Clinical trial NCT02574078
Conditions: Non-Small Cell Lung Cancer
Sponsor: Bristol-Myers Squibb
Start date: 2015-11-23; Completion date: 2020-04-15
Enrollment: 341 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether nivolumab monotherapy or in combination with Standard of care (SOC) therapies will provide clinical benefit (i.e., PFS, OS, and DOR) without unacceptable toxicity in advanced Non-Small Cell Lung Cancer patients.

Detailed description:
Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK)

\*\*Please note that the study is no longer enrolling patients for Groups A, B, C, and E.

Arms: arm 1: Opdivo specified dose on specified days arm 2: Opdivo/Bevacizumab specified dose on specified days

Opdivo/Pemetrexed specified dose on specified days arm 3: Bevacizumab specified dose on specified days

Pemetrexed specified dose on specified days arm 4: Opdivo specified dose on specified days arm 5: Therapy directed against specific symptoms of disease, i.e., palliative radiation or palliative surgery arm 6: Carboplatin/nab-paclitaxel specified dose on specified days

Carboplatin/paclitaxel specified dose on specified days

Carboplatin/pemetrexed specified dose on specified days

Carboplatin/docetaxel specified dose on specified days

Carboplatin/gemcitabine specified dose on specified days

Paclitaxel specified dose on specified days

Docetaxel specified dose on specified days

Gemcitabine specified dose on specified days

Pemetrexed specified dose on specified days arm 7: Opdivo specified dose on specified days arm 8: Erlotinib specified dose on specified days arm 9: Opdivo/Erlotnib specified dose on specified days arm 10: Opdivo/Crizotinib specified dose on specified days
Interventions: intervention 1: Nivolumab intervention 2: Bevacizumab intervention 3: Pemetrexed intervention 4: Best Supportive Care intervention 5: nab-Paclitaxel intervention 6: Paclitaxel intervention 7: Docetaxel intervention 8: Gemcitabine intervention 9: Erlotinib intervention 10: Crizotinib intervention 11: Carboplatin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: Palliative radiation, palliative surgery and/or other best supportive care treatments intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None intervention 10: None intervention 11: None

Protocol documents:
Prot_000.pdf: 
Page: 1
Protocol Number: CA209370
IND Number: 100,052
Date: 15-May-2015
Revised Date 26-Mar-2018
Clinical ProtocolCA209370
A Master Protocol of Phase 1/2 Studies of Nivolumab in Advanced NSCLC Using Nivolumab as 
Maintenance after Induction Chemotherapy or as First-line Treatment Alone or in Combination 
with Standard of Care Therapies
(CheckMate 370: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 370)
Revised Protocol Number: 05
Incorporates Amendment 04
Study Director/Medical Monitor
Wen Hong  Lin, MD
6.0
Approved
930090414
6.0
v
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 onlyon a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 


Clinical Protocol
CA209370
BMS-936558
nivolumab
Revised Protocol No.: 05
2
Date: 26-Mar-2018
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
6.0
Approved
930090414
6.0
v
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.


Clinical Protocol
CA209370
BMS-936558
nivolumab
Revised Protocol No.: 05
3
Date: 26-Mar-2018
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 05
26-Mar-2018
Incorporates Amendment 04
Amendment 04
26-Mar-2018
1. Closes enrollment for Group D
2. Clarifies of statistical treatment of subjects who received any 
subsequent anti-cancer therapy without previouslyreported 
progression
3. Updated the actual samples sizes for study groups after closing
enrollmentand statistical analyses
 
5. Updated timing of tumor assessments during study 
6. Changed the collection of survival status from 5 years to 4 years 
 
9. Updated protocol with current program safety language for dose 
modifications and discontinuations
10.Updated protocol with current program contraceptionlanguage
Revised 
Protocol 04
28-Mar-2017
Incorporates Amendment 03
Amendment 03
28-Mar-2017
1. Amendment to close enrollment for Groups A, B, C, and E. 
2. To note that Group E will receive no further treatment, and to add 
additional monitoring for liver toxicity through follow up in these 
subjects. 
3. Pregnancy language was updated. 
Revised 
Protocol 03
28-Sep-2016
1. To updates the Adverse Event Management Algorithms for 
nivolumab per Investigator Brochure Version 15 & Erratum 01 to 
Investigator Brochure Version 15
2. To  update the Study Director/Medical Monitor
3. To address inconsistencies/errors
4. To add cisplatin as one of platinum-based chemotherapies for 
consistence and for flexibility for the induction therapy
5. The adverse event collection for Group B, Arm B (Best Supportive 
Care) was updated to commerce at randomization for clarification 
and consistence
6. To clarify information fromthe previous version
Revised 
Protocol 02
29-Oct-2015
Incorporates Administrative Letter 01
Administrative 
Letter 01
29-Oct-2015
Addresses inconsistencies in the previous version
Revised 
Protocol 01
31-Jul-2015
Incorporates Amendment 01
6.0
Approved
930090414
6.0
v


Clinical Protocol
CA209370
BMS-936558
nivolumab
Revised Protocol No.: 05
4
Date: 26-Mar-2018
Document
Date of Issue
Summary of Change
Amendment 01
31-Jul-2015
1. Sample size
a. Group A corrected to 765
2. To simplify the study design for Group D 
a. Removed central testing for EGFR mutation
b. Removed independent imaging review
 
 
 
Original 
Protocol
15-May-2015
6.0
Approved
930090414
6.0
v


Clinical Protocol
CA209370
BMS-936558
nivolumab
SYNOPSIS
Clinical ProtocolCA209370
Protocol Title:  A Master Protocol of Phase 1/2 Studies of Nivolumab in Advanced NSCLC Using Nivolumab as 
Maintenance after Induction Chemotherapy or as First-line Treatment Alone or in Combination with Standard of Care 
Therapies
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):  Nivolumab (Opdivo®) administered IV either alone or in combination with other agents according to 
the groups assignments are shown below: 
Group A: Maintenance following 
an initial course (4-6 cycles) of 
investigator’s choice of platinum-
based chemotherapy, NSQ, PS 0-
1, EGFRwtand ALKwt
Arm A1: bevacizumab 15 mg/kg q 3 weeks
Arm A2: bevacizumab 15 mg/kg + nivolumab 5 mg/kgIV over 30 ± 
5mins q 3weeks 
Arm A3: nivolumab 240 mg IV over 30 ± 5mins q 2 weeks 
Arm B1: pemetrexed 500 mg/m2q 3 weeks
Arm B2: pemetrexed 500 mg/m2q 3 weeks+ nivolumab 5mg/kgq 
3weeks over 30 ± 5mins 

Arm B3: nivolumab 240 mg IV over 30 ± 5mins q 2 weeks
Group B: Maintenance following 
an initial course (4-6 cycles) of 
investigator’s choice of standard 
of care chemotherapy, SQ, PS 0-1
Arm A: Nivolumab 240 mg IV over 30±5 minsq 2 weeks
Arm B: Best Supportive Care (BSC)
Group C: First-line, NSQ and SQ, 
PS 2, EGFRwt and ALKwt
Arm A (NSQ): 
Carboplatin AUC =6 + nab-paclitaxel 100mg/m
2Days 1, 8, and 
15 q 3 weeks
Carboplatin AUC = 6 + paclitaxel 200 mg/m2q 3 weeks
Carboplatin AUC = 6 + pemetrexed 500 mg/m2q 3 weeks
Carboplatin AUC = 6 + docetaxel 75 mg/m2q 3 weeks
Paclitaxel  175-225 mg/m
2q 3 weeks
Docetaxel  60-75 mg/m
2q 3 weeks
Gemcitabine 1000 mg/m2Days 1 and 8 q 3 weeks
Pemetrexed 500 mg/m2q 3 weeks
Arm A (SQ):
Carboplatin AUC =6 + nab-paclitaxel 100mg/m
2Days 1, 8, and 
15 q 3 weeks
Carboplatin AUC = 6 + paclitaxel 200 mg/m2q 3 weeks
Carboplatin AUC = 5 + gemcitabine 1000 mg/m2Days1and 8 q 
3weeks
Carboplatin AUC = 6 + docetaxel 75 mg/m2q 3 weeks
Paclitaxel 175-225 mg/m
2q 3 weeks
Docetaxel 60-75 mg/m
2q 3 weeks
Gemcitabine 1000 mg/m2Days 1 and 8 q 3 weeks
Arm B (SQ or NSQ):
Nivolumab 240 mg IV over 30 ± 5mins q 2 weeks
Group D: First-line, PS 0-2, 
EGFRmut
Arm A: erlotinib 150 mg QD
Arm B: nivolumab 240 mg IV over 30 ± 5mins q 2 weeks + erlotinib 
150mg QD 
Group E: First-line, PS 0-2, ALK-
positive
Nivolumab 240 mg IV over 30± 5mins q 2 weeks plus crizotinib 250 
mg BID
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
5


Clinical Protocol
CA209370
BMS-936558
nivolumab
ALK=anaplastic lymphoma kinase, AUC=Area under the concentration curve; BID=twice a day; EGFR=epidermal 
growth factor receptor; mins=minutes; mut=mutation; NSQ=non-squamous; PS=performance status; q=every; 
QD=every day; SQ=squamous; WT=wild-type. 
Study Phase: Phase 1/2
Research Hypothesis:  The administration of nivolumab monotherapy or nivolumab in combination with standard of 
care(SOC)therapies torecurrent locally advanced or Stage 4 NSCLC subjects will provide clinical benefit (ie,
progression-free survival [PFS],overall survival [OS], and duration of response[DOR] without unacceptable toxicity).
Objectives:  
Primary Objectives
Secondary Objectives
Group A:
Maintenance, 
NSQ, PS 0-1, 
EGFRwtand 
ALKwt
To compare PFS and OS of 
maintenance treatment with 
bevacizumab versus nivolumab or 
bevacizumab versus nivolumab + 
bevacizumab (Arms A1, A2, A3) 
or pemetrexed versus nivolumab or 
pemetrexed versus nivolumab + 
pemetrexed (Arms B1, B2, B3)
To compare duration of response (DOR) 
and objective response rate (ORR) of 
maintenance treatment with 
bevacizumab versus nivolumab or 
bevacizumab versus nivolumab + 
bevacizumab (Arms A1, A2, A3) or 
pemetrexed versus nivolumab or 
pemetrexed versus nivolumab + 
pemetrexed (Arms B1, B2, B3)
Group B:
Maintenance, 
SQ, PS 0-1
To compare PFS and OS of 
maintenance treatment with single 
agent nivolumab versus  best 
supportive care (BSC)
To compare DOR and ORR of 
maintenance treatment with single agent 
nivolumab versus BSC
Group C: 
First-line, 
NSQ and SQ, 
PS 2, 
EGFRwt and 
ALKwt
To compare PFS and OS of single-
agent nivolumab versus 
investigator’s choice chemotherapy
To compare DOR and ORR of 
nivolumab versus investigator’s choice 
chemotherapy
Group D: 
First-line, PS 
0-2, EGFR
mut
To compare PFS with the 
combination of nivolumab plus 
erlotinib versus erlotinib
To compare OS, ORR, and DOR of the 
combination of nivolumab plus erlotinib 
versus erlotinib alone
Group E: 
First-line, PS 
0-2, ALK-
positive
To assess the incidence of 
treatment (nivolumab + crizotinib) 
related AEs leading to both study 
drugs discontinuation
To describe PFS of combination therapy
To assess ORR associated with 
combined nivolumab and crizotinib 
therapy 
AE=adverse events; ALK=anaplastic lymphoma kinase, BSC=best supportive care; DOR=duration of response; 
EGFR=epidermal growthfactor receptor; mut=mutation; NSQ=non-squamous; ORR=objective response rate; 
OS=overall survival; PFS=progression-free survival; PS=performance status; SQ=squamous; WT=wild-type.
 
Study Design: This is an open-label, Phase 1/2, Master Protocolcontaining 5 sub-studies, that will each enroll a 
unique patient population. Subjects with recurrent locally advanced or Stage 4SQ or NSQ NSCLC, with an ECOG 
Performance Status (PS) of 0-2, will receive either first-line or maintenance therapy with nivolumab as a single-agent 
or in combination with SOC therapies. Subjects will be assigned to treatment groups based on histology, PS, and 
mutation status to the one of the following five groups: 
Note: As per Amendments 03 and 04, Groups A, B, C, and D have closed enrollment and Group E was 
permanently terminated.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
6


Clinical Protocol
CA209370
BMS-936558
nivolumab
Group A:
Maintenance, NSQ 
PS 0-1, EGFRwt
and ALKwt
Group B:
Maintenance, SQ, 
PS 0-1
Group C:
First-line NSQ and 
SQ, PS 2, EGFRwt 
and ALKwt
Group D: 
First-line, PS 0-2, 
EGFRmut
Group E: 
First-line, PS 0-2, 
ALK-positive
ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; mut=mutation; NSCLC=non-small cell 
lung cancer; NSQ=non-squamous carcinoma; SQ=squamous cell carcinoma; wt=wild-type. 
Figure 1:
Group A Study Design: Maintenance Therapy in NSQ, PS 0-1, EGFRwt, ALKwt 
Subjects
ALK=anaplastic lymphoma kinase; E=enrolled, EGFR=epidermal growth factor receptor; NSQ=non-squamous 
histology; PS=performance status; R=randomized, q=every; wt=wild-type.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
7


Clinical Protocol
CA209370
BMS-936558
nivolumab
Figure 2:
Group B Study Design: Maintenance Therapy in SQ, PS 0-1, Subjects
E=enrolled, PS=performance status; R=randomized, SQ=squamous histology; q=every; 
Figure 3:
Group C Study Design: First-line Therapy in NSQor SQ, PS 2, EGFRwt, ALK wt 
Subjects
1L=first line; ALK=anaplastic lymphoma kinase; E=enrolled, EGFR=epidermal growth factor receptor; NSQ=non-
squamous histology; PS=performance status; R=randomized, q=every; SQ=squamous histology; wt=wild-type.
Figure 4: 
Group D Study Design: First-line Therapy in PS 0-2, EGFRmut Subjects
1L=first line; EGFR=epidermal growth factor receptor; E=enrolled; PS=performance status; R=randomized; q=every.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
8


Clinical Protocol
CA209370
BMS-936558
nivolumab
Figure 5:
Group E Study Design: First-line Therapy in PS 0-2, ALK-positive Subjects
1L=first line; ALK=anaplastic lymphoma kinase; E=enrolled;PS=performance status; q=every.
Study Population:  Males and Females, ≥18 years of age,meeting the following criteria:
Note: As per Amendments 03 and 04, Groups A, B, C, and D have closed enrollment and Group E was 
permanently terminated.
Table 1:
Key Inclusion (see Section 3.3.1for full inclusion criteria in specific section) 
Group A:
Group B:
Group C:
Group D:
Group E:
Histologically 
confirmed 
recurrent locally 
advanced or Stage 
4NSQ NSCLC
ECOG PS 0-1
EGFRwt 
ALKwt
Completed 4-6 
cycles of 
bevacizumab or 
pemetrexed 
containing 
induction chemo 
therapy with no 
evidence of 
disease 
progression
Histologically 
confirmed 
recurrent 
locally 
advanced or 
Stage 4SQ 
NSCLC
ECOG PS 0-1
Completed 4-6 
cycles of 
investigator 
choice 
induction 
chemo therapy 
with no 
evidence of 
disease 
progression
Histologically 
confirmed 
recurrent 
locally 
advanced or 
Stage 4 SQ or 
NSQ NSCLC
ECOG PS 2
EGFRwt 
ALKwt
Histologically 
confirmed 
recurrent 
locally 
advanced or 
Stage 4
NSCLC 
ECOG PS 0-2
EGFRmut
Histologically 
confirmed 
recurrent 
locally 
advanced or 
Stage 4 
NSCLC
ECOG PS 0-2
ALK-positive
ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; NSCLC=non-small cell lung cancer; 
NSQ=non-squamous histology; PS=performance status; R=randomized, SQ=squamous; wt=wild-type.
GeneralExclusion Criteria:Please also see Section 3.3.2for detailsof exclusion criteria for each sub-study.
Subjects with untreated CNS metastases are excluded. Exception: Subjects are eligible if CNS metastases are 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 enrollment. In addition, subjects must be either offcorticosteroids, or on a 
stable or decreasing dose of <10 mg daily prednisone (or equivalent).
Subjects with carcinomatous meningitis.
Subjects with active, known or suspected autoimmune disease. Exceptions: subjects with Type I diabetes mellitus, 
hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not 
requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted 
to enroll.
Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or 
equivalent) or other immunosuppressive medications within 14 days of first dose of study drug. Inhaled or topical 
steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence 
of active autoimmune disease.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
9


Clinical Protocol
CA209370
BMS-936558
nivolumab
Subjects with a history of interstitial lung disease (eg, sarcoidosis) that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonarytoxicity. Exception: subjects with chronic 
obstructive pulmonary disease (COPD)whose disease is controlled at study entry are allowed.
Subjects with previous malignancies (except non-melanoma skin cancers,and in situ cancers such as the 
following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete 
remission was achieved at least one years prior to study entry AND no additional therapy is required or anticipated 
to be required during the study period with the exception of anti-estrogen/androgen therapy or bisphosphonates. 
Subjects with other active malignancy requiring concurrent intervention are excluded.
All toxicities attributed to prior anti-cancer therapy other than alopecia, or fatigue, orperipheral neuropathy must 
be ≤Grade 1 (NCI CTCAE version 4) before administration of study drug.
Peripheral neuropathy ≥ Grade 2 (NCI CTCAE version 4)
Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days 
before the first dose of study treatment.
Acute or chronic infection of Hepatitis B or Hepatitis C. Known history of testing positive for Human 
Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS)
Study Assessments:OS and PFS are co-primary endpoints for Groups A through C, PFS is the primary endpoint 
for Group D, and the rate of study drugs (nivolumab+crizotinib) discontinuation due to treatment related AEs is the 
primary endpoint in Group E. Survivalendpoints will be assessed as: 
OS is defined as the time from randomization to the date of death. A subject who has not died will be censored at 
last known date alive. OS will be followed continuously while subjects are on the treatment and every 3months 
via in-person or phonecontact after subjects discontinue the study drug. 
Progression-free survival (PFS) is defined as the time fromrandomization to the date of the first documented 
tumor progression(per RECIST v1.1), as determined by investigatorsin all Groups, or death due to any cause, 
whichever occurs first. 
In Group E,PFS and OS are defined as the time of first dose to the date of event since there will be no 
randomization in this group.
Subjects who die without a reported prior progression will be considered to haveprogressed on the date of their 
death.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 the first dosing 
date.
Subjects who received any subsequent anti-cancer therapy (including on-treatment palliative radiation therapy of 
non-target bone lesions or CNS lesions) without a prior reported progression will be censored at the last evaluable 
tumor assessment prior to or on the date of initiation of the subsequent anti-cancer therapy.
On study assessments according to RECIST 1.1  criteria will be assessed beginning Week 9(± 1 week), then every 8 
weeks (±1week) for up to2 yearsas described in Section 5.4of  the protocol until disease progression, death or lost 
to follow-up. Subjects receiving nivolumab beyond investigator-assessed progression must also continue tumor 
assessments until such treatment has been discontinued (see Section 4.5.14).
Per Amendment 03, Group E subjects will proceed to follow-up or survival follow up phase. Group E subjects in the 
follow up phase will require twice weekly liver function monitoring within 60 days of the last dose of nivolumab, 
followed by once weekly liver function testing 61 through 100 days post last nivolumab dose. Any subject with an 
abnormal result on liver function testing, within 100 days of last nivolumab dose, will require twice weekly 
monitoring.  
Statistical Considerations: The overall population randomized or 
enrolled in this Master Protocol wasapproximately 
1953 subjects at maximum. Individual sample sizesand primary endpointspersub-studyare shown inthe table below. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
10


Clinical Protocol
CA209370
BMS-936558
nivolumab
Population
Maximum 
Sample 
Size
Primary 
Endpoint
Comparisons of interest
Group A:
Maintenance, 
NSQ, PS 0-1, 
EGFRwtand 
ALKwt
765
PFS/OS
1) Nivolumab vs. bevacizumab for PFS
2) Nivolumab vs. bevacizumab for OS
3) Nivolumab plus bevacizumab vs. bevacizumab for PFS
4) Nivolumab plus bevacizumab vs. bevacizumab for OS
5) Nivolumab vs. pemetrexed for PFS
6) Nivolumab vs. pemetrexed for OS
7) Nivolumab plus pemetrexed vs. pemetrexed for PFS
8) Nivolumab plus pemetrexed vs. pemetrexed for OS
Group B:
Maintenance, 
SQ, PS 0-1
500
PFS/OS
Nivolumab vs. Best supportive care
Group C: 
First-line, 
NSQ and SQ, 
PS 2, EGFRwt 
and ALK
wt
350
PFS/OS
Nivolumab vs. Investigator choice chemotherapy for 
superiority and non-inferiority
Group D: 
First-line, PS 
0-2, EGFR
mut
318
PFS
Nivolumab plus Erlotinib vs. Erlotinib
Group E: 
First-line, PS 
0-2, ALK-
positive
20
Incidence of 
treatment-related 
AEs leading to 
discontinuation 
of both 
nivolumab and 
crizotinib
Not Applicable
AE=adverse event; PFS=progression-free survival; OS=overall survival. 
Note: As per Amendments 03 and 04, Groups A, B, C, and D have closed enrollment and Group E was 
permanently terminated.
Actual samples sizes for study Groups after closed enrollment are listed below:
Group
Sample Size
A
132
B
35
C
52
D
109
E
14
The overall population randomized or enrolled in this Master Protocol is now approximately 342subjects.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
11


Clinical Protocol
CA209370
BMS-936558
nivolumab
Statistical Analysis
The OS curves for each treatment group will be estimated using the Kaplan-Meier (KM) product-limit method. 
Two-sided, 95% confidence intervals for median OS will be computed by Brookmeyer and Crowley method. 
The subjects may be followed for survival for up to 4years. Survival rates at 6, 12, 18, 24months, and up to 4 years
will also be estimated using KM estimates on the OS curve for each randomized arm. Associated two-sided 95% CIs 
will be calculated using the Greenwood’s formula.
PFS will be summarized similarly as OS. 
ORR will be computed in each treatment group along with the exact 95% CI using the Clopper-Pearson method. BOR 
will be summarized by response category for each treatment group. A by-subject listingof BOR and tumor 
measurements will be provided.
All safety data will be summarized and listed for all treated subjects.
Group E primary endpoint of safety analyses:
The number and percentage of subjects who report treatment-related adverse events that lead to study treatment 
discontinuation will be summarized for all treated subjects. The treatment-related adverse events will be tabulated 
using worst grade per NCI CTCAE version 4.0 criteria by system organ class and Medical Dictionary for Regulatory 
Affairs (MedDRA) preferred term. Safety and tolerability is also measured by incidence and severity of AEs and 
specific laboratory abnormalities in all treated subjects.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
12


TABLE OF CONTENTS 
TITLE PAGE 
................................................................................................................ 
DOCUMENT HISTORY 
.............................................................................................. 
SYNOPSIS
 ....................................................................................................................
 
TABLE OF CONTENTS 
.............................................................................................. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 Research Hypothesis 
......................................................................................... 
1.3 Objectives ......................................................................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 ETHICAL CONSIDERATIONS 
............................................................................... 
2.1 Good Clinical Practice 
...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee 
............................. 
1
3
5
13
29
29
40
40
41
6.0
Approved
930090414
6.0
v
Clinical Protocol
BMS-936558
CA209370
nivolumab
Revised Protocol No.: 05
Date: 26-Mar-2018
13


2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN 
.................................................................................... 
3.1 Study Design and Duration 
............................................................................... 
3.1.1 Treatment Group A: Maintenance, NSQ, PS 0-1, EGFRwt and ALKwt 
.. 
3.1.2 Treatment Group B: Maintenance, SQ, PS 0-1 ....................................... 
3.1.3 Treatment Group C: First-line, NSQ and SQ, PS 2, EGFRwt and ALKwt
.....................................................................................................................
3.1.4 Treatment Group D: First-line, PS 0-2, EGFRmut ................................. 
3.1.5 Treatment Group E: First-line, PS 0-2, ALK-positive 
............................. 
3.1.6 Enrollment Period 
.................................................................................... 
3.1.7 Randomization 
......................................................................................... 
3.1.8 Treatment Period 
..................................................................................... 
3.1.9 Study Duration 
......................................................................................... 
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 ........................................................... 
 
 
 
 
3.5 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 and Dispensing..................................................................................... 
4.4 Method of Assigning Subject Identification 
..................................................... 
4.5 Selection and Timing of Dose for Each Subject 
............................................... 
4.5.1 Duration of Treatment with Nivolumab for Groups A, B, C, and D 
........ 
4.5.2 Nivolumab Treatment Discontinuation 
.................................................... 
4.5.3 Dose Delay Criteria 
................................................................................. 
4.5.3.1 Nivolumab Dose Delay Criteria 
..................................................... 
4.5.3.2 Resumption of Nivolumab 
............................................................... 
4.5.4 Nivolumab Dose Modifications 
................................................................ 
4.5.5 Bevacizumab Treatment Discontinuation: 
............................................... 
4.5.6 Bevacizumab Dose Modifications 
............................................................ 
4.5.7 Pemetrexed Treatment Discontinuation .................................................. 
4.5.8 Pemetrexed Dose Reductions 
................................................................... 
4.5.9 Group C: Investigator’s Choice Chemotherapy Dose Discontinuation: 
. 
4.5.10 Group C: Investigator’s Choice Chemotherapy Dose Reductions 
........ 
4.5.10.1 Gemcitabine dosing: Adjustment for Toxicity............................... 
4.5.11 Group D: Erlotinib Treatment Discontinuation 
.................................... 
41
42
42
43
45
46
47
48
48
48
49
49
49
49
49
52
56
59
59
60
60
60
63
63
63
64
64
66
66
68
68
68
69
69
69
69
69
70
71
71
72
6.0
Approved
930090414
6.0
v
Clinical Protocol
BMS-936558
CA209370
nivolumab
Revised Protocol No.: 05
Date: 26-Mar-2018
14


4.5.12 Erlotinib Dose Modifications 
................................................................. 
4.5.13 Resumption of Erlotinib 
......................................................................... 
4.5.14 Group E: Crizotinib Treatment Discontinuation 
................................... 
4.5.15 Crizotinib Dose Modifications 
............................................................... 
4.5.16 Treatment of Nivolumab-Related Infusion Reactions 
............................ 
4.5.17 Treatment Beyond Disease Progression 
................................................ 
 
4.7 Management for Erlotinib related adverse events ............................................ 
4.8 Management of standard of care agents (chemotherapy or bevacizumab) 
related adverse events 
....................................................................................... 
4.9 Blinding/Unblinding 
......................................................................................... 
4.10 Treatment Compliance 
.................................................................................... 
4.11 Destruction of Study Drug 
.............................................................................. 
4.12 Return of Study Drug 
...................................................................................... 
5 STUDY ASSESSMENTS AND PROCEDURES 
..................................................... 
5.1 Flow Chart/Time and Events Schedule 
............................................................. 
5.1.1 Retesting During Screening Period 
......................................................... 
5.2 Study Materials 
................................................................................................. 
5.3 Safety Assessments 
........................................................................................... 
5.3.1 ECOG Performance Status 
...................................................................... 
5.3.2 Imaging Assessment for the Study............................................................ 
5.3.3 Electrocardiogram (ECG) 
....................................................................... 
5.4 Efficacy Assessments 
........................................................................................ 
5.4.1 End of Treatment, Follow-up, and Survival Procedures 
......................... 
5.4.2 EGFR mutation and ALK translocation assessments 
.............................. 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 ADVERSE EVENTS 
................................................................................................. 
6.1 Serious Adverse Events 
.................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting 
.................................... 
6.2 Nonserious Adverse Events 
.............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting 
.............................. 
6.3 Adverse Events of Interest 
................................................................................ 
6.4 Laboratory Test Result Abnormalities 
.............................................................. 
6.5 Pregnancy 
.......................................................................................................... 
73
73
73
74
75
76
78
78
78
78
78
79
80
80
114
114
114
116
116
116
117
118
118
123
124
124
125
125
126
127
127
6.0
Approved
930090414
6.0
v
Clinical Protocol
BMS-936558
CA209370
nivolumab
Revised Protocol No.: 05
Date: 26-Mar-2018
15


6.6 Overdose 
........................................................................................................... 
6.7 Potential Drug Induced Liver Injury (DILI) 
..................................................... 
6.8 Other Safety Considerations 
............................................................................. 
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
................................................................................................................................. 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination 
............................................................................... 
8.1.1 Group A through D sample size determination 
....................................... 
8.1.2 Group E sample size determination 
......................................................... 
8.2 Populations for Analyses 
.................................................................................. 
8.3 Endpoints 
.......................................................................................................... 
8.3.1 Primary Endpoints: 
.................................................................................. 
8.3.2 Secondary Endpoints: 
.............................................................................. 
 
 
 
 
 
 
 
8.4 Analyses 
............................................................................................................ 
8.4.1 Demographics and Baseline Characteristics........................................... 
8.4.2 Efficacy Analyses 
..................................................................................... 
8.4.2.1 Efficacy Analysis for Group A: Maintenance, NSQ PS 0-1, EGFRwt 
and ALKwt ............................................................................................ 
8.4.2.2 Efficacy Analysis for Group B: Maintenance, SQ, PS 0-1 ............. 
8.4.2.3 Efficacy Analysis for Group C: First-line NSQ and SQ, PS 2, 
EGFRwt and ALKwt ............................................................................. 
8.4.2.4 Efficacy Analysis for Group D: First-line, PS 0-2, EGFRmut ....... 
8.4.2.5 Efficacy Analysis for Group E: First-line, PS 0-2, ALK-positive 
... 
8.4.3 Safety Analyses......................................................................................... 
 
 
 
 
8.5 Interim Analyses 
............................................................................................... 
8.5.1 Interim Analyses for Group D 
.................................................................. 
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 
.................................................................... 
9.1.3 Investigational Site Training.................................................................... 
128
128
128
128
129
129
129
131
132
133
134
134
135
135
135
135
136
136
136
136
136
138
138
138
138
138
138
139
139
6.0
Approved
930090414
6.0
v
Clinical Protocol
BMS-936558
CA209370
nivolumab
Revised Protocol No.: 05
Date: 26-Mar-2018
16


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 and Publications 
............................................................ 
10 GLOSSARY OF TERMS 
........................................................................................ 
11 LIST OF ABBREVIATIONS 
.................................................................................. 
 
APPENDIX 2 ECOG PERFORMANCE STATUS 
..................................................... 
APPENDIX 3 RECIST 1.1 CRITERIA........................................................................ 
139
139
140
140
141
142
143
169
170
6.0
Approved
930090414
6.0
v
Clinical Protocol
BMS-936558
CA209370
nivolumab
Revised Protocol No.: 05
Date: 26-Mar-2018
17
























Clinical Protocol
CA209370
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
1.3
Objectives 
The primary, secondary, and exploratory
 objectives are summarized in Table 1.3-1.
Table 1.3-1:
Study Objectives
Primary Objectives
Secondary Objectives
Group A:
Maintenance, 
NSQ, PS 0-1, 
EGFRwtand 
ALKwt
To compare PFSa 
and OS of 
maintenance 
treatment with 
bevacizumab versus 
nivolumab or 
bevacizumab versus 
nivolumab + 
bevacizumab (Arm 
A) or pemetrexed 
versus nivolumab or
pemetrexed versus 
nivolumab + 
pemetrexed (Arm B)
To compare duration 
of response (DOR) 
and 
objective 
response rate (ORR) 
of 
maintenance 
treatment 
with 
bevacizumab versus 
nivolumab 
or 
bevacizumab versus 
nivolumab 
+ 
bevacizumab (Arms 
A1, A2, A3) or 
pemetrexed versus 
nivolumab 
or 
pemetrexed versus 
nivolumab 
+ 
pemetrexed (Arms 
B1, B2, B3)



6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
29


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 1.3-1:
Study Objectives
Primary Objectives
Secondary Objectives
Group B:
Maintenance, 
SQ, PS 0-1
To compare PFSa 
and OS of 
maintenance 
treatment with 
single-agent 
nivolumab versus  
BSC
To compare DOR 
and 
ORR 
of 
maintenance 
treatment 
with 
single-agent 
nivolumab versus 
BSC
Group C: 
First-line, 
NSQ and SQ, 
PS 2, 
EGFRwt and 
ALKwt
The primary 
objective will be to 
compare PFS and 
OS of single-agent 
nivolumab versus 
investigator’s choice 
chemotherapy
To compare DOR 
and 
ORR 
of 
nivolumab versus 
investigator’s choice 
chemotherapy
Group D: 
First-line, PS 
0-2, EGFR
mut
To compare PFS 
with the 
combination of 
nivolumab plus 
erlotinib versus 
erlotinib
To compare OS, 
ORR, and DOR of 
the combination of 
nivolumab 
plus 
erlotinib 
versus 
erlotinib alone
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
30


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 1.3-1:
Study Objectives
Primary Objectives
Secondary Objectives
Group E: 
First-line, PS 
0-2, 
ALK-positive
To estimate the 
incidence of 
treatment-related 
(nivolumab + 
crizotinib) AEs 
leading to study drug 
discontinuation
To describe PFS of 
combination therapy
To assess ORR 
associated 
with 
combined 
nivolumab 
and 
crizotinib therapy
a Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented tumor progression, 
as determined by investigators (per RECIST v1.1), or death due to any cause, whichever occurs first. 
AE=adverse events; ALK=anaplastic lymphoma kinase, BSC=best supportive care; CR=complete response; DCR=disease control 
rate; DOR=duration of response; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor receptor; 
mut=mutation; NSCLC=non-small cell lung cancer; NSQ=non-squamous; ORR=objective response rate; OS=overall survival; 
PFS=progression-free survival; PR=partial response; PS=performance status; SD=stable disease; SQ=squamous; WT=wild-type.
 
 
 
 
 
 
 
 
 
 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
31


















Clinical Protocol
CA209370
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 Conferenceon Harmonisation (ICH) and in accordance with the ethical principles 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
40


Clinical Protocol
CA209370
BMS-936558
nivolumab
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol, any amendments, and 
the subject informed consent 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 BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (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 recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the InvestigatorBrochure or product labeling 
information to be provided to subjects and any updates. 
The investigator or BMS 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 are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1) 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. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
41


Clinical Protocol
CA209370
BMS-936558
nivolumab
2) Allow time necessary for subject or subject
's legally acceptable representative to inquire about 
the details of the study.
3) 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. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informedconsent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
5) 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.
6) Revise the informed consent whenever important new informationbecomes 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 must be protected, respecting the privacy
and confidentiality rules applicable to regulatory requirements, the subjects
' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
Subjects unable to give their written consent (eg, stroke or subjects 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 are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This is an open-label, Phase 1/2, Master Protocol, containing 5 sub-studies (sub-protocols)that
will each enroll a unique patient population. Subjects with recurrent locally advanced or Stage 4 
SQ or NSQ NSCLC, with an ECOG PS of 0-2, will receive either first-line or maintenance therapy 
with nivolumab as a single-agent or in combination with SOC therapies. Subjects will be assigned 
to treatment groups based on histology, ECOG PS, and mutation status to the one of the following 
five groups: 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
42


Clinical Protocol
CA209370
BMS-936558
nivolumab
Group A subjects with NSQ NSCLC and a PS 0-1 will be randomized (1:1:1) to receive single-
agent nivolumab, single-agent pemetrexed or bevacizumab, or the combination of nivolumab 
and pemetrexed or bevacizumab, as maintenance therapy following first-line treatment with 
Investigator’s Choice chemotherapy. The primary objectives of Group A are to compare PFS 
and OS of single-agent bevacizumab versus single-agent nivolumab, or the combination of 
nivolumab and bevacizumab, or single-agent pemetrexed versus single-agent nivolumab, or 
the combination of nivolumab and pemetrexed; comparisons of DOR and ORR are the 
secondary objectives.
Group B subjects with SQ NSCLC and a PS 0-1 will be randomized (1:1) to receive either 
single-agent nivolumab or BSC as maintenance following first-line treatment with 
Investigator’s Choice chemotherapy. The primary objectives of Group B are to compare PFS 
and OS of single-agent nivolumab versus BSC; comparisons of DOR and ORR are the 
secondary objectives.
Group C subjects with NSCLC of NSQ or SQ histology with PS 2 will be randomized (1:1) to 
receive either Investigator’s Choice chemotherapy or single-agent nivolumab as first-line 
treatment. The primary objectives of Group C are to compare PFS and OS of single-agent 
nivolumab versus Investigator’s Choice chemotherapy. The secondary objectives are the 
comparisons of DOR and ORR.
Group D subjects with NSCLC histology and EGFR mutation, and a PS 0-2 will be randomized 
(1:1) to first-line treatment with erlotinib or the combination of nivolumab and erlotinib. The 
primary objective of Group D is to compare PFS of the combination of nivolumab and erlotinib 
versus erlotinib alone; comparisons of OS, ORR, and DOR are secondary objectives.
Group E will evaluate the safety of combination therapy of nivolumab and crizotinib as first-
line treatment in NSCLC, PS 0-2 ALK-positive subjects. The primary objective of Group E is 
to describe the safety and tolerability of nivolumab in combination with crizotinib; the 
secondary objectives are to describe PFS and ORR.
Subjects currently on treatment may continue to be treated and monitored as specified in the 
protocol. The decision to continue treatment should be based on the clinical judgment of the 
treating physician, in consultation with the patient.
Further details of the design of each Group A through E are provided in Sections 3.1.1to 3.1.5. 
3.1.1
Treatment Group A: Maintenance, NSQ, PS 0-1, EGFRwtand ALKwt
Following first-line therapy with 4 to 6 cycles of Investigator’s Choice of chemotherapy regimens 
(carboplatinor cisplatinplus paclitaxel plus bevacizumab or carboplatinor cisplatinplus 
pemetrexed), subjects showing no signs of progression, will be randomized (1:1:1) to receive 
maintenance therapy on 1 of 6 arms.Subjects under consideration for Group A are to completethe 
entire 4-6 week cycle of induction chemotherapy without disease progression prior to being 
consentedfor this study.  The maintenance treatment is to start within 42 days of completing 
induction chemotherapy.
Arm A1: bevacizumab 15 mg/kg every 3 weeks
Arm A2: bevacizumab 15 mg/kg + nivolumab 5 mg/kg every 3 weeks over 30 minute infusion 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
43


Clinical Protocol
CA209370
BMS-936558
nivolumab
Arm A3: nivolumab 240 mg every 2 weeks over 30 minute infusion
Arm B1: pemetrexed 500 mg/m2 every 3 weeks
Arm B2: pemetrexed 500 mg/m2every 3 weeks + nivolumab 5 mg/kg every 3 weeks over 
30minute infusion
Arm B3: nivolumab 240 mg every 2 weeks
Pemetrexedpremedication regimen: folic acid and vitamin B12, and dexamethasone are to be 
given per local institution standard and package insert. 
Pemetrexed and bevacizumab administration is to follow their package insert. 
Subjects will be considered on-study once randomized to a maintenance therapy arm (beginning 
of Cycle 1). On-study tumor assessments will begin at Week 9(± 1 week) and will be performed 
every 8 weeks (± 1 week) forup to 2 years.The schematic for Group A is presented in Figure 
3.1.1-1.
Figure 3.1.1-1:
Group A Schematic -Maintenance Therapy in subjects with NSQ 
NSCLC and PS 0-1, without EGFR and ALK Mutations
Note: The maintenance treatment is to start within 42 days of completing induction chemotherapy.  Subjects who 
completed bevacizumab-containing induction chemotherapy will only be randomized to Arm A1, A2 or A3 and 
subjects who completed pemetrexed-containing induction chemotherapy will only be randomized to Arm B1, B2 or 
B3.   
ALK=anaplastic lymphoma kinase; E=enrolled; EGFR=epidermal growth factor receptor; NSQ=non-squamous cell 
carcinoma; PS=performance status; q=every; R=randomized. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
44


Clinical Protocol
CA209370
BMS-936558
nivolumab
Per Amendment 03this group is no longer enrolling subjects. 
3.1.2
Treatment Group B: Maintenance, SQ, PS 0-1 
Following initial therapy with 4 to 6 cycles of Investigator’s Choice of chemotherapy regimens 
(carboplatin or cisplatin plus paclitaxel, carboplatinor cisplatinplus gemcitabine, carboplatin or 
cisplatin plus docetaxel, carboplatin or cisplatin plus albumin bound paclitaxel, carboplatinor 
cisplatin plus etoposide, carboplatinor cisplatinplus vinorelbine), subjects in Group B, showing 
no signs of progression, will be randomized (1:1) to maintenance therapy with either single-agent 
nivolumab (240 mg every 2weeks) or BSC. Subjects under consideration for Group B are to 
complete the entire 4-6 week cycle of induction chemotherapy without disease progression prior 
to being consentedfor this study.  Subjects will be considered on-study once randomized to a 
maintenance therapy arm (beginning of Cycle 1). 
On-study tumor assessments will begin at Week 9(± 1 week) and will be performed every 8 weeks 
(± 1 week) for up to2 years.The Group B schematic is presented in Figure 3.1.2-1. 
Best supportive care arm may include palliative radiation therapy or palliative surgery. The major 
components of BSC include:
Adequate control of pain and other symptoms
Identification of distressing symptoms
Support and assist decision making
Illness understanding/education
Coping with life-threatening illness
Indicate referrals to other care providers
Symptom management includes but is not limited to:
Pain
Pulmonary symptoms (cough, dyspnea)
Fatigue and sleep disturbance
Mood (depression and anxiety)
Gastrointestinal (anorexia and weight loss, nausea and vomiting, constipation). 
Figure 3.1.2-1:
Group B Schematic -Maintenance Therapy in Subjects with SQ 
NSCLC and PS 0-1
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
45


Clinical Protocol
CA209370
BMS-936558
nivolumab
Note: The maintenance treatment is to start within 42 days of completing induction chemotherapy. 
BSC=best supportive care; E=enrolled; R=randomized; PS=performance status; q=every; SQ=squamous cell 
carcinoma. 
Per Amendment 03this group is no longer enrolling subjects. 
3.1.3
Treatment Group C: First-line, NSQ and SQ, PS 2, EGFR
wt and ALKwt
Subjects assigned to Group C will be randomized (1:1) to receive first-line therapy with either: 4 
to 6 cycles of Investigator’s Choice of chemotherapy (Arm A) or single-agent nivolumab (Arm 
B). 
The list of Investigator’s Choice chemotherapy regimens is referenced from NCCN guideline 
2015-20th annual edition.
Investigator’s Choice chemotherapy regimens will be as follows:
Arm A (NSQ): 
Carboplatin AUC =6 + nab-paclitaxel 100mg/m
2 Days 1, 8, and 15 every3 weeks
Carboplatin AUC = 6 + paclitaxel 200 mg/m
2every 3 weeks
Carboplatin AUC = 6 + pemetrexed 500 mg/m
2every 3 weeks
Carboplatin AUC = 6 + docetaxel 75 mg/m
2 every 3 weeks
Paclitaxel 175-225 mg/m2every 3 weeks
Docetaxel 60-75 mg/m2every 3 weeks
Gemcitabine 1000 mg/m2Days 1 and 8 every 3 weeks
Pemetrexed 500 mg/m2every 3 weeks
Arm A (SQ):
Carboplatin AUC =6 + nab-paclitaxel 100mg/m
2 Days 1, 8, and 15 every3 weeks
Carboplatin AUC = 6 + paclitaxel 200 mg/m
2 every 3 weeks
Carboplatin AUC = 5 + gemcitabine 1000 mg/m
2 Days1 and 8 every3weeks
Carboplatin AUC =6 + Docetaxel 75 mg/m
2 every 3 weeks
Paclitaxel 175-225 mg/m
2 every 3 weeks
Docetaxel 60-75 mg/m
2 every3 weeks
Gemcitabine 1000 mg/m
2 days 1 and 8 every 3 weeks
Arm B (SQ or NSQ):
Nivolumab240 mg every 2 weeks over 30 minute IV infusion
Subjects may receiveoptional maintenance therapyafter initial chemotherapy in control group 
receiving Investigator’s Choice chemotherapy per investigator decision of maintenance regimen 
according to NCCN guideline.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
46


Clinical Protocol
CA209370
BMS-936558
nivolumab
Subjects will be considered on-study once randomized to a treatmentarm (beginning of Cycle 1). 
On-study tumor assessments will begin at Week 9 (± 1 week) and will be performed every 8 weeks 
(± 1 week) for up to2 years.The study design schematic is presented in Figure 3.1.3-1.
Figure 3.1.3-1:
Group C Schematic -First-line Treatment in NSQ or SQ NSCLC 
Subjects with PS 2, without EGFR and ALK Mutations
ALK=anaplastic lymphoma kinase; E=enrolled; EGFR=epidermal growth factor receptor; NSQ=non-small cell 
carcinoma; R=randomized; PS=performance status; q=every; SQ=squamous cell carcinoma; wt=wild-type. 
Per Amendment 03this group is no longer enrolling subjects. 
3.1.4
Treatment Group D: First-line, PS 0-2, EGFRmut
Subjects in Group D will be randomized (1:1) to treatment with erlotinib monotherapy or the 
combination therapy (erlotinib plus nivolumab) as follows:
Arm A: erlotinib 150 mg QD
Arm B: nivolumab 240 mg every 2 weeks + erlotinib 150 mg QD 
Treatment for both arms will continue until disease progression, discontinuation due to 
unacceptable toxicity, withdrawal ofconsent,orup to a maximum of 24 months, whichever occurs 
first.Subjects must continue to meet all applicable inclusion and exclusion criteria.
On-study tumor assessments will begin at Week 9 (± 1 week) and will be performed every 8 weeks 
(± 1 week) forup to2 years.The study design schematic is presented in Figure 3.1.4-1.
Figure 3.1.4-1:
Group D Schematic -First-line Treatment in Subjects with PS 0-2, 
and EGFR mutations
E=enrolled; EGFR=epidermal growth factor receptor; mut=mutation; R=randomized; PS=performance status; 
q=every. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
47


Clinical Protocol
CA209370
BMS-936558
nivolumab
3.1.5
Treatment Group E: First-line, PS 0-2, ALK-positive
Subjects in Group E will receive the combination therapy of nivolumab (240 mg every 2 weeks) 
and crizotinib (250 mg BID). On-study tumor assessments will begin at Week 9 and will be 
performed every
 8 weeks (± 1 week) forup to2 years.The study design schematic is presented in 
Figure 3.1.5-1.When the 20th patient is enrolled and reaches Week 17, DMC safety review of 
this cohort will be triggered. “Safe” is defined as ≤20% of treated subjects with drug-related AEs 
leading to discontinuation of both drugsby Week 17. 
Figure 3.1.5-1:
Group E Study Schematic -First-Line Treatment in Subjects with PS 
0-2, and ALK-positive
ALK=anaplastic lymphoma kinase; E=enrolled; q=every; PS=performance status. 
Per Amendment 03,this group is closed and all the ongoing subjects have been discontinuedfrom 
the combination treatment of crizotinib and nivolumab 
A close liver function monitoring has been recommended:
All subjects are to undergo twice weekly liver function testing through 60 days following the 
last dose of nivolumab.
Subjects with normal results for liver function are to undergo once weekly liver function testing 
from 61 days through 100 days following the last dose of nivolumab.
Subjectswith an abnormal result for liver function within 100 days of the last dose of nivolumab, are to undergo 
twice weekly liver function testing. 
Additional liver function monitoring should be based on the clinical judgment of the treating 
physician. 
3.1.6
Enrollment Period
Subjects will be enrolled using an Interactive WebResponse System (IWRS). During the screening 
and enrollment period, a subject will provide signed informed consent and their study eligibility 
will be established. Additionally, to determine PD-L1 status, tumor tissue (archival or recent tumor 
biopsy) must be submitted by the site to a third-party vendor.
Subjectsareassessed for Group eligibility as described in Section 3.3. 
3.1.7
Randomization
Subjects meeting enrollment criteria for Groups A, B, C, or D will be randomized to treatment 
arms as described in Sections 3.1.1, 3.1.2, 3.1.3, or 3.1.4.An interactive web response system 
(IWRS) will be utilized for randomization. Subjects in Group Eare not randomized.
For Groups A and B, randomization will be stratified by: 
1) Disease status (recurrent locally advanced vs. m
etastatic) 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
48


Clinical Protocol
CA209370
BMS-936558
nivolumab
2) Response (complete response/partial response/stable disease) to induction chemotherapy
3) History of ablative/definitive radiation therapy to oligometastasis post induction therapy.
For Group C, randomization will be stratified by: 
1) Disease status (recurrent locally advanced vs. metastatic)
2) Tumor histology (NSQ vs. SQ).
For Group D, randomization will be stratified by: 
1) Disease status (recurrent locally advanced vs. metastatic)
2) Performance status (ECOG 0, 1 or 2).
3.1.8
Treatment Period
In all treatment groups, treatment will be administered according the dosages and cycles as 
described in Sections 3.1.1, 3.1.2, 3.1.3, 3.1.4, or 3.1.5.  
3.1.9
Study Duration
As per Amendments 03 and 04, enrollment has closedfor all groups. The study is expected to end 
when the last subject in Group D has completed up to 2 years of treatment. The approximate 
duration of the study is up to 4.5 years.For Group D, the study duration will concludewhen the 
primary analysis takes place. Additional survival analysis may be conducted for up to 4years after 
the last subject’sstart of study treatment, beyond analysis of the primary endpoints. 
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 specified in
protocol Section 4.5.1.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 study drug if 
any of the following occur: a) the marketing application is rejected by the responsible health 
authority; b) the study is terminated due to safety concerns; c) the subject can obtain medication 
from a government sponsored or private health program; or d) therapeutic alternatives become 
available in the local market.
3.3
Study Population
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. For entry into the study, the following criteria MUST be met.
Note: asper Amendments 03 and 04, Groups A, B, C, and Dhave closed enrollment and 
Group E was permanently terminated.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
49


Clinical Protocol
CA209370
BMS-936558
nivolumab
Subjects must have signed and dated anIRB/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.
2. Target Population
Table 3.3.1-1:
Target Population
Criterion
Group A
Group B
Group C
Group D
Group E
i.  Histology
a) Histologically 
confirmed 
recurrent locally 
advanced or 
Stage 4 NSQ 
NSCLCa
b) Histologically 
confirmed 
recurrent locally 
advanced or 
Stage 4 SQ 
NSCLCa
c) Histologically 
confirmed 
recurrent locally 
advanced or 
Stage 4 SQ or 
NSQ NSCLCa
d) Histologically 
confirmed 
recurrent locally 
advancedor 
Stage 4 NSCLCa
e) 
Histologically 
confirmed 
recurrent 
locally 
advanced or 
Stage 4 
NSCLCa
ii. ECOG PS
a) 0-1
b) 2
c)0-2
iii. Prior 
induction 
therapy
a) 4-6 cycles of 
bevacizumab or 
pemetrexed 
containing 
induction chemo 
therapy with no 
evidence of 
disease 
progression
b) 4-6 cycles of 
induction chemo 
therapy with no 
evidence of 
disease 
progression
c) None
d) None
iv. EGFR 
mutationb
a) Negative/wild 
type, or 
indeterminate
Consult with the 
Medical Monitor 
for eligibility for 
“wild type” 
mutations (eg, 
exon 20)
b) Primary SQ 
histology tumors 
are not required 
to be tested for 
EGFR mutation
c) Negative/wild 
type, or 
indeterminate.
Primary SQ 
histology tumors 
are not required 
to be tested for 
EGFR mutation
d) Positive drug-
sensitizing 
mutation 
(including, but 
not limited to 
exon 19 
deletion, exon 
21-L858R-
substition
mutation) 
e) 
Negative/wild 
type, or 
indeterminate
v. ALK
translocationc
a) Negative/wild 
type, or 
indeterminate
b) Primary SQ 
histology tumors 
are not required 
to be tested for
ALK 
translocation
c) Negative/wild 
type, or 
indeterminate.
Primary SQ 
histology tumors 
are not required 
to be tested for 
ALK 
translocation
d)Negative/Wild 
type, or 
indeterminate
e)Positive
vi. RECIST 1.1
a) Measureable disease by CT within 21 days of study drug. Target lesions may be located in 
a previously irradiated field with radiographic evidence of disease progression in that site
post-radiation therapy. Subjectsin GroupA andB with a complete response after his/her 
induction chemotherapywill not have measureable disease and will be eligible for enrollment. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
50


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 3.3.1-1:
Target Population
Criterion
Group A
Group B
Group C
Group D
Group E
b) Groups A and B: Subjects with 
CR/PR/SDto initial induction 
therapy are allowed to enroll
c) Not Applicable
vii. Tissue 
requirementd
a) Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or minimum of 10 
unstained tumor tissue sections, with an associated pathology report, must be submitted for 
biomarker evaluation prior to randomization. Biopsies of bone lesions that do not have a soft 
tissue component or decalcified bone tumor samples or cytology samples are also not 
acceptable.
a According to the 7th edition International Association for the Study of Lung Cancer classification, with no prior 
systemic anticancer therapy (including EGFR and ALK inhibitors) given as primary therapy for advanced or 
metastatic disease.Prior adjuvant or neoadjuvant chemotherapy is permitted as longas the last administration of 
the prior regimen occurred at least 6 months prior to disease recurrence. Prior definitive chemoradiation or 
adjuvant 
radiotherapy for locally advanced disease is also permitted as long as the last administration of chemotherapy or 
radiotherapy (whichever was given last) occurred at least 6 months prior to disease recurrence.
b EGFR testing is not required if ALK or KRAS test is positive; ALK testing is not required if EGFR or KRAS test 
is positive; use of an FDA-approved testis strongly encouraged; appropriate documentation of the results must be 
available prior to randomization/treatment. 
c FDA-approved test is strongly encouraged for ALK translocation testing. Appropriate documentation of the test 
results must be availableprior to randomization/ start of treatment. Consult the Medical Monitor regarding the use 
of EGFR/ALK mutation blood tests.
d Fine needle biopsies, drainage of pleural effusions with cytospins, or punch biopsies are not considered adequate. 
Biopsies of bone lesions that do not have a soft tissue component or decalcified bone tumor samples are also not 
acceptable.
ALK=anaplastic lymphoma kinase, CR=complete response; ECOG=Eastern Cooperative Oncology Group; 
EGFR=epidermal growth factor receptor; FFPE=formalin-fixed paraffin-embedded; mut=mutation; NA=not 
applicable; NSCLC=non-small cell lung cancer; NSQ=non-squamous; PS=performance status; SQ=squamous; 
WT=wild-type. 
Treatment Legend: Group A: Maintenance, NSQ PS 0-1, EGFRwt and ALKwt; Group B: Maintenance, SQ, PS 0-1; 
Group C: First-line NSQ and SQ, PS 2, EGFRwt and ALKwt; Group D: First-line PS 0-2, EGFRmut; Group E: First-
line PS 0-2, ALK-positive
3. Age and Reproductive Status
a) Men and women,≥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 24hours 
prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug (s) nivolumab plus 5 half-lives of nivolumab (5 times the half-
life=125 days) plus 30 days (duration of ovulatory cycle) for a total of 155 days or 23 
weeks post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
51


Clinical Protocol
CA209370
BMS-936558
nivolumab
of the study drug (125 days) plus 90 days (duration of sperm turnover) for a total of 
31weeks post-treatment completion.
f) Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However, they must still undergo pregnancy 
testing as described in this section. 
4. Baseline laboratoryParameters
Table 3.3.1-2:
Baseline laboratory Parameters (All Groups)
Test
Value
i. WBC
≥2000/uL
ii. Neutrophils
≥1500/uL
iii. Platelets
≥100x103/uL
iv. Hemoglobin
≥9.0 g/dL
v. Serum 
creatinine
≤1.5 ×ULN or calculated creatinine clearance >40 mL/min using the Cockcroft-Gault 
formula:
Female CrCl = (140-age in years) x weight in kg x 0.85/72 x serum creatinine in mg/ dL
Male CrCl = (140-age in years) x weight in kg x 1.00/72 x serum creatinine in mg/ dL
vi. AST
≤3.0 ×ULN
vii. ALT
≤3.0 ×ULN
viii. Total Bilirubin
≤1.5 ×ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level 
of < 3.0 ×ULN)
ULN=upper limit of normal. 
Treatment Legend: Group A: Maintenance, NSQ PS 0-1, EGFRwt and ALKwt; Group B: Maintenance, SQ, PS 0-1; 
Group C: First-line NSQ and SQ, PS 2, EGFRwt and ALKwt; Group D: First-line PS 0-2, EGFRmut; Group E: First-
line PS 0-2, ALK-positive
3.3.2
Exclusion Criteria
1. Target Population
Table 3.3.2-1:
Target Population
Criterion
Group A
Group B
Group C
Group D
Group E
i. EGFR 
mutation
a) EGFR mutation test was not done for primary adenocarcinoma
ii. ALK 
translocation
a) ALK translocations test was not done for primary adenocarcinoma
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
52


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 3.3.2-1:
Target Population
Criterion
Group A
Group B
Group C
Group D
Group E
iii. Subjects 
with 
recurrent 
disease: 
chemo-
therapy and 
radiotherapy 
for previous 
localized 
disease
Last administration of adjuvant or neoadjuvant chemotherapy, definitive chemoradiation, or 
adjuvant radiotherapy was < 6 months prior to disease recurrence
iv. Previous 
anticancer 
therapy
a) Induction chemo therapy other 
than listed regimens (Section 3.1.1
and 3.1.2) are excluded for Groups A 
and B
b) Any prior systemic therapy for advanced or metastatic
diseaseis excluded for Groups C, D and E.
v. 
Progression 
after initial 
induction 
chemotherap
y
a) Progression after initial induction 
chemotherapy for Group A and B 
subjects
b) Not Applicable 
vi. Radiation 
therapy
a) Palliative radiation therapy completed < 2 weeks prior to randomization is excluded. 
Exception: Ablative/definitive radiation therapy to oligometastasis is allowed for Groups A and B 
before enrollment.*There is no need for a washout period prior to first nivolumab dose.
AEs from radiation therapy should resolve to Grade ≤1 prior to on study treatment. In addition, 
subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤10mg daily 
prednisone (or equivalent).
vii. CNS 
metastasis
a) Subjects with untreated CNS metastases are excluded. 
b) Exception: 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 enrollment. In addition, subjects must be either off 
corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent).
c) Subjects with carcinomatous meningitis
Treatment Legend: Group A: Maintenance, NSQ PS 0-1, EGFRwt and ALKwt; Group B: Maintenance, SQ, PS 0-1; 
Group C: First-line NSQ and SQ, PS 2, EGFRwt and ALKwt; Group D: First-line PS 0-2, EGFRmut; Group E: First-
line PS 0-2, ALK-positive
* Concurrent ablative/definitive radiation therapy with induction chemotherapy is acceptable for Group A and Group 
B.
2. Medical History 
Table 3.3.2-2:
Medical History
Description
Group A
Group B
Group C
Group D
Group E
i. 
Cardiovascular 
and 
Hematologic
a) Not Applicable.
b) Ongoing 
cardiac 
dysrhythmias of 
NCI CTCAE 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
53


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 3.3.2-2:
Medical History
Description
Group A
Group B
Group C
Group D
Group E
Grade ≥2, 
uncontrolled 
atrial fibrillation 
of any grade, or 
QTc interval 
>470 msec.
ii. 
Dermatologic 
and 
trauma/surger
y
a) Unhealed 
open wound 
b) Major 
surgery or 
significant 
traumatic injury 
within 4 weeks 
of first on-study 
treatment is 
excluded for 
bevacizumab 
containing arms.
c) Major 
surgery or 
significant 
traumatic injury 
within 2 weeks
of first on-study 
treatment is 
excluded for all 
arms
d) Unhealed open wound 
e) Major surgery or significant traumatic injury within 2 weeks of first on-
study treatment 
f) Skin disorders requiring chronic systemic steroid treatment are excluded 
iii. Neuropathy
a) Subjects with ≥ Grade 2 peripheral neuropathy are excluded 
iv. Neurologic
a) Untreated or active/progressing CNS metastases are excluded. 
b) Exceptions: 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 enrollment. 
c) Carcinomatous meningitis
v. Pulmonary
a) History of interstitial lung disease (eg, sarcoidosis) that is symptomatic or may interfere 
with the detection or management of suspected drug-related pulmonary toxicity is excluded. 
Exception: Subjects with COPD whose disease is controlled at study entry are allowed.
vi. Malignancy
a) Subjects with previous malignancies (except non-melanoma skin cancers, and in situ cancers 
such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are 
excludedunless a complete remission was achieved at least 1 year prior to study entry and no 
additional therapy is required or anticipated to be required during the study period, with the 
exception of anti-estrogen/androgen therapy or bisphosphonates.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
54


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 3.3.2-2:
Medical History
Description
Group A
Group B
Group C
Group D
Group E
b) Other active malignancy requiring concurrent intervention
vii. 
Autoimmune 
disease
a) Active, known or suspected autoimmune disease(eg, rheumatoid arthritis, multiple 
sclerosis).
b) Exceptions: skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll.
viii. Other
a) Bevacizumab 
and pemetrexed 
specific 
exclusion 
criteria are per 
individual agent 
package insert
b) Best 
supportive care 
arm excludes 
definitive 
radiation 
therapy and 
surgery (other 
than palliative 
in nature, 
chemotherapy, 
targeted, 
biologic or 
immune 
therapies
c) 
Chemotherapy 
specific 
exclusion 
criteria are per 
individual agent 
package insert
d) Erlotinib 
specific 
exclusion 
criteria are per 
package insert
e) Crizotinib 
specific 
exclusion 
criteria are per 
package insert
f) Group A and B: All toxicities 
attributed to prior anti-cancer 
therapy other than alopecia, fatigue, 
or peripheral neuropathy must have 
resolved to Grade 1 (NCI CTCAE 
version 4) or baseline before 
administration of study drug.
g) Not Applicable 
h) Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS)
i) Acute or chronic infection of hepatitis B virus or hepatitis C.
j) Subjects with a condition requiring systemic treatment with either corticosteroids (>10mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. 
k) Exceptions: Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
l) Exceptions: Subjects withtype I diabetes mellitus, hypothyroidism only requiring hormone 
replacement are eligible to enroll.
Treatment Legend: Group A: Maintenance, NSQ PS 0-1, EGFRwt and ALKwt; Group B: Maintenance, SQ, PS 0-1; 
Group C: First-line NSQ and SQ, PS 2, EGFRwt and ALKwt; Group D: First-line PS 0-2, EGFRmut; Group E: First-
line PS 0-2, ALK-positive
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
55


Clinical Protocol
CA209370
BMS-936558
nivolumab
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection
b) History of testing positive for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS)
c) Subjects with ≥ Grade 2 peripheral neuropathy
d) Women who are pregnant or breastfeeding
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to platinum-containing compounds or other study 
drug components
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
c) Any other serious or uncontrolled medical disorder, active infection, physical exam 
finding, laboratory finding, altered mental status, or psychiatric condition that, in the 
opinion of the investigator, would limit a subject’s ability to comply with the study 
requirements, substantially increase risk to the subject, or impact the interpretability of 
study results
NOTE: This study permits the re-enrollment of a subject that has discontinued the study as a pre-
treatment failure (ie, subject has been randomized/enrolled, buthas not been treated). If re-
enrolled, the subject must be re-consented.
3.3.3
Women of Childbearing Potential
A woman 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 55years must have a serum follicle stimulating hormone, (FSH) level 
>40mIU/mL to confirm menopause.
Note: 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 judgment 
in checking serum FSH levels. If the serum FSH level is >40 mIU/ml at any time during the 
washout period, the woman can be considered postmenopausal:
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.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
56


Clinical Protocol
CA209370
BMS-936558
nivolumab
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. 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the 
use of highly effective methods of contraception. Highly effective methods of contraception have 
a failure rate of < 1% when used consistently and correctly.
NOTE:Partners of male subjects are to use one highly effective method of contraception.
Subjects must agree to use one highly effective contraception methods as listed below: 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Progestogen only hormonal contraception associated with inhibition of ovulation
Hormonal methods of contraception including oral contraceptive pills (combination of 
estrogen and progesterone), vaginal ring, injectables, implants, transdermal  and intrauterine 
hormone-releasing systems (IUS)
Bilateral tubal ligation
Vasectomized Partner
Intrauterine devices (IUD)
Complete abstinence
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence 
are not required to use a second method of contraception, but female subjects must continue to 
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence.
Unacceptable METHODS OF CONTRACEPTION
Vaginal sponge with spermicide
Progestin only pills
Cervical cap with spermicide
Diaphragm with spermicide
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
Withdrawal (coitus interruptus)
Spermicide only
Lactation amenorrhea method (LAM)
A male and a female condom must not be used together
Male condoms with or without spermicide for partners of female subjects, as the only method 
of contraception.
Female condoms
 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
57


Clinical Protocol
CA209370
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
58


Clinical Protocol
CA209370
BMS-936558
nivolumab
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 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 (eg, infectious disease) illness
Additional protocol specified reasons for discontinuation or dose modifications (See Sections 
4.5.1thru 4.5.14)
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study
 drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
For the subjects who are treatedwiththe combination of nivolumab and Standard of Care, if a 
subject discontinuesone of the drugs the subject needs to discontinue the combination treatment. 
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.
3.6
Post Study Drug Study Follow-up
As the mean terminal elimination half-life of nivolumab is 17 to 25 days, the safety follow-up after 
discontinuation of nivolumab single-agent dosing will be 100 days, or approximately 5 half-lives. 
It is recognized that subsequent therapies may be initiated during the100-day safety follow-up, 
and investigators will be advised to consider the potential contribution of prior study treatment in 
addition to the subsequent therapy being administered at the time that any adverse event is 
observed when assessing causality ofthe event.
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol-defined window in Section 5. At the timeof this request, each participant will be 
contacted to determine their survival status unless the participanthas withdrawn consent for all 
contacts or is lost to follow-up.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
59


Clinical Protocol
CA209370
BMS-936558
nivolumab
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 in end of treatment and 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, whenever 
possible. The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study drug onlyor 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 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 documentedin 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
Nivolumab 100 mg (10 mg/mL) will be packaged in an open-label fashion. Ten (10) nivolumab 
10mLvials will be packaged within a carton (see Table 4-1). 
The vials are not subject or treatment 
group specific although there will be specific vial assignments by subject distributed by the IWRS 
in order to track drug usage and re-supply. 
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consists of the following:
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
60


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 4-1:
Study Drugs for CA209370
Product Description 
and Dosage Form 
Potency 
Primary Packaging 
(Volume)/ Label Type 
Secondary Packaging 
(Qty) /Label Type 
Appearance 
Storage Conditions 
(per label) 
Nivolumab 
Solution for Injection
100 mg 
(10mg/mL) 
10 mL per vial/ Open-label 5 or 10 vials per carton/ 
Open-label 
Clear to opalescent 
colorless to pale yellow 
liquid. May contain 
particles 
2 to 8°C. Protect from 
light and freezing 
Bevacizumab
100 mg/4 mL (4 mL)
a
4 ml per vial/open-label
4ml or 16 ml Open-
label
Solution
2−8°C. Protect from 
light 
Carboplatin Solution
for Injection 
450 mg/vial 
(10mg/mL)a
45 mL per vial/ Open-label 4 vials per 
carton/Open-label 
Clear, colorless or 
slightly yellow solution 
Store at or below 25°C. 
Protect from light. 
Cisplatin 
50 mg/vial, 100 
mg/vail
(1 mg/mL)
50 mL per vial  and 100 mL 
per vial/ Open-label
1 vial per carton/Open-
label
Clear, colorless, sterile 
aqueous solution
Store at 15°Cto 25°C. 
Protect from light
Crizotinib
Capsules: 250 mg 
and 200 mg.
a
Capsules: 250 mg and 200 
mg.
Bottles of 60 capsules, 
Open-label
Capsule of pink opaque 
cap and body
Store at room 
temperature 20°Cto 
25°C
Docetaxel
80 mg/2 mL and 20 
mg/0.5 mLa
Single-dose vial
In a blister pack in one 
carton, Open-label
Non-aqueous, viscous 
solution
Store between 2°C and
25°C
Erlotinib
Tablets: 25 mg,
100 mgand 150 
mg
Tablets 25 mg, 100 mgand 
150 mg
Bottles of 30 tablets
Open-label
white film-coatedtablet Store at room 
temperature 15°C to 
30°C
Gemcitabine Powder for 
Solution for Infusion 
1000 mg/viala
1000 mg per vial/ Open-
label 
1 vial per carton/Open-
label 
White to off-white plug 
or powder 
Store at 15-30°C 
Pemetrexed Powder for 
Concentrate for Solution 
for Infusion 
500 mg/viala
500 mg per vial/ Open-
label 
1 vial per carton/ Open-
label 
White to either light 
yellow or green-yellow 
lyophilized powder 
Store at 25°C. 
Excursions permitted 
(15-30°C) 
Paclitaxel Solution for 
Injection 
100 mg/viala
(6mg/mL) 
16.7 mL vial/ Open-label 
4 vials per 
carton/Open-label 
Clear, colorless or 
slightly yellow viscous 
solution 
Store at 15°C-30°C. 
Protect from light. 
Nab-paclitaxel
100 mg in a single 
use viala
Individually packaged in a 
carton.
1 vial per carton/Open-
label
Lyophilized powder
20°C to 25°C, Protect 
from bright light.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
61


Clinical Protocol
CA209370
BMS-936558
nivolumab
aThese products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. In these cases, 
products may be a different pack size/potency than listed in the table. These products should be prepared/stored/administered in accordance with the package 
insert or summary of product characteristics (SmPC).
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
62


Clinical Protocol
CA209370
BMS-936558
nivolumab
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. 
Nivolumab is to be administered intravenously (IV) for 30min ± 5 minutes in thisMaster Protocol. 
Investigational product documentation 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).
Dosing calculation for nivolumab should be based on the body weight assessed as per Table 5.1-
1. If the subject’s weight on the day of dosing differs by >±10% fromthe weight used to calculate 
the prior dose, the dose must be recalculated. All doses should be rounded to the nearest milligram. 
There will be no dose modifications allowed for nivolumab.
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. 
Gemcitabine, pemetrexed, paclitaxel, nab-paclitaxel, carboplatin, bevacizumab, erlotinib, 
crizotinib, etc. will be procured by the investigator as local commercial product. The sites will also 
procure IV bags, diluents, and micron in-line filters (ie, 0.2/0.22 micron; see current nivolumab
Investigator Brochures for required filter details).
4.3
Storage and Dispensing
The product storage manager should ensure that the study drug(Nivolumab) 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 contact BMS immediately.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
63


Clinical Protocol
CA209370
BMS-936558
nivolumab
4.4
Method of Assigning Subject Identification
CA209370 is an open-label study. All enrolled subjects will be assigned a subject number, starting 
with 00001. After it has been determined that the subject meets all eligibility criteria of the study, 
the investigator (or designee) will register the subject by following the enrollment procedures 
established by BMS. The following information is required for registration:
Date of birth
Gender at birth
Diagnosis
Date of informed consent
Planned date of 1st dose. 
The subject number will be assigned through an interactive webresponse system (IWRS) once the 
subject signs informed consent. Every subject that signs informed consent must be assigned a 
subject number in IWRS. Specific instructions for using IWRS will be provided to the 
investigational site in a separate document. Enrolled subjects meeting all eligibility criteria will be 
assigned to sub-protocols according to their mutation status, histology subtype and performance 
status to one of the treatment arms according to their histology subtype and treatment arm 
availability. 
4.5
Selection and Timing of Dose for Each Subject
Subjects will be assigned to one of 5 sub-protocols:
Group A (NSQ, Maintenance Therapy):Single-agent nivolumab, single-agent pemetrexed 
or bevacizumab, or the combination of nivolumab and pemetrexed or bevacizumab. The 
treatment arms are: 
Arm A1: bevacizumab 15 mg/kg every 3 weeks
Arm A2: bevacizumab 15 mg/kg + nivolumab 5 mg/kg every 3 weeks over 30 minute 
infusion
Arm A3: nivolumab 240 mg every 2 weeks over 30 minute infusion
Arm B1: pemetrexed 500 mg/m2every 3 weeks
Arm B2: pemetrexed 500 mg/m2every 3 weeks, plus nivolumab 5 mg/kg every 3 weeks 
over 30 minute infusion
Arm B3: nivolumab 240 mg every 2 weeks over 30 minute infusion
Nivolumab is to be administered first, bevacizumab or pemetrexedwill start at least 30 minutes 
after completion of the nivolumab infusion.
Group B (SQ, Maintenance Therapy):Either single-agent nivolumab, or BSC 
Nivolumab 240 mg, every 2 weeks over 30 minute infusion
BSC 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
64


Clinical Protocol
CA209370
BMS-936558
nivolumab
Group C (First-line, PS 2):Either Investigator’s Choice chemotherapy or single-agent 
nivolumab as first-line treatment. 
Nivolumab: 240 mg every 2weeks, OR Investigator’s Choice chemotherapy regimens will be 
as follows:
Arm A(Investigator’s Choice chemotherapy, NSQ): 
Carboplatin AUC =6 + nab-paclitaxel (100mg/m
2)Days 1, 8, and 15 every 3 weeks
Carboplatin AUC = 6 + paclitaxel (200 mg/m
2)every 3 weeks
Carboplatin AUC = 6 + pemetrexed (500 mg/m
2)every 3 weeks
Carboplatin AUC = 6 + docetaxel (75 mg/m
2)every 3 weeks
Paclitaxel (175-225 mg/m2)every 3 weeks
Docetaxel (60-75 mg/m2)every 3 weeks
Gemcitabine (1000 mg/m2)Days 1 and 8 every 3weeks
Pemetrexed (500 mg/m
2)every 3 weeks
ArmA(Investigator’s Choice chemotherapy, SQ):
Carboplatin AUC =6 + nab-paclitaxel (100mg/m
2)Days 1, 8, and 15 every 3 weeks
Carboplatin AUC = 6 + paclitaxel (200 mg/m
2)every 3 weeks
Carboplatin AUC = 5 + gemcitabine (1000 mg/m2)days1, and 8 every 3 weeks
Carboplatin AUC =6 + docetaxel (75 mg/m
2)every 3 weeks
Paclitaxel (175-225 mg/m2)every 3 weeks
Docetaxel (60-75 mg/m2)every 3 weeks
Gemcitabine (1000 mg/m2)Days 1 and 8 every 3 weeks
Arm B(Nivolumab, SQ or NSQ)
Nivolumab: (240 mg) every 2weeks over 30 minute infusion
GroupD (First-line, EGFR mutation):First-line treatment with erlotinib or the combination 
of nivolumab + erlotinib. 
Arm A: erlotinib (150 mg QD) 
Arm B: nivolumab (240 mg) every 2 weeks over 30 minute infusion + erlotinib (150 
mgQD)
Group E (First-line, ALK positive): First-line treatment with nivolumab and crizotinib 
Subjects will receive the combination of nivolumab (240 mg) every 2 weeks over 
30minute infusion and crizotinib (250 mg BID).
All subjects who discontinue study treatment should comply with protocol specified end of 
treatment and follow-up procedures as outlined in the schedule of events. Subjects will continue 
with the on-study visit schedule until disease progression following retreatment or upon a decision 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
65


Clinical Protocol
CA209370
BMS-936558
nivolumab
to not receive retreatment, unacceptable toxicity, or withdrawal of informed consent. The only 
exception to this requirement is when a subject withdraws consent for all study procedures 
including post-treatment study follow-up or loses theability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness). If study 
treatment is discontinued prior to the 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 CRF page.
4.5.1
Duration of Treatment with Nivolumabfor Groups A, B, C,and D
The optimal duration of immunotherapy is currently unknown. However, because immunotherapy 
engages the immune system to control the tumor, continuous treatment as is required with targeted 
agents or cytotoxic therapy may not be necessary. 
Accumulating evidence from different clinical trials in different tumors types with nivolumab 
indicates that most of the responses are generally occurring early, with a median time to response 
of 2-4 months including in subjects with NSCLC,
89,90and a recentanalysis in a melanoma study 
suggests the majority of subjects who discontinue nivolumab for toxicity maintain disease control 
in the absence of further treatment.
91
For these reasons,treatmentswith 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. 
With the early closure of groups A, B,C, and D, subjects currently on treatment in these groups 
may continue to be treated and monitored asspecified in theprotocol. The decision to continue 
treatment should be based on the clinical judgment of thetreating physician, in consultation with 
the subject.
4.5.2
Nivolumab Treatment Discontinuation
Nivolumab treatment should be permanently discontinued for the following:
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 
Any Grade 3 non-skin, drug-related AE lasting > 7 daysor recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm,
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, 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 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
66


Clinical Protocol
CA209370
BMS-936558
nivolumab
Grade 3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
* In most cases of Grade 3 AST or ALT elevation, study treatment will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment, a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
Any Grade 4 drug-related adverse event or laboratory abnormality(including but not limited 
to creatinine, AST, ALT, or Total Bilirubin),except for the following events which do not 
require discontinuation:
Grade 4 neutropenia ≤7 days
Grade 4 lymphopenia or leukopeniaor asymptomatic amylase or lipase
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72hours 
of their onset
Grade 4 drug-related endocrinopathy adverse events, such as ACTH deficiency, hyper-or 
hypothyroidism, or glucose intolerance, which resolveor 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 or designee.
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 
weeks from the previous dose, the BMS medical monitor or designee must be consulted. 
Tumor assessments should continue as per protocol even if dosing is delayed. Periodic 
study visits to assess safety and laboratory studies should also continue every 6 weeks or 
more frequently if clinically indicated during such dosing delays.
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 or designee. Prior to re-
initiating treatment in a subject with a dosing delay lasting > 6 weeks, the BMS medical 
monitor or designee must be consulted. Tumor assessments should continue as per protocol 
even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
should also continue every 6 weeks or more frequently if clinically indicated during such 
dosing delays.
Any 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.
Subjects will be monitored continuously for AEs while on study. Treatment modifications (eg, 
dose-delay or discontinuation) will be based on specific laboratory and AE criteria. Early 
recognition and management may mitigate severe toxicity. Evaluation and Management 
Guidelines were developed to assist investigators and can be found in the Investigator Brochure 
and in Appendix 1 of this protocol:
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
67


Clinical Protocol
CA209370
BMS-936558
nivolumab
Suspected Pulmonary Toxicity
Diarrhea and Colitis
Suspected Hepatotoxicity (including asymptomatic liver function tests [LFT] elevations)
Suspected Endocrinopathy
Nephrotoxicity
Neurotoxicity
4.5.3
Dose Delay Criteria
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed.
4.5.3.1
Nivolumab Dose Delay Criteria
Nivolumab administration should be delayed for the following:
Grade ≥ 2 non-skin, drug-related AE, with the exception of fatigue
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
Any Grade 3 skin, drug-related AE
Any Grade 3 drug-related laboratory abnormality, with the following exceptions
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
Grade 3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section 
4.5.3.1)
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Participantswho require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
4.5.3.2
Resumption of Nivolumab
Treatment may resume when the AE(s) resolve(s) to Grade 1 or baseline value. If treatm
ent must 
be delayed for > 6 weeks from the last dose, please contact the Study Director/Medical Monitor 
before resuming dosing.
In subjects receiving corticosteroids to treat a drug-related AE, nivolumab may not be resumed 
until the corticosteroid has been tapered to a dose less than or equivalent to prednisone 10 mg/day.
Tumor assessments for subjects who delay study treatment should continue as per protocol until 
radiographic progression is assessed by the investigator. 
Subjects may resume treatment with nivolumab when the suspected drug-related AE(s) 
resolve(s) to Grade ≤1 or baseline, with the following exceptions:
Subjects may resume treatment in the presence of Grade 2 fatigue.
Subjects who have not experienced a Grade 3 suspected drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity.
For subjectswith Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may resume 
when laboratory values return to baseline and management with corticosteroids, if needed, is 
complete.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
68


Clinical Protocol
CA209370
BMS-936558
nivolumab
Subjects with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters (see Section 4.5.2) should have treatment permanently discontinued.
Drug-related pulmonary toxicity,diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor (or designee).
Subjectswith drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor 
(or designee). Adrenal insufficiency requires discontinuation regardless of control with 
hormone replacement.
Dose delay of nivolumab which results in treatment interruption of > 6 weeks requires 
treatment discontinuation, with exceptions as noted in Section 4.5.3.1.
4.5.4
Nivolumab Dose Modifications
There will be no dose reductions for nivolumab.
4.5.5
Bevacizumab Treatment Discontinuation:
Bevacizumab should be discontinued for gastrointestinal perforations, fistula formation involving 
an internal organ, wound dehiscence and wound healing complications requiring medical 
intervention, serious hemorrhage, severe arterial thrombotic events, hypertensive crisis or 
hypertensive encephalopathy, reversible posterior leukoencephalopathy syndrome, or nephrotic 
syndrome (see Boxed Warning, Warnings and Precautions in the bevacizumab label). 
Bevacizumab should be held for severe hypertension not controlled with medical management, 
moderate to severe proteinuria, and severe infusion reactions.
4.5.6
Bevacizumab Dose Modifications
There are no dose modifications for bevacizumab. 
4.5.7
Pemetrexed Treatment Discontinuation 
Pemetrexed therapy should be discontinued if a subject experiences any hematologic or non-
hematologic Grade 3 or 4 toxicity after 2 dose-reductions (except Grade 3 transaminase elevations) 
or immediately if Grade 3 or 4 neurotoxicity is observed.
4.5.8
Pemetrexed Dose Reductions 
If subjects develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment 
should be withheld until resolution to less than or equal to the subject’s pre-therapy value. 
If subjects develop any Grade 3 or 4 toxicities except mucositis, any diarrhea requiring 
hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea, the subsequent pemetrexed dose 
will be reduced by 25%. 
If subject develops Grade 3 or 4 mucositis, subsequent pemetrexed dose will be reduced by 50%. 
Dose Reduction for Pemetrexed (single-agent or in combination)-Hematologic Toxicities
Pemetrexed dose reductions should follow the guidelines below: 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
69


Clinical Protocol
CA209370
BMS-936558
nivolumab
Nadir ANC <500/mm3and nadir platelets ≥50,000/mm3, or Nadir platelets <50,000/mm3
without bleeding regardless of nadir ANC, subsequent pemetrexed dose will be reduced by 
25%. 
Nadir platelets <50,000/mm3with bleeding, regardless of nadir ANC, subsequent pemetrexed 
dose will be reduced by 50%.
In the event of neurotoxicity, therapy should be held until resolution of symptom to ≤Grade1. 
Subjects should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.
Pemetrexed should not be administered to subjects whose creatinine clearance is <45 mL/min 
using the standard Cockcroftand Gault formula (below) or GFR measured by Tc99m-DPTA serum 
clearance method.
Growth factors are permissible to allow for hematological recovery. Please use local standards of 
care in the use of these supportive measures. Additionally, the use of prophylactic dose antibiotics 
is to be used according to local standards of care. Please note any antibiotic or growth factor use 
on the eCRF. 
4.5.9
Group C: Investigator’s Choice Chemotherapy Dose Discontinuation:
Except where specified below, both chemotherapy drugs in the investigator’s choice chemotherapy 
regimen should be discontinued for any of the following: 
Any Grade ≥3 peripheral neuropathy
Grade ≥ 3 drug-related thrombocytopenia associated with clinically significant bleeding 
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
AST or ALT > 5-10×ULN for > 2 weeks
AST or ALT > 10×ULN
Total bilirubin > 5 ×ULN
Concurrent AST or ALT > 3 ×ULN and total bilirubin > 2 ×ULN
Any drug-related AE which recurs after two 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.
Any event that leads to delay in dosing of any study drug(s) for >6 weeks from the previous 
dose requires discontinuation of that drug(s) with the following exception:
Dosing delays lasting >6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor or designee. Prior to re-
initiating treatment in a subject with adosing delay lasting >6 weeks, the BMS medical 
monitor or designee must be consulted. Periodic study visits to assess safety and laboratory 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
70


Clinical Protocol
CA209370
BMS-936558
nivolumab
studies should also continue every 6 weeks or more frequently if clinically indicated during 
such dosing delays.
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued investigator’s 
choice chemotherapy dosing. Investigators should consult local labeling forthe chemotherapy 
drugs being administered to any given subject for additional guidance on dose discontinuation.
4.5.10
Group C: Investigator’s Choice Chemotherapy Dose Reductions
Dose reductions of Investigator’s Choice chemotherapy may be required, and will be performed 
according to Table 4.5.10.1-1. Chemotherapy dose reductions are permanent; once the dose of any 
chemotherapy agent is reduced, it may not be re-escalated in subsequent cycles. The dose 
reductions for each agent in the Investigator’s Choice chemotherapy regimen are not linked and 
may be adjusted independently.
4.5.10.1 Gemcitabine dosing: Adjustment for Toxicity 
Non-hematologic toxicity (all indications):
Hold or decrease gemcitabine dose by 50% for the following: Severe (Grade 3 or 4) non-
hematologic toxicity until resolved (excludes nausea, vomiting, or alopecia [no dose 
modifications recommended])
Permanently discontinue gemcitabine for any of the following: Unexplained dyspnea (or other 
evidence of severe pulmonary toxicity), severe hepatotoxicity, hemolytic uremic syndrome 
(HUS), capillary leak syndrome (CLS), posterior reversible encephalopathy syndrome (PRES)
Investigator’s Choice Chemotherapy -Dose Reductions for Hematologic Toxicity
Dose adjustments are based on nadir blood counts (assessed as perlocal standards) since the 
preceding drug administration. Dose level adjustments for investigator’s choice chemotherapy are 
relative to that of the preceding administration. After the first cycle, growth factors may be used 
to assist hematologic recovery.Use local standards of care in the use of these supportive measures. 
Additionally, prophylactic antibiotics may be used according to local standards of care. Please 
report any antibiotic or growth factor use on the eCRF.
Table 4.5.10.1-1:
Dose Modifications for Non-hematologic Toxicity 
Toxicity
Gemcitabine
Pemetrexed
Carboplatin
Paclitaxel/Docetaxel
Febrile Neutropenia 
Grade ≥3
Reduce one 
dose level
Reduce one dose 
level
Reduce one dose 
level
Reduce one dose 
level
Diarrhea Grade ≥3
Reduce one 
dose level
Reduce one dose 
level
No change
Reduce one dose 
level
Allergic reaction Grade 
≥3a
Discontinue 
Discontinue
Discontinue
Discontinue
Neuropathy Grade 2
No change
No change
No change
Reduce one dose 
level
Neuropathy Grade ≥3
Discontinue
Discontinue
Discontinue
Discontinue
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
71


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 4.5.10.1-1:
Dose Modifications for Non-hematologic Toxicity 
Toxicity
Gemcitabine
Pemetrexed
Carboplatin
Paclitaxel/Docetaxel
Calculated creatinine 
clearance <50 ml/min
No change
No change
No change
No change
Other Grade ≥3 
toxicity, except for 
fatigue and transient 
arthralgia and myalgia  
Adjust as 
medically 
indicated 
Adjust as medically 
indicated 
Adjust as medically 
indicated 
Adjust as medically 
indicated 
a Only the drug causing the hypersensitivity or acute infusion reaction (≥3 Grade 3) require(s) discontinuation. All 
other drugs may continue. 
Growth factors are permissible to allow for hematological recovery. Please use local standards of 
care in the use of these supportive measures. Additionally, the use of prophylactic dose antibiotics 
is to be used according to local standards of care. Please note any antibiotic or growth factor use 
on the eCRF.
4.5.11
Group D: Erlotinib Treatment Discontinuation 
Discontinue erlotinib for:
Interstitial Lung Disease (ILD) 
Severe hepatic toxicity that does not improve significantly or resolve within 3 weeks
Gastrointestinal perforation
Severe bullous, blistering or exfoliating skin conditions 
Corneal perforation or severe ulceration
Because TKI and nivolumab may both cause gastrointestinal (GI), hepatic, skin, pulmonary, 
renal, and ocular toxicity, it is recommended that TKI also be discontinued if any such 
toxicities meeting nivolumab dose discontinuation criteria (above) occur.
In addition, erlotinib should be discontinued for: 
Any AEs specified in the local product label for erlotinib. 
Any AE, laboratory abnormality, or intercurrentillness which, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued erlotinib 
dosing.
Any erlotinib dosing interruption > 6 weeks with the following exceptions: 
Dosing interruptions to allow for prolonged steroid tapers to manage drug-related 
pneumonitis or interstitial lung disease. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 6 weeks, the BMS Study Director/Medical Monitor must be 
consulted. Tumor assessments shouldcontinue as per protocol even if dosing is interrupted
For non-drug-related reasons may be allowed if approved by the BMS medical monitor. 
Prior to re-initiating treatment in a subject with a dosing interruption lasting > 6 weeks, the 
BMS Study Director/Medical Monitor must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted
Note: In Group D if the investigator assesses the drug-related AE to be related to nivolumab only 
and not related to erlotinib, nivolumab-dosing alone may be discontinued while erlotinib-dosing 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
72


Clinical Protocol
CA209370
BMS-936558
nivolumab
is delayed until the subject meets criteria to resume erlotinib treatment. The case must be discussed 
with the BMS Study Director/Medical Monitor, and therelationship to nivolumab should be well 
documented in the source documents.
Discontinuation of erlotinib alone with delay of nivolumab-dosing may be permitted if the 
investigator assesses an AE meeting discontinuation criteria to be related to erlotinib-only and not 
to nivolumab, and the case is discussed with and approved by the BMS Study Director/Medical 
Monitor. In such cases, nivolumab dosing may resume when the criteria for resuming treatment 
(specified in Section4.5.3.2) are met. Relationship to erlotinib should be well documented in the 
source documents. 
4.5.12
Erlotinib Dose Modifications 
Dose modifications for erlotinib should follow the labeled recommendations for modification.
4.5.13
Resumption of Erlotinib 
Treatment may resume when the drug-related AE(s) resolve(s) to Grade 1 or baseline value. If 
treatment must be delayed for 6 weeks, please contact the Study Director/Medical Monitor before 
resuming dosing.
If a subject fails to meet criteria for re-treatment, then re-treatment should be delayed and the 
subject should be re-evaluated weekly or more frequently as clinically indicated.
If dosing of both nivolumab and erlotinib have been delayed, it is acceptable to resume dosing of 
nivolumab and erlotinib independently of each other. Erlotinib may be resumed in the setting of 
an ongoing corticosteroid taper, even at doses equivalent to or higher than prednisone 10 mg/day, 
as long as the drug-related AE has otherwise resolved to Grade 1 or baseline. 
Any subject who fails to recover from toxicity attributable to erlotinib to baseline or Grade 1 
within 6 weeks from the last dose given should discontinue erlotinib.
For erlotinib specifically, when resuming, please follow the local label recommendations for dose 
reductions.
4.5.14
Group E: Crizotinib Treatment Discontinuation 
ALT or AST elevation greater than 3×ULNwith total bilirubin elevation greater than 2×ULN 
in the absence of cholestasis or hemolysis. 
Recurrent Grade 3 or 4 ALT or AST elevation or recurrent Grade 4 hematologic toxicity on 
250 mg once daily:
Any Grade treatment-related ILD/pneumonitis
Grade 4QTc prolongation or QTc interval prolongation in combination with Torsade de 
pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia, or 
recurrent Grade 3 QTc prolongation at 250 mg once daily.
Life-threatening bradycardia in subjects who are not taking a concomitant medication also 
known to cause bradycardia or known to cause hypotension
All subjects who discontinue investigational product should comply with protocol specified end 
of treatment and follow-up procedures as outlined in the schedule of events. Subjects will continue 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
73


Clinical Protocol
CA209370
BMS-936558
nivolumab
with the on-study visit schedule. 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 treatment 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 CRF page.
4.5.15
Crizotinib Dose Modifications 
If dose reduction is necessary, reduce dose to 200 mg orally twice daily; if necessary, further 
reduce to 250 mg once daily. If unable to tolerate 250 mg once daily, permanently discontinue 
therapy.
Hematologic toxicity (except lymphopenia, unless lymphopenia is associated with clinical 
events such as opportunistic infection):
Grade 3 toxicity (WBC 1000-2000/mm3, ANC 500-1000/mm3, platelets 25,000-
50,000/mm3), Grade 3 anemia: Withhold treatment until recovery to ≤Grade 2, then 
resume at the same dose and schedule.
Grade 4 toxicity (WBC <1000/mm3, ANC <500/mm3, platelets <25,000/mm3), Grade 4 
anemia: Withhold treatment until recovery to ≤ Grade2, then resume at 200 mg twice daily.
Recurrent Grade 4 toxicity on 200 mg twice daily: Withhold treatment until recovery to 
≤Grade 2, then resume at 250 mg once daily.
Recurrent Grade 4 toxicity on 250 mg once daily: Permanently discontinue.
Non-hematologictoxicities:
Cardiovascular toxicities:
QTcprolongation:
o Grade 3 QTcprolongation (QT
c>500 msec without life-threatening signs or 
symptoms) on at least 2 separate ECGs: Withhold treatment until recovery to 
baseline or to ≤ Grade 1 (QTc≤480 msec), then resume at 200 mg twice daily. 
o Recurrent Grade 3 QTc prolongation at 200 mg twice daily: Withhold treatment 
until recovery to baseline or to ≤ Grade 1, then resume at 250 mg once daily.
o Recurrent Grade 3 QTc prolongation at 250 mg once daily: Permanently 
discontinue.
o Grade 4 QTc prolongation (QTc >500 msec or ≥60 msec change from baseline 
with life-threatening symptoms): Permanently discontinue.
Bradycardia:
o Grade 2 bradycardia (symptomatic with medical intervention indicated) or Grade3 
bradycardia (severe/medically significant with intervention indicated): Withhold 
until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats/minute 
and evaluate concomitant medications. If contributing concomitant medication is 
identified and discontinued (or dose adjusted), then resume crizotinib at the 
previous dose. If no contributing concomitant medication is identified (or cannot 
be discontinued or dose-adjusted), resume crizotinib at a reduced dose.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
74


Clinical Protocol
CA209370
BMS-936558
nivolumab
o Grade 4 bradycardia due to crizotinib (life-threatening with urgent intervention 
indicated): Permanently discontinue.
o Grade 4 bradycardia associated with concurrent medications known to cause 
bradycardia or hypotension (life-threatening with urgent intervention indicated): 
Withhold until recovery to asymptomatic bradycardia or to a heart rate of ≥60 
beats/minute, and if concurrent medication can be discontinued or dose adjusted, 
resume at 250 mg once daily with frequent monitoring. 
Hepatotoxicity: Hepatotoxicityduringtreatment:
o Grade 3 or 4 ALT or AST elevation (ALT or AST >5 ×ULN) with ≤ Grade 1 total 
bilirubin elevation (total bilirubin ≤1.5 ×ULN): Withhold treatment until recovery 
to ≤ Grade 1 (<3 ×ULN) or baseline, then resume at 200 mg twice daily.
o Recurrent Grade 3 or 4 ALT or AST elevation with ≤Grade 1 total bilirubin 
elevation: Withhold treatment until recovery to ≤Grade 1, then resume at 250 mg 
once daily. 
o Recurrent Grade 3 or 4 ALT or AST elevation on 250 mg once daily: Permanently 
discontinue.
o Grade 2, 3, or 4 ALT or AST elevation (ALT or AST >3 ×ULN) with concurrent 
Grade 2, 3, or 4 total bilirubin elevation (>1.5 ×ULN) in the absence of cholestasis 
or hemolysis: Permanently discontinue.
o Pulmonary toxicity: ILD/pneumonitis (any grade; not attributable to disease 
progression, infection, other pulmonary disease or radiation therapy): Permanently 
discontinue.
4.5.16
Treatment of Nivolumab-Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is 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 3or 4 
infusion reactions should be reported within 24 hours to the study medical monitor or designee
and reported as an SAE if it meets the criteria. Infusion reactions should be graded according to 
NCI CTCAE (Version 4.0) guidelines. Treatment recommendations are provided below and may 
be modified based on local treatment standards and guidelines, as appropriate:
For Grade 1 symptom: (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 administrations.Infusion time can be increased to 60 minute 
or longer if needed. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption 
but responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
75


Clinical Protocol
CA209370
BMS-936558
nivolumab
inflammatory drugs,narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤24 hours).
Stop the nivolumab infusion, begin an IV infusionof 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 at50% 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 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 
1000mg should be administered at least 30 minutes before nivolumab infusions. If 
necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used. Infusion 
time can be increased to 60 minute or longer if needed. 
For Grade 3 or 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence 
of symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [eg, renal impairment, pulmonary infiltrates]. Grade 4: Life-threatening; 
pressor or ventilatory support indicated).
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline 
and treat the 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 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 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).
4.5.17
TreatmentBeyond Disease Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD. Subjects treated with nivolumab or nivolumab-
containing regimens will be permitted to continue treatment beyond initial RECIST v1.1 defined 
PD as long as the following criteria are met:
1) Investigator-assessed clinical benefit and do not have rapid disease progression
2) Tolerance of study drug
3) Stable performance status
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
76


Clinical Protocol
CA209370
BMS-936558
nivolumab
4) Treatment beyond progression will not delay an imminent intervention to prevent serious
complications of disease progression (eg, CNS metastases)
5) The decision to continue treatment beyond initial progression hasbeendiscussed with the BMS 
Medical Monitor or designee and is documented in the study records. The written informed 
consent signed by the subject at study entry prior to receiving nivolumab (ie, prior to PD)will 
serve as documentation that the subjectunderstands any foreseeable risks or discomforts, or 
other alternative treatment options if the subject decides to continue nivolumab treatment post-
progression. No separate post-progression informed consent form is required.  
A radiographic assessment/ scan isperformed within 8 weeks of original PD 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.
If the investigator feels that the nivolumab subject continues to achieve clinical benefit by 
continuing treatment, the subject should remain on the trial and continue to receive monitoring. 
For the subjects who continue nivolumab study therapy beyond progression, further progression 
is defined as an additional 10% increase in tumor burden according to RECIST v1.1 from time of 
initial PD. This includes an increase in the sum of all target lesions and/ or the development of 
new measurable lesions. Treatment should be discontinued permanently upon documentation of 
further disease 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).
Subjects with global deterioration of health status who require discontinuation of treatment without 
objective evidence of disease progression at the time of treatment discontinuation should be 
reported as ‘symptomatic deterioration’. Every effort should be made to document objective 
progression (ie,radiographic confirmation) even after discontinuation of treatment. 
 
 
 
 
 
 
 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
77


Clinical Protocol
CA209370
BMS-936558
nivolumab
 
 
 
 
4.7
Management for Erlotinib related adverse events 
No specific algorithm exists to manage toxicities related to erlotinib. Recommendations provided 
in local label recommendations should be followed by the investigator. Additionally, a recently 
published review article on the management of common toxicities in metastatic NSCLCrelated to 
anti-lung cancer therapies with EGFR–TKIs
92can be consulted and is included in Appendix 1.
4.8
Management of standard of care agents(chemotherapy or 
bevacizumab) related adverse events 
No specific algorithm exists to manage toxicities related to SOC agents. Recommendations 
provided in local label recommendations should be followed by the investigator.
4.9
Blinding/Unblinding
This is an open-label study. Blinding is not applicable. However, to reduce bias, the study team 
from the Sponsor and the CRO/vendors who are involved in the trial conduct will be blinded for 
the aggregated data at the treatment level until the trial database lock.
The Data Monitoring Committee (DMC) will be provided with unblinded data in order to ensure 
the ongoing safety and efficacy of the trial. Data unblinding as required for the DMC review will 
be conducted on an ongoing basis by a data manager/statistician or CRO not involved in the trial 
conduct in order to keep the trial team blinded.
4.10
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.11
Destruction of Study Drug
For this study, 
study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers,vials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible Study Monitor unless study drug containers must be immediately destroyed as required 
for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
On-site disposal practices must not expose humans to risks from the drug.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
78


Clinical Protocol
CA209370
BMS-936558
nivolumab
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met, the responsible Study Monitor will arrange for return 
of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provi
ded that appropriate records of disposal are 
kept.
4.12
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. 
The return of study 
drug will be arranged by the responsible Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provi
ded that appropriate records of disposal are 
kept. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
79


Clinical Protocol
CA209370
BMS-936558
nivolumab
5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Assessments and Procedures (28 days) -All Subjects
* Note: as per Amendments 03 and 04, Groups A, B, C, and D have closed enrollment and Group E was permanently terminated.
Procedure
Screening
Notes
ELIGIBILITY ASSESSMENTS
Informed Consent
X
Inclusion/Exclusion Criteria
X
Assessed prior to randomization
Medical History
X
SAFETY ASSESSMENTS
Physical Measurements (including weight andheight)
X
Within 28 days prior to first dose
Physical Examination
X
Within 28 days prior to first dose
ECOG Performance Status
X
Within 28 days prior to first dose
Vital Signs and Oxygen Saturation
X
Temperature, BP, HR, RR, O2saturation by pulse oximetry (also 
monitor amount of supplemental oxygen if applicable)
Obtainvital signs at screening visit and within 72 hours of first 
dose.  For oxygen saturation, please see Section 5.3 for details.
SAE Assessment
X
Following the subject’s written consent to participate in the study, 
all SAEs, whether related or not related to study drug, must be 
collected, including those thought to be associated with protocol-
specified procedures.
Assessment of Signs and Symptoms 
X
After obtaining Informed Consent, assess all signs and symptoms 
within 14 days of study randomization, priorto study treatment 
initiation.
Pregnancy Testing (WOCBP Only)
X
Serum or urine pregnancy test to be performed locally within 24 
hoursprior to first dose
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
80


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-1:
Screening Assessments and Procedures (28 days) -All Subjects
* Note: as per Amendments 03 and 04, Groups A, B, C, and D have closed enrollment and Group E was permanently terminated.
Procedure
Screening
Notes
Hematology Test, Chemistry Test, and Liver Function 
Test
X
Labs performed locally within 14 days prior to first dose: 
Hematology Test includesWBC count with 3-part differential, 
ANC, lymphocyte count, hemoglobin, hematocrit, and platelet 
count. 
ChemistryTest include BUN or serum urea level, serum creatinine, 
sodium, potassium, calcium, magnesium, phosphate, chloride, and 
bicarbonate, glucose, LDH.
Liver Function Test includes aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), total bilirubin, alkaline 
phosphatase and albumin.
Thyroid Function Testing
X
Includes TSH, free T3 and free T4. Performed locally within 14 
days prior to first dose.
Hepatitis B & C Testing
(HBV sAg and HCV Ab or HCVRNA)
X
Includes HBV sAg and HCV Ab or HCVRNA. Performed locally 
within 28 days prior to first dose.
ECG (12-lead)
X
ECG will be performed and assessed locally.
EFFICACY ASSESSMENTS
Radiographic Tumor Assessment (chest, abdomen, pelvis, 
brain) 
X
Performed within 21 days prior to first dose. CT of chest, 
abdomen, pelvis,and additional sites of known or suspected 
disease. MRI of brain or CT with contrast for subjects with known 
brain metastasis or if clinically indicated.  See Section 5.4for 
details. 
Subjects with evidence of disease progression after completion of 
induction therapy (Groups A and B) are not eligible to enroll. 
Assignment and Distribution of ActiGraph Monitoring 
Device to Group C patients
X
All subjects eligible for Group C will be provided with an 
ActiGraph device at screening tobe used continuously for at least 7 
days prior to the first dose. Subjects who become screen failures 
will return their device.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
81


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-1:
Screening Assessments and Procedures (28 days) -All Subjects
* Note: as per Amendments 03 and 04, Groups A, B, C, and D have closed enrollment and Group E was permanently terminated.
Procedure
Screening
Notes
 
 
 
 
 
 
 
IWRS / CLINICAL DRUG SUPPLIES
IWRS
X 
For subject number assignment at the time informed consent is 
obtained.
ALK=anaplastic lymphoma kinase; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor receptor; 
FPFPE=formalin-fixed paraffin-embedded; IWRS=interactive webresponse service; NSQ=non-squamous. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
82


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-2:
Group A-On-Study Assessments -Treatment Phase 
Note:  Subjects start Cycle 1 once randomized to a maintenance therapy arm. Investigator’s choice chemotherapy is not on-study.
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1 
(Cycle 2 onwards)
End of 
Treatmenta
Notes
SAFETY ASSESSMENTS
Physical Measurements 
(including weight)
X
X
X
Targeted physical examination
X
X
X
ECOG Performance Status
X
X
X
ECOG within 72 hours prior to each dose
Vital Signs and Oxygen Saturation
X
X
X
Within 72 hours prior to dosing and at EOT. Include 
temperature, blood pressure, heart rate, respiratory 
rate. For oxygen saturation, please see Section 5.3 for 
details.
Adverse Events Assessment
Continuously during study
Monitoring for AEs in pemetrexed or bevacizumab 
receiving subjects should follow recommendations 
specified in the respective package inserts.
 
Hematology Tests
X
X
Includes WBC count with 3-part differential, ANC, 
lymphocyte count, hemoglobin, hematocrit, and 
platelet count
Chemistry Tests
X
X
Chemistry (BUN or serum urea level, serum 
creatinine, sodium, potassium, calcium, magnesium, 
phosphate, chloride, and bicarbonate, glucose), LDH
Liver Function Test
X
X
Includes aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, alkaline 
phosphatase, albumin
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
83


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-2:
Group A-On-Study Assessments -Treatment Phase 
Note:  Subjects start Cycle 1 once randomized to a maintenance therapy arm. Investigator’s choice chemotherapy is not on-study.
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1 
(Cycle 2 onwards)
End of 
Treatmenta
Notes
Thyroid Function Testing
X
TSH should be evaluated every 6 weeks and EOT. 
However,reflexive free T3 and free T4 should be 
performed if TSH is abnormal.
Pregnancy Testing (WOCBP 
Only)
X
Every 3 weeks 
Every 4 weeks 
for nivolumab 
monotherapy 
arms
X
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 24hours prior to first dose, and then a 
negative test every 3weeks (every 4 week for the 
nivolumab monotherapy arms).
EFFICACY ASSESSMENTS
Radiographic Tumor Assessment 
(chest, abdomen, and known sites 
of disease)
Beginning at week 9(± 1 week), then every 8 weeks (± 1 
week) forup to2 years.
CT/MRI of brain (with contrast, unless 
contraindicated) required every 12 weeks for subjects 
who have known history of brain metastases or if 
clinically indicated.
OUTCOMES RESEARCH ASSESSMENTS
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
84


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-2:
Group A-On-Study Assessments -Treatment Phase 
Note:  Subjects start Cycle 1 once randomized to a maintenance therapy arm. Investigator’s choice chemotherapy is not on-study.
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1 
(Cycle 2 onwards)
End of 
Treatment
a
Notes
Patient Outcomes Assessment 
(PRO) (FACT-L and EQ-5D)
X
From 0-3 
months: every 2 
weeks for 
nivolumab-
monotherapy 
subjects and; 
every 3 weeks 
for all other 
arms.
Between Months 
4 and 12:every 6 
weeks for both 
treatment arms 
After 12 months: 
every 12 weeks 
for both arms.
X
Obtained at the site prior to any study procedures or 
dosing.
Health Care Resource Utilization
Every 6 weeks 
for the first year
Every 12 weeks 
thereafter 
X
First assessment at Week 6. 
CLINICAL DRUG SUPPLIES AND STUDY DRUG ADMINISTRATION
IWRS 
X
X
X
Patients’ screening, all drug assignment, and EOT 
visits will be collected in the IWRS system  
IWRS Vial Assignment
X
X
Within 1 week prior to first dose on study.
Note: The first dose on treatment must be within 
42 days of last induction chemotherapy 
treatment. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
85


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-2:
Group A-On-Study Assessments -Treatment Phase 
Note:  Subjects start Cycle 1 once randomized to a maintenance therapy arm. Investigator’s choice chemotherapy is not on-study.
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1 
(Cycle 2 onwards)
End of 
Treatmenta
Notes
Nivolumab 240mg every2 weeks
OR
Nivolumab 5 mg/kg every 3 
weeks with Bevacizumab or 
Pemetrexed
X
X
Nivolumab administration is ± 3 days but no less than 
18 days from previous dose (no less than 12 days 
from previous dose in nivolumab monotherapy arms). 
Study drug infusion start and stop times (± 5mins) 
will be recorded.Nivolumab is to be administered 
first, bevacizumab or pemetrexed start at least 30 
minutes after completion of the nivolumab infusion.
Treatment to continue until progression, withdrawal 
of consent, unacceptable toxicity,  a maximum of 24 
monthsor study closure, whichever occurs first
Termination of study medication
X
aIf the decision to permanently discontinue the study treatments is taken during a scheduled visit, the End Of Treatment (EOT)visit should be performed instead 
of the scheduled visit ( or within 7 calendar days afterlast drug administration)
AEs=adverse events; ECOG=Eastern Cooperative Oncology Group; EQ-5D=EuroQol Five Dimension; EOT=end of treatment; FACT-L=Functional Assessment 
of Cancer Therapy-Lung Cancer Subscale; IWRS=interactive webresponse system; PRO=patient-reported outcomes; WOCBP=women of child-bearing potential. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
86


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-3:
Group A-Follow-Up Procedural Outline
Procedure
Follow-Up 
Visits 1 & 2a
Survival Visitsb
Notes
SAFETY ASSESSMENTS
Targeted Physical Examination
X
To assess for potential lateemergent study drug-related issues.
Vital Signs
X
Adverse Event Assessment
X
At least 100 days from the last dose of therapy, subjects will be 
followed for ongoing drug-related AEs until resolved, return to 
baseline or deemed irreversible, or until lost to follow-up, 
withdrawal of study consent, or start of subsequent therapy.
Chemistry Test
X
Required at Visit 1. Repeat at Visit 2 only if study drug-related 
toxicity persists. 
Hematology Test
X
Required at Visit 1. Repeat at Visit 2 only if study drug-related 
toxicity persists. 
EFFICACY ASSESSMENTS
Radiographic Tumor Assessment (chest, 
abdomen,and known sites of disease)
X
X
Only for subjects not assessed to have progression by the 
radiology review prior to entering Post-treatment Phase. 
Every 8 weeks (± 1 week) forup to2 years.
OUTCOMES RESEARCH ASSESSMENTS
Patient Outcomes Assessment (PRO): 
FACT-L, EQ-5D
X
EQ-5D only
PRO to be collected at both Follow-up Visits 1 and 2.
In Survival Visits, EQ-5D is collected every 3months (± 1 
week)for the first year of the Follow-Up Phase, then every 
6months(± 2 weeks)thereafter. 
PRO can be collected by mail/phonefor long-term 
assessments occurring after Follow-up Visit 2. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
87


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-3:
Group A-Follow-Up Procedural Outline
Procedure
Follow-Up 
Visits 1 & 2a
Survival Visitsb
Notes
Health Care Resource Utilization
X
Assessments to be taken at the both follow up visits following 
discontinuation
Collection of Survival Status 
X
X
Collect every 3 months(±1 week)in Survival Visits until 
death, lost to follow-up, withdrawal of study consent, or for 
4years after the start of study treatment. 
May be performed by phone contact or office visit 
Will include collection of subsequent anti-cancer therapy 
information
a Follow-Up Visit 1 is to occur 35 days from the last dose of study treatment (±7 days). Follow-Up Visit 2 to occur 80 days from Follow-Up Visit 1 (± 7 days).
b Survival Follow-Up Visits to occur approximately every 3 months(± 1 week)from Follow-Up Visit 2.
AEs=adverse events; ECOG=Eastern Cooperative Oncology Group; EQ-5D=EuroQol Five Dimension; EOT=end of treatment; FACT-L=Functional Assessment 
of Cancer Therapy-Lung Cancer Subscale; IWRS=interactive webresponse system; PRO=patient-reported outcomes; WOCBP=women of child-bearing potential. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
88


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-4:
Group B-On-Study Assessments -Treatment Phase ( 1 cycle =2 weeks, Arm A: nivolumab 240 mg 
every 2weeks; Arm B: Best Supportive Careevery 2 weeks)
Note:  Subjects start Cycle 1 once randomized to a maintenance therapy arm. Investigator’s Choice chemotherapy is not on-study.
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle  Day1 
(Cycle 2 onwards)
End of Treatmenta
Notes
SAFETY ASSESSMENTS
Physical Measurements 
(including weight)
X
X
X
Targeted physical 
examination
X
X
X
ECOG Performance Status
X
X
X
ECOG within 72 hours prior to each dose
Vital Signs and Oxygen 
Saturation
X
X
X
Within 72 hours prior to dosing and at EOT. Include 
temperature, blood pressure, heart rate, respiratory rate. 
For oxygen saturation, please see Section 5.3 for 
details.
Adverse Events Assessment
Continuously during study
Hematology Tests
X
X
Includes WBC count with 3-part differential, ANC, 
lymphocyte count, hemoglobin, hematocrit, and 
platelet count
Chemistry Tests
X
X
Chemistry (BUN or serum urea level, serum creatinine, 
sodium, potassium, calcium, magnesium, phosphate, 
chloride, and bicarbonate, glucose), LDH
Liver Function Test
X
X
Includes aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, alkaline 
phosphatase, albumin
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
89


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-4:
Group B-On-Study Assessments -Treatment Phase ( 1 cycle =2 weeks, Arm A: nivolumab 240 mg 
every 2weeks; Arm B: Best Supportive Careevery 2 weeks)
Note:  Subjects start Cycle 1 once randomized to a maintenance therapy arm. Investigator’s Choice chemotherapy is not on-study.
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle  Day1 
(Cycle 2 onwards)
End of Treatmenta
Notes
Thyroid Function Testing
X
TSH should be evaluated every 6 weeks and EOT. 
However,reflexive free T3 and free T4 should be 
performed if TSH is abnormal.
Pregnancy Testing (WOCBP 
Only)
X
Arm A
X
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 
24hours prior to the start of study drug, and at least 
every 4 weeks on study, and every cycle for Arm A. 
EFFICACY ASSESSMENTS
Radiographic Tumor 
Assessment (chest, abdomen, 
and known sites of disease)
Beginning Week 9(±1 week), then every 8 weeks (±1 week)for 
up to 2 years.
CT/MRI of brain (with contrast, unless 
contraindicated) required every 12 weeks for subjects 
who have known history of brain metastases or if 
clinically indicated.
OUTCOMES RESEARCH ASSESSMENTS
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
90


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-4:
Group B-On-Study Assessments -Treatment Phase ( 1 cycle =2 weeks, Arm A: nivolumab 240 mg 
every 2weeks; Arm B: Best Supportive Careevery 2 weeks)
Note:  Subjects start Cycle 1 once randomized to a maintenance therapy arm. Investigator’s Choice chemotherapy is not on-study.
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle  Day1 
(Cycle 2 onwards)
End of Treatmenta
Notes
Patient Outcomes 
Assessment (PRO) (FACT-L 
and EQ-5D)
X
From 0-3 
months: every 
2 weeks 
Between 
Months 4 and 
12: Every 6 
weeks 
After 12 
months:: every 
12 weeks.
X
Obtained at the site prior to any study procedures or 
dosing. 
CLINICAL DRUG SUPPLIES AND STUDY DRUG ADMINISTRATION
IWRS 
X
X
X
Patients screening, all drug assignment, and EOTvisits 
will be collected in the IWRS system  
IWRS Vial Assignment
X
X
Within 1 week prior to first dose on study. 
Note: The first dose on treatment must be within 42 
days of last induction chemotherapy treatment.
Nivolumab 240mg every 
2weeks
X
X
Nivolumab administration is ± 3 days but no less than 
12 days from previous dose. Study drug infusion start 
and stop times (± 5mins) will be recorded.
Treatment to continue until progression, withdrawal of 
consent, unacceptable toxicity, a maximum of 24 
months or study closure,whichever occurs first.
Termination of study 
medication
X
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
91


Clinical Protocol
CA209370
BMS-936558
nivolumab
a If the decision to permanently discontinue the study treatments is taken during a scheduled visit, the End Of Treatment (EOT) visit should be performed instead 
of the scheduled visit (within 7 calendar days after last drug administration)
AEs=adverse events; ECOG=Eastern Cooperative Oncology Group; EQ-5D=EuroQol Five Dimension; EOT=end of treatment; FACT-L=Functional Assessment 
of Cancer Therapy-Lung Cancer Subscale; IWRS=interactive webresponse system; PRO=patient-reported outcomes; WOCBP=women of child-bearing potential.  
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
92


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-5:
Group B-Follow-Up Procedural Outline
Procedure
Visits 1 & 2a
Survival Visitsb
Notes
SAFETY ASSESSMENTS
Targeted Physical Examination
X
To assess for potential late emergent study drug-related issues.
Vital Signs
X
Adverse Event Assessment
X
At least 100 days from the last dose of therapy, subjects will be 
followed for ongoing drug-related AEs until resolved, return to 
baseline or deemed irreversible, or until lost to follow-up, 
withdrawal of study consent, or start of subsequent therapy.
Chemistry Test
X
Required at Visit 1. Repeat at Visit 2 only if study drug-related 
toxicity persists. 
Hematology Test
X
Required at Visit 1. Repeat at Visit 2 only if study drug-related 
toxicity persists. 
 
 
 
 
EFFICACY ASSESSMENTS
Radiographic Tumor Assessment (chest, 
abdomen,and known sites of disease)
X
X
Only for subjects not assessed to have progression by the 
radiology review prior to entering Post-treatment Phase. 
Every 8 weeks (± 1 week) for up to 2 years.
OUTCOMES RESEARCH ASSESSMENTS
Patient Outcomes Assessment (PRO): 
FACT-L and EQ-5D
X
EQ-5D only
PRO to be collected at both Follow-up Visits 1 and 2.
In Survival Visits, EQ-5D is collected every 3months (± 1 
week)for the first year of the Follow-Up Phase, then every 
6months(± 2 weeks) thereafter. 
PRO can be collected by mail/phonefor long-term 
assessments occurring after Follow-up Visit 2. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
93


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-5:
Group B-Follow-Up Procedural Outline
Procedure
Visits 1 & 2a
Survival Visitsb
Notes
Collection of Survival Status
X
X
Collect every 3 months(± 1 week)in Survival Visits until 
death, lost to follow-up, withdrawal of study consent, or for 
4years afterthe start of the study treatment 
May be performed by phone contact or office visit. 
Will include collection of subsequent anti-cancer therapy 
information
a For Arm A, Follow-Up Visit 1 is to occur 35 days from the last dose of study treatment (± 7 days). Follow-Up Visit 2 to occur 80 days from Follow-Up Visit 1 
(± 7 days). For Arm B, Follow-up Visit 1 to occur 35 days from the lastclinic visit date(±7 days). 
b Survival Follow-Up Visits to occur approximately every 3 months(± 1 week)from Follow-Up Visit 2. 
AEs=adverse events; EQ-5D=EuroQol Five Dimension; EOT=end of treatment; FACT-L=Functional Assessment of Cancer Therapy-Lung Cancer Subscale; 
IWRS=interactive webresponse system; PRO=patient-reported outcomes; WOCBP=women of child-bearing potential. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
94


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-6:
Group C-On-Study Assessments -Treatment Phase Arm A (Investigator’s Choice cycle = every 3 
weeksa), Arm B (nivolumab cycle=2 weeks, nivolumab 240 mg every 2 weeks)
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1 
(Cycle 2 
onwards)
End of 
Treatmentb
Notes
SAFETY ASSESSMENTS
Physical Measurements 
(including weight)
X
X
X
Targeted physical 
examination
X
X
X
ECOG Performance Status
X
X
X
ECOG within 72 hours prior to each dose
Vital Signs and Oxygen 
Saturation
X
X
X
Within 72 hours prior to dosing and at EOT. Include 
temperature, blood pressure, heart rate, respiratory rate. For 
oxygen saturation, please see Section 5.3 for details.
Adverse Events Assessment
Continuously during study
Monitoring for adverse events related to chemotherapy drugs 
should follow recommendations specified in the local labels.
 
Hematology Tests
X
X
Includes WBC count with 3-part differential, ANC, 
lymphocyte count, hemoglobin, hematocrit, and platelet 
count
Chemistry Tests
X
X
Chemistry (BUN or serum urea level, serum creatinine, 
sodium, potassium, calcium, magnesium, phosphate, 
chloride, and bicarbonate, glucose), LDH
Liver Function Test
X
X
Includes aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, alkaline 
phosphatase, albumin
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
95


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-6:
Group C-On-Study Assessments -Treatment Phase Arm A (Investigator’s Choice cycle = every 3 
weeksa), Arm B (nivolumab cycle=2 weeks, nivolumab 240 mg every 2 weeks)
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1 
(Cycle 2 
onwards)
End of 
Treatmentb
Notes
Thyroid Function Testing
X
TSH should be evaluated every 6 weeks and EOT. However,
reflexive free T3 and free T4 should be performed if TSH is 
abnormal.
Pregnancy Testing (WOCBP 
Only)
X
X
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 24hours prior to 
the start of study drug, and at least every 4 weeks on study.
EFFICACY ASSESSMENTS
Radiographic Tumor 
Assessment (chest, abdomen, 
and known sites of disease)
Beginning Week 9(±1 week) then every 8weeks (± 1 week) 
for up to 2 years.
CT/MRI of brain (with contrast, unless contraindicated) 
required every 12 wks for subjects who have known history 
of brain metastases or if clinically indicated.
  
 
OUTCOMES RESEARCH ASSESSMENTS
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
96


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-6:
Group C-On-Study Assessments -Treatment Phase Arm A (Investigator’s Choice cycle = every 3 
weeksa), Arm B (nivolumab cycle=2 weeks, nivolumab 240 mg every 2 weeks)
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1 
(Cycle 2 
onwards)
End of 
Treatmentb
Notes
Patient Outcomes 
Assessment (PRO) : FACT-L 
and EQ-5D
X
From 0 to 3 
months: every 
2 weeks for 
nivolumab-
monotherapy  
subjects and; 
those 
receiving IC 
every 2 
weeks; every 
3 weeks for 
subjects 
receiving IC 
therapy every 
1 or 3 weeks.
Between 
Months 4 and 
12: Every 6 
weeks for all 
treatment 
arms 
After 12 
months: every 
12 weeks for 
all treatment 
arms.
X
Obtained at the site prior to anystudy procedures or dosing.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
97


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-6:
Group C-On-Study Assessments -Treatment Phase Arm A (Investigator’s Choice cycle = every 3 
weeksa), Arm B (nivolumab cycle=2 weeks, nivolumab 240 mg every 2 weeks)
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1 
(Cycle 2 
onwards)
End of 
Treatmentb
Notes
ActiGraph
Continuous 24 hour monitoring will 
begin from screening at least 1 
week prior to initiation of therapy, 
and continue to 6 months of 
treatment
At end of 
treatment or 
discontinuation, 
subjects will 
undergo 24 hour 
monitoring for 7 
days. 
ActiGraph device will be removed for MRIsor 
charging. 
The ActiGraph device will be provided at enrollment
Health Care Resource 
Utilization
Every 6 
weeks for the 
first year
Every 12 
weeks 
thereafter
X
First assessment at Week 6. 
CLINICAL DRUG SUPPLIES AND STUDY DRUG ADMINISTRATION
IWRS 
X
X
X
Patients’ screening, all drug assignment, and EOT visits will 
be collected in the IWRS system  
IWRS Vial Assignment
X
X
Within 1 week prior to dosing.
Nivolumab 240mg every 
2weeks
OR
Investigator’s Choice 
Chemotherapy
X
X
Nivolumab administration is ± 3 days but no less than 12 
days from previous dose. Study drug infusion start and stop 
times (± 5mins) will be recorded. 
Nivolumab will continue until progression, withdrawal of 
consent, unacceptable toxicity, a maximum of 24monthsor 
study closure, whichever occurs first
Termination of study 
medication
X
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
98


Clinical Protocol
CA209370
BMS-936558
nivolumab
a Investigators have option of following up subject every 1-3 weeks on chemo therapy, using local institutional standard for supportive management including 
growth factor support.
b If the decision to permanently discontinue the study treatments is taken during a scheduled visit, the End Of Treatment (EOT)visit should be performed instead 
of the scheduled visit (within 7 calendar days after last drug administration)
ECOG=Eastern Cooperative Oncology Group; EQ-5D=EuroQol Five Dimension; EOT=end of treatment; FACT-L=Functional Assessment of Cancer Therapy-
Lung Cancer Subscale; IC=Investigator’s Choice; IWRS=interactive webresponse system; PRO=patient-reported outcomes; WOCBP=women of child-bearing 
potential. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
99


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-7:
Group C-Follow-Up Procedural Outline
Procedure
Visits 1 & 2a
Survival Visitsb
Notes
SAFETY ASSESSMENTS
Targeted Physical Examination
X
To assess for potential late emergent study drug-related issues.
Vital Signs
X
Adverse Event Assessment
X
At least 100 days from the last dose of therapy, subjects will be 
followed for ongoing drug-related AEs until resolved, return to baseline 
or deemed irreversible, or until lost to follow-up, withdrawal of study 
consent, or start of subsequent therapy.
Chemistry Test
X
Required at Visit 1. Repeat at Visit 2 only if study drug-related toxicity 
persists. 
Hematology Test
X
Required at Visit 1. Repeat at Visit 2 only if study drug-related toxicity 
persists. 
 
 
 
EFFICACY ASSESSMENTS
Radiographic Tumor Assessment (chest, 
abdomen,and known sites of disease)
X
X
Only for subjects not assessed to have progression by the radiology 
review prior to entering Post-treatment Phase. 
Every 8 weeks (± 1 week) for up to 2 years.
OUTCOMES RESEARCH ASSESSMENT 
Patient Outcomes Assessment (PRO): 
FACT-L and EQ-5D
X
EQ-5D only
PRO to be collected at both Follow-up Visits 1 and 2.
In Survival Visits, EQ-5D is collected every 3months(± 1 week)
for the first year of the Follow-Up Phase, then every 6months(± 2 
weeks) thereafter. 
PRO can be collected by mail/phonefor long-term assessments 
occurring after Follow-up Visit 2. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
100


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-7:
Group C-Follow-Up Procedural Outline
Procedure
Visits 1 & 2a
Survival Visitsb
Notes
ActiGraph
X
At Follow-up Visit 1, subjects will undergo 7 days of continuous 24-
hour monitoring. The device will be removed for MRIs, and charging.
Return of ActiGraphDevice
X
The ActiGraph device will be returned at Follow-up Visit2.
Health Care Resource Utilization
X
Assessments to be taken at the both follow up visits following 
discontinuation
Collection of Survival Status 
X
X
Collect every 3 months(± 1 week)in Survival Visits until death, 
lost to follow-up, withdrawal of study consent, or for 4years after 
the start of study treatment. May be performed by phone contact or 
office visit.
Will include collection of subsequent anti-cancer therapy 
information
a Follow-Up Visit 1 is to occur 35 days from the last dose of study treatment (±7 days). Follow-Up Visit 2 to occur 80 days from Follow-Up Visit 1 (± 7 days). 
b Survival Follow-Up Visits to occur approximately every 3 months(± 1 week)from Follow-Up Visit 2.
ECOG=Eastern Cooperative Oncology Group; EQ-5D=EuroQol Five Dimension; FACT-L=Functional Assessment of Cancer Therapy-Lung Cancer Subscale; 
IWRS=interactive webresponse system; PRO=patient-reported outcomes; WOCBP=women of child-bearing potential. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
101


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-8:
Group D: On-Study Assessments -Treatment Phase (1 cycle = 2 weeks, Arm A: erlotinib; Arm B: 
nivolumab 240 mg every 2 weeks)
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1
(Cycle 2 onwards)
End of 
Treatmenta
Notes
SAFETY ASSESSMENTS
Physical Measurements 
(including weight)
X
X
X
Targeted physical 
examination
X
X
X
ECOG Performance Status
X
X
X
ECOG within 72 hours prior to each dose
Vital Signs and Oxygen 
Saturation
X
X
X
Within 72 hours prior to dosing and at EOT. Include 
temperature, blood pressure, heart rate, respiratory rate. For 
oxygen saturation, please see Section 5.3 for details.
Adverse Events Assessment
Continuously during study
Monitoring for AEs related to erlotinib should follow 
recommendations specified in the local labels.
 
Hematology Tests
X
X
Includes WBC count with 3-part differential, ANC, 
lymphocyte count, hemoglobin, hematocrit, and platelet 
count.  Except for Cycle 1 Day 1, the local lab tests should 
be repeated within 3 days prior to each dose.
Chemistry Tests
X
X
Chemistry (BUN or serum urea level, serum creatinine, 
sodium, potassium, calcium, magnesium, phosphate, 
chloride, and bicarbonate, glucose), LDH.  Except for Cycle 
1 Day 1, the local lab tests should be repeated within 3 days 
prior to each dose.
Liver Function Test
X
X
Includes aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, alkaline phosphatase
andalbumin.  Except for Cycle 1 Day 1, the local lab tests 
should be repeated within 3 days prior to each dose.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
102


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-8:
Group D: On-Study Assessments -Treatment Phase (1 cycle = 2 weeks, Arm A: erlotinib; Arm B: 
nivolumab 240 mg every 2 weeks)
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1
(Cycle 2 onwards)
End of 
Treatmenta
Notes
Thyroid Function Testing
X
TSH should be evaluated every 6 weeks and EOT. However,
reflexive free T3 and free T4 should be performed if TSH is 
abnormal.
Pregnancy Testing (WOCBP 
Only)
X
X
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 24hours prior to 
the start of study drug, and at least every 4 weeks on study.
EFFICACY ASSESSMENTS
Radiographic Tumor 
Assessment (chest, abdomen, 
and known sites of disease)
Beginning Week 9(±1 week), then every 8 weeks (± 1 week) 
forup to 2 years.
CT/MRI of brain (with contrast, unless contraindicated) 
required every 12 weeks for subjects who have known 
history of brain metastases or if clinically indicated.
 
 
 
OUTCOMES RESEARCH ASSESSMENTS
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
103


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-8:
Group D: On-Study Assessments -Treatment Phase (1 cycle = 2 weeks, Arm A: erlotinib; Arm B: 
nivolumab 240 mg every 2 weeks)
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1
(Cycle 2 onwards)
End of 
Treatmenta
Notes
Patient Outcomes 
Assessment (PRO): FACT-L 
and EQ-5D
X

From 0-3 
months: every 2 
weeks 

Between 
Months 4 and 
12: Every 6 
weeks 

After 12 
months:: every 
12 weeks
X
Obtained at the site prior to any study procedures or dosing. 
Health Care Resource 
Utilization
Every 6 
weeks for the 
first year
Every 12 
weeks 
thereafter 
X
First assessment at Week 6. 
CLINICAL DRUG SUPPLIES AND STUDY ADMINISTRATION
IWRS 
X
X
X
Patients’ screening, all drug assignment, and EOT visits will 
be collected in the IWRS system 
IWRS Vial Assignment
X
X
Within 1 week prior to dosing.
Nivolumab 240 mg every 2 
weeks
OR
Erlotinib 150 mg QD
X
X
Erlotinibdosing is daily throughout each cycle.
Nivolumab administration is ±3 days but no less than 12 
days from previous dose. Study drug infusion start and stop 
times (± 5mins) will be recorded. 
Nivolumab willcontinue until progression, withdrawal of 
consent,unacceptable toxicity, a maximum of 24 months, or 
study closure, whichever occurs first.
Termination of study 
medication
X
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
104


Clinical Protocol
CA209370
BMS-936558
nivolumab
a If the decision to permanently discontinue the study treatments is taken during a scheduled visit, the End Of Treatment (EOT) visit should be performed instead 
of the scheduled visit (within 7 calendar days after last drug administration).
ECOG=Eastern Cooperative Oncology Group; EQ-5D=EuroQol Five Dimension; FACT-L=Functional Assessment of Cancer Therapy-Lung Cancer Subscale; 
IWRS=interactive webresponse system; PRO=patient-reported outcomes; WOCBP=women of child-bearing potential. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
105


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-9:
Group D-  Follow-Up Procedural Outline
Procedure
Visits 1 & 2a
Survival Visitsb
Notes
SAFETY ASSESSMENTS
Targeted Physical Examination
X
To assess for potential late emergent study drug-related issues.
Vital Signs
X
Adverse Event Assessment
X
At least 100 days from the last dose of therapy, subjects will be followed for 
ongoing drug-related AEs until resolved, return to baseline or deemed 
irreversible, or until lost to follow-up, withdrawal of study consent, or start of 
subsequent therapy.
Chemistry Test
X
Required at Visit 1. Repeat at Visit 2 only if study drug-related toxicity persists. 
Hematology Test
X
Required at Visit 1. Repeat at Visit 2 only if study drug-related toxicity persists. 
 
 
 
 
EFFICACY ASSESSMENTS
Radiographic Tumor Assessment 
(chest, abdomen, and known sites of 
disease)
X
X
Only for subjects not assessed to have progression by the radiology review 
prior to entering Post-treatment Phase. 
Every 8 weeks (± 1 week)for up to 2 years.
OUTCOMES RESEARCH ASSESSMENTS
Patient Outcomes Assessment (PRO): 
FACT-L and EQ-5D
X
EQ-5D only
PRO to be collected at both Follow up Visits 1 and 2.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
106


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-9:
Group D-  Follow-Up Procedural Outline
Procedure
Visits 1 & 2a
Survival Visitsb
Notes
In Survival Visits, EQ-5D is collected every 3months (± 1 week)for the 
first year of the Follow-Up Phase, then every 6months(± 2 weeks)
thereafter. 
PRO can be collected by mail for long-term assessments occurring after 
Follow-up Visit 2. 
Health Care Resource Utilization
X
Assessments to be taken at the both follow up visits following discontinuation
Collection of Survival Status
X
X
Collect every 3 months (± 1 week)in Survival Visits until death, lost to 
follow-up, withdrawal of study consent, or for 4years after the start of 
study treatment. 
May be performed by phone contact or office visit.
Will include collection of subsequent anti-cancer therapy information
a Follow-Up Visit 1 is to occur 35 days from the last dose of study treatment (± 7 days). Follow-Up Visit 2 to occur 80 days from Follow-Up Visit 1 (± 7 days).
b Survival Follow-Up Visits tooccur approximately every 3 months (± 1 week)from Follow-Up Visit 2.
ECOG=Eastern Cooperative Oncology Group; EQ-5D=EuroQol Five Dimension; FACT-L=Functional Assessment of Cancer Therapy-Lung Cancer Subscale; 
IWRS=interactive webresponse system; PRO=patient-reported outcomes; WOCBP=women of child-bearing potential. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
107


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-10:
Group E-On-Study Assessments -Treatment Phase (1 cycle =2 weeks, nivolumab 240 mg every 
2weeks)
*NOTE: Prior to Amendment 03, all subjects in Group E have enteredthe Follow-up phase. No additional combination treatment is to be given.
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1: 
(Cycle 2 onwards)
End of Treatment
Notes
SAFETY ASSESSMENTS
Physical Measurements 
(including weight)
X
X
X
Targeted physical 
examination
X
X
X
ECOG Performance Status
X
X
X
ECOG within 72 hours prior to each dose
Vital Signs and Oxygen 
Saturation
X
X
X
Within 72 hours prior to dosing and at EOT. Include 
temperature, blood pressure, heart rate, respiratory rate. 
For oxygen saturation, please see Section 5.3 for details.
Adverse Events Assessment
Continuously during study
Monitoring for adverse events related to Crizotinib should 
follow recommendations specified in the local labels.
 
Hematology Tests
X
X
Includes WBC count with 3-part differential, ANC, 
lymphocyte count, hemoglobin, hematocrit, and platelet 
count
Chemistry Tests
X
X
Chemistry (BUN or serum urea level, serum creatinine, 
sodium, potassium, calcium, magnesium, phosphate, 
chloride, and bicarbonate, glucose), LDH
Liver Function Test
X
X
Includes aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, alkaline 
phosphatase, albumin
Thyroid Function Testing
X
TSH should be evaluated every 6 weeks and EOT. 
However,reflexive free T3 and free T4 should be 
performed if TSH is abnormal.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
108


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-10:
Group E-On-Study Assessments -Treatment Phase (1 cycle =2 weeks, nivolumab 240 mg every 
2weeks)
*NOTE: Prior to Amendment 03, all subjects in Group E have enteredthe Follow-up phase. No additional combination treatment is to be given.
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1: 
(Cycle 2 onwards)
End of Treatment
Notes
ECG (12-lead)
X
X
Evaluated every 8 weeks until 1 year, then every 12 weeks 
thereafter, and EOT
Pregnancy Testing 
(WOCBP Only)
X
X
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 
24hours prior to the start of study drug, and at least every 
4 weeks on study.
EFFICACY ASSESSMENTS
Radiographic Tumor 
Assessment (chest, 
abdomen, and known sites 
of disease)
Beginning Week 9(±1 week), then every 8weeks (± 1 week) for 
up to 2 years.
CT/MRI of brain (with contrast, unless contraindicated) 
required every 12 weeks for subjects who have known 
history of brain metastases or if clinically indicated.
  
 
 
OUTCOMES RESEARCH ASSESSMENTS
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
109


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-10:
Group E-On-Study Assessments -Treatment Phase (1 cycle =2 weeks, nivolumab 240 mg every 
2weeks)
*NOTE: Prior to Amendment 03, all subjects in Group E have enteredthe Follow-up phase. No additional combination treatment is to be given.
Procedure
Cycle 1 Day 1
Each Subsequent 
Cycle Day1: 
(Cycle 2 onwards)
End of Treatment
Notes
Patient Outcomes 
Assessment (PRO): 
FACT-L and EQ-5D 
X
From 0-3 
months: every 
2 weeks 
Between 
Months 4 and 
12:  every 6 
weeks 
After 12 
months:: every 
12 weeks 
X
Obtained at the study site prior to any study procedures or 
dosing.
CLINICAL DRUG SUPPLIES AND STUDY DRUG ADMINISTRATION
IWRS
X
X
X
Patients’ screening, all drug assignment, and EOT visits 
will be collected in the IWRS system  
IWRS Vial Assignment
X
X
Within 1 week prior to first dose on study
Nivolumab  240mg every 
2weeks
OR
Crizotinib 250 mg BID
X
X
Crizotinib is given BID throughout cycle.
Drug administration is ± 3 days but no less than 12 days 
from previous dose. Study drug infusion start and stop 
times (± 5mins) will be recorded. 
Nivolumab is administered every 2 weeks over 30 minute 
infusion. 
Prior to Amendment 03, no additionalcombination 
treatment will be administered in Group E. All subjects 
previously enrolled in this Group will be monitored per 
the Follow up assessment schedule. 
Termination of study 
medication
X
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
110


Clinical Protocol
CA209370
BMS-936558
nivolumab
BID=twice a day; ECOG=Eastern Cooperative Oncology Group; EQ-5D=EuroQol Five Dimension; FACT-L=Functional Assessment of Cancer Therapy-Lung 
Cancer Subscale; IWRS=interactive webresponse system; PRO=patient-reported outcomes; WOCBP=women of child-bearing potential.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
111


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-11:
Group E-Follow-Up Procedural Outline
Procedure
Visits 1 & 2a
Survival Visitsb
Notes
SAFETY ASSESSMENTS
Targeted Physical Examination
X
To assess for potential late emergent study drug-related issues.
Vital Signs
X
Adverse Event Assessment
X
At least 100 days from the last dose of therapy, subjects will be 
followed for ongoing drug-related AEs until resolved, return to 
baseline or deemed irreversible, or until lost to follow-up, 
withdrawal of study consent, or start of subsequent therapy.
Chemistry Test
X
Required at Visit 1. Repeat at Visit 2 only if study drug-related 
toxicity persists. 
Hematology Test
X
Required at Visit 1. Repeat at Visit 2 only if study drug-related 
toxicity persists. 
Liver Function Testing
X
X
All subjects are to undergo twice weekly  liver functiontesting
through 60 days following thelast dose of nivolumab
Subjects with normal results for liver function are to undergo 
once weekly liver function testing from 61 days through 100 
days following the last dose of nivolumab 
Subjectswith an abnormal result for liver function within 100 
days of the last dose of nivolumab, are to undergo twice weekly 
liver functiontesting. 
Additional liver function monitoring  should be based on the 
clinical judgment of thetreating physician
ECG (12-lead)
X
Evaluated at Visit 1. Repeat at Visit 2 only if clinically indicated
 
 
 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
112


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 5.1-11:
Group E-Follow-Up Procedural Outline
Procedure
Visits 1 & 2a
Survival Visitsb
Notes
EFFICACY ASSESSMENTS
Radiographic Tumor Assessment (chest, 
abdomen, and known sites of disease)
X
X
Only for subjects not assessed to have progression by the 
radiology review prior to entering Post-treatment Phase. 
Every 8 weeks (±1week) forup to 2 years.
OUTCOMES RESEARCH ASSESSMENTS
Patient Outcomes Assessment (PRO): 
FACT-L and EQ-5D
X
EQ-5D only
PRO to be collected at both Follow-up Visits 1 and 2.
In Survival Visits, EQ-5D is collected every 3months(± 1 
week)for the first year of the Follow-Up Phase, then every 
6months (± 2 weeks)thereafter. 
PRO can be collected by mail/phone for long-term 
assessments occurring after Follow-up Visit 2. 
Collection of Survival Status and 
Subsequent Therapy Information
X
X
Collect every 3 months(± 1 week)in Survival Visits until 
death, lost to follow-up, withdrawal of study consent, or for 
4years after the start of study treatment. 
May be performed by phone contact or office visit.
Will include collection of subsequent anti-cancer therapy 
information
a Follow-Up Visit 1 is to occur 35 days from the last dose of study treatment (± 7 days). Follow-Up Visit 2 to occur 80 days from Follow-Up Visit 1 (± 7 days).
b Survival Follow-Up Visits to occur approximately every 3 months (± 1 week)from Follow-Up Visit 2.
AEs=adverse events; ECOG=Eastern Cooperative Oncology Group; EQ-5D=EuroQol Five Dimension; FACT-L=Functional Assessment of Cancer Therapy-Lung 
Cancer Subscale; IWRS=interactive webresponse system; PRO=patient-reported outcomes; WOCBP=women of child-bearing potential. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
113


Clinical Protocol
CA209370
BMS-936558
nivolumab
5.1.1
Retesting During Screening Period
Retesting of laboratory parameters and/or other assessments during the Screening Period will be 
permitted (in addition to anyparameters that require a confirmatory result).
Any new result will override the previous result (ie, the most current result prior to dosing) and is the 
value by which study inclusion will be assessed, as it represents the subject’s most current, clinical 
state.
5.2
Study Materials
NCI CTCAE version 4.0
Nivolumab Investigator Brochure 
Laboratory manuals for collection and handling of blood and tissue specimens
FACT-L, EQ-5D questionnaires 
Site manual for operation of interactive webresponse system
Pharmacy Manual
Serious Adverse Events (or eSAE) case report form pages
Pregnancy Surveillance Forms
RECIST v1.1 pocket guide
BMS will provide ActiGraph accelerometers for measurement of Group C subject activity 
levels.
Subject Brochure Card
Patient Alert Card
Electronic Case Report Form (eCRF) Completion Guidelines
Reference Ring
Safety Monitoring Call Guide
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include weight, height, ECOG Performance Status, blood pressure 
(BP), heart rate (HR), respiratory rate (RR), temperature, and oxygen saturation by pulse oximetry 
at rest and on exertion (also monitor amount of supplemental oxygen if applicable) should be 
performed within 28 days prior to first dose. Baseline signs and symptoms are those that are 
assessed within 14 days prior to first dose.
Concomitant medications will be collected from 14 days prior to the first dose through the study 
treatment period (see Table 5.1-1and within the assessment tables for each sub-protocol).
Physical measurements including height, and weight (and calculated BSA for subjects receiving 
chemotherapy if needed) at screening. During treatment period and EOT, only body weight will 
be measured.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
114


Clinical Protocol
CA209370
BMS-936558
nivolumab
Baseline local laboratory assessments should be done within 14 days prior to first dose and are to 
include: WBC count with 3-part differential, ANC, lymphocyte count, hemoglobin, hematocrit, 
and platelet count, chemistry (BUN or serum urea level, serum creatinine, sodium, potassium, 
calcium, magnesium, phosphate, chloride, and bicarbonate, glucose, and LDH), liver function test 
(aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, alkaline 
phosphatase, albumin), and thyroid function test (TSH, free T3, and free T4).
The following baseline local laboratory assessments should be done within 28 days prior to first 
dose: Hepatitis B and C testing (HBV sAg and HCV Ab or HCV RNA).
Pregnancy testing for WOCBP (done locally) must be performed within 24 hours prior to the initial 
administration of study drug at baseline and then every 4 weeks (2 cycles)for subjects receiving 
nivolumab and every 3 weeks (each cycle) for subjects receiving chemotherapy.Pregnancy testing 
should also be performed at EOT for all subjects.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be continuous during the treatment phase. During the Post-Chemotherapy and Nivolumab 
Follow-Up Phase at Visits 1 and 2, toxicity assessments should be done in person. Once subjects 
reach the survival follow-up phase, either in-person visitsor 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 4.0. 
On-study weight, ECOG performance status, and vital signs shouldbe assessed within 72 hours 
prior to each dose and EOT and at any time a subject has any new or worsening respiratory 
symptoms. Vital signs including temperature, blood pressure, heart rate, respiratory rate. The start 
and stop time of the study therapy infusions should be documented.
Physical examinations are to be performed at screening. Targeted physical examination should be 
performed while on treatment and EOT. 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. During Follow-up visits, targeted physical examination is also required to assess potential 
late emergent study drug-related AEs.
Except for Cycle 1, Day 1, while on-study the local laboratory assessments at screening should be 
repeated within 3 days prior to each dose. The hematology, chemistry, and liver function tests will 
be required at every cycle. Thyroid function testing should be performed every 6 weeksand at 
EOT. At Screening,thyroid function testing is to include TSH, free T3, and free T4. At subsequent 
time points, thyroid function testing consists of TSH only. However, if the TSH is abnormal, 
reflexive testing of free T3 and free T4 are to be performed(Please note that Endocrinopathy 
Management Algorithm in Appendix 1of theprotocol includes free T4only if the TSH is 
abnormal).
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.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
115


Clinical Protocol
CA209370
BMS-936558
nivolumab
Oxygen saturation by pulse oximetry should be obtained prior to each dosing and at any time a 
subject has any new or worsening respiratory symptoms. A reading at rest and on exertion should 
be obtained at each time pointpost-baseline. The extent of the exertion should be based on the 
judgment of the investigator but should remain consistent for each individual subject throughout 
the study. If the subject’s status changes the investigator can alter the extent of exertion based on 
their medical judgment. If a subject shows changes on pulse oximetry or other pulmonary-related 
signs (hypoxia, fever) or symptoms (eg dyspnea, cough, fever) consistent with possible  pulmonary 
adverse events, the subject should be immediately evaluated to rule out pulmonary toxicity, 
according to the suspected pulmonary toxicity management algorithm in the Nivolumab 
Investigator Brochure and Appendix 1 of this protocol. 
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
Monitoring for AEs in subjects treated with bevacizumab or pemetrexed receiving subjects in 
Group A, Investigator’s Choice chemotherapy (Group C), erlotinib (Group D) and Crizotinib 
(Group E) should follow recommendations specified in the respective package inserts.
For Group E, the primary objective is safety and tolerability of nivolumab in combination with 
crizotinib. TheAE and SAE occurring during the treatment and follow-up period will be closely 
monitored. 
5.3.1
ECOG Performance Status
ECOG PS will be evaluated and documented at Screening and within 72 hours prior to each dosing 
visit as outlined in the assessment tables for each group (see Appendix2 for details of ECOG PS). 
5.3.2
Imaging Assessment for the Study
The review of images, assessment of eligibility, response, and resultant treatment decisions for all 
Groups (A, B, C, D,and E), will be made by the investigators. 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.
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled timepoints and/or at an outside institution) should be collected for 
RECIST 1.1 tumor assessment.
5.3.3
Electrocardiogram (ECG)
All subjectsat screening, are required to have a 12-lead ECG performed during Screening. 
Subjects in Group E will be required to have a 12-lead ECG at time points following screening as 
detailed in assessment tables. 
Crizotinib is associated with two main cardiac side-effects: QT interval prolongation and 
bradycardia, therefore 12-lead ECG monitoring will be mandated for Group E patients at baseline, 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
116


Clinical Protocol
CA209370
BMS-936558
nivolumab
during treatment (every 8 weeks until first year and every 12 weeks thereafter), EOT, and follow-
up visit. See Table 5.1-10and Table 5.1-11for details.
The ECG recordings must be analyzed and checked for abnormality by the investigator. Any ECG 
finding that meets AE criteria should be reported. Positive findings on QT prolongation must be 
followed up sufficientlyas deemed by the investigator. Additional ECGs should be done whenever 
the investigator deems necessary.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the tables in Section 5.1, according to 
RECIST1.1 criteria.93High resolution CT with oral/intravenous contrast or contrast-enhanced 
MRI is the preferred imaging modalities for assessing radiographic tumor response. If a subject 
has a known allergy to contrast material, please use local prophylaxis standards 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 
and pelvis may be obtained. Every attempt should be made to image each subject using an identical 
acquisition protocol on the same scanner for all imaging time points.
Screening assessments should be performed within 21days of start of study treatment. In addition 
to the chest, abdomen, pelvis, all known/suspected sites of disease should be assessed at baseline. 
Subsequent assessments should include chest, abdomen, and all known/suspected sites of disease 
using the same imaging method and technique as was used at baseline. Brain MRI is the preferred 
imaging method for evaluating CNS metastasis, and assessment is required during screening in 
subjects with a known history of treated/suspected brain metastases. If more than one method is 
used at screening, then the most accurate method according to RECIST v1.1 should be used when 
recording data, and should again be used for all subsequent assessments. Bone scan, PET scan, or 
ultrasound are not adequate for assessment of RECIST response. In selected circumstances where 
such modalities are the sole modality used to assess certain non-target organs, those non-target 
organs may be evaluated less frequently. For example, bone scans may need to be repeated only 
when complete response is identified in target disease or when progression in bone is suspected. 
Previously treated CNS metastases are not considered measurable lesions for purposes of RECIST 
determined response. Subjects with a history of brain metastasis should have surveillance MRI 
approximately every 12weeks, or sooner if clinically indicated.
Radiographic tumor assessments will be conducted within 21 days prior to first study dose, at 
Week 9 (1 week) and then every 8weeks (1 week) forup to2 years.Subjects with a history 
of brain metastasis may have surveillance MRI approximately every 12 weeks from the date of 
first dose, or sooner if clinically indicated. In subjects who discontinue the study treatment without 
evidence of disease progression, the same tumor assessment schedule should be followed. Tumor 
assessments for all subjects should continue as per protocol even if dosing is interrupted. Tumor 
measurements should be made by the same investigator or radiologist for each assessment 
whenever possible. Changes in tumor measurements and tumor responses to guide ongoing study 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
117


Clinical Protocol
CA209370
BMS-936558
nivolumab
treatment decisions will be assessed by the investigator using RECIST 1.1 (see Appendix3 for 
details of RECIST 1.1). 
5.4.1
End of Treatment, Follow-up, and Survival Procedures
When treatment is to be discontinued, 1 EOT visit, and 2 follow-up visits will be scheduled. End 
of Treatment (EOT) visit should be scheduled between 0 -7 calendar days of last drug 
administration. If the decision to permanently discontinue the study treatments is taken during a 
scheduled visit, the EOT visit should be performed instead of the scheduled visit. Follow-up Visit1 
is to occur within 35 days (± 7 days) after the last doseof study treatment, follow-up Visit2 is to 
occur within 80 days (± 7 days) of follow-up Visit 1. See Follow-up Tables for specific 
assessments for each sub-protocol (see Table 5.1-3, Table 5.1-5, Table 5.1-7, Table 5.1-9, and 
Table 5.1-11). Survival visits will occur approximately every 3 months, beginning from Follow-
up Visit 2. Survival will be assessed every 3 months following end of treatment, until death, lost 
to follow-up, withdrawal of study consent, or for 4years after the initiation of the study treatment.
Subjects who discontinue study treatment prior to progression, and subjects being treated beyond 
disease progression, will continue to be followed with radiographic tumor assessments every 
8weeks (1 week) for up to 2 years. Radiographic assessments should be performed according to 
Section5.4. At documented progression or recurrence, a blood samples will be taken for 
exploratory assessments of biomarkers.  
Survival will be followed after progression, either by direct contact (office visits) or via telephone 
contact, until death, withdrawal of study consent, or lost to follow-up for 4years following start
of therapy.
For any study Group which is stopped early due to futility, continued treatment of the individual 
patient on the study will be at the discretion of the investigator. However, once a decision is made 
to discontinue the study treatment, the end of treatment and 2 follow-up visits are mandated for 
the safety of the patient. The survival visits are no longer required.
5.4.2
EGFR mutation and ALK translocation assessments
Appropriate documentation of EGFR mutation and ALK translocation tests results must be 
available before randomization. 
The presence of a common EGFRmutation (Deletion 19and/or exon 21-L858R substitutionor 
other drug-sensitizing EGFR mutations) is mandatory for the enrollment of Group D patientsprior 
to randomization. The use of an FDA approved assay (ie, cobas® EGFR Mutation Test, 
therascreen® EGFR RGQ PCR Kit) is strongly encouraged.
The presence of ALK translocation is mandatory for enrollment in Group E. The use of an FDA 
approved assay (ie, VYSISALK Break Apart FISH Probe Kit) is strongly encouraged.
Consult the Medical Monitor regarding the use of EGFR/ALK mutation blood tests.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
118






Clinical Protocol
CA209370
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
121


Clinical Protocol
CA209370
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
122


Clinical Protocol
CA209370
BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 drugand that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study 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. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one ormore AEs.)
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
123


Clinical Protocol
CA209370
BMS-936558
nivolumab
6.1
Serious Adverse Events
A Serious Adverse Event (SAE)is 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 notrefer 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 forallergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential DILI is also considered an important medical event. (See Section 
6.7for the definition of potential DILI.)
Suspected transmission of an infectious agent (eg, 
pathogenic or nonpathogenic) via the study drug 
is an SAE. 
Although pregnancy, overdose, cancer, and potential DILI are not always serious by regulatory 
definition, these events must be handled as SAEs. (See Section6.1.1for reporting pregnancies).
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent 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, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures.All SAEs must be collected that occur during the screening period and within 
100 days of discontinuation of dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periodsand that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but ispotentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should 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 preferred 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
124


Clinical Protocol
CA209370
BMS-936558
nivolumab
method forSAE 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. 
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. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. 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.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should 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, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
Note: All treatment-related SAEs collected on subjects receivingcombination therapy must have 
causality assigned to nivolumab, SOC treatment, or combination therapyby the Investigator.
6.2
Nonserious Adverse Events
Anonserious adverse eventis an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
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.
The collection of nonserious AE informationfor Groups A, C, D,E and Group B Arm A should 
begin at initiation of study drug. The collection of nonserious AE information for Group B Am B 
(Best Supportive Care) should commence at randomization.  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 subjectsifapplicable. 
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). 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
125


Clinical Protocol
CA209370
BMS-936558
nivolumab
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Adverse Events of Interest 
IMAEs are specific events occurring within 100 days of the last dose of study drug (which includes 
pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, and endocrine 
abnormalities [adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes 
mellitus, and hypophysitis]), regardless of causality, for which subjects received 
immunosuppressive medication for treatment of the event.The exception to the 
immunosuppressive 
medication 
criteria 
for 
IMAEs 
is 
endocrine 
events 
(hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, diabetes mellitus, adrenal 
insufficiency), which are included regardless of treatment since these events are often managed 
without immunosuppression. 
Per FDA guidance, IMAE analyses included events, regardless of causality, occurring within 100 
days of the last dose. These analyses are limited to subjects who received immunosuppressive 
medication for treatment of the event, with the exception of endocrine events 
(hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, diabetes mellitus, adrenal 
insufficiency), which were included in the analysis regardless of treatment since these events are 
often managed without immunosuppression. 
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Every adverse event must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
Table 6.3-1below provides a summary of the IMAEs category and their respective Preferred 
Terms.
Table 6.3-1: 
Preferred Terms Included in Analysis of IMAEs to Support 
Warning and Precautions
IMAE Category
Preferred Terms included under IMAE Category
Pneumonitis
Pneumonitis, Interstitial lung disease
Diarrhea/Colitis
Diarrhea, Colitis, Enterocolitis
Hepatitis
Hepatotoxicity, Hepatitis, Hepatitis acute, 
Autoimmune Hepatitis, AST Increased, ALT 
increased, Bilirubin Increased, ALP increased
Adrenal Insufficiency
Adrenal Insufficiency
Hypothyroidism/Thyroiditis
Hypothyroidism, Thyroiditis
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
126


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 6.3-1: 
Preferred Terms Included in Analysis of IMAEs to Support 
Warning and Precautions
IMAE Category
Preferred Terms included under IMAE Category
Thyroiditis acute (collapsed with thyroiditis for 
frequency), Autoimmune Thyroiditis (collapsed with 
thyroiditis for frequency)
Hyperthyroidism
Hyperthyroidism
Hypophysitis
Hypophysitis
Diabetes Mellitus
Diabetes Mellitus, Diabetic ketoacidosis
Nephritis and renal dysfunction
Nephritis, Nephritis allergic, Tubulointerstitial 
nephritis, Acute renal failure, Renal Failure, Increased 
Creatinine
Rash
Rash, Rash maculo-papular
IMEAs=immune-mediated adverse events. 
6.4
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
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).
6.5
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 5half-
lives after product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in 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).
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug after a thorough discussion 
of benefits and risk with the subject 
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
127


Clinical Protocol
CA209370
BMS-936558
nivolumab
of awareness of the event and in accordance with SAE reporting procedures described in 
Section6.1.1. 
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 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.6
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section6.1.1for reporting details.).
6.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section6.1.1for reporting details).
Potential drug induced liver injury
 is defined as: 
1. AT (ALT or AST) elevation > 3 ×ULN
AND
2. Total bilirubin > 2 ×ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
6.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
A DMC will be established to provide oversight of safety and efficacy considerations in protocol 
CA209370, and to provide advice to thesponsor regarding actions the committee deems necessary 
for the continuing protection of subjects enrolled in the trial. The DMC will be charged with 
assessing such actions in light of an acceptable benefit/risk profile for nivolumab. The DMC will 
act in an advisory capacity to BMS and will monitor subject safety and evaluate the efficacy data 
for the study. Efficacy will also be reviewed by the DMC -as part of the benefit-to-risk assessment 
and for the formal analyses of PFS and OS.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
128


Clinical Protocol
CA209370
BMS-936558
nivolumab
The DMC will be advisory to the clinical study leadership team. The clinical study leadership team 
will have responsibility for overall conduct of the study including managing the communication 
of study data. The group will be responsible for promptly reviewing the DMC recommendations, 
for providing guidance regarding the continuation or termination of the study, and for determining 
whether to continue enrollment or follow-up as pre-specified by the rules that govern the adaptive 
design, which are described in detail in the statistical analysis plan (SAP).
After meeting, the DMC will notify the clinical study leadership group that it has met and will 
provide recommendations about the study by telephone or email. Detailed procedures to deliver 
and address the DMC recommendations are described in the BMS Standard Operating Procedure, 
which specifies the establishment and operation of clinical trial DMCs. Any recommendation by 
the DMC regarding study modification will be submitted to the clinical study leadership team 
within pre-specified business days of the DMC meeting.
The oncology therapeutic area of BMS has primary responsibility for design and conduct of the 
study. Details of DMC responsibilities and procedures will be specified in the DMC charter.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
8.1.1
Group A through D sample size determination
A decision was made in December 2016 to stop enrollment forGroups A, B,and C, and stop 
enrollment and treatment forGroup E. Sample sizes for these groups will be the number of patients 
already randomized (treated in Group E).
A decision was made inDecember 2017 to stop enrollment forGroup D. As a result of this 
decision, the actual sample sizes for these groups are indicated in thefollowing table. Therefore, 
the overall population randomized or enrolled in this Master Protocol is now approximately 342
subjects.
Group
Sample Size
A
132
B
35
C
52
D
109
E
14
The following is the rationale of the original sample size determination. 
This is a Phase 1/2, open-label, Master Protocol with 5 groups/sub-studies. The planned overall 
population to be enrolled in this Master Protocol was approximately 1953 subjects at maximum. 
Individual sample sizes per group are shown in Table 8.1.1-1.The sample size for each Group 
depends on the population, treatment effect, and primary endpoint for each group.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
129


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 8.1.1-1:
Maximum Sample Size and Comparisons of Interest
Population
Maximum 
Sample Size
Primary 
Endpoint
Comparisons of interest
Group A:
Maintenance, 
NSQ, PS 0-1, 
EGFRwtand 
ALKwt
765
1:1:1 
randomization in 
bevacizumab 
containing arms.
1:1:1 
randomization in 
pemetrexed 
containing arms
PFS/OS
1. Nivolumab vs. bevacizumab for PFS
2. Nivolumab vs. bevacizumab for OS
3. Nivolumab plus bevacizumab vs.
bevacizumab for PFS
4. Nivolumab plus bevacizumab vs. 
bevacizumab for OS
5. Nivolumab vs. pemetrexed for PFS
6. Nivolumab vs. pemetrexed for OS
7. Nivolumab plus pemetrexed vs. 
pemetrexed for PFS
8. Nivolumab plus pemetrexed vs. 
pemetrexed for OS
Group B:
Maintenance, 
SQ, PS 0-1
500
1:1 
randomization
PFS/OS
Nivolumab vs. Best supportive care
Group C: 
First-line, NSQ 
and SQ, PS 2, 
EGFRwt and 
ALKwt
350
1:1 
randomization
PFS/OS
Nivolumab vs. Investigator choice chemotherapy 
for superiority and non-inferiority
Group D: 
First-line, PS 0-
2, EGFR
mut
318
1:1 
randomization
PFS
Nivolumab plus Erlotinib vs. Erlotinib
Group E: 
First-line, PS 0-
2, ALK-
positive
20
Single arm,  
No 
randomization
Incidence of 
drug-related 
AEs leading 
to 
discontinuati
on
Not Applicable
AE=adverse event; PFS=progression-free survival; OS=overall survival. 
The adaptive trial is designed to identify an appropriate sample size and follow-up duration based 
upon accruing information to produce sufficient power in each group for a range of potential effect 
sizes and PFS/OS rates rather than provide a fixed power for one particular expected effect size 
and PFS/OS rate which may prove to be incorrect once we observe trial data.  
The values below illustrate high power for one possible value of expected benefit in the nivolumab 
vs. control arms. Full operating characteristics over a broader range of possible median PFS values, 
OS values, and hazard ratios are shown in the full adaptive design plan, available upon request.
For example, Group A, assuming median control (Pem or Bev) PFS of 5 months and a median of 
7.5 months in the nivolumab and nivolumab combination arms to produce a hazard ratio of 0.67, 
the design offers 91% power in the Nivo vs. Pem comparisons and 64/74% in the Nivo alone/Nivo-
combination vs. Bev comparisons, respectively. This also assumes that 80% of patients will have 
previously taken pemetrexed vs. 20% on bevacizumab.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
130


Clinical Protocol
CA209370
BMS-936558
nivolumab
Group A, assuming median control (Pem or Bev) OS of 21 months and a median of 29 months in 
the nivolumab and nivolumab combination arms to produce a hazard ratio of 0.72, 
the design offers 
86% power in the Nivo vs. Pem comparisons and 57% inthe Nivo vs. Bev comparisons. This also 
assumes that 80% of patients will have previously taken pemetrexed vs. 20% on bevacizumab.
Group B, assuming true but unknown hazard ratios of 0.75 for both PFS (5.5 vs. 7.3 months) and 
OS (13.1 vs. 17.4 months), 500 patients provides 86% power for PFS and 99% power for OS. If 
the OS hazard ratio decreases to 0.79 (13.1 vs. 16.6 months),then 500 patients still offers 93% 
power for OS.
Group C, assuming true but unknown hazard ratios of 0.73for both PFS (3.5 vs. 4.8months) and 
OS (7.2 vs. 9.9months), 350patients provides80% powerfor PFS and96% powerfor OS. If the 
OS hazard ratio decreases to 0.79 (7.2 vs. 9.3months), then 350patients still offers84% power
for OS.
Group D, assuming true but unknown hazard ratios of 0.63 for PFS (10 vs. 16 months), the design
patients provides 91% power for PFS. 
Full operating characteristics over a broader range of possible median PFS values, OS values, and 
hazard ratios are shown in the full adaptive design plan, and available upon request.
8.1.2
Group E sample size determination
 
 
 
 
In order to characterize the safety and tolerability, this study will treat with novel combination: 
nivolumab and crizotinib in 20 subjects who have recurrent locally advanced or metastatic 
NSCLC. This sample size will allow estimating an approximate incidence rate of 5% (n=1 subjects 
with nivolumab treatment-related adverse events) with a 95% CI (confidence interval) of (0.13%, 
24.9%), or an incidence rate of 40% (n=8 subjects with events) with a 95% CI of (19.12%, 
63.95%). 
Estimated 95% CIs for various event rates for a population of 20 subjects are described inTable 
8.1.2-1. The goal is to identify safe regimen for future development and “safe” is defined as ≤20% 
treated subjects with drug-related AEs leading to drug discontinuation by Week 17.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
131


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 8.1.2-1:
Estimated Incidence
Estimated Incidence Rates and 95% CIs 
Sample Size 
Incidence Rate (%) 
Lower 95% CI (%) 
Upper 95% CI (%) 
20 
5.0 
0.13 
24.90 
20 
10.0 
1.23 
31.70 
20 
15.0 
3.21 
37.89 
20 
20.0 
5.73 
43.66 
20 
25.0 
8.66 
49.10 
20 
30.0 
11.89 
54.28 
20 
35.0 
15.39 
59.22 
20 
40.0 
19.12 
63.95 
20 
45.0 
23.06 
68.47 
20 
50.0 
27.20 
72.80 
CI=confidence interval.
Due to observed hepatic toxicity, Group E was permanently terminated with 13 subjects treated 
with the combination treatment of nivolumab and crizotinib.
8.2
Populations for Analyses
Efficacy will be analyzed for all randomized patients (except Group E for treated patients) and 
safety for all treated patients. Population for each Group is summarized briefly below. 
Group A: 
Subjects who have completed at least 4 cycles (up to 6 cycles) of bevacizumab, carboplatinor 
cisplatin, and paclitaxel 
Subjects who have completed at least 4 cycles (up to 6 cycles) of pemetrexed and 
carboplatinor cisplatin, and without disease progression.
Group B: 
Subjects with histologically confirmed Stage 4 or recurrent locally advanced SQ NSCLC. 
Enrolled subjects must have completed at least 4 cycles (up to 6 cycles) of SOC chemotherapy, 
and without disease progression.
Group C
First-line treatment of subjects with histologically confirmed Stage 4 or recurrent locally 
advanced NSCLCand with ECOG Performance Status of 2 with wild-type EGFR and ALK 
alleles.
Group D: 
First-line treatment for subjects with histologically confirmed Stage 4 or recurrent locally 
advanced EGFR-mutated NSCLC.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
132


Clinical Protocol
CA209370
BMS-936558
nivolumab
Group E:
First-line treatment for subjects with histologically confirmed Stage 4 or recurrent locally 
advanced ALK-positive NSCLC.
8.3
Endpoints
Duration of response (DOR) is defined as the time from first confirmed response (CR or PR) 
to the date of the initial objectively documented tumor progression as determined using 
RECIST 1.1 criteria or death due to any cause, whichever occurs first. For subjects who neither 
progress nor die, the DOR will be censored on the date of their last evaluable tumor assessment. 
DOR will only be evaluated in subjects with objective response of CR or PR.
Objective response rate (ORR) is defined as the number and percentage of subjects with a best 
overall response (BOR) of confirmed complete response (CR) orpartial response (PR). Best 
overall response (BOR) is defined as the best response designation, recorded between the date 
of first dose and the date of the initial objectively documented tumor progression per 
RECISTv1.1 or the date of subsequent therapy,whichever occurs first. For subjects without 
documented progression or subsequent therapy, all available response designations will 
contribute to the BOR determination.
Overall survival (OS) is defined as the time from randomization to the date of death. A subject 
who has not died will be censored at last known date alive. OS will be followed continuously 
while subjects are on the treatment and every 3 months via in-person or phone contact after 
subjects discontinue the study drug. 
Progression-free survival (PFS) is defined as the time from randomization to the date of the 
first documented tumor progression, as determined by investigators (per RECIST v1.1), or 
death due to any cause, whichever occurs first. Subjects who die without areported prior 
progression will be considered to have progressed on the date of their death. 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 assessment and did not die will be censored on 
the first dosing date.
Subjects who received any subsequent anti-cancer therapy (including on-treatment palliative 
radiation therapyof non-target bone lesions or CNS lesions) without a prior reported 
progression willbe censored at the last evaluable tumor assessment prior to or on the date of 
initiation of the subsequent anti-cancer therapy.
Group E PFS and OS are defined as the time from first treatment to the date of event since 
there is no randomization in this group.
Group C Patient Reported Outcome (PRO) data from the EQ-5D, FACT-L, and ActiGraph 
will be assessed by measuring change from baseline at each assessment point, and disease-
related symptom improvement rate as reported by the FACT-L.
All safety data will be summarized and listed for all treated subjects. All on-study AEs, SAEs, 
treatment-related AEs, and treatment-related SAEs, etc. will be summarized using worst grade 
per NCI CTCAE v4.0 by system organ class and preferred term. On-study lab abnormalities 
including hematology, chemistry, liver function, thyroid function, and renal function will be 
summarized using worst grade per NCI CTCAE v4.0 criteria.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
133


Clinical Protocol
CA209370
BMS-936558
nivolumab
8.3.1
Primary Endpoints: 
Group A: PFS and OS 
Group B: PFS and OS 
Group C: PFS and OS
Group D: PFS
Group E: Incidence of treatment-related AEs leading to both study drugs discontinuation. 
8.3.2
Secondary Endpoints: 
Group A: DOR and ORR
Group B: DOR and ORR
Group C: DOR and ORR
Group D: OS, DOR, and ORR 
Group E: PFS, and ORR
 
 
 
 
 
 
 
 
 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
134


Clinical Protocol
CA209370
BMS-936558
nivolumab
 
 
 
 
8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Demographics, baseline disease characteristics and baseline laboratory results will be summarized 
using descriptive statistics for all treated subjects and all randomized subjects for in each Group. 
8.4.2 
Efficacy Analyses
8.4.2.1
Efficacy Analysis for Group A: Maintenance, NSQ PS 0-1, EGFRwtand 
ALKwt
This group will enroll 2 subject cohorts, subjects who have completed at least 4 cycles of 1) 
bevacizumab, carboplatinor cisplatin, and paclitaxel or 2) pemetrexed and carboplatinor cisplatin. 
Within each subject cohort, subjects will be randomized 1:1:1 to either 1) SOC maintenance 
therapy 2) nivolumab alone or 3) nivolumab plus SOC maintenance therapy. PFS and OS are co-
primaryendpoints. 
The OS curves for each treatment group will be estimated using the Kaplan-Meier (KM) product-
limit method. Two-sided, 95% confidence intervals for median OS will be computed by 
Brookmeyer and Crowley method. 
The subjects may be followed for survival up to 4years.  Survival rates at6, 12, 18, 24, and up to 
4year will also be estimated using KM estimates on the OS curve for each randomized arm. 
Associated two-sided 95% CIs will be calculated using the Greenwood’s formula.
PFS will be summarized similarly as OS. 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
135


Clinical Protocol
CA209370
BMS-936558
nivolumab
ORR will be computed in each treatment group along with the exact 95% CI using the Clopper-
Pearson method. BOR will be summarized by response category for each treatment group. A by 
subject listing of BOR and Tumor Measurements will beprovided.
Duration of response in each treatment group will be estimated using the KM product-limit method 
for subjects who achieve PR or CR. Median values along with two-sided 95% CI will be calculated 
using the Brookmeyer and Crowley method.
8.4.2.2 
Efficacy Analysis for Group B: Maintenance, SQ, PS 0-1
The efficacy analysis for Group B will be same as the efficacy analysis for Group A.
8.4.2.3
Efficacy Analysis for Group C: First-line NSQ and SQ, PS 2, EGFRwt and 
ALKwt
The efficacy analysis for Group C will be same as the efficacy analysis for Group A.
8.4.2.4
Efficacy Analysis for Group D: First-line, PS 0-2, EGFRmut
The efficacy analysis for Group D will be similar tothe efficacy analysis for Group A.In addition, 
DCR, which is not evaluated in Group A, will be computed ineach treatment group along with the 
exact 95% CI using the Clopper-Pearson method.
8.4.2.5
Efficacy Analysis for Group E: First-line, PS 0-2, ALK-positive
The OS and PFS curves will be estimated using the Kaplan-Meier (KM) product-limit method. 
A by subject listing of BOR and Tumor Measurements will be provided.
8.4.3
Safety Analyses
All safety data will be summarized and listed for all treated subjects. All AEs, SAEs, treatment-
related AEs, and treatment-related SAEs will be summarized using worst grade per NCI CTCAE 
v4.0 by system organ class and preferred term. Lab abnormalities including hematology, 
chemistry, liver function, thyroid function, and renal function will be summarized using worst 
grade per NCI CTCAE v4.0 criteria.
Descriptive statistics of safety (AE and lab data) including incidence, median values using the 
Kaplan-Meier product-limit method with 95% CI using the Brookmeyer and Crowley method of 
time to onset and time to resolution, and rate of discontinuation due to event occurrence will be 
presented for all treated subjects. Time to onset is calculated from first dosing date to the event 
onset date. If a subject never experienced the given AE, the subject will be censored at the last 
contact date. Time to resolution is calculated from the AE onset date to AE end date. If an AE is 
ongoing at the time of analysis, the time to resolution will be censored at the last contact date. 
Frequency, management and resolution of IMAEs are to be analyzed. A tabular of the incidence 
of overall IMAEs (by preferred term) and serious IMAEs will be performed. A descriptive analysis 
of IMAEs including time-to-onset, severity, duration, action taken with the study drug, dosing 
delays of the study drug, corticosteroid details, re-challenge information and outcome of the AE 
are individually characterized in the following subsections:
pneumonitis IMAEs
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
136


Clinical Protocol
CA209370
BMS-936558
nivolumab
diarrhea/colitis IMAEs
hepatitis IMAEs: 
nephritis and renal dysfunction IMAEs
rash IMAEs
endocrine IMAEs by subcategories including adrenal insufficiency, hypophysitis, 
hypothyroidism/thyroiditis, hyperthyroidism, and diabetes.
For Group E, the primary objective is safety and tolerability of nivolumab in combination with 
crizotinib. The primary objective will be measured by: 
1) Frequency of adverse events occurring up to 100 days after the last dose of study drug 
2) Frequency of serious adverse events occurring up to100 days after the last dose of study drug 
3) Frequency of clinical laboratory test by worst toxicity grade (as assessed at screening and every 
cycle).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
137


Clinical Protocol
CA209370
BMS-936558
nivolumab
 
  
 
8.5
Interim Analyses
At the time of Amendment 4, one safety interim analysis was conducted. Due to early closure of 
the enrollment for Groups A, B, C,and E, no further interim analysis isplanned for these groups. 
8.5.1
Interim Analyses for Group D 
Safety interim analyses are planned for Group D approximately yearly. 
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be 
submitted to:
IRB/IEC for review and approval/favorable opinion BMS
Regulatory Authority(ies), if required by local regulations
Documentationof approval signed by the chairperson or designee of the IRB(s)/IEC(s) 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 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS 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 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
138


Clinical Protocol
CA209370
BMS-936558
nivolumab
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 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. 
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 
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. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior to study initiation. 
Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
electronic CRFs, studydocumentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigatormust retain all study recordsand source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator 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, IRB). Notice of such 
transfer will be given in writing to BMS.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
139


Clinical Protocol
CA209370
BMS-936558
nivolumab
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of study drug 
(inventoried and dispensed) ismaintained at the study site to include investigational product and 
the following non-investigational product(s): Gemcitabine, pemetrexed, paclitaxel, Nab-
paclitaxel, carboplatin, bevacizumab, etc.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/sitefor dispensing or storage
Non-study disposition (eg, lost, wasted) 
Amount destroyed at study site, if applicable
Amount returned to BMS (for nivolumab)
Retain samples for bioavailability/bioequivalence, if applicable 
Dates and initials of person responsible for investigational product dispensing/accountability, 
as per the delegation of authority form.
BMS 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 toenhance 
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 BMS 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 
paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be left 
blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a subinvestigator and 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
140


Clinical Protocol
CA209370
BMS-936558
nivolumab
who is delegated this task on the Delegation of Authority Form. 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 BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
External Principal Investigator designated at protocol development
National Coordinating Investigator 
Study Steering Committee chair or their designee
Subject recruitment (eg, among the top quartile of enrollers)
Involvement in trial design
Regional representation (eg, 
among top quartile of enrollers from a specified region or country)
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study must 
adhere to the publication requirements set forth in the clinical 
trial agreement (CTA) governing [Study site or Investigator] participation in the study. These 
requirements include, but are not limited to, submitting proposed publications to BMS at the 
earliest practicable time prior to submission or presentation and otherwise within the time period 
set forth in the CTA.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
141


Clinical Protocol
CA209370
BMS-936558
nivolumab
10
GLOSSARY OF TERMS
Term
Definition
Complete Abstinence
If one form of contraception is required, Complete 
Abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly 
effective contraception must be discussed in the event that 
the subject chooses to forego complete abstinence.
If two forms of contraception is required, Complete 
abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all 
study drugs. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence.
Expanded definitionComplete abstinence as defined as 
complete avoidance of heterosexual intercourse isan 
acceptable form of contraception for all study drugs. This 
also means that abstinence is the preferred and usual lifestyle 
of the subject. 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. Subjects who choose complete abstinence are 
not required to use a second method of contraception, but 
female subjects must continue to havepregnancy tests. 
Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject 
chooses to forego complete abstinence
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
142


Clinical Protocol
CA209370
BMS-936558
nivolumab
11
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ALK
Anaplastic lymphoma kinase
ALT
alanine aminotransferase
APC
antigen-presenting cells
AST
aspartate aminotransferase
AT
Aminotransaminases
AUC
Area under the concentration curve
BID
Twice a day
BMS
Bristol-Myers Squibb
BOR
Best overall response
BSC
Best supportive care
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
CBC
complete blood count
CI
confidence interval
CLS
capillary leak syndrome
CNS
Central nervous system
CR
Complete response
CRF
Case Report Form, paper or electronic
CTA
Clinical trial agreement
CTL4-1
cytotoxic T-lymphocyte antigen-4
CV
Coefficient of variation
CYP
cytochrome p-450
DCR
Disease control rate
DILI
Drug-induced liver injury
DOR
Duration of response
dL
Deciliter
EBUS
Endobronchial Ultrasound
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
143


Clinical Protocol
CA209370
BMS-936558
nivolumab
Term
Definition
ECG
Electrocardiogram
ECOG
EasternCooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
Electroencephalogram
Eg
exempli gratia (for example)
EGFR
Epidermal Growth Factor Receptor
EQ-5D
EuroQoL Five Dimension
FACT-L
Functional Assessment of Cancer Therapy-Lung 
FDA
Food and Drug Administration
FISH
fluorescent in-situ hybridization
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
H
Hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
Hazard ratio
HRQoL
Health-related quality of life
HRT
hormone replacement therapy
HUS
hemolytic uremic syndrome 
ICH
International Conference on Harmonisation
Ie
id est (that is)
IEC
Independent Ethics Committee
ILD
interstitial lung disease
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
144


Clinical Protocol
CA209370
BMS-936558
nivolumab
Term
Definition
IHC
Immunohistochemistry
IU
International Unit
IV
Intravenous
IWRS
Interactive webresponse system
Kg
Kilogram
LCSS
Lung Cancer Symptom Scale
LDH
lactate dehydrogenase
LFT
liver function test
MET
Metabolic equivalents
Mg
Milligram
Min
Minute
mL
Milliliter
MLR
mixed lymphocyte reaction
mmHg
millimeters of mercury
MVPA
moderate to vigorous physical activity 
MTD
maximum tolerated dose
Mut
Mutation
N
number of subjects or observations
N/A
not applicable
NIMP
non-investigational medicinal products
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
NSQ
Non-squamous
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD-1
Programmed death-1
PD-L1
Programmed death-ligand 1
PK
Pharmacokinetics
PFS
Progression free survival
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
145


Clinical Protocol
CA209370
BMS-936558
nivolumab
Term
Definition
PO
By mouth
PPK
population pharmacokinetic
PR
Partial response
PRES
posterior reversible encephalopathy syndrome
PRO
Patient-reported outcomes
PS
Performance status
QD
Every day
RBC
red blood cell
RCC
renal cell carcinoma
SAE
serious adverse event
SAP
statisticalanalysis package
SD
standard deviation
SED
sedentary time 
SOC
standard of care
SQ
Squamous
TCR
T-cell receptor
T-HALF
Half life
TILs
tumor-infiltrating lymphocytes
TKI
Tyrosine-kinase inhibitor 
TTO
Time to trade-off
ULN
upper limit of normal
VAS
visual analog rating scale
VEGF
vascular endothelial growth factor
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
wt
Wild-type/mutation negative/
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
146














































Clinical Protocol
CA209370
BMS-936558
nivolumab
APPENDIX 2
ECOG PERFORMANCE STATUS 
ECOG PERFORMANCE STATUSa
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 ofa 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about morethan 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
 
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
169


Clinical Protocol
CA209370
BMS-936558
nivolumab
APPENDIX 3
RECIST 1.1 CRITERIA
This Appendix has been excerpted from the full RECIST 1.1 criteria. For information pertaining 
to RECIST 1.1 criteria not contained in the study protocol or in this Appendix, please refer to the 
full publication.8
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 forsubsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion.
1.1
Measurability of tumor
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows. All baseline evaluations should be performed as close as possible to the treatment start 
and never more than 4 weeks before the beginning of the treatment.
Measurable lesions must be accurately measured in at least one dimension (longest diameter in 
the plane of the measurement to be recorded) with a minimum size of:
10 mm by CT scan -(CT 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 non-measurable)
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, onlythe short axis 
will be measured and followed.
All measurements should be recorded in metric notation, using calipers if clinically assessed.
Special considerations regarding lesion measurability
Bone lesions:
Bone scan, PET scan or plain films are not considered adequate imaging techniques to
measure bone lesions. However, these techniques can be used to confirm the presence or
disappearance of bone lesions.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components,
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be
considered as measurable lesions if the soft tissue component meets the definition of
measurability described above.
Blastic bone lesions are non-measurable.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
170


Clinical Protocol
CA209370
BMS-936558
nivolumab
Cystic lesions:
Lesions that meet the criteria for radiographically defined simple cysts should not 
beconsidered as malignant lesions (neither measurable nor non-measurable) 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 patient, these are preferred for selection as target lesions.
Lesions with prior local treatment:
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.
Non-measurable lesions are all other lesions, including small lesions (longest diameter<10 
mm or pathological lymph nodes with ≥10 to < 15 mm short axis), as well asnon-measurable 
lesions. Lesions considered non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques.
1.2
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 performed rather than clinical examination unless the lesion(s) being followed cannot 
beimaged but are assessable by clinical examination. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. Measurability of lesions on CT scan is based on the assumption that CT 
slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.
Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is an
important endpoint, since CT is more sensitive than x-ray, particularly in identifying new lesions.
However, lesions on chest x-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung.
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 noted 
above, when lesions can be evaluated by both clinical exam and imaging, imaging evaluation 
should be undertaken since it is more objective and may be reviewed at the end of the study.
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.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
171


Clinical Protocol
CA209370
BMS-936558
nivolumab
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised.
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response.
2
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-
TARGET’LESIONS
Target lesions: When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
baseline.
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.
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. All other 
pathological nodes (those with short axis ≥10 mm but < 15 mm) should not be considered non-
target lesions. Nodes that have a short axis < 10 mm are considered non-pathological and should 
not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease.
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 followedas ‘present’, ‘absent’, or ‘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 AND RESPONSE CRITERIA
3.1
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions,
taking as reference the smallest sum on study (this includes the baseline sum if that is the
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
172


Clinical Protocol
CA209370
BMS-936558
nivolumab
absolute increase of at least 5 mm. Note: the appearance of one or more new lesions is also
considered progression.
Stable Disease (SD): Neither sufficient shrinkage from the baseline study to qualify for PR nor
sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on
study.
Special notes on the assessment of target lesions
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short
axis measurement recorded and should be measured in the same anatomical plane as the
baseline examination, even if the nodes regress to below 10 mm on study. This means that
when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if
complete response criteria are met, since a normal lymph node is defined as having a short
axis of < 10 mm.
Target lesions that become ‘too small to measure’: All lesions (nodal and non-nodal)
recorded at baseline should have their actual measurements recorded at each subsequent
evaluation, even when very small (eg, 2 mm). If the radiologist is able to provide an actual
measure, 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:
1) if it is the opinion of the radiologist that the lesion has likely disappeared, the measurement
should be recorded as 0 mm.
2) 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
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).
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest
diameters of the fragmented portions should be added together to calculate the target lesion sum.
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in
obtaining maximal diameter measurements of each individual lesion. If thelesions have
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.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor
marker level above the normal limits.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the
appearance of one or more new lesions is also considered progression).
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
173


Clinical Protocol
CA209370
BMS-936558
nivolumab
The concept of progression of non-target disease requires additional explanation as follows:
When the patient also has measurable disease: Toachieve ‘unequivocal progression’ on the
basis of the non-target disease, there must be an overall level of substantial worsening innon-
target disease such that, even in presence of SD or PR in target disease, the overall tumor
burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in
the size of one or more non-target lesions is usually not sufficient to qualify for unequivocal
progression status.
When the patient 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 one 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 non-measurable) a useful
test that can be applied when assessing patients for unequivocal progression is to consider if
the increase in overall disease burden based on the change in non-measurable disease is
comparable in magnitude to the increase that would be required to declare PD for measurable
disease: ie, an increase in tumor burden representing an additional 73% increase in ‘volume’
(which is equivalent to a 20% increase diameter in a measurable lesion). Examples include
an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease
from localized to widespread, or may be described in protocols as ‘sufficient to require a
change in therapy’. If ‘unequivocal progression’ is seen, the patient should be considered to
have had overall PD at that point.
3.3
New lesions
The appearance of new malignant lesions denotes disease progression. The finding of a new
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in
imaging modality or findings thought to represent something other than tumor (for example,
some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is
particularly important when the patient’s baseline lesions show partial or complete response. For
example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion,
which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at
baseline is considered a new lesion and will indicate disease progression. An example of this is
the patient who has visceraldisease at baseline and while on study has a CT or MRI brain
ordered which reveals metastases. The patient’s brain metastases are considered to be constitute
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 andfollow-
up evaluation will clarify if it represents new disease. If repeat scans confirm that there isa new 
lesion, then progression should be declared using the date of the initial scan.
3.4
Tumor markers
Tumor markers alone cannot be used to assess objective tumor responses. If markers are initially
above the upper normal limit, however, they must normalize in order for a patient to be
considered as having attained a complete response.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
174


Clinical Protocol
CA209370
BMS-936558
nivolumab
4
EVALUATION OF BEST OVERALL RESPONSE
4.1
Time point response
A response assessment should occur at each time point specified in the protocol.
For patients who have measurable disease at baseline Appendix Table 1 provides a summary of
the overall response status calculation at each time point.
Table 1:
Appendix Table 1 -Summary of the Overall Response Status 
Calculation [Time point response -patients with target (+/-) non-
target disease] 
Target lesions 
Non-target lesions 
New 
lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, and NE=inevaluable
4.2
Missing assessments and inevaluable designation
When no imaging/measurement is done at all at a particular time point, the patient is not
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an
assessment, usually 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 change
theassigned time point response. This would be most likely to happen in the case of PD.
4.3
Best overall response: all timepoints
Best response determination in trials where confirmation of complete or partial response IS
required: Complete or partial responses may be claimed only if the criteria for each are met at a
subsequent time point as specified in the protocol. In this circumstance, the best overall response
can be interpreted as in Appendix Table 2.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
175


Clinical Protocol
CA209370
BMS-936558
nivolumab
Table 2:
Appendix Table 2 -Best overall response when confirmation of CR 
and PR required 
Overall Response 
First Timepoint 
Overall Response 
Subsequent 
Timepoint 
Best Overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa
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 
CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, and NE=inevaluable
aIf a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
4.4
Special notes on response assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’
size (< 10 mm), they may still have a measurement reported on scans. This measurement should
be recorded even though the nodes are normal in order not to overstate progression should it be
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not
have a total sum of ‘zero’ on the case report form (CRF).
Patients with a global deterioration of health status requiring discontinuation of treatment
without objective evidence of disease progression atthat time should be reported as
‘symptomatic deterioration’. Every effort should be made to document objective progression
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an
objective response: it is a reason for stopping study therapy. The objective response status of
such patients is to be determined by evaluation of target and non-target disease as shown in
Appendix Table 1 and Table 2.
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
176


Clinical Protocol
CA209370
BMS-936558
nivolumab
the next scheduled assessment, progression is confirmed, the date of progression should be the
earlier date when progression was suspected.
5
ADDITIONAL CONSIDERATIONS
5.1
Duration of response
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 progressive
disease 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.
Duration of stable disease: Stable disease is measured from the start of the treatment(in 
randomized trials, from date of randomization) until the criteria for progression are met,taking 
as reference the smallest sum on study (if the baseline sum is the smallest, this is thereference 
for calculation of PD).
5.2
Lesions that disappear and reappear
If a lesion disappears and reappears at a subsequent time point it should continue to be measured.
However, the patient’s response at the point in time when the lesion reappears will depend upon
the status of his/her other lesions. For example, if the patient’s tumour had reached a CR status
and the lesion reappeared, then the patient would be considered PDat the time of reappearance.
In contrast, if the tumour status was a PR or SD and one lesion which had disappeared then
reappears, its maximal diameter should be added to the sum of the remaining lesions for a
calculated response: in other words, the reappearance of an apparently ‘disappeared’ single
lesion amongst many which remain is not in itself enough to qualify for PD: that requires the
sum of all lesions to meet the PD criteria. The rationale for such a categorization is based upon
the realization that most lesions do not actually ‘disappear’ but are not visualized because they
are beyond the resolving power of the imaging modality employed.
5.3
Use of FDG-PET
While FDG-PET response assessments need additional study, it is sometimes reasonable to
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging
can be identified according to the following algorithm:
1) Negative FDG-PET at baseline,with a positive FDG-PET at follow-up is a sign of PD based
on a new lesion. Confirmatory CT is recommended.
2) No FDG-PET at baseline and a positive FDG-PET at follow-up:
a) If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT,this is PD.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
177


Clinical Protocol
CA209370
BMS-936558
nivolumab
b) If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT,
additional follow-up CT scans are needed to determine if there is progression occurring at
that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).
c) If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that isnot progressing on the basis of the anatomic images, this is not PD.
6.0
Approved
930090414
6.0
v
Revised Protocol No.: 05
Date: 26-Mar-2018
178

SAP_001.pdf: 
Official Title of Study: 
A Master Protocol of Phase 1/2 Studies of Nivolumab in Advanced NSCLC Using Nivolumab as 
Maintenance after Induction Chemotherapy or as First-line Treatment Alone or in Combination 
with Standard of Care Therapies 
NCT Number: NCT02574078 
Document Date (Date in which document was last revised): July 25, 2018 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
SUSTAIN: A MASTER PROTOCOL OF PHASE 1/2 STUDIES OF NIVOLUMAB IN 
ADVANCED NSCLC USING NIVOLUMAB AS MAINTENANCE AFTER INDUCTION
CHEMOTHERAPY OR AS FIRST-LINE TREATMENT ALONE OR IN COMBINATION 
WITH STANDARD OF CARE THERAPIES
PROTOCOLS CA209370
VERSION # 2.0
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
2
DOCUMENT HISTORY
Document 
Date of Issue
Summary of Changes
Version 1
13-Jun-2016
Original Issue
Version 2
25-Jul-2018
Changes for Revised Protocol 05 
Amendment 04 dated 26MAR2018
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
3
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT................................... 1
DOCUMENT HISTORY ........................................................................................................... 2
TABLE OF CONTENTS ........................................................................................................... 3
LIST OF TABLES ..................................................................................................................... 5
LIST OF FIGURES.................................................................................................................... 5
2
STUDY DESCRIPTION ......................................................................................... 8
2.1
Study Design ........................................................................................................... 9
2.1.1
Treatment Group A: Maintenance, NSQ, PS 0-1, EGFRwt and ALKwt..................... 9
2.1.2
Treatment Group B: Maintenance, SQ, PS 0-1........................................................11
2.1.3
Treatment Group C: First-line, NSQ and SQ, PS 2, EGFRwt and ALKwt................12
2.1.4
Treatment Group D: First-line, PS 0-2, EGFRmut..................................................13
2.1.5
Treatment Group E: First-line, PS 0-2, ALK-positive..............................................14
2.2
Treatment Assignment ............................................................................................15
2.3
Blinding and Unblinding.........................................................................................15
2.4
Protocol Amendments.............................................................................................15
2.5
Data Monitoring Committee and Other External Committees..................................17
3
OBJECTIVES.........................................................................................................18
4
ENDPOINTS..........................................................................................................20
4.1
Primary Endpoints ..................................................................................................21
4.2
Secondary Endpoints ..............................................................................................21
 
 
5
SAMPLE SIZE AND POWER ...............................................................................23
5.1
Group A through D sample size determination........................................................23
5.2
Group E sample size determination.........................................................................25
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES ...........................................................................................................26
6.1
Study Periods..........................................................................................................26
6.2
Treatment Regimens...............................................................................................27
6.3
Populations for Analyses.........................................................................................29
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
4
7
STATISTICAL ANALYSES..................................................................................30
7.1
General Methods.....................................................................................................30
7.1.1
Randomization Stratification Factors......................................................................30
7.1.2
Unblinding..............................................................................................................30
7.2
Study Conduct ........................................................................................................31
7.2.1
Accrual...................................................................................................................31
7.2.2
Relevant Protocol Deviations..................................................................................31
7.3
Study Population.....................................................................................................33
7.3.1
Disposition of Subjects............................................................................................33
7.3.2
Demographic and Other Baseline Characteristics...................................................33
7.3.3
Medical History ......................................................................................................34
7.3.4
Baseline Examinations............................................................................................35
7.3.5
Prior Medications...................................................................................................35
7.3.6
Prior Cancer Therapy.............................................................................................35
7.3.7
Baseline Laboratory................................................................................................35
7.4
Extent of Exposure..................................................................................................35
7.4.1
Administration of Study Therapy.............................................................................35
7.4.2
Modifications of Study Therapy...............................................................................37
7.4.2.1
Infusion Interruptions and Rate Changes ................................................................37
7.4.2.2
Dose Escalations ....................................................................................................37
7.4.2.3
Dose Reductions .....................................................................................................37
7.4.4
Immune modulating medication ..............................................................................38
7.5
Efficacy ..................................................................................................................38
7.5.1
Efficacy Analysis: PFS and OS ...............................................................................40
7.5.1.1
Subset Analyses of Progression-Free Survival and OS ............................................40
7.5.1.2
Current status of OS follow-up................................................................................40
7.5.2
Efficacy Analysis: DOR and ORR ...........................................................................40
7.5.3
Efficacy Analysis: DCR...........................................................................................41
7.5.4
Subsequent Therapy................................................................................................41
7.6
Safety .....................................................................................................................42
7.6.1
Deaths ....................................................................................................................42
7.6.2
Adverse Events........................................................................................................42
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................42
7.6.4
Adverse Events Leading to Dose Modification ........................................................42
7.6.5
Serious Adverse Events ...........................................................................................42
7.6.6
Select Adverse Events .............................................................................................43
7.6.6.1
Incidence of select AE.............................................................................................43
7.6.6.2
Time-to onset of select AE.......................................................................................43
7.6.6.3
Time-to resolution of select AE ...............................................................................43
7.6.7
Immune-Mediated Adverse Events ..........................................................................43
7.6.7.1
Incidence of IMAEs.................................................................................................45
7.6.8
Clinical laboratory evaluations...............................................................................45
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
5
7.8
Outcomes Research Analyses..................................................................................46
7.8.1
Eligible population .................................................................................................46
7.8.2
FACT-L questionnaire ............................................................................................46
7.8.3
EQ-5D-3L questionnaire.........................................................................................47
7.8.3.1
Calculation of Total Scores for Scales/Items ...........................................................48
7.8.4
Handling of Missing Data.......................................................................................48
8
CONVENTIONS....................................................................................................48
9
CONTENT OF REPORTS......................................................................................50
11
LIST OF ABBREVIATIONS .................................................................................54
12
CHANGES FROM PROTOCOL............................................................................59
APPENDIX 1
SELECT ADVERSE EVENTS DEFINITION AND 
CONVENTIONS....................................................................................60
LIST OF TABLES
Table 3-1:
Study Objectives.....................................................................................18
Table 5.1-1:
Maximum Sample Size and Comparisons of Interest...............................24
Table 5.2-1:
Estimated Incidence................................................................................26
Table 7.4.1-1:
Administration of Study Therapy: Definition of Parameters....................36
Table 7.5-1:
Censoring Scheme for Primary Definition of PFS...................................39
Table 7.6.7-1:
Preferred Terms Included in Analysis of IMAEs to Support Warning 
and Precautions.......................................................................................44
Table 10-1:
Derivation of clustered select AE............................................................61
LIST OF FIGURES
Figure 2.1.1-1:
Group A Schematic - Maintenance Therapy in subjects with NSQ 
NSCLC and PS 0-1, without EGFR and ALK Mutations ........................10
Figure 2.1.2-1:
Group B Schematic - Maintenance Therapy in Subjects with SQ 
NSCLC and PS 0-1.................................................................................12
Figure 2.1.3-1:
Group C Schematic - First-line Treatment in NSQ or SQ NSCLC 
Subjects with PS 2, without EGFR and ALK Mutations..........................13
Figure 2.1.4-1:
Group D Schematic - First-line Treatment in Subjects with PS 0-2, 
and EGFR mutations...............................................................................14
Figure 2.1.5-1:
Group E Study Schematic - First-Line Treatment in Subjects with PS 
0-2, and ALK-positive ............................................................................14
2.0
Approved
930106945
3.0
v






Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
8
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
2
STUDY DESCRIPTION
This is an open-label, Phase 1/2, Master Protocol (revised protocol 05), containing 5 sub-studies (sub-
protocols), that will each enroll a unique patient population. Subjects with recurrent locally advanced 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
9
or Stage 4 SQ or NSQ NSCLC, with an ECOG PS of 0-2, will receive either first-line or maintenance
therapy with nivolumab as a single-agent or in combination with SOC therapies. Subjects will be
assigned to one of the following treatment groups based on histology, ECOG PS, and mutation status:
•
Group A subjects with NSQ NSCLC and a PS 0-1 will be randomized (1:1:1) to receive single-
agent nivolumab, single-agent pemetrexed or bevacizumab, or the combination of nivolumab and 
pemetrexed or bevacizumab, as maintenance therapy following first-line treatment with 
Investigator’s Choice chemotherapy. The primary objectives of Group A are to compare PFS and 
OS of single-agent bevacizumab versus single-agent nivolumab, or the combination of nivolumab 
and bevacizumab, or single-agent pemetrexed versus single-agent nivolumab, or the combination 
of nivolumab and pemetrexed.; comparisons of DOR and ORR are the secondary objectives.
•
Group B subjects with SQ NSCLC and a PS 0-1 will be randomized (1:1) to receive either single-
agent nivolumab or best supportive care (BSC) as maintenance following first-line treatment with
Investigator’s Choice chemotherapy. The primary objectives of Group B are to compare PFS and 
OS of single-agent nivolumab versus BSC; comparisons of DOR and ORR are the secondary 
objectives.
•
Group C subjects with NSCLC of NSQ or SQ histology with PS 2 will be randomized (1:1) to 
receive either Investigator’s Choice chemotherapy or single-agent nivolumab as first-line
treatment. The primary objectives of Group C are to compare PFS and OS of single-agent
nivolumab versus Investigator’s Choice chemotherapy. The secondary objectives are the
comparisons of DOR and ORR.
•
Group D subjects with NSCLC histology and EGFR mutation, and a PS 0-2 will be randomized 
(1:1) to first-line treatment with erlotinib or the combination of nivolumab and erlotinib. The 
primary objective of Group D is to compare PFS of the combination of nivolumab and erlotinib 
versus erlotinib alone; comparisons of OS, ORR, and DOR are secondary objectives.
•
Group E will evaluate the safety of combination therapy of nivolumab and crizotinib as first-line 
treatment in NSCLC, PS 0-2 ALK-positive subjects. The primary objective of Group E is to 
describe the safety and tolerability of nivolumab in combination with crizotinib; the secondary 
objectives are to describe PFS and ORR.
Subjects currently on treatment may continue to be treated and monitored as specified in the protocol. 
The decision to continue treatment should be based on the clinical judgment of the treating physician, 
in consultation with the patient.
As per Amendments 03 and 04, enrollment has closed for all groups.
Further details of the design of each Group A through E are provided in Section.2.1
2.1
Study Design
2.1.1
Treatment Group A: Maintenance, NSQ, PS 0-1, EGFRwt and ALKwt
Following first-line therapy with 4 to 6 cycles of Investigator’s Choice of chemotherapy regimens 
(carboplatin or cisplatin plus paclitaxel plus bevacizumab or carboplatin or cisplatin plus 
pemetrexed), subjects showing no signs of progression, will be randomized (1:1:1) to receive 
maintenance therapy on 1 of 6 arms. Subjects under consideration for Group A are to complete the
entire cycle 4 to 6-week of induction chemotherapy without disease progression prior to being
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
10
consented for this study. The maintenance treatment is to start within 42 days of completing induction
chemotherapy.
•
Arm A1: bevacizumab 15 mg/kg every 3 weeks
•
Arm A2: bevacizumab 15 mg/kg + nivolumab 5 mg/kg every 3 weeks over 30-minute infusion
•
Arm A3: nivolumab 240 mg every 2 weeks over 30-minute infusion
•
Arm B1: pemetrexed 500 mg/m2 every 3 weeks
•
Arm B2: pemetrexed 500 mg/m2 every 3 weeks + nivolumab 5 mg/kg every 3 weeks over 30-
minute infusion
•
Arm B3: nivolumab 240 mg every 2 weeks
Pemetrexed premedication regimen: folic acid and vitamin B12, and dexamethasone are to be given 
per local institution standard and package insert.
Pemetrexed and bevacizumab administration is to follow their package insert. Subjects will be 
considered on-study once randomized to a maintenance therapy arm (beginning of Cycle 1). On-study 
tumor assessments will begin at Week 9 (± 1 week) and be performed every 8 weeks (± 1 week) for 
up to 2 years. 
The schematic for Group A is presented in Figure 2.1.1-1.
Figure 2.1.1-1:
Group A Schematic - Maintenance Therapy in subjects with NSQ 
NSCLC and PS 0-1, without EGFR and ALK Mutations 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
11
Note: The maintenance treatment is to start within 42 days of completing induction chemotherapy.  Subjects who 
completed bevacizumab-containing induction chemotherapy will only be randomized to Arm A1, A2 or A3 and 
subjects who completed pemetrexed-containing induction chemotherapy will only be randomized to Arm B1, B2 or B3.   
ALK=anaplastic lymphoma kinase; E=enrolled; EGFR=epidermal growth factor receptor; NSQ=non-squamous cell 
carcinoma; NSCLC = non-small cell lung cancer; PS=performance status; q=every; R=randomized; wt=wild type.
2.1.2
Treatment Group B: Maintenance, SQ, PS 0-1
Following initial therapy with 4 to 6 cycles of Investigator’s Choice of chemotherapy regimens
(carboplatin or cisplatin plus paclitaxel, carboplatin or cisplatin plus gemcitabine, carboplatin or 
cisplatin plus docetaxel, carboplatin or cisplatin plus albumin bound paclitaxel, carboplatin or 
cisplatin plus etoposide, carboplatin or cisplatin plus vinorelbine), subjects in Group B, showing no 
signs of progression, will be randomized (1:1) to maintenance therapy with either single-agent 
nivolumab (240 mg every 2 weeks) or BSC. Subjects under consideration for Group B are to complete 
the entire 4-6 week cycle of induction chemotherapy without disease progression prior to being 
consented for this study. Subjects will be considered on-study once randomized to a maintenance 
therapy arm (beginning of Cycle 1).On-study tumor assessments will begin at Week 9 (± 1 week) and 
be performed every 8 weeks (± 1 week) for up to 2 years.
The Group B schematic is presented in Figure 2.1.2-1.
Best supportive care arm may include palliative radiation therapy or palliative surgery. The major 
components of BSC include:
•
Adequate control of pain and other symptoms
•
Identification of distressing symptom
•
Support and assist decision making
•
Illness understanding/education
•
Coping with life-threatening illness
•
Indicate referrals to other care providers
Symptom management includes but is not limited to:
•
Pain
•
Pulmonary symptoms (cough, dyspnea)
•
Fatigue and sleep disturbance
•
Mood (depression and anxiety)
•
Gastrointestinal (anorexia and weight loss, nausea and vomiting, constipation).
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
12
Figure 2.1.2-1:
Group B Schematic - Maintenance Therapy in Subjects with SQ NSCLC 
and PS 0-1
Note: The maintenance treatment is to start within 42 days of completing induction chemotherapy. 
BSC=best supportive care; E=enrolled; NSCLC=non-small cell lung cancer; R=randomized; PS=performance status; 
q=every; SQ=squamous cell carcinoma. 
2.1.3
Treatment Group C: First-line, NSQ and SQ, PS 2, EGFRwt and ALKwt
Subjects assigned to Group C will be randomized (1:1) to receive first-line therapy with either: 4 to 
6 cycles of Investigator’s Choice of chemotherapy (Arm A) or single-agent nivolumab (Arm B).
The list of Investigator’s Choice chemotherapy regimens is referenced from NCCN guideline 2015-
20th annual edition.
Investigator’s Choice chemotherapy regimens will be as follows:
•
Arm A (NSQ):
−
Carboplatin AUC = 6 + nab-paclitaxel 100mg/m2 Days 1, 8, and 15 every 3 weeks
−
Carboplatin AUC = 6 + paclitaxel 200 mg/m2 every 3 weeks
−
Carboplatin AUC = 6 + pemetrexed 500 mg/m2 every 3 weeks
−
Carboplatin AUC = 6 + docetaxel 75 mg/m2 every 3 weeks
−
Paclitaxel 175-225 mg/m2 every 3 weeks
−
Docetaxel 60-75 mg/m2 every 3 weeks
−
Gemcitabine 1000 mg/m2 Days 1 and 8 every 3 weeks
−
Pemetrexed 500 mg/m2 every 3 weeks
•
Arm A (SQ):
−
Carboplatin AUC = 6 + nab-paclitaxel 100mg/m2 Days 1, 8, and 15 every 3 weeks
−
Carboplatin AUC = 6 + paclitaxel 200 mg/m2 every 3 weeks
−
Carboplatin AUC = 5 + gemcitabine 1000 mg/m2 Days1 and 8 every 3weeks
−
Carboplatin AUC =6 + docetaxel 75 mg/m2 every 3 weeks
−
Paclitaxel 175-225 mg/m2 every 3 weeks
−
Docetaxel 60-75 mg/m2 every 3 weeks
−
Gemcitabine 1000 mg/m2 days 1 and 8 every 3 weeks
•
Arm B (SQ or NSQ):
−
Nivolumab 240 mg every 2 weeks over 30 minute IV infusion
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
13
Subjects may receive optional maintenance therapy after initial chemotherapy in control group
receiving Investigator’s Choice chemotherapy per investigator decision of maintenance regimen
according to NCCN guideline.
Subjects will be considered on-study once randomized to a treatment arm (beginning of Cycle 1). 
On-study tumor assessments will begin at Week 9 (± 1 week) and will be performed every 8 weeks
(± 1 week) for up to 2 years. The study design schematic is presented in Figure 2.1.3-1.
Figure 2.1.3-1:
Group C Schematic - First-line Treatment in NSQ or SQ NSCLC 
Subjects with PS 2, without EGFR and ALK Mutations
ALK=anaplastic lymphoma kinase; E=enrolled; EGFR=epidermal growth factor receptor; NSCLC=non-small cell lung 
cancer; NSQ=non-small cell carcinoma; R=randomized; PS=performance status; q=every; SQ=squamous cell carcinoma; 
wt=wild-type. 
2.1.4
Treatment Group D: First-line, PS 0-2, EGFRmut
Subjects in Group D will be randomized (1:1) to treatment with erlotinib monotherapy or the
combination therapy (erlotinib plus nivolumab) as follows:
•
Arm A: erlotinib 150 mg QD
•
Arm B: nivolumab 240 mg every 2 weeks + erlotinib 150 mg QD
Treatment for both arms will continue until disease progression, discontinuation due to unacceptable 
toxicity, withdrawal of consent, or up to a maximum of 24 months, whichever occurs first. Subjects 
must continue to meet all applicable inclusion and exclusion criteria.
On-study tumor assessments will begin at Week 9 (± 1 week) and be performed every 8 weeks (± 1 
week) for up to 2 years. The study design schematic is presented in Figure 2.1.4-1.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
14
Figure 2.1.4-1:
Group D Schematic - First-line Treatment in Subjects with PS 0-2, and 
EGFR mutations
E=enrolled; EGFR=epidermal growth factor receptor; mut=mutation; R=randomized; PS=performance status; q=every. 
2.1.5
Treatment Group E: First-line, PS 0-2, ALK-positive
Subjects in Group E will receive the combination therapy of nivolumab (240 mg every 2 weeks) and 
crizotinib (250 mg BID). On-study tumor assessments will begin at Week 9 and will be performed 
every 8 weeks (± 1 week) for up to 2 years.
The study design schematic is presented in Figure 2.1.5-1.
When the 20th patient is enrolled and reaches Week 17, DMC safety review of this cohort will be 
triggered. “Safe” is defined as ≤20% of treated subjects with drug-related AEs leading to 
discontinuation of both drugs by Week 17.
Figure 2.1.5-1:
Group E Study Schematic - First-Line Treatment in Subjects with PS 0-
2, and ALK-positive
ALK=anaplastic lymphoma kinase; E=enrolled; q=every; PS=performance status.
Per Amendment 03, this group is closed and all the ongoing subjects have been discontinued from 
the combination treatment of crizotinib and nivolumab 
Close liver function monitoring has been recommended:
•
All subjects are to undergo twice weekly liver function testing through 60 days following the last 
dose of nivolumab.
•
Subjects with normal results for liver function are to undergo once weekly liver function testing 
from 61 days through 100 days following the last dose of nivolumab.
•
Subjects with an abnormal result for liver function within 100 days of the last dose of nivolumab, 
are to undergo twice weekly liver function testing. 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
15
Additional liver function monitoring should be based on the clinical judgment of the treating 
physician.
2.2
Treatment Assignment
Subjects will be enrolled using an Interactive Response System (IVRS). During the enrollment period, 
a subject will provide signed informed consent and their study eligibility will be established. Subjects 
meeting enrollment criteria for Groups A, B, C, or D will be randomized to treatment arms as 
described in Sections 2.1.1, 2.1.2, 2.1.3, or 2.1.4 using IVRS. Subjects in Group E are not randomized.
For Groups A and B, randomization will be stratified by:
1) Disease status (recurrent locally advanced vs. metastatic)
2) Response (complete response/partial response/stable disease) to induction chemotherapy
3) History of ablative/definitive radiation therapy to oligometastasis post induction therapy (yes vs. 
no).
For Group C, randomization will be stratified by:
1) Disease status (recurrent locally advanced vs. metastatic)
2) Tumor histology (NSQ vs. SQ).
For Group D, randomization will be stratified by:
1) Disease status (recurrent locally advanced vs. metastatic)
2) Performance status (ECOG 0, 1 or 2).
2.3
Blinding and Unblinding
This is an open-label study. Blinding is not applicable. However, to reduce bias, the study team from 
the Sponsor and the CRO/vendors who are involved in the trial conduct will be blinded for the 
aggregated data at the treatment level until the trial database lock.
The Data Monitoring Committee (DMC) will be provided with unblinded data in order to ensure the 
ongoing safety and efficacy of the trial. Data unblinding as required for the DMC review will be 
conducted on an ongoing basis by a data manager/statistician or CRO not involved in the trial conduct 
in order to keep the trial team blinded.
2.4
Protocol Amendments
Revised Protocol 01 (31-Jul-2015) incorporates Amendment 01:
1) Sample size
a) Group A corrected to 765
2) To simplify the study design for Group D
a) Removed central testing for EGFR mutation
b) Removed independent imaging review
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
16
3) To modify biomarker sample collection
a) The timing on whole blood, serum and tissue collection is simplified to be consistent with 
project standard.
b) Plasma sample for circulating tumor DNA is added to Group D
c) Addition of HCRU assessments to Groups A, C and D
Revised Protocol 02 (29-Oct-2015) incorporates Administrative Letter 01:
1) Addresses inconsistencies in the previous version
Revised Protocol 03 (28-Sep-2016) incorporates Amendment 02:
To updates the Adverse Event Management Algorithms for
1) Nivolumab per Investigator Brochure Version 15 & Erratum 01 to Investigator Brochure 
2) Version 15
3) To update the Study Director/Medical Monitor
4) To address inconsistencies/errors
5) To add cisplatin as one of platinum-based chemotherapies for consistence and for flexibility for 
the induction therapy
6) The adverse event collection for Group B, Arm B (Best Supportive Care) was updated to 
commerce at randomization for clarification and consistence
7) To clarify information from the previous version
Revised Protocol 04 (28-Mar-2017) incorporates Amendment 03
1) Amendment to close enrollment for Groups A, B, C, and E.
2) To note that Group E will receive no further treatment, and to add additional monitoring for liver 
toxicity through follow up in these subjects.
3) Pregnancy language was updated.
Revised Protocol 05 (26-Mar-2018) incorporates Amendment 04
1) Amendment to closes enrollment for Group D
2) Clarified statistical treatment of subjects who received any subsequent anti-cancer therapy 
without previously reported progression
3) Updated the actual samples sizes for study groups after closing enrollment and statistical analyses
4) Added rationale for closing enrollment for Group D
5) Updated timing of tumor assessments during study
6) Changed the collection of survival status from 5 years to 4 years
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
17
9) Updated protocol with current program safety language for dose modifications and 
discontinuations
10) Updated protocol with current program contraception language
2.5
Data Monitoring Committee and Other External Committees
A DMC will be established to provide oversight of safety and efficacy considerations in protocol
CA209370, and to provide advice to the sponsor regarding actions the committee deems necessary 
for the continuing protection of subjects enrolled in the trial. The DMC will be charged with assessing 
such actions in light of an acceptable benefit/risk profile for nivolumab. The DMC will act in an 
advisory capacity to BMS and will monitor subject safety and evaluate the efficacy data for the study. 
Efficacy will also be reviewed by the DMC - as part of the benefit-to-risk assessment and for the 
formal analyses of PFS and OS.
The DMC will be advisory to the clinical study leadership team. The clinical study leadership team 
will have responsibility for overall conduct of the study including managing the communication of 
study data. The group will be responsible for promptly reviewing the DMC recommendations, for 
providing guidance regarding the continuation or termination of the study, and for determining 
whether to continue enrollment or follow-up.The oncology therapeutic area of BMS has primary 
responsibility for design and conduct of the study. Details of DMC responsibilities and procedures 
are specified in the DMC charter [25].
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
18
3
OBJECTIVES
The primary, secondary, and exploratory objectives are summarized in Table 3-1.
Table 3-1:
Study Objectives
Primary Objectives
Secondary Objectives
Group A: 
Maintenance, 
NSQ, PS 0-1, 
EGFRwt and 
ALKwt
To compare PFSa and
OS of maintenance 
treatment with 
bevacizumab versus 
nivolumab or 
bevacizumab versus 
nivolumab + 
bevacizumab (Arm 
A) or pemetrexed 
versus nivolumab or 
pemetrexed versus 
nivolumab + 
pemetrexed (Arm B)
•
To compare duration 
of response (DOR)
and objective
response rate (ORR) 
of 
maintenance 
treatment 
with 
bevacizumab versus 
nivolumab 
or
bevacizumab versus 
nivolumab 
+ 
bevacizumab (Arms 
A1,
A2, A3)
or 
pemetrexed 
versus
nivolumab 
or 
pemetrexed 
versus 
nivolumab 
+ 
pemetrexed 
(Arms 
B1, B2, B3)
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
19
Table 3-1:
Study Objectives
Primary Objectives
Secondary Objectives
Group B: 
Maintenance, 
SQ, PS 0-1
To compare PFSa 
and OS of 
maintenance 
treatment with 
single-agent 
nivolumab versus 
BSC
•
To compare DOR 
and ORR of 
maintenance 
treatment with 
single-agent 
nivolumab versus 
BSC
Group C: 
First-line, 
NSQ and SQ, 
PS 2,
EGFRwt and
ALKwt
The primary 
objective will be to 
compare PFS and 
OS of single-agent 
nivolumab versus
investigator’s choice 
chemotherapy
•
To compare DOR and 
ORR of nivolumab 
versus investigator’s 
choice chemotherapy
Group D:
First-line, PS
0-2, EGFRmut
To compare PFS 
with the 
combination of 
nivolumab plus 
erlotinib versus 
erlotinib
•
To 
compare 
OS, 
ORR, and DOR of the
combination 
of 
nivolumab 
plus 
erlotinib 
versus 
erlotinib alone
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
20
Table 3-1:
Study Objectives
Primary Objectives
Secondary Objectives
Group E:
First-line, PS
0-2,
ALK-positive
To estimate the 
incidence of 
treatment-related 
(nivolumab + 
crizotinib) AEs 
leading to study drug 
discontinuation
•
To describe PFS of 
combination therapy
•
To
assess
ORR 
associated 
with 
combined Nivolumab 
and crizotinib therapy
a Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented tumor
progression, as determined by investigators (per RECIST v1.1), or death due to any cause, whichever occurs first.
AE=adverse events; ALK=anaplastic lymphoma kinase, BSC=best supportive care; CR=complete response;
DCR=disease control rate; DOR=duration
of response;
ECOG=Eastern
Cooperative
Oncology Group;
EGFR=epidermal growth factor receptor; mut=mutation; NSCLC=non-small cell lung cancer; NSQ=non-
squamous; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; PR=partial
response; PS=performance status; SD=stable disease; SQ=squamous; WT=wild-type.
4
ENDPOINTS
•
Disease control rate (DCR) is defined as the number of subjects that achieved a best overall
response of CR, PR, or SD, divided by the total number of randomized subjects with 
measurable disease at baseline. (This endpoint is for Group D only.)
•
Duration of response (DOR) is defined as the time from first confirmed response (CR or PR)
to the date of the initial objectively documented tumor progression as determined using
RECIST 1.1 criteria or death due to any cause, whichever occurs first. For subjects who neither 
progress nor die, the DOR will be censored on the date of their last evaluable tumor assessment. 
DOR will only be evaluated in subjects with objective response of CR or PR
•
Objective response rate (ORR) is defined as the number and percentage of subjects with a best 
overall response (BOR) of confirmed complete response (CR) or partial response (PR). Best 
overall response (BOR) is defined as the best response designation, recorded between the date 
of first dose and the date of the initial objectively documented tumor progression per RECIST 
v1.1 or the date of subsequent therapy, whichever occurs first. For subjects without
documented progression or subsequent therapy, all available response designations will
contribute to the BOR determination.
•
Overall survival (OS) is defined as the time from randomization to the date of death. A subject 
who has not died will be censored at last known date alive. OS will be followed continuously 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
21
while subjects are on the treatment and every 3 months via in-person or phone contact after 
subjects discontinue the study drug.
•
Progression-free survival (PFS) is defined as the time from randomization to the date of the
first documented tumor progression, as determined by investigators (per RECIST v1.1), or
death due to any cause, whichever occurs first. Subjects who die without a reported prior 
progression will be considered to have progressed on the date of their death. 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 assessment and did not die will be censored on 
the first dosing date.
•
Subjects who received any subsequent anti-cancer therapy (including on-treatment palliative 
radiation therapy of non-target bone lesions or CNS lesions) without a prior reported 
progression will be censored at the last evaluable tumor assessment prior to or on the date of 
initiation of the subsequent anti-cancer therapy.
•
Group E PFS and OS are defined as the time from first treatment to the date of event since
there is no randomization in this group.
•
Group C Patient Reported Outcome (PRO) data from the EQ-5D and FACT-L, will be assessed 
by measuring change from baseline at each assessment point and disease-related symptom 
improvement rate as reported by the FACT-L.
•
All safety data will be summarized and listed for all treated subjects. All on-study AEs, SAEs, 
treatment-related AEs, and treatment-related SAEs, etc. will be summarized using worst grade 
per NCI CTCAE v4.0 by system organ class and preferred term. On-study lab abnormalities 
including hematology, chemistry, liver function, thyroid function, and renal function will be 
summarized using worst grade per NCI CTCAE v4.0 criteria.
4.1
Primary Endpoints
Group A: PFS and OS
Group B: PFS and OS
Group C: PFS and OS
Group D: PFS
Group E: Incidence of treatment-related AEs leading to both study drugs discontinuation.
4.2
Secondary Endpoints
Group A: DOR and ORR
Group B: DOR and ORR
Group C: DOR and ORR
Group D: OS, DOR, and ORR
Group E: PFS, and ORR
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
22
 
 
 
 
 
 
 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
23
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5
SAMPLE SIZE AND POWER
5.1
Group A through D sample size determination
A decision was made in December 2016 to stop enrollment for Groups A, B, and C, and stop 
enrollment and treatment for Group E. Sample sizes for these groups will be the number of 
patients already randomized (treated in Group E).
A decision was made in December 2017 to stop enrollment for Group D. As a result of this 
decision, the actual sample sizes for these groups are indicated in the following table. Therefore, 
the overall population randomized or enrolled in this Master Protocol is now approximately 342 
subjects.
Group
Sample Size
A
132
B
35
C
52
D
109
E
14
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
24
The following is the rationale of the original sample size determination.
This is a Phase 1/2, open-label, Master Protocol with 5 groups/sub-studies. The planned overall 
population to be enrolled in this Master Protocol was approximately 1953 subjects at maximum. 
Individual sample sizes per group are shown in Table 5.1-1. The sample size for each Group 
depends on the population, treatment effect, and primary endpoint for each group.
Table 5.1-1:
Maximum Sample Size and Comparisons of Interest
Population 
Maximum 
Sample Size
Primary 
Endpoint
Comparisons of Interest
Group A:
Maintenance,
NSQ, PS 0-1,
EGFRwt and
ALKwt
765
1:1:1
randomization 
in bevacizumab
containing arms.
1:1:1
randomization 
in
pemetrexed
containing arms
PFS/OS
1. Nivolumab vs. bevacizumab for PFS
2. Nivolumab vs. bevacizumab for OS
3. Nivolumab plus bevacizumab vs. bevacizumab for 
PFS
4. Nivolumab plus bevacizumab vs. bevacizumab for 
OS
5. Nivolumab vs. pemetrexed for PFS
6. Nivolumab vs. pemetrexed for OS
7. Nivolumab plus pemetrexed vs. pemetrexed for PFS
8. Nivolumab plus pemetrexed vs. pemetrexed for OS
Group B:
Maintenance,
SQ, PS 0-1
500
1:1
randomization
PFS/OS
Nivolumab vs. Best supportive care
Group C: First-
line, NSQ and
SQ, PS 2,
EGFRwt and
ALKwt
350
1:1
randomization
PFS/OS
Nivolumab vs. Investigator choice chemotherapy for 
superiority and non-inferiority
Group D: First-
line, PS 0-2,
EGFRmut
318
1:1
randomization
PFS
Nivolumab plus Erlotinib vs. Erlotinib
Group E: First-
line, PS 0-2,
ALK-positive
20
Single arm,
No
randomization
Incidence of
drug-related
AEs leading
to
discontinuatio
n
Not Applicable
AE=adverse event; PFS=progression-free survival; OS=overall survival.
The adaptive trial is designed to identify an appropriate sample size and follow-up duration based 
upon accruing information to produce sufficient power in each group for a range of potential effect 
sizes and PFS/OS rates rather than provide a fixed power for one particular expected effect size 
and PFS/OS rate which may prove to be incorrect once we observe trial data.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
25
The values below illustrate high power for one possible value of expected benefit in the nivolumab 
vs. controlarms. Full operating characteristics over a broader range ofpossible median PFS values, 
OS values, and hazard ratios are shown in the full adaptive design plan, available upon request.
For example, Group A, assuming median control (Pem or Bev) PFS of 5 months and a median of 
7.5 months in the nivolumab and nivolumab combination arms to produce a hazard ratio of 0.67, 
the design offers 91% power in the Nivo vs. Pem comparisons and 64/74% in the Nivo alone/Nivo-
combination vs. Bev comparisons, respectively. This also assumes that 80% of patients will have 
previously taken pemetrexed vs. 20% on bevacizumab.
Group A, assuming median control (Pem or Bev) OS of 21 months and a median of 29 months in 
the nivolumab and nivolumab combination arms to produce a hazard ratio of 0.72, the design offers 
86% power in the Nivo vs. Pem comparisons and 57% in the Nivo vs. Bev comparisons. This also 
assumes that 80% of patients will have previously taken pemetrexed vs. 20% on bevacizumab.
Group B, assuming true but unknown hazard ratios of 0.75 for both PFS (5.5 vs. 7.3 months) and 
OS (13.1 vs. 17.4 months), 500 patients provides 86% power for PFS and 99% power for OS. If 
the OS hazard ratio decreases to 0.79 (13.1 vs. 16.6 months), then 500 patients still offers 93% 
power for OS.
Group C, assuming true but unknown hazard ratios of 0.73 for both PFS (3.5 vs. 4.8 months) and 
OS (7.2 vs. 9.9 months), 350 patients provides 80% power for PFS and 96% power for OS. If the 
OS hazard ratio decreases to 0.79 (7.2 vs. 9.3 months), then 350 patients still offers 84% power 
for OS.
Group D, assuming true but unknown hazard ratios of 0.63 for PFS (10 vs. 16 months), the design 
provides 91% power for PFS.
Full operating characteristics over a broader range of possible median PFS values, OS values, and 
hazard ratios are shown in the full adaptive design plan, and available upon request.
5.2
Group E sample size determination
In order to characterize the safety and tolerability, this study will treat with novel combination:
nivolumab and crizotinib in 20 subjects who have recurrent locally advanced or metastatic
NSCLC. This sample size will allow estimating an approximate incidence rate of 5% (n=1 subjects 
with nivolumab treatment-related adverse events) with a 95% CI (confidence interval) of (0.13%, 
24.9%), or an incidence rate of 40% (n=8 subjects with events) with a 95% CI of (19.12%, 
63.95%).
Estimated 95% CIs for various event rates for a population of 20 subjects are described in Table 
5.2-1. The goal is to identify safe regimen for future development and “safe” is defined as ≤20% 
treated subjects with drug-related AEs leading to drug discontinuation by Week 17.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
26
Table 5.2-1:
Estimated Incidence
Estimated Incidence Rates and 95% CIs
Sample Size
Incidence Rate (%)
Lower 95% CI (%)
Upper 95% CI (%)
20
5.0
0.13
24.90
20
10.0
1.23
31.70
20
15.0
3.21
37.89
20
20.0
5.73
43.66
20
25.0
8.66
49.10
20
30.0
11.89
54.28
20
35.0
15.39
59.22
20
40.0
19.12
63.95
20
45.0
23.06
68.47
20
50.0
27.20
72.80
CI=confidence interval.
Due to observed hepatic toxicity, Group E was permanently terminated with 13 subjects treated 
with the combination treatment of nivolumab and crizotinib.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
•
Unless otherwise specified, the below definitions are applied to all groups/sub-studies.
Baseline period:
−
Baseline evaluations or events will be defined as evaluations or events that occur before 
the date and time of the first dose/randomization of study treatment for safety 
analyses/efficacy analyses.
−
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, vital signs and other safety assessments) 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, the assessment that is closest to day (and time if 
collected) of the first dose of study treatment will be used as the baseline in the analyses. If 
multiple assessments are collected on the same date (and time, if collected), the assessment 
with the latest database entry date (and time, if collected) will be considered as baseline. 
•
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 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
27
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.
−
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.
6.2
Treatment Regimens
•
For randomized sub-studies (Groups A-D), treatment group “as randomized” corresponds 
to the treatment group assigned by the IVRS system
•
The treatment group “as treated” will be same as the treatment group “as randomized” by IVRS 
unless a subject received the incorrect study treatment for the entire period of treatment, in 
which case the subject’s treatment group “as treated” will be defined as the incorrect study 
treatment.
Unless otherwise specified, the safety analysis will be based on the treatment group “as treated”.
Group A: This group will enroll 2 cohorts, subjects who have completed 4-6 cycles of 1) 
bevacizumab, carboplatin, and paclitaxel or 2) pemetrexed and carboplatin. In the first cohort,
subjects will be randomized 1:1:1 to 
1) Arm A1: bevacizumab (15 mg/kg IV q3 weeks)
2) Arm A2: bevacizumab (15 mg/kg IV q3 weeks) + nivolumab (5 mg/kg IV q3 weeks)
3) Arm A3: nivolumab (240 mg IV q2 weeks)
In the second cohort, subjects will be randomized 1:1:1 to
1) Arm B1: pemetrexed (500 mg/m2 IV q3 weeks)
2) Arm B2: pemetrexed (500 mg/m2 IV q3 weeks) + nivolumab (5 mg/kg IV q3 weeks)
3) Arm B3: nivolumab (240 mg IV q2 weeks)
Treatment Arms Comparisons for Group A:
Arm A3 vs. Arm A1
Arm A2 vs. Arm A1
Arm B3 vs. Arm B1
Arm B2 vs. Arm B1  
Group B: The subjects in this group will be randomized 1:1 to
1) Arm A: nivolumab (240 mg IV q2 weeks)
2) Arm B: Best Supportive Care
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
28
Treatment Arms Comparisons for Group B:
Arm A vs. Arm B
Group C: The subjects in this group will be randomized 1:1 to
1) Arm A (NSQ): Investigator’s Choice of Chemotherapy:
•
Carboplatin AUC = 6 + nab-paclitaxel (100 mg/m2) Days 1, 8, and 15 q3 weeks
•
Carboplatin AUC = 6 + paclitaxel (200 mg/m2) q3 weeks
•
Carboplatin AUC = 6 + pemetrexed (500 mg/m2) q3 weeks
•
Carboplatin AUC = 6 + docetaxel (75 mg/m2) every 3 weeks
•
Paclitaxel (175-225 mg/m2) q3 weeks
•
Docetaxel (60-75 mg/m2) q3 weeks
•
Gemcitabine (1000 mg/m2) Days 1 and 8 q3 weeks
•
Pemetrexed (500 mg/m2) q3 weeks
Arm A (SQ): Investigator’s Choice of Chemotherapy:
•
Carboplatin AUC = 6 + nab-paclitaxel (100 mg/m2) Days 1, 8, and 15 q3 weeks
•
Carboplatin AUC = 6 + paclitaxel (200 mg/m2) q3 weeks 
•
Carboplatin AUC = 5 + gemcitabine (1000 mg/m2) Days1 and 8 q3 weeks
•
Carboplatin AUC =6 + docetaxel (75 mg/m2) q3 weeks
•
Paclitaxel (175-225 mg/m2) q3 weeks
•
Docetaxel (60-75 mg/m2) q3 weeks
•
Gemcitabine (1000 mg/m2) days 1 and 8 q3 weeks
2) Arm B (NSQ or SQ): nivolumab (240 mg IV q2 weeks)
Treatment Arms Comparisons for Group C:
Arm B vs. Arm A
Group D: Subjects in Group D will be randomized (1:1) to treatment with erlotinib monotherapy 
or the combination therapy (erlotinib plus nivolumab) as follows:
1) Arm A: erlotinib (150 mg QD)
2) Arm B: nivolumab (240 mg IV q2 weeks) + erlotinib (150 mg QD)
Treatment Arms Comparisons for Group D:
Arm B vs. Arm A
Group E: randomization is not applicable, single arm study: nivolumab (240 mg IV q2 weeks) + 
crizotinib (250 mg BID)
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
29
6.3
Populations for Analyses
Group A: Subjects with histologically confirmed Stage 4 or recurrent locally advanced NSQ 
NSCLC. Subjects enrolled must have completed 4-6 cycles of bevacizumab, carboplatin, and 
paclitaxel and without disease progression; or have completed 4-6 cycles of pemetrexed and 
carboplatin without disease progression. ECOG 0 – 1.
Group B: Subjects with histologically confirmed Stage 4 or recurrent locally advanced SQ 
NSCLC. Enrolled subjects must have completed 4-6 cycles of SOC chemotherapy, and without 
disease progression. ECOG performance status 0-1.
Group C: First-line treatment of subjects with histologically confirmed Stage 4 or recurrent 
locally advanced NSCLC and with ECOG Performance Status of 2 with wild-type EGFR and ALK 
alleles.
Group D: First-line treatment for subjects with histologically confirmed Stage 4 or recurrent 
locally advanced EGFR-mutated NSCLC, with ECOG performance status of 0 – 2.
Group E: First-line treatment for subjects with histologically confirmed Stage 4 or recurrent 
locally advanced ALK-positive NSCLC, with ECOG performance status of 0 – 2.
•
All randomized subjects: All subjects who were randomized (applies to Groups A-D) to any 
treatment arm in the study. This is the primary dataset for analyses of demography, protocol 
deviations, baseline characteristics, efficacy, outcome research and biomarker PD-L1 
expression.
•
All enrolled subjects: All subjects who signed an informed consent form. Analyses of the 
patients enrolled into the study but not randomized and the reason for not being randomized 
will be performed on the data set of all enrolled subjects. All enrolled subjects set will be used
as primary dataset for the Group E analyses of study population. 
•
All treated subjects: All subjects who received at least one dose of any study drug. This is the 
primary dataset for analyses of exposure and safety analysis (applies to Groups A-E). This is 
the primary dataset for analyses of study conduct, demography, baseline characteristics, 
efficacy, outcome research and biomarker for Group E.
•
All response evaluable subjects: All randomized subjects who have baseline and at least one 
on-study evaluable tumor measurement
•
All PD-L1 tested subjects: All subjects, randomized or not, who had a tumor biopsy specimen 
available for PD-L1 expression testing (validated assay). This includes both randomized and 
screen failure subjects.
•
All randomized subjects with quantifiable PD-L1 expression at baseline: see definition of 
baseline and quantifiable PD-L1 expression in Section 4.3.6.
•
Randomized subject with measurable disease at baseline – A randomized subject is 
considered to have measurable disease at baseline if they have one or more baseline target 
lesion assessments where at least one target lesion measurement is at least (>=) 10 mm for a 
non-Lymph node tumor location or at least (>=) 15 mm for a Lymph node tumor location.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
30
In general, efficacy will be analyzed for all randomized patients (except Group E for treated 
patients and for Groups A and B BOR will be evaluated for subjects with measurable disease at 
baseline) and safety will be analyzed for all treated patients. 
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise specified: 
•
All analyses described below, summaries and listings are applicable for each Group A-E
•
All analyses will be performed for each Group separately;
•
Group A will be further separated for each Cohort in analyses;
•
Summaries will be produced by treatment arms and total for all groups except Group E.
Unless otherwise noted, discrete variables will be tabulated by the frequency and proportion of 
subjects falling into each category, grouped by treatment (with total). Percentages given in these 
tables will be rounded to one decimal and, therefore, may not always sum to 100%. Percentages 
less than 0.1 will be indicated as ‘< 0.1’. Continuous variables will be summarized by treatment 
arm (with total) using mean, standard deviation, median, minimum, and maximum values.
Since Group E is a single arm study, analyses by treatment arm will consist only of one arm.
The conventions to be used for imputing partial dates for analyses requiring dates are described in 
Section 8.
7.1.1
Randomization Stratification Factors
Groups A-B: Disease Status (Recurrent Locally Advanced vs. Metastatic), Response to Prior 
Chemo (Complete Response vs. Partial Response vs. Stable Disease), History of ablative 
/definitive Radiation Therapy to oligometastasis post induction therapy (yes vs. no).
Group C: Disease Status (Recurrent Locally Advanced vs. Metastatic), Tumor Histology (NSQ 
vs. SQ)
Group D: Disease Status (Recurrent Locally Advanced vs. Metastatic), Performance Status 
(ECOG 0 vs.1 vs. 2). 
Summaries of stratification factors by treatment arms will be provided for Group A, B and D.
7.1.2
Unblinding
Summaries and listings in this statistical analysis plan will be created using dummy treatment 
codes in order to reduce the study bias (section 2.3). The unblinding will be done by a separate 
biostatistics team not involved in the analysis of the study. The unblinded team will produce the 
summaries and listings using the developed SAS programs on true treatment codes and will 
provide the unblinded outputs to the DMC.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
31
7.2
Study Conduct
7.2.1
Accrual
The accrual pattern will be summarized per country, investigational site and per month for all 
enrolled subjects. Randomization date, first dosing date, country, investigational site will be 
presented in a by subject listing of accrual.
7.2.2
Relevant Protocol Deviations
The relevant protocol deviations will be summarized for all randomized (treated for Group E)
subjects, by treatment arm and overall. Non-programmable significant eligibility and on-treatment 
protocol deviations will be reported through Clinical Trial Management System listings.
A subject listing will also be produced.
The following programmable deviations from protocol will be considered as relevant protocol 
deviations.
At Entrance:
−
Eligibility criteria not met. 
Criterion
Group A
Group B
Group C
Group D
Group E
i.  Histology
a) Histologically 
confirmed 
recurrent locally 
advanced or
Stage 4 NSQ 
NSCLCa
b) 
Histologically 
confirmed 
recurrent locally 
advanced or 
Stage 4 SQ 
NSCLCa
c) Histologically 
confirmed 
recurrent locally 
advanced or 
Stage 4 SQ or 
NSQ NSCLCa
d) 
Histologically 
confirmed 
recurrent locally 
advanced or 
Stage 4 
NSCLCa
e) Histologically 
confirmed 
recurrent locally 
advanced or 
Stage 4 
NSCLCa
ii. ECOG PS
a) 0-1
b) 2
c) 0-2
iii. Prior 
induction 
therapy
a) 4-6 cycles of 
bevacizumab or 
pemetrexed 
containing 
induction chemo 
therapy with no 
evidence of 
disease 
progression
b) 4-6 cycles of 
induction chemo 
therapy with no 
evidence of 
disease 
progression
c) None
d) None
iv. EGFR 
mutationb
a) Negative/wild 
type, or 
indeterminate
b) Primary SQ 
histology 
tumors are not 
required to be 
tested for EGFR 
mutation
c) Negative/wild 
type, or 
indeterminate.
Primary SQ 
histology 
tumors are not 
required to be 
tested for EGFR 
mutation
d) Positive 
sensitizing 
mutation (exon 
19 deletion, 
exon 21-L858R-
substition) 
e) Negative/wild 
type, or 
indeterminate
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
32
Criterion
Group A
Group B
Group C
Group D
Group E
v. ALK 
translocationc
a) Negative/wild type, or indeterminate
b)Positive
vi. RECIST 1.1
a) Measureable disease by CT within 21 days of study drug. Target lesions may be located in 
a previously irradiated field with radiographic evidence of disease progression in that site 
post-radiation therapy
b) Groups A and B: Subjects with 
CR/PR/SD to initial induction 
therapy are allowed to enroll
c) Not Applicable
vii. Tissue 
requirement 
a) Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or minimum of 10 
unstained tumor tissue sections, with an associated pathology report, must be submitted for 
biomarker evaluation prior to randomization. Biopsies of bone lesions that do not have a soft 
tissue component or decalcified bone tumor samples or cytology samples are also not 
acceptable.
a According to the 7th International Association for the Study of Lung Cancer classification
b EGFR testing is not required if ALK or KRAS test is positive; ALK testing is not required if EGFR or KRAS test is 
positive; use of an FDA-approved test is strongly encouraged; appropriate documentation of the results must be 
available prior to randomization/treatment
c FDA-approved test is strongly encouraged for ALK translocation testing. Appropriate documentation of the test 
results must be available prior to randomization/ start of treatment
ALK=anaplastic lymphoma kinase, CR=complete response; ECOG=Eastern Cooperative Oncology Group; 
EGFR=epidermal growth factor receptor; FFPE=formalin-fixed paraffin-embedded; mut=mutation; NA=not 
applicable; NSCLC=non-small cell lung cancer; NSQ=non-squamous; PS=performance status; SQ=squamous; 
WT=wild-type.
Treatment Legend: Group A: Maintenance, NSQ PS 0-1, EGFRwt and ALKwt; Group B: Maintenance, SQ, PS 0-1; 
Group C: First-line NSQ and SQ, PS 2, EGFRwt and ALKwt; Group D: First-line PS 0-2, EGFRmut; Group E: First-
line PS 0-2, ALK-positive
−
Baseline laboratory criteria not met. 
Test
Value
i. WBC
≥2000/uL
ii. Neutrophils
≥1500/uL
iii. Platelets
≥100x103/uL
iv. Hemoglobin
≥9.0 g/dL
v. Serum creatinine
≤1.5 ×ULN or 
calculated creatinine clearance > 40 mL/min using the Cockcroft-Gault formula:
Female CrCl = (140- age in years) x weight in kg x 0.85/72 x serum creatinine in mg/ dL
Male CrCl = (140- age in years) x weight in kg x 1.00/72 x serum creatinine in mg/ dL
vi. AST
≤3.0 ×ULN
vii. ALT
≤3.0 ×ULN
viii. Total Bilirubin
≤1.5 ×ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level 
of < 3.0 ×ULN)
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
33
On-study:
•
Subjects receiving prohibitive medications during treatment:
−
Immunosuppressive agents
−
Immunosuppressive doses of systemic corticosteroids (except as stated in protocol Section 
3.4.3 permitted therapy)
−
Concurrent anti-cancer therapy (chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy, standard or investigational agents for treatment of NSCLC).
•
Subjects treated differently as randomized (subjects who received the wrong treatment, 
excluding the never treated).
  
7.3
Study Population
Summaries of study population will be based on all enrolled subjects and will present the number 
of subjects enrolled, randomized, not randomized, treated, not treated, all response evaluable and 
response not evaluable by treatment arms.
7.3.1
Disposition of Subjects 
The total number of subjects randomized, randomized treated and randomized but not treated will 
be presented along with the reason for not being treated by treatment arm as randomized. This 
analysis will be performed on the all randomized population for Group A-D.
The total number of subjects enrolled, enrolled treated and enrolled but not treated will be 
presented along with the reason for not being treated. This analysis will be performed on the all 
enrolled population for Group E.
End of treatment period with the number of subjects who discontinued study treatment along with 
corresponding reason will be tabulated by treatment arm as treated.
A subject listing for all treated subjects will be provided showing the subject’s randomization date, 
first and last dosing date and reason for going off-treatment, based on the treatment phase of the 
study. A subject listing for subjects not randomized or treated will also be provided, showing the 
subject’s race, gender, age, consent date and reason for not being randomized or treated.
7.3.2
Demographic and Other Baseline Characteristics 
Demographic, baseline disease characteristics and baseline laboratory results will be summarized 
using descriptive statistics for all treated subjects and all randomized subjects in each Group.
Demographic characteristics:
•
Age 
•
Age category I (<65,65-<75, ≥75)
•
Age category II (<70, ≥70)
•
Gender
•
Race/Ethnicity
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
34
Initial Disease Characteristics:
•
Disease Stage at Diagnosis (Stage 0/IA/IB/IIA/IIB/IIIA/IIIB/IVA/IVB)
•
Cell Type (Adenocarcinoma, Squamous Cell Carcinoma, Large Cell Carcinoma, Broncho-
alveolar Carcinoma, Other)
•
Time from initial diagnosis to randomization/start of treatment (mean, SD; categories will be 
defined based on the data)
Current Disease Characteristics:
•
Disease Stage at Study Entry (Stage IIIA/IIIB/IVA/IVB)
•
Cell Type (Adenocarcinoma, Squamous Cell Carcinoma, Large Cell Carcinoma, Broncho-
alveolar Carcinoma, Other)
Other Baseline Characteristics:
•
Baseline tumor histology
•
Previously irradiated tumor lesions appeared/progressed since the completion of radiotherapy
(Yes/No)
•
Tobacco Use (current, former, never, unknown)
•
Baseline Height
•
Baseline Weight
•
Body surface area (BSA)
•
Performance Status ECOG (0,1,2)
•
Target Lesions: Assessment of target lesions (Yes/No), if Yes: Tumor code (list from the 
database), site of target lesion, procedures for evaluating target lesion (list from the database), 
target lesion measurement in mm, target lesion evaluation for non-measurable lesions (too 
small to measure, lesion split, lesion merged, unable to determine, procedure not done, lesion 
not evaluated)
•
Non-target lesions: Assessment of target lesions (Yes/No), if Yes: Tumor code (list from the 
database), site of target lesion, procedures for evaluating target lesion (list from the database).
•
Baseline EGFR Mutation Status: Assay results available (Yes/No), if Yes: Mutations (list from 
the database), Method (list from the database) (for Group D)
•
Baseline ALK Mutation Status: Assay results available (Yes/No), if Yes: Mutations (list from 
the database), Method (list from the database) (for Group E)
•
Baseline K-RAS mutation status
•
Baseline MET receptor status
•
Baseline any other mutation status reported
7.3.3
Medical History
General medical history will be listed by subject and pretreatment events will be tabulated.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
35
7.3.4
Baseline Examinations
Subjects with abnormal baseline physical exam results will be tabulated by examination criteria 
(e.g., neck, cardiovascular, lungs, etc.) and by treatment arm as randomized. A by subject listing
will be provided.
7.3.5
Prior Medications
Prior medications, defined as medications other than study medications which are taken prior 
treatment start (i.e., prior to the first day of study therapy) other than those anti-cancer therapy will 
be coded using the WHO Drug Dictionary.
The following summary table will be provided:
•
Prior/current non-study medications (classified by medication classes and generic term) 
A by-subject listing will accompany the table. 
7.3.6
Prior Cancer Therapy
The following will be summarized by treatment arms as randomized or treated:
Prior anti-cancer therapy:
•
Prior Surgery (Yes/No, if Yes: type of surgery from the database)
•
Prior Radiotherapy (Yes/No, if Yes: sites of radiotherapy from the database)
•
Prior Systemic Cancer Therapy (regimen and setting, best response to most recent regimen
[CR/PR vs. SD vs. PD], reason for regimen discontinuation)
•
Setting of prior systemic therapy regimen received (adjuvant, metastatic disease, recurrent 
disease, neo-adjuvant).
7.3.7
Baseline Laboratory
Baseline laboratory will be summarized by treatment arm for all subjects. 
7.4
Extent of Exposure
Analyses in this section will be performed in all treated subjects by treatment group as treated.
7.4.1
Administration of Study Therapy
The following parameters will be summarized (descriptive statistics) by treatment arm:
•
Time from randomization to first dose of study therapy (0 to 3 days, > 3 to 7, > 7 to 14, > 14 to 
21, > 21 to 28, > 28). For Group E, time from enrollment to first dose of study therapy will be 
considered.
The following parameters will be summarized (descriptive statistics) for each drug within the 
regimen for different arms:
•
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 90 
- < 110%; ≥ 110%. 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
36
•
Number of doses received (except for BSC in Group B where the dose is not collected on the 
CRF).
•
Cumulative dose (except for BSC in Group B where the dose is not collected on the CRF).
Duration of treatment will be presented by treatment arm using a Kaplan-Meier curve whereby the 
last dose date will be the event date for those subjects who are off study therapy. Median duration 
of treatment will be provided. Subjects who are still on study therapy will be censored on their last 
dose date. Summary table for the duration of treatment will be also provided.
A by-subject listing of dosing of study medication (record of study medication, infusion details, 
and dose changes) will be also provided. A listing of batch numbers for nivolumab will also be 
provided.
Below table summarizes the key parameters used to calculate dosing data.
Summary table to describe the Investigator’s Choice Chemotherapy for Group C will be provided.
The summary table to describe the Best Supportive Care will be provided for Group B. 
Table 7.4.1-1:
Administration of Study Therapy: Definition of Parameters
Group A
Nivolumab
Nivolumab + 
Bevacizumab / 
Pemetrexed
Bevacizumab / 
Pemetrexed
Dosing schedule per 
protocol
240 mg IV q2 weeks
5 mg/kg IV q3 weeks +  15 
mg/kg IV q3 weeks /     
500 mg/m2 IV q3 weeks
15 mg/kg IV q3 weeks
/500 mg/m2 IV q3 weeks
Group B
Nivolumab
Best Supportive Care
-----
Dosing schedule per 
protocol
240 mg IV q2 weeks
-----
-----
Group C
Nivolumab
Investigator’s Choice of 
Chemotherapy
-----
Dosing schedule per 
protocol
240 mg IV q2 weeks
See section 6.2 Group C
-----
Group D
-----
Nivolumab + Erlotinib
Erlotinib
Dosing schedule per 
protocol
-----
240 mg IV q2 weeks + 150 
mg QD
150 mg QD
Group E
-----
Nivolumab + Crizotinib
-----
Dosing schedule per 
protocol
-----
240 mg IV q2 weeks + 250 
mg BID
Dose
Dose (mg) is defined as 
total dose administered 
(mg) at each dosing date 
and is collected on the 
CRF.
Dose (mg) is defined as 
total dose administered.
Dose administered in mg 
at each dosing date is
collected on the CRF.
Cumulative Dose
Cum dose (mg) is sum of 
the doses (mg) 
Cum dose (mg) is sum of 
the doses (mg)
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
37
Table 7.4.1-1:
Administration of Study Therapy: Definition of Parameters
administered to a subject 
during the treatment 
period.
administered to a subject 
during the treatment 
period.
Duration of treatment  
Last dose date - Start dose 
date + 1
Last dose date - Start dose 
date + 1
Relative dose intensity   
(%)
Cum dose (unit) / [(Last 
dose date - Start dose date 
+ a) x b/a] x 100; where a 
is the number of days per 
cycle & b is the number 
per unit. Values for a & b 
vary per drug. 
For example nivolumab at 
3 mg/kg every 2 weeks: 
Cum dose (mg/kg) / [(Last 
dose date - Start dose date 
+ 14) x 3 / 14] x 100]
7.4.2
Modifications of Study Therapy
The following analyses will be performed for Group D only.
7.4.2.1
Infusion Interruptions and Rate Changes
Each nivolumab, pemetrexed, paclitaxel, nub-paclitaxel, bevacizumab, carboplatin, docetaxel, 
gemcitabine infusion can be interrupted and/or the IV infusion rate can be reduced. This 
information will be retrieved from CRF dosing pages.
The following parameters will be summarized by treatment arm:
•
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 and the reason for reduction.
In addition, nivolumab infusion time (mean, SD, percentage of patients with infusion <= 30 
minute, 30 - < =60 minutes, >60 minutes will also be summarized by treatment arms.
7.4.2.2
Dose Escalations
Dose escalations are not permitted for any study drug except erlotinib, for which the dose may be 
increased if concomitant use with CYP3A4 inducers or concomitant use with the drugs affecting 
gastric pH according to the drug label.
7.4.2.3
Dose Reductions
Dose reductions are not permitted for nivolumab and bevacizumab.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
38
Carboplatin, pemetrexed, paclitaxel, nab-paclitaxel, docetaxel, gemcitabine, erlotinib, and 
crizotinib may have dose reductions with the reason collected on Dose Change/Oral Study 
Medication CRF.
The reason for dose reduction as reported by the investigator will be tabulated for all instances of 
dose reduction. A category ‘Unknown’ will be defined for all reductions with no reason reported 
by the investigator.
The following will be summarized by treatment arm:
•
Number and percentage of subjects with at least one dose reduction and reason of the dose 
reduction.
 
 
 
 
7.4.4
Immune modulating medication 
See the CA209 Core Safety SAP. Only 100-day safety window will be applied.
7.5
Efficacy
•
OS is defined as the time from randomization to the date of death. A subject who has not died 
will be censored at last known date alive.
•
Progression-free survival (PFS) is defined as the time from randomization (start of treatment 
for Group E) to the date of the first documented tumor progression as determined by the 
investigator using RECIST 1.1 criteria or death due to any cause. Clinical deterioration in the 
absence of unequivocal evidence of progression (per RECIST 1.1) is not considered 
progression for purposes of determining PFS. Subjects who die without a reported prior 
progression will be considered to have progressed on the date of their death. 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 the date they were randomized. Subjects who received any subsequent anti-cancer therapy 
(including on-treatment palliative RT of non-target bone lesions or CNS lesions) without a 
prior reported progression will be censored at the last evaluable tumor assessment prior to or 
on the date of initiation of the subsequent anti-cancer therapy.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
39
Table 7.5-1:
Censoring Scheme for Primary Definition of PFS
Situation
Date of Progression or Censoring
Outcome
No baseline tumor assessments and no 
death 
Randomization (first dose date for Group E)
Censored
No on study tumor assessments and no 
death 
Randomization (first dose date for Group E)
Censored
New anticancer treatment started 
without a prior reported progression per 
RECIST 1.1 or death 
Date of last evaluable tumor assessment prior to 
or on the date of initiation of the subsequent 
anti-cancer therapy
Censored 
Progression per RECIST 1.1 
documented at scheduled or unscheduled 
visit and no new anticancer treatment 
started before
Date of the first documented tumor progression
Progressed
Subject progression free (per RECIST 
1.1) and no new anticancer treatment 
started 
Date of last tumor assessment
Censored
Death without prior progression per 
RECIST 1.1 and no new anticancer 
treatment started
Date of death
Progressed
•
DOR (Duration of Objective Response) is defined as the time between the date of first 
confirmed response to the date of the first documented tumor progression (per RECIST 1.1), 
as determined by the investigator, or death due to any cause, whichever occurs first. For 
subjects who neither progress nor die, the duration of objective response will be censored on 
the date of their last evaluable tumor assessment. Subjects who started any subsequent anti-
cancer therapy without a prior reported progression will be censored at the last evaluable tumor 
assessment prior to or on the date of initiation of the subsequent anti-cancer therapy. DOR will 
be evaluated for confirmed responders (i.e. subjects with confirmed CR or PR) only with 
measurable disease at baseline.
•
Objective response rate (ORR) is defined as the number of subjects whose best objective 
response (BOR) is a confirmed CR or confirmed PR, as determined by the investigator, divided 
by the number of randomized (or treated for Group E) subjects. BOR is defined as the best 
response designation, recorded between the date of randomization and the date of objectively 
documented progression per RECIST v1.1 or the date of subsequent anticancer therapy, 
whichever occurs first. For subjects without documented progression or subsequent anticancer 
therapy, all available response designations will contribute to the BOR determination. For 
subjects who continue treatment beyond progression, the BOR will be determined based on 
response designations recorded up to the time of the initial RECIST 1.1-defined progression.
ORR will be evaluated only for subjects with measurable disease at baseline.
•
Time to Objective Response (TTR) is defined as the time from randomization to the date of 
the first confirmed response. TTR will be evaluated for confirmed responders only.
•
Disease control rate (DCR) is defined as the number of subjects that achieved a best overall 
response of CR, PR, or SD, divided by the total number of randomized/enrolled subjects with 
measurable disease at baseline.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
40
7.5.1
Efficacy Analysis: PFS and OS
The analyses of PFS and OS described below will be performed for all groups.
The distribution of PFS and OS will be compared in two randomized arms via a two-sided (unless 
otherwise specified), log-rank test stratified by respective stratification factors (see section 7.1.1).
The hazard ratio (HR) and the corresponding 100(1-adjusted α)% CI will be estimated in a 
stratified Cox proportional hazards model using randomized arm as a single covariate.
The PFS and OS curves for each treatment group will be estimated using the Kaplan-Meier (KM) 
product-limit method and graphically displayed. Two-sided, 95% confidence intervals for median 
PFS and OS will be constructed based on a log-log transformed CI for the survivor function S(t)[30]
[31]. More specific details on these comparisons are provided in the efficacy analysis sections for 
each group.
PFS and OS rates at 6, 12, 18, 24, etc. months will also be estimated using KM estimates on the 
PFS curve for each randomized arm. Minimum follow-up must be longer than time point to
generate the rate. Associated two-sided 95% CIs will be calculated using the Greenwood’s
formula[32] for variance derivation and on log-log transformation applied on the survivor function 
S(t)[33] . 
By subject listing of PFS per Investigator will be provided.
By subject listing of OS per Investigator will be provided.
7.5.1.1
Subset Analyses of Progression-Free Survival and OS
The influence of baseline and demographic characteristics on the treatment effect will be explored 
via exploratory subset analyses for the following factor:
•
Age categorization (<65, >=65, >=75 (if sufficient subjects are available))
This analysis will be performed for Group D only.
7.5.1.2
Current status of OS follow-up
Current status of OS follow-up will be summarized in months, by computing the time from “last 
known alive” date to data cut-off date for all randomized/treated subjects separately. Subjects who 
have a death event will be considered as current for this analysis.
By-subject listings along with IVRS stratification factor will also be produced to accompany the 
subject time from last known alive date assessment table for all randomized/treated subjects.
7.5.2
Efficacy Analysis: DOR and ORR
The analyses of DOR and ORR described below will be performed for all groups.
Duration of response in each treatment arm 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. 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
41
Summary statistics will be computed constructed based on a log-log transformed CI for the
survivor function S(t). Summary statistics of time to objective response will be provided for each 
treatment arm for subjects who achieve PR or CR. 
To assess further tumor response kinetics, time to response will be analyzed descriptively for 
randomized subjects with median coming from the KM estimate. 
BOR will be summarized by response category for each treatment arm. ORR will be computed in 
each treatment arm along with the exact 95% CI using Clopper-Pearson method [33].
Individual subject’s best overall response (BOR) will be listed based on response evaluation 
criteria in solid tumor (RECIST) 1.1. BOR will be evaluated for subjects with measurable disease 
at baseline for Group A and B. For other Groups, it will be evaluated for all randomized/treated 
subjects.
To assess consistency of treatment effect on ORR in different subsets, ORR will be computed 
across the same subsets as defined in the PFS and OS analysis.
Additionally, for Group D only, an estimate of the difference in ORRs and corresponding 95% CI 
will be calculated using CMH methodology and adjusted by the same stratification factors as for
analysis of OS. In addition, the stratified odds ratios (Mantel-Haenszel estimator) between the 
treatments will be provided along with the 95% CI. The difference will be tested via the Cochran
Mantel-Haenszel (CMH) test using a two-sided, 5% α level.
7.5.3
Efficacy Analysis: DCR
The analyses of DCR described below will be performed for Group D.
DCR will be summarized by response category for each treatment arm. DCR will be computed in 
each treatment arm along with the exact 95% CI using Clopper-Pearson method [34]. An estimate 
of the difference in DCRs and corresponding 95% CI will be calculated using CMH methodology 
and adjusted by the same stratification factors as for analysis of OS. In addition, the stratified odds 
ratios (Mantel-Haenszel estimator) between the treatments will be provided along with the 95%
CI. The difference will be tested via the Cochran Mantel-Haenszel (CMH) test using a two-sided, 
5% α level.
7.5.4
Subsequent Therapy
The following information pertaining to subsequent therapies will be summarized for all 
randomized/treated subjects separately by treatment arm for Group D only:
Number and percentage of subjects receiving subsequent therapies including:
•
Immunotherapy (anti-PD1 agents, anti-PD-L1 agents, anti-CTLA-4 agents and others) by drug 
name
•
Other agents excluding immunotherapy (approved and investigational) by drug name
•
Surgery (limited to: tumor resection, curative; tumor resection, palliative; incisional biopsy; 
excisional biopsy)
•
Radiotherapy
•
Any combination of the above
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
42
7.6
Safety
All safety data will be summarized and listed for all treated subjects unless otherwise specified.
All AEs, SAEs, treatment-related AEs, and treatment-related SAEs will be summarized using the 
worst grade per NCI CTCAE v4.0 by system organ class and preferred term. Lab abnormalities 
including hematology, chemistry, liver function, thyroid function, and renal function will be 
summarized using worst grade per NCI CTCAE v4.0 criteria.
Additionally, subject level listings of death, adverse events, serious adverse events, adverse events 
leading to discontinuation, immune-mediated adverse events, select adverse events will be 
provided.
7.6.1
Deaths
See Core Safety SAP. Only 100-day safety window will be applied.
7.6.2
Adverse Events
See Core Safety SAP. Only the following summaries will be provided for the 30-day safety 
window. 
•
Overall Summary of Any Adverse Events by Worst CTC Grade (Any Grade, Grade 3-4, Grade 
5) 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 Drug-Related Adverse Events by Worst CTC Grade (Any Grade, Grade 
3-4, Grade 5) presented by SOC/PT.
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
See Core Safety SAP.
Only the following summaries will be provided for the 30-day safety 
window.
•
Summary of Adverse Events Leading to Discontinuation by Worst CTC Grade (Any Grade, 
Grade 3-4, Grade 5) presented by SOC/PT
•
Summary of Drug-Related Adverse Events Leading to Discontinuation by Worst CTC Grade 
(Any Grade, Grade 3-4, Grade 5) presented by SOC/PT
7.6.4
Adverse Events Leading to Dose Modification
Not applicable.
7.6.5
Serious Adverse Events
See Core Safety SAP. Only the following summaries will be provided for the 30-day safety 
window.
•
Summary of Serious Adverse Events by Worst CTC Grade (Any Grade, Grade 3-4, Grade 5) 
presented by SOC/PT. 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
43
•
Summary of Drug-Related Serious Adverse Events by Worst CTC Grade (Any Grade, Grade 
3-4, Grade 5) presented by SOC/PT.
7.6.6
Select Adverse Events
Unless otherwise specified, analyses will be performed by select AE category. Select AEs and 
Drug-related select AEs (based on list provided by BMS every 6 months) will be summarized for 
all treated subjects for Group D. Only 30-day safety window will be applied.
•
Summary of Any Select Adverse Events by Worst CTC Grade (Any Grade, Grade 3-4, Grade 
5)
•
Summary of Drug-Related Select Adverse Events by Worst CTC Grade (Any Grade, Grade 3-
4, Grade 5)
•
Summary of Any Select Endocrine Adverse Events by Worst CTC Grade (Any Grade, Grade 
3-4, Grade 5)
•
Summary of Drug-Related Select Endocrine Adverse Events by Worst CTC Grade (Any 
Grade, Grade 3-4, Grade 5)
7.6.6.1
Incidence of select AE
Not applicable.
7.6.6.2
Time-to onset of select AE
Not applicable.
7.6.6.3
Time-to resolution of select AE
See Core Safety SAP. Only 30-day safety window will be applied.
The analyses of time to resolution of drug related select AE will be conducted for Group D.
7.6.7
Immune-Mediated Adverse Events
Immune-mediated AEs (IMAEs) are specific events occurring within 100 days of the last dose of 
study drug (which includes pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, 
rash, Immune-mediated encephalitis, and endocrine abnormalities [adrenal insufficiency, 
hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis and diabetis melitus), regardless of 
causality, for which subjects received immunosuppressive medication for treatment of the event. 
The exception to the immunosuppressive medication criteria for IMAEs is endocrine events 
(hypothyroidism/thyroiditis, 
hyperthyroidism, 
hypophysitis, 
diabetes 
mellitus, 
adrenal 
insufficiency), which are included regardless of treatment since these events are often managed 
without immunosuppression.
Table below provides a summary of the IMAEs category and their respective Preferred Terms.
The table might be updated at the time of analysis.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
44
Table 7.6.7-1:
Preferred Terms Included in Analysis of IMAEs to Support 
Warning and Precautions
IMAE 
Category
Group
Preferred Terms included under IMAE Category
Pneumonitis
Pneumonitis, Interstitial lung disease, Idiopathic interstitial pneumonia
Diarrhea/Colitis
Autoimmune Colitis, Diarrhea, Colitis, Colitis Ulcerative, Enteritis, 
Enetrocolitis, Enterocolitis haemorrhagic
Hepatitis
Acute Hepatic Failure, Acute on chronic liver failure, Hepatotoxicity, 
Hepatitis, Hepatitis acute, Autoimmune Hepatitis, AST Increased, ALT 
Increased, Bilirubin Increased, Transaminases Increased, Drug-induced Liver 
Injury, Hepatic Failure, Hyperbilirubinaemia, 
Adrenal 
Insufficiency
Endocrine
Adrenal Insufficiency, Hypothalamic Pituitary Adrenal Axis Suppression, 
Primary adrenal insufficiency, Secondary Adrenocortical Insufficiency, 
Adrenocortical insufficiency acute
Hypothyroidism/
Thyroiditis
Endocrine
Atrophic Thyroiditis, Autoimmune Hypothyroidism, Autoimmune Thyroiditis,
Hypothyroidism, Primary Hypothyroidism, Silent thyroiditis,Thyroiditis, 
Thyroiditis acute 
Hypothyroidism
Endocrine
Autoimmune Hypothyroidism, Hypothyroidism, Primary Hypothyroidism
Thyroiditis
Endocrine
Atrophic Thyroiditis, Autoimmune Thyroiditis, Thyroiditis, Thyroiditis Acute, 
Silent thyroiditis
Diabetes 
Mellitus
Endocrine
Diabetes Mellitus, Diabetic ketoacidosis, Fulminant Type 1 Diabetes Mellitus, 
Latent Autoimmune Diabetes in Adults, Type 1 Diabetes Mellitus, Diabetic 
ketosis
Nephritis and 
renal 
dysfunction
Acute Kidney Injury, Autoimmune Nephritis, Blood Creatinine Increased, 
Creatinine Renal Clearance Decreased, Hypercreatininaemia, Nephritis, 
Nephritis Allergic, Paraneoplastic Glomerulonephritis, Renal Failure, Renal 
Tubular Necrosis, Tubulointerstitial Nephritis
Rash
Autoimmune Dermatitis, Dermatitis, Dermatitis allergic, Dermatitis 
Exfoliative, Drug Eruption, Erythema Multiforme, Exfoliative Rash, Fixed 
eruption, Nodular Rash, Pemphigoid, Pemphigus, Rash, Rash Erythematous, 
Rash Generalised, Rash Macular, Rash Maculo-Papular, Rash morbilliform, 
Rash Papular, Rash Pruritic, Rash vesicular, Stevens-Johnson Syndrome, Toxic 
Epidermal Necrolysis, Toxic skin eruption
Hypersensitivity
Anaphylactic Reaction, Anaphylactic Shock, Hypersensitivity, Infusion 
Related Reaction
Hyperthyroidism
Endocrine
Basedow’s Disease, Hyperthyroidism, Primary Hyperthyroidism
Hypophysitis
Endocrine
Hypophysitis, Hypopituitarism, Lymphocytic Hypophysitis
IMEAs = immune-mediated adverse events
The analysis of IMAEs will be done separately for endocrine IMAEs and IMAEs where immune-
modulating medication was initiated.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
45
7.6.7.1
Incidence of IMAEs
See Core Safety SAP. Only 100-day safety window will be applied. Following summaries will be 
provided.
Summary of Immune-Mediated Adverse Events by Worst CTC Grade (Any Grade, Grade 3-4, 
Grade 5) Where Immune Modulating Medication Was Initiated by Category with Extended 
Follow-Up
Summary of Endocrine Immune-Mediated Adverse Events by Worst CTC Grade (Any Grade, 
Grade 3-4, Grade 5) with Extended Follow-Up
7.6.8
Clinical laboratory evaluations
See Core Safety SAP. Only 30-day safety window will be applied.
 
 
 
 
 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
46
 
 
 
 
 
 
 
7.8
Outcomes Research Analyses
7.8.1
Eligible population
The analysis of FACT-L and EQ-5D will be performed for Group C in all randomized patients 
who have a screening/baseline assessment and at least 1 follow-up assessment depending on 
sample size at the data base lock. Same analysis may be performed for Group D.
The questionnaire completion rate for the FACT-L and the EQ-5D, defined as the proportion of
questionnaires received out of the expected number (i.e., the number of patients still on treatment
in follow-up), will be calculated and summarized at each assessment time point.
7.8.2
FACT-L questionnaire
The FACT-L, including its subscales, will be scored using a 5-point Likert scale (0 = not at all; 1 
= a little bit, 2 = somewhat; 3 = quite a bit; 4 = very much). The general subscales include physical 
well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), and functional 
well-being (FWB). The seven-item Lung Cancer Subscale (LCS) assesses the impact of symptoms 
commonly reported by lung cancer patients, including shortness of breath, loss of weight, and chest 
tightness. A Trial Outcome Index (TOI) can be derived by adding scores on the PWB and FWB
subscales to the LCS. The ranges of possible total scores are 0 - 136 for the FACT-L, 0 - 28 for 
the LCS and 0 - 84 for the TOI, with a higher score representing better quality of life, improved 
symptomatology and enhanced physical/ functional outcomes, respectively. According to 
Functional Assessment of Chronic Illness Therapy (FACIT) scoring guidelines [21], in the event of 
missing responses for some of the questions/ items, scores will be prorated using the average of 
the other answers in that scale.
The overall FACT-L will be analyzed using descriptive statistics in each treatment arm of the study 
at each of the assessment time points. Summary statistics including the reporting of means, 
medians, ranges and standard deviation will be calculated at each assessment point for both 
categorical and continuous variables. 
Baseline and change from baseline of the FACT-L scores at each assessment point will be 
summarized using descriptive statistics
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
47
A determination of whether the ‘change’ between assessments is clinically meaningful will be 
assessed by the minimally importance difference (MID) [35] for the FACT-L as validated through 
published literature. An MID is the "smallest difference in score in the domain of interest that 
patients perceive as important, either beneficial or harmful, and that would lead the clinician to 
consider a change in the patient's management [36].
A more detailed description of the FACT-L analyses and results may be presented separately in an 
independent PRO-Health Economics SAP.
7.8.3
EQ-5D-3L questionnaire
EQ-5D-3L is a standardized measure of self-reported health status. The EQ-5D-3L consists of the 
EQ-5D-3L five dimension three-level scale descriptive system and the EQ visual analogue scale 
(EQ VAS). The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: 
“no problems”, “some problems” and “severe problems”, which are scored as 1, 2 and 3, 
respectively. Note that these numerals do not have arithmetic properties and cannot be used as an
ordinal scale. Nevertheless, the EQ-5D-3L descriptive system will be converted into EQ-5D-3L
index score which provides a measure of health on a scale of 0 to 1 (0 = death and 1 = perfect 
health).
The EQ VAS records the respondent’s self-rated health on a vertical VAS where the endpoints are 
labeled ‘best imaginable health state’ (equivalent to a score of 100) and ‘worst imaginable health 
state’ (score of zero). This information can be used as a quantitative measure of health outcome as 
judged by the individual respondents. 
Subject’s overall health state on a visual analog scale (EQ-VAS) at each assessment time point 
will be summarized using descriptive statistics (N, mean, SD, median, 25th and 75th percentiles) 
by treatment arm, as randomized.
Proportion of subjects reporting problems for the five EQ-5D-3L dimensions at each assessment 
time point will be summarized by level of problem and by treatment arm, as randomized. 
Percentages will be based on number of subjects assessed at assessment time point.
A by-subject listing of EQ-5D-3L with the problem levels for each of the five dimensions
(mobility, self-care, usual activities, pain/discomfort and anxiety/depression), health state (five
dimensions digits combined in a 5-digit number) and EQ-VAS will be provided. 
Baseline and change from baseline of the EQ-5D-3L scores at each assessment point will be 
summarized using descriptive statistics.
A determination of whether the ‘change’ between assessments is clinically meaningful will be 
assessed by the minimally importance difference (MID) [35] for the EQ-5D-3L as validated through 
published literature [37]. 
A more detailed description of the EQ-5D-3L analyses and results may be presented separately an 
in an independent PRO-Health Economics SAP.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
48
7.8.3.1
Calculation of Total Scores for Scales/Items
U.S. Population-based EQ-5D-3L Index Score The EQ-5D-3L descriptive system will be 
converted into an index score which provides a measure of health on a scale of 0 to 1 (0 = death 
and 1 = perfect health) using the scoring algorithm based on the modeling work[39]:
X = 1 - 0.146016*MO2 - 0.557685*MO3 - 0.1753425*SC2 - 0.4711896*SC3 -    0.1397295*UA2 
- 0.3742594*UA3 - 0.1728907*PD2 - 0.5371011*PD3 - 0.156223*AD2 - 0.4501876*AD3 + 
0.1395949*D1 - 0.0106868*I2^2 + 0.1215579*I3 + 0.0147963*I3^2,
where 
•
MO2, SC2, UA2, PD2, and AD2 are dummy variables for level 2 in dimensions mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression, respectively;
•
MO3, SC3, UA3, PD3, and AD3 are dummy variables for level 3 in dimensions mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression, respectively;
•
D1 is an ordinal variable: the number of movements away from Full health (level 1) beyond 
the first (i.e. it takes on values ranging from 0 to 4);
•
I2 is an ordinal variable: the number of dimensions at level 2 beyond the first;
•
I3 is an ordinal variable: the number of dimensions at level 3 beyond the first.
7.8.4
Handling of Missing Data
For FACT-L, if at least 50% of items within a subscale are completed, each missing item will be 
imputed by the average of the completed items; if more than 50% of items within a subscale are 
missing, the score of the subscale will be treated as missing [38]. 
The total FACT-L and the TOIs will be scored only if at least 80% of the items for each measure 
are completed and at least 50% of the items are completed within each of the subscales, where the 
Total FACT-L is made up of the following subscales: PWB + SWB + EWB + FWB + LCS and 
the Lung TOI is made up of: PWB + FWB + LCS. As long as these two conditions are satisfied, 
each missing item within for each subscale will be imputed by the average of the completed items.
Any missing scores in the EQ-5D questionnaire will be considered missing.
8
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates: 
•
For missing and partial adverse event onset dates, imputation will be performed using the 
Adverse Event Domain Requirements Specification [22]
•
For missing and partial adverse event resolution dates, imputation will be performed as 
follows:
−
If only the day of the month is missing, the last day of the month will be used to replace the 
missing day
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
49
•
Missing and partial non-study medication domain dates will be imputed using the derivation 
algorithm described in 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 + 1 day 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
+ 1 day. 
•
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 + 1 day
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 will 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 (e.g. time-to onset, time-to resolution) will be calculated as follows:
Duration = (Last date - first date + 1)
Last known date alive will be defined based on all appropriate dates collected on the CRF.
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
Safety conventions from Programming are summarized in the core safety SAP [24].
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
50
9
CONTENT OF REPORTS
All analyses described in this SAP will be included in the Clinical Study Report(s) except where 
otherwise noted. Refer to the Data Presentation Plan for mock-ups of all tables and listings.
2.0
Approved
930106945
3.0
v








Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
54
11
LIST OF ABBREVIATIONS
AE -- adverse event
ALK -- anaplastic lymphoma kinase
ALT -- alanine aminotransferase
APC -- antigen-presenting cells
AST -- aspartate aminotransferase
AT -- aminotransaminases
AUC -- area under the concentration curve
BID -- twice daily
BMS -- Bristol-Myers Squibb
BOR -- best overall response
BSC -- best supportive care
BP -- blood pressure
BUN -- blood urea nitrogen
C -- Celsius
CBC -- complete blood count
CI -- confidence interval
CLS -- capillary leak syndrome
CNS -- central nervous system
CR -- complete response
CRF -- Case Report Form, paper or electronic
CTA -- Clinical Trial Agreement
CTL4-1 -- cytotoxic T-lymphocyte antigen-4
CV -- coefficient of variation
CYP -- cytochrome p-450
DCR -- disease control rate
DILI -- Drug-induced liver injury
DOR -- Duration of response
dL -- deciliter
ECG -- electrocardiogram
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
55
ECOG -- Eastern Cooperative Oncology Group
eCRF -- Electronic Case Report Form
EDC -- Electronic Data Capture
EEG -- electroencephalogram
eg -- for example
EGFR -- epidermal growth factor receptor
EQ-5D -- EuroQoL Five Dimension
EWB -- emotional well-being
FACIT – Functional Assessment of Chronic Illness Therapy
FACT-L -- Functional Assessment of Cancer Therapy-Lung
FDA -- Food and Drug Administration
FISH -- fluorescent in-situ hybridization
FSH -- follicle stimulating hormone
FWB -- functional well-being
GCP -- Good Clinical Practice
GI -- gastrointestinal
h -- hour
HBsAg -- hepatitis B surface antigen
HBV -- hepatitis B virus
HCV -- hepatitis C virus
HIV -- human immunodeficiency virus
HR -- hazard ratio
HRQoL -- Health-related Quality of Life
HRT -- hormone replacement therapy
HUS -- hemolytic uremic syndrome
ICH -- International Conference on Harmonisation
ie -- that is
IEC -- Independent Ethics Committee
ILD -- interstitial lung disease
IMP -- investigational medicinal products
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
56
IND -- Investigational New Drug
IRB -- Institutional Review Board
IHC -- immunohistochemistry
IU -- international units
IV -- intravenous
IVRS -- Interactive Voice Response System
kg -- kilogram
LCS -- Lung Cancer Subscale
LCSS -- Lung Cancer Symptom Scale
LDH -- lactate dehydrogenase
LFT -- liver function test
MET -- metabolic equivalents
MID -- minimally important difference
mg -- milligram
min -- minute
mL -- milliliter
MLR -- mixed lymphocyte reaction
mmHg -- millimeters of mercury
MVPA -- moderate to vigorous physical activity
MTD -- maximum tolerated dose
mut -- mutation
N -- number 
N/A -- not applicable
NIMP -- non-investigational medicinal products
NSAID -- nonsteroidal anti-inflammatory drug
NSCLC -- non-small cell lung cancer
NSQ -- non-squamous
ORR -- objective response rate
OS -- overall survival
PD -- progressive disease
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
57
PD-1 -- programmed death-1
PD-L1 -- programmed death- ligand 1
PK -- pharmacokinetics
PFS -- Progression free survival
PO -- oral
PPK -- population pharmacokinetic
PR -- partial response
PRES -- posterior reversible encephalopathy syndrome
PRO -- Patient-reported Outcomes
PS -- performance status
PWB – physical well-being
QD -- once daily
QOL – quality of life
RBC -- red blood cell
RCC -- renal cell carcinoma
SAE -- serious adverse event
SAP -- statistical analysis package
SD -- standard deviation
SED -- sedentary time
SOC -- standard of care
SPP – survival post-progression
SQ -- squamous
SWB – social/family well-being
TCR -- T-cell receptor
T-HALF -- half life
TILs -- tumor-infiltrating lymphocytes
TKI -- tyrosine-kinase inhibitor
TOI -- trial Outcome Index
TTO -- time to trade-off
ULN -- upper limit of normal
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
58
VAS -- visual analog rating scale
VEGF -- vascular endothelial growth factor
WBC -- white blood cell
WHO -- World Health Organization
WOCBP -- women of childbearing potential
wt -- wild-type/mutation negative/
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
59
12
CHANGES FROM PROTOCOL
•
ORR and Duration of Response (DOR): will be evaluated in subjects with measurable disease 
at baseline.
•
Table 7.6.7-1 summary of the IMAEs category and their respective Preferred Terms has been 
updated with additional terms.
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
60
APPENDIX 1
SELECT ADVERSE EVENTS DEFINITION AND CONVENTIONS
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category (e.g. pulmonary events, gastrointestinal events categories) and by subcategory (e.g. 
thyroid disorders, diabetes, pituitary, adrenal disorders subcategories). These categories and 
subcategories are defined by the Sponsor and the list that is most current at the time of analysis 
will be used.  Also, changes may be made to this list with each new version of MedDRA.
The final list used for the clinical study report will be included in an Appendix of the CSR.
Time-to onset definition
Time-to onset of select AE (any grade) for a specific category (i.e. pulmonary events, 
gastrointestinal events, etc.) is defined as the time between the day of the first dose of study 
treatment and the onset date of the earliest select AE (of any grade) in this category.
If the subject did not experience a select AE (of any grade) in the category, time-to onset will be 
censored at the maximum follow-up time of all subjects in their respective treatment group (i.e.
for subjects without an event, follow-up time is defined from first dosing date up to last dosing 
date +30 days (or 100 days depending on the analysis) if subjects are off treatment and followed 
for at least  30 days (or 100 days depending on the analysis) , otherwise it is defined up to the last 
known alive date). The resulting Kaplan-Meier plot will represent the cumulative rate of the select 
AE (any grade) in the category over time.
Time-to onset of select AE (grade 3-5) for a specific category is defined similarly but restricted to 
grade 3-5 select AEs.
Time-to onset of drug-related (grade 3-5 or any grade) select AE for a specific category is defined 
similarly but restricted to drug-related select AEs.
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 select AEs within a specific 
category (defined in Core Safety SAP Table 11-3) will be collapsed into what will be termed 
“clustered” select 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 select 
AE from 1st to 12th January. Table 10-1 (or Core Safety SAP Table 11-2) is summarizing key 
derivation steps for each type of clustered select AEs.
Time-to resolution of select 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 
select AEs in this category experienced by the subject. 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 
select AE is considered as unresolved, the resolution date will be censored to the last known date 
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
61
alive. Improvement to the grade at baseline implies that all different AE events in the clustered 
select adverse event should at least have improved to the corresponding (i.e. with same preferred 
term) baseline grade. This measure is defined only for subjects who experienced at least one select 
AE in the specific category.
The time-to resolution of select AE (grade 3-5) for a specific category is defined similarly with an 
onset date corresponding to a grade 3-5 select AE.
Time-to resolution of drug-related select AE (any grade or grade 3-5) is defined similarly but 
restricted to drug-related select AE.
Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory.
Table 10-1:
Derivation of clustered select AE
Type of clustered select AE
Derivation
Any grade
Collapse any on-treatment select AE from the same category
Drug-related of any grade
Collapse any on-treatment drug-related
select AE from the same category
Grade 3-5
Collapse any on-treatment select 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 select AE is 
excluded)
Drug-related of Grade 3-5
Collapse any on-treatment drug-related select 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 select AE is 
excluded)
The algorithm for collapsing select 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).
2.0
Approved
930106945
3.0
v


Statistical Analysis Plan
CA209370
BMS-936558
nivolumab
62
Please refer to CA209 Core Safety SAP for full detail. Note: Table 11-3 from Core Safety SAP
might be updated at the time of analysis.
2.0
Approved
930106945
3.0
v