the planned treatment cycles. Supportive care (for example, colony-stimulating 
factors [CSFs], blood and blood products, etc. can be administered in accordance with the latest 
American Society of Clinical Oncology (ASCO) or other equivalent guidelines. 

Dose modification, for non-serious and non-life-threatening toxicities like alopecia, altered taste 
or nail changes may not be required and the final decision is left to the discretion of the treating 
investigator. 

In situations where concomitant toxicities of varying severity exist, dose modification will be 
tailored for the toxicity with highest CTCAE grading. 

If there is a delay or modification in administration of study drug(s) due to toxicity, treatment 
with the other study agent(s) should continue as scheduled. If clinically appropriate, the 
investigator can delay all treatment components up to a maximum of 7 days to allow 
synchronized administration of all agents. 
If toxicity related to any component of chemotherapy does not resolve in the same treatment cycle, 
the administration of that component can be delayed up to 6 weeks. If the toxicity does not resolve 
within 6 weeks, that component will be discontinued unless it is determined by the treating 
investigator that the patient might benefit from continuation of the component.
4.6.2.2
Dose Modification Criteria for XELOX
Capecitabine
Toxicity due to capecitabine administration may be managed by symptomatic treatment and/or 
treatment interruption or dose reduction. Dose modifications of capecitabine are presented in Table 
4.6.2.2-1. Once the dose has been reduced, it should not be increased at a later time. For those 
toxicities considered by the treating physician to be unlikely to become serious or life-threatening, 
eg alopecia, altered taste, or nail changes, treatment can be continued at the same dose without 
reduction or interruption. Subjects taking capecitabine should be informed of the need to interrupt 
treatment immediately if moderate or severe toxicity occurs. Doses of capecitabine omitted for 
toxicity are not replaced. 
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nivolumab
Table 4.6.2.2-1:
Recommended Dose Modifications of Capecitabine
Toxicitya
During a course of therapy
Dose adjuvant for next 
treatments (% of starting dose)
Grade 1
Maintain dose level 
Maintain dose level
Grade 2 
1st appearance 
Interrupt until resolved to 
Grade 0 1
100% (1000 mg/m2)
2nd appearance
75% (750 mg/m2)
3rd appearance
50% (500 mg/m2)
4th appearance
Discontinue treatment permanently 
-
Grade 3
1st appearance
Interrupt until resolved to 
Grade 0 1
75% (750 mg/m2)
2nd appearance
50% (500 mg/m2)
3rd appearance
Discontinue treatment permanently
-
Grade 4
1st appearance
Discontinue treatment permanently 
or,
if physician deems it to be in the 
patient’s best interest to continue, 
interrupt until resolved to 
Grade 0 - 1 
50% (500 mg/m2)
a According to the National Cancer Institute of Canada Clinical Trial Group (NCIC CTG) Common Toxicity Criteria 
(version 1) or the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy Evaluation 
Program, US National Cancer Institute, version 4.0.
Oxaliplatin
Dose Modifications for Neurotoxicity

For Grade 2 peripheral sensory neuropathy (moderate paresthesia or dysesthesia), or limiting 
instrumental activities of daily living, skip oxaliplatin. When toxicity resolves to Grade 1, 
resume oxaliplatin to 75% of initial dose. If oxaliplatin is skipped for 4 weeks (2 consecutive 
doses) for neurologic toxicity, discontinue oxaliplatin.

For Grade 3 or greater peripheral sensory neuropathy (severe paresthesia or dysesthesia), or 
limiting self-care activities of daily living), discontinue oxaliplatin. 
Dose Modifications for Subjects with Renal Impairment

For normal renal function or mild to moderate renal impairment (CrCl > 50 mL/min), the full 
dose of oxaliplatin can be administered.

For severe renal impairment, the oxaliplatin dose should be reduced to 75% of initial dose. 
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nivolumab
Dose Modifications for Subjects with Hematological Toxicity

For Grade 2 or Grade 3 thrombocytopenia, oxaliplatin should be reduced to 75% of initial dose. 
For Grade 4 thrombocytopenia, the dose should be reduced to 50% of initial dose.

For Grade 3 or Grade 4 neutropenia or febrile neutropenia, the oxaliplatin dose should be 
reduced to 75% of initial dose.
4.6.2.3
Dose Modification Criteria for FOLFOX
Recommended dose modifications of FOLFOX are provided in Table 4.6.2.3-1 and Table 4.6.2.3-
2.
Table 4.6.2.3-1:
Recommended Dose Modifications of FOLFOX
Drug
Starting Dose
Dose Modification
Dose Level - 1
Dose Level - 2
Oxaliplatin
85 mg/m2
70 mg/m2
50 mg/m2
5-FU
Bolus 5-FU: 400 mg/m2
Leucovorin: 400 mg/m2
Infusion 5-FU: 2400 mg/m2/48 
hours
Bolus 5-FU: 300 mg/m2
Leucovorin: 300 mg/m2
Infusion 5-FU: 
2000 mg/m2/48 hours
Bolus 5-FU: 200 mg/m2
Leucovorin: 200 mg/m2
Infusion 5-FU: 
1600 mg/m2/48 hours
5-FU: 5-fluorouracil
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nivolumab
Table 4.6.2.3-2:
Dose Modifications of FOLFOX
Toxicity 
Definition
During a course of 
therapy
Dose adjustment for next 
treatments
Neutropenia
Grade 3 or greater
Interrupt until resolved to 
Grade 2
Dose level -1
*If treatment delayed for 
4 consecutive weeks, discontinue all 
treatment
Thrombocytopenia
Grade 2
Interrupt until resolved to 
Grade 1
Dose level -1
*If Grade 2 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1 
Grade 3
Interrupt until resolved to 
Grade 1
Dose level -1
*If Grade 3 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
Grade 4
Interrupt until resolved to 
Grade 1
Dose level -2
*If Grade 4 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
Neurologic toxicity
Grade 2 peripheral 
sensory neuropathy
Interrupt until resolved to 
Grade 1
Oxaliplatin dose -1
Continue 5-FU and leucovorin
*If oxaliplatin delayed for 
neurologic toxicity for 4 
consecutive weeks, discontinue 
oxaliplatin, continue 5-FU and 
leucovorin
Grade 3 or greater 
peripheral sensory 
neuropathy
Discontinue oxaliplatin
Continue 5-FU and leucovorin
Gastrointestinal 
toxicities
Grade 2 or greater 
diarrhea
Interrupt until resolved to 
Grade 1
Dose level -1
If dose delayed for diarrhea for 
4 consecutive weeks, discontinue all 
treatment
For toxicities not listed above, dose modifications are permitted per local standards. 
Subjects may also discontinue oxaliplatin following multiple cycles if, in the investigator’s 
judgment, cumulative toxicity is likely to increase over time and become problematic.
4.7
Criteria for Oxaliplatin-plus-Fluoropyrimidine Discontinuation  
Except where specified below, both chemotherapy drugs in the platinum doublet chemotherapy 
regimen should be discontinued for any of the following:

Any Grade 4 peripheral neuropathy requires discontinuation of oxaliplatin.

In case of persistent Grade 3 paraesthesia, oxaliplatin should be discontinued.
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
Any Grade ≥ 3 mucocutaneous reaction possibly attributable to capecitabine or leucovorin 
requires permanent discontinuation.

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 > 5-10 x upper limit of normal (ULN) for > 2 weeks

AST or ALT > 10 x ULN

Total bilirubin > 5 x ULN

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN

Any oxaliplatin-related decrease in creatinine clearance to < 30 mL/min (using the Cockroft 
Gault formula) requires discontinuation of oxaliplatin.

Any drug-related AE which recurs after 2 prior dose reductions for the same drug-related AE 
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 AE 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.

If any toxicity does not resolve within 42 days, that component will be discontinued unless it 
is determined by the treating investigator that the subject might benefit from continuation of 
the component.
For toxicities that are not listed above, the treating investigators can decide to discontinue any 
individual chemotherapy agent or all chemotherapy agents if it is not the best interest in the subject 
per the local standards. 
Post-treatment study follow-up is critically important and is essential to preserving subject safety 
and the integrity of the study. Subjects who discontinue study treatment will continue to be 
followed for collection of tumor surveillance assessments, safety, QoL questionnaires and 
biomarker sampling as per protocol. 
4.8
Blinding/Unblinding
Not applicable.
4.9
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.10
Destruction or Return of Investigational Product
For this study, IP (those supplied by BMS, a vendor or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. 
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nivolumab
If...
Then...
IP supplied by BMS (including its vendors)
Any unused IP supplied by BMS can only be 
destroyed after being inspected and reconciled 
by the responsible Study Monitor unless IP 
containers must be immediately destroyed as 
required for safety, or to meet local regulations 
(e.g., cytotoxics or biologics).
If IP will be returned, the return will be 
arranged by the responsible Study Monitor.
IP sourced by site, not supplied by BMS (or its 
vendors) (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug.

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 IP provided by BMS (or its vendors). Destruction of non-IP sourced by the site, not 
supplied by BMS, is solely the responsibility of the investigator or designee.
Please refer to Section 9.2.2 for additional guidance on IP records and documentation.
4.11
Retained Samples for Bioavailability/Bioequivalence/Biocomparability
Not applicable.
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nivolumab
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline - All Subjects (CA209649)
Procedure
Screening Visit
Notes
Eligibility Assessments
Informed Consent
X
Contact IRT to obtain study subject number. Study allows for re-enrollment of 
a subject that has discontinued the study as a pre-treatment failure. If 
re-enrolled, the subject must be re-consented and assigned a new subject 
number from IRT.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed during screening and 
confirmed prior to randomization.
Disease Status
Medical History
X
-
Tumor Tissue Samples
X
Recent sample or archival. Sufficient tumor tissue (either a formalin-fixed, 
paraffin-embedded [FFPE] tissue block or minimum 20 positively charged 
slides*) must be available within 6 months prior to randomization and sent to a 
central laboratory for biomarker analysis. PDL1 status must be assessed prior 
to randomization.
Tissue must be a core needle biopsy, excisional biopsy, or incisional biopsy. 
Fine needle biopsies are not considered adequate for biomarker review and 
randomization. Biopsies of bone lesions that do not have a soft tissue 
component or decalcified bone tumor samples are also not acceptable. 
* If, despite best efforts, a minimum 20 slides are not obtainable, discuss with 
Sponsor. 
Safety Assessments
Physical Examination
X
Within 14 days prior to randomization.
Physical Measurements
X
Include Height, Weight and BSA.
Within 14 days prior to randomization.
Vital Signs 
X
Obtain vital signs at the screening visit and within 72 hours prior to first dose. 
Including BP, heart rate, and temperature.
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Table 5.1-1:
Screening Procedural Outline - All Subjects (CA209649)
Procedure
Screening Visit
Notes
Performance Status (ECOG)
X
Within 14 days prior to randomization. See protocol Appendix 3.
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization.
Serious Adverse Event (SAE) Assessment
X
After informed consent is signed.
Review of concomitant medications
X
Within 28 days prior to randomization.
Electrocardiogram (ECG)
X
Within 14 days prior to randomization.
Laboratory Tests
X
On site/local complete blood count (CBC) w/differential, chemistry panel 
including: LDH, AST, ALT, ALP, total bilirubin, blood urea nitrogen (BUN)
or serum urea level, creatinine, Ca, Na, K, Cl, fasting glucose and albumin 
within 14 days prior to randomization.
Endocrine panel (TSH, Free T4, Free T3; Total T3/T4 are acceptable if Free 
T3/T4 are not available), Hep B/C (HBV HBsAG, HCV antibody or HCV
RNA), within 28 days prior to randomization.
Pregnancy Test (WOCBP only)
X
Serum or urine to be done at screening visit and repeated within 24 hours prior 
to first dose of study drug.
Efficacy Assessment
Baseline Tumor Imaging Assessment
X
CT/MRI scan of chest, abdomen, pelvis and any clinically indicated sites 
within 28 days prior to randomization. CT/MRI scan prior to ICF signature 
might be acceptable if performed within 28 days prior to randomization.   
IRT
IRT contact
X
The IRT must be contacted for subject number assignment at the time informed 
consent is obtained.
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nivolumab
Table 5.1-2:
On-Treatment Assessments - Subjects in Nivolumab-plus-Ipilimumab Arm (CA209649)
Procedure
Cycle 1 Day 1
(3-week cycle)
C1D1
Cycles 2 - 4 
(Every 3 weeks) 
on Day 1
Cycle 5 and beyond
(Every 2 weeks)
on Day 1a
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
Safety Assessments
Physical Examination
X
X
X
To be performed within 72 hours of dosing.
Vital Signs
X
X
X
Obtain vital signs within 72 hours prior to dose. Including 
BP, heart rate, and temperature.
Weight and ECOG 
Performance Status
X
X
X
Within 72 hours of dosing. See protocol Appendix 3 for 
ECOG Performance Status scale.
Adverse Events Assessment
Continuously
Assessed using NCI CTCAE v.4
Serious Adverse Event 
(SAE)
Continuously
Assessed using NCI CTCAE v.4
Review of concomitant 
medications
X
X
X
-
Laboratory Tests
See Note
See Note
See Note
Within 72 hours prior to each dose through Week 23 visit 
and every alternate dose thereafter. 
Include CBC w/differential, ALT, AST, total bilirubin, 
BUN or serum urea level, creatinine, Ca, Na, K, Cl, LDH 
and glucose. 
TSH (with reflexive Free T4 and Free T3; Total T3/T4 are 
acceptable if Free T3/T4 are not available) every 6 weeks 
(7 days) starting at C1D1.
Note: Laboratory tests do not need to be repeated on C1D1 
if performed within 14 days prior to first dose.
Pregnancy Test (WOCBP 
only)
X
See Note
See Note
Serum or urine within 24 hours prior to the initial 
administration of study drug and then every 4 weeks 
(7 days) regardless of dose delays; if collected with a 
dosing visit, then obtain within 24 hours prior to 
administration of study drug: urine or serum.
Revised Protocol No.: 09
Date: 16-Sep-2019
83
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Assessments - Subjects in Nivolumab-plus-Ipilimumab Arm (CA209649)
Procedure
Cycle 1 Day 1
(3-week cycle)
C1D1
Cycles 2 - 4 
(Every 3 weeks) 
on Day 1
Cycle 5 and beyond
(Every 2 weeks)
on Day 1a
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
PK and Immunogenicity Sampling
PK samples
See Table 5.5-1 for details regarding specific sample timing.
Immunogenicity blood 
sample
See Table 5.5-1 for details regarding specific sample timing.
Efficacy Assessments
Tumor Imaging Assessment
See Note
See Note
CT/MRI scan of chest, abdomen, pelvis, and any clinically 
indicated sites.
Every 6 weeks (7 days) from first dose up to and 
including Week 48, then every 12 weeks (7 days) 
regardless of treatment schedule until disease progression 
(unless treatment beyond PD is permitted; see 
Section 4.5.1.6), or the subject withdraws consent, 
whichever comes first. Subjects who discontinue study 
treatment for reasons other than PD will continue to have 
tumor assessments until their disease progresses or they 
withdraw consent.
Use same imaging method as was used at 
screening/baseline
Collection of biomarker 
sampling
Outcomes Research Assessments
FACT-Ga
X
See Note
See Note
Assessed every 6 weeks (3 days) from C1D1, regardless 
of treatment schedule; if administered on a dosing day, 
assessment should take place prior to any other study 
procedures.
EQ-5D-3L
X
Health Care Resource 
Utilization
X
X
X
Revised Protocol No.: 09
Date: 16-Sep-2019
84
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-2:
On-Treatment Assessments - Subjects in Nivolumab-plus-Ipilimumab Arm (CA209649)
Procedure
Cycle 1 Day 1
(3-week cycle)
C1D1
Cycles 2 - 4 
(Every 3 weeks) 
on Day 1
Cycle 5 and beyond
(Every 2 weeks)
on Day 1a
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
Study Drug
Randomization
X
Contact IRT for randomization
Note: Randomization to the nivolumab plus ipilimumab 
arm was closed as of 05-June-2018
Dispense Study Treatment
X
X
X
First dose to be administered within 3 calendar days after 
randomization. See Table 4.5.1.1-1. 
Cycles 2 - 4: subsequent nivolumab and ipilimumab doses 
may be administered within 3 days before or after the 
scheduled date if necessary. Subjects may be dosed no less 
than 18 days between doses.
Cycle 5 till EOT: nivolumab 240 mg may be administered 
up to 2 days before or 3 days after the scheduled date if 
necessary. Subjects may be dosed no less than 12 days 
between doses.
Nivolumab 480 mg should be given 2 weeks following the 
last administration of nivolumab 240 mg. Nivolumab 
480 mg may be administered up to 3 days before or 3 days 
after the scheduled date, if necessary. Subjects may be 
dosed no less than 25 days between doses.
Vials may be assigned through IRT up to 3 calendar days 
prior to every dose date.
a For subjects receiving nivolumab 480 mg Q4W alone, schedule of study procedures will be aligned with dosing visits (every 4 weeks on Day 1). Laboratory test 
should be done prior each dose. TSH (with reflexive Free T4 and Free T3; Total T3/T4 are acceptable if Free T3/T4 are not available) is acceptable to perform 
at alternative dose.
Revised Protocol No.: 09
Date: 16-Sep-2019
85
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments - Subjects in Nivolumab-plus-Chemotherapy (XELOX or FOLFOX) Arm 
(CA209649)
Procedure
Nivolumab-
plus-XELOX 
and 
Nivolumab-
plus-
FOLFOX 
Cycle 1 Day 1 
(C1D1)
Nivolumab-plus-
XELOX 
Cycle 2 and 
beyond
(Every 3 weeks)
on Day 1
Nivolumab-plus-
FOLFOX
Cycle 2 and 
beyond
(Every 2 weeks)
on Day 1a
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
Safety Assessments
Targeted Physical Examination
X
X
X
To be performed within 72 hours of dosing.
Vital Signs
X
X
X
Obtain vital signs within 72 hours prior to dose. Including 
BP, heart rate and temperature.
Weight, BSA and ECOG 
Performance Status
X
X
X
Within 72 hours of dosing. See protocol Appendix 3 for 
ECOG Performance Status scale
Adverse Events Assessment
Continuously
Assessed using NCI CTCAE v.4
Serious Adverse Event (SAE)
Continuously
Assessed using NCI CTCAE v.4
Review of concomitant 
medications
X
X
X
-
Laboratory Tests
See Note
See Note
See Note
Nivolumab + XELOX: Within 72 hours prior to each 
dose.
Nivolumab + FOLFOX: Within 72 hours prior to each 
dose through Week 23 and every alternate dose thereafter. 
Include CBC w/differential, ALT, AST, total bilirubin, 
BUN or serum urea level, creatinine, Ca, Na, K, Cl, LDH 
and glucose.
TSH (with reflexive Free T4 and Free T3; Total T3/T4 are 
acceptable if Free T3/T4 are not available) every 6 weeks 
(7 days) starting at C1D1.
Note: Laboratory tests do not need to be repeated on 
C1D1 if performed within 14 days prior to first dose.
Revised Protocol No.: 09
Date: 16-Sep-2019
86
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments - Subjects in Nivolumab-plus-Chemotherapy (XELOX or FOLFOX) Arm 
(CA209649)
Procedure
Nivolumab-
plus-XELOX 
and 
Nivolumab-
plus-
FOLFOX 
Cycle 1 Day 1 
(C1D1)
Nivolumab-plus-
XELOX 
Cycle 2 and 
beyond
(Every 3 weeks)
on Day 1
Nivolumab-plus-
FOLFOX
Cycle 2 and 
beyond
(Every 2 weeks)
on Day 1a
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
Pregnancy Test (WOCBP only)
X
See Note
See Note
Serum or urine within 24 hours prior to the initial 
administration of study drug and then every 4 weeks 
(± 7 days) regardless of dose delays; if collected with a 
dosing visit, then obtain within 24 hours prior to 
administration of study drug: urine or serum.
PK and Immunogenicity Sampling
PK samples
See Table 5.5-2 and Table 5.5-3 for details regarding specific sample timing.
Immunogenicity blood sample
See Table 5.5-2 and Table 5.5-3 for details regarding specific sample timing.
Revised Protocol No.: 09
Date: 16-Sep-2019
87
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments - Subjects in Nivolumab-plus-Chemotherapy (XELOX or FOLFOX) Arm 
(CA209649)
Procedure
Nivolumab-
plus-XELOX 
and 
Nivolumab-
plus-
FOLFOX 
Cycle 1 Day 1 
(C1D1)
Nivolumab-plus-
XELOX 
Cycle 2 and 
beyond
(Every 3 weeks)
on Day 1
Nivolumab-plus-
FOLFOX
Cycle 2 and 
beyond
(Every 2 weeks)
on Day 1a
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
Efficacy Assessments
Tumor Imaging Assessment
See Note
See Note
CT/MRI scan of chest, abdomen, pelvis, and any 
clinically indicated sites.
Every 6 weeks (7 days) from first dose up to and 
including Week 48, then every 12 weeks (7 days) 
regardless of treatment schedule until disease progression 
(unless treatment beyond PD is permitted; see 
Section 4.5.1.6), or the subject withdraws consent, 
whichever comes first. Subjects who discontinue study 
treatment for reasons other than PD will continue to have 
tumor assessments until their disease progresses or they 
withdraw consent.
Use same imaging method as was used at 
screening/baseline
Collection of biomarker sampling 
data
Outcomes Research Assessments
FACT-Ga
X
See Note
See Note
Assessed every 6 weeks (3 days) from C1D1, regardless 
of treatment schedule; if administered on a dosing day, 
assessment should take place prior to any other study 
procedures.
EQ-5D-3L
X
Health Care Resource Utilization
X
X
X
Revised Protocol No.: 09
Date: 16-Sep-2019
88
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments - Subjects in Nivolumab-plus-Chemotherapy (XELOX or FOLFOX) Arm 
(CA209649)
Procedure
Nivolumab-
plus-XELOX 
and 
Nivolumab-
plus-
FOLFOX 
Cycle 1 Day 1 
(C1D1)
Nivolumab-plus-
XELOX 
Cycle 2 and 
beyond
(Every 3 weeks)
on Day 1
Nivolumab-plus-
FOLFOX
Cycle 2 and 
beyond
(Every 2 weeks)
on Day 1a
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
Study Drug
Randomization
X
Contact IRT for randomization
Dispense Study Treatment
X
X
X
First dose to be administered within 3 calendar days after 
randomization. Nivolumab and chemotherapy (XELOX or 
FOLFOX) should be administered on the same day.

Nivolumab dose schedule: in the nivolumab-plus-
XELOX arm (every-3-week dosing), nivolumab may 
be administered within 3 days before or after the 
scheduled date if necessary, but subjects may be 
dosed no less than 18 days between doses; in the 
nivolumab-plus-FOLFOX arm (every-2-week 
dosing), nivolumab may be administered up to 2 days 
before or 3 days after the scheduled date if necessary, 
but subjects may be dosed no less than 12 days 
between doses.
Nivolumab 480 mg should be given  2 weeks following 
the last administration of 240 mg, or 3 weeks following 
the last administration of 360 mg. Nivolumab 480 mg 
may be administered up to 3 days before or 3 days after 
Revised Protocol No.: 09
Date: 16-Sep-2019
89
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-3:
On-Treatment Assessments - Subjects in Nivolumab-plus-Chemotherapy (XELOX or FOLFOX) Arm 
(CA209649)
Procedure
Nivolumab-
plus-XELOX 
and 
Nivolumab-
plus-
FOLFOX 
Cycle 1 Day 1 
(C1D1)
Nivolumab-plus-
XELOX 
Cycle 2 and 
beyond
(Every 3 weeks)
on Day 1
Nivolumab-plus-
FOLFOX
Cycle 2 and 
beyond
(Every 2 weeks)
on Day 1a
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
the scheduled date, if necessary. Subjects may be dosed 
no less than 25 days between doses.

XELOX dose schedule: see Table 4.6.1-1. Subsequent 
XELOX doses may be administered within dosing 
windows per package insert or local standard.

FOLFOX dose schedule: see Table 4.6.1-2. 
Subsequent FOLFOX doses may be administered 
within dosing windows per package insert or local 
standard.
Vials may be assigned up to 3 calendar days prior to every 
dose date.
a For subjects in nivo-plus-chemotherapy arm, a 480 mg Q4W nivolumab treatment regimen will be permitted when all chemotherapy is discontinued  and 
nivolumab is continued alone, subjects in this arm must be in the study for a minimum of 6 months from Cycle 1, Day 1 before switching to 480 mg Q4W 
nivolumab. For subjects receiving nivolumab 480 mg Q4W alone, schedule of study procedures will be aligned with dosing visits (every 4 weeks on Day 1).
Laboratory test should be done prior each dose. TSH (with reflexive Free T4 and Free T3; Total T3/T4 are acceptable if Free T3/T4 are not available) is 
acceptable to perform at alternative dose.
Revised Protocol No.: 09
Date: 16-Sep-2019
90
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-4:
On-Treatment Assessments - Subjects in Chemotherapy (XELOX or FOLFOX) Arm (CA209649)
Procedure
XELOX and 
FOLFOX 
Cycle 1 Day 1 
(C1D1)
XELOX 
Cycle 2 and 
beyond
(Every 3 weeks)
on Day 1
FOLFOX
Cycle 2 and
beyond
(Every 2 weeks)
on Day 1
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
Safety Assessments
Targeted Physical Examination
X
X
X
To be performed within 72 hours of dosing.
Vital Signs
X
X
X
Obtain vital signs within 72 hours prior to dose. 
Including BP, heart rate and temperature.
Weight, BSA and ECOG 
Performance Status
X
X
X
Within 72 hours of dosing. See protocol Appendix 3 for 
ECOG Performance Status scale
Adverse Events Assessment
Continuously
Assessed using NCI CTCAE v.4
Serious Adverse Event (SAE)
Continuously
Assessed using NCI CTCAE v.4
Review of concomitant 
medications
X
X
X
-
Laboratory Tests
See Note
See Note
See Note
XELOX: Within 72 hours prior to each dose.
FOLFOX: Within 72 hours prior to each dose through 
Week 23 and every alternate dose thereafter. 
Include CBC w/differential, ALT, AST, total bilirubin, 
BUN or serum urea level, creatinine, Ca, Na, K, Cl, LDH 
and glucose. 
Note: Laboratory tests do not need to be repeated on 
C1D1 if performed within 14 days prior to first dose.
Pregnancy Test (WOCBP only)
X
See Note
See Note
Serum or urine within 24 hours prior to the initial 
administration of study drug and then every 4 weeks 
(± 7 days) regardless of dose delays; if collected with a 
dosing visit, then obtain within 24 hours prior to 
administration of study drug: urine or serum.
Revised Protocol No.: 09
Date: 16-Sep-2019
91
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-4:
On-Treatment Assessments - Subjects in Chemotherapy (XELOX or FOLFOX) Arm (CA209649)
Procedure
XELOX and 
FOLFOX 
Cycle 1 Day 1 
(C1D1)
XELOX 
Cycle 2 and 
beyond
(Every 3 weeks)
on Day 1
FOLFOX
Cycle 2 and
beyond
(Every 2 weeks)
on Day 1
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
Efficacy Assessments
Tumor Imaging Assessment
See Note
See Note
CT/MRI scan of chest, abdomen, pelvis, and any 
clinically indicated sites.
Every 6 weeks (7 days) from first dose up to and 
including Week 48, then every 12 weeks (7 days) 
regardless of treatment schedule until disease progression 
or the subject withdraws consent, whichever comes first. 
Subjects who discontinue study treatment for reasons 
other than PD will continue to have tumor assessments 
until their disease progresses or they withdraw consent.
Use same imaging method as was used at 
screening/baseline
Collection of biomarker sampling 
data
Outcomes Research Assessments
FACT-Ga
X
See Note
See Note
Assessed every 6 weeks (3 days) from C1D1, 
regardless of treatment schedule; if administered on a 
dosing day, assessment should take place prior to any 
other study procedures.
EQ-5D-3L
X
Health Care Resource Utilization
X
X
X
Revised Protocol No.: 09
Date: 16-Sep-2019
92
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-4:
On-Treatment Assessments - Subjects in Chemotherapy (XELOX or FOLFOX) Arm (CA209649)
Procedure
XELOX and 
FOLFOX 
Cycle 1 Day 1 
(C1D1)
XELOX 
Cycle 2 and 
beyond
(Every 3 weeks)
on Day 1
FOLFOX
Cycle 2 and
beyond
(Every 2 weeks)
on Day 1
Note
*Treatment till PD, unacceptable toxicity, withdraw 
from IC
Study Drug
Randomization
X
Contact IRT for randomization
Dispense Study Treatment
X
X
X
First dose to be administered within 3 calendar days after 
randomization.
XELOX dose schedule: see Table 4.6.1-1. Subsequent 
XELOX doses may be administered within dosing 
windows per package insert or local standard.
FOLFOX dose schedule: see Table 4.6.1-2. Subsequent 
FOLFOX doses may be administered within dosing 
windows per package insert or local standard.
Vials may be assigned up to 3 calendar days prior to 
every dose date.
Revised Protocol No.: 09
Date: 16-Sep-2019
93
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-5:
Follow-Up Procedural Outline - All Subjects (CA209649)
Procedure
Follow-up Visits 1 and 2
FU1: 30 days (7 days) 
after last dose
FU2: 84 days (7 days) 
after FU1
Survival Follow-Up Visits
every 3 months (14 
days) from FU2
Notes
Safety Assessments
Physical Examination
X
Adverse Events Assessment
X
Assessed using NCI CTCAE v.4
Review of Subsequent Cancer Therapy
X
X
Additional subsequent cancer therapy details such as 
regimen, setting of the regimen, line of therapy, start 
date and end date of each regimen, best response to the 
regimen and date of progression after second line 
therapy will be collected. 
The above information will be also collected during 
survival follow up period
Review of Concomitant Medications
X
Laboratory Tests
See Note
Include CBC w/differential, ALT, AST, total bilirubin, 
BUN or serum urea level, creatinine, Ca, Na, K, Cl, 
LDH and glucose. 
If there are ongoing AE, monthly lab tests will be 
conducted till FU2.
Pregnancy Test (WOCBP only)
See Note
Serum or urine, only for FU1, unless testing is required 
for a longer period, per local regulations.
Efficacy Assessments
Tumor Imaging Assessment
See Note
See Note
For subjects who discontinue study drug for reasons 
other than PD, follow-up scans should be performed 
every 6 weeks (7 days) up to and including Week 48, 
then every 12 weeks (7 days) until PD, lost to 
follow-up, or withdrawal of consent.
Radiographic assessments should not be delayed until 
follow-up visits 1 & 2.
Revised Protocol No.: 09
Date: 16-Sep-2019
94
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Table 5.1-5:
Follow-Up Procedural Outline - All Subjects (CA209649)
Procedure
Follow-up Visits 1 and 2
FU1: 30 days (7 days) 
after last dose
FU2: 84 days (7 days) 
after FU1
Survival Follow-Up Visits
every 3 months (14 
days) from FU2
Notes
CT/MRI scan of chest, abdomen, pelvis, and any 
clinically indicated sites. 
Use same imaging method as was used at 
screening/baseline.
Outcomes Research Assessments
GaCS from the FACT-Ga
X
See Note
Every 3 months (14 days) after FU2, via a phone 
contact or in-person visit.
FACT-G7
X
EQ-5D-3L
X
Health Care Resource Utilization
X
Collection of biomarker sampling
Subject Status
Survival status
X
X
Every 3 months (14 days) or more frequently as 
needed after FU2, may be accomplished by in-person 
visit or phone contact.
Revised Protocol No.: 09
Date: 16-Sep-2019
95
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
5.1.1
Retesting During Screening or Lead-in Period
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (i.e., the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-1, Screening Procedural 
Outline, may be repeated in an effort to find all possible well-qualified subjects. Consultation with 
the Medical Monitor may be needed to identify whether repeat testing of any particular parameter 
is clinically relevant.
5.2
Study Materials

NCI CTCAE version 4

Nivolumab IB

Ipilimumab IB

Pharmacy Binder

Laboratory manuals for collection and handling of blood (including biomarker and 
immunogenicity) and tissue specimens

Site manual for operation of IRT system, including enrollment/randomization worksheets

Site manual for imaging process and requirements

Manual for entry of local laboratory data

Serious Adverse Events (or eSAE) case report form pages

Subject Questionnaires: FACT-Ga (GaCS, FACT-G7), EQ-5D-3L

Pregnancy Surveillance Forms

RECIST 1.1 pocket guide.
5.3
Safety Assessments
5.3.1
Screening Safety Assessments
At screening, a medical history will be obtained to capture relevant underlying conditions. The 
screening examinations should include physical examination, weight, height, BSA, ECOG 
Performance Status, ECG, and assessment of signs and symptoms. Vital signs (blood pressure 
[BP], heart rate and temperature) will be obtained at the screening visit and within 72 hours prior 
to first dose.
Screening local laboratory assessments should be done within 14 days prior to randomization and 
are to include: CBC with differential, chemistry panel including LFTs (ALT, AST, total bilirubin, 
alkaline phosphatase), BUN or serum urea level, creatinine, Ca, Na, K, Cl, LDH, fasting glucose 
and albumin. The endocrine panel including TSH, free T3, and free T4 (Total T3/T4 are acceptable 
if Free T3/T4 are not available). Hep B/C testing (HBV HBsAG, HCV antibody or HCV RNA) 
should be done within 28 days prior to randomization.
Revised Protocol No.: 09
Date: 16-Sep-2019
96
Approved
10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
Pregnancy tests for WOCBP must be performed at the screening visit and within 24 hours prior to 
the initial administration of study drug. 
Tumor tissue samples, recent or archival, must be available within 6 months prior to randomization 
and sent to a central laboratory for PD-L1 status and biomarker analysis. See Section 3.1.1 for 
details. 
Serious AEs are to be collected as soon as the informed consent form is signed.
5.3.2
On-Treatment Safety Assessments
Subjects will be evaluated for safety if they have received any study drug. Adverse event (AEs and 
SAEs) assessments will be continuous during the treatment phase as well as during the first two 
safety follow-up visits. Once subjects reach the survival follow-up phase, either in-person visits or 
documented telephone calls/email correspondence to assess the subject’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: CBC with differential, LFTs (ALT, AST, total bilirubin), BUN or serum urea level, 
creatinine, Ca, Na, K, Cl, LDH and glucose.
Thyroid function testing (TSH with reflexive fT3 and fT4; Total T3/T4 are acceptable if Free 
T3/T4 are not available) is to be done every 6 weeks (7 days) starting at C1D1 (every 3 cycles 
for subjects receiving nivolumab at 240 mg Q2W and every 2 cycles for subjects receiving 
nivolumab at 360 mg Q3W or 480 mg Q4W).
On-treatment pregnancy tests should be performed as per the schedule in Table 5.1-2, Table 5.1-
3, and Table 5.1-4.
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 subject shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, or 
fever) consistent with possible pulmonary AEs, the subject should be immediately evaluated to 
rule out pulmonary toxicity, according to the suspected pulmonary toxicity management algorithm 
in the BMS-936558 (nivolumab) IB.
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 
Revised Protocol No.: 09
Date: 16-Sep-2019
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10.0
v
Approved
1.0
v


Clinical Protocol
CA209649
BMS-936558
nivolumab
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.3.3
Follow-up Safety Assessments
Adverse events will be assessed and subsequent cancer therapy will be reviewed as described in
Table 5.1-5. A physical examination will be performed at follow-up visits FU1 and FU2. 
Laboratory and pregnancy tests will be performed as described in Table 5.1-5.
5.3.4
Imaging Assessment for the Study
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.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.1. Baseline tumor 
assessments should be performed within 28 days prior to randomization, utilizing CT or MRI. In 
addition to chest, abdomen, and pelvis, clinically indicated sites as determined by the treating 
investigator should be assessed at baseline. Subsequent assessments should include all sites that 
were assessed at baseline and should use the same imaging method as was used at baseline. 
Subjects will be evaluated for disease progression every 6 weeks from the date of first dose 
(± 7 days) up to and including Week 48, and then every 12 weeks (± 7 days) thereafter, regardless 
of treatment schedule, until disease progression (unless treatment beyond PD is permitted; see 
Section 4.5.1.6), or the subject withdraws consent, whichever comes first. Subjects who 
discontinue study treatment for reasons other than PD will continue to have tumor assessments 
until their disease progresses or they withdraw consent.
Contrast-enhanced CT with PO/IV contrast or contrast-enhanced MRI are the preferred imaging 
modalities for assessing radiographic tumor response. If a subject has a known allergy to contrast 
material, local prophylaxis standards may be used to obtain the assessment with contrast if at all 
possible, or use the alternate modality. In cases where contrast is strictly contraindicated, a 
non-contrast scan will suffice. Should a subject have a contraindication for CT IV contrast, a 
non-contrast CT of the chest and a contrast enhanced MRI of the abdomen, pelvis, and clinically 
indicated sites may be obtained. Every attempt should be made to image each subject using an 
identical acquisition protocol and the same method for all imaging time points.
Tumor measurements should be made by the same investigator or radiologist for each assessment 
whenever possible. Change in tumor measurements and tumor response will be assessed by the 
Investigator using the RECIST 1.1 criteria (Appendix 4). Correction: the Verification of Response 
stated in the Appendix 4.1.2 should be confirmation of PR and CR is required ≥ 4 weeks to ensure 
that the responses identified are not the result of measurement error.
All radiologic imaging from this study will be transmitted to a centralized imaging core laboratory 
for Blinded Independent Central Review (BICR).
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5.4.1
Independent Review of Progression 
The clinical management of subjects during the study will be based upon local radiologic tumor 
measurements. Tumor assessments for each subject should be submitted to the radiology vendor 
as they are performed, on an ongoing basis. The blinded, independent radiologists will review all 
available tumor assessments for that given subject and determine if RECIST 1.1 criteria for 
progression have been met. 
If clinically acceptable, subsequent therapy should begin only after RECIST 1.1 progression has 
been assessed by BICR. Subjects who start palliative local therapy or subsequent therapy without 
prior assessment of RECIST 1.1 progression by central review, the BICR must continue tumor 
assessments (if clinically feasible) according to the protocol-specified schedule and submit them 
to the third-party radiology vendor. When RECIST 1.1 progression is assessed by the investigator 
(whether assessed before or after the start of palliative local therapy or subsequent therapy), the 
BICR must be requested. Tumor assessments may be discontinued when the independent 
radiologist assesses the subject to have met RECIST 1.1 criteria for progression.
In addition, subjects receiving treatment beyond progression must continue tumor assessments 
until such treatment has been discontinued.
Details of the Independent Review of Progression process will be specified in the BICR charter.
5.5
Pharmacokinetic Assessments
Pharmacokinetic (PK) and immunogenicity (IMG) assessment data will be collected from study 
subjects assigned to the nivolumab-plus-ipilimumab and nivolumab-plus-chemotherapy arms at 
the time points indicated in Table 5.5-1, Table 5.5-2, and Table 5.5-3. All time points are relative 
to the start of study drug administration. All on-treatment time points are intended to align with 
days on which study drug is administered; if dosing occurs on a different day, the PK and IMG 
sampling should be adjusted accordingly. 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. Further details of sample collection, processing, and shipment will be provided in the 
laboratory procedures manual.
Table 5.5-1:
Pharmacokinetic and Immunogenicity Sampling Schedule for the 
Nivolumab + Ipilimumab Arm followed for Nivolumab 
monotherapy 240 mg every 2 weeks or 480 mg every 4 weeks
Study 
Cycle/Day
Cycles 
1 - 4 = every 
3 weeks
Cycle 5 and 
beyond = every 
2 weeks
Event 
(Relative 
to Start of 
Nivolumab 
Infusion)
Time 
(Relative to 
Start of 
Nivolumab 
Infusion)
Hour:Min
Nivolumab 
PK Blood 
Sample
Nivolumab 
IMG Blood 
Sample
Ipilimumab 
PK Blood 
Sample
Ipilimumab 
IMG Blood 
Sample
Cycle 1 Day 1 
Predosea
00:00
X
X
X
X
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Table 5.5-1:
Pharmacokinetic and Immunogenicity Sampling Schedule for the 
Nivolumab + Ipilimumab Arm followed for Nivolumab 
monotherapy 240 mg every 2 weeks or 480 mg every 4 weeks
Study 
Cycle/Day
Cycles 
1 - 4 = every 
3 weeks
Cycle 5 and 
beyond = every 
2 weeks
Event 
(Relative 
to Start of 
Nivolumab 
Infusion)
Time 
(Relative to 
Start of 
Nivolumab 
Infusion)
Hour:Min
Nivolumab 
PK Blood 
Sample
Nivolumab 
IMG Blood 
Sample
Ipilimumab 
PK Blood 
Sample
Ipilimumab 
IMG Blood 
Sample
Cycle 2 Day 1
Predosea
00:00
X
X
X
X
Cycle 4 Day 1
Predosea
00:00
X
X
X
X
Cycle 5 Day 1
Predosea
00:00
X
X
X
X
Cycle 11 Day 1
Predosea
00:00
X
X
X
X
Cycle 17 Day 1
Predosea
00:00
X
X
Cycle 23 Day 1
Predosea
00:00
X
X
Cycle 35 Day 1
Predosea
00:00
X
X
Cycle 47 Day 1
Predosea
00:00
X
X
a All predose samples should be taken just prior to the start of nivolumab infusion (preferably within 30 minutes).
Table 5.5-2:
Pharmacokinetic and Immunogenicity Sampling Schedule for the 
Nivolumab + Chemotherapy Arm - Q3W Dosing with XELOX
Study Cycle/Day
Nivolumab + XELOX= 
every 3 weeks
Event 
(Relative to Start 
of Nivolumab 
Infusion)
Time 
(Relative to Start of 
Nivolumab Infusion)
Hour:Min
Nivolumab 
PK Blood 
Sample
Nivolumab 
IMG Blood 
Sample
Cycle 1 Day 1 
Predosea
00:00
X
X
Cycle 2 Day 1
Predosea
00:00
X
X
Cycle 5 Day 1
Predosea
00:00
X
X
Cycle 11 Day 1
Predosea
00:00
X
X
Cycle 17 Day 1
Predosea
00:00
X
X
Cycle 25 Day 1
Predosea
00:00
X
X
Cycle 33 Day 1
Predosea
00:00
X
X
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a All predose samples should be taken just prior to the start of nivolumab infusion (preferably within 30 minutes). If 
nivolumab is discontinued, then PK and IMG samples should be collected for the next 2 cycles scheduled for 
PK/IMG sampling following discontinuation.
Table 5.5-3:
Pharmacokinetic and Immunogenicity Sampling Schedule for the 
Nivolumab + Chemotherapy Arm - Q2W Dosing with FOLFOX
Study Cycle/Day
Nivolumab + FOLFOX= 
every 2 weeks
Event 
(Relative to Start 
of Nivolumab 
Infusion)
Time 
(Relative to Start of 
Nivolumab Infusion)
Hour:Min
Nivolumab 
PK Blood 
Sample
Nivolumab 
IMG Blood 
Sample
Cycle 1 Day 1 
Predosea
00:00
X
X
Cycle 2 Day 1
Predosea
00:00
X
X
Cycle 3 Day 1
Predosea
00:00
X
X
Cycle 7 Day 1
Predosea
00:00
X
X
Cycle 9 Day 1
Predosea
00:00
X
X
Cycle 17 Day 1
Predosea
00:00
X
X
Cycle 25 Day 1
Predosea
00:00
X
X
Cycle 37 Day 1
Predosea
00:00
X
X
Cycle 49 Day 1
Predosea
00:00
X
X
a All predose samples should be taken just prior to the start of nivolumab infusion (preferably within 30 minutes). If 
nivolumab is discontinued, then PK and IMG samples should be collected for the next 2 cycles scheduled for 
PK/IMG sampling following discontinuation.
5.5.1
Pharmacokinetic and Immunogenicity Collection and Processing 
Pharmacokinetic samples will be analyzed for nivolumab/ipilimumab by a validated ligand 
binding 
assay. 
Immunogenicity 
samples 
will 
be 
analyzed 
for 
anti-nivolumab 
antibodies/anti-ipilimumab antibodies by a validated IMG assay; samples may also be analyzed 
for neutralizing antibodies by a validated method. Serum samples may be analyzed by an
exploratory method that measures ADAs for technology exploration purposes; exploratory results 
will not be reported. Serum samples designated for PK or biomarker assessments may also be used 
for IMG analysis if required (eg, insufficient volume for complete IMG assessment or to follow 
up on suspected IMG-related AE).
Designated staff of Bristol-Myers Squibb Research & Development may be unblinded (obtain the 
randomization codes) prior to database lock to facilitate the bioanalytical analysis of 
pharmacokinetic samples and immunogenicity. A bioanalytical scientist in the Bioanalytical 
Sciences department of Bristol-Myers Squibb Research & Development (or a designee in the 
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external central bioanalytical laboratory) will be unblinded to (may obtain) the randomized 
treatment assignments in order to minimize unnecessary bioanalytical analysis of samples.
5.6
Biomarker Assessments
Peripheral blood and tumor tissue will be collected prior to therapy. Peripheral blood samples will 
also be collected at selected timepoints on treatment, up to 5 days prior to dosing. If a biopsy or 
surgical resection is performed at the time of progression or suspected progression, tumor samples 
(block or slides) should be submitted for analysis. If biomarker samples are drawn but study 
drug(s) is not administered, samples will be retained (e.g., if an event occurs between biomarker 
sampling and dosing that prevents dosing from taking place). A detailed description of each assay 
system is described below.
 
 
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5.6.1
Tumor Samples
Tumor specimens will be obtained from consenting subjects prior to treatment to characterize 
immune cell populations and expression of selected tumor markers. Tumor tissue (block or slides) 
must be available for submission prior to randomization. In situations where on-treatment biopsies 
or surgeries are performed, tumor samples should be sent for central pathology reading.
5.6.1.1
Tumor Sample Collection Details
Collection of tumor tissue at diagnostic surgery is required for study eligibility. If clinically 
appropriate, additional biopsies obtained at any time, eg, if progression is suspected, may also be 
collected. 
Biopsy samples from resections should be fixed in 10% neutral-buffered formalin for 24 to 
48 hours prior to paraffin embedding. Tumor tissue samples should not be shipped in formalin as 
the temperature and length of fixation cannot be controlled during shipping.
An assessment of tissue quality by a pathologist is strongly encouraged at the time of the 
procedure. The tumor tissue that is obtained will be formalin fixed and paraffin embedded.
Sample shipments should include a completed requisition form containing collection date, 
collection method, primary/metastatic, site, fixation conditions, and a copy of the pathology report, 
if available.
Detailed instructions of the obtaining, processing, labeling, handling, storage and shipment of 
specimens will be provided in a separate Procedure Manual at the time of study initiation.
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5.6.1.7
Microsatellite Instability Testing
MSI-H (Microsatellite Instability-High) in tumors refers to changes in 2 or more of the 5 National 
Cancer Institute-recommended panels of microsatellite markers in tumor tissue compared to a 
reference whole blood sample (baseline SNP collection). The original (1997) Bethesda guidelines 
proposed a panel of 5 microsatellite markers for the uniform analysis of MSI in hereditary 
nonpolyposis colorectal cancer (HNPCC). This panel, which is referred to as the Bethesda Panel, 
included 2 mononucleotide (BAT-25 and BAT-26) and 3 dinucleotide (D5S346, D2S123, and 
D17S250) repeats.90 Individual testing sites may utilize a slightly different panel of markers 
incorporating alternative mononucleotide or dinucleotide markers. Regardless of the panel of 
markers, samples with instability in 2 or more of these markers are defined as MSI-High (MSI-H), 
whereas those with one unstable marker are designated as MSI-Low (MSI-L). Samples with no 
detectable alterations are MSI-stable (MSS). 
Alternative assay platforms could also be used for MSI testing.
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5.7
Outcomes Research Assessments
Subjects will be asked to complete the EQ-5D-3L and FACT-Ga before any clinical activities are 
performed during the treatment and follow-up phases. Questionnaires will be provided in the 
subject’s preferred language, if available. Table 5.1-2, Table 5.1-3, Table 5.1-4, and Table 5.1-5
provide information regarding the timing of patient-reported outcomes assessments.
Subjects’ reports of general health status will be measured using the EQ-5D-3L. 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 to 243 health states. Empirically derived weights can be applied to an individual’s 
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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 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 FACT-Ga questionnaire and selected components, including the FACT-G7 and GaCS, will 
be used to assess the effects of underlying disease and its treatment on health-related quality of life 
(HRQoL) for patients.   
As a generic cancer-related core, the FACT-Ga includes the 27-item FACT-General (FACT-G) to 
assess symptoms and treatment-related effects impacting physical well-being (PWB; seven items), 
social/family well-being (SWB; seven items), emotional well-being (EWB; six items), and 
functional well-being (FWB; seven items). Seven of these items comprise the FACT-G7, an 
abbreviated version of the FACT-G that provides a rapid assessment of general HRQoL in cancer 
patients. 
In addition to the FACT-G, The FACT-Ga includes a 19-item disease-specific GaCS that assesses 
additional disease specific symptoms and impacts relating to pain, reflux, dysphagia, eating 
difficulties, tiredness, weakness, interference, and difficulty planning. Each FACT-Ga item is rated 
on a five-point scale ranging from 0 (not at all) to 4 (very much).
Scores for the PWB, FWB, SWB, and EWB subscales can be combined to produce a FACT-G 
total score, which provides an overall indicant of generic HRQoL. The FACT-G and GaCS scores, 
can be combined to produce a total score for the FACT-Ga, which provides a composite measure 
of general and targeted HRQoL. Higher scores indicate better HRQoL. The full FACT-Ga will be 
administered to subjects during the on-treatment phase and at follow up visits 1 and 2.  However, 
to minimize subject response and administrative burden, only the FACT GaCS and FACT-G7 will 
be administered during the survival follow-up phase. 
In addition to the aforementioned patient-reported outcomes, health care resource utilization data 
will be collected for all randomized subjects using an internal case report form developed for use 
in previous trials. The form, which is completed by study staff, records information about hospital 
admissions, including number of days spent in various wards and discharge diagnosis, as well as 
non-protocol specified visits related to study therapy, including date of visit, reason for visit, and 
type of visit. The health care resource utilization data will be used to support subsequent economic 
evaluations.
5.8
Other Assessments
Not applicable.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug 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 
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temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following:

Related: There is a reasonable causal relationship between study drug administration and the 
AE.

Not related: There is not a reasonable causal relationship between study drug administration 
and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. Care should be taken not to introduce bias when collecting 
AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in the context 
of known adverse events, when appropriate for the program or protocol.
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.
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).
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6.1
Serious Adverse Events
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.
A 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 subject 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)

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 subject or may require intervention [eg, 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 6.6 for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE. 
Pregnancy, Section 6.4, and potential drug induced liver injury (DILI), Section 6.6, must follow 
the same transmission timing and processes to BMS as used for SAEs. (See Section 6.1.1 for 
reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported) (see Section 6.1.1 for reporting details).
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 
(eg, 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
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
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (eg, 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).
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.
6.1.1
Serious Adverse Event Collection and Reporting
Section 5.6.1 in the nivolumab and ipilimumab IBs presents the Reference Safety Information to 
determine expectedness of serious adverse events for expedited reporting. Following the subject’s 
written consent to participate in the study, information on 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 from the time of signing the consent, including those 
thought to be associated with protocol-specified procedures and within 100 days of discontinuation 
of dosing. For subjects randomized/assigned to treatment and never treated with study drug, SAE 
information should be collected for 30 days from the date of randomization.
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. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
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If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or 
designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE Report 
Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The required
method for SAE data reporting collection is through the eCRF. The paper SAE/pregnancy 
surveillance forms are only intended as a back-up option when the eCRF system is not functioning. 
When paper forms are used, the original paper forms are to remain on site. In this case, the paper 
forms are to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list.
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 drug 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.
BMS 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.
6.2
Nonserious Adverse Events
A nonserious adverse event is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. 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 subjects. 
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Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug 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.
Information on all nonserious adverse events (not only those deemed to be treatment-related) 
should be collected continuously during the treatment period and for a minimum of 100 days 
following discontinuation of study treatment. 
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the subject’s case report form.
6.3
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 subject to have study drug discontinued 
or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject 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 Sponsor or 
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 Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg, dose 
tapering if necessary for subject safety). Please call the Sponsor or designee within 24 hours of 
awareness of the pregnancy.
The investigator must immediately notify the Sponsor or designee of this event and complete and 
forward a Pregnancy Surveillance Form to Sponsor or designee within 24 hours of awareness of 
the event and in accordance with SAE reporting procedures described in Section 6.1.1. 
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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 BMS 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.
6.5
Overdose
All occurrences of overdose must be reported as SAEs (see Section 6.1.1 for reporting details).
6.6
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 6.1.1 for reporting details).
Potential drug induced liver injury is defined as: 

AT (ALT or AST) elevation > 3 times upper limit of normal (ULN), 

AND

Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 

AND

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.
6.7
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.
6.7.1
Adverse Events of Interest
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 subject’s case report form.
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
An independent Data Monitoring Committee (DMC) will be utilized. A DMC will be established 
to provide oversight of safety and efficacy considerations in CA209649. Additionally, the DMC 
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will provide advice to the sponsor regarding actions the committee deems necessary for the 
continuing protection of subjects enrolled in the study. The DMC will be charged with assessing 
such actions in light of an acceptable benefit/risk profile for nivolumab, nivolumab plus 
ipilimumab and nivolumab plus chemotherapy. The DMC will act in an advisory capacity to BMS 
and will monitor subject 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.
Details of the DMC responsibilities and procedures will be specified in the DMC charter.
As of 05-June-2018, the nivolumab plus ipilimumab arm was closed to enrollment based on the 
DMC recommendation. Subjects randomized to treatment in this arm prior to or on 05-June-2018 
will continue to receive treatment with study drugs per protocol, and the study data will remain 
blinded until planned primary analysis.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
8.1.1
Randomization Schema
The original study design (before Amendment 08) had 2 arms, with subjects being randomized in 
a 1:1 ratio to the nivolumab plus ipilimumab or to the oxaliplatin plus fluoropyrimidine arm 
(XELOX or FOLFOX; arm will be further referred to as chemotherapy arm). Amendment 08 
added a new arm: nivolumab in combination with oxaliplatin plus fluoropyrimidine (XELOX or 
FOLFOX; arm will be further referred to as nivolumab plus chemotherapy arm). The IRT switched 
to a 1:1:1 randomization at all the participating sites when this third arm was ready to be opened 
on 27-Mar-2017. Up until that point, there were 83 subjects randomized in the 1:1 randomization 
to nivolumab plus ipilimumab and chemotherapy arm. In Amendment 08, it was planned to 
randomize 1266 subjects at 1:1:1 ratio to nivolumab plus ipilimumab, chemotherapy and 
nivolumab plus chemotherapy arms. The total number of subjects to be randomized was planned 
to be 1349.
Newly available internal and external data suggested a stronger predictability of PD-L1 CPS than 
TPS of immunotherapy treatment effects (See Section 1.1.13). However, uncertainty still exists of 
CPS at different cutoffs when extrapolated to first line (1L) metastatic setting in GC and GEJ. To 
ensure sufficient sample size for evaluating the correlation of efficacy and different CPS cutoffs 
and to keep continuity of enrollment of the study, on 29-May-2018, Amendment 19 was approved
to allow additional 300 subjects to be randomized under 1:1:1 ratio for a total sample size of 1566 
to the 3 treatment arms.
Per DMC recommendation, randomization to the nivolumab plus ipilimumab arm was stopped on 
05-June-2018. The subjects who were already randomized to treatment in this arm prior to or on 
05-June-2018 continued to receive study treatment per protocol, and the study data remained
blinded for the planned analysis (see Section 1.5). As such, the 1:1:1 randomization was carried 
through on 05-Jun-2018. These changes were implemented in Amendment 20. At this point, a total 
of 1098 subjects were randomized under 1:1:1 ratio. In addition there were 83 subjects randomized 
to nivolumab plus ipilimumab and to chemotherapy arms (prior to Amendment 08). Following 
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Amendment 20, subjects were to be randomized in 1:1 ratio to either the nivolumab plus 
chemotherapy or the chemotherapy arm.
 
 Therefore, the enrollment was extended 
to ensure that the study was appropriately powered for PFS and OS primary endpoints in the 
CPS population. To allow for this, Amendment 26 increased the total sample size from 1649
to approximately 2005. This resizing of the total population was to ensure that the sample size of 
the enriched population for the primary analyses (subjects with CPS was the same as was
specified in Amendment 23 to maintain the same power under the statistical assumptions as stated 
in Amendment 23.
The accrual was completed in May 2019 and in total 2032 subjects were randomized. It is 
estimated that 1582 subjects were concurrently randomized to nivolumab plus chemotherapy and 
to chemotherapy and that 815 subjects were concurrently randomized to nivolumab + ipilimumab 
and chemotherapy (see Section 8.1.3).
Table 8.1.1-1 presents the randomization schema and sample size.
Table 8.1.1-1:
Randomization Allocation and Sample Size
Protocol Periods
Randomization allocation
Number of 
Randomized Subjects
Current/ Cumulative
First patient randomized -
Amendment 8
1:1 (Nivolumab +Ipilimumab : Chemotherapy)
83/83
Amendment 08 -
Amendment 20
1:1:1 (Nivolumab + Ipilimumab : Chemotherapy: 
Nivolumab + Chemotherapy)
1098/1181
Amendment 20 to 
amendment 26
1:1 (Chemotherapy : Nivolumab + Chemotherapy)
468/1649
Amendment 26 to the end 
of enrollment
1:1 (Chemotherapy : Nivolumab + Chemotherapy)
383/2032
8.1.2
Changes of Statistical Analyses and Timing of Analyses in
Amendment 29
Per protocol Amendment 23 (November 2018), the primary population of both primary endpoints 
PFS and OS was changed to randomized subjects with PD-L1 CPS 5 and the PD-L1 CPS scoring 
process started for subjects already randomized in the study to date. In March 2019, the need for 
additional steps for the PD-L1 CPS scoring process was established (see Section 1.1.14) and 
consequently the expected completion date of PD-L1 CPS scoring will be delayed and is now 
projected to complete approximately 6 months or later after the completion of enrollment.
As discussed in Section 1.1.14, recent data in 1L GC Phase 3 study suggested a longer delay of 
separation of KM curves of I-O+ chemo vs chemo for PFS and OS76. These data suggested that a 
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longer follow-up would warrant the full capture of the treatment effect for the primary endpoints 
of PFS and OS in the N+CT vs CT.
Considering the delay of completion of PD-L1 CPS scoring, and the need to have longer minimum 
follow-up for PFS and OS to ensure data maturity, Amendment 29 documents the changes on the 
timing of PFS and OS analyses from event driven to time driven. In addition, Amendment 29 
specifically, documents the changes of the primary population of PFS. 
The primary analysis of PFS in all randomized subjects with PD-L1 CPS 5 will be conducted 
after a 12-month minimum follow-up (from the date last patient was concurrently randomized to 
N+CT or CT). The primary analysis of OS in all randomized subjects with PD-L1 CPS 5
includes one interim and final analysis. The interim analysis will be conducted after 12-month 
minimum follow-up along with the primary PFS analysis. The final OS analysis will be conducted 
after a 24-month minimum follow-up, ie, 12 months after the OS interim analyses.
The analysis of OS in N+I vs CT in all randomized subjects with PD-L1 CPS 5 will be conducted 
at approximately 36-month minimum follow-up (after the last patient was randomized to N+I or 
CT). This analysis will be at the time of the final analysis of N+CT vs CT.
The timing of the efficacy analyses is described in Table 8.1.2-1.
Table 8.1.2-1:
Timing of Analyses
Endpoints
Timing of Analysis
PFS N+CT vs CT
in all randomized 
subjects with PD-L1 
CPS 5
OS N+CT vs CT
in all randomized 
subjects with PD-L1 
CPS 5
OS N+I vs CT
in all randomized 
subjects with PD-L1 
CPS 5
12-month minimum FU
X
X (IA)
24-month minimum FUa
X (FA)
X
a FU: follow-up. Twenty-four months minimum follow-up from last patient randomized to N+CT or CT, corresponds 
to 36-month minimum follow-up for N+I vs CT.
For the primary analyses of the endpoints stated above, all events observed in the locked database 
will be used.
As of May 2019, study enrollment has been completed. Therefore in Amendment 29, the total 
sample size is fixed; however, the sample size for the primary population (subjects with PD-L1 
CPS 5 ) remains unknown as CPS scoring is still ongoing. While BMS has no knowledge of the 
actual prevalence of CPS 5 in this study, the prevalence is assumed to be 35% consistent with 
sample size and power calculations in Amendment 23. Sections 8.1.4 and 8.1.5 are updated to 
reflect design characteristics for time driven analyses and using 35% prevalence for PD-L1 
CPS 5. Once the PD-L1 CPS scoring is completed and data is available, the actual prevalence of 
PD-L1 CPS 5 will be assessed in pooled blinded fashion for all randomized subjects in this study. 
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The power statement of the primary endpoints of PFS and OS will be updated using the actual 
prevalence and documented in the final SAP prior to first database lock for efficacy analysis.
8.1.3
General Assumptions of Sample Size Determinations
Primary Endpoints Family:
For the comparison of nivolumab plus chemotherapy vs chemotherapy both PFS and OS are 
primary endpoints. 
Type I Error Splitting for Primary Endpoints Family:
For sample size calculation purpose, the family-wise error rate of 5% will be split as follows:
1. Comparison of PFS between nivolumab plus chemotherapy and chemotherapy in subjects with 
PD-L1 CPS with alpha of 2
2. Comparison of OS between nivolumab plus chemotherapy and chemotherapy in subjects with 
PD-L1 CPS with alpha of 
Population for Primary Endpoints:
As mentioned in Section 1.1.13 the population for the primary endpoints will be all randomized 
subjects with PD-L1 CPS . For the design purpose, the prevalence was assumed to be 35% of 
all randomized subjects.
Concurrently Randomized
For the comparison of nivolumab plus chemotherapy and chemotherapy only subjects who were 
randomized to those 2 arms concurrently will be used. This means subjects randomized to 
chemotherapy before the nivolumab plus chemotherapy arm was introduced will not be included 
in the analysis of this comparison. 
For the comparison of nivolumab + ipilimumab and chemotherapy only subjects who were 
randomized to those 2 arms concurrently will be used. This means subjects randomized to 
chemotherapy after the closure of nivolumab plus ipilimumab randomization will not be included 
in the analysis of this comparison.
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Figure 8.1.3-1:
Randomization Schema
Assumptions for Control Arm of Chemotherapy:
In previous protocol versions (up to amendment 20), PD-L1≥1% per TPS was assumed as negative 
prognostic factor (ie the median OS for chemotherapy was assumed to be smaller for subjects with
tumor PD-L1≥1% per TPS than for all randomized subjects). However, for PD-L1 CPS, recent 
data does not suggest such a negative prognostic effect for chemotherapy.62 Therefore, in 
Amendment 23, the OS and PFS distributions for the chemotherapy arm are assumed to be the 
same regardless of CPS cutoffs, eg, in PD-L1 CPS 5 and in all randomized subjects. 
The PFS and OS data from the external data14,18,91 were considered the most relevant to the studied 
chemotherapy arm (control). Therefore, the chemotherapy arm is assumed to have a 4-piece 
exponential distribution with a median PFS of 5.5 months (see Figure 8.1.3-2) and a 4-piece 
exponential distribution with a median OS of 11.1 months (see Figure 8.1.3-3).
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Figure 8.1.3-2:
PFS for Chemotherapy from External Data and Assumed 
Distribution for Chemotherapy
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Figure 8.1.3-3:
OS for Chemotherapy from External Data and Assumed Distribution 
for Chemotherapy
Statistical Software for Sample Size Calculation
Sample size calculations of the primary endpoints were based on simulations in EAST 6.4.1.
8.1.4
Sample Size: Nivolumab plus Chemotherapy vs Chemotherapy
Progression Free Survival
All concurrently randomized subjects to N+CT and CT arms with PD-L1 CPS 5 will be used for 
the PFS analysis. Given the delayed separation in the PFS distributions between pembrolizumab 
+ chemotherapy and chemotherapy,76 the PFS analysis will be conducted after a minimum of 
12 months follow-up after the last patient is randomized.
As such, the PFS analysis will be conducted after the following criteria are all met: 

CPS scoring by central laboratories is complete

a minimum follow-up of 12 months 
Based on the observed delay in the PFS KM curved of Pem+CT vs. CT, the HR is modelled as a 
2-piece hazard ratio with a delayed effect between 3 and 6 months (a HR of 1 versus chemotherapy 
for the first 3 or 6 months) followed by a constant HR of 0.56 (see Table 8.1.4-1). With 12 months 
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minimum follow-up it is expected that the number of events will range between 497 and 506
respectively and the power will range approximately between 99% and 60% with a Type I error of 
2% (two-sided) (See Table 8.1.4-2).
The primary PFS analysis will be based on all the events observed at time of database lock. 
Table 8.1.4-1:
Assumed PFS Hazard Rates and Hazard Ratios (Nivolumab plus 
Chemotherapy vs Chemotherapy)
Periods
Hazard Rates for 
Chemotherapy 
Hazard Ratios 
(3 months delay)
Hazard Ratios
(6 months delay)s
0-3 months
0.09
1
1
3-6 months
0.17
0.56
1
6-10 months
0.2
0.56
0.56
> 10 months
0.13
0.56
0.56
Table 8.1.4-2:
Summary of Sample Size Parameters and Schedule of Analyses for 
PFS (Nivolumab plus Chemotherapy vs Chemotherapy)
3 months Delay
6 months Delay
# subjects with PD-L1 CPS 5a
554
554
Hypothesized delayed period
3
6
Hypothesized HR after delayed 
period
0.56
0.56
Hypothesized median in control arm
5.5 months
5.5 months
Significance level (2-sided)
0.02
0.02
Enrollment Period (from start of 
1:1:1)
25.4 months
25.4 months
Minimum follow-up / Expected 
number of eventsa,b,c
12 months / 497
12 months / 506
Time of Analysis 
37.4 months
37.4 months
Powerb
99% 
60%
Average HRb
0.66
0.8
a Based on 35% prevalence of PD-L1 CPS5
b Results based on simulations.
c Number of events for the nivolumab plus chemotherapy vs. chemotherapy comparison in total.
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Overall Survival 
A delayed separation of at least 6 months between the OS distribution of pembrolizumab + 
chemotherapy and chemotherapy was observed.76 To fully capture the treatment effect, the interim 
and final analyses of OS will be conducted after a minimum follow up after the last patient 
randomized. 
The interim analysis will be conducted after at least 12 months minimum follow-up, and the final 
analysis will be conducted after at least 24 months minimum follow-up. 
With 24 months minimum follow-up at final analysis, it is expected that 466 events will be 
observed. With an average HR of 0.74 modelled as a 2-piece hazard ratio, a delayed effect with a 
HR of 1 versus chemotherapy for the first 6 months followed by a constant HR of 0.65 (see Table 
8.1.4-3) the power will be approximately 85% with a Type I error of 3% (two-sided) (See Table 
8.1.4-4).
For the OS interim and final analyses, all the events reported in the database at time of database 
lock will be used for the primary analyses.
Table 8.1.4-3:
Assumed OS Hazard Rates and Hazard Ratios (Nivolumab plus 
Chemotherapy vs Chemotherapy)
Periods 
Hazard Rates for 
Chemotherapy
Hazard Ratio
0-3 months
0.036
1
3-6 months
0.06
1
6-24 months
0.08
0.65
>24 months 
0.05
0.65
Table 8.1.4-4:
Summary of Sample Size Parameters and Schedule of Analyses 
for OS (Nivolumab plus Chemotherapy vs Chemotherapy)
# with PD-L1 CPS a
554
Hypothesized delayed period
6 months
Hypothesized HR after delayed period
0.65
Hypothesized median in control arm
11.1 months
Significance level (2-sided)
0.03
Enrollment Period (from start of 1:1:1)
25.4 months
INTERIM ANALYSIS #1 for OS
Minimum follow-up/Expected number of eventsa,b,c
12 months/395
Time of analysisd
37.4 months
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Table 8.1.4-4:
Summary of Sample Size Parameters and Schedule of Analyses 
for OS (Nivolumab plus Chemotherapy vs Chemotherapy)
Significance levele
0.0164
Power
64%
FINAL ANALYSIS
Minimum follow-up/Expected number of eventsa,b,c
24 months/466
Time of analysisd
49.4 months
Significance level
0.0252
Powerb
85%
Average HR
0.74
a Based on a 35% prevalence of PD-L1 CPS 
b Results based on simulations
c Number of events for the nivolumab plus chemotherapy vs. chemotherapy comparison in total.
d After first patient randomized to nivolumab + chemotherapy or chemotherapy in 1:1:1 randomization.
e Significance levels will be calculated based on the actual number of deaths at each interim analysis
Once the CPS scoring is complete and data is available for all randomized subjects, the target 
number of OS events at interim and final analyses will be estimated. This will be done using the 
actual PD-L1 CPS 5 prevalence and under the following piecewise HR (HR of 1 vs 
chemotherapy for the first 6 months followed by a constant HR of 0.65). The number of events 
based on above assumptions at interim and final OS analyses timing will be estimated and the 
significance levels for OS at interim and final analyses will be determined using the Lan-DeMets 
spending function with O’Brien and Fleming type of boundary.92 At time of these interim and 
final analyses, significance levels will be adjusted according to actual events observed at OS 
interim and final analyses. All the details will be documented in the statistical analysis plan.
8.1.5
Power Considerations for Nivolumab Plus Ipilimumab vs Chemotherapy
OS between nivolumab + ipilimumab vs chemotherapy will be tested as a secondary objective. 
This comparison will be tested if at least one primary endpoint (PFS or OS of nivolumab +
chemotherapy vs chemotherapy in subjects with PD-L1 CPS 5) meets statistical significance.
The nivolumab + ipilimumab vs chemotherapy OS comparison will be conducted at the planned 
final comparison of OS for nivolumab + chemotherapy vs chemotherapy. This corresponds to 
approximately 36 months of minimum follow-up for the nivolumab + ipilimumab and 
chemotherapy arm. 
Based on the observed data from Keynote 62 study (see Section 1.1.14) where a detriment was 
observed in the OS KM curves of pembrolizumab vs chemotherapy, a 4-piece HR is assumed for 
the OS of N+I vs CT with an average HR of 0.7 (see Table 8.1.5-1). With approximately 36 months
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minimum follow-up at final analysis it is expected that 240 events will be observed and the power 
will be range between 63% and 73% for Type I error of 1.5% and 3.5% (two-sided) respectively
(see Table 8.1.5-2). See also Section 8.4.2.1 for further details on the type I error control. 
Table 8.1.5-1:
Assumed OS Hazard Rates and Hazard Ratios (Nivolumab plus 
Ipilimumab vs Chemotherapy)
Periods 
Hazard Rates for 
Chemotherapy
Hazard Rates for Nivo + 
Ipilimumab
Hazard Ratio
0-6 months
0.036
0.099
2.75
3-6 months
0.06
0.054
0.9
6-24 months
0.08
0.0328
0.41
>24 months 
0.05
0.0205
0.41
Table 8.1.5-2:
Summary of Sample Size Parameters and Schedule of Analyses for 
OS (Nivolumab plus Ipilimumab vs Chemotherapy)
# with PD-L1 CPS a
285
285
Hypothesized distribution 
See Table 8.1.5-1
See Table 8.1.5-1
Hypothesized median in control arm
11.1 months 
11.1 months 
Significance level (two-sided)
0.015
0.035
Enrollment Period (from start of 1:1)
18.7 months
18.7 months
Time of analysis /Expected number of eventsa,b,c
54.4/240
54.4/240
Powerc
63%
73%
Average HRc
0.7
0.7
a Based on a 35% prevalence of PD-L1 CPS 
b After first patient randomized to nivolumab + ipilimumab or chemotherapy in 1:1 randomization.
c Results based on simulations.
8.2
Populations for Analyses
Unless indicated otherwise, the populations below apply to both the nivolumab plus ipilimumab 
vs. chemotherapy and nivolumab plus chemotherapy vs. chemotherapy comparisons.

All Enrolled Subjects: All subjects who signed an informed consent form and were registered 
into the IRT

All Randomized Subjects: All enrolled subjects who were randomized concurrently to any 
treatment arm

All Measurable Subjects: All randomized subjects who have at least one target/measurable 
lesion at baseline

All Subjects with PD-L1 CPS 5: All randomized subjects with PD-L1 CPS 5. Similar 
population will be defined for other CPS cut off values (eg CPS 10, 1)
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
All Treated Subjects: All randomized subjects who received at least one dose of study drug 
during the study

PK Subjects: All randomized subjects with available serum time-concentration data.

Outcome Research Subjects: All randomized subjects who have an assessment at 
screening/baseline and at least 1 follow-up assessment

Immunogenicity Subjects: All randomized subjects who have an assessment at 
screening/baseline and at least 1 follow-up assessment

Biomarker Subjects: All randomized subjects with available biomarker data (PD-L1 
expression by TPS and other assays).
8.3
Endpoints
Table 8.3-1 summarizes the most important efficacy endpoints.
Table 8.3-1:
Summary of Key Efficacy Endpoints
Nivolumab plus Chemotherapy vs 
Chemotherapy 
Nivolumab plus Ipilimumab vs 
Chemotherapy
Primary 
endpoints

PFS by BICR in subjects with PD-L1 
CPS ≥5)

OS in subjects with PD-L1 CPS ≥5
Secondary 
endpoints

OS in subjects with PD-L1 CPS ≥1, and in 
all randomized subjects.

OS in subjects PD-L1 CPS ≥ 10

PFS by BICR in subjects with  PD-L1 CPS 
≥ 10, 1, or all randomized subjects 

ORR by BICR in subjects with PD-L1 
CPS ≥ 10, 5, 1 or all randomized subjects

OS in subjects with PD-L1 CPS ≥ 5, and 
in all randomized subjects.

OS in subjects PD-L1 CPS ≥ 10 or 1

ORR, PFS by BICR in subjects with 
PD-L1 CPS ≥10, 5, 1 or all randomized 
subjects.

TTSD in subjects with PD-L1 CPS ≥ 5 
and in all randomized subjects
Exploratory 
Endpoints

ORR, PFS by investigator in subjects with 
PD-L1 CPS ≥10, 5, 1 or all randomized 
subjects

OS, PFS,a ORRa in subjects with TPS 
across cutoffs

OS rates at 18, 24, and 36 months

PFS2 or TSST of next line treatment

DORa

DRRa

TTSD in subjects with PD-L1 CPS 10, 5, 
1, or all randomized subjects

Biomarkers

ORR, PFS by investigator in subjects 
with PD-L1 CPS ≥10, 5, 1 or all 
randomized subjects

OS, PFS,a ORRa in subjects with TPS 
across cutoffs

OS rates at 18, 24, and 36 months

PFS 2 or TSST of next line treatment

DORa

DRRa

TTSD in subjects with PD-L1 CPS 10, 
or 1

Biomarkers
a By BICR and investigator.
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8.3.1
Primary Efficacy Measures
Overall survival (OS). OS is defined as the time between the date of randomization and the date 
of death. For subjects without documentation of death, OS will be censored on the last date the 
subject was known to be alive. 
Progression-free Survival (PFS) as assessed by BICR is defined as the time from randomization 
to the date of the first documented PD per BICR or death due to any cause. Subjects who die 
without a reported prior PD per BICR (and die without start of subsequent therapy) will be 
considered to have progressed on the date of death. Subjects who did not have documented PD per 
BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable 
tumor assessment on or prior to initiation of subsequent anti-cancer therapy. Subjects who did not 
have any on-study tumor assessments and did not die (or died after initiation of subsequent anti-
cancer therapy) will be censored at the randomization date. Subjects who started any subsequent 
anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor 
assessment prior to or on the initiation of the subsequent anti-cancer therapy.
The same definition will be used for OS and PFS for nivolumab plus ipilimumab, which are 
secondary endpoints.
8.3.2
Secondary Efficacy Measures
Time to Symptom Deterioration (TTSD) is defined as the time from randomization until a 
clinically meaningful decline from baseline in GaCS score. A clinically meaningful deterioration 
is defined as a reduction of 8.2 points in the GaCS score. Subjects who do not deteriorate will be 
censored at the time of their last GACS assessment. Subjects without baseline GaCS assessment 
will be censored on the randomization date. Those with baseline GaCS, who do not have any GaCS 
assessments after randomization will be censored on the day after randomization.
Objective Response Rate (ORR) as assessed by BICR is defined as the number of subjects with a 
best overall response (BOR) of CR or PR divided by the number of measurable subjects with target 
lesion at baseline. BOR is defined as the best response designation as determined by the BICR, 
recorded between the date of randomization and the date of objectively documented progression 
(per RECIST 1.1 as determined by the BICR) or the date of subsequent anti-cancer therapy, 
whichever occurs first. For subjects without documented progression or subsequent anti-cancer 
therapy, all available response designations will contribute to the BOR determination.
8.3.3
Exploratory Measures 

PFS by investigator and ORR by investigator are defined the same way as PFS by BICR and 
ORR by BICR, except that only tumor assessments by investigators will be taken into account.

Duration of Response (DOR) (as assessed by BICR and as assessed by investigator) is defined 
as the time between the date of first documented response (CR or PR) to the date of the first 
disease progression, per RECIST 1.1 or death due to any cause, whichever occurs first. For 
subjects who neither progress nor die, the duration of objective response will be censored at 
the same time they were censored for the primary definition of PFS.
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
Durable Response Rate (DRR) (as assessed by BICR and as assessed by investigator) is 
defined as the number of subjects with objective response whose response lasted for at least 
6 months, divided by the number of randomized subjects for each treatment group.

Overall survival rate at 18, 24, and 36 months is defined as the probability that a subject is 
alive at 18, 24, and 36 months, respectively, following randomization.

PFS2/TSST is defined as the time from randomization to the date of investigator-defined 
documented second objective disease progression or start of second subsequent line therapy or 
death due to any cause, whichever comes first. Clinical deterioration will not be considered as 
progression. Details for censoring will be provided in the SAP

Safety and tolerability objective will be measured by the incidence of adverse events (AEs), 
serious adverse events (SAEs), deaths, and laboratory abnormalities.

PK will be measured using serum concentration-time data.
Assessments for other exploratory endpoints are discussed, including biomarker analysis 
(Section 5.6), immunogenicity (Section 5.5.1), and outcomes research (Section 5.7). 
Corresponding endpoints will be detailed in the statistical analysis plan(s) (SAP[s]).
8.4
Analyses
8.4.1
Demographics and Baseline Characteristic
Demographic and baseline characteristics will be summarized by treatment arm as randomized 
using descriptive statistics.
A description of the participant population will be included in a statistical output report, including 
subgroups of age, gender, and race.
8.4.2
Efficacy Analyses
8.4.2.1
Strong Control Of Type I Error for Primary and Secondary endpoints
For design purposes, the alpha was split using Bonferroni method between the 2 primary 
endpoints: 
1) Comparison of PFS between nivolumab plus chemotherapy and chemotherapy in subjects with 
PD-L1 CPS with alpha of 2 
2) Comparison of OS between nivolumab plus chemotherapy and chemotherapy in subjects with 
PD-L1 CPS with alpha of 
For analyses purposes of primary and key secondary endpoints the Bonferroni-based graphical 
approach93 will be used and full details will be provided in the statistical analysis plan.
The alpha from the PFS of N+CT vs CT in PD-L1 CPS testing will be carried to the testing of
OS of N+I vs CT in PD-L1 CPS analysis, should the PFS analysis be statistically significant. 
If OS of N+CT vs CT is significantly superior in subjects with PD-L1 CPS then the inherited 
alpha will be shared equally to secondary endpoints of OS of N+CT vs CT in PD-L1 CPS 
subjects and OS of N+I vs CT in PD-L1 CPS . The comparison of OS for N+I vs CT in PD-L1 
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CPS may inherit alpha independently from the two primary endpoints and will be tested only 
once after 36 months of minimum follow-up. The alpha that will be allocated to the comparison 
of OS for N+I vs CT in PD-L1 CPS 5 will be 1.5%, 2% or 3.5% depending on the outcome of 
the primary endpoints for N+CT vs CT. The SAP will document the details of the actual alpha 
allocation to the secondary endpoints.
8.4.2.2
Analyses for Primary Objectives
Nivolumab plus Chemotherapy vs Chemotherapy
PFS by BICR in subjects expressing PD-L1 with  CPS ≥5 will be compared between nivolumab 
plus chemotherapy vs chemotherapy using a two-sided log rank test, stratified by region (Asia vs 
US vs rest of world), ECOG status (0 vs 1), chemotherapy regimen (XELOX vs FOLFOX) and 
TPS PD-L1 (1% vs < 1% or indeterminate) as recorded in the IRT. A significance level of 2% 
will be used. The HR with its associated two-sided 98% CI will be estimated via a stratified Cox 
model with treatment arm as the only covariate in the model. PFS for each treatment arm will be 
estimated and plotted using the KM product-limit method. Median survival time along with 95% 
CI will be constructed based on a log-log transformed CI for the survival function.
Overall Survival in subjects with PD-L1 by CPS ≥5 will be compared between nivolumab plus 
chemotherapy vs chemotherapy using a two-sided log rank test, stratified by region (Asia vs US 
vs rest of world), ECOG status (0 vs 1), chemotherapy regimen (XELOX vs FOLFOX) and TPS 
PD-L1 (1% vs < 1% or indeterminate) as recorded in the IRT. The significance level will be 
determined using the Bonferroni-based graphical approach. The HR with its associated two-sided 
CI will be estimated via a stratified Cox model with treatment arm as the only covariate in the 
model. OS for each treatment arm will be estimated and plotted using the KM product-limit 
method. Median survival time along with 95% CI will be constructed based on a log-log 
transformed CI for the survival function.
8.4.2.3
Analyses for Secondary Objectives in Hierarchy
Nivolumab plus Chemotherapy vs Chemotherapy 
OS in CPS and all randomized will be compared using a two-sided log rank test stratified by 
the same stratification factors as the primary endpoint. The HR with its associated two-sided CI 
will be estimated via a stratified Cox model with treatment arm as the only covariate in the model. 
OS for each treatment arm will be estimated and plotted using the Kaplan-Meier (KM) product-
limit method. Median survival time along with 95% CI will be constructed based on a log-log 
transformed CI for the survival function.
Nivolumab plus Ipilimumab vs Chemotherapy
Overall survival in subjects with PD-L1 by CPS ≥5 and all randomized will be compared between 
nivolumab plus ipilimumab vs chemotherapy using a two-sided log rank test stratified by region 
(Asia vs US vs rest of world), ECOG status (0 vs 1) and TPS PD-L1 (vs < 1% or 
indeterminate) and as recorded in the IRT.
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The HR with its associated two-sided CI will be estimated via a stratified Cox model with treatment 
arm as the only covariate in the model. OS for each treatment arm will be estimated and plotted 
using the Kaplan-Meier (KM) product-limit method. Median survival time along with 95% CI will 
be constructed based on a log-log transformed CI for the survival function.
Same methods will be used to analyze OS in subjects with PD-L1 by CPS ≥10 and 1.
Similar methodology will be used for TTSD.
Exploratory Endpoints
Progression-free Survival (PFS) as assessed by BICR/ investigator will be estimated and plotted 
using the KM product limit method for each treatment arm. Median survival time along with 95% 
CI will be constructed based on a log-log transformed CI for the survival function. The HR with 
its associated two-sided 95% CI will be estimated via a stratified Cox model with treatment arm 
as the only covariate in the model. 
Best Overall Response will be summarized by response category for each treatment group. 
ORR (as assessed by BICR and as assessed by investigator) and DRR (as assessed by BICR and 
as assessed by investigator) will be computed in each treatment group along with the exact 95% 
CI using Clopper-Pearson method.94 An estimate of the difference in ORRs and DRRs, and 
corresponding 95% CI will be calculated using Cochran-Mantel-Haenszel methodology and 
adjusted by the randomization stratification factors. The stratified odds ratios (Mantel-Haenszel 
estimator) between the treatments will be provided along with the 95% CI. 
Duration of Response (as assessed by BICR and as assessed by investigator) in each treatment 
group will be estimated using KM product-limit method for subjects who achieve PR or CR. 
Median values along with two-sided 95% CI will be calculated.
Survival rate analysis will be carried out only for those time points which are mature enough by 
the time of the given database-lock. Point estimates will be provided using KM product-limit 
method. For each survival rate per treatment arm, two-sided 95% CIs using log-log transformation 
will be computed.
8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using NCI CTCAE version 4 by treatment group. All on-study AEs, treatment-related 
AEs, SAEs, and treatment-related SAEs will be tabulated using worst grade per NCI CTCAE 
version 4 criteria by system organ class and preferred term (PT). On-study lab parameters 
including hematology, chemistry, liver function, and renal function will be summarized using 
worst grade NCI CTCAE version 4 criteria.
8.4.4
Pharmacokinetic Analyses
The nivolumab and/or ipilimumab concentration vs time data obtained in this study may be 
combined with data from other studies in the clinical development program to develop population 
PK models. These models may be used to evaluate the effects of intrinsic and extrinsic covariates 
on the PK of nivolumab and/or ipilimumab and to determine measures of individual exposure 
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(such as steady state peak, trough and time averaged concentration). Model determined exposures 
may be used for exposure response analyses of selected efficacy and safety endpoints. If the 
analyses are conducted, the results of population PK and exposure response analyses will be 
reported separately.
8.4.5
Biomarker Analyses
 MSI, TMB 
 status will be evaluated where possible, as predictive biomarkers, for 
OS and PFS. Details for these biomarker analyses will be described in the SAP(s). These analyses 
will be descriptive and not adjusted for multiplicity. 
8.4.6
Outcomes Research Analyses
The analysis of EQ-5D-3L and FACT-Ga (including FACT-G, FACT-G7 and GaCS) data will be 
performed in all randomized subjects and in subjects with CPS who have an assessment at 
baseline (Day 1, assessment prior to administration of drug on day of first dose) and at least 1 
subsequent assessment while on treatment. The 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.
The analyses may also be performed for population defined by other CPS cutoff.
EQ-5D-3L data will be described by treatment group as randomized in the following ways:

EQ-5D-3L index scores will be summarized at each assessment time point using descriptive 
statistics (ie, N, mean with SD and 95% CI, median, first and third quartiles, minimum, 
maximum). The UK scoring algorithm will be applied as a reference case.

EQ-VAS scores will be summarized at each assessment time point using descriptive statistics 
(ie, N, mean with SD and 95% CI, median, first and third quartiles, minimum, maximum).

The proportion (N) of subjects reporting no, moderate, or extreme problems will be presented 
for each of the 5 EQ-5D-3L dimensions at each assessment time point. Subjects with missing 
data will be excluded from the analysis.

A by-subject 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-VAS score will be provided.
From the beginning of the on-treatment phase through follow-up Visit 2, data for the FACT-Ga 
will be described by treatment group as randomized in the following ways:

GaCS, FACT-G7, FACT-G, and FACT-Ga total scores will be summarized at each assessment 
time point using descriptive statistics (ie, N, mean with SD and 95% CI, median, first and third 
quartiles, minimum, maximum).

Changes from baseline in GaCS, FACT-G7, FACT-G, FACT-Ga total scores will be 
summarized at each post-baseline assessment time point using descriptive statistics (ie, N, 
mean with SD and 95% CI, median, first and third quartiles.
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During the survival follow-up phase, data for the GaCS and FACT-G7 will be described by 
treatment group as randomized in the following ways:

GaCS and FACT-G7 scores will be summarized at each assessment time point using 
descriptive statistics (ie, N, mean with SD and 95% CI, median, first and third quartiles, 
minimum, maximum).

Changes from baseline in GaCS and FACT-G7 scores will be summarized at each 
post-baseline assessment time point using descriptive statistics (ie, N, mean with SD and 
95% CI, median, first and third quartiles, minimum, maximum).
8.4.7
Other Analyses 
Immunogenicity may be reported for ADA-positive status (such as persistent positive, only last 
sample positive, other positive, baseline positive) and ADA-negative status, relative to baseline. 
In addition, presence of neutralizing antibodies may be reported, if applicable. Effect of 
immunogenicity on safety, efficacy, biomarkers and PK may be explored. Additional details will 
be described in the SAP.
8.5
Interim Analyses
For the nivolumab plus chemotherapy vs chemotherapy comparison, the primary PFS analysis in 
PD-L1 CPS is planned to be conducted after 12 months minimum follow-up in all randomized 
subjects with PD-L1 CPS . An independent statistician external to BMS will perform the 
analysis; results will be evaluated by the DMC.
The formal interim analyses for OS is also planned at 12 months minimum follow-up after the last 
patient was randomized. (See Section 8.1.4 for details). Lan-DeMets α spending function with 
O’Brien and Fleming type of boundary will be used. The stopping boundary will depend on the 
actual number of deaths at the time of each analysis. An independent statistician external to BMS 
will perform the analysis; results will be evaluated by the DMC. For all analyses, all events 
reported in the database at the time of the lock will be used.
For the nivolumab plus ipilimumab vs chemotherapy there no interim analysis planned. 
The full details of using the graphical approach will be described in the SAP. 
In addition to the formal planned PFS and interim analyses for OS, the DMC will have access to 
periodic unblinded interim reports to allow a risk/benefit assessment. No formal test will be 
performed and the study will not stop for superiority. Details will be included in the DMC charter. 
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
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/participants. If a deviation or change to a protocol is implemented to 
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eliminate an immediate hazard(s) prior to obtaining relevant approval/favorable opinion(s), the 
deviation or change will be submitted as soon as possible to:

IRB/IEC

Regulatory Authority(ies), if applicable by local regulations per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority, must be sent to BMS. If an 
amendment substantially alters the study design or increases the potential risk to the subject: (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/participants 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/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS or designee representatives will review data centrally to identify potential issues to determine 
a schedule of on-site visits for targeted review of study records.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by BMS 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 BMS or designee. 
9.1.2.1
Source Documentation
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 
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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. 
9.2
Records
9.2.1
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 or designee prior to destroying 
any records associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
9.2.2
Study Drug Records 
Records for IP (whether supplied by BMS, its vendors, or the site) must substantiate IP 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 subject, including unique 
subject 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/biocomparability, 
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 
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...
sites stock or 
commercial supply, 
or a specialty 
pharmacy)

label identification number or batch number 

amount dispensed to and returned by each subject, including unique 
subject 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.
9.2.3
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 of designee. 
The confidentiality of records that could identify subjects/participants 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.
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9.3
Clinical Study Report
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:

External Principal Investigator designated at protocol development
9.4
Scientific Publications
The data collected during this study are confidential and proprietary to BMS or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
BMS or designee at the earliest practicable time prior to submission or presentation and otherwise 
within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered. 
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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GLOSSARY OF TERMS
Term
Definition
Complete 
Abstinence
Complete Abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. This also means that abstinence is the 
preferred and usual lifestyle of the patient. This does not mean periodic abstinence (eg, calendar, 
ovulation, symptothermal, profession of abstinence for entry into a clinical trial, post-ovulation 
methods) and withdrawal, which are not acceptable methods of contraception. Women must 
continue to have pregnancy tests. Acceptable alternate methods of highly or less effective 
contraception’s must be discussed in the event that the subject chooses to forego complete 
abstinence.
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LIST OF ABBREVIATIONS
Term
Definition
ADA
anti-drug antibody
AE
adverse event
AIDS
Acquired Immunodeficiency Syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APC
antigen presenting cell
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AT
aminotransferase
BA/BE
bioavailability/bioequivalence
BMS
Bristol-Myers Squibb
BICR
Blinded Independent Review Committee
BOR
best overall response
BP
blood pressure
BSA
body surface area
BSC
best supportive care
BUN
blood urea nitrogen
Ca
calcium
Cavgss
average concentration at steady state
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
CL
clearance
Cmax
maximum observed concentration
CMV
cytomegalovirus
CNS
Central Nervous System
CPS
combined positive score
CR
complete response
CrCl
creatinine clearance
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Term
Definition
CRF
case report form, paper or electronic
CT
computed tomography
CT
chemotherapy
CTAg
clinical trial agreement
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-cell lymphoma 4
CV
coefficient of variation
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DOR
duration of response
EC50
concentration of a drug producing half-maximal response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
eg
exempli gratia (for example)
EHR/EMR
electronic health record/electronic medical record
EOT
end of treatment
EQ-5D-3L
EuroQol questionnaire comprising 5 dimensions, with each dimension 
having 3 levels
EQ-VAS
EuroQol Visual Analog Scale
EWB
emotional well-being
FACT-Ga
Functional Assessment of Cancer Therapy-Gastric
FACT-G7
7-item version of FACT-General
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FLP
5-fluorouracil plus leucovorin and cisplatin
FOLFOX
oxaliplatin + leucovorin + 5-fluorouracil
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Term
Definition
FPFV
First patient first visit
FSH
follicle stimulating hormone
FU or F/U
follow-up
FWB
functional well-being
g
gram
GaCS
Gastric Cancer Subscale
GC
gastric cancer
GCP
Good Clinical Practice
GEJ
gastroesophageal junction
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
Her2
human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HNPCC
hereditary nonpolyposis colorectal cancer
HR
hazard ratio
HRT
hormone replacement therapy
IB
Investigator Brochure
IC50
concentration of an inhibitor where binding is reduced by half
ICF
informed consent form
ICH
International Council on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IFN-γ
interferon gamma
IHC
immunohistochemistry
IMAE
immune-mediated adverse event
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Term
Definition
IMG
immunogenicity
IMP/IP
investigational (medicinal) products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IRC
Independent Review Committee
irPFS
immune-related progression-free survival
IRT
Interactive (voice/web) Response Technology 
IU
International Unit
IV
intravenous
K
potassium
kg
kilogram
KM
Kaplan-Meier
1L/2L
first-line/second-line
L
liter
LDH
lactate dehydrogenase
LFT
liver function test
LLN
lower limit of normal
mg
milligram
min
minute
mL
milliliter
mOS
median overall survival
MRI
magnetic resonance imaging
MSI
microsomal instability
MTD
maximum tolerated dose
g
microgram
N
number of subjects or observations
N/A
not applicable
NaCl
sodium chloride
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Term
Definition
NCI
National Cancer Institute
nM
nano-molar
NSCLC
non-small cell lung cancer
N+CT
nivolumab plus chemotherapy
N+I
nivolumab plus ipilimumab
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PEM + CT
pembrolizumab + chemotherapy
PD
progressive disease
PD-1/PD-L1/PD-L2
programmed cell death protein 1/programmed cell death ligand 1 or 2
PFS
progression-free survival
PFS2
progression after the next line of therapy 
PK
pharmacokinetics
PO
per os (oral route of administration)
PPK
population PK
PR
partial response
PT
Preferred Term
PWB 
physical well-being
Q2W/Q3W
every 2 weeks/every 3 weeks
QD
quaque die, once daily
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
ROW
Rest of the World
RT-PCR
reverse transcription-polymerase chain reaction
S1
tegafur/gimeracil/oteracil potassium
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
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Term
Definition
SNP
single nucleotide polymorphism
SOC
System Organ Class
SUSAR
Suspected, Unexpected Serious Adverse Reaction
SWB
social/family well-being
t1/2
half-life; time of clearance of 1/2 of drug concentration 
Tmax
time of maximum observed concentration
TSH
thyroid stimulating hormone
TTSD
time to symptom deterioration
TSST
Time to second subsequent therapy
ULN
upper limit of normal
Vc
volume of central compartment
Vz
Volume of distribution at terminal phases
WBC
white blood cell
WOCBP
women of childbearing potential
XELOX
Oxaliplatin + Capecitabine
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25 Summary 
of 
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38 Bang YJ, et al. Relationship between PD-L1 expression and clinical outcomes in patients with 
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51 Fuchs CS, Ohtsu A, Tabernero J et al. Preliminary safety data from KEYNOTE-059: 
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advanced gastric or gastroesophageal junction (G/GEJ) cancer: Phase 3 KEYNOTE-061 trial. 
ASCO 2018 abstract. 4062
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63 Kang H, Kauh J. Chemotherapy in the Treatment of Gastric Cancer: Is there a global standard? 
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66 Jatoi A, Murphy BR, Foster NR, et al. Oxaliplatin and capecitabine in patients with metastatic 
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68 Park YH, Lee JL, Ryoo BY, et al. Capecitabine in combination with Oxaliplatin (XELOX) as 
a first-line therapy for advanced gastric cancer. Cancer Chemother Pharmacol 
2008;61:623-629.
69 I Chau, AR Norman, D Cunningham, et al. Multivariate prognostic factor analysis in locally 
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70 Chen G, Emens LA. Chemoimmunotherapy: reengineering tumor immunity.Cancer Immunol 
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6736(18)31257-1
75 Yung-Jue Bang, K Muro, CS. Fuchs et al. KEYNOTE-059 cohort 2: Safety and efficacy of 
pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment 
of advanced gastric cancer. ASCO 2017 abstract 4012
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76 Tabernero J, Bang Y-J, Fuchs CS et al. KEYNOTE-062: Phase III study of pembrolizumab 
(MK-3475) alone or in combination with chemotherapy versus chemotherapy alone as first-
line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. ASCO 
2019 abstract LBA4007.
77 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39.
78 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6:715-27.
79 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8.
80 Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2004;23:515-48.
81 Zhang Y, Huang S, Gong D, et al. Programmed death-1 upregulation is correlated with 
dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. 
Cell and Mol Immunol 2010;7:389-95.
82 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nature Immunol. 2007;8:237-45.
83 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Eng J Med 2012; 366: 2443-54.)
84 Alegre ML, Noel PJ, Eisfelder BJ, et al. Regulation of surface and intracellular expression of 
CTLA4 on mouse T cells. J Immunol 1996; 157:4762-70.
85 Postow MA, Harding J, Wolchok JD. Targeting immune checkpoints: Releasing the restraints 
on anti-tumor immunity for patients with melanoma. Cancer J 2012; 18:153-159.
86 Nivolumab Investigator Brochure Version 15; 24-Jun-2016.
87 Ipilimumab population pharmacokinetics and exposure-response analyses in subjects with 
advanced melanoma (CA184004, CA184007, CA184008, and CA184022). Bristol-Myers 
Squibb; 2010. Document Control No. 
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88 Ipilimumab Investigator Brochure Version 19; 02-Mar-2016.
89 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-20.
90 Umar A, Boland Cr, Terdiman JP, et al. Revised Bethesda Guidelines for Hereditary 
Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability. J Nat 
Cancer Inst 2004;96:261-68.
91 Fuchs C , Shitara K, Di Bartolomeo M et al RAINFALL: A randomized, double-blind, 
placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or 
without ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or 
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gastroesophageal junction (G-GEJ) adenocarcinoma.ASCO GI Cancers Symposium 2018, 
abstract # 5.
92 Lan KKG, Lachin JM, Implementation of Group Sequential Logrank Tests in a Maximum 
Duration Trial, Biomatrics 46, 759-770, September 1990.
93 Bretz, F., Maurer, W., Brannath, W., and Posch, M. (2009). A graphical approach to 
sequentially rejective multiple test procedures. Statistics in Medicine, 28(4):586–604.
94 Clopper, CJ and Pearson, ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 26: 404-413, 1934
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APPENDIX 1
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 2
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 

oral 

injectable 
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Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)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 5. 

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.
Unacceptable Methods of Contraception

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
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Unacceptable Methods of Contraception

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 for 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 6.4.
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APPENDIX 3
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS
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, e.g., 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
Source: Oken MM, Creech RH, Tomey 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
RADIOLOGIC EVALUATION CRITERIA IN SOLID TUMOURS 
VERSION 1.1 (RECIST CRITERIA 1.1)
1
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the overall tumor
burden at baseline and use this as a comparator for subsequent measurements. Measurable disease 
is defined by the presence of at least 1 measurable tumor lesion. When computed tomography (CT)
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.
At baseline, tumor lesions/lymph nodes will be categorized measurable or nonmeasurable, which 
are discussed below.
1.1
Measurable Lesions
Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of:

10 mm by CT/magnetic resonance imaging (MRI) scan - (CT/MRI scan slice thickness no 
greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as nonmeasurable)

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). At baseline and in follow-up, only the short axis 
will be measured and followed.
1.2
Non-measurable Lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with 10 to < 15 mm short axis), as well as truly non-measurable lesions

Lesions considered truly nonmeasurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
and abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
1.3
Special Considerations Regarding Lesion Measurability
1.3.1
Bone Lesions

Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be used 
to confirm the presence or disappearance of bone lesions. 
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
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that 
can be evaluated by cross sectional imaging techniques such as CT or MRI, can be considered
measurable lesions if the soft tissue component meets the definition of measurability described 
above.

Blastic bone lesions are nonmeasurable.
1.3.2
Cystic Lesions

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts. 

‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same subject, these are preferred for selection as target lesions.
1.3.3
Lesions with Prior Local Treatment
Tumor lesions situated in a previously irradiated area or in an area subjected to other locoregional 
therapy are usually not considered measurable, unless there has been demonstrated progression in 
the lesion. Measurable lesions may be in an irradiated field as long as there is documented 
progression, and the lesion(s) can be reproducibly measured.
1.4
Specifications by Methods of Measurements
1.4.1
Measurement of Lesions
All measurements should be recorded in metric notation (mm). All baseline evaluations should be 
performed as close as possible to the treatment start and never more than 30 days before the 
beginning of the treatment.
1.4.2
Method of Assessment
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation should 
always be done rather than clinical examination, unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
1.4.2.1
CT/MRI Scan
CT/MRI is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT/MRI scan is based on the assumption that 
CT/MRI slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice thickness.
1.4.2.2
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint,
since CT is more sensitive than X-ray in identifying new lesions. However, lesions on chest X-ray 
may be considered measurable if they are clearly defined and surrounded by aerated lung.
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1.4.2.3
Clinical Lesions
Clinical lesions will only be considered measurable when they are superficial and 10 mm 
diameter as assessed using calipers. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested. As previously noted, 
when lesions can be evaluated by both clinical examination and imaging, imaging evaluation 
should be undertaken since it is more objective and may also be reviewed at the end of the study.
1.4.2.4
Ultrasound
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. 
1.4.2.5
Endoscopy, Laparoscopy
The utilization of these techniques for objective tumor evaluation is not advised.
1.4.2.6
Tumor Markers
Tumor markers alone cannot be used to assess objective tumor response.
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’
LESIONS
2.1
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated
measurements.
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 below, 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.
2.1.1
Lymph Nodes
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. Nodes 
that have a short axis < 10 mm are considered nonpathological and should not be recorded or 
followed.
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2.2
Non-target Lesions
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’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).
3
TUMOR RESPONSE EVALUATION
3.1
Evaluation of Target Lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to < 10 mm.

Partial Response (PR): 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 1 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 on study.
3.1.1
Special Notes on the Assessment of Target Lesions
3.1.1.1
Lymph Nodes
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. Nodes 
that have a short axis <10 mm are considered nonpathological and should not be recorded or 
followed.
3.1.1.2
Target Lesions That Become ‘Too Small to Measure’
All lesions (nodal and nonnodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (eg, 2 mm). If the radiologist is able 
to provide an actual measurement, that should be recorded even if it is below 5 mm.
However, when such a lesion becomes difficult to assign an exact measure to then:

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: In case of a lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
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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).
3.1.1.3
Target 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.

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
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. 

CR: Disappearance of all non-target lesions. All lymph nodes must be nonpathological in size 
(< 10 mm short axis).

PD: Unequivocal progression of existing non-target lesions. (Note: The appearance of 1 or 
more new lesions is also considered progression).

NonCR/NonPD: Persistence of 1 or more non-target lesion(s).
3.2.1
Special Notes on Assessment of Non-target Lesions
The concept of progression of non-target disease requires additional explanation as discussed 
below.
3.2.1.1
When the Subject Also has Measurable Disease

To achieve unequivocal progression on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease, such that even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.

A modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to 
quality for unequivocal progression status.
3.2.1.2
When the Subject has Only Non-measurable Disease

To achieve unequivocal progression on the basis of the non-target disease, there must be an 
overall level of substantial worsening, such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.

A modest increase in the size of 1 or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status.

Because worsening in non-target disease cannot be easily quantified (by definition, if all 
lesions are nonmeasurable), a useful test that can be applied when assessing subjects 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 
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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 subject should be considered to have had overall PD at 
that point. 
3.2.1.3
Tumor Markers
Tumor markers will not be used to assess objective tumor responses.
3.3
New Lesions
The appearance of new malignant lesions denotes disease progression. The finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, change in 
imaging modality, or findings thought to represent something other than tumor (for example, some 
new bone lesions may be simply healing or flare of preexisting lesions). This is particularly 
important when the subject’s baseline lesions show PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a new cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the subject
who has visceral disease at baseline and while on study, has a CT or MRI brain scan ordered that
reveals metastases. The subject’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.
4
RESPONSE CRITERIA
4.1
Time Point Response
A response assessment should occur at each time point specified in the protocol.
For subjects who have measurable disease at baseline, Table 4.1-1 provides a summary of the 
overall response status calculation at each time point.
Table 4.1-1:
Subjects with Target (+/– Non-target) Disease
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
NonCR/nonPD
No
PR
CR
Not evaluated
No
PR
PR
NonPD or not all evaluated
No
PR
SD
NonPD or not all evaluated
No
SD
Not all evaluated
NonPD
No
NE
PD
Any
Yes or No
PD
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nivolumab
Table 4.1-1:
Subjects with Target (+/– Non-target) Disease
Target Lesions
Non-target Lesions
New Lesions
Overall Response
Any 
PD
Yes or No
PD
Any
Any 
Yes
PD
Abbreviations: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = not evaluable.
4.1.1
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at a particular time point, the subject is not evaluable 
(NE) at that time point. If only a subset of lesion measurements are made at an assessment, the 
case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not have changed the assigned time point 
response.
4.1.2
Confirmation Scans
Verification of Response: Confirmation of PR and CR is required within 4 weeks to ensure that 
the responses identified are not the result of measurement error.
4.2
Best Overall Response: All Time Points
The best overall response is determined once all the data for the subject is known. It 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 subject’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.
Best response is defined as the best response across all time points with subsequent confirmation. 
CRs or PRs may be claimed only if the criteria for each are met at a subsequent time point as 
specified in the protocol (generally 4 weeks later).
In this circumstance, the best overall response can be interpreted as specified in Table 4.2-1. When 
SD is believed to be best response, it must meet the protocol specified minimum time from 
baseline. Measurements must have met the SD criteria at least once after study entry at a minimum 
interval (in general not less than 6 to 8 weeks) that is defined in the study protocol.
Table 4.2-1:
Best Overall Response When Confirmation of CR and PR is 
Required
Overall Response
Overall Response
Best Overall Response
First Time Point
Subsequent Time Point
CR
CR
CR
CR
PR
SD, PD, or PRa
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Table 4.2-1:
Best Overall Response When Confirmation of CR and PR is 
Required
Overall Response
Overall Response
Best Overall Response
First Time Point
Subsequent Time Point
CR
SD
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for 
SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for 
SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for 
SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for 
SD duration met, otherwise NE
NE
NE
NE
a Abbreviations: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = not evaluable.
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 subject 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.
4.3
Duration of Response
4.3.1
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for PD the smallest measurements recorded on study).
The duration of overall complete response is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented.
4.3.2
Duration of Stable Disease
SD is measured from the start of the treatment (in randomized trials, from date of randomization) 
until the criteria for progression are met, taking as reference the smallest sum on study (if the 
baseline sum is the smallest, this is the reference for calculation of PD).
Reference: Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247.
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Date: 16-Sep-2019
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SAP_001.pdf: 
Official Title of Study: 
A Randomized, Multicenter, Open-Label, Phase 3 Study of Nivolumab plus Ipilimumab or 
Nivolumab in Combination with Oxaliplatin plus Fluoropyrimidine versus Oxaliplatin plus 
Fluoropyrimidine in Subjects with Previously Untreated Advanced or Metastatic Gastric or 
Gastroesophageal Junction Cancer 
(CheckMate 649: CHECKpoint pathway and nivoluMab clinical Trial Evaluation 649) 
 
NCT Number: NCT02872116 
Document Date (Date in which document was last revised): 19-MAY-2021 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE 3 STUDY OF NIVOLUMAB 
PLUS IPILIMUMAB OR NIVOLUMAB IN COMBINATION WITH OXALIPLATIN PLUS 
FLUOROPYRIMIDINE VERSUS OXALIPLATIN PLUS FLUOROPYRIMIDINE IN
SUBJECTS WITH PREVIOUSLY UNTREATED ADVANCED OR METASTATIC 
GASTRIC OR GASTROESOPHAGEAL JUNCTION CANCER
PROTOCOL CA209649
VERSION # 5.0
DATE: 19-MAY-2021
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................6
LIST OF FIGURES ....................................................................................................................8
1
BACKGROUND AND RATIONALE......................................................................9
2
STUDY DESCRIPTION ........................................................................................10
2.1
Study Design ..........................................................................................................10
2.2
Treatment Assignment............................................................................................14
2.3
Blinding and Unblinding.........................................................................................15
2.4
Protocol Amendments.............................................................................................15
2.5
Blinded Independent Central Review of Progression...............................................17
2.6
Data Monitoring Committee ...................................................................................17
3
OBJECTIVES ........................................................................................................17
3.1
Primary...................................................................................................................17
3.2
Secondary...............................................................................................................17
3.3
Exploratory.............................................................................................................18
4
ENDPOINTS..........................................................................................................19
4.1
Primary Endpoints for Nivolumab plus Chemotherapy ...........................................20
4.1.1
Overall Survival .....................................................................................................20
4.1.2
Progression-Free Survival......................................................................................20
4.1.2.1
Primary Definition of Progression-Free Survival (Accounting for Subsequent 
Therapy).................................................................................................................21
4.1.2.2
Secondary Definition of Progression Free Survival (Irrespective of 
Subsequent Therapy) ..............................................................................................23
4.2
Secondary Endpoints ..............................................................................................24
4.2.1
For Nivo + Chemo versus Chemo...........................................................................24
4.2.1.1
Overall Survival .....................................................................................................24
4.2.1.2
Progression-Free Survival......................................................................................24
4.2.1.3
Objective Response Rate.........................................................................................24
4.2.2
For Nivo + Ipi versus Chemo..................................................................................25
4.2.2.1
Overall Survival .....................................................................................................25
4.2.2.2
Progression Free Survival ......................................................................................25
4.2.2.3
Objective Response Rate.........................................................................................25
4.2.2.4
Time to Symptom Deterioration ..............................................................................25
4.3
Exploratory Endpoints............................................................................................25
4.3.1
Efficacy Exploratory Endpoints ..............................................................................25
4.3.2
Safety Exploratory Endpoints..................................................................................26
4.3.3
Outcomes Research Exploratory Endpoints ............................................................27
4.3.4
Pharmacokinetics Exploratory Endpoints...............................................................28
4.3.5
Immunogenicity Exploratory Endpoints..................................................................28
5
SAMPLE SIZE DETERMINATION......................................................................28
5.1
Randomization Schema ..........................................................................................28
5.1.1
Changes of Statistical Analyses and Timing of Analyses in Protocol 
Amendment 29........................................................................................................29
5.2
General Assumptions of Sample Size Determinations.............................................30
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5.2.1
Sample Size: Nivolumab plus Chemotherapy vs. Chemotherapy..............................33
5.2.2
Power Considerations for Nivolumab plus Ipilimumab vs. Chemotherapy ..............36
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................37
6.1
Study Periods..........................................................................................................37
6.2
Treatment Regimens...............................................................................................38
6.3
Populations for Analyses ........................................................................................39
6.3.1
Analyses of Nivolumab plus Chemotherapy versus Chemotherapy ..........................39
6.3.2
Analyses of Nivolumab plus Ipilimumab versus Chemotherapy ...............................40
7
STATISTICAL ANALYSES..................................................................................41
7.1
General Methods ....................................................................................................41
7.1.1
Adverse Events, Serious Adverse Events, Multiple Events, Select Adverse 
Events, Other Events of Special Interest and Immune-Mediated Adverse 
Events.....................................................................................................................41
7.1.1.1
Select Adverse Events (EU Submission) ..................................................................42
7.1.1.2
Other Events of Special Interest..............................................................................43
7.1.1.3
Immune-Mediated Adverse Events (US Submission)................................................43
7.1.2
Laboratory Tests.....................................................................................................43
7.1.3
Immunogenicity Data..............................................................................................44
7.1.4
Efficacy ..................................................................................................................44
7.2
Study Conduct........................................................................................................44
7.2.1
Accrual...................................................................................................................44
7.2.2
Relevant Deviations................................................................................................44
7.3
Study Population ....................................................................................................45
7.3.1
Subject Disposition.................................................................................................45
7.3.2
Demographics and Other Baseline Characteristics.................................................46
7.3.3
Medical History......................................................................................................47
7.3.4
Prior Therapy Agents .............................................................................................47
7.3.5
Physical Examinations............................................................................................47
7.3.6
Baseline Physical Measurements ............................................................................47
7.3.7
Discrepancies between IRT Stratification Factors and Other Datasets ...................47
7.4
Extent of Exposure .................................................................................................48
7.4.1
Administration of Study Therapy.............................................................................48
7.4.2
Modification of Study Therapy................................................................................54
7.4.2.1
Dose Delays ...........................................................................................................54
7.4.2.2
Infusion Interruptions and Rate Changes................................................................54
7.4.2.3
Dose Reductions.....................................................................................................55
7.4.3
Concomitant Medications.......................................................................................55
7.4.3.1
Immune Modulating Medication .............................................................................55
7.4.3.2
Subsequent Therapy................................................................................................56
7.5
Efficacy..................................................................................................................57
7.5.1
Strong Control of Type I Error for Primary and Secondary endpoints: ...................57
7.5.2
Nivo + Chemo vs. Chemo Comparison ...................................................................60
7.5.2.1
Analysis of Progression-Free Survival....................................................................60
7.5.2.2
Supportive Analyses of Progression-Free Survival..................................................61
7.5.2.3
Subset Analyses of Progression-Free Survival ........................................................65
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7.5.2.4
Analysis of Overall Survival....................................................................................66
7.5.2.5
Supportive Analyses of Overall Survival .................................................................67
7.5.2.6
Subset Analyses of Overall Survival........................................................................69
7.5.2.7
Current Status of PFS and OS Follow-up................................................................69
7.5.2.8
Analysis of OS by Tumor Response:........................................................................69
7.5.2.9
Secondary Efficacy Endpoints.................................................................................70
7.5.2.10
Exploratory Efficacy Endpoints ..............................................................................72
7.5.3
Nivo + Ipi vs. Chemo Comparison..........................................................................73
7.5.3.1
Analysis of Overall Survival....................................................................................73
7.5.3.2
Supportive Analyses of Overall Survival .................................................................74
7.5.3.3
Subset Analyses of Overall Survival........................................................................76
7.5.3.4
Analysis of OS by Tumor Response:........................................................................77
7.5.3.5
Analysis of Progression-Free Survival....................................................................78
7.5.3.6
Subset Analyses of Progression-Free Survival ........................................................78
7.5.3.7
Current Status of PFS and OS Follow-up................................................................79
7.5.3.8
Other Secondary Efficacy Endpoints.......................................................................80
7.5.3.9
Exploratory Efficacy Endpoints ..............................................................................81
7.6
Safety.....................................................................................................................82
7.6.1
Deaths ....................................................................................................................82
7.6.2
Serious Adverse Events...........................................................................................83
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................83
7.6.4
Adverse Events Leading to Dose Modification........................................................83
7.6.5
Adverse Events .......................................................................................................83
7.6.6
Select Adverse Events .............................................................................................84
7.6.6.1
Incidence of Select AE ............................................................................................84
7.6.6.2
Time-to Onset of Select AE .....................................................................................85
7.6.6.3
Time-to Resolution of Select AE..............................................................................85
7.6.7
Immune-Mediated Adverse Events ..........................................................................85
7.6.8
Other Events of Special Interest..............................................................................86
7.6.9
Multiple Events.......................................................................................................87
7.6.10
Laboratory Parameters...........................................................................................87
7.6.10.1
Hematology ............................................................................................................87
7.6.10.2
Serum Chemistry ....................................................................................................87
7.6.10.3
Electrolytes.............................................................................................................87
7.6.10.4
Additional Analyses................................................................................................88
7.6.11
Vital Signs ..............................................................................................................88
7.6.12
Physical Measurements ..........................................................................................88
7.6.13
Immunogenicity Analysis ........................................................................................89
7.6.14
Pregnancy ..............................................................................................................90
7.6.15
Adverse Events By Subgroup ..................................................................................90
7.7
Pharmacokinetic Analysis.......................................................................................90
7.8
Biomarker Analysis ................................................................................................90
7.8.1
Tumor and Immune PD-L1 (CPS)...........................................................................90
7.8.1.1
Distribution of CPS PD-L1.....................................................................................91
7.8.1.2
Association between PD-L1 Status and Efficacy .....................................................91
7.8.1.3
Predictive Relationship between PD-L1 Status and Efficacy...................................92
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7.8.2
Tumor PD-L1 .........................................................................................................92
7.8.2.1
Distribution of Tumor Cell PD-L1 ..........................................................................92
7.8.2.2
Association between Tumor Cell PD-L1 Status and Efficacy...................................93
7.8.2.3
Predictive Relationship between Tumor Cell PD-L1 Status and Efficacy.................94
7.8.3
MSI.........................................................................................................................94
7.8.3.1
MSI Distribution.....................................................................................................94
7.8.3.2
Association between MSI Status and Efficacy .........................................................94
7.8.3.3
Predictive Relationship between MSI Status and Efficacy .......................................95
7.9
Clinical Outcome Assessments...............................................................................95
7.9.1
FACT-Ga and TTSD...............................................................................................96
7.9.2
EuroQol EQ-5D-3L................................................................................................97
7.10
COVID-19 Related Analyses..................................................................................98
8
ANALYSES TO EVALUATE THE CONTRIBUTION OF COMPONENTS 
IN THE N+I REGIMEN.........................................................................................98
8.1
Ipilimumab contribution .........................................................................................98
8.1.1
OS and PFS............................................................................................................99
8.1.2
ORR and DOR......................................................................................................100
9
CONVENTIONS..................................................................................................100
10
CONTENT OF REPORTS ...................................................................................102
11
DOCUMENT HISTORY......................................................................................102
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..........................................................................105
APPENDIX 2
MISSING AND PARTIAL RADIOTHERAPY AND SURGERY 
DATES IMPUTATION ALGORITHMS .............................................107
APPENDIX 3
IMMUNOGENICITY ANALYSIS: BACKGROUND AND 
RATIONALE.......................................................................................109
APPENDIX 4
ANALYSES OF DATA FROM CHINA ..............................................112
APPENDIX 5
SAMPLE SIZE UPDATE ....................................................................113
12
REFERENCES.....................................................................................................116
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LIST OF TABLES
Table 1-1:
Timing of Analyses ................................................................................10
Table 2.4-1:
Relevant Protocol Amendments..............................................................15
Table 4-1:
Summary of Key Efficacy Endpoints......................................................19
Table 4.1.2.1-1:
Censoring Scheme Used in Primary Definition of PFS ...........................22
Table 4.1.2.2-1:
Censoring Scheme for Secondary Definition of PFS...............................24
Table 5.1-1:
Randomization Allocation and Sample Size............................................29
Table 5.2.1-1:
PFS Hazard Rates and Hazard Ratios (Nivolumab plus 
Chemotherapy vs. Chemotherapy)..........................................................34
Table 5.2.1-2:
Summary of Sample Size Parameters and Schedule of Analyses for 
PFS (Nivolumab plus Chemotherapy vs. Chemotherapy)........................34
Table 5.2.1-3:
Assumed OS Hazard Rates and Hazard Ratios (Nivolumab plus 
Chemotherapy vs. Chemotherapy)..........................................................35
Table 5.2.1-4:
Summary of Sample Size Parameters and Schedule of Analyses for 
OS (Nivolumab plus Chemotherapy vs. Chemotherapy) .........................35
Table 5.2.2-1:
Assumed OS Hazard Rates and Hazard Ratios (Nivolumab plus 
Ipilimumab vs. Chemotherapy)...............................................................37
Table 5.2.2-2:
Summary of Sample Size Parameters and Schedule of Analyses for 
OS (Nivolumab plus Ipilimumab vs. Chemotherapy)..............................37
Table 7.4.1-1:
Administration of Study Therapy in the Nivolumab plus 
Ipilimumab Arm.....................................................................................49
Table 7.4.1-2:
Formula for Relative Dose Intensity for Nivolumab in Nivolumab 
plus Ipilimumab Regimen.......................................................................50
Table 7.4.1-3:
Administration of Study Therapy for Subjects Treated with 
XELOX..................................................................................................50
Table 7.4.1-4:
Formula for Relative Dose Intensity for Nivolumab in Nivolumab 
plus XELOX Regimen:...........................................................................51
Table 7.4.1-5:
Administration of Study Therapy for Subjects Treated with 
FOLFOX................................................................................................51
Table 7.4.1-6:
Formula for Relative Dose Intensity for Nivolumab Nivolumab 
plus FOLFOX Regimen..........................................................................53
Table 7.4.2.1-1:
Dose Delays ...........................................................................................54
Table 7.5-1:
Stratification Factors Used for Stratified Analyses..................................57
Table 7.5.1-1:
Significance Levels for Primary and Secondary Endpoints .....................59
Table 8.1-1: Stratification Factors Used for Stratified Analyses Supporting CoC.......................99
Table 11-1:
Document History ................................................................................102
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Table 1
Derivation of Clustered AE ..................................................................106
Table 1
Updated Summary of Sample Size Parameters and Schedule of 
Analyses for PFS (Nivolumab + Chemotherapy vs. Chemotherapy) .....114
Table 2
Updated Summary of Sample Size Parameters and Schedule of 
Analyses for OS (Nivolumab + Chemotherapy vs. Chemotherapy).......114
Table 3:
Updated Summary of Sample Size Parameters and Schedule of 
Analyses for OS (Nivolumab + Ipilimumab vs. Chemotherapy)............115
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LIST OF FIGURES
Figure 2.1-1:
Study Scheme.........................................................................................11
Figure 4.1.2.1-1:
PFS Primary Definition ..........................................................................22
Figure 4.1.2.2-1:
PFS Secondary Definition ......................................................................23
Figure 5.2-1:
Randomization Schema ..........................................................................31
Figure 5.2-2:
PFS for Chemotherapy from External Data and Assumed 
Distribution for Chemotherapy ...............................................................32
Figure 5.2-3:
OS for Chemotherapy from External Data and Assumed 
Distribution for Chemotherapy ...............................................................33
Figure 7.5.1-1:
Graphical Approach for Primary and Secondary Endpoints.....................58
Figure 8.1-1:
Randomization to the 3 Arms .................................................................99
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1
BACKGROUND AND RATIONALE
This document provides the statistical analyses that will be conducted to support the clinical study 
report (CSR) of the study and reflects the revised protocol 09.
CA209649 is a Phase 3, randomized, open-label study of nivolumab plus ipilimumab or nivolumab 
in combination with oxaliplatin plus fluoropyrimidine vs. oxaliplatin plus fluoropyrimidine in 
subjects with previously untreated advanced or metastatic gastroesophageal junction (GEJ) or 
gastric cancer (GC). This study will determine if nivolumab plus ipilimumab improves overall 
survival (OS) vs. the standard of care, oxaliplatin plus fluoropyrimidine, in subjects with GC/GEJ 
cancer with enriched PD-L1 expression by combined positive score (CPS); or whether nivolumab 
in combination with oxaliplatin plus fluoropyrimidine improves OS or PFS vs. the standard of 
care, oxaliplatin plus fluoropyrimidine, in subjects with GC/GEJ cancer with enriched PD-L1
expressing by CPS. Additional objectives include further characterization of efficacy, safety and 
tolerability, pharmacokinetics (PK), patient-reported outcomes, and potential predictive 
biomarkers of nivolumab in combination with ipilimumab or nivolumab in combination with 
oxaliplatin plus fluoropyrimidine in subjects with GC/GEJ whose tumors do or do not express 
PD-L1.
Research Hypotheses:  
In subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS ≥ 5, the administration 
of nivolumab in combination with oxaliplatin plus fluoropyrimidine (nivo+chemo) will improve 
PFS or OS compared to oxaliplatin plus fluoropyrimidine (chemo).
In subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS ≥ 5, the administration 
of nivolumab plus ipilimumab (nivo+ipi) will improve OS compared to oxaliplatin plus 
fluoropyrimidine (chemo).
Schedule of Analyses:
The primary analysis of PFS of nivo+chemo vs. chemo in randomized subjects with PD-L1 
CPS ≥5 will be conducted after a 12-month follow-up (12 months after the last subjects was 
randomized in the study). The primary analysis of OS of nivo+chemo vs. chemo in randomized 
subjects with PD-L1 CPS ≥5 includes one interim and final analysis. The interim OS analysis will 
be conducted after a 12-month follow-up, concurrently with the primary PFS analysis. The final 
OS analysis of nivo+chemo vs. chemo will be conducted after a 24-month follow-up, ie, 12 months 
after the OS interim analysis.
The analysis of OS of nivo+ipi vs. chemo in randomized subjects with PD-L1 CPS ≥5 will be 
conducted after 24 months follow-up after the last subjects was randomized in the study. Because 
the nivo + ipi arm was closed to enrolment earlier, this translates to approximately 36 months 
follow-up for subjects randomized to nivo+ipi or chemo. This analysis will be conducted at the 
time of the OS final analysis of nivo+chemo vs. chemo.
The timing of the efficacy analyses is described in Table 1-1.
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Table 1-1:
Timing of Analyses
Endpoints
Timing of Analysis
PFS nivo+chemo vs.
chemo in randomized 
subjects with PD-L1 
CPS ≥5
OS nivo+chemo vs.
chemoin randomized 
subjects with PD-L1 
CPS ≥5
OS nivo+ipi vs. chemo
in randomized subjects 
with PD-L1 CPS ≥5
12 months after last 
subject randomized
X
X (IA)
24 months after last 
subject randomizeda
X (FA)
X
a Twenty-four months follow-up from last patient randomized to nivo+chemo vs. chemo, corresponds to 36-month 
minimum follow-up for nivo+ipi vs chemo.
2
STUDY DESCRIPTION
2.1
Study Design
The study design described in this section reflects the revised protocol 09 (including protocol 
amendment 29).
This is a Phase 3, randomized, open-label, three-arm study of nivolumab plus ipilimumab or 
nivolumab in combination with oxaliplatin plus fluoropyrimidine vs.
oxaliplatin plus 
fluoropyrimidine in subjects with previously untreated advanced or metastatic GC or GEJ cancer.
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Figure 2.1-1:
Study Scheme
The accrual was complete in May 2019 and the sample size is 2031 subjects randomized, with 
83 subjects randomized in 1:1 ratio to nivo + ipi vs. chemo, followed by ~1098 subjects 
randomized in 1:1:1 ratio to the 3 arms until the closure of enrollment of the nivo+ipi arm, and 
finally 850 subjects randomized to nivo+chemo vs. chemo (see also Table 5.1-1).
The treatment administration is as follows:
•
Nivo+Ipi Arm: nivolumab 1mg/kg administered IV over 30 minutes followed by ipilimumab
3mg/kg administered IV over 30 minutes on Day 1 of each treatment cycle every 3 weeks for
4 doses (Cycles 1 to 4), followed by nivolumab 240mg administered IV over 30 minutes on
Day 1 of each treatment cycle every 2 weeks (Cycle 5 and beyond)
Subjects treated in the nivolumab 240mg Q2W have an option to switch nivolumab 480mg Q4W, 
the nivolumab 480mg should be given 2 weeks following the last administration of nivolumab 
240 mg dose.
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•
Nivo+Chemo Arm (XELOX or FOLFOX):
−
Nivolumab plus XELOX: 
♦Nivolumab 360mg IV over 30 minutes on Day 1 of each treatment cycle, every 3 weeks 
♦Oxaliplatin 130mg/m2 IV on Day 1 of each treatment cycle + capecitabine 1000mg/m2
orally twice daily on Days 1 to 14 of each treatment cycle, every 3 weeks
−
Nivolumab plus FOLFOX: 
♦Nivolumab 240mg IV over 30 minutes on Day 1 of each treatment cycle, every 2 weeks 
♦Oxaliplatin 85mg/m2 + leucovorin 400mg/m2 + fluorouracil 400mg/m2 IV on Day 1 of 
each treatment cycle, and fluorouracil 1200 mg/m2 IV continuous infusion over 
24 hours daily or per local standard on Days 1 and 2 of each treatment cycle, every 
2 weeks
Nivolumab 480mg Q4W is permitted when all chemotherapy components are discontinued and 
nivolumab is continued alone. Subjects must be in the study for a minimum of 6 months from 
Cycle 1, Day 1 before switching to 480mg Q4W nivolumab. Nivolumab 480mg should be given 
2 weeks or 3 weeks following the last administration of nivolumab 240mg Q2W or 360mg Q3W, 
respectively. 
•
Chemo Arm (XELOX or FOLFOX):
−
XELOX: Oxaliplatin 130mg/m2 IV on Day 1 of each treatment cycle + capecitabine 
1000mg/m2 orally twice daily on Days 1 to 14 of each treatment cycle, every 3 weeks
−
FOLFOX: Oxaliplatin 85mg/m2 + leucovorin 400mg/m2 + fluorouracil 400mg/m2 IV on 
Day 1 of each treatment cycle, and fluorouracil 1200mg/m2 IV continuous infusion over 
24 hours daily or per local standard on Days 1 and 2 of each treatment cycle, every 2 weeks.
The treatment will be administered until disease progression (PD) (unless treatment beyond 
progression is permitted, in nivo + chemo and nivo + ipi arms), unacceptable toxicity, or subject 
withdrawal of consent, whichever occurs first.
The treatment with nivolumab will be given for up to 24 months in the absence of disease
progression or unacceptable toxicity. Chemotherapy will be given as per the study dosing schedule.
Upon fulfillment of protocol pre-specified criteria, and providing written informed consent, 
treatment with nivolumab could be reinitiated as per the initial schedule for subsequent disease
progression and administered for up to 1 additional year.
The study will consist of 3 phases: screening, treatment, and follow-up.
Screening Phase
•
Begins by establishing the subject’s initial eligibility and signing of the informed consent form 
(ICF).
•
Subject is enrolled using the Interactive Response Technology (IRT) system.
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•
The choice of chemotherapy regimen XELOX or FOLFOX must be decided before placing the 
randomization call to the IRT system.
•
Subjects must have PD-L1 immunohistochemistry (IHC) testing, with results, performed by
the central lab during the Screening period. Without evaluable PD-L1 result, the subject may 
not be randomized.
•
Subject is assessed for study eligibility according to the inclusion and exclusion criteria. All 
screening assessments and procedures must be performed within 28 days prior to 
randomization unless otherwise specified.
Treatment Phase
•
Begins after the randomization call to the IRT system. The subject is randomly assigned in a 
1:1:1 ratio to the nivo+chemo, nivo+ipi or the chemo arm up to protocol amendment 20. After 
amendment 20, the subject is randomized to 1:1 the nivo+chemo or the chemo arm as 
enrollment to nivo+ipi was closed.
•
Administration of study treatment is to begin within 3 calendar days of randomization.
•
The treatment phase ends when the subject is discontinued from study therapy.
•
Treated subjects will be evaluated for tumor assessments every 6 weeks (± 7 days) up to and
including Week 48, then every 12 weeks (± 7 days) thereafter.
Dosing in the Nivo+Ipi Arm:
•
On the day of infusion, nivolumab is to be administered first. The second infusion will always 
be ipilimumab, and will start at least 30 minutes after completion of the nivolumab infusion.
•
Nivolumab (as flat dose) is allowed to be administrated alone in case ipilimumab has to be 
discontinued due to toxicity. Ipilimumab is also allowed to be administrated alone in case 
nivolumab has to be discontinued due to toxicity. 
•
Treatment beyond initial, investigator-assessed, RECIST 1.1-defined progression is permitted 
if the subject has investigator-assessed clinical benefit and is tolerating treatment.
Dosing in the Nivo+Chemo Arm: 
•
On the day of infusion, nivolumab is to be administered first. The administration procedures 
of chemotherapy will follow local standards. 
•
Nivolumab is allowed to be administrated alone in case the chemotherapy has to be 
discontinued due to toxicity. Chemotherapy alone is also allowed to be administered in doublet 
or monotherapy in case nivolumab has to be discontinued due to unacceptable toxicity. 
•
Nivolumab treatment beyond initial, investigator-assessed, RECIST 1.1-defined progression 
is permitted if the subject has investigator-assessed clinical benefit and is tolerating treatment. 
Chemotherapy alone is not allowed to treat beyond progression. 
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•
No cross-over is allowed between XELOX and FOLFOX. 
Dosing in the Chemo Arm:
•
The administration procedures will follow local standards.
•
No cross-over is allowed between XELOX and FOLFOX.
Follow-up Phase
•
Begins when the decision is made to discontinue a subject from study therapy.
•
After completion of the first 2 follow-up (FU) visits (30 days [± 7 days] from last dose and
84 days [± 7 days] from FU1), subjects will be followed by clinic visit or phone contact every 
3 months (±14 days) or more frequently as needed for survival status and subsequent anti-
cancer therapy.
•
Subjects who discontinue treatment for reasons other than PD will continue to have tumor
assessments (until PD) every 6 weeks (± 7 days) up to and including Week 48, then every
12 weeks (±7 days) thereafter.
•
Subjects will be followed for drug-related toxicities until these toxicities resolve, return to
baseline or are deemed irreversible. All drug-related toxicities will be documented for a 
minimum of 100 days after the last dose of study drug.
2.2
Treatment Assignment
After the subject’s initial eligibility is established and informed consent has been obtained, the 
subject must be enrolled into the study by entering information into the IRT system to obtain the 
subject number. Every subject that signs the ICF must be assigned a subject number in the IRT.
Once enrolled in the IRT, subjects that have met all eligibility criteria (the required tumor tissue 
received and result obtained by the central laboratory) will be ready to be randomized through the 
IRT. 
Randomization will be stratified by the following factors:
•
PD-L1 expression level (tumor cells) (≥1% vs. < 1% or indeterminate)
•
Region: Asia vs. US vs. RoW
•
ECOG performance status: 0 vs. 1
•
Planned chemotherapy regimen (XELOX vs. FOLFOX)*
*
Chemotherapy was added as a randomization stratification factor with Amendment 08. Information has been 
collected in IRT even for subjects randomized prior to amendment 08.
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2.3
Blinding and Unblinding
The trial is open label, however the Sponsor will handle the study as a blinded study and no 
analyses or summaries by randomized treatment arms will be produced during the conduct of the 
study by the Sponsor.
The final PFS analysis in randomized subjects with PD-L1 CPS ≥5 and interim OS analyses in 
randomized subjects with PD-L1 CPS ≥5 will be reviewed by the Data Monitoring Committee 
(DMC). The DMC will also review interim OS analyses in randomized subjects with PD-L1 CPS
≥1 and the interim OS analysis in all randomized subjets. The analyses, by unblinded arms, will 
be provided by the DMC independent reporting statistician to the DMC members.
If the formal efficacy interim analysis meets the pre-specified statistical criteria for at least one of 
the primary endpoints (PFS in PD-L1 CPS ≥5 or OS in PD-L1 CPS ≥5), the DMC Chairman will 
notify the BMS Head of Oncology Clinical Development by releasing the DMC closed report with 
unblinded treatment arms. The BMS Head of Oncology Clinical Development may in turn choose 
to release the closed report to additional members of the BMS restricted team after reviewing the 
closed DMC report. The BMS Head of Oncology Clinical Development will inform the DMC 
members and the independent statistician by email on whether the restricted BMS team has
decided that the BMS study team should be unblinded to the study results.
The closed report, which will be shared with the BMS restricted team, will only contain the 
aggregated OS results by treatment arms for the CPS cutoffs which meet statistical significance. It 
will not contain OS results for the CPS cutoffs that do not meet statistical significance unless it is 
requested by health authorities. The PFS results will be included in the closed report if at least one 
of the PFS endpoint and OS endpoint meets statistical significance as this is the final and unique 
analysis for PFS.
In addition, the Blinded Independent Central Review (BICR) Committee will perform the central 
imaging review without knowledge of the treatment group assignment.
The Lab vendor performing the tumor cell PD-L1 and CPS PD-L1 scoring is also blinded to the 
treatment group assignment.
2.4
Protocol Amendments
Global amendments incorporated in the protocol with relevant changes are described in 
Table 2.4-1. 
Table 2.4-1:
Relevant Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
Amendment 29
16-sep-2019
•
Based on the data from the Keynote 062 study, PFS and OS Kaplan-
Meier curves showed an observed delayed separation, the timing of 
PFS and OS analyses are updated with minimum follow up 12 and 
24 months. In addition, to reduce variability of efficacy results, PFS 
population was expanded to all randomized subjects with PD-L1 
CPS ≥5.
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Table 2.4-1:
Relevant Protocol Amendments
Amendments
Date of Issue
Summary of Major Changes
•
A 480mg Q4W nivolumab dosing option for subjects who receive 
nivolumab alone after treatment with nivolumab in combination 
with ipilimumab or FOLFOX/XELOX is allowed.
Amendment 26
15-Nov-2018
•
Based on recent internal data, added approximately 356 subjects 
into randomization, in total of approximately 2005 subjects will be
randomized to keep sample size for primary analyses of PFS and 
OS in PD-L1 CPS ≥5 subjects for nivolumab in combination with
chemotherapy vs. chemotherapy.
Amendment 23
14-Sep-2018
•
Incorporates the combined positive score (CPS) for PD-L1 
expression,
the primary population is now subjects with
PD-L1 expression ≥5 by CPS rather than by the tumor proportion
score (TPS) for subjects with nivolumab in combination with
oxaliplatin and fluoropyrimidine compared to oxaliplatin and
fluoropyrimidine.
•
The planned analysis of overall survival (OS) for nivolumab plus
ipilimumab arm is changed to a secondary objective.
•
Objective response rate (ORR) has been changed to a secondary
endpoint.
•
The primary, secondary, and exploratory objectives have been
updated to reflect changes in subject population definition.
•
Second disease progression (PFS2) and time to secondary 
subsequent therapy (TSST) have been added as exploratory 
analyses. 
•
Statistical assumptions and considerations revised to reflect changes
in study population and revised objectives.
Amendment 20
11-Jun-2018
•
Per recommendation of the Data Monitoring Committee (DMC), as 
of 05-June-2018, the nivolumab plus ipilimumab arm is now closed.
Subjects randomized to this arm prior to or on 05-June-2018 will
continue to receive treatment with study drugs per protocol, and the
study data will remain blinded until planned primary analysis.
Amendment 19
29-May-2018
•
Added that randomization of an additional 300 subjects beyond the
originally planned 1349 subjects across the 3 study arms will allow
for more robust analysis of the treatment effect of nivolumab in
combination with ipilimumab or chemotherapy across different
PD-L1 cutoffs in 1L GC/GEJ cancer.
Amendment 08
07-Dec-2016 
•
Added a new randomization arm, N+C to the study.
•
Added chemotherapy as randomization stratification factor.
•
Added Blinded Independent Central Review (BICR) of tumor 
images.
•
Clarified some study procedures, including limiting the treatment 
period with nivolumab to 2 years.
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2.5
Blinded Independent Central Review of Progression
The clinical management of subjects during the study will be based upon local radiologic tumor 
measurements. Tumor assessments for each subject should be submitted to the radiology vendor 
as they are performed, on an ongoing basis. The blinded, independent radiologists will review all 
available tumor assessments for that given subject and determine if RECIST 1.1 criteria for 
progression have been met. 
If clinically acceptable, subsequent therapy should begin only after RECIST 1.1 progression has 
been assessed by blinded independent central review. When RECIST 1.1 progression is assessed 
by the investigator (whether assessed before or after the start of subsequent therapy), confirmation 
by the BICR must be requested. Tumor assessments may be discontinued when the independent 
radiologist assesses the subject to have met RECIST 1.1 criteria for progression. 
In addition, subjects receiving treatment beyond progression must continue tumor assessments 
until treatment has been discontinued. 
2.6
Data Monitoring Committee
An independent DMC will be utilized to provide oversight of safety and efficacy considerations. 
Additionally, the DMC will provide advice to the sponsor regarding actions the committee deems 
necessary for the continuing protection of subjects enrolled in the study. The DMC will be charged 
with assessing such actions in light of an acceptable benefit/risk profile for nivolumab plus 
ipilimumab and nivolumab plus chemotherapy. The DMC will act in an advisory capacity to BMS 
and will monitor subject 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. 
The DMC will also be responsible for conducting formal interim efficacy analysis of the study for
final PFS analysis and interim analysis of OS for nivo + chemo vs. chemo.
3
OBJECTIVES
3.1
Primary
Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs. oxaliplatin plus 
fluoropyrimidine:
To compare OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS ≥ 5.
To compare PFS, as assessed by BICR in subjects with advanced or metastatic GC or GEJ cancer 
with PD-L1CPS ≥ 5.
3.2
Secondary
Nivolumab plus ipilimumab vs. oxaliplatin plus fluoropyrimidine:
•
To compare OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS ≥5 or all randomized subjects.
•
To compare the time to symptom deterioration (TTSD) as assessed using the Gastric Cancer 
Subscale (GaCS) of the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) in 
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subjects with advanced or metastatic GC or GEJ cancer with PD-L1 CPS ≥5 or all randomized 
subjects.
•
To evaluate OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS ≥10 or subjects with PD-L1 CPS ≥1.
•
To evaluate PFS, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS ≥ 10, 5, 1 or all randomized subjects.
•
To evaluate ORR, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS ≥10, 5, 1 or all randomized subjects.
Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs. oxaliplatin plus 
fluoropyrimidine:
•
To compare OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS ≥1 or all randomized subjects
•
To evaluate OS in subjects with advanced or metastatic GC or GEJ cancer with PD-L1 
CPS ≥10.
•
To evaluate PFS, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS ≥10, 1 or all randomized subjects.
•
To evaluate ORR, as assessed by BICR, in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS ≥10, 5, 1, or all randomized subjects.
3.3
Exploratory
Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs. oxaliplatin plus 
fluoropyrimidine:
•
To assess TTSD using GaCS of FACT-Ga in subjects with advanced or metastatic GC or GEJ 
cancer with PD-L1 CPS ≥5 or all randomized subjects.
For both comparisons: Nivolumab in combination with oxaliplatin plus fluoropyrimidine vs.
oxaliplatin plus fluoropyrimidine and Nivolumab plus ipilimumab vs. oxaliplatin plus 
fluoropyrimidine: 
•
To assess PFS and ORR, as assessed by the investigator in subjects with advanced or metastatic 
GC or GEJ cancer across PD-L1 CPS cut-offs.
•
To evaluate Duration of Response (DOR) as assessed by BICR and by investigator, in subjects 
with advanced or metastatic GC or GEJ.
•
To evaluate the durable response rate (DRR) (defined as objective response lasting 
continuously > 6 months) as assessed by BICR and by investigator, in subjects with advanced
or metastatic GC or GEJ cancer.
•
To evaluate at 18, 24, and 36 months survival rates in subjects with advanced or metastatic GC 
or GEJ cancer.
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•
To evaluate second disease progression (PFS2) or time to second subsequent therapy (TSST) 
in subjects with advanced or metastatic GC or GEJ cancers.
•
To assess PFS, ORR as assessed by either BICR or investigator, OS in subjects with advanced 
or metastatic GC or GEJ cancer across PD-L1 tumor proportion score (TPS) cut-offs.
•
To assess the overall safety and tolerability of nivolumab plus ipilimumab or nivolumab in 
combination with oxaliplatin plus fluoropyrimidine and oxaliplatin plus fluoropyrimidine in 
subjects with advanced or metastatic GC or GEJ cancer.
•
To explore potential biomarkers predictive of or associated with clinical efficacy (OS, PFS and 
ORR) and/or incidence of AEs of nivolumab plus ipilimumab or nivolumab in combination 
with oxaliplatin plus fluoropyrimidine including but not limited to microsatellite instability 
(MSI) 
status, 
tumor 
mutational 
burden 
(TMB), 
 
 
 
 
 and inflammatory signatures in subjects with advanced 
or metastatic GC or GEJ cancer. 
•
To assess TTSD as assessed using GaCS of FACT-Ga in subjects with advanced or metastatic 
GC or GEJ cancer with PD-L1 CPS ≥10, or 1.
•
To assess changes from baseline in the subject̓s overall health status using the 3-level version
of the EQ-5D (EQ-5D-3L) index and visual analog scale (EQ-VAS).
•
To assess the subject̓s cancer-related quality of life using the FACT-Ga questionnaire and
selected components, including the GaCS and 7-item version of the FACT-General (FACT-
G7).
4
ENDPOINTS
A summary of the efficacy endpoints is presented in Table 4-1
Table 4-1:
Summary of Key Efficacy Endpoints
Nivolumab plus Chemotherapy vs 
Chemotherapy
Nivolumab plus Ipilimumab vs 
Chemotherapy
Primary endpoints
•
PFS by BICR in subjects with 
PD-L1 CPS ≥5 (controlled for 
Type I error)
•
OS in subjects with PD-L1 CPS 
≥5 (controlled for Type I 
error)
Secondary endpoints
•
OS in subjects with PD-L1 CPS 
≥1, and in all randomized 
subjects (controlled for Type I 
error)
•
OS in subjects PD-L1 CPS ≥10
•
PFS by BICR in subjects with 
PD-L1 CPS ≥10, 1 or all 
randomized subjects
•
OS in subjects with PD-L1 CPS ≥5
and in all randomized subjects.
(controlled for Type I error)
•
OS in subjects PD-L1 CPS ≥10,1
•
ORR, PFS by BICR in subjects with 
PD-L1 CPS ≥10, 5, 1 or all 
randomized subjects.
•
TTSD in subjects with PD-L1 CPS 
≥5 and in all randomized subjects
(controlled for Type I error)
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Table 4-1:
Summary of Key Efficacy Endpoints
Nivolumab plus Chemotherapy vs 
Chemotherapy
Nivolumab plus Ipilimumab vs 
Chemotherapy
•
ORR by BICR in subjects with 
PD-L1 CPS ≥10, 5, 1 or all 
randomized subjects
•
ORR, PFS by investigator in 
subjects with PD-L1 CPS ≥10, 
5, 1 or all randomized subjects
Exploratory 
Endpoints
•
OS, PFSa, ORRb in subjects 
with PD-L1 TPS across cut-offs
•
OS rates at 18, 24, and 36 
months
•
PFS 2 or TSST on next line 
treatment
•
DOR
•
DRR
•
TTSD in subjects with PD-L1 
CPS ≥10, 5, 1 or all 
randomized subjects
•
Biomarkers
•
ORR, PFS by investigator in 
subjects with PD-L1 CPS ≥10, 5, 1 
or all randomized subjects
•
OS, PFSc, ORRd in subjects with 
PD-L1 TPS across cutoffs
•
OS rates at 18, 24, and 36 months
•
PFS 2 or TSST on next line 
treatment
•
DOR
•
DRR
•
TTSD in subjects with PD-L1 CPS 
≥10, or 1
•
Biomarkers
a Per BICR and investigator assessments 
4.1
Primary Endpoints for Nivolumab plus Chemotherapy
For nivo+chemo versus chemo.
4.1.1
Overall Survival
Overall Survival is defined as the time from the date of randomization to the date of death from 
any cause. For subjects that are alive, their survival time will be censored at the date of last contact 
date (or “last known alive date”). Overall survival will be censored at the date of randomization 
for subjects who were randomized but had no follow-up.
Primary objective of the study is the comparison of OS between nivo+chemo and chemo in PD-L1 
CPS ≥5 subjects.
4.1.2
Progression-Free Survival
Two definitions are used for analysis of Progression-Free Survival. The primary definition 
accounts for subsequent therapy by censoring at the last evaluable tumor assessment on or prior to 
the date of subsequent therapy. This definition will be used to run the primary analysis of PFS 
(per BICR) for this trial and to declare statistical significance for the PFS endpoint.
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The secondary definition is irrespective of subsequent therapy and will be presented as supportive 
analysis of the primary PFS analysis. This definition is considered primary by EMA.
Clinical deterioration in the absence of unequivocal evidence of progression (per RECIST v1.1 
criteria) is not considered progression for purposes of determining PFS.
PFS rates at fixed time points (eg, 6 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.
The first on-study tumor assessment is scheduled to be conducted at 6 weeks (± 1 week) following 
first dose. Subsequent tumor assessments are scheduled every 6 weeks (± 1 week) up to and 
including Week 48, then every 12 weeks (± 7 days) regardless of treatment schedule until disease 
progression.
4.1.2.1
Primary Definition of Progression-Free Survival (Accounting for 
Subsequent Therapy)
The primary definition of PFS (PFS truncated at subsequent therapy) is defined as the time between 
the date of randomization and the date of first documented tumor progression, based on BICR 
assessments (per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. 
The following censoring rules will be applied for the primary definition of PFS:
•
Subjects who did not progress or die will be censored on the date of their last evaluable tumor 
assessment.
•
Subjects who did not have any on-study tumor assessments and did not die will be censored 
on their date of randomization.
•
Subjects who received subsequent anti-cancer therapy prior to documented progression 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 and received subsequent anti-cancer 
therapy will be censored at the date of the last evaluable tumor assessment conducted on or 
prior to the initiation of the subsequent anti-cancer therapy.
In the above, subsequent anti-cancer therapy is all systemic therapies, surgery with reason of tumor 
resection palliative or tumor resection curative, radiotherapy with reason curative or palliative.
Censoring rules for the primary definition of PFS (PFS truncated at subsequent therapy) are 
presented in Figure 4.1.2.1-1 and in Table 4.1.2.1-1.
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Figure 4.1.2.1-1:
PFS Primary Definition
Table 4.1.2.1-1:
Censoring Scheme Used in Primary Definition of PFS
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments*
Date of randomization 
Censored 
No on study tumor assessments and 
no death* 
Date of randomization
Censored
Subsequent anti-cancer therapy 
started without prior progression 
per RECIST v1.1 or death
Date of last evaluable tumor 
assessment prior to or on the date of 
initiation of the subsequent anti-
cancer therapy
Censored 
Documented progression per 
RECIST v1.1 and no subsequent
anti-cancer therapy started before
Date of the first documented 
progression per RECIST v1.1 
(excludes clinical progression)
Progressed 
No progression and no death, and 
no new anti-cancer therapy started
Date of last evaluable tumor 
assessment 
Censored 
Death without progression per 
RECIST v1.1 and no prior 
subsequent anti-cancer therapy
Date of death 
Progressed 
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* Tumor assessments and death if any, occurring after start of subsequent anti-cancer therapy are not considered.
Primary objective of the study is the comparison of PFS between nivo+chemo and chemo in 
PD-L1 CPS ≥5 subjects.
4.1.2.2
Secondary Definition of Progression Free Survival (Irrespective of 
Subsequent Therapy)
The secondary definition of PFS (ITT definition) is defined as the time between the date of 
randomization and the date of first documented tumor progression, based on BICR assessments 
(per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. 
The following censoring rules will be applied for the secondary definition of PFS:
•
Subjects who did not progress or die will be censored on the date of their last evaluable tumor
assessment.
•
Subjects who did not have any on study tumor assessments and did not die will be censored on
their date of randomization.
Censoring rules for the secondary definition of PFS (ITT definition) are presented in Figure 
4.1.2.2-1 and in Table 4.1.2.2-1.
Figure 4.1.2.2-1:
PFS Secondary Definition
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Table 4.1.2.2-1:
Censoring Scheme for Secondary Definition of PFS
Situation
Date of Progression of Censoring
Outcome
No baseline tumor assessment
Date of randomization
Censored
No on-study tumor assessments and 
no death
Date of randomization
Censored
Documented progression per 
RECIST v1.1  
Date of first documented 
progression per RECIST v1.1 
criteria (excludes clinical 
progression)
Progressed
No progression and no death
Date of last evaluable tumor 
assessment
Censored
Death without progression per 
RECIST v1.1
Date of death
Progressed
4.2
Secondary Endpoints
4.2.1
For Nivo + Chemo versus Chemo
4.2.1.1
Overall Survival
Secondary objectives are the comparison of OS between nivo+chemo and chemo in PD-L1 CPS 
≥1 subjects and in all randomized subjects. OS will also be evaluated for subjects with CPS ≥10. 
Overall survival is as defined in Section 4.1.1.
4.2.1.2
Progression-Free Survival
Secondary objectives are the evaluation of PFS per BICR for nivo+chemo and chemo in PD-L1 
CPS ≥1 subjects, CPS ≥10 subjects and in all randomized subjects. Progression free survival is 
as defined in Section 4.1.2.
4.2.1.3
Objective Response Rate
Objective Response Rate (ORR) is defined as the number of randomized subjects who achieve a 
best overall response of confirmed complete response (CR) or confirmed partial response (PR)
based on BICR assessment (using RECISTS v1.1) divided by the number of randomized subjects.
Best Overall Response (BOR) is defined as the best response, as determined by the BICR, recorded 
between the date of randomization and the date of objectively documented progression per 
RECIST v1.1 criteria or the date of subsequent anti-cancer therapy (including all systemic 
therapies, surgery with reason of tumor resection palliative or tumor resection curative, 
radiotherapy with reason curative or palliative), whichever occurs first. For subjects without 
documented progression or subsequent therapy, all available response designations will contribute 
to the BOR determination.
ORR will be evaluated for nivo + chemo and chemo in PD-L1 CPS ≥10, 5, 1 or all randomized 
subjects.
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4.2.2
For Nivo + Ipi versus Chemo.
4.2.2.1
Overall Survival
Secondary objectives are the comparison of OS between nivo+ipi and chemo in PD-L1 
CPS ≥5 subjects and in all randomized subjects. OS will also be evaluated for subjects with 
CPS ≥10 and CPS ≥1 subjects. Overall survival is as defined in Section 4.1.1.
4.2.2.2
Progression Free Survival
Secondary objectives are the evaluation of PFS per BICR for nivo+ipi and chemo in PD-L1
CPS ≥10, CPS ≥5, CPS ≥1and in all randomized subjects. Progression free survival is as defined 
in Section 4.1.2.
4.2.2.3
Objective Response Rate
Secondary objectives are the evaluation of ORR per BICR for nivo+ipi and chemo in PD-L1 
CPS ≥10, CPS ≥5, CPS ≥1 and in all randomized subjects. Objective response rate is as defined 
in Section 4.2.1.3.
4.2.2.4
Time to Symptom Deterioration
Time to symptom deterioration is defined as the time from randomization until a clinically 
meaningful decline from baseline in GaCS score. A clinically meaningful deterioration is defined 
as a reduction of 8.2 points in the GaCS score. Only events before treatment discontinuation will 
be taken into account: patients who do not deteriorate before treatment discontinuation will be 
censored at the time of their last on-treatment GaCS assessment. Those who have no GaCS 
assessments after randomization and those who were never treated will be censored on the date of 
randomization. For more details on the GaCS scale, see Section 4.3.3. Secondary objectives are 
the comparison of TTSD between nivo+ipi and chemo in PD-L1 CPS ≥ 5 subjects and all 
randomized subjects.
4.3
Exploratory Endpoints
4.3.1
Efficacy Exploratory Endpoints
All the following exploratory endpoints may be explored on the different CPS population 
(ie, CPS ≥ 10, CPS ≥ 5, CPS ≥ 1 and all randomized).
Progression-Free Survival
Progression-free Survival as assessed by investigator is defined similarly as the corresponding
endpoints as assessed by BICR.
Objective Response Rate
Objective Response Rate (as assessed by investigator) is defined similarly as the corresponding 
endpoint as assessed by BICR.
Duration of Response
Duration of response is defined as the time between the date of first confirmed documented 
response (CR or PR) and the date of the first documented tumor progression as determined by the 
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BICR or investigator (per RECIST v1.1 criteria) or death due to any cause, whichever occurs first. 
Censoring rules for DOR follow the censoring rules for PFS primary definition.
Durable Response rate
Durable Response Rate is defined as the number of subjects with confirmed documented response 
(CR or PR) as determined by the BICR or investigator (per RECIST v1.1 criteria) whose response 
lasted for at least 6 months, divided by the number of randomized subjects.
Survival Rate
OS rates at fixed time points (eg, 18, 14, 16 months, depending on the minimum follow-up) are 
defined as the probability that a subject is alive at time T following randomization. Overall 
survival rates at other timepoints are defined similarly.
PFS2/TSST
PFS on next-line therapy (PFS2) is defined as the time from randomization to objectively 
documented progression, per investigator assessment, on the start of the next line of therapy or the 
start of the second next line therapy or to death from any cause, whichever occurs first. Subjects 
who are alive and without progression on the next line of therapy will be censored at last known 
alive date. 
The following censoring rules will be applied for PFS2:
•
Subjects who did not receive subsequent anti-cancer therapy (ie, next-line therapy):
−
Subjects who died, the death date is the event date;
−
Else the subject’s PFS2 is censored at the last known alive date.
•
Subjects who received subsequent anti-cancer therapy (ie, next-line therapy):
−
Subjects who had a disease progression after the start of subsequent next line 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;
−
Else the subject’s PFS2 is censored at the last known alive date.
4.3.2
Safety Exploratory Endpoints
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, and immunogenicity (ie, development of anti-drug antibody) will be analyzed.
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4.3.3
Outcomes Research Exploratory Endpoints
EQ-5D
Subjects’ reports of general health status will be measured using the EuroQoL 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 set.1
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.2
A change from baseline of 0.08 for the EQ-5D-3L utility index score and of 7 for the EQ-5D-3L 
VAS are considered minimally important differences for the EQ-5D-3L.3
FACT-Ga
The FACT-Ga questionnaire and selected components, including the FACT-G7 and GaCS, will 
be used to assess the effects of underlying disease and its treatment on health-related quality of life 
(HRQoL) for patients.
As a generic cancer-related questionnaire, the FACT-Ga includes the 27-item FACT-General 
(FACT-G) to assess symptoms and treatment-related effects impacting physical well-being (PWB; 
seven items), social/family well-being (SWB; seven items), emotional well-being (EWB; six 
items), and functional well-being (FWB; seven items). Seven of these items comprise the 
FACT-G7, an abbreviated version of the FACT-G that provides a rapid assessment of general 
HRQoL in cancer patients.
In addition to the FACT-G, The FACT-Ga includes a 19-item disease-specific GaCS that assesses 
additional disease specific symptoms and impacts relating to pain, reflux, dysphagia, eating 
difficulties, tiredness, weakness, interference, and difficulty planning. Each FACT-Ga item is rated
on a five-point scale ranging from 0 (not at all) to 4 (very much).
Scores for the PWB, FWB, SWB, and EWB subscales can be combined to produce a FACT-G 
total score, which provides an overall indicant of generic HRQoL. The FACT-G and GaCS scores 
can be combined to produce a total score for the FACT-Ga, which provides a composite measure 
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of general and targeted HRQoL. Higher scores indicate better HRQoL. The full FACT-Ga will be 
administered to subjects during the on-treatment phase and at follow up visits 1 and 2. However, 
to minimize subject response and administrative burden, only the FACT GaCS and FACT-G7 will 
be administered during the survival follow-up phase.
4.3.4
Pharmacokinetics Exploratory Endpoints
PK will be determined from serum nivolumab and ipilimumab concentrations. Samples will be 
collected to characterize pharmacokinetics of nivolumab and ipilimumab and to explore exposure-
safety and exposure-efficacy relationships. 
4.3.5
Immunogenicity Exploratory Endpoints
Serum samples collected will be analyzed by a validated immunogenicity assay. Selected serum 
samples may be analyzed by an exploratory orthogonal method that measures anti-nivolumab and 
anti-ipilimumab.
In addition, ad hoc serum samples designated for pharmacokinetic or biomarker assessments may 
also be used for immunogenicity analysis if required (eg, insufficient volume for complete 
immunogenicity assessment or to follow up on suspected immunogenicity related AE).
Immunogenicity endpoints are defined in APPENDIX 3.
5
SAMPLE SIZE DETERMINATION
5.1
Randomization Schema
The original study design (before Amendment 08) had 2 arms, with subjects being randomized in 
a 1:1 ratio to the nivolumab plus ipilimumab or to the oxaliplatin plus fluoropyrimidine arm 
(XELOX or FOLFOX; arm will be further referred to as chemotherapy arm). Amendment 08 
added a new arm: nivolumab in combination with oxaliplatin plus fluoropyrimidine (XELOX or 
FOLFOX; arm will be further referred to as nivolumab plus chemotherapy arm). The IRT switched 
to a 1:1:1 randomization at all the participating sites when this third arm was ready to be opened 
on 27-Mar-2017. Up until that point, there were 83 subjects randomized in the 1:1 randomization 
to nivolumab plus ipilimumab and chemotherapy arm. In Amendment 08, it was planned to 
randomize 1266 subjects at 1:1:1 ratio to nivolumab plus ipilimumab, chemotherapy and 
nivolumab plus chemotherapy arms. The total number of subjects to be randomized was planned 
to be 1349.
Newly available internal and external data suggested a stronger predictability of PD-L1 CPS than 
TPS of immunotherapy treatment effects. However, uncertainty still exists of CPS at different 
cutoffs when extrapolated to first line metastatic setting in GC and GEJ. To ensure sufficient 
sample size for evaluating the correlation of efficacy and different CPS cutoffs and to keep 
continuity of enrollment of the study, on 29-May-2018, Amendment 19 was approved to allow 
additional 300 subjects to be randomized under 1:1:1 ratio for a total sample size of 1566 to the 3 
treatment arms.
Per DMC recommendation, randomization to the nivolumab plus ipilimumab arm was stopped on 
05-June-2018. The subjects who were already randomized to treatment in this arm prior to or on 
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05-June-2018 continued to receive study treatment per protocol, and the study data remained 
blinded for the planned analysis. As such, the 1:1:1 randomization was carried through on 05-Jun-
2018. These changes were implemented in Amendment 20. At this point, a total of 1098 subjects 
were randomized under 1:1:1 ratio. In addition, there were 83 subjects randomized to nivolumab 
plus ipilimumab and to chemotherapy arms (prior to Amendment 08). Following Amendment 20, 
subjects were to be randomized in 1:1 ratio to either the nivolumab plus chemotherapy or the 
chemotherapy arm.
In November 2018, data suggested that the PD-L1 CPS ≥ 5 prevalence was ~27% (unpublished 
data), which was lower than the original estimate of 35%. Therefore, the enrollment was extended 
to ensure that the study was appropriately powered for PFS and OS primary endpoints in the 
CPS ≥ 5population. To allow for this, Amendment 26 increased the total sample size from 1649
to approximately 2005. This resizing of the total population was to ensure that the sample size of 
the enriched population for the primary analyses (subjects with CPS ≥ 5) was the same as was 
specified in Amendment 23 to maintain the same power under the statistical assumptions as stated 
in Amendment 23.
The accrual was completed in May 2019 and in total 2031 subjects were randomized. It is 
estimated that 1582 subjects were concurrently randomized to nivolumab plus chemotherapy and 
to chemotherapy and that 815 subjects were concurrently randomized to nivolumab plus
ipilimumab and chemotherapy.
Table 5.1-1 present the randomization schema and sample size.
Table 5.1-1:
Randomization Allocation and Sample Size
Protocol Periods
Randomization allocation
Number of 
Randomized Subjects
Current / Cumulative
First patient randomized -
Amendment 8
1:1 (Nivolumab +Ipilimumab: Chemotherapy)
83/83
Amendment 08 -
Amendment 20
1:1:1 (Nivolumab + Ipilimumab: Chemotherapy: 
Nivolumab + Chemotherapy)
1098/1181
Amendment 20 to 
amendment 26
1:1 (Chemotherapy: Nivolumab + Chemotherapy)
468/1649
Amendment 26 to the end 
of enrollment
1:1 (Chemotherapy: Nivolumab + Chemotherapy)
382/2031
5.1.1
Changes of Statistical Analyses and Timing of Analyses in Protocol 
Amendment 29
Per protocol Amendment 23 (November 2018), the primary population of both primary endpoints 
PFS and OS was changed to randomized subjects with PD-L1 CPS ≥5 and the PD-L1 CPS scoring 
process started for subjects already randomized in the study to date. In March 2019, the need for 
additional steps for the PD-L1 CPS scoring process was established and consequently the expected 
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completion date of PD-L1 CPS scoring will be delayed and is now projected to complete 
approximately 6 months or later after the completion of enrollment.
Recent data in 1L GC Phase 3 study suggested a longer delay of separation of KM curves of 
immuno-oncology drug plus chemo vs chemo for PFS and OS.4 These data suggested that a longer 
follow-up would warrant to fully capture of the treatment effect for the primary endpoints of PFS 
and OS in the N+CT vs. CT.
Considering the delay of completion of PD-L1 CPS scoring, and the need to have longer minimum 
follow-up for PFS and OS to ensure data maturity, Amendment 29 documents the changes on the 
timing of PFS and OS analyses from event driven to time driven. In addition, Amendment 29 
specifically, documents the changes of the primary population of PFS. 
The primary analysis of PFS in randomized subjects with PD-L1 CPS ≥5 will be conducted after 
a 12-month minimum follow-up (from the date last patient was concurrently randomized to N+CT 
or CT). The primary analysis of OS in randomized subjects with PD-L1 CPS ≥5 includes one 
interim and final analysis. The interim analysis will be conducted after 12-month minimum follow-
up along with the primary PFS analysis. The final OS analysis will be conducted after a 24-month 
minimum follow-up, ie, 12 months after the OS interim analyses.
The analysis of OS in N+I vs. CT in randomized subjects with PD-L1 CPS ≥5 will be conducted 
at approximately 36-month minimum follow-up (after the last patient was randomized to N+I or 
CT). This analysis will be at the time of the final analysis of N+CT vs. CT.
The timing of the efficacy analyses is described in Table 1-1.
For the primary analyses of the endpoints stated above, all events observed in the locked database 
will be used.
As of May 2019, study enrollment has been completed. Therefore in Amendment 29, the total 
sample size was fixed; however, the sample size for the primary population (subjects with PD-L1 
CPS ≥5) remained unknown as CPS scoring was still ongoing. The prevalence was assumed to be 
35% consistent with sample size and power calculations in Amendment 23. Sections 8.1.4 and 
8.1.5 of the Protocol were updated to reflect design characteristics for time driven analyses and 
using 35% prevalence for PD-L1 CPS ≥5. 
5.2
General Assumptions of Sample Size Determinations
Primary Endpoints Family:
For the comparison of nivolumab plus chemotherapy vs. chemotherapy both PFS and OS are 
primary endpoints. 
Type I Error Splitting for Primary Endpoints Family:
For sample size calculation purpose, the family-wise error rate of 5% will be split as follows:
1) Comparison of PFS between nivolumab plus chemotherapy and chemotherapy in subjects with 
PD-L1 CPS ≥ 5, with alpha of 2%
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2) Comparison of OS between nivolumab plus chemotherapy and chemotherapy in subjects with 
PD-L1 CPS ≥ 5, with alpha of 3%
Population for Primary Endpoints:
The population for the primary endpoints will be randomized subjects with PD-L1 CPS ≥ 5. For 
the design purpose, the prevalence was assumed to be 35% of all randomized subjects and is used 
the power statement in Sections 5.2.1 and 5.2.2
Concurrently Randomized:
For the comparison of nivolumab plus chemotherapy and chemotherapy only subjects who were 
randomized to those 2 arms concurrently will be used. This means subjects randomized to 
chemotherapy before the nivolumab plus chemotherapy arm was introduced will not be included 
in the analysis of this comparison. 
For the comparison of nivolumab + ipilimumab and chemotherapy only subjects who were 
randomized to those 2 arms concurrently will be used. This means subjects randomized to 
chemotherapy after the closure of nivolumab plus ipilimumab randomization will not be included 
in the analysis of this comparison.
Figure 5.2-1:
Randomization Schema
Assumptions for Control Arm of Chemotherapy:
In previous protocol versions (up to amendment 20), PD-L1 ≥ 1% per TPS was assumed as 
negative prognostic factor (ie, the median OS for chemotherapy was assumed to be smaller for 
subjects with tumor PD-L1 ≥1% per TPS than for all randomized subjects). However, for PD-L1 
CPS, recent data does not suggest such a negative prognostic effect for chemotherapy5. Therefore, 
in Amendment 23, the OS and PFS distributions for the chemotherapy arm are assumed to be the 
same regardless of CPS cutoffs, eg, in PD-L1 CPS ≥ 5 and in all randomized subjects. 
1:1
Nivo+Ipiand 
Chemotherapy
N=83
Nivo + Ipi
Chemotherapy
Nivo + Chemotherapy 
1:1:1
Nivo+Ipi, 
Chemotherapy and 
Nivo+Chemotherapy
N=1098
1:1
Chemotherapy and 
Nivo+Chemotherapy
N=850
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The PFS and OS data from the external data6,7,8 were considered the most relevant to the studied 
chemotherapy arm (control). Therefore, the chemotherapy arm is assumed to have a 4-piece 
exponential distribution with a median PFS of 5.5 months (see Figure 5.2-2) and a 4-piece 
exponential distribution with a median OS of 11.1 months (see Figure 5.2-3).
Figure 5.2-2:
PFS for Chemotherapy from External Data and Assumed Distribution 
for Chemotherapy
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Figure 5.2-3:
OS for Chemotherapy from External Data and Assumed Distribution 
for Chemotherapy
Statistical Software for Sample Size Calculation 
Sample size calculations of the primary endpoints were based on simulations in EAST 6.4.1.
Sections 5.2.1 and 5.2.2 describe the sample size and power as stated in protocol. 
5.2.1
Sample Size: Nivolumab plus Chemotherapy vs. Chemotherapy
Progression Free Survival
Concurrently randomized subjects to nivo+chemo and chemo arms with PD-L1 CPS ≥5 will be 
used for the PFS analysis. Given the delayed separation in the PFS distributions between 
pembrolizumab + chemotherapy and chemotherapy4, the PFS analysis will be conducted after a 
minimum of 12 months follow-up after the last patient is randomized.
As such, the PFS analysis will be conducted after the following criteria are all met: 
•
CPS scoring by central laboratories is complete
•
a minimum follow-up of 12 months
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The HR is modelled as a 2-piece hazard ratio with a delayed effect of 3 and 6 months (a HR of 1 
versus chemotherapy for the first 3 or 6 months) followed by a constant HR of 0.56 (see Table 
5.2.1-1). With 12 months minimum follow-up it is expected that the number of events will range 
between 497 and 506 respectively and the power will range between approximately 99% and 60% 
with a Type I error of 2% (two-sided) (see Table 5.2.1-2).
The primary PFS analysis will be based on all the events observed at time of database lock. 
Table 5.2.1-1:
PFS Hazard Rates and Hazard Ratios (Nivolumab plus 
Chemotherapy vs. Chemotherapy)
Periods
Hazard Rates for 
Chemotherapy 
Hazard Ratios 
(3 months delay)
Hazard Ratios 
(6 months delay)
0-3 months
0.09
1
1
3-6 months
0.17
0.56
1
6-10 months
0.2
0.56
0.56
> 10 months
0.13
0.56
0.56
Table 5.2.1-2:
Summary of Sample Size Parameters and Schedule of Analyses for 
PFS (Nivolumab plus Chemotherapy vs. Chemotherapy)
3 months Delay 
6 months Delay
# subjects with PD-L1 CPS ≥5a
554
554
Hypothesized delayed period
3
6
Hypothesized HR after delayed 
period
0.56
0.56
Hypothesized median in control arm
5.5 months
5.5 months
Significance level (2-sided)
0.02
0.02
Enrollment Period (from start of 
1:1:1) 
25.4 months
25.4 months
Minimum follow-up / Expected 
number of eventsa,b,c
12 months /497
12 months / 506
Time of Analysis 
37.4 months
37.4 months
powerb
99%
66%
average HRb
0.66
0.80
a Based on 35% prevalence of PD-L1 CPS ≥5
b Results based on simulations.
c Number of events for the nivolumab plus chemotherapy vs. chemotherapy comparison in total.
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Overall Survival 
A delayed separation of at least 6 months between the OS distribution of pembrolizumab + 
chemotherapy and chemotherapy was observed.4 To fully capture the treatment effect, the interim 
and final analyses of OS will be conducted after a minimum follow up after the last patient 
randomized. 
The interim analysis will be conducted after at least 12 months minimum follow-up, and the final 
analysis will be conducted after at least 24 months minimum follow-up. 
With 24 months minimum follow-up at final analysis it is expected that 466 events will be 
observed. With an average HR of 0.74 modelled as a 2-piece hazard ratio, a delayed effect with a 
HR of 1 versus chemotherapy for the first 6 months followed by a constant HR of 0.65 (see
Table 5.2.1-3 ) the power will be approximately 85% with a Type I error of 3% (two-sided) (see 
Table 5.2.1-4).
For the OS interim and final analyses, all the events reported in the database at time of database 
locks will be used for the primary analyses.
Table 5.2.1-3:
Assumed OS Hazard Rates and Hazard Ratios (Nivolumab plus 
Chemotherapy vs. Chemotherapy)
Periods 
Hazard Rates for 
Chemotherapy
Hazard Ratio
0-3 months
0.036
1
3-6 months
0.06
1
6-24 months
0.08
0.65
>24 months 
0.05
0.65
Table 5.2.1-4:
Summary of Sample Size Parameters and Schedule of Analyses for 
OS (Nivolumab plus Chemotherapy vs. Chemotherapy)
# with PD-L1 CPS ≥5a
554
Hypothesized delayed period
6 months
Hypothesized HR after delayed period
0.65
Hypothesized median in control arm
11.1 months
Significance level (2-sided)
0.03
Enrollment Period (from start of 1:1:1) 
25.4 months
INTERIM ANALYSIS #1 for OS
Minimum follow-up/Expected number of eventsa,b,c
12 months/395
Time of analysisd
37.4 months
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Table 5.2.1-4:
Summary of Sample Size Parameters and Schedule of Analyses for 
OS (Nivolumab plus Chemotherapy vs. Chemotherapy)
Significance levele
0.0164
Power
64%
FINAL ANALYSIS
Minimum follow-up/Expected number of eventsa,b,c
24 months/466
Time of analysisd
49.4 months
Significance level
0.0252
Powerb
85%
Average HR
0.74
a Based on a 35% prevalence of PD-L1 CPS ≥ 5.
b Results based on simulations
c Number of events for the nivolumab plus chemotherapy vs. chemotherapy comparison in total.
d After first patient randomized to nivolumab + chemotherapy or chemotherapy in 1:1:1 randomization.
e Significance levels will be calculated based on the actual number of deaths at each interim analysis
With an assumed PD-L1 CPS ≥5 prevalence of 35% and under the following piecewise HR (HR 
of 1 vs. chemotherapy for the first 6 months followed by a constant HR of 0.65) the target number 
of OS events at interim and final analyses is estimated to be 395 and 466 respectively. Using the 
Lan-DeMets α spending function with O’Brien and Fleming type of boundary,9 the significance 
levels for OS at interim and final analyses are 0.0164 and 0.0252 respectively. At time of interim 
analysis, the significance level will be adjusted according to actual events observed at OS interim 
and using the estimated final number of events. At final analysis the significance level will be 
calculated using the number of events in the database at time of database lock and considering the 
α-level already spent at interim analysis as well as the actual correlation among the test statistics.
5.2.2
Power Considerations for Nivolumab plus Ipilimumab vs.
Chemotherapy
OS between nivolumab+ipilimumab vs chemotherapy will be tested as a secondary objective. This 
comparison will be tested if at least one primary endpoint (PFS or OS of nivolumab + 
chemotherapy vs. chemotherapy in PD-L1 CPS ≥5 subjects) meets statistical significance. The 
nivolumab+ipilimumab vs. chemotherapy OS comparison will be conducted at the planned final 
comparison of OS for nivolumab+chemotherapy vs. chemotherapy. This corresponds to 
approximately 36 months of minimum follow-up for the nivolumab + ipilimumab and 
chemotherapy arm. 
With approximately 36 months minimum follow-up at final analysis it is expected that 240 events 
will be observed. With an average HR of 0.7 modelled as a 4-piece hazard ratio (see Table 5.2.2-
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1) the power will range between 63% and 73% for Type I error of 1.5% and 3.5% (two-sided) (see
Table 5.2.2-2).
Table 5.2.2-1:
Assumed OS Hazard Rates and Hazard Ratios (Nivolumab plus 
Ipilimumab vs. Chemotherapy)
Periods 
Hazard Rates for 
Chemotherapy
Hazard Rates for Nivo + 
Ipilimumab
Hazard Ratio
0-3 months
0.036
0.099
2.75
3-6 months
0.06
0.054
0.9
6-24 months
0.08
0.0328
0.41
>24 months 
0.05
0.0205
0.41
Table 5.2.2-2:
Summary of Sample Size Parameters and Schedule of Analyses for 
OS (Nivolumab plus Ipilimumab vs. Chemotherapy)
Alpha =0.015
Alpha=0.035
# with PD-L1 CPS ≥ 5a  
285
285
Hypothesized distribution 
See Table 5.2.2-1
See Table 5.2.2-1
Hypothesized median in control arm
11.1 months 
11.1 months 
Significance level (two-sided)
0.015
0.035
Enrollment Period (from start of 1:1)
18.7 months
18.7 months
Time of analysis /Expected number of eventsa,b,c
54.4/240
54.4/240
Powerb
63%
73%
Average HRb
0.70
0.70
a Based on 35% prevalence of PD-L1 CPS ≥5
b Results based on simulations.
c Number of events for the nivolumab plus ipilimumab vs. chemotherapy comparison in total.
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, 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.
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−
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 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 assessments on or prior to the first dose of study treatment:
♦For PD-L1, among the records prior to or on first dose date (and time if collected), 
identify first those with quantifiable test result. If there are no records with quantifiable 
test result, then select those with indeterminate result (“INDETERMINATE”). If there 
are no records with indeterminate test result, then select those with unavailable result 
(“NOT EVALUABLE). If there are no records with unavailable test result, then select 
those with not reported or not available result (all other records). The latest record will 
be used as the baseline in the analyses. If there is more than one record for the latest 
date, then choose the one with the greatest specimen ID. This derivation will apply to 
tumor positive score (TPS) and composite positive score (CPS)
♦For Anti-Drug Antibody (ADA), the record related to the most recent assessment 
among those records where date (and time if collected) of nivolumab or ipilimumab
immunoglobulin (IMG) assessment is less than or equal to the date (and time if 
collected) of the first nivolumab or ipilimumab dose date respectively.
•
Post baseline period:
−
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 study treatment (or with an onset date on or after the day of 
first dose of study treatment if time is not collected or is missing). For subjects who are off 
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 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.
−
On-treatment evaluations (laboratory tests and vital signs) will be defined as evaluations 
taken after the day (and time, if collected and not missing) of first dose of study treatment. 
For subjects who are off study treatment, evaluations should be within a safety window of 
30 days (or 100 days depending on the analysis) after the last dose of study treatment.
Late-emergent drug-related AEs will be defined as drug-related AEs with an onset date greater 
than 100 days after the last dose of study treatment in subjects who are off study treatment.
6.2
Treatment Regimens
The treatment group “as randomized” will be retrieved from the IRT system
•
Arm A, C in the IRT system: Experimental arm Nivolumab plus Ipilimumab (Arm A: before 
Amendment08; Arm C: after Amendment08)
•
Arm B, D in the IRT system: Control arm Chemotherapy (Arm B: before Amendment08; Arm 
D: after Amendment08)
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•
Arm E in the IRT system: Experimental arm Nivolumab plus Chemotherapy
The treatment group “as treated” will be, in general, the same as the arm randomized by IRT 
unless a subject received the incorrect drug for the entire period of treatment, in which case the 
subject’s treatment group will be defined as the incorrect drug the subject actually received.
Subjects in the nivo+chemo and in the chemotherapy arm may receive two types of chemotherapy 
regimen (as per investigator’s choice): XELOX or FOLFOX. Chemotherapy regimen “as 
randomized” (referred to as “planned chemotherapy regimen”) will be retrieved from the IRT 
system. Chemotherapy regimen “as treated” will be, in general, the same as the planned 
chemotherapy regimen. However, if a subject received the other chemotherapy regimen for the 
entire period of treatment, the subject’s chemotherapy regimen will be defined as the regimen the 
subject actually received. Discrepancies between these two classifications will be reported,
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”.
6.3
Populations for Analyses
6.3.1
Analyses of Nivolumab plus Chemotherapy versus Chemotherapy
All Enrolled Subjects: subjects who were
•
randomized concurrently to nivo + chemo or chemo from 27-Mar-2017 (start date of 
randomization to the 3 arms)
•
enrolled from 27-Mar-2017 (included) but were never randomized (enrolled means subjects 
who signed an informed consent form and were registered into the IRT). These subjects had 
equal chances to be randomized to any of the 3 arms.
All Randomized Subjects: all subjects concurrently randomized to Nivo + Chemo or Chemo from 
27-Mar-2017 (included).
Randomized CPS ≥5 Subjects: randomized subjects with CPS ≥5. Similar population will be 
defined for other biomarker and cutoff (eg, All randomized CPS ≥1 Subjects).
Randomized Subjects with Measurable Disease (BICR): randomized subjects who have at least 
one target/measurable lesion at baseline (per BICR). Similar population will be defined based 
investigator assessment of baseline lesions.
Randomized CPS ≥5 Subjects with Measurable Disease (BICR): randomized subjects with 
CPS ≥5 who have at least one target/measurable lesion at baseline (per BICR). Similar population 
will be defined based investigator assessment of baseline lesions and also for other biomarker and 
cutoff (eg, randomized CPS≥1 Subjects).
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All Treated Subjects: All randomized subjects who received at least one dose of study drug during 
the study.
Treated CPS ≥5 Subjects: randomized CPS ≥ 5 subjects who received at least one dose of study 
drug during the study. Similar population will be defined for other biomarker and cutoff 
(eg, treated CPS ≥1 Subjects).
PK Subjects: randomized subjects with available serum time-concentration data.
Outcome Research Subjects: randomized subjects who have an assessment at screening/baseline 
and at least 1 follow-up assessment. 
Immunogenicity Subjects: randomized subjects who have an assessment at screening/baseline 
and at least 1 follow-up assessment.
Randomized Subjects with Quantifiable Biomarker: randomized subjects with quantifiable 
biomarker expression (eg, TPS, CPS, MSI 
).
6.3.2
Analyses of Nivolumab plus Ipilimumab versus Chemotherapy
All Enrolled Subjects: subjects who were
•
randomized concurrently to nivo + ipi or chemo from start of randomization
•
enrolled up to 05-June-2018 (date at which the nivo + ipi arm was closed to accrual) but were 
never randomized (enrolled means subjects who signed an informed consent form and were 
registered into the IRT). These subjects had equal chances to be randomized to any of the 3 
arms.
All Randomized Subjects: all subjects concurrently randomized to Nivo + Ipi or Chemo.
Randomized CPS ≥5 Subjects: randomized subjects with CPS ≥5. Similar population will be 
defined for other biomarker and cut-off (eg, randomized CPS ≥1 subjects).
Randomized Subjects with Measurable Disease (BICR): randomized subjects who have at least 
one target/measurable lesion at baseline (per BICR). Similar population will be defined based 
investigator assessment of baseline lesions.
Randomized CPS ≥5 Subjects with Measurable Disease (BICR): randomized subjects with 
CPS ≥5 who have at least one target/measurable lesion at baseline (per BICR). Similar population 
will be defined based investigator assessment of baseline lesions and also for other biomarker and 
cut-off (eg, randomized CPS ≥ 1 Subjects).
All Treated Subjects: All randomized subjects who received at least one dose of study drug 
during the study.
Treated CPS ≥5 Subjects: randomized CPS ≥5 subjects who received at least one dose of study 
drug during the study. Similar population will be defined for other biomarker and cut-off 
(eg, treated CPS ≥1 subjects).
PK Subjects: randomized subjects with available serum time-concentration data.
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Outcome Research Subjects: randomized subjects who have an assessment at screening/baseline 
and at least 1 follow-up assessment.
Immunogenicity Subjects: randomized subjects who have an assessment at screening/baseline 
and at least 1 follow-up assessment.
Randomized Subjects with Quantifiable Biomarker: randomized subjects with quantifiable 
biomarker expression (eg, TPS, CPS, MSI 
).
7
STATISTICAL ANALYSES
7.1
General Methods
Unless mentioned otherwise (eg, see Section 8), outputs will be provided separately for the 
nivo+chemo vs. chemo comparison and the nivo+ipi vs. chemo comparison. All analyses, unless 
otherwise noted, will be repeated for population of subjects with PD-L1 CPS ≥5 and for all 
subjects (ie, all comers). For the nivo+chemo vs. chemo comparison, analyses will be repeated for 
subjects with PD-L1 CPS ≥1 if the secondary endpoint of OS in CPS ≥1 randomized subjects 
meets the pre-specified statistical criteria.
Unless otherwise noted, the following subsections describe tabulations of discrete variables, by 
the frequency and proportion of subjects falling into each category, grouped by treatment (with 
total, as needed). Percentages given in these tables will be rounded to the first decimal and, 
therefore, may not always sum to 100%. Continuous variables will be summarized by treatment 
group (with total, as needed) using the mean, standard deviation, median, minimum and maximum 
values, unless specified otherwise.
Time-to-event variables (eg, time-to resolution) 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 intervals).11
The conventions to be used for imputing missing and partial dates for analyses requiring dates are 
described in Section 8.
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”. 
Adverse events leading to dose delay are AEs with action taken regarding study drug(s) = “Drug 
was delayed”.
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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 most recent version of the criteria at the time of the database lock will 
be used.
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 7.6.9). To prepare these analyses, the CRF data will be processed according to 
standard BMS algorithms12 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’ 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 (EU Submission)
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category (eg, 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 (eg, adrenal disorders, diabetes, pituitary disorders, and thyroid 
disorders are subcategories of the endocrine event category). 
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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 of select adverse event, time-to onset and time-to resolution are 
described in APPENDIX 1.
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 (eg, 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 (US Submission)
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, 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, 
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.
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Clinical laboratory data will be analyzed using International System of Units (SI) and 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.
7.1.3
Immunogenicity Data
Blood samples for immunogenicity analysis will be collected from subjects assigned to the 
experimental treatment group(s) according to the protocol schedule. Samples will be evaluated for 
development of Anti-Drug Antibody (ADA) by a validated electrochemiluminescent (ECL) 
immunoassay.
7.1.4
Efficacy
General Methods for Time-to-event Variables
Time to event distribution (eg, OS, PFS, DoR) will be estimated using Kaplan-Meier (KM) 
techniques.
Median survival time along with 95% (or adjusted) confidence interval (CI) will be constructed 
based on a log-log transformed CI for the survivor function S(t).10,11 Rates at fixed timepoints 
(eg, OS at 6 months) will be derived from the KM estimate and corresponding CI will be derived 
based on Greenwood formula13 for variance derivation and on log-log transformation applied on 
the survivor function S(t).14
Unless otherwise specified, the stratified log-rank test will be performed to test the comparison 
between time to event distributions. Unless otherwise specified, the stratified HR between 
2 treatment groups along with CI will be obtained by fitting a stratified Cox model with the 
treatment group variable as unique covariate. 
7.2
Study Conduct
A by-subject listing of batch numbers for all treated subjects will be provided.
7.2.1
Accrual
The accrual pattern will be summarized per region, country, investigational site and month. 
Randomization date, first dosing date, country, investigational site will be presented in a by subject 
listing of accrual. These analyses will be performed on the all enrolled subjects population only.
7.2.2
Relevant Deviations
The relevant Protocol Deviations will be summarized on randomized CPS ≥5 subjects and on all 
randomized subjects by treatment group and overall. The following programmable deviations from 
inclusion and exclusion criteria will be considered as relevant protocol deviations. Non-
programmable relevant eligibility and on-treatment protocol deviations, as well as significant (both 
programmable and nonprogrammable) eligibility and on-treatment protocol deviations will be 
reported through 
 listings.
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At Entrance:
•
Subjects without inoperable, advanced or metastatic GC or GEJ or distal esophageal carcinoma 
and have histologically confirmed predominant adenocarcinoma.
•
Subjects who have received prior systemic therapy (adjuvant and neoadjuvant is allowed).
•
Subject with baseline ECOG performance status > 1.
•
Subjects without any disease at baseline.
•
Subjects without any PD-L1 result. (“Indeterminate” is not a deviation).
On-study:
•
Subjects receiving concurrent anti-cancer therapy (surgery, chemotherapy, hormonal therapy, 
immunotherapy, non-palliative radiation therapy, standard or investigational agents for 
treatment of gastric cancer).
•
Subjects treated differently as randomized (subjects who received the wrong treatment, 
excluding the never treated).
A subject listing will also be produced.
7.3
Study Population
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. A subject listing for subjects not randomized will also 
be provided, showing the subject’s race, gender, age, consent date and reason for not being 
randomized. The number of subjects enrolled but not randomized will be reported for the 3 arms 
not knowing to which arm the subject would have been randomized to. Therefore, the number of 
screen failures will be overestimated when reporting separately the comparison of nivo+chemo vs.
chemo and the comparison of nivo+ipi vs. chemo.
Number of subjects randomized but not treated along with the reason for not being treated 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. For the nivo+ipi arm, number of subjects who discontinued 
study treatment during the nivo-plus-ipi phase and during the nivo mono phase (along with 
corresponding reason) will be also tabulated. Reason for discontinuation will be derived from 
subjects status CRF page.
A by-subject listing for all treated subjects will be provided showing the subject’s off treatment 
date and whether the subject continue in the treatment period long with the reason for going off 
treatment period. 
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7.3.2
Demographics and Other Baseline Characteristics
The following baseline characteristics will be summarized by treatment group as randomized and 
overall. All baseline presentations identify subjects with missing measurements. Listings will also 
be provided.
In addition to the presentations defined previously in Section 6.3 (ie, for N+C vs C and N+I vs C), 
these baseline characteristics will be summarized to support the Contribution of Components 
(Section 8) by presenting this analysis for the All Concurrently Randomized Subjects to 3 Arms 
group (N~1098, see Figure 8.1-1) and the All Randomized Subjects to 3 Arms group (N~2031).
•
Age (continuous)
•
Age category (< 65, ≥65 and < 75, ≥ 75 and < 85, ≥ 85; ≥75, ≥ 65)
•
Sex (male, female)
•
Race (White, Black or African American, Asian [Asian Indian, Chinese, Japanese, Asian 
Other], American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, Other)
•
Region (Asia [including China], US, RoW, Asia[excluding China], China)
•
ECOG PS
•
Weight (descriptive statistics)
•
Primary tumor location at initial diagnosis (GC, GEJ cancer, or Esophageal adenocarcinoma)
•
Disease stage at initial diagnosis (Stage I, Stage II, Stage III, Stage IV)
•
Disease status (locally recurrent, metastatic, locally advanced)
•
Lauren classification (intestinal type, diffuse type, mixed, unknown)
•
Siewert-Stein classification (reported for GEJ only) (type I, type II, type III)
•
WHO histologic classification (adenosquamous carcinoma, mucinous adenocarcinoma, 
papillary serous adenocarcinoma, signet ring cell, tubular adenocarcinoma, other)
•
TNM classification:
−
Tumor (Tx, T0, Tis, T1, T2, T3, T4, unknown)
−
Nodes (Nx, N0, N1, N2, N3, unknown)
−
Metastasis (Mx, M0, M1, unknown)
•
Smoking status (current/former, never smoker, unknown)
•
All lesions at baseline (investigator and BICR): sites of disease, number of disease sites per 
subject, number of subjects with no measurable lesion
•
Target lesions (investigator and BICR): presence of target lesions, site of target lesion, sum of 
diameters of target lesions
•
CNS metastases (yes/no)
•
Liver metastases (yes/no)
•
Peritoneal metastases (yes/no) 
•
Time from Initial Disease Diagnosis to Randomization (< 6 months, 6 months - < 1 year, 1 -
< 2 year, 2 - < 3 year, 3 -< 4 year, 4 - < 5 year, ≥ 5 year)
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•
Time from randomization to first dose date (≤3, 4 - 5, 6 - 7, 8 - 14, 15 - 21, > 21 days, Not 
Reported or Not Treated)
•
HER-2 status at study entry (negative, positive, unknown)
•
Microsatellite instability (MSI-H, MSS, invalid, unknown)
•
H.pylori (no, yes, unknown)
•
Baseline hemoglobin (< 10g/dL, ≥ 10g/dL)
•
Baseline albumin (< LLN, ≥ LLN)
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 will be provided for all randomized subjects.
7.3.4
Prior Therapy Agents
Prior cancer therapy will be summarized by treatment group as randomized and overall.
Prior anti-cancer therapy
•
Setting of prior systemic therapy regimen received (adjuvant, metastatic disease, neo-
adjuvant).
•
Time from completion of prior adjuvant/neo-adjuvant therapy to treatment (for subjects who 
received prior adjuvant/neo-adjuvant therapy), (< 6 months, 6 - < 12month, ≥12 months)
•
Prior surgery related to current cancer (yes or no).
•
Prior radiotherapy (yes or no).
•
Prior systemic therapy classified by therapeutic class and generic name.
7.3.5
Physical Examinations
Subjects with abnormal baseline physical examination will be listed by subject for all randomized 
subjects.
7.3.6
Baseline Physical Measurements
Baseline physical measurements will be listed by subject for all randomized subjects.
7.3.7
Discrepancies between IRT Stratification Factors and Other Datasets
Summary tables (cross-tabulations), by treatment group as randomized, for stratification factor 
(except for region) will be provided to show any discrepancies between what was reported through 
IRT vs. other data sources (CRF data and laboratory data) at baseline. This analysis will be 
provided for randomized CPS ≥5 subjects and all randomized subjects.
•
PD-L1 expression level (≥1% vs. < 1% or indeterminate) (IRT vs. laboratory data)
•
ECOG performance status (0 vs. 1) (IRT vs. CRF)
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•
Planned chemotherapy regimen (XELOX vs. FOLFOX) (randomization in IRT vs. actual 
treatment received) – only for subjects in the nivo+chemo and in the chemotherapy arms
7.4
Extent of Exposure
Analyses in this whole section will be performed by treatment group as treated for treated 
CPS ≥5 subjects and for all treated subjects. For chemotherapy (FOLFOX or XELOX) the 
Chemotherapy regimen “as treated” will be reported (see Section 6.2).
7.4.1
Administration of Study Therapy
For details on the dosing schedule per protocol, see Section 2.1.
The following parameters will be summarized (descriptive statistics) by treatment group:
•
Number of cycles received (summary statistics).
•
Duration of treatment 
−
using a KM curve whereby the last dose date will be the event date for those subjects who 
are off study therapy. Subjects who are still on study therapy will be censored on their last 
dose date. Median duration of treatment and associated 95% CI will be provided.
The following parameters will be summarized (descriptive statistics) by study therapy and 
treatment group:
•
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 
90 - < 110%; ≥110%.
•
Cumulative dose
A by-subject listing of dosing of study medication (record of study medication, infusion details, 
dose change).
Key parameters used to characterize dosing data for the nivo+ipi arm are defined in Table 7.4.1-
1; for subjects treated with XELOX in the nivo+chemo and chemotherapy arms in Table 7.4.1-3; 
for subjects treated with FOLFOX in the N+C and chemotherapy arms in Table 7.4.1-5.
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Table 7.4.1-1:
Administration of Study Therapy in the Nivolumab plus Ipilimumab Arm
Nivolumab
Ipilimumab
Dosing schedule per protocol
1mg/kg Q3Wx4 then 240mg Q2W, IV
Or
240mg Q2W, IV
or 480 Q4W, IV
3mg/kg Q3W, IV
Dose*
Total dose administered (mg)/most recent 
weight (kg)
Or Total dose administered (mg)
Total dose administered (mg)/most recent weight (kg)
Cumulative Dose
The sum of all doses (mg) administered to a 
subject during the treatment period
The sum of all doses (mg/kg) administered to a subject during the 
treatment period
Relative Dose Intensity (%)
See equation in Table 7.4.1-2
100x [Cum dose (mg/kg) / [(Last ipilimumab dose date in the nivo-plus-
ipi phase – ipilimumab Start dose date + 21) x 3 / 21]]
Duration of Treatment
Last dose date (of the last administered study therapy) - Start dose date (of the first administered study therapy) + 1
* Dose administered in mg at each dosing date and weight are collected on the CRF
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Table 7.4.1-2:
Formula for Relative Dose Intensity for Nivolumab in Nivolumab plus Ipilimumab Regimen
Overall 
duration 
of Nivo 
treatment 
(last dose date of nivo - start dose date of nivo +X)
X= 14 days if last dose is 240 mg
X= 21 days if last dose is 360 mg (some patients take 360 mg despite protocol instruction)
X= 28 days if last dose is 480 mg
Overall 
RDI*
ܟ૚∗܀۲۷૚൅ሺ૚െܟ૚ሻ∗܀۲۷૛
ࡾࡰࡵ૚
100 x[Cum dose (mg/kg))in nivo-plus-ipi phase / [(Last nivolumab dose date in the nivo-plus-ipi phase – nivolumab
Start dose date + X) x 1 / 21]]
ࡾࡰࡵ૛
૚૙૙ൈ
ࢉ࢛࢓࢛࢒ࢇ࢚࢏࢜ࢋࢊ࢕࢙ࢋ࢏࢔࢓࢕࢔࢕࢖ࢎࢇ࢙ࢋሺ࢓ࢍሻ
ቄቂሺ࢔࢏࢜࢕࢒ࢇ࢙࢚ࢊ࢕࢙ࢋࢊࢇ࢚ࢋ࢏࢔࢓࢕࢔࢕࢖ࢎࢇ࢙ࢋെ࢙࢚ࢇ࢚࢘ࢊࢇ࢚ࢋ࢏࢔࢚ࢎࢋ࢔࢏࢜࢕࢓࢕࢔࢕࢖ࢎࢇ࢙ࢋ൅ࢄሻൈ૚૛૙
ૠቃቅ
X as above
࢝૚
[(First nivolumab dose date in the mono phase ̽ nivolumab Start dose date in nivo-plus-ipi phase)]/overall duration of Nivo treatment
* if patient did not start the combo phase then overall RDI= RDI1
Table 7.4.1-3:
Administration of Study Therapy for Subjects Treated with XELOX
Nivolumab
Oxaliplatin
Capecitabine
Dosing schedule per 
protocol
360mg Q3WK, IV
or 480 mg Q4WK, IV (nivo mono)
130mg/m2 Q3WK, IV
1000mg/m2 twice daily D1-14, Q3WK,
oral
Dose*
Total dose administered (mg)
Total dose administered (mg) / most 
recent BSA
Total dose administered (mg) / most recent 
BSA
Cumulative Dose
The sum of all doses (mg) administered to 
a subject during the treatment period
The sum of all doses (mg/m2)
administered to a subject during the 
treatment period
The sum of all doses (mg/m2)
administered to a subject during the 
treatment period
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Table 7.4.1-3:
Administration of Study Therapy for Subjects Treated with XELOX
Nivolumab
Oxaliplatin
Capecitabine
Relative Dose 
Intensity (%)
see formula in Table 7.4.1-4
100x[Cumulative dose (mg/m2) / [Last
oxaliplatin dose date – oxaliplatin Start 
dose date + 21) x 130/21]]
100x[Cumulative dose (mg/m2) / [First
dose of capecitabine in the last cycle –
capecitabine Start dose date + 21) x 
28000/21]]
Duration of 
Treatment
Last dose date (of the last administered study therapy) - Start dose date (of the first administered study therapy) + 1
* Dose administered in mg at each dosing date and BSA (computed using recent weight and baseline height) are collected on the CRF.
Table 7.4.1-4:
Formula for Relative Dose Intensity for Nivolumab in Nivolumab plus XELOX Regimen:
૚૙૙ൈ
ࢉ࢛࢓࢛࢒ࢇ࢚࢏࢜ࢋࢊ࢕࢙ࢋሺ࢓ࢍሻ
ەۖ۔
ۖۓ
ቂሺ࢒ࢇ࢙࢚ࢊ࢕࢙ࢋࢊࢇ࢚ࢋ࢕ࢌ࢔࢏࢜࢕૜૟૙࢓ࢍെ࢙࢚ࢇ࢚࢘ࢊࢇ࢚ࢋ࢕ࢌ࢔࢏࢜࢕൅૛૚ሻൈ૜૟૙
૛૚ቃ
൅ቂሺ࢒ࢇ࢙࢚ࢊ࢕࢙ࢋࢊࢇ࢚ࢋ࢕ࢌ࢔࢏࢜࢕૝ૡ૙࢓ࢍെ࢙࢚ࢇ࢚࢘ࢊࢇ࢚ࢋ࢕ࢌ࢔࢏࢜࢕૝ૡ૙࢓ࢍ൅૛ૡሻൈ૝ૡ૙
૛ૡቃۙۖۘ
ۖۗ
Table 7.4.1-5:
Administration of Study Therapy for Subjects Treated with FOLFOX
Nivolumab
Oxaliplatin
Leucovorin
Fluorouracil
Dosing schedule 
per protocol
240mg Q2WK, IV
or 480 mg Q4WK, IV 
(nivo mono)
85mg/m2 Q2WK
400mg/m2 Q2WK
Bolus 5-FU: 400mg/m2 Q2WK, IV on Day 1 of the
cycle
Continuous 5-FU: 1200mg/m2 Q2WK, IV
continuous infusion on Day1-2 of the cycle
Dose*
Total dose administered 
(mg)
Total dose administered 
(mg) / most recent BSA
Total dose administered 
(mg) / most recent BSA
Total dose administered (mg) / most recent BSA
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Table 7.4.1-5:
Administration of Study Therapy for Subjects Treated with FOLFOX
Nivolumab
Oxaliplatin
Leucovorin
Fluorouracil
Cumulative 
Dose
The sum of all doses 
(mg) administered to a 
subject during the 
treatment period
The sum of all doses 
(mg/m2) administered to 
a subject during the 
treatment period
The sum of all doses 
(mg/m2) administered to 
a subject during the 
treatment period
The sum of all doses (mg/m2) administered to a 
subject during the treatment period
Relative Dose 
Intensity (%)
See formula in 
Table 7.4.1-6
100 x [Cumulative dose 
(mg/m2) / [Last 
oxaliplatin dose date –
oxaliplatin Start dose 
date + 14) x 85/14]]
100 x [Cumulative dose 
(mg/m2) / [Last 
leucovorin dose date –
leucovorin Start dose 
date + 14) x 400/14]]
Bolus 5-FU: 100 x [Cumulative dose (mg/m2) / [First 
dose of fluorouracil in the last cycle – fluorouracil 
Start dose date + 14) x 400/14]]
Continuous 5-FU: 100 x [Cumulative dose (mg/m2) 
/ [First dose of continuous fluorouracil in the last 
cycle – continuous fluorouracil Start dose date + 14) x 
2400 / 14]]
Duration of 
Treatment
Last dose date (of the last administered study therapy) - Start dose date (of the first administered study therapy) + 1
* Dose administered in mg at each dosing date and BSA (computed using recent weight and baseline height) are collected on the CRF.
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Table 7.4.1-6:
Formula for Relative Dose Intensity for Nivolumab Nivolumab plus FOLFOX Regimen
૚૙૙ൈ
ࢉ࢛࢓࢛࢒ࢇ࢚࢏࢜ࢋࢊ࢕࢙ࢋሺ࢓ࢍሻ
ەۖ۔
ۖۓቂሺ࢒ࢇ࢙࢚ࢊ࢕࢙ࢋࢊࢇ࢚ࢋ࢕ࢌ࢔࢏࢜࢕૛૝૙࢓ࢍെ࢙࢚ࢇ࢚࢘ࢊࢇ࢚ࢋ࢏࢔࢚ࢎࢋ࢔࢏࢜࢕࢓࢕࢔࢕࢖ࢎࢇ࢙ࢋ൅૚૝ሻൈ૛૝૙
૚૝ቃ
൅ቂሺ࢒ࢇ࢙࢚ࢊ࢕࢙ࢋࢊࢇ࢚ࢋ࢕ࢌ࢔࢏࢜࢕૝ૡ૙࢓ࢍെ࢙࢚ࢇ࢚࢘ࢊࢇ࢚ࢋ࢕ࢌ࢔࢏࢜࢕૝ૡ૙࢓ࢍ൅૛ૡሻൈ૝ૡ૙
૛ૡቃ
ۙۖۘ
ۖۗ
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7.4.2
Modification of Study Therapy
7.4.2.1
Dose Delays 
A dose will be considered as actually delayed if the delay is exceeding the number of days in 
Table 7.4.2.1-1.
Table 7.4.2.1-1:
Dose Delays
Ipilimumab
Q3W 
Nivolumab 
(a)
Q2W 
Nivolumab 
(b)
Q4W 
Nivolumab 
(c) 
XELOX (d)
FOLFOX (d)
Specifications per Protocol
Dose 
considered 
as actually 
delayed
If the delay is 
exceeding 
3 days
If the delay is 
exceeding 
3 days
If the delay 
is exceeding 
2 days
If the delay is 
exceeding 
3 days
If the delay 
is exceeding 
3 days
If the delay is 
exceeding 
2 days
Maximum 
delay 
allowed 
between 
doses
42 days
42 days
42 days
42 days
Not 
specified
Not specified
Definitions for the Analysis
Dose Delay
duration of 
preceding 
cycle in days –
21
duration of 
preceding 
cycle in days 
– 21
duration of 
preceding 
cycle in days
– 14
duration of 
preceding 
cycle in days 
– 28
duration of 
preceding 
cycle in 
days – 21
duration of 
preceding 
cycle in days 
– 14
Categories 
of dose 
delays
on-time, 
4 - 7 days, 
8 - 14 days, 
15 - 42 days, 
> 42 days
on-time, 
4 - 7 days, 
8 - 14 days, 
15 - 42 days, 
> 42 days
on-time, 
3 – 4 days, 
5 - 7 days, 
8 - 14 days, 
15 - 42 days, 
> 42 days
on-time, 
4 - 7 days, 
8 - 14 days, 
15 - 42 days, 
> 42 days
on-time,
4 - 7 days, 
8 - 14 days, 
15 - 42 
days, 
> 42 days
on-time, 
3 – 4 days, 
5 - 7 days, 
8 - 14 days, 
15 - 42 days, 
> 42 days
(a) nivo-plus-ipi phase in the nivo+ipi arm, FOLFOX-treated subjects in the nivo+chemo arm
(b) nivo mono phase in the nivo+ipi arm, XELOX-treated subjects in the nivo+chemo arm
(c) applicable to all arms with nivolumab, when nivolumab administered alone after treatment 
with nivolumab in combination with ipilimumab, FOLFOX or XELOX.
(d) in the nivo+chemo and in the chemotherapy arms
The following parameters will be summarized by study therapy and treatment group:
•
Number of subjects with at least one dose delayed, the number of doses delayed per subject, 
the reason for dose delay and the length of dose delay.
7.4.2.2
Infusion Interruptions and Rate Changes
Each study therapy given as infusion can be interrupted and/or the IV infusion rate can be reduced. 
This information will be retrieved from CRF dosing pages.
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For capecitabine, which is oral, interruption will be programmatically derived. 
The following parameters will be summarized by study therapy and treatment group:
•
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 (not for capecitabine).
7.4.2.3
Dose Reductions
Per protocol, there will be no dose escalations or reductions of nivolumab and ipilimumab. 
However, for chemotherapy, dose reduction is permitted according to local standard or local 
package insert. This information will be retrieved from CRF dosing pages.
For subjects treated with chemotherapy, the following will be summarized by treatment group:
•
Number of subjects with at least one dose reduction along with the reason for the dose
reduction.
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (ie, on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the WHO Drug Dictionary.
The following summary tables will be provided:
•
Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term).
A by-subject listing will accompany the table.
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 UMC WHO Drug Global 
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 
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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 categorywill 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:
•
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 Therapy
Number and percentage of subjects receiving subsequent therapies will be summarized for 
randomized subjects with PD-L1 CPS≥5 subjects and all randomized subjects. Categories include: 
•
Immunotherapy including commercial Nivolumab (anti-PD1 agents, anti-PD-L1 agents, 
anti-CTLA-4 agents and others) by drug name 
•
Other anti-cancer agents excluding all immunotherapy (approved and investigational) by drug 
name 
•
Surgery for treatment of tumors (ie reason of tumor resection palliative or tumor resection 
curative)
•
Radiotherapy  for treatment of tumors (ie, radiotherapy with reason curative or palliative)
•
Any combination of the above
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A subject listing of follow-up therapy will also be produced for subjects who had any subsequent 
therapy.
7.5
Efficacy
Analyses of progression free survival and objective response rate will be based on the Blinded 
Independent Central Review (BICR) evaluation, unless noted otherwise. 
Analyses in this section will be tabulated for all randomized subjects by treatment group as 
randomized, unless otherwise specified.
Unless stated otherwise, whenever a stratified analysis is specified, the following stratifications 
factors (recorded at randomization as per IRT) will be used see Table 7.5-1
Table 7.5-1:
Stratification Factors Used for Stratified Analyses
Nivo+ipi vs. Chemotherapy
Nivo+chemo vs. Chemotherapy
• Region (Asia vs. US vs. RoW)
• ECOG performance status (0 vs. 1)
• PD-L1 expression level (≥1% vs. < 1% 
or indeterminate)
• Region (Asia vs. US vs. RoW)
• ECOG performance status (0 vs. 1)
• PD-L1 expression level (≥1% vs. < 1% 
or indeterminate)
• Chemotherapy (XELOX vs. FOLFOX)
7.5.1
Strong Control of Type I Error for Primary and Secondary endpoints: 
The following testing strategy guarantees a strong control of FWER at level α of 5% for the 
primary and key secondary endpoints. 
For the 2 primary endpoints of PFS and OS in the comparison of nivo+chemo vs. chemo in
randomized CPS ≥5 subjects, 2% is allocated to PFS and 3% is allocated to OS. For the first 
secondary endpoint of OS in nivo+ipi vs. chemo in randomized CPS ≥5 subjects, alpha will be 
passed from both PFS and OS as shown in Figure 7.5.1-1, the other secondary endpoints formally 
tested are also illustrated in the figure15.
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Figure 7.5.1-1:
Graphical Approach for Primary and Secondary Endpoints
In the graph, each vertex corresponds to a hypothesis to be tested. The square represent the 
hypotheses for the primary endpoints and the circles for secondary endpoints, light blue color 
represent comparison for nivo+ipi vs. chemo and dark blue represent comparison of nivo+chemo 
vs. chemo. The numbers next to the vertices are the initially allocated (endpoint-specific) 
significance levels. It is 0 for all secondary endpoints meaning that they cannot be tested until 
alpha is passed to them from the primary endpoints. The weight (in rectangular frame) associated 
with a directed edge (line) between any two vertices indicates the fraction of the (local) 
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significance level at the initial vertex that is added to the significance level at the terminal vertex, 
if the hypothesis at the tail is rejected.
Table 7.5.1-1 shows the significance levels for the primary and key secondary endpoints. For 
endpoints which have an interim analysis, the significance level will be distributed using the Lan-
DeMets alpha spending function with O’Brien-Fleming boundaries. The nominal significance 
levels for OS in randomized PD-L1 CPS ≥5 subjects in Table 7.5.1-1 are those obtained with the
number of events exactly as in the table and assuming a prevalence rate of 35% for PD-L1 CPS
≥5. At time of analysis, the significance levels will be adjusted according to actual number of 
events and using the estimated final number of events. For interim analyses of OS in randomized 
PD-L1 CPS ≥1 subjects and all randomized subjects, the nominal significance levels will be 
obtained using the same information fraction as for randomized PD-L1 CPS ≥5 subjects. At the 
final analysis the significance level will be calculated using the number of events in the database 
at time of database lock and considering the α-level already spent at interim analysis as well as the 
actual correlation among the test statistics.
Table 7.5.1-1:
Significance Levels for Primary and Secondary Endpoints
Analysis Timepoint 
PFS Nivo+chemo 
in CPS ≥5
OS Nivo+chemo 
in CPS ≥5 
OS Nivo+ipi 
in CPS ≥5
Event
Sign. level
Event
Sign. level
Event
Sign. level
12 months follow-
up
497a
0.02
395b
0.0164
NA
NA
24 months follow-
up
NA
NA
466b
0.0252
240c
0.015d
0.02
0.035
a Estimated based on 2-piece hazard ratio with HR of 1 for the first 3 months followed by constant HR of 0.56 and 
assuming 35% prevalence for PD-L1 CPS ≥5.
b Estimated based on 2-piece hazard ratio with HR of 1 for the first 6 months followed by constant HR of 0.65 and 
assuming 35% prevalence for PD-L1 CPS ≥5.
c Estimated based on hazard ratios as in Table 5.2.1-3
d The significance level will depend on whether only one primary endpoint was positive or both. If only OS of 
nivo+chemo in CPS ≥5 is positive then the significance level is 0.015, if only PFS of nivo+chemo in CPS ≥5 is 
positive then the significance level is 0.02 and if both are positive then the significance level is 0.035. The other 
secondary endpoints for nivo+ipi vs. chemo (OS in all randomized and TTSD) will be tested hierarchically at the 
same significance level as OS nivo+ipi in CPS ≥5 subjects.
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At the first analysis timepoint, PFS final analysis and OS interim analysis for nivo+chemo vs.
chemo in CPS ≥5 subjects will be tested.
•
If none of the primary endpoints can be rejected then no secondary endpoints are tested, and 
the study continues to proceed to the final OS analysis.
•
If PFS is rejected, its entire alpha is passed to OS of nivo+ipi vs. chemo in PD-L1 CPS ≥5 
subjects. 
•
If OS is rejected at interim analysis, then its alpha (0.03) will be shared equally to OS of 
nivo+ipi vs. chemo in PD-L1 CPS ≥5 subjects and to OS of nivo+chemo vs. chemo in PD-L1 
CPS ≥1 subjects.
At the second analysis timepoint, OS final analysis for nivo+chemo vs. chemo in CPS ≥5 subjects 
will be tested.
•
If this endpoint cannot be rejected then none of the other secondary endpoints for nivo+chemo 
will be tested. OS for nivo+ipi vs. chemo in CPS ≥5 subjects can be tested only if PFS for 
nivo+chemo in CPS ≥5 subjects was positive, the testing will be done at the significance level 
of 0.02.
•
If OS of nivo+chemo vs. chemo in PD-L1 CPS ≥5 subjects is statistically significant then its 
alpha (0.03) will be shared equally to OS of nivo+ipi vs. chemo in PD-L1 CPS ≥5 subjects 
and to OS of nivo+chemo vs. chemo in PD-L1 CPS ≥1 subjects. The testing of OS for nivo+ipi 
vs chemo will be conducted with significance level of 0.015 or 0.035 (if PFS for nivo+chemo 
in CPS ≥5 subjects was positive).
7.5.2
Nivo + Chemo vs. Chemo Comparison
7.5.2.1
Analysis of Progression-Free Survival
PFS (primary definition) as assessed by BICR in randomized CPS ≥5 subjects will be compared 
between nivo+chemo vs. chemo, using a two-sided log rank test, stratified by the stratification 
factors as specified in Table 7.5-1. A significance level of 0.02 will be used. The estimate of the 
PFS hazard ratio between treatment groups will be calculated using a stratified Cox proportional 
hazards model, with treatment as the sole indicator covariate (for nivo+chemo vs. chemo arms). 
Ties will be handled using the exact method. A two-sided 98% CI for the hazard ratio will also be 
presented.
The PFS function for each treatment group will be estimated using the KM product limit method 
and will be displayed graphically. A two-sided 95% CI for median PFS in each treatment group 
will be computed via the log-log transformation method. PFS rates at fixed time points (eg, 6, 12, 
18 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 Greenwood13 formula for variance derivation and on log-log 
transformation applied on the survivor function14.
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The source of PFS event (progression or death) will be summarized by treatment group. The status 
of subjects who are censored (as per primary definition of PFS) in the PFS KM analysis will be 
tabulated for each treatment group including the following categories:
•
On-study (on-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 of lesion evaluations per BICR will be presented.
7.5.2.2
Supportive Analyses of Progression-Free Survival
Sensitivity analyses to examine assumptions of the stratified Log-rank test and Cox model:
1) 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. If the two-sided Wald Chi-square p-value of the treatment by time interaction 
is less than 0.1 or if a visual examination of the K-M plot of the PFS indicates a delayed 
separation of the curves, the following analyses and potential other exploratory analyses will 
be conducted in order to report the treatment effect when taking into consideration of the 
delayed effect.
a) Delayed effect of immunotherapy interventions may cause a late separation in the PFS KM 
curves and non-proportional hazards. PFS (as determined by BICR) will be compared 
between treatment groups via a 2-sided max-combo test. The max-combo test statistic is 
the maximum of 4 different 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 weights at the median.
b) The estimates of the PFS hazard ratios will be estimated in 2 periods. The periods will be 
defined by a cut-off point. The optimal cut off point will be calculated using a stratified 
time-dependent Cox model with effects for treatment and period-by-treatment interaction. 
The optimal 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.
2) The stratified log rank-rank test assumes same treatment effect among the different strata. The 
method of Gail and Simon16 will be used to test for a qualitative interaction between treatment 
and strata. This test will be conducted at α=0.10 level. The p-value reported from this specific 
analysis is for descriptive purposes alone.
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Assess impact of Potential Prognostic Factors on Treatment Effect:
3) 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:
a) Age categorization (< 65, ≥ 65)
b) Gender (Male vs. Female)
c) Primary tumor location at initial diagnosis (GC, GEJ cancer, Esophageal Adenocarcinoma)
d) Disease status (locally recurrent/advanced, metastatic)
e) Lauren classification (intestinal type, diffuse type, mixed, unknown)
f)
Peritoneal metastases (yes/no) 
g) Prior surgery related to current cancer OR radiotherapy finished more than 6 months before 
randomization (yes/no)
h) Number of organs with baseline lesion (target or non-target; ≤1, ≥2) outside primary 
location (gastric, gastroesophageal junction and esophagus)
i)
WHO histologic classification presence of signet ring cell (yes/no)
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.
4) The identification of the primary population using PD-L1 CPS ≥5 was introduced close to 
accrual completion. Therefore the randomization was not stratified by PD-L1 CPS ≥5. The 
overall study population was stratified by 
•
PD-L1 expression level (tumor cells) (≥1% vs. < 1% or indeterminate)
•
Region: Asia vs. US vs. RoW
•
ECOG performance status: 0 vs. 1
•
Planned chemotherapy regimen (XELOX vs. FOLFOX)
As CPS≥5 is not a stratification factor, while pronounced imbalance is not expected due to 
the large sample size in this group, thorough review of data will be conducted and a sensitivity 
analysis may be conducted. 
The distribution of baseline characteristics (demographics, disease characteristics and the 
stratification factors) between the two treatment arms will be inspected for potential 
imbalance in the subgroup of subjects with PD-L1 CPS ≥5. 
The distribution of these characteristics will also be assessed between the CPS PD-L1 ≥5 
subgroup and the overall population, regardless of treatment.
If a pronounced imbalance between the treatment arms is observed  for one or several factors 
(eg, >=10% difference between the frequency of the treatment arms for any level of the 
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categorical variables) a multivariate Cox regression model will be used in order to estimate 
the treatment effect after adjustment for those factors identified. The factors used in the 
randomization, will be included in the model as stratification factors and the factors identified 
with imbalance will be incorporated as covariates. For the purpose of fitting the multivariate 
model and easy interpretation of the results, any continuous variable identified will be 
dichotomized using a cut-off around median value and some sub-categories of a categorical 
covariate could collapsed due to small size of the sub-categories.
Assess Impact of Stratification: 
5) PFS using stratification factors as obtained from the baseline CRF pages (instead of IRT). The 
hazard ratio associated with treatment will be presented along with the associated two-sided 
98% CIs. This analysis will be performed only if at least one stratification variable/factor at 
randomization (as per IRT) and baseline are not concordant for at least 10% of the PD-L1 CPS
≥5 randomized subjects for the 2 arms.
6) PFS using an un-stratified log-rank test. The hazard ratio associated with treatment will be 
presented along with the associated two-sided 98% CIs.
7) PFS using an unstratified Cox proportional hazards model, adjusted, using as covariates only 
the stratification factors used in randomization. The hazard ratio associated with treatment will 
be presented along with the associated two-sided 98% CIs.
PFS using different sources or definition:
8) PFS by BICR using secondary definition of PFS (ITT) will be compared between nivo+chemo 
vs. chemo, using a two-sided log rank test, stratified by the stratification factors as specified in 
Table 7.5-1.  In addition, for PFS by BICR using secondary definition, PFS using the 
investigator’s assessment the primary definition and PFS using investigator’s assessment and 
the secondary definition the hazard ratio associated with treatment with its 98% CI. The PFS 
function for each treatment group will be estimated using the KM product limit method and 
will be displayed graphically. A two-sided 95% CI for median PFS in each treatment group 
will be computed via the log-log transformation method. PFS rates at fixed time points (eg, 6, 
12, 18 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 Greenwood13 formula for variance derivation and 
on log-log transformation applied on the survivor function14.
A by-subject listing will be presented including treatment group, PFS duration under the 
primary definition, PFS duration on the ITT definition (secondary definition), whether the 
subject was censored under the primary definition, and if censored, the reason, and whether 
the subject was censored under the ITT definition, and if censored, the reason.
9) A cross tabulation of PFS assessment by BICR versus PFS assessment by investigator will be 
presented, by treatment group. The concordance rate of events will be computed as the 
frequency with which investigator and BICR agree on classification of a subject as progression 
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vs. death vs. censored as a proportion of the total number of randomized PD-L1 CPS ≥5 
subjects assessed by both the investigator and BICR.
A by-subject listing of PFS (primary definition) assessment per BICR and investigator will be 
presented.
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Assessment of PFS in case of relevant protocol deviation:
10) If there are more than 10% PD-L1 CPS ≥5 randomized subjects with relevant protocol 
deviations the PFS (BICR primary definition) analysis will be conducted on subjects with no 
relevant protocol deviations. The hazard ratio associated with treatment will be presented along 
with the associated two-sided 98% CIs.
11) The stratified log rank test will be repeated on PFS (BICR) primary definition based on the 
first 228 events among the first 298 randomized subjects with CPS ≥5. The hazard ratio 
associated with treatment with its 98% CI will also be provided. This analysis will reflect the
primary analysis per original design (see Amendment 23).
12) PFS accounting for two or more consecutively missing disease assessments prior to PFS event: 
This analysis will be performed only if at least 10% of PFS events have missing prior disease 
assessments. In case a subject has two or more consecutively missing disease assessments, the 
subject will be censored at the last disease assessment date prior the PFS event.
13) Analysis in which progression-free subjects who are lost to follow-up for any cause will be
considered as having an event at the time of the last tumor assessment date prior to loss to 
follow-up. This analysis will be performed only if at least 10% of the progression-free subjects 
are lost to follow-up.
7.5.2.3
Subset Analyses of Progression-Free Survival
The influence of baseline and demographic characteristics on the treatment effect among 
randomized CPS ≥5 subjects will be explored via exploratory subset analyses. The median PFS
(primary definition) based on KM product-limit method along with two-sided 95% CIs will be 
produced for the following subgroups:
•
Region (Asia vs US vs. RoW; from CRF)
•
Region (Asia [without China] vs. US vs. RoW [including China])
•
ECOG performance status (0 vs. 1; from CRF)
•
Age category (< 65, ≥ 65 and < 75, ≥ 75, ≥ 65)
•
Gender (male, female)
•
Race (Asian, White, Other)
•
Primary tumor location at initial diagnosis (GC, GEJ cancer, Esophageal Adenocarcinoma)
•
Disease stage at initial diagnosis (Stage I-II, Stage III, Stage IV)
•
Disease status (locally recurrent/advanced, metastatic)
•
Prior surgery related to current cancer (yes/no)
•
Prior radiotherapy (yes/no)
•
Lauren classification (intestinal type, diffuse type, mixed, unknown)
•
WHO histologic classification presence of signet ring cell (yes/no)
•
TNM classification Metastasis (M0, M1, unknown/Mx)
•
At least one target lesion (yes/no)
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•
Number of organs with baseline lesion (target or non-target; ≤1, ≥2) outside primary location 
(gastric, gastroesophageal junction and esophagus)
•
Time from Initial Disease Diagnosis to Randomization (< 6 months, 6 months -< 1 year, ≥ 1
year)
•
Peritoneal metastases (yes/no) 
•
Liver metastases (yes/no)
•
H.pylori (no, yes, unknown)
•
HER-2 status at study entry (negative, positive, unknown)
•
Baseline albumin (< LLN, ≥ LLN)
•
Microsatellite instability (MSI-H, MSS, invalid, unknown)
A forest plot of the PFS unstratified hazard ratios (along with the 95% CIs) will be produced for 
each level of the subgroups listed above. The unstratified analysis comparing treatment (ie, Hazard 
Ratio) will be conducted if the number of subjects in the subgroup category is more than 10. 
7.5.2.4
Analysis of Overall Survival
OS in randomized CPS ≥5 subjects will be compared between nivo+chemo vs. chemo at the 
interim and final analyses, using stratified log-rank test, stratified by the stratification factors as 
specified in Table 7.5-1. An O’Brien and Fleming α-spending function will be employed to 
determine the nominal significance levels for the interim and final analyses (see Table 7.5.1-1). 
The stratified hazard ratio between the treatment groups will be presented along with 100*
(1 - α)% CI (adjusted for interim) and will be calculated using a stratified Cox proportional hazards 
model, with treatment as the sole indicator covariate (for the nivo+chemo and chemo arm). Ties 
will be handled using the exact method. 
OS will be estimated using the KM techniques. A two-sided 95% CI for median OS in each 
treatment group will be computed via the log-log transformation method. OS rates at fixed time 
points (eg, 12, 18, 24, 36 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 Greenwood13formula for variance derivation and 
on log-log transformation applied on the survivor function14.
The status of subjects who are censored in the OS KM analysis will be tabulated for each treatment 
group using the following categories:
•
On-study (on-treatment, in follow-up)
•
Off-study (lost to follow-up, withdraw consent, never treated)
A by-subject listing will be presented including treatment group, first and last dose date, whether 
the subject died, and if censored, the reason, event/censored date and OS duration.
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7.5.2.5
Supportive Analyses of Overall Survival
Sensitivity analyses to examine assumptions of the stratified Log-rank test and Cox model:
1) 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. If the two-sided Wald Chi-square p-value of the treatment by time interaction 
is less than 0.1 or if a visual examination of the K-M plot of the OS indicates a delayed 
separation of the curves, the following analyses and potential other exploratory analyses will 
be conducted in order to report the treatment effect when taking into consideration of the 
delayed effect.
a) Delayed effect of immunotherapy interventions may cause a late separation in the OS KM 
curves and non-proportional hazards. OS will be compared between treatment groups via 
a 2-sided max-combo test. The max-combo test statistic is the maximum of 4 different 
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 weights at the median.
b) The estimates of the OS hazard ratios will be estimated in 2 periods. The periods will be 
defined by a cut-off point. The optimal cut off point will be calculated using a stratified 
time-dependent Cox model with effects for treatment and period-by-treatment interaction. 
The optimal 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.
2) The method of Gail and Simon16 will be used to test for a qualitative interaction between 
treatment and strata. This test will be conducted at α=0.10 level. The p-value reported from 
this specific analysis is for descriptive purposes alone.
Assess impact of Potential Prognostic Factors on Treatment Effect:
3) 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 the same factors as in the PFS analysis.
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.
4) The identification of the primary population using PD-L1 CPS ≥5 was introduced close to 
accrual completion. Therefore the randomization was not stratified by PD-L1 CPS ≥5. The 
overall study population was stratified by:
•
PD-L1 expression level (tumor cells) (≥1% vs. < 1% or indeterminate)
•
Region: Asia vs. US vs. RoW
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•
ECOG performance status: 0 vs. 1
•
Planned chemotherapy regimen (XELOX vs. FOLFOX)
As CPS ≥5 is not a stratification factor, while pronounced imbalance is not expected due to 
the large sample size in this group, thorough review of data will be conducted and a sensitivity 
analysis may be conducted. 
The distribution of baseline characteristics (demographics, disease characteristics and the 
stratification factors) between the two treatment arms will be inspected for potential 
imbalance in the subgroup of subjects with PD-L1 CPS ≥5. 
The distribution of these characteristics will also be assessed between the PD-L1 CPS ≥5 
subgroup and the overall population, regardless of treatment.
If a pronounced imbalance between the treatment arms is observed  for one or several factors 
(eg, >=10% difference between the frequency of the treatment arms for any level of the 
categorical variables) a multivariate Cox regression model will be used in order to estimate 
the treatment effect after adjustment for those factors identified. The factors used in the 
randomization, will be included in the model as stratification factors and the factors identified 
with imbalance will be incorporated as covariates. For the purpose of fitting the multivariate 
model and easy interpretation of the results, any continuous variable identified will be 
dichotomized using a cutoff around median value and some sub-categories of a categorical 
covariate could collapsed due to small size of the sub-categories.
Assess Impact of Stratification: 
5) OS using stratification factors as obtained from the baseline CRF pages (instead of IRT). The 
hazard ratio associated with treatment will be presented along with the associated two-sided 
(1 - α)% CIs. This analysis will be performed only if at least one stratification variable/factor 
at randomization (as per IRT) and baseline are not concordant for at least 10% of the 
randomized subjects.
6) OS using an un-stratified log rank test. The hazard ratio associated with treatment will be 
presented along with the associated two-sided (1 - α)% CIs.
7) OS using an unstratified Cox proportional hazards model, adjusted, using as covariates only 
the stratification factors used in randomization. The hazard ratio associated with treatment will 
be presented along with the associated two-sided (1 - α)% CIs.
Assessment of OS in case of relevant protocol deviation:
8) If there are more than 10% subjects with relevant protocol deviations the OS analysis for 
subjects with no relevant protocol deviations will be conducted. The hazard ratio associated 
with treatment will be presented along with the associated two-sided (1 - α)% CIs.
9) The OS analysis (stratified log rank) will be conducted based on the first 420 randomized 
subjects with PD-L1 CPS ≥ 5 (see Protocol Amendment 23) and all events observed in this 
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population. The hazard ratio associated with treatment will be presented along with the 
associated two-sided (1 - α)% CIs.
10) The OS analysis (stratified log rank) will be conducted based on the original planned number 
of events (ie, first 354 deaths) observed among randomized subjects with CPS ≥5. The hazard 
ratio associated with treatment will be presented along with the associated two-sided 
(1 - α)% CIs.
7.5.2.6
Subset Analyses of Overall Survival
The influence of baseline and demographic characteristics on the treatment effect among all 
randomized CPS ≥5 subjects will be explored via exploratory subset analyses. The median OS 
based on KM product-limit method along with two-sided 95% CIs will be produced for the same 
subgroups as in the PFS analysis (see Section 7.5.2.3).
A forest plot of the OS unstratified hazard ratios (along with the 95% CIs) will be produced for 
each level of the subgroups listed above. The unstratified analysis comparing treatment (ie, Hazard 
Ratio) will be conducted if the number of subjects in the subgroup category is more than 10. 
7.5.2.7
Current Status of PFS and OS Follow-up
The extent of follow-up for survival, defined as the time between randomization date and last 
known alive date (for subjects who are alive) or death date (for subjects who died), will be 
summarized descriptively (median, min, max, etc.) in months for randomized CPS ≥5 subjects
and all randomized subjects.
The currentness of follow-up for survival, defined as the time between last OS contact (ie, last 
known alive date or death date) and cutoff date (defined by last patient last visit date), will be 
summarized in months for randomized CPS≥5 subjects and all randomized subjects. Subjects who 
died and subjects with last known alive date on or after data cut-off date will have zero value for 
currentness of follow-up.
Minimum follow-up of OS for all randomized subjects, defined as the time from cutoff date to last 
subject’s randomization date, will be summarized in months.
Time from last evaluable tumor assessment to cut-off date in months will be summarized by 
treatment group and overall for randomized CPS ≥5 subjects and all randomized subjects. Subjects 
who have a PFS event will be considered as current for this analysis. The secondary definition of 
PFS will be used for this summary. 
A by-subject listing will also be produced to accompany the subject time from last evaluable tumor 
assessment.
7.5.2.8
Analysis of OS by Tumor Response:
Survival by response category will be analyzed by arm using the landmark method.17 Subjects still 
on study at the landmark time will be separated into two response categories according to whether 
they have responded before that time. This will assess whether survival from the landmark depends 
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on the subject's response status at the landmark. Subjects who go off protocol (eg, subjects who 
die) before the time of landmark will be excluded from the analysis.
The survival curves from Week 6, Week 12, Week 18, Month 6, Month 9, Month 12, by response 
status, for each randomized arm will be produced using the KM product-limit method. Two sided, 
95% CIs for median OS will be constructed based on a log-log transformed CI for the survivor 
function S(t).
7.5.2.9
Secondary Efficacy Endpoints
Overall Survival in CPS ≥1 subjects and All Randomized Subjects
If the OS primary endpoint in randomized CPS ≥5 subjects is significantly superior then OS in 
randomized CPS ≥1 subjects will be compared using a two-sided log rank test and a significance 
level of 1.5%, stratified by the stratification factors as specified in Table 7.5-1. Similarly if OS 
testing in  randomized CPS ≥1 subjects is significantly superior then OS in all randomized subjects 
(all comers) will be compared using a two-sided log rank test and a significance level of 1.5%, 
stratified by the stratification factors as specified in Table 7.5-1.
The stratified hazard ratio between the treatment groups will be presented along with 100*
(1 - α)% CI (adjusted for interim). In addition, two-sided p-value will also be reported for the 
analysis of OS.
OS will be estimated using the KM techniques. A two-sided 95% CI for median OS in each 
treatment group will be computed via the log-log transformation method. OS rates at fixed time 
points (eg, 6, 12, 18, 24 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 Greenwood13 formula for variance derivation and 
on log-log transformation applied on the survivor function.14
Additional Analyses for OS in CPS ≥1 subjects and All Randomized Subjects
As OS in CPS ≥1 subjects and OS in all randomized subjects are tested hierarchically, the 
following analyses will only be conducted if the endpoint is statistically significant:
All analyses as described in Sections 7.5.2.5, 7.5.2.6 and 7.5.2.8.
Overall Survival in CPS ≥10 subjects
This endpoint will not be formally tested. The stratified hazard ratio between the treatment groups 
will be presented along with 95% CI. OS will be estimated using the KM techniques. A two-sided 
95% CI for median OS in each treatment group will be computed via the log-log transformation 
method. OS rates at fixed time points (eg, 6, 12, 18, 24 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.
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PFS (BICR) in CPS ≥10, 1 and in all randomized: 
These endpoints will not be formally tested. PFS using primary definition per BICR will be 
analyzed. The stratified HR with its associated two-sided 95% CI will be estimated via a stratified 
Cox model with treatment arm as the only covariate in the model. PFS will be estimated using the 
KM techniques. A two-sided 95% CI for median PFS in each treatment group will be computed 
via the log-log transformation method. PFS rates at fixed time points (eg, 6, 12, 18 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.
Best Overall Response and ORR (BICR) in CPS ≥10, 5, 1 and in all Randomized Subjects 
These endpoints will not be formally tested. The analyses will repeated for the 4 populations: 
CPS ≥10, CPS ≥5, CPS ≥1 and all randomized. The analyses using BICR data are considered as 
secondary endpoints (no formal testing). The analyses will be repeated on subjects with 
measurable disease at baseline (see Section 6.3) 
•
The number and percentage of subjects in each category of BOR (complete response [CR], 
partial response [PR], stable disease [SD], progressive disease [PD], or unable to determine 
[UTD]) will be presented, by treatment group.
•
Estimates of response rate, along with its exact two-sided 95% CI by Clopper and Pearson18
will be presented, by treatment group. 
•
A 2-sided, 95% CI for the difference of ORR between treatment groups will also be computed 
by the method of DerSimonian and Laird,19 using a fixed-effects model (setting Δ2 equal to 
zero), adjusting for the stratification factors. The weighted response rate difference and 95% 
CI can be determined using the following formula:
ߠ෠ൌ
∑
ߠప෡ݓ௜
ଶସ
௜ୀଵ
∑
ݓ௜
ଶସ
௜ୀଵ
∼ܰሺߠ, 1/ ෍ݓ௜ሻ
ଶସ
௜ୀଵ
where ߠప෡is the response rate difference of the ith stratum and ݓ௜ൌ1/ݒܽݎሺߠ෠௜ሻ.
•
In addition, the stratified (source: IVRS) odds ratios (Mantel-Haenszel estimator) between the 
treatments will be provided along with the 95% CI.
•
ORR based on BICR assessment per RECIST 1.1 will be compared between two treatment 
groups using a two-sided Cochran-Mantel-Haenszel (CMH) test, stratified by the stratification 
factors. This is p-value is descriptive only.
The following subject-level graphics will also be provided:
•
For the responders only, time courses of the following events of interest will be graphically 
displayed: tumor response, progression, last dose received, and death.
•
For response evaluable subjects (randomized subjects with evaluable* baseline and at least one 
evaluable* on-study tumor assessment), 
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−
A bar plot showing the best % reduction from baseline in sum of diameter of target lesions 
based on BICR assessment for each subject will be produced (excluding assessments after 
PD and assessments after start of subsequent anti-cancer therapy).
−
A plot of individual time course of tumor burden change per BICR assessment will be 
produced. 
*Evaluable is defined according to RECIST v1.1
Subset Analyses of Objective Response
The influence of baseline and demographic characteristics on the treatment effect will be explored 
via exploratory subset analysis. BICR assessment of ORR in CPS ≥5 subjects will be summarized 
for the same subgroups than for PFS (see Section 7.5.2.3).
A forest plot of treatment effect on ORR per BICR in CPS ≥5 subjects will be produced. The un-
weighted differences in ORR between the two treatment groups and corresponding 95% two-sided 
CI using the method of Newcombe20 will be provided. The analysis comparing treatment (ie, ORR 
difference) will be conducted if the number of subjects in the subgroup category is more than 10. 
7.5.2.10
Exploratory Efficacy Endpoints
PFS (investigator) in CPS ≥10, 5, 1 and all randomized subjects
Similar analyses than for PFS (BICR) in CPS ≥10, 1 and in all randomized will be produced but 
using investigator assessment using primary definition.
ORR (investigator) in CPS ≥10, 5, 1 and in all randomized subjects: 
Similar analyses than for Best Overall Response and ORR per BICR will be produced but using 
investigator assessment of response and progression.
Duration of Response (BICR and investigator) in CPS ≥10, 5, 1 and all randomized subjects
Duration of response (DoR) will be evaluated per BICR assessment and per investigator 
assessment. DoR will be estimated using the KM techniques. A two-sided 95% CI for median in 
each treatment group will be computed via the log-log transformation method. For the DoR 
analyses the population is restricted to subjects with measurable disease at baseline.
For DoR, type of event (PD, death) and status of subjects censored (received subsequent therapy, 
ongoing follow-up [current, non-current], off study [withdrew consent] will be presented by 
treatment arm.
Time to objective response (BICR) in randomized CPS ≥5 subjects and all randomized 
subjects.
Time to response will be evaluated per BICR assessment. Summary statistics will be provided for 
each treatment group for subjects who achieve PR or CR. For these analyses the population is 
restricted to subjects with measurable disease at baseline.
To assess further tumor response kinetics, time to response will be analyzed using the KM 
methodology. Kaplan-Meier curve will represent the cumulative rate of response over time. For 
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the non-responders, time to response will be censored at the maximum time of response + 1 day 
of all subjects in their respective treatment group. Cumulative Response Rates will be tabulated 
for Week 6, Week 12, Months 4, 6, 8, and 12, and overall Response Rate will be provided for each 
treatment group.
Durable response rate (BICR and investigator) in all randomized CPS ≥5 subjects
Durable response will be evaluated per BICR assessment and per investigator assessment for 
subjects with measurable disease at baseline. The durable response rate will be computed in each 
treatment group along with the exact 95% CI using Clopper-Pearson method.18 An estimate of the 
difference in DRRs and corresponding 95% CI will be calculated using DerSimonian and Laird 
methodology and adjusted by the stratification factors as specified in Table 7.5-1. The stratified 
odds ratios (Mantel-Haenszel estimator) between the treatments will be provided along with the 
95% CI.
PFS and ORR as assessed by either BICR or investigator and OS across TPS cut-offs.
See Section 7.8 for Biomarker Analysis.
PFS2 in randomized CPS ≥5 subjects and in all randomized subjects
PFS2 will be analyzed similarly to PFS:  
•
Median values based on KM method, along with two-sided 95% CI using Brookmeyer and 
Crowley method will be calculated. The estimate of standard error will be calculated using the 
Greenwood formula;
•
PFS2 will be graphically displayed along with the median and 95% CI.
A by-subject listing of PFS and PFS2 will be provided.
TTSD in CPS ≥10, 5, 1 and all randomized subjects
See Section 7.9.1 in Clinical Outcome Assessment.
7.5.3
Nivo + Ipi vs. Chemo Comparison
7.5.3.1
Analysis of Overall Survival
OS in randomized CPS ≥5 subjects will be compared between nivo+ipi vs. chemo using stratified 
log-rank test, stratified by the stratification factors as specified in Table 7.5-1. The significance 
level α will depend on which primary endpoints was statistically significant (see Section 7.5.1). 
The estimate of the OS hazard ratio between treatment groups will be calculated using a stratified 
Cox proportional hazards model, with treatment as the sole indicator covariate (for nivo+ipi and 
chemo). Ties will be handled using the exact method. A two-sided (1 - α)% CI for the hazard ratio 
will also be presented.
OS will be estimated using the KM techniques. A two-sided 95% CI for median OS in each 
treatment group will be computed via the log-log transformation method. OS rates at fixed time 
points (eg, 12, 18, 24, 36 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 
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and, corresponding CIs will be derived based on Greenwood13formula for variance derivation and 
on log-log transformation applied on the survivor function.14
The status of subjects who are censored in the OS KM analysis will be tabulated for each treatment 
group using the following categories:
•
On-study (on-treatment, in follow-up)
•
Off-study (lost to follow-up, withdraw consent, never treated)
A by-subject listing will be presented including treatment group, first and last dose date, whether 
the subject died, and if censored, the reason, event/censored date and OS duration.
7.5.3.2
Supportive Analyses of Overall Survival
Sensitivity analyses to examine assumptions of the stratified Log-rand test and Cox model:
1) 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. If the two-sided Wald Chi-square p-value of the treatment by time interaction 
is less than 0.1 or if a visual examination of the K-M plot of the OS indicates a delayed 
separation of the curves, the following analyses and potential other exploratory analyses will 
be conducted in order to report the treatment effect when taking into consideration of the 
delayed effect..
a) Delayed effect of immunotherapy interventions may cause a late separation in the OS KM 
curves and non-proportional hazards. OS will be compared between treatment groups via 
a 2-sided max-combo test. The max-combo test statistic is the maximum of 4 different 
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 weights at the median.
b) The estimates of the OS hazard ratios will be estimated in 2 periods. The periods will be 
defined by a cut-off point. The optimal cut off point will be calculated using a stratified 
time-dependent Cox model with effects for treatment and period-by-treatment interaction. 
The optimal 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.
2) The method of Gail and Simon16 will be used to test for a qualitative interaction between 
treatment and strata. This test will be conducted at α=0.10 level. The p-value reported from 
this specific analysis is for descriptive purposes alone.
Assess impact of Potential Prognostic Factors on Treatment Effect:
3) 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 
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additional factors will be incorporated as covariates. The additional factors, which are all 
measured at baseline, will include the same factors as in the nivo+chemo vs. chemo analysis.
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.
4) The identification of the primary population using PD-L1 CPS≥5 was introduced close to 
accrual completion. Therefore, the randomization was not stratified by PD-L1 CPS ≥5. The 
overall study population was stratified by:
•
PD-L1 expression level (tumor cells) (≥1% vs. < 1% or indeterminate)
•
Region: Asia vs. US vs. RoW
•
ECOG performance status: 0 vs. 1
•
Planned chemotherapy regimen (XELOX vs. FOLFOX)
As CPS ≥5 is not a stratification factor, while pronounced imbalance is not expected due to 
the large sample size in this group, thorough review of data will be conducted and a sensitivity 
analysis may be conducted. 
The distribution of baseline characteristics (demographics, disease characteristics and the 
stratification factors) between the two treatment arms will be inspected for potential imbalance 
in the subgroup of subjects with PD-L1 CPS ≥5. 
The distribution of these characteristics will also be assessed between the PD-L1 CPS ≥5 
subgroup and the overall population, regardless of treatment.
If a pronounced imbalance between the treatment arms is observed  for one or several factors 
(eg, ≥10% difference between the frequency of the treatment arms for any level of the 
categorical variables) a multivariate Cox regression model will be used in order to estimate the 
treatment effect after adjustment for those factors identified. The factors used in the 
randomization, will be included in the model as stratification factors and the factors identified 
with imbalance will be incorporated as covariates. For the purpose of fitting the multivariate 
model and easy interpretation of the results, any continuous variable identified will be 
dichotomized using a cutoff around median value and some sub-categories of a categorical 
covariate could collapsed due to small size of the sub-categories
Assess Impact of Stratification: 
5) OS using stratification factors as obtained from the baseline CRF pages (instead of IRT). The 
hazard ratio associated with treatment will be presented along with the associated two-sided 
(1 - α)% CIs. This analysis will be performed only if at least one stratification variable/factor 
at randomization (as per IRT) and baseline are not concordant for at least 10% of the 
randomized subjects.
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6) OS using an un-stratified log rank test. The hazard ratio associated with treatment will be 
presented along with the associated two-sided (1 - α)% CIs.
7) OS using an unstratified Cox proportional hazards model, adjusted, using as covariates only 
the stratification factors used in randomization. The hazard ratio associated with treatment will 
be presented along with the associated two-sided (1 - α)% CIs.
Assessment of OS in case of relevant protocol deviation:
8) If there are more than 10% subjects with relevant protocol deviations the OS analysis for 
subjects with no relevant protocol deviations will be conducted. The hazard ratio associated 
with treatment will be presented along with the associated two-sided (1- α)% CIs.
7.5.3.3
Subset Analyses of Overall Survival
The influence of baseline and demographic characteristics on the treatment effect among 
randomized CPS ≥5 subjects will be explored via exploratory subset analyses. The median OS 
based on KM product-limit method along with two-sided 95% CIs will be produced for the 
following subgroups 
•
Region (Asia vs. US vs. RoW; from CRF)
•
Region (Asia [without China] vs. US vs. RoW [including China])
•
ECOG performance status (0 vs. 1; from CRF)
•
Age category (< 65, ≥ 65 and < 75, ≥75, ≥65)
•
Gender (male, female)
•
Race (Asian, White, Other)
•
Primary tumor location at initial diagnosis (GC, GEJ cancer, Esophageal Adenocarcinoma)
•
Disease stage at initial diagnosis (Stage I-II, Stage III, Stage IV)
•
Disease status (locally recurrent/advanced, metastatic)
•
Prior surgery related to current cancer (yes/no)
•
Prior radiotherapy (yes/no)
•
Lauren classification (intestinal type, diffuse type, mixed, unknown)
•
WHO histologic classification presence of signet ring cell (yes/no)
•
TNM classification Metastasis (M0, M1, unknown/Mx)
•
At least one target lesion (yes/no)
•
Number of organs with baseline lesion (target or non-target; ≤1, ≥2) outside primary location 
(gastric, gastroesophageal junction and esophagus)
•
Time from Initial Disease Diagnosis to Randomization (< 6months, 6months - < 1 year, ≥1
year)
•
Peritoneal metastases (yes/no) 
•
Liver metastases (yes/no)
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•
H.pylori (no, yes, unknown)
•
HER-2 status at study entry (negative, positive, unknown)
•
Baseline albumin (< LLN, ≥ LLN)
•
Microsatellite instability (MSI-H, MSS, invalid, unknown)
A forest plot of the OS unstratified hazard ratios (along with the 95% CIs) will be produced for 
each level of the subgroups listed above. The unstratified analysis comparing treatment (ie, Hazard 
Ratio) will be conducted if the number of subjects in the subgroup category is more than 10. 
7.5.3.4
Analysis of OS by Tumor Response:
Survival by response category will be analyzed by arm using the landmark method.21 Subjects still 
on study at the landmark time will be separated into two response categories according to whether 
they have responded before that time. This will assess whether survival from the landmark depends 
on the subject's response status at the landmark. Subjects who go off protocol (eg, subjects who 
die) before the time of landmark will be excluded from the analysis.
The survival curves from Week 6, Week 12, Week 18, Month 6, Month 9, Month 12, by response 
status, for each randomized arm will be produced using the KM product-limit method. Two sided, 
95% CIs for median OS will be constructed based on a log-log transformed CI for the survivor 
function S(t).
Overall Survival in All Randomized Subjects
If the OS secondary endpoint in randomized CPS ≥5 subjects is significantly superior then OS in 
all randomized subjects will be compared using a two-sided log rank test at the same significance
level of α%, stratified by the stratification factors as specified in Table 7.5-1. 
The stratified hazard ratio between the treatment groups will be presented along with 100*
(1 - α)% CI (adjusted for interim). In addition, two-sided p-value will also be reported for the 
analysis of OS.
OS will be estimated using the KM techniques. A two-sided 95% CI for median OS in each 
treatment group will be computed via the log-log transformation method. OS rates at fixed time 
points (eg, 6, 12, 18, 24 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.
Additional Analyses for OS in all Randomized Subjects
As OS in all randomized subjects is tested hierarchically, the following analyses will only be 
conducted if the endpoint is statistically significant:
All analyses as described in Sections 7.5.3.2, 7.5.3.3 and 7.5.3.4.
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Overall Survival in CPS≥10, 1 subjects
These endpoints will not be formally tested. The stratified hazard ratio between the treatment 
groups will be presented along with 95% CI. OS will be estimated using the KM techniques. A 
two-sided 95% CI for median OS in each treatment group will be computed via the log-log 
transformation method. OS rates at fixed time points (eg, 6, 12, 18, 24, 36 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.
7.5.3.5
Analysis of Progression-Free Survival 
PFS (BICR) in CPS ≥10, 5, 1 and in all randomized subjects: 
These endpoints will not be formally tested. PFS using primary definition and secondary definition 
per BICR will be analyzed. The stratified HR with its associated two-sided 95% CI will be 
estimated via a stratified Cox model with treatment arm as the only covariate in the model. PFS 
will be estimated using the KM techniques. A two-sided 95% CI for median PFS in each treatment 
group will be computed via the log-log transformation method. PFS rates at fixed time points (eg,
6, 12, 18 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.
The source of PFS event (progression or death) will be summarized by treatment group. The status 
of subjects who are censored (as per primary definition of PFS) in the PFS KM analysis will be 
tabulated for each treatment group including the following categories:
•
On-study (on-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, PFS duration under the primary 
definition, PFS duration on the ITT definition (secondary definition), whether the subject was 
censored under the primary definition, and if censored, the reason, and whether the subject was 
censored under the ITT definition, and if censored, the reason.
A by-subject listing of lesion evaluations per BICR will be presented.
7.5.3.6
Subset Analyses of Progression-Free Survival
The influence of baseline and demographic characteristics on the treatment effect among all 
randomized subjects will be explored via exploratory subset analyses. The median PFS (primary 
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definition) based on KM product-limit method along with two-sided 95% CIs will be produced for 
the following subgroups in subjects with CPS≥5:
•
Region (Asia vs. US vs. RoW; from CRF)
•
Region (Asia [without China] vs. US vs. RoW [including China])
•
ECOG performance status (0 vs. 1; from CRF)
•
Chemotherapy regimen (XELOX vs. FOLFOX; from CRF)
•
Age category (< 65, ≥ 65 and < 75, ≥ 75, ≥ 65)
•
Gender (male, female)
•
Race (Asian, White, Other)
•
Primary tumor location at initial diagnosis (GC, GEJ cancer, Esophageal Adenocarcinoma)
•
Disease stage at initial diagnosis (Stage I-II, Stage III, Stage IV)
•
Disease status (locally recurrent/advanced, metastatic)
•
Prior surgery related to current cancer (yes/no)
•
Prior radiotherapy (yes/no)
•
Lauren classification (intestinal type, diffuse type, mixed, unknown)
•
WHO histologic classification presence of signet ring cell (yes/no)
•
TNM classification Metastasis (M0, M1, unknown/Mx)
•
At least one target lesion (yes/no)
•
Number of organs with baseline lesion (target or non-target; ≤1, ≥2) outside primary location 
(gastric, gastroesophageal junction and esophagus)
•
Time from Initial Disease Diagnosis to Randomization (< 6 months, 6 months -< 1 year, ≥ 1
year)
•
Peritoneal metastases (yes/no) 
•
Liver metastases (yes/no)
•
H.pylori (no, yes, unknown)
•
HER-2 status at study entry (negative, positive, unknown)
•
Baseline albumin (< LLN, ≥ LLN)
•
Microsatellite instability (MSI-H, MSS, invalid, unknown)
A forest plot of the PFS unstratified hazard ratios (along with the 95% CIs) will be produced for 
each level of the subgroups listed above. The unstratified analysis comparing treatment (ie, Hazard 
Ratio) will be conducted if the number of subjects in the subgroup category is more than 10.
7.5.3.7
Current Status of PFS and OS Follow-up
The extent of follow-up for survival, defined as the time between randomization date and last 
known alive date (for subjects who are alive) or death date (for subjects who died), will be 
summarized descriptively (median, min, max, etc.) in months for all randomized CPS ≥5 subjects 
and all randomized subjects.
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The currentness of follow-up for survival, defined as the time between last OS contact (ie, last 
known alive date or death date) and cutoff date (defined by last patient last visit date), will be 
summarized in months for all randomized CPS ≥5 subjects and all randomized subjects. Subjects 
who died and subjects with last known alive date on or after data cut-off date will have zero value 
for currentness of follow-up.
Minimum follow-up of OS for all randomized subjects, defined as the time from cut-off date to 
last subject’s randomization date, will be summarized in months.
Time from last evaluable tumor assessment to cut-off date in months will be summarized by 
treatment group and overall for all randomized CPS ≥5 subjects and all randomized subjects. 
Subjects who have a PFS event will be considered as current for this analysis. The secondary 
definition of PFS will be used for this summary. 
7.5.3.8
Other Secondary Efficacy Endpoints
Best Overall Response and ORR (BICR) in CPS ≥10, 5, 1 and in all randomized subjects 
These endpoints will not be formally tested. The analyses will repeated for the 4 populations: 
CPS ≥10, CPS ≥5, CPS ≥1 and all randomized. The analyses using BICR data are considered as 
secondary endpoints (no formal testing). The analyses will be repeated on subjects with 
measurable disease at baseline (see Section 6.3).
•
The number and percentage of subjects in each category of BOR (complete response [CR], 
partial response [PR], stable disease [SD], progressive disease [PD], or unable to determine 
[UTD]) will be presented, by treatment group.
•
Estimates of response rate, along with its exact two-sided 95% CI by Clopper and Pearson18
will be presented, by treatment group. 
•
A 2-sided, 95% CI for the difference of ORR between treatment groups will also be computed 
by the method of DerSimonian and Laird,19 using a fixed-effects model (setting Δ2 equal to 
zero), adjusting for the stratification factors. The weighted response rate difference and 95% 
CI can be determined using the following formula:
ߠ෠ൌ
∑
ߠప෡ݓ௜
ଵଶ
௜ୀଵ
∑
ݓ௜
ଵଶ
௜ୀଵ
∼ܰሺߠ, 1/ ෍ݓ௜ሻ
ଵଶ
௜ୀଵ
where ߠప෡is the response rate difference of the ith stratum and ݓ௜ൌ1/ݒܽݎሺߠ෠௜ሻ.
•
In addition, the stratified (source: IVRS) odds ratios (Mantel-Haenszel estimator) between the 
treatments will be provided along with the 95% CI.
•
ORR based on BICR assessment per RECIST 1.1 will be compared between two treatment 
groups using a two-sided Cochran-Mantel-Haenszel (CMH) test, stratified by the stratification 
factors. This is p-value is descriptive only.
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The following subject-level graphics will also be provided:
•
For the responders only, time courses of the following events of interest will be graphically 
displayed: tumor response, progression, last dose received, and death.
•
For response evaluable subjects (randomized subjects with evaluable* baseline and at least one 
evaluable* on-study tumor assessment), 
−
A bar plot showing the best % reduction from baseline in sum of diameter of target lesions 
based on BICR assessment for each subject will be produced (excluding assessments after 
PD and assessments after start of subsequent anti-cancer therapy).
−
A plot of individual time course of tumor burden change per BICR assessment will be 
produced. 
−
*Evaluable is defined according to RECIST v1.1
Time to Symptom Deterioration in in CPS ≥5 and all randomized Subjects
TTSD in CPS ≥5 and all randomized will be analyzed. See details Section 7.9.1 “Clinical Outcome
Assessment”.
7.5.3.9
Exploratory Efficacy Endpoints
PFS (investigator) in CPS ≥10, 5, 1 and in All randomized subjects
Similar analyses than for PFS (BICR) will be produced but using investigator assessment and
primary definition.
ORR (investigator) in CPS ≥10, 5, 1 and in all randomized subjects: 
Similar analyses than for Best Overall Response and ORR per BICR will be produced but using 
investigator assessment of response and progression.
Duration of Response (BICR and investigator) in CPS ≥10, 5, 1 and all randomized subjects
Duration of response (DoR) will be evaluated per BICR assessment and per investigator 
assessment. DoR will be estimated using the KM techniques. A two-sided 95% CI for median in 
each treatment group will be computed via the log-log transformation method. For the DoR 
analyses the population is restricted to subjects with measurable disease at baseline.
For DoR, type of event (PD, death) and status of subjects censored (received subsequent therapy, 
ongoing follow-up [current, non-current], off study [withdrew consent] will be presented by 
treatment arm.
Time to objective response (BICR) in CPS ≥5 and all randomized subjects
Time to response will be evaluated per BICR assessment. Summary statistics will be provided for 
each treatment group for subjects who achieve PR or CR. For these analyses the population is 
restricted to subjects with measurable disease at baseline.
To assess further tumor response kinetics, time to response will be analyzed using the KM 
methodology. Kaplan-Meier curve will represent the cumulative rate of response over time. For 
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the non-responders, time to response will be censored at the maximum time of response + 1 day 
of all subjects in their respective treatment group. Cumulative Response Rates will be tabulated 
for Week 6, Week 12, Months 4, 6, 8, and 12, and overall Response Rate will be provided for each 
treatment group.
Durable response rate (BICR) in CPS ≥5 and all randomized subjects
Durable response will be evaluated per BICR assessment and per investigator assessment for 
subjects with measurable disease at baseline. The durable response rate will be computed in each 
treatment group along with the exact 95% CI using Clopper-Pearson method.18 An estimate of the 
difference in DRRs and corresponding 95% CI will be calculated using CMH methodology and 
adjusted by the stratification factors as specified in Table 7.5-1. The stratified odds ratios (Mantel-
Haenszel estimator) between the treatments will be provided along with the 95% CI.
PFS and ORR as assessed by either BICR or investigator and OS across TPS cut-offs
See Section 7.8 for Biomarker Analysis. 
PFS2 in CPS ≥5 and in all randomized subjects
PFS2 will be analyzed similarly to PFS:  
•
Median values based on KM method, along with two-sided 95% CI using Brookmeyer and 
Crowley method will be calculated. The estimate of standard error will be calculated using the 
Greenwood formula;
•
PFS2 will be graphically displayed along with the median and 95% CI.
A by-subject listing of PFS and PFS2 will be provided.
TTSD in CPS ≥10, 5, 1 and all randomized
See Section 7.9.1 in Clinical Outcome Assessment.
7.6
Safety
Analyses in this section will be tabulated for all treated subjects by treatment group as treated, 
unless otherwise specified. In addition some safety selected outputs will be presented for treated 
CPS ≥5 Subjects.
For chemotherapy (FOLFOX or XELOX) the Chemotherapy regimen “as treated” will be reported 
(see Section 6.2).
7.6.1
Deaths
Deaths will be summarized by treatment group:
•
All deaths, reasons for death.
•
Deaths within 30 days of last dose received, reasons for death. This output will also be 
presented for CPS ≥5 treated subjects.
•
Deaths within 100 days of last dose received, reasons for death.
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A by-subject listing of deaths will be provided for the all enrolled subjects population.
7.6.2
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. This output will also be presented for CPS ≥5 treated subjects.
•
Overall summary of drug-related SAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT. This output will also be presented for CPS ≥5 treated subjects.
All analyses will be conducted using the 30-day safety window. 
A by-subject SAE listing will be provided for the “enrolled subjects” population.
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
AEs leading to discontinuation 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. This output will also be presented for CPS ≥5 
treated subjects.
•
Overall summary of drug-related AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT. This output will also be presented for CPS ≥
5 treated subjects.
The analyses will be conducted using the 30-day safety window. 
A by-subject AEs leading to discontinuation listing will be provided.
7.6.4
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.
7.6.5
Adverse Events
Adverse events will be summarized by treatment group.
The following analyses will be conducted using the 30 days safety window only:
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•
Overall summary of any AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) presented 
by SOC/PT. This output will also be presented for CPS ≥5 treated subjects.
•
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. This output will also be presented for CPS ≥5 treated subjects.
•
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.
•
Overall summary of drug-related AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) 
presented by SOC/PT. This output will also be presented for CPS ≥5 treated subjects.
•
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. This output will also be presented for CPS ≥5 treated subjects.
A by-subject AE listing will be provided. A by-subject listing of any AE requiring immune 
modulating medications will also be provided.
7.6.6
Select Adverse Events 
Unless otherwise specified, analyses will be performed by select AE category. Analyses will also 
be repeated by subcategory of endocrine events.
7.6.6.1
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. This output will also be presented for CPS ≥5 
treated subjects.
•
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. This output will also be presented for CPS
≥5 treated subjects.
•
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.
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A by-subject select AE listing will be provided.
7.6.6.2
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.
Additional details regarding the time-to onset definition are described in time-to onset definition 
subsection of APPENDIX 1.
7.6.6.3
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.
7.6.7
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. This 
output will also be presented for CPS ≥5 treated subjects.
•
Overall summary of endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by Category / PT. This output will also be presented for CPS ≥5 treated subjects.
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•
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. This output will also be presented for CPS ≥5 treated subjects.
•
Overall summary of endocrine IMAEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category / PT. This output will also be presented for 
CPS ≥5 treated subjects.
•
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. This output will also be presented for CPS ≥5 treated subjects.
•
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. This output will also be presented 
for CPS ≥5 treated subjects.
•
Summaries of time-to onset and time-to resolution of non-endocrine IMAEs where immune 
modulating medication was initiated presented by Category. This output will also be presented 
for CPS ≥5 treated subjects.
•
Summaries of time-to onset and time-to resolution of endocrine IMAEs presented by Category.
This output will also be presented for CPS ≥5 treated subjects.
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.
In addition, for all nivolumab treated subjects who experienced at least one IMAE, the following 
data presentation will be provided:
•
Summary of subjects who were re-challenged with nivolumab by IMAE category, with 
extended follow-up. This output will also be presented for CPS ≥5 treated subjects.
For these, re-challenge is considered to have occurred when last nivolumab infusion was 
administered after the onset of an IMAE.
7.6.8
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.
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7.6.9
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.
A listing displaying the unique instances of all AEs, ie, after duplicates have been eliminated and 
overlapping and contiguous occurrences of the same event (ie, same PT) have been collapsed will 
be provided. No formal comparisons will be made between treatment groups.
7.6.10
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.
7.6.10.1
Hematology
The following will be summarized by treatment group 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). This output will also 
be presented for CPS ≥5 treated subjects.
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.10.2
Serum Chemistry
The following will be summarized by treatment group as shift table of worst on-treatment CTC 
grade compared to baseline CTC grade per subject: ALT, AST, total bilirubin and creatinine. This 
output will also be presented for CPS ≥5 treated subjects.
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.10.3
Electrolytes
The following will be summarized by treatment group 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) and Glucose Serum (fasting hyperglycemia and hypoglycemia 
regardless of fasting status). This output will also be presented for all ≥5 treated subjects.
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
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7.6.10.4
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
•
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:
•
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.
7.6.11
Vital Signs 
Vital signs will be listed by subject.
7.6.12
Physical Measurements
Physical measurements will be listed by subject.
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7.6.13
Immunogenicity Analysis
Further details on immunogenicity background and rationale, definitions, population for analyses 
and endpoints are described in APPENDIX 3.
Incidence of ADA
Number (%) of subjects will be reported for the following parameters based on nivolumab treated 
subjects with baseline and at least one post-baseline assessment. For the nivo +chemo arm the 
following parameters will be reported for nivolumab and for the nivolumab + ipilimumab arm the 
following parameters will be reported for nivolumab and ipilimumab.
•
Baseline ADA-positive
•
ADA-positive
−
Persistent Positive (PP)
−
Not PP-Last Sample Positive
−
Other positive
−
Neutralizing Positive
•
ADA-negative
A listing of all ADA assessments will be provided together with results for neutralizing antibody.
A spider plot of nivolumab ADA test result (titers) over time may be provided for nivolumab ADA 
positive subjects.
Clinical implications 
Clinical implications of nivolumab or ipilimumab immunogenicity will be primarily focused on 
subjects with persistent ADA-positive relative to ADA-negative. Subjects with any ADA-positive 
samples after initiation of treatment (relative to baseline) may be used to explore clinical 
implications. Effect of immunogenicity on clearance of nivolumab or ipilimumab will be explored 
by comparison of clearance estimates (determined by PPK analysis). Effect of immunogenicity on 
safety will be explored by examining the frequency and type of AEs of special interest such as 
hypersensitivity/infusion reaction. Summary tables for incidence of overall and each of the 
preferred terms will be provided, if the number of subjects is of sufficient size (eg, at least 
10 subjects). Otherwise, individual subject’s safety profile will be examined and described based 
on a listing. Clinical implications on efficacy will also be explored similarly. Association between 
trough concentrations of nivolumab or combination drug (eg, ipilimumab) and ADA assessments 
may be explored, as needed.
The following data presentation will be provided:
•
Swimmer plot of occurrence of ADA and NAb Occurrence in Relation to PFS per BICR, BOR
per BICR and OS
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7.6.14
Pregnancy
A by-subject listing of pregnancy tests results will be provided for randomized female subjects.
7.6.15
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 (Asia [including China], US, RoW)
7.7
Pharmacokinetic Analysis
The nivolumab 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. 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. 
7.8
Biomarker Analysis
These analyses will be descriptive and not adjusted for multiplicity.
The analyses will be conducted on the following populations:
•
For PFS and OS analyses of nivo + chemo versus chemo, the analyses will be performed on 
all randomized subjects or randomized subjects with quantifiable biomarker (see Section 6.3.1)
•
For OS analyses of nivolumab + ipilimumab versus chemotherapy, the analyses will be 
performed on all randomized subjects or randomized subjects with quantifiable biomarker (see 
Section 6.3.2)
7.8.1
Tumor and Immune PD-L1 (CPS)
The Combined Positivity Score (CPS) is a scoring system taking into account immunoreactivity 
for PD-L1 in both tumor cells and tumor infiltrating immune cells (restricted to lymphocytes and 
macrophages) within or directly associated with tumor cell strands. As such, CPS is calculated as 
the ratio of the number of PD-L1 positive cells (tumor cells, lymphocytes and macrophages) 
divided by the total number of viable tumor cells within the evaluated tumor area, multiplied by 
100. Although the maximum of this calculation may be greater than 100, the maximum CPS is 
defined as 100. The CPS score will be reported on a continuous scale.
CPS PD-L1 expression missing: Subjects without an available tumor biopsy specimen for PD-L1 
evaluation will be considered CPS PD-L1 expression missing.
For subjects with an available tumor biopsy specimen(s), the following will be considered:
CPS PD-L1 expression not quantifiable will be further classified as
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Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology 
of the tumor biopsy specimen and not because of improper sample preparation or handling 
•
Not evaluable: Tumor biopsy specimen was not optimally collected or prepared (eg, PD-L1 
expression is neither quantifiable nor indeterminate)
CPS PD-L1 status is a dichotomized variable and will use different cutoffs (1, 5, and 10).
7.8.1.1
Distribution of CPS PD-L1
Descriptive statistics of CPS PD-L1 expression:
•
Listing of all CPS PD-L1 data, all randomized subjects.
•
Summary of tumor specimen acquisition and characteristics, all randomized subjects.
•
Summary statistics of CPS PD-L1 expression in all randomized subjects with quantifiable 
PD-L1 expression.
•
Cumulative distribution plot of baseline CPS PD-L1 expression versus population percentile 
in all randomized subjects with quantifiable CPS PD-L1 expression.
7.8.1.2
Association between PD-L1 Status and Efficacy
CPS PD-L1 categories used for these analyses are: 
•
Each CPS PD-L1 status subgroup (CPS < 5 and CPS ≥5, CPS < 1 and CPS ≥1, CPS < 10 and 
CPS ≥10)
•
PD-L1 indeterminate or not evaluable subgroup
For both OS and PFS (using primary definition, per BICR and per Investigator), the following 
analyses will be provided and within each category above:
•
curves will be estimated using the KM product limit method for each treatment group. Two-
sided, 95% CIs for median OS and PFS will be computed by Brookmeyer and Crowley method 
Two-sided log-rank test comparing treatment arms 
•
HR (with corresponding two-sided 95% CI) will be estimated via a Cox model with treatment 
arm as the only covariate in the model 
•
Forest plot of HR with 95% CIs 
•
Figure with 6 KM curves for each combination of CPS PD-L1 status subgroup and treatment 
group.
For DOR (BICR) the following analyses will be provided and within each category above:
•
curves will be estimated using the KM product limit method for each treatment group. Two-
sided, 95% CIs for median DOR will be computed by Brookmeyer and Crowley method Two-
sided log-rank test comparing treatment arms 
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•
Figure with 6 KM curves for each combination of CPS PD-L1 status subgroup and treatment 
group.
For ORR, the following analysis will be provided using BICR data within each category:
•
An estimate of the response rate and an associated exact two-sided 95% CI (Clopper and 
Pearson) will be presented for each subgroup categorized by treatment arm. An associated odds 
ratio and 95% CI will be computed. An estimate of the difference in ORRs and corresponding 
95% CI will be calculated. 
7.8.1.3
Predictive Relationship between PD-L1 Status and Efficacy
For both OS and PFS (using primary definition, per BICR and per Investigator), a Cox proportional 
hazards regression model will be fitted with treatment, CPS PD-L1 status, and treatment by CPS 
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 CPS PD-L1 status 
subgroup
•
HR CPS PD-L1 ≥cutoff vs. < cutoff and its associated 95% CI within each treatment group
7.8.2
Tumor PD-L1
The tumor cell PD-L1 positive scoring takes into account the percent of tumor cell membrane 
staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC assay unless 
otherwise specified.
Tumor Cell PD-L1 expression missing: Subjects without an available tumor biopsy specimen for 
PD-L1 evaluation will be considered as Tumor Cell PD-L1 expression missing.
For subjects with an available tumor biopsy specimen(s), the following will be considered:
Tumor Cell PD-L1 expression is not quantifiable will be further classified as  
•
Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology 
of the tumor biopsy specimen and not because of improper sample preparation or handling 
•
Not evaluable: Tumor biopsy specimen was not optimally collected or prepared (eg, PD-L1 
expression is neither quantifiable nor indeterminate)
Tumor Cell PD-L1 status is a dichotomized variable and will use different cutoffs (1,5, and 10)
7.8.2.1
Distribution of Tumor Cell PD-L1
Descriptive statistics of Tumor Cell and CPS PD-L1 expression:
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•
Listing of all Tumor Cell PD-L1 IHC data, all randomized subjects.
•
Summary of tumor specimen acquisition and characteristics, all randomized subjects.
•
Summary statistics of Tumor Cell PD-L1 expression in all randomized subjects with 
quantifiable PD-L1 expression.
•
Cumulative distribution plot of baseline Tumor Cell PD-L1 expression versus population 
percentile in all randomized subjects with quantifiable PD-L1 expression.
7.8.2.2
Association between Tumor Cell PD-L1 Status and Efficacy
Analyses will be based on all randomized subjects if not otherwise specified. PD-L1 categories 
used for these analyses are: 
•
Each PD-L1 status subgroup (< 5 and ≥5, < 1 and ≥1, < 10 and ≥10)
•
Tumor Cell PD-L1 indeterminate or not evaluable subgroup
For both OS and PFS (using primary definition, per BICR and per Investigator), the following 
analyses will be provided and within each category above:
•
curves will be estimated using the KM product limit method for each treatment group. Two-
sided, 95% CIs for median OS and PFS will be computed by Brookmeyer and Crowley method 
Two-sided log-rank test comparing treatment arms 
•
HR (with corresponding two-sided 95% CI) will be estimated via a Cox model with treatment 
arm as the only covariate in the model 
•
Forest plot of HR with 95% CIs 
•
Figure with 6 KM curves for each combination of Tumor Cell PD-L1 status subgroup and 
treatment group.
For DOR (BICR) the following analyses will be provided and within each category above:
•
curves will be estimated using the KM product limit method for each treatment group. Two-
sided, 95% CIs for median DOR will be computed by Brookmeyer and Crowley method Two-
sided log-rank test comparing treatment arms 
•
Figure with 6 KM curves for each combination of Tumor Cell PD-L1 status subgroup and 
treatment group.
For ORR, the following analysis will be provided using BICR data within each category.
•
An estimate of the response rate and an associated exact two-sided 95% CI (Clopper and 
Pearson) will be presented for each subgroup categorized by treatment arm. An associated odds 
ratio and 95% CI will be computed. An estimate of the difference in ORRs and corresponding 
95% CI will be calculated.
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7.8.2.3
Predictive Relationship between Tumor Cell PD-L1 Status and Efficacy
For both OS and PFS (using primary definition, per BICR and per Investigator), a Cox proportional 
hazards regression model will be fitted with treatment, Tumor Cell PD-L1 status, and treatment by 
Tumor Cell 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 Tumor Cell PD-L1 status 
subgroup
•
HR Tumor Cell PD-L1 ≥cutoff vs. < cutoff and its associated 95% CI within each treatment 
group.
7.8.3
MSI 
7.8.3.1
MSI Distribution 
MSI categories (MSI-H, MSS, Invalid, unknown) will be summarized once on all randomized and 
once on all randomized subjects with MSI status available.
7.8.3.2
Association between MSI Status and Efficacy
For OS and PFS ((using primary definition, per BICR and per Investigator), the following analyses 
will be provided within each MSI category above for all randomized subjects.
•
curves will be estimated using the KM product limit method for each treatment group. Two-
sided, 95% CIs for median OS and PFS will be computed by Brookmeyer and Crowley method 
Two-sided log-rank test comparing treatment arms 
•
HR (with corresponding two-sided 95% CI) will be estimated via a Cox model with treatment 
arm as the only covariate in the model 
•
Forest plot of HR with 95% CIs
•
Figure with 8 KM curves for each combination of MSI status subgroup and treatment group
For DOR (BICR) the following analyses will be provided and within each category above for all 
randomized subjects:
•
curves will be estimated using the KM product limit method for each treatment group. Two-
sided, 95% CIs for median DOR will be computed by Brookmeyer and Crowley method Two-
sided log-rank test comparing treatment arms 
•
Figure with 8 KM curves for each combination of CPS PD-L1 status subgroup and treatment 
group
For ORR, the following analysis will be provided using BICR data within each category for all 
randomized subjects:
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•
An estimate of the response rate and an associated exact two-sided 95% CI (Clopper and 
Pearson) will be presented for each subgroup categorized by treatment arm. An associated odds 
ratio and 95% CI will be computed. An estimate of the difference in ORRs and corresponding 
95% CI will be calculated. 
7.8.3.3
Predictive Relationship between MSI Status and Efficacy
For both OS and PFS, a Cox proportional hazards regression model will be fitted with treatment, 
MSI status, and treatment by MSI 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. The 
following analyses will be produced for all randomized subjects:
•
Interaction p-value
•
HR of treatment vs. control and its associated 95% CI for each of the MSI status subgroup
•
HR between MSI categories and associated 95% CI’s within each treatment group
7.9
Clinical Outcome Assessments
All questionnaires completed at baseline and on-study will be assigned to a time-point according 
to the windowing criteria in the table below 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. In the case of two assessments at a similar distance to the time-point, the latest one will be 
chosen. If there are two assessments reported on the same date, the assessment corresponding to 
the earliest visit would be used for analysis reporting purposes. 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.
Time Windows for EQ-5D-3L, FACT-Ga
Nominal Time-Point
Time Window
Baseline
Treated subjects:
Prior to first dose on Day 1 (assessment date <= first dose date; assessment 
time should not be used because of its unreliability)
Randomized never treated subjects:
Assessment date <= randomization date
Week 7
Treated subjects only:
Nominal day is 43 
Day 2 thru Day 64, inclusive
Week X (Every 6 weeks 
thereafter)
Treated subjects only:
Nominal Day of previous visit + 42
Range of window: [nominal day -20, nominal day +21]
Note: any assessment that is after the last dose will be slotted 
to the follow-up visit (see below).
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Time Windows for EQ-5D-3L, FACT-Ga
Nominal Time-Point
Time Window
Follow-Up 1a
Compute Day as (Assessment date - last dose date +1)
if Day is in [2, 73]
Follow-Up 2
compute day as (Assessment date - last dose date +1)
if day is in [74, 160]
Survival Follow-up visit i (every 
3 months from follow-up 2)
I=1,2,3....
Compute Day as (Assessment date - last dose date +1)
Nominal day is 115 + i * 91
If Day is in [Nominal day -45, Nominal day + 45]
a Only FACT-GaCS, FACT G7 and EQ-5D-3L are collected in follow-up 1, follow-up 2 and survival follow-up.
The analysis of FACT-Ga and EQ-5D-3L will be restricted to randomized subjects who have an 
assessment at baseline and at least one post-baseline assessment.
The analyses will be conducted on the following populations:
•
For PFS and OS analyses of nivo+chemo versus chemo, the analyses will be performed on 
randomized CPS ≥5 subjects, randomized CPS ≥1 subjects and on all randomized subjects 
(see Section 6.3.1)
•
For OS analyses of nivo+ipi versus chemotherapy, the analyses will be performed on 
randomized CPS ≥5 subjects, randomized CPS ≥1 subjects and on all randomized subjects 
(see Section 6.3.2)
7.9.1
FACT-Ga and TTSD
TTSD is an exploratory endpoint for the comparison of nivo+chemo vs. chemo and the analyses 
of TTSD will be descriptive. TTSD is a secondary objective for the comparison of nivo+ipi vs.
chemo in the hierarchy and will be tested formally if the preceding secondary endpoint in the 
hierarchy is significant. See section 4.2.2.4 for the definition of TTSD.
TTSD will be assessed for the different CPS cutoffs and for all randomized subjects.
TTSD will be compared between nivo+ipi and chemo via stratified log-rank test at a two-sided α 
level with α inherited from the preceding endpoint in hierarchy. The two-sided log-rank p-value 
will be reported.
The estimate of the TTSD hazard ratio between treatment groups will be calculated using a 
stratified Cox proportional hazards model, with treatment as the sole indicator covariate (for each 
pair of treatment arms separately). Ties will be handled using the exact method. A two-sided 95% 
for the hazard ratio will also be presented. CI In case TTSD is formally tested the 100 x (1 - α)% 
CI will be provided.
The TTSD function for each treatment group will be estimated using the KM product limit method 
and will be displayed graphically. Medians and two-sided 95% CI in each treatment group will be 
computed via the log-log transformation method. 
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Sensitivity Analyses for TTSD 
•
Stratified analysis using stratification factors as obtained from the baseline CRF pages
(instead of IRT). This analysis will be performed only if at least one stratification factor at 
randomization (as per IRT) and baseline are not concordant for at least 10% of the population.
•
Analysis accounting for death. TTSD will be defined similarly to the primary definition except 
that for patients who die without deterioration, death will be counted as an event.
•
Analysis accounting for assessment on/after treatment discontinuation: TTSD will be defined
similarly to the primary definition except that events (deterioration or death) and assessments
that occurred on or after treatment discontinuation will be considered (no time point truncation)
For the FACT-Ga items are scored on categorical scales. Some items (score between 0 and 4) are 
reversed so that a higher score represents a better quality of life. 
The following descriptive analyses will be conducted:
•
FACT-Ga questionnaire completion rate, defined as the proportion of questionnaires actually 
received out of the expected number (ie, number of subjects on treatment or in follow up) will 
be calculated and summarized for each assessment time point by treatment group. As of follow-
up visit 1 and after, limited questionnaire are collected for GaCS and Fact-G7. Completion rate 
will be provided for the follow up visits only for those two scales.
•
Mean score and mean change from baseline in individual wellbeing scales, GaCS, FACT-G7, 
FACT-G, and FACT-Ga total scores will be summarized at each assessment time point using 
descriptive statistics (ie, N, mean with SD and 95% CI, median, first and third quartiles, 
minimum, maximum). As of follow-up visit 1 and after, limited questionnaire are collected for 
GaCS and Fact-G7. Summary statistics will be provided for the follow up visits only for those 
two scales. 
•
A line graph summarizing the mean changes from baseline will be produced for GaCS, FACT-
G7, FACT-G, and FACT-Ga total scores.
7.9.2
EuroQol EQ-5D-3L
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 (ie, 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 (ie, 5-digit vector) 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 VAS scores and utility index:
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−
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.
7.10
COVID-19 Related Analyses
In this study, in order to evaluate the impact of COVID-19 pandemic, the following CRF pages 
were implemented. 
•
Disposition: The subjects who discontinue the study treatment or discontinue the study due to 
COVID-19.
•
Exposure: The subjects who have study therapy modification due to COVID-19.
•
Contact Information: The subjects who miss visits due to COVID-19.
Listings will be provided based on the data collected on each CRF pages and additional analyses 
may be performed in order to evaluate the impact of COVID-19 on this study.
8
ANALYSES TO EVALUATE THE CONTRIBUTION OF COMPONENTS IN 
THE N+I REGIMEN
8.1
Ipilimumab contribution
The analyses described in this section will help to evaluate the contribution of components (CoC);
specifically that ipilimumab contributes to the N+I combination. With nivolumab treatment 
common to both regimes, an analysis that isolates the ipilimumab contribution in N+I relative to 
chemo in the N+C combination will be conducted.
The concurrently randomized analysis is understood to be the valid comparison. To support this 
analysis, a sensitivity analysis on all randomized subjects will be conducted in consideration of
the non-overlapping randomization, which has the potential to introduce bias. The analysis of this 
broader group considering the totality of the data is intended to be supportive with a balance of 
increased precision and less validity.
The following two populations will be used for these analyses comparing N+I to N+C:
All Concurrently Randomized Subjects to 3 Arms: all subjects concurrently randomized to 
nivo+chemo or chemo or nivo+ipi from 27-Mar-2017 (included) to 05-Jun-2018 (N~1098, see 
Figure 8.1-1).
All Randomized Subjects to 3 Arms: all subjects randomized to nivo+chemo or chemo or 
nivo+ipi. This entails all subjects randomized in the study (N~2031).
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Figure 8.1-1:
Randomization to the 3 Arms
All the analyses that will be conducted to support the contribution of components are considered 
exploratory intended for descriptive purpose. These analyses will not be adjusted for multiplicity 
(no p-value will be provided) and estimates will be accompanied by 95% CI. 
The following analyses will be produced for the 2 populations described above and for those 2 
populations restricted to subjects with PD-L1 CPS ≥5 and for PD-L1 CPS <5.
Unless stated otherwise, whenever a stratified analysis is specified in this section, the following 
stratifications factors (recorded at randomization as per IRT) will be used see Table 7.5-1
Table 8.1-1: Stratification Factors Used for Stratified Analyses Supporting CoC 
• Region (Asia vs. US vs. RoW)
• ECOG performance status (0 vs. 1)
• PD-L1 expression level (≥1% vs. < 1% or indeterminate)
8.1.1
OS and PFS
For OS and PFS as assessed by BICR the HR between nivo+ipi and nivo+chemo with its associated 
two-sided 95% CIs will be estimated via a stratified Cox model with treatment arm as the only 
covariate in the model. For the smaller subset some small stratum are possible, so in addition the 
unstratified Cox model will be implemented as a sensitivity analysis. The HR of nivo+chemo vs.
chemo and nivo+ipi vs. chemo will also be estimated using the same population. Overall survival 
and PFS as assessed by BICR (using both primary and secondary definitions, as defined in Sections
4.1.2.1 and 4.1.2.2, respectively) for each of the three treatment arms will be estimated and 
overlayed using the KM product-limit method. Median survival time along with 95% CI will be 
constructed based on a log-log transformed CI for the survival function.
The analyses above will be repeated for the following populations:
•
All concurrently randomized subjects to the 3 arms
•
All concurrently randomized subjects to the 3 arms with PD-L1 CPS ≥5 
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All concurrently randomized subjects with PD-L1 CPS < 5
•
All randomized subjects to the 3 arms 
•
All randomized subjects to the 3 arms with PD-L1 CPS ≥5
•
All randomized subjects to the 3 arms with PD-L1 CPS < 5
For OS, considering that the survival function may potentially have different shapes for the N+I 
arm and the N+C arm, the restricted mean survival time (RMST) will be evaluated for each of 
these two arms. The difference of RMST with its associated two-sided 95% CIs will be estimated. 
The RMST will be estimated by the area under the KM curve up to several time points (12 months, 
24 months, 36 months, and the minimum of the longest survival time in each treatment arm, 
regardless of censoring). Since follow-up differs for the arms, these analyses will be done solely 
on all subjects concurrently randomized subjects to the 3 arms, all concurrently randomized 
subjects to the 3 arms with PD-L1 CPS ≥5 and for all concurrently randomized subjects to the 3 
arms with PD-L1 CPS <5.
8.1.2
ORR and DOR
For ORR and DOR as assessed by BICR, ORR will be computed in each of the 3 treatment groups
along with the exact 95% CI using Clopper-Pearson method. An estimate of the difference in ORRs 
and corresponding 95% CI between each pair of treatment arms will be calculated using CMH 
methodology and adjusted by the stratification factors as specified in Section 7.1.1. The stratified 
odds ratios (Mantel-Haenszel estimator) between each pair of treatment arms will be provided 
along with the 95% CI. DOR for each of 3 treatment groups will be estimated and overlayed using 
KM product limit method for subjects who achieve PR or CR. Median values along with two-sided 
95% CI will be calculated.
These analyses will be produced for
•
All concurrently randomized subjects to the 3 arms with measurable disease (BICR)
•
All concurrently randomized subjects to the 3 arms with measurable disease (BICR) and 
PD-L1 CPS ≥5 
•
All concurrently randomized subjects to the 3 arms with measurable disease (BICR) and with 
PD-L1 CPS < 5.
•
All randomized subjects to the 3 arms with measurable disease (BICR)
•
All randomized subjects to the 3 arms with measurable disease (BICR) and PD-L1 CPS ≥5 
•
All randomized subjects to the 3 arms with measurable disease (BICR) and PD-L1 CPS < 5.
9
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 Specification22.
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•
Missing and partial Non-Study Medication Domain dates will be imputed using the derivation 
algorithm described in Section 4.3.3 of BMS Non-Study Medication Domain Requirements 
Specification.23
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 date alive 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 date alive. 
•
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, 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.
•
In case of the date of death is present and complete, the imputed progression date will be 
compared to the date of death. The minimum of the imputed progression date and date of death 
will be considered as the date of progression.
For other partial/missing dates, the following conventions may be 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 (eg, DoR, etc) will be calculated as follows:
Duration = (Last date - first date + 1)
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
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10
CONTENT OF REPORTS
At the time of first analysis time point (12 months minimum follow-up), the final analysis of PFS 
and interim analysis of OS in PD-L1 CPS≥5 randomized subjects in the nivo+chemo vs chemo 
arms will be performed. Below are potential scenarios for the planning of contents report:
1) If both of the primary endpoints are not meeting the pre-specified statistical significance 
criteria, the study will continue and there is no unblinding of either endpoint. As such, no report 
is planned.
2) If PFS meets the pre-specified statistical criteria, a clinical study report for nivo+chemo vs. 
chemo will be written with all the analyses listed in this SAP except for these analyses related 
to OS.
3) If both primary endpoints meet the pre-specified statistical significance or only OS meets the 
statistical significance, a clinical study report for nivo+chemo vs. chemo will be written with 
all analyses listed in this SAP.
4) There will be no analysis performed for the nivo+ipi vs. chemo comparison.
At the second analysis time point (24 months minimum follow-up), a report for nivo+ipi vs. chemo 
will be written with all analyses listed in this SAP. A report for nivo+chemo vs chemo will be 
written with the primary endpoint(s) that have not yet reported at the first time point if any.
Refer also to the Data Presentation Plan for mock-ups of all tables and listings.
11
DOCUMENT HISTORY
Table 11-1:
Document History
Version 
Number
Author(s)
Description
1
25-Apr-2017
 
Original SAP based on revised Protocol 02
2
02-Dec-2019
 
Updated to align with IO CORE SAP
Updated to reflect revised protocol 09.
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Table 11-1:
Document History
Version 
Number
Author(s)
Description
3
29-May-2020
Based on revised protocol 09.
Minor updates from SAP version 2.0 to add/modify sensitivity 
analyses and other minor edits. Details are summarized below:
•
Section 7.5.2.2, 7.5.2.5 and 7.5.3.2 Replace the Fleming-
Harrington test F(0,1) by the max combo in case of NPH.
•
added potential sensitivity analysis in case of imbalance in 
PD-L1 CPS≥5 group in Sections 7.5.2.2, 7.5.2.5 and 7.5.3.2
•
Update blinding and unblinding Section 2.3 regarding 
unblinding of the PFS results but not OS results in case that 
PFS is positive but OS is negative at the interim.
•
Section 4.1.2, added some text to state that PFS regardless 
of subsequent therapy is considered as primary analysis by 
EMA. The PFS account for subsequent therapy is the 
primary endpoint of the study and will be the basis of the 
primary test. 
•
For swimmer plot for ADA and Nab in relation to efficacy 
endpoint, added BOR per BICR 
•
Section 7.8.3.2, corrected typo, 6 KM curves for each 
combination of biomarker status and treatment
•
Corrected 24-Mar to 27-Mar in definition of All 
randomized subjects for nivo+chemo vs chemo. It has no 
impact on datasets, change was made for consistency.
•
Added AE tables for the all treated subjects with CPS>=5. 
Added IMAE outputs for all treated subjects with CPS>=5.
•
Added surgery to the list of concurrent prohibited anti-
cancer therapy to reflect protocol.
•
Changed “Planned Chemotherapy” to “Chemotherapy” for 
subgroup analyses as we will use the Chemotherapy as 
treated. 
•
Correction to Time Window for EQ-5D-3L, FACT-Ga, for 
the survival for follow-up.
•
Removed Siewert-Stein classification from the list of 
subsets for PFS, OS and ORR as this is collected only for 
GEJ.
•
Added Baseline albumin (< LLN, ≥LLN) to the list of 
subsets for PFS, OS and ORR
•
Censoring efficacy endpoints for subsequent therapy. 
Subjects are censored for radiotherapy with reason 
curative and added reason palliative.
•
Added UNKNOWN category for MSI
•
added appendix 4 with analyses of data from China 
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Table 11-1:
Document History
Version 
Number
Author(s)
Description
4.0
04-Aug-2020
Added Appendix 5 to update the expected number of subjects, 
expected number of PFS and OS events and updated power 
based on the actual CPS>=5 prevalence. The prevalence was 
estimated using the locked database of July 10, 2020. The 
estimation was done in a blinded manner using the pooled 
estimate for the 3 arms.
5.0
14-May-2021
 
This update was implemented after the analysis of PFS and OS 
IA for nivo+chemo vs chemo for which the CSR was written.
The updates do not affect any of the planned analyses for 
nivo+ipi vs chemo. The updates include:
•
Update to Section 7.4.1, to allow reporting of the 
overall RDI for nivolumab in the nivo+ipi treatment 
arm, the formula was changed.
•
Specific section (Section 7.10) related to COVID 19 
data reporting.
•
Specific section (Section 8) with exploratory 
analyses to support the justification of the 
ipilimumab contribution in the nivo+ipi regimen.
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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 
(ie, 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:
1) Multiple adverse event records have the same onset date.
2) 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).
3) 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; 
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•
If date is completely missing or invalid then leave missing.
B. For data collected on other CRF pages (deemed to be on-treatment/subsequent surgeries): 
•
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. 
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APPENDIX 3
IMMUNOGENICITY ANALYSIS: BACKGROUND AND 
RATIONALE
The following summary is from the FDA Guidance for Industry Immunogenicity Assessment for 
Therapeutic Protein Products and White Paper on Assessment and Reporting of the Clinical 
Immunogenicity of Therapeutic Proteins and Peptides – Harmonized Terminology and Tactical 
Recommendations by Shankar et al. The program-level definitions of sample- and subject-level 
ADA status are based on recommendation from the BMS Immunogenicity Council.
Immune responses to therapeutic protein products may pose problems for both patient safety and 
product efficacy. Immunologically based adverse events, such as anaphylaxis and infusion 
reactions, have caused termination of the development of therapeutic protein products or limited 
the use of otherwise effective therapies. Unwanted immune responses to therapeutic proteins may 
also neutralize the biological activity of therapeutic proteins and may result in adverse events not 
only by inhibiting the efficacy of the therapeutic protein product, but by cross-reacting to an 
endogenous protein counterpart, if present. Because most of the adverse effects resulting from 
elicitation of an immune response to a therapeutic protein product appear to be mediated by 
humoral mechanisms, circulating antibody has been the chief criterion for defining an immune 
response to this class of products.
ADA is defined as biologic drug-reactive antibody, including pre-existing host antibodies that are 
cross-reactive with the administered biologic drug (baseline ADA). Titer is a quasiquantitative 
expression of the level of ADA in a sample. By employing a serial dilution-based test method, titer 
is defined as the reciprocal of the highest dilution of the sample (eg, dilution of 1/100 = titer of 
100). The ADA is also tested, via a cell-based biologic assay or a non cell-based competitive 
ligand-binding assay for a subpopulation of ADA known as neutralizing antibodies (NAb), which 
inhibits or reduces the pharmacological activity of the biologic drug molecule regardless of its in 
vivo clinical relevance. Non-neutralizing ADA (non-NAb) is ADA that binds to the biologic drug 
molecule but does not inhibits its pharmacological activity.
ADA should be tested using sensitive and valid methods and employing an appropriate strategy 
for elucidating immunogenicity. Detection of ADA is typically performed in three tiers (screening, 
confirmatory, and titer) using statistically determined cutpoints and samples testing positive in the 
ADA assay are analyzed for neutralizing activity, especially in late-stage clinical studies. 
“Detection” of ADA implies that drug-specific ADA was confirmed. The ‘drug tolerance” of an 
assay (highest drug concentration that does not interfere in the ADA detection method) is not an 
absolute value and differs between individuals due to the varying avidities of ADA immune 
responses. An ADA sampling strategy of collecting samples at times when the least drug 
concentration is anticipated (trough concentrations) can increase the likelihood of accurate ADA 
detection.
It is useful to present ADA results from clinical studies as (a) characteristics of the ADA immune 
response, (b) relationship of ADA with pharmacokinetics (PK) and, when relevant, 
pharmacodynamics (PD) biomarkers, and (c) relationship of ADA with clinical safety and 
efficacy.
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Clinical consequences of ADA can range from no apparent clinical effect to lack of efficacy 
(primary treatment failure), loss of efficacy (secondary treatment failure) or heightened effect due 
to altered exposure to the biologic drug, adverse drug reactions (administration-related systemic 
or site reactions), and severe adverse drug reactions (anaphylaxis and unique clinical problems 
associated with cross-reactivity and neutralization of endogenous molecules). Thus it becomes 
important to examine any associations between ADA or any of its attributes with the various 
clinical sequelae. The presence of ADA may or may not preclude the administration of drug to 
ADA-positive subjects because the outcome is dependent upon the magnitude of the impact of 
ADA on PK and PD. Hence, the relationship of ADA with PK/PD is an important additional 
consideration, but does not necessarily result in a clinically impactful consequence per se.
Immunogenicity Endpoints
A fundamental metric that informs clinical immunogenicity interpretation is the incidence of ADA 
in a study or across comparable studies. ADA incidence is defined as the proportion of the study 
population found to have seroconverted or boosted their pre-existing ADA during the study period.
Terms and Definitions
Validated ADA test methods enable characterization of samples into ADA-positive vs. ADA-
negative. To classify the ADA status of a subject using data from an in vitro test method, each 
sample from the subject is categorized based on the following definitions:
Sample ADA Status:
•
Baseline ADA-positive sample: ADA is detected in the last sample before initiation of 
treatment
•
Baseline ADA-negative sample: ADA is not detected in the last sample before initiation of 
treatment
•
ADA-positive sample: After initiation of treatment, (1) an ADA detected (positive 
seroconversion) sample in a subject for whom ADA is not detected at baseline, or (2) an ADA 
detected sample with ADA titer to be at least 4-fold or greater (≥) than baseline positive titer
•
ADA-negative sample: After initiation of treatment, ADA not positive sample relative to 
baseline
Next, using the sample ADA status, subject ADA status is defined as follows:
Subject ADA Status:
•
Baseline ADA-positive subject: A subject with baseline ADA-positive sample
•
ADA-positive subject: A subject with at least one ADA positive-sample relative to baseline at 
any time after initiation of treatment
1) Persistent Positive (PP): ADA-positive sample at 2 or more consecutive time points, where 
the first and last ADA-positive samples are at least 16 weeks apart
2) Not PP-Last Sample Positive: Not persistent positive with ADA-positive sample at the last 
sampling time point
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3) Other Positive: Not persistent positive but some ADA-positive samples with the last sample 
being negative
4) Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies detected
•
ADA-negative subject: A subject with no ADA-positive sample after the initiation of 
treatment.
(Note: 16 weeks was chosen based on a long half-life of IgG4.)
Population for Analyses
Analysis of immunogenicity data will be based on ADA evaluable subjects defined as all treated 
subjects with baseline and at least 1 post-baseline immunogenicity assessment. Analysis dataset 
and data listing will include all available ADA samples. However, subject-level ADA status will 
be defined based on only adequate samples (eg, excluding 1-hour post-infusion samples when 
clearly indicated).
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APPENDIX 4
ANALYSES OF DATA FROM CHINA
Analysis methods for China
Most analyses detailed in SAP will be repeated for the patients randomized in China using the 
analysis sets described in this appendix. The analysis methods for the China subpopulation will be 
the same as for the global population unless otherwise noted. No formal hypothesis testing will be 
performed to evaluate consistency of China subpopulation. Instead, descriptive statistics will be 
provided to assess the consistency. All statistical analyses for China will be considered exploratory 
and only performed when at least one of the primary endpoints is statistically significant. 
No adjustment for multiplicity will be made.
Given that all patients in China subpopulation are from geographic region Asia, region (Asia vs. 
US vs. RoW) will be not be used as stratification factors in stratified analyses conducted for the 
China.
Definition of analysis sets
China subpopulation 
Chinese subpopulation is defined as China subgroup. It should contain subjects that are Chinese 
by race and enrolled from China. 
Asian subpopulation
Asian subpopulation is defined as Asian subgroup. It should contain subjects that are Asian by 
race and enrolled from Asian countries.
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APPENDIX 5
SAMPLE SIZE UPDATE
This appendix is completed after the database lock for the efficacy interim analysis (dated July 10, 
2020) and before the DMC efficacy review meeting (planned on August 6, 2020). The interim 
analysis consists of the final analysis of PFS and interim analysis of OS in subjects with PD-L1 
CPS ≥ 5 for the comparison of nivolumab plus chemotherapy vs chemotherapy.
During the development of the SAP v3.0 the actual prevalence of PD-L1 CPS ≥ 5 in study 
CA209649 was unknown. For that reason, it was not possible to estimate the expected number of 
PFS and OS events. The expected final number of OS events is needed to derive the adjusted 
significance level for the interim analysis of OS using the Lan-DeMets α spending function with 
O’Brien and Fleming type of boundary. The significance level will be adjusted according to the 
fraction of actual OS events observed at the interim against the estimated final number of events. 
At final analysis of OS, the significance level will be calculated using the number of events in the 
database at time of database lock and considering the α-level already spent at interim analysis 
using the EAST Interim Monitoring Tool.
There were 2031 subjects randomized to the study. Based on the different periods of randomization 
(see Table 5.1-1 Randomization Allocation and Sample Size), it is estimated that approximately 
1582 subjects were randomized concurrently to nivolumab+chemotherapy or chemotherapy.
The prevalence of PD-L1 CPS ≥ 5 using the data from July 10, 2020 (blinded and pooled over the 
3 arms) is 60% among all randomized subjects. Based on this prevalence, it is estimated that the 
number of subjects with PD-L1 CPS ≥ 5 who were randomized to nivolumab + chemotherapy and 
chemotherapy will be 949.
OS Events Estimation Using Actual CPS prevalence
The final number of OS events is obtained via simulations in EAST 6.4.1. The OS model is 
described in Section 5.2.1 and consists of a 2-piece hazard ratio; a delayed effect with a HR of 1 
versus chemotherapy for the first 6 months followed by a constant HR of 0.65. The distribution 
for the OS of the chemotherapy arm is a 4-piece hazard (see Table 5.2.1-3). Based on these 
simulations the final number of events at final analysis among 949 subjects is estimated to be 800.
Update of Power Calculation for PFS and OS
As indicated in section 8.1.2 of the protocol, “the power statement of the primary endpoints of PFS 
and OS will be updated using the actual prevalence and documented in the final SAP prior to first 
database lock for efficacy analysis.” Based on the observed prevalence of PD-L1 CPS ≥5 of 60% 
among all randomized subjects, Table 5.2.1-2 and Table 5.2.1-4 are therefore updated with Table 1
and Table 2. Specifically, the number of subjects with PD-L1 CPS≥5, the expected number of 
events at interim and final, and the power at interim and final were updated and are highlighted in 
the tables.
Similarly for the nivolumab+ipilimumab comparions, based on the observed prevalence of PD-L1 
CPS ≥5 of 60% among all randomized subjects and α=0.035 hierarchically passed from the 
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primary nivolumab+chemotherapy versus chemotherapy results at the primary database lock on 
10Jul2020, Table 5.2.1-2 is therefore updated with Table 3.
Table 1
Updated Summary of Sample Size Parameters and Schedule of 
Analyses for PFS (Nivolumab + Chemotherapy vs. Chemotherapy)
3 months Delay 
6 months Delay
# subjects with PD-L1 CPS ≥5a
949
949
Hypothesized delayed period
3
6
Hypothesized HR after delayed 
period
0.56
0.56
Hypothesized median in control arm
5.5 months
5.5 months
Significance level (2-sided)
0.02
0.02
Enrollment Period (from start of 
1:1:1) 
25.4 months
25.4 months
Minimum follow-up / Expected 
number of eventsa,b,c
12 months /841
12 months /857
Time of Analysis 
37.4 months
37.4 months
powerb
99.9% 
84.0%
average HRb
0.66
0.80
a Based on 60% prevalence of PD-L1 CPS ≥5
b Results based on simulations.
c Number of events for the nivolumab plus chemotherapy vs. chemotherapy comparison in total.
Table 2
Updated Summary of Sample Size Parameters and Schedule of 
Analyses for OS (Nivolumab + Chemotherapy vs. Chemotherapy)
# with PD-L1 CPS ≥5a
949
Hypothesized delayed period
6 months
Hypothesized HR after delayed period
0.65
Hypothesized median in control arm
11.1 months
Significance level (2-sided)
0.03
Enrollment Period (from start of 1:1:1) 
25.4 months
INTERIM ANALYSIS #1 for OS
Minimum follow-up/Expected number of eventsa,b,c
12 months/680
Time of analysisd
37.4 months
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Table 2
Updated Summary of Sample Size Parameters and Schedule of 
Analyses for OS (Nivolumab + Chemotherapy vs. Chemotherapy)
Significance levele
0.0164
Power
87.3%
FINAL ANALYSIS
Minimum follow-up/Expected number of eventsa,b,c
24 months/800
Time of analysisd
49.4 months
Significance level
0.0252
Powerb
97.9%
Average HR
0.74
a Based on a 60% prevalence of PD-L1 CPS ≥ 5.
b Results based on simulations
c Number of events for the nivolumab plus chemotherapy vs. chemotherapy comparison in total.
d After first patient randomized to nivolumab + chemotherapy or chemotherapy in 1:1:1 randomization.
e Significance levels will be calculated based on the actual number of deaths at each interim analysis
Table 3:
Updated Summary of Sample Size Parameters and Schedule of 
Analyses for OS (Nivolumab + Ipilimumab vs. Chemotherapy)
Alpha=0.035
# with PD-L1 CPS ≥ 5a
489
Hypothesized distribution 
See Table 5.2.2-1
Hypothesized median in control arm
11.1 months 
Significance level (two-sided)
0.035
Enrollment Period (from start of 1:1)
18.7 months
Time of analysis /Expected number of eventsa,b,c
54.4/411
Powerb
93%
Average HRb
0.70
a Based on 60% prevalence of PD-L1 CPS ≥5
b Results based on simulations.
c Number of events for the nivolumab plus ipilimumab vs. chemotherapy comparison in total.
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