Conditions: Non-Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 719
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether Nivolumab, Ipilimumab combined with chemotherapy is more effective than chemotherapy by itself when treating stage IV NSCLC as the first treatment given for the disease

Detailed description:

Arms:
arm 1: Chemotherapy/Biologics combined arm 2: Chemotherapy Combination

Interventions: intervention 1: Ipilimumab intervention 2: Nivolumab intervention 3: Carboplatin intervention 4: Paclitaxel intervention 5: Pemetrexed intervention 6: Cisplatin
Intervention descriptions: intervention 1: Specified dose on specified day intervention 2: Specified dose on specified day intervention 3: Specified dose on specified day intervention 4: Specified dose on specified day intervention 5: Specified dose on specified day intervention 6: Specified dose on specified day

Protocol document:
Prot_000.pdf: 


Clinical Protocol
CA2099LA
BMS-936558
nivolumab
Date: 10-May-2017
2
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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Clinical Protocol
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BMS-936558
nivolumab
Date: 10-May-2017
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Original Protocol
10-May-2017
Not applicable
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Clinical Protocol
CA2099LA
BMS-936558
nivolumab
1
SYNOPSIS
Protocol Title: A Study of Nivolumab plus Ipilimumab in Combination with Chemotherapy 
vs Chemotherapy alone as First Line Therapy in Stage IV Non-Small Cell Lung Cancer 
(NSCLC) 
Study Phase: Phase 3
 
 
 
 
 
 
 
 
 
 
 
 
Study Population:
•
Participants with histologically confirmed stage IV non-small cell lung cancer (NSCLC),
squamous or non-squamous histology. (Defined by the 7th International Association for the 
Study of Lung Cancer Classification) 
•
No prior systemic therapy for stage IV disease. 
•
EGFR/ALK wild type and ECOG Performance Status of ≤1
•
Participants are to have tumor tissue sample for biomarker analysis
•
Participants must have PD-L1 IHC testing with results available for randomization or PD-L1 
testing will be performed by the central laboratory during the screening period. 
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To compare the efficacy of nivolumab + ipilimumab 
with chemotherapy vs chemotherapy in participants 
with histologically confirmed stage IV NSCLC
•
Overall survival (OS)
Secondary
•
To compare the efficacy of nivolumab + ipilimumab 
combined with chemotherapy vs chemotherapy in 
•
Progression free survival (PFS) by blinded 
independent central review
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Clinical Protocol
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nivolumab
for subsequent disease progression (which occurred during the off-treatment period) and 
administered for up to 1 additional year.
The 2 cycles of histology-based platinum doublet chemotherapy in the treatment arm during 
induction are the same chemotherapy regimens as in the control arm:
•
Squamous histology: carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous histology: carboplatin AUC 5 or 6 + pemetrexed 500 mg/m2 or cisplatin 
75 mg/m2 + pemetrexed 500 mg/m2. The investigator must decide prior to randomization 
whether or not the participant with non-squamous histology will receive cisplatin, if eligible.
Control arm: 4 cycles of histology-based platinum doublet chemotherapy.
•
Squamous histology: carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous histology: carboplatin AUC 5 or 6 + pemetrexed 500 mg/m2 or cisplatin 
75 mg/m2 + pemetrexed 500 mg/m2. The investigator must decide prior to randomization 
whether or not the participant with non-squamous histology will receive cisplatin, if eligible.
•
Chemotherapy will be on day 1 of each 3 week cycle; participants with non-squamous 
histology who have stable disease or response after induction chemotherapy are permitted to 
receive optional pemetrexed maintenance therapy: 500 mg/m2 pemetrexed on day 1 of each 
3 week cycle until disease progression or unacceptable toxicity, or other reasons specified in 
the protocol.
Number of Participants: 
Approximately 420 participants will be randomized to treatment arm and control arm in a 1:1 ratio.
Study treatment: 
Study Drugs for CA2099LA 
Medication 
Potency 
IP/Non-IP 
Nivolumab
10 mg/ml
IP
Ipilimumab
5 mg/ml
IP
Carboplatin 
10 mg/ml  
IP
Paclitaxel
6 mg/ml
IP
Pemetrexed 
500 mg/vial
IP
Cisplatin
100 mg/vial (1 mg/mL)
IP
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Clinical Protocol
CA2099LA
BMS-936558
nivolumab
Study Schema for CA2099LA
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Clinical Protocol
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BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA2099LA)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed prior to first dose
Medical History
X
Safety Assessments
Physical Measurements/Physical Examination
X
Include height and weight. Within 28 days prior to first dose
Vital Signs and Oxygen Saturation
X
Including BP, HR, and temperature. Obtain at the screening visit and within 72 hours prior to 
first dose
Assessment of Baseline Signs and Symptoms
X
Within 14 days prior to first dose
Serious Adverse Event Assessment
X
Serious Adverse Events from time of consent. 
 
Pregnancy Test (WOCBP only) 
X
Within 24 hours prior to Day 1. Negative pregnancy test required at Screening. 
(An extension up to 72 hours prior to start of study drug may be permissible in situations 
where results cannot be obtained within the standard 24 hour window).
Laboratory Tests
X
Must be performed within 14 days prior to randomization:
•
CBC w/differential
•
Chemistry panel including: AST, ALT, ALP, T. bili, BUN or serum urea level, 
creatinine, phosphate, albumin, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase,
•
Thyroid panel including TSH, Free T4, Free T3
•
Hep B/C (HBV sAg, HCV antibody or HCV RNA) within 28 days prior to first dose.
•
Testing for HIV must be performed as per local regulations. 
ECG (12-lead) 
X
Obtained only for participants who have met all eligibility criteria
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Clinical Protocol
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BMS-936558
nivolumab
Table 2-2:
On Study Assessments Treatment Phase- Nivolumab+ Ipilimumab with Platinum-based Doublet 
Chemotherapy Combination vs Chemotherapy
Procedure
Cycle 1 
Day 1
Each 
Subsequent 
Cycle Day1
(± 3 Days)
Every 2 Cycles
Day 1
(± 3 Days)
Notes
1 Cycle = 3 weeks
Nivolumab + ipilimumab + platinum-
doublet chemotherapy (q3 weeks) for 2 
cycles followed by nivolumab q3 weeks
+ ipilimumab q6 weeks
(see note)
q3weeks and ipilimumab 1mg/kg q6 weeks until 
progression or maximum 24 month treatment duration)
Control Arm
Platinum-doublet chemotherapy q 3w 
x4 cycles with optional pemetrexed 
maintenance for non-squamous 
histology 
X
X
3 weeks per cycle x4
Non-squamous histology may have option of pemetrexed 
maintenance therapy until progression or unacceptable 
toxicity
NOTES: 
1) If a dose is delayed, the procedures scheduled for that same time point should be delayed to coincide with when the time point’s dosing actually occur (except 
radiographic tumor assessments) continue until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent, or study closure.
2)
During retreatment upon progression (with post maximum 24 month therapy), laboratory and tumor assessment schedules will be the same. No PK/PRO 
collection are required. 
3)
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.
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BMS-936558
nivolumab
b Survival Follow-up visits to occur every 3 months (± 14 days) from Follow-up Visit 2. Survival visit may be conducted in person or by telephone. BMS may
request that survival data be collected on all treated participants outside of the 3 month specified window. At the time of this request, each participant will be 
contacted to determine their survival status unless the subject has withdrawn consent for all contact. If retreatment starts, then follow-up visits will cease.
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Clinical Protocol
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BMS-936558
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Clinical Protocol
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nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BMS-936558
nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To compare the efficacy of nivolumab + ipilimumab 
combined with chemotherapy vs chemotherapy in 
participants with histologically confirmed stage IV 
NSCLC
•
OS
Secondary
•
To compare the efficacy of nivolumab + ipilimumab 
combined with chemotherapy vs chemotherapy in 
participants with histologically confirmed stage IV 
NSCLC
•
PFS by BICR
•
ORR by BICR
•
To evaluate efficacy outcomes in participants with 
histologically confirmed stage IV NSCLC treated 
with
nivolumab + ipilimumab combined with 
chemotherapy vs chemotherapy with different PD-
L1 expression levels 
•
ORR and PFS by BICR and OS in participants 
with different PD-L1 levels
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Clinical Protocol
CA2099LA
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nivolumab
•
PD-L1 negative (< 1% tumor cell membrane staining in a minimum of a hundred evaluable 
tumor cells)
•
PD-L1 not quantifiable (participants with tumor biopsy specimens without quantifiable PD-L1 
expression)
Participants are to have tumor tissue sample available for PD-L1 IHC testing performed by a
central laboratory during screening period. PD-L1 status is required for randomization. 
The enrollment will end when approximately 420 patients are randomized. IWRS will be used to 
track the enrollment number. Testing of PD-L1 through a central laboratory is required prior to 
randomization. Participants tested but with not quantifiable PD-L1 will stratify with PD-L1 
negative participants. PD-L1 not quantifiable population will be capped to 10% of total 
randomized population. The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
Approximately 420 participants will be randomized in a 1:1 ratio to the treatment arm or control 
arm. The stratification factors for randomization are PD-L1 level (≥1% vs < 1%), histology
(squamous vs non-squamous histology), and gender (male vs female). Participants without
quantifiable PD-L1 status can be stratified with PD-L1 < 1% population and capped to 10% of the 
total randomized participants. 
The investigator must decide prior to randomization if participant with non-squamous histology 
will receive cisplatin therapy, based on cisplatin eligibility criteria.
Treatment Arm: Nivolumab will be administered with ipilimumab, plus 2 cycles of 
histology-based platinum doublet chemotherapy: 
•
Squamous histology: carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous histology: carboplatin AUC 5 or 6 + pemetrexed 500
mg/m2
or 
cisplatin 75 mg/m2 + pemetrexed 500 mg/m2
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nivolumab
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.1
Data Monitoring Committee and Other External Committees
5.1.1.1
Data Monitoring Committee
A DMC will be utilized to provide general oversight and safety considerations for this study 
CA2099LA. The DMC will provide advice to the Sponsor regarding actions the committee deems 
necessary for the continuing protection of participants enrolled in this study. The DMC will be 
charged with assessing such actions in light of an acceptable risk/benefit profile for 
nivolumab/ipilimumab. The DMC will act in an advisory capacity to BMS and will monitor 
participant safety data for the study.
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BMS-936558
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The DMC will be advisory to the clinical study leadership team. The clinical study leadership 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 amendments to the protocol or changes to the study conduct are required.
Details of the DMC responsibilities and procedures will be specified in the DMC charter. 
5.1.1.2
Blinded Independent Radiology Central Review 
Tumor assessments for each participant should be submitted to the radiology vendor as will be
performed on an ongoing basis. At the time of investigator-assessed initial radiographic 
progression per RECIST 1.1 in any given participant, the site must request the Independent Central 
Review from the third party radiology vendor for confirmation of progression. The blinded, 
independent radiologists will review all available tumor assessments for that given participant and 
determine if RECIST 1.1 criteria for progression have been met. The independent assessment of 
whether or not the given participant met RECIST 1.1 criteria for progression will be provided to 
the site. Participants whose disease progression is not confirmed centrally will be required to 
continue tumor assessments (if clinically feasible) according to the protocol-specified schedule. 
Subsequent tumor assessments must be submitted to the third party radiology vendor for 
subsequent review and may be discontinued when the investigator and independent radiologists 
both assess the participant to have met RECIST 1.1 criteria for progression.
BICR will review tumor images in all treated participants to determine RECIST 1.1 response for 
analyses of ORR or PFS. Details of the BICR procedures will be specified in the imaging manual.
5.2
Number of Participants
Approximately 420 participants will be randomized to treatment arm and control arm in a 1:1 ratio.
5.3
End of Study Definition
The start of the trial is defined as first visit for first participant screened. End of trial is defined as 
the last visit or scheduled procedure shown in the Schedule of Activities for the last participant.
Study completion is defined as the final date on which data for the primary endpoint was or is 
expected to be collected, if this is not the same.
 
 
 
 
 
 
 
 
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Clinical Protocol
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Clinical Protocol
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BMS-936558
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Clinical Protocol
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report, must be submitted for biomarker evaluation prior to treatment. The tumor tissue 
sample may be fresh or archival, (archival tissue is to be obtained within 3 months prior to 
enrollment), and there can have been no systemic therapy (eg, adjuvant or neoadjuvant 
chemotherapy) given after the sample was obtained. Tissue must be from a core needle 
biopsy, excisional or incisional biopsy. Fine needle biopsies or drainage of pleural 
effusions with cytospins are not considered adequate for biomarker review. Biopsies of 
bone lesions that do not have a soft tissue component or decalcified bone tumor samples 
are also not acceptable.
i)
Participants must have PD-L1 IHC testing with results performed by a central laboratory
during the screening period. 
j)
Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2 weeks 
prior to treatment. Subjects with symptomatic tumor lesions at baseline that may require 
palliative radiotherapy within 4 weeks of first treatment are strongly encouraged to receive 
palliative radiotherapy prior to treatment.
k) Screening laboratory values must meet the following criteria (using CTCAE v4):
i)
WBC ≥2000/ȣL
ii) Neutrophils ≥1500/ȣL
iii) Platelets ≥100 x 103/ȣL
iv) Hemoglobin ≥9.0 g/dL
v) Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥50 mL/min 1(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/ALT ≤3.0 x ULN (≤5 x ULN if liver metastases are present)
vii)Total bilirubin ≤1.5 x ULN except subjects with Gilbert Syndrome who must have a
total bilirubin level < 3.0 mg/dL).
Subject Re-enrollment: This study permits the re-enrollment of a subject who has discontinued the 
study as a pre-treatment failure (ie, subject has not been treated). If re-enrolled, the subject must 
be re-consented.
3) Age and Reproductive Status
a) Males and Females, ages ≥18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for methods(s) of contraception for the 
duration of treatment with nivolumab and 5 months after the last dose of nivolumab (ie 
30 days [duration of ovulatory cycle] plus the time required for nivolumab to undergo 
approximately five half-lives).
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 and up to 
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Clinical Protocol
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7 months after the last dose of nivolumab (ie 90 days [duration of sperm turnover] plus 
the time required for nivolumab to undergo approximately five half-lives).
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 these sections.
Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male participants 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.
6.2
Exclusion Criteria
1) Medical Conditions
a) Participants with known EGFR mutations which are sensitive to available targeted inhibitor 
therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] 
substitution mutations) are excluded. All participants with non-squamous histology must 
have been tested for EGFR mutation status. EGFR test is to be done locally. EGFR test is 
not provided by a third party laboratory. Use of a FDA-approved test (PCR based assay 
from tumor tissue) is strongly encouraged. Tests other than PCR or next generation 
sequencing will be requested to repeat using PCR or next generation sequencing based 
methods. Participants of non-squamous histology with unknown or indeterminate EGFR 
status are excluded.
b) Participants with known ALK translocations which are sensitive to available targeted 
inhibitor therapy are excluded. If tested, use of an FDA-approved test is strongly 
encouraged. Participants with unknown or indeterminate ALK status may be enrolled.
c) Participants with untreated CNS metastases are excluded. Participants are eligible if CNS 
metastases are adequately treated and participants are neurologically returned to baseline 
(except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks 
prior to first treatment. In addition, participants must be either off corticosteroids, or on a 
stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 2 weeks 
prior to first treatment.
d) Participants with carcinomatous meningitis.
e) Participants must have recovered from the effects of major surgery or significant traumatic 
injury at least 14 days before first treatment.
f)
Participants with previous malignancies (except non-melanoma skin cancers, and in situ 
cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or 
breast) are excluded unless a complete remission was achieved at least 2 years prior to first 
treatment and no additional therapy is required or anticipated to be required during the 
study period.
g) Participants with an active, known or suspected autoimmune disease. Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
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6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from regulatory 
authorities. Minimal information includes date of consent, demography, screen failure details, 
eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening Period
This study permits the re-enrollment of a participant that has discontinued the study as a 
pre-treatment failure (ie, participant has not been randomized / has not been treated). If re-enrolled, 
the participant must be re-consented
Retesting of laboratory parameters and/or other assessments within any single screening will be 
permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation
Study 
treatment
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
In this protocol, investigational product(s) is/are:
•
Nivolumab 
•
Ipilimumab
•
Carboplatin
•
Pemetrexed
•
Paclitaxel
•
Cisplatin
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products.
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Table 7-1:
Study treatments for CA2099LA
Product Description 
and Dosage Form
Potency
IP/Non-IP
Blinded or 
Open Label
Primary Packaging 
(Volume)/Label Type and 
Secondary Packaging 
(Qty)/Label Type
Appearance
Storage Conditions 
(per label)
BMS-936558-01 
Nivolumab Solution for 
Injectiona
100 mg 
(10 mg/mL)
IP
Open label
10 mL per vial and 5 or 10 
vials per carton
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles
2 to 8° C. Protect from 
light and freezing
Ipilimumab Solution for 
Injection
200 mg
(5mg/mL)
IP
Open label
40 mL vial and 4 vials per
carton
Clear to opalescent 
colorless to pale 
yellow liquid. May 
contain particles
2 to 8° C. Protect from 
light and freezing
Carboplatin Solution for 
Injectionb
450 mg/vial 
(10 mg/mL)
IP
Open label
45 mL per vial and 4 vials 
per carton/
Clear, colorless or 
slightly yellow 
solution
Product should be stored 
as per market product 
conditions
Paclitaxel Solution for 
Injectionb
100 mg/vial (6 
mg/mL)
IP
Open label
16.7 mL vial and 4 vials per 
carton
Clear, colorless, or 
slightly yellow viscous 
solution
Product should be stored 
as per market product 
conditions
Pemetrexed Powder for 
Concentrate for Solution 
for Infusionb
500 mg/vial
IP
Open label
500 mg per vial and 1 vial 
per carton
White to either light 
yellow or green-
yellow lyophilized 
powder
Product should be stored 
as per market product 
conditions
Cisplatin Solution for 
Infusionb
100 mg/vial 
(1 mg/mL)
IP
Open label
100 mL per vial and 4 vials 
per carton
Clear, colorless 
solution
Product should be stored 
as per market product 
conditions
NOTES:
a May be labeled as either “BMS-936558-01” or “Nivolumab”
b These products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. In these cases,
products may be a different pack size/potency than listed in the table. These products should be prepared/stored/administered in accordance with the package
insert or summary of product characteristics (SmPC).
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Clinical Protocol
CA2099LA
BMS-936558
nivolumab
7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Treatments Administered
Week 1, 
Cycle 1 Day 1
± 3 Days
Week 4, 
Cycle 2 Day 1
± 3 days
Week 7, 
Cycle 3 Day 1 
± 3 Days
Nivolumab + ipilimumab + platinum-doublet 
chemotherapy q 3wk x 2 cycles followed by
nivolumab (360 mg q 3weeks) + ipilimumab 
(1mg/kg q 6weeks)
Cycle 1 
Nivolumab
+
Ipilimumab
+
Histology-based 
chemotherapy
Cycle 2
Nivolumab
+
Histology-based 
chemotherapy
Cycle 3
Nivolumab
+
Ipilimumab
Platinum doublet chemotherapy q 3wk x 4 
followed by optional maintenance
Pemetrexed for non-squamous histology
Cycle 1
Histology-based 
chemotherapy
Cycle 2
Histology-based 
chemotherapy
Cycle 3 
Histology-based 
chemotherapy
Both nivolumab and ipilimumab should be administered as 30 minute infusions. Nivolumab will 
be administered first. Ipilimumab will be administered after at least 30 minutes after completion 
of the nivolumab infusion. Platinum-doublet will start at least 30 minutes after completion of the 
nivolumab or ipilimumab infusion (if ipilimumab is scheduled to be given). At the investigator’s 
discretion, nivolumab or ipilimumab may be administered over a longer infusion time (60 minutes) 
if the participant developed a prior infusion reaction.
Nivolumab and ipilimumab treatment will continue until disease progression, discontinuation due 
to unacceptable toxicity, withdrawal of consent, or study closure. Participants will be treated up to 
24 months in the absence of disease progression or inacceptable toxicity. Treatment with 
nivolumab and ipilimumab could be reinitiated as per the initial schedule for subsequent disease 
progression after maximum 24 months of treatment and administered for up to 1 additional year. 
Maximum 24 months of treatment also applies to treatment beyond progression.
All participants will be monitored continuously for AEs while on study treatment. Treatment 
modifications (eg, dose delay, reduction, retreatment, or discontinuation) will be based on specific 
laboratory and adverse event criteria, as described in Sections 7.4.1, 7.4.2, 7.4.3, and 8.1.
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7.1.1
Dosing
7.1.1.1
Nivolumab and Ipilimumab Dosing for Treatment Arm
Participants will receive nivolumab and ipilimumab (induction dose and treatment interval will be 
determined by safety lead-in phase in study CA209568), followed by chemotherapy on day 1 of 
every 3 weeks cycle. The 2 cycles of chemotherapy during induction are same regimens as control 
arm (without chemotherapy maintenance) as in Section 7.1.1.2. At the time of completion of 
2 cycles of chemotherapy, participants who have not experienced disease progression will continue 
to receive nivolumab at a dose of 360 mg as 30 minute infusion every 3 weeks, and ipilimumab 
1 mg/kg as 30 minute infusion IV every 6 weeks starting on day 1. Treatment will continue until 
progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs 
first. Treatment with nivolumab with ipilimumab will be given for up to 24 months in the absence 
of disease progression or inacceptable toxicity. A maximum 24 months of treatment also applies 
to treatment beyond progression. Treatment with nivolumab and ipilimumab could be reinitiated 
as per the initial schedule for subsequent disease progression and administered for up to 
1 additional year (investigators may decide not to re-treat with ipilimumab and nivolumab at 
progression if there is significant risk of recurrent severe toxicity). Ipilimumab and/or nivolumab 
must not be reinitiated if it was permanently discontinued on study due to treatment related 
toxicities. All exceptions must require approval by Medical Monitor. Participants may discontinue 
only ipilimumab and continue treatment with nivolumab if certain circumstances are met 
(Section 8.1.2). 
Ipilimumab is not permitted to continue on study after nivolumab is discontinued. The assessment 
for discontinuation of nivolumab should be made separately from the assessment made for 
discontinuation of ipilimumab. Although there is overlap among the discontinuation criteria, if 
discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with nivolumab 
may continue if ipilimumab is discontinued. The assessment for discontinuation of 
nivolumab/ipilimumab should be made separately from chemotherapy.
If criteria for 
discontinuation for nivolumab and ipilimumab are met, platinum doublet chemotherapy may 
continue until 2 cycles have been completed. If a participant meets criteria for discontinuation and 
investigator is unable to determine whether the event is related to all or any one study drug, the 
participant should discontinue all study drugs and be taken off the treatment phase of the study. 
7.1.1.2
Chemotherapy Dosing
In control arm, 4 cycles of histology-based platinum doublet chemotherapy options will be selected 
by investigator and administered on day 1 every 3 weeks; participants with non-squamous 
histology may also receive optional maintenance therapy with 500 mg/m2 pemetrexed alone on 
day 1 of each 3 week cycle until disease progression or unacceptable toxicity or other reasons 
specified in the protocol (Section 8.1.3). 
In treatment arm, 2 cycles of chemotherapy during induction are same regimens as control arm 
(without chemotherapy maintenance).
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Histology-based chemotherapy:
•
Squamous histology: carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous histology: 
−
carboplatin AUC 5 or 6 + pemetrexed 500 mg/m2
−
cisplatin 75 mg/m2 + pemetrexed 500 mg/m2
All chemotherapy agents’
preparation, premedication, administration, monitoring, and 
management of complications are to follow local prescription guideline and regulation. The dose 
of chemotherapy may be capped per local standards.
Note: The investigator must decide prior to randomization whether or not a
participant with 
non-squamous histology will receive cisplatin, if eligible.
7.1.1.2.1
Paclitaxel and Carboplatin 
Participants will receive paclitaxel 200 mg/m2 as a 180-minute IV infusion with carboplatin at a 
dose of AUC 6 as a 30-minute IV infusion, on Day 1 of a 3-week cycle, or at doses per the local 
prescribing information. The infusion time can follow local institutional standard. 
Paclitaxel dosing calculations should be based on the body surface area calculation. The dose may 
remain the same if the participant’s weight is within 10% of the baseline weight or prior dose 
weight.
Carboplatin should be given following paclitaxel on Day 1 of each cycle, and the carboplatin dose 
will be calculated using the Calvert formula as follows:
•
Carboplatin dose (mg) = target AUC x ([CrCl (ml/min) + 25]
•
Creatinine clearance (CrCl) calculation is based on the Cockcroft-Gault formula) and should 
include the most recent serum creatinine and most recent weight. NOTE: If calculation of the 
CrCl by the Cockcroft-Gault formula yields a result of > 125 mL/min, then a CrCl should be 
calculated by an alternative formula per institutional standards or capped at 125 mL/min.
•
The dose of carboplatin may be capped per local standards.
Premedications for use with paclitaxel
Oral corticosteroid should be given according to local standard at a dose equivalent to 
dexamethasone 20 mg 12 hours and 6 hours prior to paclitaxel administration. Oral or intravenous 
(IV) diphenhydramine (or its equivalent) 50 mg and H2-blocker (per local standard of care) should 
be administered 30 to 60 minutes prior to paclitaxel infusion.
Doses of paclitaxel and/or carboplatin may be interrupted, delayed, reduced, or discontinued 
depending on how well the participant tolerates the treatment. 
7.1.1.2.2
Pemetrexed and Cisplatin
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% weight used to calculate the previous 
dose.
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nivolumab
Premedications with pemetrexed use
1) Oral corticosteroid should be given according to local standards at a dose equivalent to 
dexamethasone 4 mg BID on the day prior to, the day of, and the day after the administration 
of pemetrexed. Oral folic acid 350 to 1000 mcg daily should be given starting 1 week prior to 
the first dose of pemetrexed, with at least 5 doses of folic acid administered in the 7 days prior 
to the first dose. Oral folic acid should be continued daily throughout the treatment with 
pemetrexed and for 21 days after the last dose of pemetrexed. Intramuscular (IM) injection of 
vitamin B12 1000 mcg should be given approximately one week prior to the first dose of 
pemetrexed and repeated every 3 cycles thereafter during pemetrexed treatment. Subsequent 
injections of vitamin B12 may be given on the same day as pemetrexed. (Participant with 
non-squamous histology may begin folic acid and vitamin B12 prior to randomization in 
anticipation of pemetrexed)
2) Antiemetic premedication will be administered according to local standards. Recommended 
antiemetic treatments are dexamethasone (dosing according to local standards; an equivalent 
dose of another corticosteroid may be substituted) and a 5-HT3 receptor antagonist (type per 
investigator discretion and local standards-of-care). Additional use of antiemetic 
premedications may be employed at the discretion of the Investigator.
Participants will receive pemetrexed at a dose of 500 mg/m2 as a 10 minute IV infusion on day 1 
with cisplatin at a dose of 75mg/m2 infusion as per local standard practice on day 1 of a 3-week 
treatment cycle for up to 2 cycles in treatment arm or 4 cycles in control arm.
Dosing calculations should be based on the body surface area calculation and may be capped per 
local standards. The dose may remain the same if the participant’s weight is within 10% of the 
baseline weight or prior dose weight.
Cisplatin will be administered to participants at least 30 minutes following the end of the 
pemetrexed infusion. Pretreatment hydration for cisplatin can follow local standard of care, or use 
1 to 2 liters of fluid (per local standards) infused IV for 8 to 12 hours prior to cisplatin infusion is 
recommended. Adequate hydration and urinary output must be maintained for at least 24 hours 
following cisplatin administration. Administration and monitoring should be performed according 
to local standards. Use of mannitol following the cisplatin infusion should also follow local 
standards-of-care.
Doses of pemetrexed and/or cisplatin may be interrupted, delayed, reduced, or discontinued 
depending on how well the participant tolerates the treatment See the following sections for more
details: Section 7.4.1 (dose delays);, Section 7.4.2 (dose reductions); Section 7.4.3 (retreatment), 
and Section 8.1 (dose discontinuations).
All participants who will be receiving cisplatin should have audiometric testing performed prior 
to initiation of therapy and prior to subsequent doses of cisplatin, or as per local standards of care.
Participants who discontinue cisplatin alone may, at the investigator’s discretion, be switched to 
pemetrexed/carboplatin for the remainder of the platinum doublet cycles (up to 2 cycles in 
treatment arm or 4 cycles in control arm in total). Dosing for pemetrexed/carboplatin for such 
participants should follow the instructions in the pemetrexed/carboplatin with or without 
Pemetrexed Continuation Maintenance section below.
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7.1.1.2.3
Pemetrexed/Carboplatin
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% weight used to calculate the previous 
dose.
Oral corticosteroid premed for pemetrexed should be given according to local standards at a dose 
equivalent to dexamethasone 4 mg BID on the day prior to, the day of, and the day after the 
administration of pemetrexed. Oral folic acid 350 to 1000 mcg daily should be given starting 
1 week prior to the first dose of pemetrexed, with at least 5 doses of folic acid administered in the 
7 days prior to the first dose. Oral folic acid should be continued daily throughout the treatment 
with pemetrexed and for 21 days after the last dose of pemetrexed. Intramuscular (IM) injection 
of vitamin B12 1000 mcg should be given approximately one week prior to the first dose of 
pemetrexed and repeated every 3 cycles thereafter during pemetrexed treatment. Subsequent 
injections of vitamin B12 may be given on the same day as pemetrexed. (Participant with non-
squamous histology may begin folic acid and vitamin B12 prior to randomization in anticipation 
of pemetrexed).
Participants will receive pemetrexed at a dose of 500 mg/m2 as a 10-minute IV infusion on Day 1, 
followed by carboplatin at a dose of AUC 5 or 6 as a 30-minute IV infusion, on Day 1 of a 3-week 
treatment cycle, for up to 4 cycles.
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% weight used to calculate the previous 
dose.
The carboplatin dose will be calculated using the Calvert formula as follows:
•
Carboplatin dose (mg) = Target AUC x (CrCl [ml/min] + 25)
•
Creatinine clearance (CrCl) calculation is based on the Cockcroft-Gault formula (see Inclusion 
criterion in Section 6.1) and should include the most recent serum creatinine and most recent 
weight. NOTE: If calculation of the CrCl by the Cockcroft-Gault formula yields a result of 
> 125 mL/min, then a CrCl should be calculated by an alternative formula per institutional 
standards or capped at 125 mL/min. 
Doses of pemetrexed and/or carboplatin may be interrupted, delayed, reduced, or discontinued 
depending on how well the participant tolerates the treatment. All chemotherapy agents 
preparation, premedication, administration, monitoring, and management of complications are to 
follow local prescription guideline and regulation. The dose of chemotherapy may be capped per 
local standards.
7.1.1.3
Optional Continuation-Maintenance
After cycle 4 in control arm, participants with non-squamous histology who have stable disease or 
response after induction chemotherapy are permitted to receive pemetrexed 500 mg/m² alone as 
maintenance therapy until disease progression or unacceptable toxicity. 
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7.1.2
Treatment of Nivolumab or Ipilimumab Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the BMS Medical Monitor and reported as an SAE 
if criteria are met. Infusion reactions should be graded according to 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 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated)
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab or ipilimumab administrations.
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal 
anti-inflammatory 
drugs,
narcotics, 
corticosteroids, 
bronchodilators, 
IV 
fluids]; 
prophylactic medications indicated for ≤24 hours)
•
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat 
the 
participant
with 
diphenhydramine 
50 
mg 
IV 
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor participant
closely. If symptoms recur, then no further nivolumab or ipilimumab will be administered at 
that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the 
participant until resolution of symptoms. The amount of study drug infused must be recorded 
on the electronic case report form (eCRF).
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab or ipilimumab infusions. If 
necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae [eg, renal 
impairment, pulmonary infiltrates]. Grade 4: Life threatening; pressor or ventilatory 
support indicated)
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•
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 
mg of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab or 
ipilimumab will be permanently discontinued. Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis. Remain at bedside and monitor participant until 
recovery of the symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.1.3
Treatment Beyond Disease Progression 
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.21
Participants will be permitted to continue on nivolumab + ipilimumab for treatment beyond initial 
RECIST 1.1 defined PD as long as they meet the following criteria:
•
Investigator-assessed clinical benefit and no rapid disease progression
•
Participant is tolerating study treatment
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
•
Participant provides written informed consent prior to receiving additional nivolumab and 
ipilimumab treatment, using an ICF describing any reasonably foreseeable risks or 
discomforts, or other alternative treatment options.
The decision to continue treatment beyond initial investigator-assessed progression should be 
discussed with the BMS Medical Monitor and documented in the study records. A follow-up scan 
should be performed within six (6) weeks ± 7 days of original PD to determine whether there has 
been a decrease in the tumor size, or continued progression of disease. Subsequent scans should 
be performed per protocol defined schedule ± 7 days until further progression is determined.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Time and Events Schedule in Section 2.
For the participants who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden from time of initial PD. This includes an increase 
in the sum of diameters of all target lesions and/ or the diameters of new measurable lesions 
compared to the time of initial PD. Nivolumab and ipilimumab treatment should be discontinued 
permanently upon documentation of further progression.
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New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm.
7.2
Method of Treatment Assignment
After the participant’s initial eligibility is established and informed consent has been obtained, the 
participant must be enrolled into the study by calling an interactive web response system (IWRS) 
to obtain the participant number. Every participant that signs the informed consent form must be 
assigned a participant number in IWRS. Specific instructions for using IWRS will be provided to 
the investigational site in a separate document. The investigator or designee will register the 
participant for enrollment by following the enrollment procedures established by BMS. The 
following information is required for enrollment:
•
Date that informed consent was obtained
•
Participant number
•
Date of birth
Participants enrolled will be grouped according to PD-L1 status (positive, negative, or not 
quantifiable, using membranous staining in ≥1% tumor cells vs membranous staining in < 1% 
tumor cells). PD-L1 expression data will be transferred directly from analyzing lab to IWRS. 
IWRS will be used to track the enrollment number.
Once enrolled in IWRS, enrolled participants that have met all eligibility criteria will be
randomized through IWRS. The following information is required for participant randomization:
•
Participant number
•
Date of birth
•
Gender
•
Histology (squamous or non-squamous). 
−
Participants with mixed histology should be classified according to the predominant 
histology. 
−
Participants with adenosquamous histology should be classified as non-squamous 
histology.
•
PD-L1 status
•
Will participant be treated with cisplatin, if eligible?
Participants meeting all eligibility criteria will be stratified by tumor histology (squamous vs 
non-squamous), gender (male vs female), and PD-L1 level (< 1% vs ≥ 1% expression levels) 
Participants will be randomized in a 1:1 ratio to treatment and control arms.
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Note: participants whose PD-L1 status is not quantifiable will be classified as PD-L1 < 1%. The 
total number of participants with not quantifiable PD-L1 status should not exceed 10% of total 
randomized participants for Part 2.
Enrollment will end after approximately 420 participants are randomized.
The exact procedures for using the IWRS will be detailed in the IWRS manual.
7.3
Blinding
Not applicable. This is an open-label study, blinding procedures are not applicable.
7.4
Dosage Modification
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered immuno-
oncology agents in this protocol. Early recognition and management of AEs associated with 
immuno-oncology agents may mitigate severe toxicity. Management Algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
The above algorithms are found in both the nivolumab and ipilimumab Investigator Brochures, as 
well as in Appendix 6.
7.4.1
Dose Delay Criteria
7.4.1.1
Dose Delay Criteria for Nivolumab and Ipilimumab
Tumor assessments for all participants should continue as per protocol even if dosing is delayed.
Nivolumab and ipilimumab administration should be delayed for the following:
•
Any Grade ≥2 non-skin, drug-related adverse event, except for fatigue and laboratory 
abnormalities
•
Any Grade ≥3 skin drug-related AE
•
Any Grade ≥3 drug-related laboratory abnormality with the following exceptions for 
lymphopenia, AST, ALT, or total bilirubin or asymptomatic amylase or lipase:
−
Grade 3 lymphopenia does not require a dose delay
−
If a participant has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade 2 toxicity
−
If a participant has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥3 toxicity
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−
Any Grade ≥3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay. 
•
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Participants receiving ipilimumab in combination with nivolumab that have drug-related toxicities 
that meet the criteria for dose delay, should have both drugs (ipilimumab and nivolumab) delayed 
until retreatment criteria are met. (Exceptions apply to the retreatment criteria after dose delay of 
ipilimumab and nivolumab for Grade ≥3 amylase and lipase abnormalities that are not associated 
with symptoms or clinical manifestations of pancreatitis and that are attributed to ipilimumab 
alone.)
Participants who require delay should be re-evaluated weekly or more frequently if clinically
indicated. Participants should resume dosing when re-treatment criteria are met.
Rescheduling:
•
Nivolumab may be delayed until the next planned ipilimumab dose if the next ipilimumab dose 
is scheduled within the next 12 days. This will permit periodic ipilimumab dosing to be 
synchronized with nivolumab dosing.
•
Ipilimumab should be dosed at the specified interval regardless of any delays in intervening 
nivolumab doses. However, in order to maintain periodic synchronized dosing of ipilimumab 
and nivolumab, the dosing days of nivolumab and ipilimumab may be adjusted within the 
permitted ± 5 day window, as long as consecutive nivolumab doses are given at least 12 days 
apart. Ipilimumab may be delayed beyond the 5 day window if needed to synchronize with the 
next nivolumab dose.
•
If an ipilimumab dose is delayed beyond 6 weeks from the prior ipilimumab dose, then 
subsequent ipilimumab doses should rescheduled to maintain the 6 week interval between 
consecutive ipilimumab doses. 
•
A dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 8.1.
•
Treatment arm: if any adverse event meeting the dose delay criteria for chemotherapy is felt to 
be related to only one particular agent in the platinum doublet chemotherapy regimen, then 
that chemotherapy agent alone may be omitted for that cycle while the other agents (nivolumab 
and one themotherapy agent) are given. Dosing of nivolumab and both chemotherapy agents 
should be delayed if any criteria for nivolumab or “both platinum-doublet chemotherapy
agents” are met.
7.4.1.2
Dose Delay Criteria for Chemotherapy
Chemotherapy drugs should be delayed for any of the following on the Day 1 of each cycle:
•
Absolute neutrophil count (ANC) < 1500/μL
•
Platelets < 100,000/mm3
•
Any Grade ≥2 non-skin, non-hematologic, drug-related adverse event (excluding Grade 2 
alopecia, Grade 2 fatigue, and Grade 2 laboratory abnormalities)
•
Any Grade ≥3 skin, drug-related adverse event
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•
Any Grade ≥3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, AST, ALT, or total bilirubin:
•
Grade 3 lymphopenia does not require dose delay.
•
If a participant has a baseline AST, ALT or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥2 toxicity. 
•
If a participant has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥3 toxicity. 
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication. Investigators should consult 
local labeling for the chemotherapy drugs being administered to any given participant for 
additional guidance on dose delays.
•
Participants receiving cisplatin with pemetrexed must discontinue cisplatin if the calculated 
creatinine clearance decreases to < 50 mL/min (based on the Cockroft Gault formula). The 
other drug (pemetrexed) may be continued, and the platinum agent may, at the investigator’s 
discretion, be switched to carboplatin for the rest of cycles when the participant meets 
retreatment criteria. Note that pemetrexed can only be administered if CrCl is ≥ 45 ml/min 
(calculated per Cockroft-Gault formula)
•
In addition, if participants receiving carboplatin with paclitaxel and must discontinue 
carboplatin, the paclitaxel may be continued at the investigator’s discretion. 
•
If any non-hematologic adverse event meeting the dose delay criteria above is felt to be related 
to only one particular agent in the platinum doublet chemotherapy regimen, then that agent 
alone may be omitted for that cycle while the other agent is given. In order to maintain 
synchronized dosing of the regimen, the omitted agent should be resumed with the next 
scheduled cycle once the AE has improved and retreatment criteria are met. Please refer to 
Section 7.4.2.2 to determine if dose reduction of the resumed agent is required.
•
If both drugs in the platinum doublet chemotherapy regimen are delayed, then the participant
should be re-evaluated weekly or more frequently if clinically indicated until re-treatment 
criteria are met (as per Section 7.4.3.3).
•
Treatment arm: Dosing of nivolumab and both chemotherapy agents should be delayed if any 
criteria for nivolumab or “both platinum-doublet chemotherapy agents” are met.
7.4.2
Dose Reductions
7.4.2.1
Dose Reduction for Nivolumab or Ipilimumab 
There will be no dose reductions for nivolumab or ipilimumab.
7.4.2.2
Dose Reduction for Chemotherapy 
Dose reductions of chemotherapy may be required, and will be performed according to Table 
7.4.2.2-1. Chemotherapy dose reductions are permanent; once the dose of any chemotherapy agent 
is reduced, it may not be re-escalated in subsequent cycles, except as noted when starting 
pemetrexed maintenance therapy. The dose reductions for each agent in the platinum doublet 
chemotherapy regimen are not linked and may be adjusted independently as summarized below.
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Table 7.4.2.2-1:
Dose Modifications of Chemotherapeutic Agents
Dose Level
Carboplatin
Pemetrexed
Paclitaxel
Cisplatin
Starting dose
AUC 6 or AUC 5
500 mg/m²
200 mg/m²
75 mg/m²
First dose 
reduction
AUC 5 (if starting dose is 
AUC 6) or AUC 4 (if 
starting dose is AUC of 5)
375 mg/m²
150 mg/m²
56 mg/m²
Second dose 
reduction
AUC 4 (if starting dose is 
AUC 6) or AUC 3 (if 
starting dose is AUC 5)
250 mg/m²
100 mg/m²
38 mg/m²
Third dose 
reduction
Discontinue
Discontinue
Discontinue
Discontinue
Any participants with two prior dose reductions for one agent who experiences a toxicity that 
would cause a third dose reduction must be discontinued from that agent.
7.4.2.3
Dose Reductions for Hematologic Toxicity 
Dose modifications for hematologic toxicities (according to CTCAE version 4) are summarized in 
Table 7.4.2.3-1. Dose adjustments are based on nadir blood counts (assessed as per local standards) 
since the preceding drug administration. Dose level adjustments for platinum doublet 
chemotherapy are relative to that of the preceding administration. Generally, both chemotherapy 
agents in the platinum doublet chemotherapy regimen should be dose reduced together for 
hematologic toxicity. After the first cycle, growth factors may be used to assist hematologic 
recovery. Use local standards of care in the use of these supportive measures. Additionally, 
prophylactic antibiotics may be used according to local standards of care. Please report any 
antibiotic or growth factor use on the eCRF.
Table 7.4.2.3-1:
Dose Modifications for Hematologic Toxicity (Based on Nadir 
Counts)
Toxicity
Carboplatin
Paclitaxel
Pemetrexed
Cisplatin
Neutrophil Count Decreased
Grade 4 
(< 500/mm3 or < 0.5 x 109/L)
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Platelet Count Decreased
Grade 3
(25,000 - < 50,000/mm3; 25.0 -< 50.0 x 109/L)
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Grade 4 
(< 25,000/mm3; < 25.0 x 109/L)
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
Reduce one 
dose level
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7.4.2.4
Chemotherapy - Dose Reductions for Non-Hematologic Toxicities 
Dose adjustments for chemotherapy for non-hematologic toxicities during treatment are described 
in Section 7.4.2.2. All dose reductions should be made based on the worst grade toxicity. 
Participants experiencing any of the toxicities during the previous cycle should have their 
chemotherapy delayed until retreatment criteria are met and then reduced for all subsequent cycles 
by 1 dose level or discontinued as appropriate. Dose levels for the two drugs in the 
platinum-doublet chemotherapy regimen are not linked and may be reduced independently, as 
summarized in Table 7.4.2.4-1.
Table 7.4.2.4-1:
Dose Modifications for Non-hematologic Toxicity
Toxicity
Paclitaxel
Carboplatin
Pemetrexed
Cisplatin
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
No change
Reduce one 
dose level
No change
Allergic reactiona
Grade ≥3
Discontinue
Discontinue
Discontinue
Discontinue
Neuropathy
Grade 2
Reduce one dose 
level
No change
No change
Reduce one 
dose level
Neuropathy
Grade ≥3
Discontinue
Discontinue
Discontinue
Discontinue
Calculated creatinine clearance
< 50 mL/min
No change
Discontinue if 
creatinine clearance 
< 20 ml/min
No change
Discontinue
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(s) causing the hypersensitivity reaction or acute infusion reaction (≥Grade 3) require(s) 
discontinuation. All other drugs may be continued.
7.4.3
Criteria to Resume Dosing
7.4.3.1
Criteria to Resume Nivolumab Dosing
Participants may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue.
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.
•
Participants with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the 
presence of Grade 2 AST/ALT OR total bilirubin.
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•
Participants with combined Grade 2 AST/ALT and total bilirubin values meeting 
discontinuation parameters (Section 8.1) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the BMS Medical Monitor.
•
Participants who received systemic corticosteroids for management of any drug-related 
toxicity must be off corticosteroids or have tapered down to an equivalent dose of prednisone
≤10 mg/day.
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment.
•
Dose delay of nivolumab which results in treatment interruption of > 6 weeks requires 
treatment discontinuation, with exceptions as noted in Section 8.1.
•
Participants who delay study treatment due to any Grade 3 amylase or lipase abnormality that 
is not associated with symptoms or clinical manifestations of pancreatitis, which is assessed 
by the investigator to be related to ipilimumab and not to nivolumab, may resume nivolumab 
when the amylase or lipase abnormality has resolved to Grade < 3. The BMS Medical Monitor 
should be consulted prior to resuming nivolumab in such participants. 
7.4.3.2
Criteria to Resume Ipilimumab Dosing
Participants may resume treatment with nivolumab and ipilimumab when drug-related AE(s) 
resolve(s) to Grade 1 or baseline value, with the following exceptions: 
•
Participants may resume treatment in the presence of Grade 2 fatigue.
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.
•
Participants with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the 
presence of Grade 2 AST/ALT or total bilirubin.
•
Participants with combined Grade 2 AST/ALT and total bilirubin values meeting 
discontinuation parameters (Section 8.1) should have treatment permanently discontinued.
•
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed.
•
Participants who received systemic corticosteroids for management of any drug-related 
toxicity must be off corticosteroids or have tapered down to an equivalent dose of prednisone 
≤10 mg/day.
•
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the BMS Medical Monitor.
•
Dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires 
ipilimumab discontinuation, with exceptions as noted in Section 8.1.
•
Ipilimumab may not be resumed sooner than 6 weeks (± 5days) after the prior ipilimumab 
dose.
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•
In general, participants who meet criteria to resume ipilimumab will also have met criteria to 
resume nivolumab, so it should be feasible to synchronize dosing of both drugs when resuming 
ipilimumab. In order to facilitate this, the dosing days of nivolumab and ipilimumab may be 
adjusted within the permitted ± 5 day window, as long as consecutive nivolumab doses are 
given at least 12 days apart.
•
NOTE: One exception occurs when ipilimumab and nivolumab doses are delayed due to 
drug-related Grade 3 amylase or lipase abnormalities not associated with symptoms or clinical 
manifestations of pancreatitis. If the investigator assesses the Grade 3 amylase or lipase 
abnormality is related to ipilimumab and not related to nivolumab, nivolumab may be resumed 
when the amylase or lipase abnormality resolves to Grade < 3 but ipilimumab may only resume
when the amylase or lipase abnormality resolves to Grade 1 or baseline. Investigator attribution 
of this toxicity to the ipilimumab dosing must be clearly noted in the participant's medical 
chart. The BMS Medical Monitor should be consulted prior to resuming ipilimumab in the
participant. 
7.4.3.3
Criteria to Resume Treatment with Chemotherapy 
•
Participants may resume treatment with chemotherapy when the ANC returns to 1500/μl. l, the 
platelet count returns to 100,000/mm3, and all other drug-related toxicities have returned to 
baseline or Grade 1 (or Grade 2 for alopecia and fatigue).
•
If a participant fails to meet criteria for re-treatment, then re-treatment should be delayed, and 
the participant should be re-evaluated weekly or more frequently as clinically indicated. Any 
participant who fails to recover from toxicity attributable to chemotherapy to baseline or Grade 
1 (except Grade 2 alopecia and fatigue) within 6 weeks from the last dose given should 
discontinue the drug(s) that caused the delay.
•
When resuming chemotherapy treatment, please follow the dose reduction recommendations 
in Section 7.4.2.2.
7.5
Preparation/Handling/Storage/Accountability
For nivolumab and ipilimumab, please refer to the current version of the Investigator Brochures 
and/or pharmacy manual for complete storage, handling, dispensing, and infusion information. 
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
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7.7.2.1
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Regular concomitant use of bisphosphonates and RANK-L inhibitors for prevention or reduction 
of skeletal-related events in patients with bone metastases is allowed if initiated prior to first dose 
of study therapy. Prior palliative radiotherapy must have been completed at least 2 weeks prior to 
treatment.
7.7.2.2
Palliative Local Therapy
Palliative local therapy, including palliative radiation therapy- and palliative surgical resection, to 
symptomatic non-target bone lesions, skin lesions, or CNS lesions is permitted prior to 
discontinuation of study treatment for participants who do not have evidence of overall clinical or 
radiographic progression per RECIST 1.1. Palliative local therapy to lesions causing hemoptysis 
may also be permitted prior to discontinuation of study treatment in participants who do not have 
evidence of overall clinical or radiographic progression per RECIST 1.1, provided that the lesions 
undergoing palliative local therapy are not the only sites of measurable disease and the case is 
discussed with and approved by the BMS Medical Monitor.
Participants requiring palliative local therapy should be evaluated for objective evidence of disease 
progression prior to the initiation of such therapy, particularly if the most recent tumor assessment 
was more than 4 weeks prior to the start of local therapy. If progression per RECIST 1.1 is 
identified on any tumor assessments prior to the initiation of palliative local therapy, then 
participants must either discontinue study drug treatment or they must meet criteria to continue 
treatment beyond progression (Section 7.1.3) in order to resume immunotherapy after palliative 
local therapy. If radiographic progression per RECIST 1.1 is identified prior to the initiation of 
palliative local therapy, sites must request a BICR from the third party radiology vendor
(Section 5.1.1.2). However, the initiation of palliative local therapy need not be delayed to await 
the assessment by the BICR.
The potential for overlapping toxicities with radiotherapy and nivolumab/ipilimumab currently is 
not known; however, anecdotal data suggests that it is tolerable. As concurrent radiotherapy and 
nivolumab/ipilimumab have not been formally evaluated, in cases where palliative radiotherapy is 
required for a tumor lesion, then nivolumab/ipilimumab should be withheld for at least 1 week 
before, during, and 1 week after radiation. Participants should be closely monitored for any 
potential toxicity during and after receiving radiotherapy, and AEs should resolve to Grade 
≤1 prior to resuming nivolumab or nivolumab plus ipilimumab.
7.7.2.3
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg, allergy history, diabetic history and renal status), the appropriate imaging modality and 
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contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participants with renal insufficiency should be assessed as to 
whether or not they should receive contrast and if so, what type and dose of contrast is appropriate. 
Should a participant 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.
Specific to MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration 
rate (eGFR) < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI 
contrast should not be given to this participant population. In addition, participants are excluded 
from MRI if they have tattoos, metallic implants, pacemakers, etc. The ultimate decision to 
perform MRI in an individual participant in this study rests with the site radiologist, the 
investigator and the standard set by the local Ethics Committee.
7.8
Treatment After the End of the Study
At the end of the study, BMS will not continue to provide BMS supplied study treatment to 
participants/investigators unless BMS chooses to extend the study. The investigator should ensure 
that the participant receives appropriate standard of care to treat the condition under study.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b)the development of the nivolumab or 
ipilimumab is terminated for other reasons, including but not limited to lack of efficacy and/or not 
meeting the study objectives; c) the participant can obtain medication from a government 
sponsored or private health program. In all cases BMS will follow local regulations
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
For all participants, global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’ in the source data and in the case report form. Tumor assessments for participants 
who discontinue study treatment without radiographic progression, confirmed by BICR
(Section 5.1.1.2), should continue as per protocol until radiographic progression is determined by 
blinded independent central review.
If participant is intolerant of nivolumab treatment during the chemotherapy cycles, participant
should be withdrawn from the treatment phase of the study.
Chemotherapy dose reduction is allowed on study. Any participant with two prior dose reductions 
to one agent who experiences a toxicity that would cause a third dose reduction must be 
discontinued from that agent. A participant in treatment arm who is discontinued from the 
chemotherapy treatment will remain on the study and receive nivolumab and ipilimumab therapy 
with option of pemetrexed maintenance (non-squamous histology only).
If the investigator assesses the drug-related AE to be related to ipilimumab only and not related to 
nivolumab, ipilimumab dosing alone may be discontinued while nivolumab dosing is delayed until 
the participant meets criteria to resume nivolumab treatment.
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8.1.1
Nivolumab Dose Discontinuation
Treatment with nivolumab should be permanently discontinued for any of the following:
•
Any Grade ≥2 drug-related uveitis or 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 ≥2 drug-related pneumonitis or interstitial lung disease that does not resolve to 
dose delay and systemic steroids (also see Pulmonary Adverse Event Management Algorithm);
•
Any Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction, 
regardless of duration;
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
hypersensitivity reactions, infusion reactions, endocrinopathies, and laboratory abnormalities:
•
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
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.
−
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation (also see Hepatic Adverse Event Management Algorithm):
•
Any drug related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation 
−
Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
* In most cases of Grade 3 AST or ALT elevation, study drugs(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drugs(s), a discussion between the investigator and the BMS 
medical monitor or designee must occur.
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
−
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events, which do not require discontinuation:
♦Grade 4 neutropenia ≤7 days
♦Grade 4 lymphopenia or leukopenia
♦Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis and decrease to < Grade 4 within 1 week of 
onset. The BMS Medical Monitor should be consulted for Grade 4 amylase or lipase
abnormalities.
♦Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset
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♦Grade 4 drug-related endocrinopathy adverse events such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or 
are adequately controlled with physiologic hormone replacement (corticosteroids, 
thyroid hormones) or glucose controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the BMS Medical Monitor.
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. Prior to re-initiating 
treatment in a participant with a dosing delay lasting > 6 weeks, the BMS medical monitor 
must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue 
every 6 weeks or more frequently if clinically indicated during such dosing delays.
−
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the Investigator, presents a substantial clinical risk to the participant with continued 
nivolumab dosing.
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of ipilimumab. Although there is overlap among the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued. 
If a participant meets criteria for discontinuation and investigator is unable to determine whether 
the event is related to nivolumab, ipilimumab or chemotherapy (if chemotherapy is part of the 
treatment regimen), the participant should discontinue all treatment: nivolumab, ipilimumab and 
chemotherapy (if chemotherapy is part of the treatment regimen), and be taken off the treatment 
phase of the study. Continuation of ipilimumab after discontinuation of nivolumab is not allowed 
on study. The assessment for discontinuation of nivolumab and ipilimumab should be made 
separately from the assessment made for discontinuation of chemotherapy doublet. If criteria for 
discontinuation for nivolumab and ipilimumab are met before the nivolumab and ipilimumab plus 
platinum doublet chemotherapy cycles have been completed, platinum doublet chemotherapy may 
continue until 2 cycles have been completed. 
8.1.2
Ipilimumab Dose Discontinuation
Ipilimumab should be permanently discontinued if any of the following criteria are met:
•
Any Grade ≥2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within 2 weeks OR requires systemic 
treatment;
•
Any Grade ≥3 bronchospasm or other hypersensitivity reaction;
•
Any other Grade 3 non-skin, drug-related adverse with the following exceptions for laboratory 
abnormalities, grade 3 nausea and vomiting, grade 3 neutropenia and thrombocytopenia, and 
symptomatic endocrinopathies which resolved (with or without hormone substitution);
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation:
−
Grade ≥3 drug related AST, ALT or Total Bilirubin required discontinuation
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♦* In most cases of Grade 3 AST, ALT evaluation study drug(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug(s), a discussion between the investigator and the 
BMS medical monitor or designee must occur.
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2X ULN
•
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following 
events, which do not require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia
−
Isolated Grade 4 amylase or lipase abnormalities which are not associated with symptoms 
or clinical manifestations of pancreatitis. 
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events such as adrenal insufficiency, ACTH 
deficiency, hyper- or hypothyroidism, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (corticosteroids, thyroid 
hormones) or glucose controlling agents, respectively, may not require discontinuation 
after discussion with and approval from the BMS Medical Monitor.
•
Any treatment delay resulting in no ipilimumab dosing for > 12 weeks with the following 
exceptions: Dosing delays to manage drug-related adverse events, such as prolonged steroid 
tapers, are allowed. Prior to re-initiating treatment in a participant with a dosing delay lasting 
> 12 weeks, the BMS medical monitor must be consulted. Tumor assessments should continue 
as per protocol even if dosing is delayed.
•
Dosing delays resulting in no ipilimumab dosing for > 12 weeks that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. Prior to re-initiating 
treatment in a participant with a dosing delay lasting > 12 weeks, the BMS medical monitor 
must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued 
ipilimumab dosing
The assessment for discontinuation of ipilimumab should be made separately from the assessment 
made for discontinuation of nivolumab. Although there is overlap among the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued.
If a participant meets criteria for discontinuation and investigator is unable to determine whether 
the event is related to nivolumab, ipilimumab or chemotherapy (if chemotherapy is part of the 
treatment regimen), the participant should discontinue nivolumab, ipilimumab or chemotherapy 
(if chemotherapy is part of the treatment regimen) and be taken off the treatment phase of the 
study. The assessment for discontinuation of nivolumab and ipilimumab should be made separately 
from the assessment made for discontinuation of chemotherapy doublet. If criteria for 
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discontinuation for nivolumab and ipilimumab are met before the nivolumab and ipilimumab plus 
platinum doublet chemotherapy cycles have been completed, platinum doublet chemotherapy may 
continue until 2 cycles have been completed. 
8.1.3
Chemotherapy Dose Discontinuation 
Except where specified below, chemotherapy drugs in the platinum doublet chemotherapy regimen 
or pemetrexed should be discontinued for any of the following:
•
Any Grade ≥3 peripheral neuropathy
•
Grade ≥3 drug-related thrombocytopenia associated with clinically significant bleeding
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
−
AST or ALT > 5-10x ULN for > 2 weeks
−
AST or ALT > 10x ULN
−
Total bilirubin > 5 x ULN
−
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
•
Any drug-related adverse event which recurs after two prior dose reductions for the same 
drug-related adverse event requires discontinuation of the drug(s) which was/were previously 
dose reduced.
•
Any Grade ≥3 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) felt to be causing the reaction. The drug not felt to be related to 
the hypersensitivity reaction or infusion reaction may be continued.
•
Any Grade 4 drug-related adverse event which the investigator deems is inappropriate to be 
managed by dose reduction(s) requires discontinuation of the drug(s) felt to be causing the 
event. The drug not felt to be related to the event may be continued.
•
Any event that leads to delay in dosing of any study drug(s) for > 6 weeks from the previous 
dose requires discontinuation of that drug(s) with the following exception:
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS medical monitor. Prior to re-initiating 
treatment in a participant with a dosing delay lasting > 6 weeks, the BMS medical monitor 
must be consulted. Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such dosing 
delays.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued platinum 
doublet chemotherapy dosing. Investigators should consult local labeling for the chemotherapy 
drugs being administered to any given participant for additional guidance on dose 
discontinuation.
•
For participants in control arm for whom it was indicated that maintenance pemetrexed therapy 
would be administered, 4 cycles of chemotherapy should be given prior to starting the 
maintenance treatment. However, participants who experience grade 4 treatment-related 
hematologic toxicity, or grade 3 treatment-related non-hematologic toxicity, may start 
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maintenance therapy after 3 cycles of chemotherapy. The nature and grade of the toxicity must 
be clearly noted, and the medical monitor must be notified.
•
In addition, participants receiving cisplatin with pemetrexed must discontinue cisplatin if the 
calculated creatinine clearance decreases to < 50 mL/min based on the Cockcroft Gault 
formula) The other drug (pemetrexed) may be continued, and the platinum agent may, at the 
investigator’s discretion, be switched to carboplatin for the remainder of the platinum doublet 
cycles when the participant meets retreatment criteria.
Note: For participants in treatment arm, if the investigator is unable to determine whether an 
adverse event is due to nivolumab or ipilimumab or platinum doublet chemotherapy, then all drugs 
must be discontinued. The assessment for discontinuation of nivolumab and ipilimumab should be 
made separately from the assessment made for discontinuation of chemotherapy doublet. If criteria 
for discontinuation for nivolumab and ipilimumab are met before the nivolumab and ipilimumab 
plus platinum doublet chemotherapy cycles have been completed, platinum doublet chemotherapy 
may continue until 2 cycles have been completed. 
A participant in treatment arm who is discontinued from the chemotherapy treatment due to 
toxicities related to chemotherapy only, will remain on the study and receive nivolumab and 
ipilimumab therapy.
8.2
Discontinuation from Study 
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In the event a normal healthy female participant becomes pregnant 
during a clinical trial, the study treatment must be discontinued immediately. In most cases, the 
study treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Please call the BMS Medical Monitor within 24 hours of 
awareness of the pregnancy. If the investigator determines a possible favorable benefit/risk ratio 
that warrants continuation of study treatment, a discussion between the investigator and the BMS 
Medical Monitor/designee must occur.
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All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
8.2.1
Post Study Treatment Study Follow-up
In this study, OS is a key endpoint of the study. Post study follow-up is of critical importance and 
is essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study treatment must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 5 until death or the conclusion of the study.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities. 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
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•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
9.1
Efficacy Assessments
Study evaluations will take place in accordance with the Schedule of Activities in Section 2.
Images will be submitted to an imaging core lab. Sites should be trained prior to scanning the first 
study participant. Image acquisition guidelines and submission process will be outlined in the 
CA2099LA Imaging Charter to be provided by the core lab. 
9.1.1
Methods of Measurements
The following imaging assessments should be performed at pre-specified intervals: CT of the 
chest, CT or MRI of the abdomen, pelvis, and other known sites of disease.
•
Baseline assessment must occur prior to dosing
•
CT scans should be acquired with slice thickness of 5 mm or less with no intervening gap 
(continuous) 
•
Should a participant have a contraindication for CT IV contrast, a non-contrast CT of the chest 
and a contrast enhanced MRI of the abdomen and pelvis and other sites of disease may be 
obtained. MRIs should be acquired with slice thickness of 5 mm or less with no gap 
(continuous).
•
Every attempt should be made to image each participant using an identical acquisition protocol 
on the same scanner for all imaging time points. 
NOTE: Use of CT component of a PET/CT scanner: Combined modality scanning, such as with 
FDG-PET/CT, is increasingly used in clinical care and is a modality/technology that is in rapid 
evolution; therefore, the recommendations outlined here may change rather quickly with time. If 
a site can document that the CT performed as part of a FDG-PET/CT is of identical diagnostic 
quality to a diagnostic CT (with IV contrast), then the CT portion of the FDG-PET/CT can be used 
for RECIST 1.1 measurements. Note, however, that the FDG-PET portion of the scan introduces 
additional data which may bias an investigator if it is not routinely or serially performed. 
MRI of brain is required at screening in order to rule out active metastatic disease. 
Bone scan or PET scan is not adequate for assessment of RECIST 1.1 response in target lesions. 
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.
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9.1.2
Imaging and Clinical Assessment 
Screening baseline tumor assessments must be performed within 28 days prior to randomization. 
In addition to the chest, abdomen, pelvis, and brain (to rule out brain metastases), all known sites 
of disease should be assessed at baseline. Subsequent assessments should include chest, abdomen, 
pelvis, and all known sites of disease using the same imaging method and technique as was used 
at baseline. 
Radiographic tumor response will be assessed at week 6 (± 7 days) from first dose date, then every 
6 weeks (± 7 days) for the first 12 months (until Week 48) and every 12 weeks (± 7 days) thereafter, 
until disease progression is documented or treatment is discontinued (whichever occurs later). 
Participants with a history of brain metastasis may have surveillance MRI approximately every 12 
weeks (± 7 days) from the date of first dose, or sooner if clinically indicated.
Tumor assessments for each participant should be submitted to the radiology vendor, as they are 
performed on an ongoing basis. The blinded, independent radiologists will review all available 
tumor assessments for that given participant and determine if RECIST 1.1 criteria for progression 
have been met. The independent assessment of whether or not the given participant met RECIST 
1.1 criteria for progression will be provided to the site. Participants whose disease progression is 
not confirmed centrally will be required to continue tumor assessments (if clinically feasible) 
according to the protocol-specified schedule. 
The BICR will also review tumor images in all treated participants to determine RECIST 1.1 
response for the analyses of ORR and PFS. Details of the BICR responsibilities and procedures 
will be specified in the BICR charter.
9.1.2.1
Assessment of Baseline Tumor Assessment
Screening/baseline imaging (ie, CT of the chest, CT or MRI of the abdomen, pelvis, and other 
known sites of disease) should be submitted to the imaging core lab. MRI preferred or CT scan of 
the brain should be performed within 28 days of randomization and submitted to the imaging core 
lab. 
9.1.2.2
BICR Assessment of Progression
Sites should submit all scans to BICR on a rolling basis, preferably within 7 days of scan 
acquisition, throughout the duration of the study. BICR will review scans on a rolling basis and 
remain blinded to treatment arm and investigator assessment of submitted scans. When progression 
is diagnosed by the investigator, the site will inform the imaging core lab, so that the BICR 
assessment of progression can be performed. 
Participants whose progression is not confirmed by the BICR will be required to continue tumor 
assessments (if clinically feasible) according to the protocol-specified schedule or sooner if 
clinically indicated until the BICR confirms progression on a subsequent tumor assessment. Also, 
if participants discontinue treatment without radiographic progression, tumor assessments will 
continue according to the protocol specified schedule, as noted in Section 2, until progression has 
been confirmed by BICR.
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9.1.3
Study Outcomes Research Assessments
The evaluation of health related quality of life is an increasingly important aspect of a clinical 
efficacy. Such data provides an understanding of the impact of treatment from the participants’ 
perspective and offers insights into the patient experience that may not be captured through 
physician reporting. Generic health related quality of life scales additionally provide data 
necessary in calculating utility values for health economic models. In this study, the EQ-5D (EQ-
5D-3L) will be collected in order to assess the impact of study treatment on generic health related 
quality of life, which will also be used in populating health economic models most notably, cost 
effectiveness analysis. The Lung Cancer Symptom Scale (LCSS) will be collected to assess the 
impact of study treatment on patient reported disease-related symptoms.
The EQ-5D is a standardized instrument for use as a measure of self-reported health status. The 
EQ-5D includes a 5-dimension descriptive system as well as a visual analog rating scale (VAS). 
The EQ-5D descriptive system is comprised of the following 5-dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Utility data generated from the EQ-5D
3L are recommended for use in cost effectiveness analysis. The EQ-5D VAS records the 
participant’s self-rated health status on a 100-point vertical visual analogue scale (0=worst 
imaginable health state, 100 = best imaginable health state).
The LCSS is a validated instrument designed to assess the impact of treatment on disease-related 
symptoms. It consists of 6 symptom-specific questions related to dyspnea, cough, fatigue, pain, 
hemoptysis and anorexia plus 3 summary items: symptom distress, interference with activity, and 
global health related quality of life (HRQoL). The questionnaire uses a 24-hour recall period. For 
the six individual symptom measures, the degree of impairment is recorded on a 100 mm visual 
analogue scale with scores from 0 to 100 with zero representing the best score. The LCSS average 
symptom burden index (ASBI) can be derived as the average of scores for the six symptom-related 
items. A clinically meaningful change in ASBI score has been defined as 10 points.
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment and 
within 100 days of discontinuation of dosing at the timepoints specified in the Schedule of 
Activities (Section 2). 
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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 participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected that occur during the screening period (after signing the consent) and 
within 100 days of discontinuation of dosing. For participants randomized to treatment and never 
treated with study drug, SAEs should be collected for 30 days from the date of randomization. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a 
follow-up skin biopsy).
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.)
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
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Section 9.2.6 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3
In most cases, the study treatment will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.
Protocol-required procedures for study discontinuation and follow-up must be performed on the
particpant.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Adverse Events of Special Interest
Definition of Immune-mediated Adverse Events (IMAEs)
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Immune-mediated AEs are specific events that include pneumonitis, diarrhea/colitis, hepatitis, 
nephritis/renal 
dysfunction, 
rash, 
and 
endocrine 
(adrenal 
insufficiency, 
hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis) for which 
participants received immunosuppressive medication for treatment of the event, with the exception 
of endocrine events (hypothyroidism/thyroiditis, hyperthyroidism, hypophysitis, diabetes mellitus, 
adrenal insufficiency), which are included regardless of treatment since these events are often 
managed without immunosuppression.
IMAEs include events, regardless of causality, occurring within 100 days of the last dose. This list 
is subject to change based on Health Authority feedback or change of MedDRA version. The final 
list used will be described in the CSR.
Table 9.2.6-1 below provides a summary of the IMAEs category and their respective preferred 
terms. This list is subject to change based on Health Authority feedback or change of MedDRA 
version. The final list used will be described in the CSR.
Table 9.2.6-1:
Preferred Terms Included in Analysis of IMAEs to Support 
Warnings and Precautions
IMAE Category
PTs 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/Thyroiditi
s
Hypothyroidism, Thyroiditis
Thyroiditis acute (collapsed with thyroiditis for frequency), Autoimmune 
thyroiditis (collapsed with thyroiditis for frequency)
Hyperthyroidism
Hyperthyroidism
Hypophysitis
Hypophysitis
Diabetes mellitus
Diabetes mellitus, Diabetic ketoacidosis
Nephritis and renal 
dysfunction
Nephritis, Nephritis allergic, Tubulointerstitial nephritis, Acute renal failure, Renal 
failure, Increased creatinine
Rash
Rash, Rash maculopapular
9.2.7
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
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Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.8
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
1.
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN)
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase),
AND
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic.
9.2.9
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
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 Section 9.2).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
9.4.1
Physical Examinations
See Section 2 Schedule of Activities.
9.4.2
Vital signs
See Section 2 Schedule of Activities.
9.4.3
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
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Hematology (CBC)
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN)
Glucose
Albumin
Sodium
Potassium
Chloride
Calcium, Corrected calcium
Phosphorus
Magnesium
Amylase
Lipase
Serology
Serum for hepatitis C antibody or HCV RNA, hepatitis B surface antigen (screening only)
HIV testing (if mandated locally)
Other Analyses
TSH with reflexive fT3 and fT4 if TSH is abnormal
Pregnancy test (WOCBP only: screening and during study)
9.4.4
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.4.5
Electrocardiogram (ECG)
All subjects who have met the eligibility criteria are required to have a 12-lead ECG performed
during Screening. If clinically indicated, additional ECGs may be obtained during the study
 
 
 
 
 
 
 
 
 
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Population
Description
Enrolled 
All participants who sign informed consent and were registered 
into the IWRS
Randomized
All participants who were randomized to either treatment arm. 
This is the primary dataset for analyses of demography, protocol 
deviations, baseline characteristics, efficacy,
and outcome 
research.
Treated
All participants who received at least one dose of any study 
medication. This is the primary dataset for dosing and safety 
analysis.
The efficacy analysis for secondary endpoints will be performed by treatment group as randomized
for all randomized participants.
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints.
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
Primary endpoint is OS with nivolumab and ipilimumab plus chemotherapy vs. 
chemotherapy alone. OS is defined as the time between the date of the 
randomization date and the date of death due to any cause. OS will be censored 
on the last date a participant was known to be alive.
Secondary
•
BICR assessed PFS with nivolumab and ipilimumab plus chemotherapy vs. 
chemotherapy alone
•
BICR ORR with nivolumab and ipilimumab plus chemotherapy vs. 
chemotherapy alone
•
ORR, PFS, and OS in nivolumab and ipilimumab plus chemotherapy vs. 
chemotherapy in subgroups with different PD-L1 expression levels
•
Tumor cell total somatic mutations and their association with ORR, PFS, 
and OS
PFS is defined as the time from the randomization date to the date of the first 
documented tumor progression as determined by the BICR (per RECIST 1.1), 
or death due to any cause. Participants who die without a reported prior 
progression will be considered to have progressed on the date of their death. 
Participants who did not progress or die will be censored on the date of their 
last evaluable tumor assessment. Participants who did not have any on study 
tumor assessments will be censored on the randomization date. Participants
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Endpoint
Statistical Analysis Methods
who started any palliative local therapy or subsequent anti-cancer therapy 
without a prior reported progression will be censored at the last evaluable tumor 
assessment prior to initiation of the palliative local therapy or subsequent anti-
cancer therapy, whichever procedure occurred first.
ORR is defined as the number of participants with a best overall response 
(BOR) of confirmed CR or PR divided by the number of treated participants. 
BOR is defined as the best response designation, as determined by the BICR, 
recorded between baseline and the date of objectively documented progression 
per RECIST 1.1 or the date of initiation of palliative local therapy or the date 
of initiation of subsequent anti-cancer therapy, whichever occurs first. For 
participants without documented progression or palliative local therapy or 
subsequent anti-cancer therapy, all available response designations will 
contribute to the BOR determination. For participants 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. Complete or partial responses may be claimed only if the criteria 
for each are met at a subsequent time point of ≥4 weeks later. Further 
characterization of the response will include time to OR (time from first dosing 
date to first CR or PR) and depth of response (maximum tumor shrinkage in 
target lesions).
10.3.1.1
Methods for Primary Endpoints
The efficacy analysis will be performed by treatment group as randomized. For the primary 
endpoint, the distribution of OS will be compared in two randomized arms at the two interim and 
final analysis via a two-sided, log-rank test stratified by PD-L1, histology and gender with an 
overall significance level of 0.05. A group sequential testing procedure will be applied to OS to 
control the overall type I error for interim and final analyses. Hazard ratios and corresponding 
two-sided 95% confidence intervals (CI) will be estimated using a Cox proportional hazard model, 
with treatment group as a single covariate, stratified by above factors. OS curves OS medians with 
95% CIs, and OS rates at 6, 12, 18, 24, 36, and 48 months with 95% CIs will be estimated using 
Kaplan-Meier methodology if follow-up requirement is met.
10.3.1.2
Methods for Secondary Endpoints
The efficacy analysis for secondary endpoints will be performed by treatment group as randomized
for all randomized participants. PFS comparison will be conducted. The comparison will be based 
on a two-sided stratified log-rank test, stratified by PD-L1, histology and gender at a two-sided 
alpha of 0.05 level. Hazard ratios and corresponding two-sided 95% confidence intervals (CI) will 
be estimated using a Cox proportional hazard model, with treatment group as a single covariate, 
stratified by above factors. PFS curves, PFS medians with 95% CIs, and PFS rates at 6, 12, 18, 24, 
36, and 48 months with 95% CIs will be estimated using Kaplan-Meier methodology if follow-up 
requirement is met. 
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The comparison of ORR as per BICR assessment will be conducted using a two-sided Cochran-
Mantel-Haenszel (CMH) test stratified by PD-L1, histology and gender to compare the treatment 
group to the control group. An estimate of the difference in ORRs and their corresponding 95% 
exact CI will also be calculated. The number and percentage of participants in each category of 
best overall response per BICR (confirmed complete response [CR], confirmed partial response 
[PR], stable disease [SD], progressive disease [PD], or unable to determine [UD]) according to the 
BICR will be presented, by treatment group. An estimate of the response rate and an associated 
exact two-sided 95% CI (Clopper and Pearson) will be presented, by treatment group.
ORR, PFS and OS will also be assessed by treatment groups within subgroups of PD-L1 
expression levels: PD-L1 positive, PD-L1 negative, PD-L1 not quantifiable. The pre-specified 
TMB thresholds will be used to categorize participants in subgroups. ORR, PFS and OS will be 
assess by TMB subgroups.
10.3.2
Safety Analyses
Safety analysis will be performed in all treated participants. Analysis on randomization phase will 
be based on treatment groups. Descriptive statistics of safety will be presented using National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
All on-study AEs, drug related AEs, SAEs and drug-related SAEs, AEs and drug-related AEs 
leading to drug discontinuation will be tabulated using worst grade per NCI CTCAE v 4.0 criteria 
by system organ class and preferred term, based on MedDRA terminology. On-study lab 
parameters including hematology, coagulation, chemistry, liver function and renal function will 
be summarized using worst grade per NCI CTCAE v 4.0 criteria.
A tabular summary of the incidence of overall IMAEs (by preferred term) and serious IMAEs will 
be performed. Frequency, management and resolution of IMAEs will be analyzed and a descriptive 
analysis of IMAEs including time-to-onset, severity, duration, action taken with the study drug, 
dosing delays of the study drug, corticosteroid details, re-challenge information and outcome of 
the AE will be individually characterized by IMAE category (see Section 9.2.6).
Endpoint
Statistical Analysis Methods
Exploratory
Safety and tolerability objectives will be measured by the incidence of adverse 
events, serious events, deaths, and laboratory abnormalities. 
 
 
 
 
 
 
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10.3.6
Interim Analyses 
Two formal interim analysis for the OS are planned after 163 and 198 deaths have been observed 
respectively, which are expected to occur approximately 18 and 21 months after study initiation. 
At the time of the interim analysis, the DMC will review efficacy and safety data as specified in 
the DMC charter. This formal comparison of OS will allow for early stopping for superiority. Lan-
DeMets alpha spending function with O’Brien and Fleming type of boundary will be used. The 
stopping boundary will depend on the actual number of deaths at the time of the interim analysis. 
In addition to the formal planned interim analyses for OS, the DMC will have access to periodic 
unblinded interim reports of efficacy and safety to allow a risk/benefit assessment. The Statistical 
Analysis Plan will further describe the planned interim analyses.
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SAP_001.pdf: 
Statistical Analysis Plan for 
 
Official Title of Study 
A Phase 3, Randomized Study of Nivolumab plus Ipilimumab in Combination with 
Chemotherapy vs Chemotherapy alone as First Line Therapy in Stage IV Non-Small Cell Lung 
Cancer (NSCLC) 
(CheckMate 9LA, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 9LA) 
 
NCT03215706 
06-Aug-2019 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
A PHASE 3, RANDOMIZED STUDY OF NIVOLUMAB PLUS IPILIMUMAB IN 
COMBINATION WITH CHEMOTHERAPY VS CHEMOTHERAPY ALONE AS FIRST
LINE THERAPY IN STAGE IV NON-SMALL CELL LUNG CANCER (NSCLC)
PROTOCOL CA209-9LA
VERSION # 1.0
DATE: 06-AUG-2019
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................4
LIST OF FIGURES ....................................................................................................................5
2
STUDY DESCRIPTION ..........................................................................................7
2.1
Study Design: ...........................................................................................................7
2.2
Treatment Assignment..............................................................................................8
2.3
Blinding and Unblinding...........................................................................................9
2.4
Protocol Amendments...............................................................................................9
2.5
Data Monitoring Committee ...................................................................................10
2.6
Blinded Independent Radiology Central Review.....................................................11
3
OBJECTIVES ........................................................................................................11
3.1
Primary...................................................................................................................11
3.2
Secondary...............................................................................................................11
4
ENDPOINTS..........................................................................................................12
4.1
Efficacy Endpoints .................................................................................................12
4.1.1
Overall Survival .....................................................................................................12
4.1.2
Progression-Free Survival......................................................................................13
4.1.2.1
Primary Definition of Progression-Free Survival (Accounting for Subsequent 
Therapy).................................................................................................................13
4.1.2.2
Secondary Definition of Progression Free Survival (Irrespective of 
Subsequent Therapy) ..............................................................................................15
4.1.3
Objective Response Rate.........................................................................................16
4.1.3.1
Time to Response....................................................................................................16
4.1.3.2
Duration of Response .............................................................................................16
4.1.4
PFS2 ......................................................................................................................17
4.2
Safety endpoints .....................................................................................................18
4.3.2.1
PD-L1 Expression ..................................................................................................18
4.3.2.2
Tumor Mutation Burden (TMB)..............................................................................18
5
SAMPLE SIZE AND POWER...............................................................................21
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................22
6.1
Study Periods..........................................................................................................22
6.2
Treatment Regimens...............................................................................................23
6.3
Populations for Analyses ........................................................................................23
7
STATISTICAL ANALYSES..................................................................................24
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7.1
General Methods ....................................................................................................24
7.1.1
Adverse Events, Serious Adverse Events, Multiple events, Select Adverse 
Events, Other Events of Special Interest and Immune-Mediated Adverse 
Events.....................................................................................................................24
7.1.1.1
Select Adverse Events (EU/ROW Submissions) .......................................................25
7.1.1.2
Other Events of Special Interest..............................................................................26
7.1.1.3
Immune-Mediated Adverse Events (US Submission)................................................26
7.1.2
Laboratory Tests.....................................................................................................26
7.2
Study Conduct........................................................................................................27
7.3
Study Population ....................................................................................................27
7.3.1
Subject Disposition.................................................................................................27
7.3.2
Demographics and Other Baseline Disease Characteristics....................................28
7.3.3
Medical History......................................................................................................29
7.3.4
Prior Therapy Agents .............................................................................................29
7.3.5
Physical Examinations............................................................................................29
7.3.6
Baseline Physical Measurements ............................................................................29
7.4
Extent of Exposure .................................................................................................29
7.4.1
Administration of Study Therapy.............................................................................29
7.4.2
Modifications of Study Therapy ..............................................................................32
7.4.2.1
Dose Delays ...........................................................................................................32
7.4.2.2
Infusion Interruptions and Rate Changes................................................................33
7.4.2.3
Dose Escalations ....................................................................................................33
7.4.2.4
Dose Reductions.....................................................................................................33
7.4.2.5
Partial Discontinuation of Ipilimumab....................................................................34
7.4.3.1
Immune modulating medication..............................................................................35
7.4.3.2
Subsequent Cancer Therapy ...................................................................................36
7.5
Efficacy..................................................................................................................36
7.5.1
Analysis of Overall Survival....................................................................................37
7.5.2
Supportive Analyses of Overall Survival .................................................................38
7.5.3
Subset Analyses of Overall Survival........................................................................39
7.5.4
Interim Analysis of Overall Survival .......................................................................40
7.5.5
Analysis of Progression-Free Survival....................................................................40
7.5.6
Supportive Analyses of Progression-Free Survival..................................................41
7.5.7
Subset Analyses of Progression-Free Survival ........................................................42
7.5.8
Current Status of PFS and OS Follow-up................................................................43
7.5.9
Analysis of Objective Response Rate.......................................................................43
7.5.10
Subset Analyses of Objective Response ...................................................................44
7.5.11
Time to Tumor Response and Duration of Response ...............................................45
7.5.12
PFS2 ......................................................................................................................46
7.6
Safety.....................................................................................................................46
7.6.1
Deaths ....................................................................................................................46
7.6.2
Serious Adverse Events...........................................................................................46
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................46
7.6.4
Adverse Events Leading to Dose Modification........................................................47
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7.6.5
Adverse Events .......................................................................................................47
7.6.6
Select Adverse Events (EU/ROW Submissions) .......................................................47
7.6.6.1
Incidence of Select AE ............................................................................................47
7.6.6.2
Time-to Onset of Select AE .....................................................................................48
7.6.6.3
Time-to Resolution of Select AE..............................................................................48
7.6.7
Immune-Mediated Adverse Events (US Submission)................................................49
7.6.8
Other Events of Special Interest..............................................................................49
7.6.9
Multiple Events.......................................................................................................50
7.6.10
Laboratory Parameters...........................................................................................50
7.6.10.1
Hematology ............................................................................................................50
7.6.10.2
Serum Chemistry ....................................................................................................50
7.6.10.3
Electrolytes.............................................................................................................51
7.6.10.4
Additional Analyses................................................................................................51
7.6.11
Vital Signs and Pulse Oximetry...............................................................................52
7.6.12
Physical Measurements ..........................................................................................52
7.6.13
Non-Protocol Medical Procedures..........................................................................52
7.6.14
Immunogenicity Analysis ........................................................................................52
7.6.15
Pregnancy ..............................................................................................................53
7.6.16
Adverse Events By Subgroup ..................................................................................53
7.8.1
Distribution of PD-L1 Expression...........................................................................54
7.8.2
Tumor Mutation Burden (TMB)..............................................................................54
7.8.2.1
Tumor Tissue TMB .................................................................................................54
7.8.2.2
Blood TMB.............................................................................................................55
7.8.2.3
Correlation between Tissue TMB and Blood TMB ..................................................56
7.9
Clinical Outcomes Assessments..............................................................................56
7.9.1
EuroQol EQ-5D-3L................................................................................................56
7.9.2
LCSS ......................................................................................................................56
8
CONVENTIONS....................................................................................................57
9
CONTENT OF REPORTS .....................................................................................58
10
DOCUMENT HISTORY........................................................................................58
 
 
 
 
LIST OF TABLES
Table 2.4-1:
Protocol Amendments ..............................................................................9
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Table 4.1.2.1-1:
Censoring Scheme used in Primary Definition of PFS ............................14
Table 4.1.2.2-1:
Censoring Scheme for Secondary definition of PFS................................16
Table 7.4.1-1:
Administration of study therapy - Nivolumab and Ipilimumab................29
Table 7.4.1-2:
Administration of study therapy - Carboplatin/Paclitaxel........................30
Table 7.4.1-3:
Administration of study therapy - Carboplatin and Pemetrexed...............31
Table 7.4.1-4:
Administration of study therapy - Cisplatin/Pemetrexed .........................31
Table 7.4.2.4-1:
Dose Modifications of Chemotherapeutic Agents ...................................33
Table 10-1:
Document History ..................................................................................58
Table 10-2:
Derivation of clustered AE .....................................................................60
LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic...........................................................................7
Figure 4.1.2.1-1:
PFS Primary Definition ..........................................................................14
Figure 4.1.2.2-1:
PFS Secondary Definition ......................................................................15
Figure 4.1.4-1:
PFS2 Definition......................................................................................17
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2
STUDY DESCRIPTION
2.1
Study Design:
Adult (≥ 18 years) male and female participants, with stage IV NSCLC, previously untreated for 
advanced disease are eligible for enrollment, irrespectively of PD-L1 expression. Tumor tissue is 
required for study enrollment.
Participants will be assessed by PD-L1 expression, and categorized into 3 groups (PD-L1 positive, 
PD-L1 negative, and PD-L1 not quantifiable). PD-L1 status will be determined by Dako PD-L1 
IHC 28-8 pharmDx test for immunohistochemical (IHC) staining of PD-L1 protein in submitted 
tumor sample.
•
PD-L1 positive (≥ 1% tumor cell membrane staining in a minimum of a hundred evaluable 
tumor cells)
•
PD-L1 negative (< 1% tumor cell membrane staining in a minimum of a hundred evaluable 
tumor cells)
•
PD-L1 not quantifiable (participants with tumor biopsy specimens without quantifiable PD-L1 
expression)
Participants are to have tumor tissue sample available for PD-L1 IHC testing performed by a 
central laboratory during screening period. PD-L1 status is required for randomization.
The enrollment will end when approximately 700 participants are randomized. The Interactive 
Response Technology (IRT) system will be used to track the enrollment number. Testing of PD-L1 
through a central laboratory is required prior to randomization. Participants tested but with non 
quantifiable PD-L1 will stratify with PD-L1 negative participants. PD-L1 not quantifiable 
population will be capped to 10% of total randomized population. The study design schematic is 
presented in Figure 2.1-1
Figure 2.1-1:
Study Design Schematic
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Approximately 700 participants will be randomized in a 1:1 ratio to the treatment arm or control 
arm. The stratification factors for randomization are PD-L1 level (≥ 1% vs < 1%), histology 
(squamous vs non-squamous), and sex (male vs female).
The investigator must decide prior to randomization if participant with non-squamous histology 
will receive cisplatin therapy, based on cisplatin eligibility criteria.
Treatment Arm: Nivolumab will be administered with ipilimumab, plus 2 cycles of histology-
based platinum doublet chemotherapy:
•
Squamous histology: carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous 
histology: 
carboplatin 
AUC 5 or 6 
+ 
pemetrexed 
500 mg/m2
or 
cisplatin 75 mg/m2 + pemetrexed 500 mg/m2
The dosing schedule of nivolumab and ipilimumab during induction will be determined by safety 
lead-in phase of study CA209568. After 2 cycles of induction treatment, nivolumab and 
ipilimumab treatment (nivolumab 360 mg every 3 weeks and ipilimumab 1 mg/kg every 6 weeks) 
will continue until progression, unacceptable toxicity, or other reasons specified in the protocol. 
In this study CA2099LA, treatment with nivolumab and ipilimumab will be given for up to 24 
months in the absence of disease progression or unacceptable toxicity.
Treatment beyond initial investigator assessed RECIST 1.1 defined progression is permitted in 
treatment arm only, if the participant as specified in Protocol Section 7.1.3 has investigator 
assessed clinical benefit and is tolerating nivolumab and ipilimumab. Participants receiving 
nivolumab plus ipilimumab beyond investigator assessed progression must also continue tumor 
assessments until further progression at subsequent tumor assessment as indicated in Protocol 
Section 7.1.3. A maximum of 24 months of treatment also applies to treatment beyond progression.
Control Arm: In the control arm, histology-based platinum doublet chemotherapy options will be 
selected by the investigator and administered on day 1 every 3 weeks for 4 cycles; participants 
with non-squamous histology may also receive optional maintenance therapy with 400 mg/m2
pemetrexed alone on day 1 of each 3 weeks until disease or unacceptable toxicity.
Histology-based platinum doublet chemotherapy:
•
Squamous histology: carboplatin AUC 6 + paclitaxel 200 mg/m2
•
Non-squamous 
histology: 
carboplatin 
AUC 5 or 6 
+ 
pemetrexed 
500 mg/m2
or 
cisplatin 75 mg/m2 + pemetrexed 500 mg/m2
On-study tumor assessments will begin at week 6 post first dose date (± 7 days) and be performed 
every 6 weeks (± 7 days) until Week 48. After Week 48, tumor assessments will be performed 
every 12 weeks (± 7 days) until Blinded Independent Central Review (BICR) assessed 
progression.
2.2
Treatment Assignment
After the participant’s initial eligibility is established and informed consent has been obtained the 
participant must be enrolled into the study by calling an IRT system to obtain the participant 
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number. Every participant that signs the informed consent form must be assigned a participant 
number in the IRT system.
Participants enrolled will be grouped according to PD-L1 status (positive, negative, or not 
quantifiable, using membranous staining in ≥ 1% tumor cells vs membranous staining in < 1% 
tumor cells). PD-L1 expression data will be transferred directly from the analyzing lab to the IRT 
system. The IRT system will be used to track the enrollment number.
Once enrolled in IRT, enrolled participants that have met all eligibility criteria will be randomized 
through the IRT system. Randomization will be stratified by PD-L1 level (≥ 1% vs < 1%), 
histology (squamous vs non-squamous), and sex (male vs female). Participants will be randomized 
in a 1:1 ratio to treatment and control arms.
Enrollment will stop once approximately 700 participants have been randomized.
The exact procedures for using the IRT system will be detailed in the IRT manual.
2.3
Blinding and Unblinding
This is an open label study.
2.4
Protocol Amendments
Table 2.4-1:
Protocol Amendments
Document
Date of Issue
Rationale/Summary of Changes
Revised Protocol 04
08-Mar-2019
Since the original design of CA2099LA study, several studies assessing 
PD-1(L1) inhibitor plus chemotherapy in first line NSCLC in 
nonsquamous and squamous subtypes have been published. Data from 
these studies have shown that PD-L1 inhibitor plus chemotherapy 
treatment were superior to chemotherapy alone in most efficacy 
endpoints. However, most studies shows a delayed effect in terms of 
overall survival with a late separation of the OS.2345 To ensure 
sufficient power to detect a survival benefit in such a scenario, the 
CA2099LA study was revised to update the statistical assumption with a 
delayed effect on survival, which has led to updated projected timelines 
and events. 
 
 
:
•
Updated the two planned interim analyses to one single interim 
analysis
•
The interim and final analyses were updated with number of events, 
power, hazard ratios, and projected timing of events
•
Blood TMB moved to secondary endpoint from exploratory endpoint
Revised Protocol 03
24-Jan-2019
The CA2099LA study was revised to update the protocol with program 
level language for safety.
Summary of Changes:
•
Updated Appendix 3 Adverse Events and Serious Adverse Events: 
Definitions and Procedures For Recording, Evaluating, Follow Up 
and Reporting
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Table 2.4-1:
Protocol Amendments
Document
Date of Issue
Rationale/Summary of Changes
•
Updated Appendix 4 Women of Childbearing Potential Definitions 
and Methods of Contraception
•
•
Excluded vaccine use
Amendment 02 (site 
specific)
23-Jan-2019
As the global sample size neared its target number in November 2018, 
clinical sites in China enrolled < 10 participants. This China-specific 
amendment adds a China-specific substudy to extend enrollment of 
participants in China to ensure sufficient sample size for subgroup 
analysis for safety and efficacy evaluation for participants in China.
Summary of Changes:
•
Add a China specific sub-study to extend enrollment of participants 
from China (up to 70 randomized subjects)
Revised Protocol 02
02-Jul-2018
After completion of 2 years of treatment, retreatment with nivolumab and 
ipililumab for subsequent disease progression does not appear to re-
induce responses or provide clinical benefit derived from continuing I-O 
treatment beyond two years in advanced tumors. Participant number 
information was updated to enable adequate power to address the study 
primary objective based on revised design assumptions. Additionally, 
program updates were added and internal inconsistencies were corrected.
Summary of Changes:
•
Removed 1 year re-treatment after progression
•
Expanded study sample size; updated study endpoints
•
Updated document with program standards and corrected internal 
inconsistencies
Revised Protocol 01
10-Aug-2017
 
Summary of Changes:
•
Confirmed dosing language in the study
 
•
Typographical and formatting errors were corrected
Original Protocol
10-May-2017
Not applicable
2.5
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be utilized to provide general oversight and safety 
considerations for this study, CA2099LA. The DMC will provide advice to the Sponsor regarding 
actions the committee deems necessary for the continuing protection of participants enrolled in 
this study. The DMC will be charged with assessing such actions in light of an acceptable 
risk/benefit profile for nivolumab/ipilimumab. The DMC will act in an advisory capacity to BMS 
and will monitor participant safety data for the study.
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The DMC will be advisory to the clinical study leadership team. The clinical study leadership 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 amendments to the protocol or changes to the study conduct are required.
An independent statistician external to BMS will perform the form interim analysis of OS and will 
provide it to the DMC. If OS achieves the above pre-specified boundary for declaring statistical 
significance, the DMC chair will notify BMS following procedures specified in Section 6.1.2 of 
the DMC Charter. Additional details of the DMC responsibilities and procedures will be specified 
in the DMC Charter.
2.6
Blinded Independent Radiology Central Review
Tumor assessments for each participant should be submitted to the radiology vendor as they will 
be performed on an ongoing basis. At the time of investigator-assessed initial radiographic 
progression per RECIST 1.1 in any given participant, the site must request the Independent Central 
Review from the third party radiology vendor for confirmation of progression. The blinded, 
independent radiologists will review all available tumor assessments for that given participant and 
determine if RECIST 1.1 criteria for progression have been met. The independent assessment of 
whether or not the given participant met RECIST 1.1 criteria for progression will be provided to 
the site. Participants whose disease progression is not confirmed centrally will be required to 
continue tumor assessments (if clinically feasible) according to the protocol-specified schedule. 
Subsequent tumor assessments must be submitted to the third party radiology vendor for 
subsequent review and may be discontinued when the investigator and independent radiologists 
both assess the participant to have met RECIST 1.1 criteria for progression.
BICR will review tumor images in all treated participants to determine RECIST 1.1 response for 
analyses of ORR or PFS. Details of the BICR procedure will be specified in the imaging manual.
3
OBJECTIVES
3.1
Primary
To compare overall survival (OS) of nivolumab + ipilimumab combined with chemotherapy vs 
chemotherapy in participants with histologically confirmed stage IV NSCLC.
3.2
Secondary
•
To compare progression free survival (PFS), based on BICR assessment, of nivolumab + 
ipilimumab combined with chemotherapy vs chemotherapy in participants with histologically 
confirmed stage IV NSCLC.
•
To compare objective response rate (ORR), based on BICR assessment, of nivolumab + 
ipilimumab combined with chemotherapy vs chemotherapy in participants with histologically 
confirmed stage IV NSCLC. Further characterization of the response will include time to ORR 
and duration of response.
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•
To evaluate ORR, PFS, and OS in participants with histologically confirmed stage IV NSCLC 
treated with nivolumab + ipilimumab combined with chemotherapy vs chemotherapy with 
different PD-L1 expression levels.
•
To evaluate tumor mutation burden as a potential predictive biomarker of efficacy (such as 
ORR, PFS, and OS) of nivolumab + ipilimumab in combination with chemotherapy using 
DNA derived from tumor and blood specimens.
 
 
 
 
 
 
 
 
 
4
ENDPOINTS
4.1
Efficacy Endpoints
4.1.1
Overall Survival
The primary objective will be measured by the primary endpoint of Overall survival (OS). OS is 
defined as the time from randomization to the date of death from any cause. For subjects that are 
alive, their survival time will be censored at the date of last contact date (or “last known alive 
date”). Overall survival will be censored at the date of randomization for subjects who were 
randomized but had no follow-up.
OS rate at time T is defined as the probability that a subject is alive at time T following 
randomization. OS rates at fixed time points (e.g. 6 months, depending on minimum follow-up) 
are defined as the probability that a subject is alive at time T following randomization.
Survival follow-up will be conducted every 3 months after subject’s off-treatment date.
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4.1.2
Progression-Free Survival
Two definitions are used for analysis of Progression-Free Survival (PFS). The primary definition 
accounts for subsequent therapy by censoring at the last evaluable tumor assessment on or prior to 
the date of subsequent therapy. The secondary definition is irrespective of subsequent therapy and 
does not account for subsequent therapy.
Clinical deterioration in the absence of unequivocal evidence of progression (per RECIST v1.1 
criteria) is not considered progression for purposes of determining PFS.
PFS rate at time T is defined as the probability that a subject has not progressed and is alive at 
time T following randomization. PFS rates at fixed time points (e.g. 6 months, depending on the 
minimum follow-up) are defined as the probability that a subject has not progressed and is alive at 
time T following randomization.
The first on-study tumor assessment is scheduled to be conducted at 6 weeks (± 1 week) following 
first dose date. Subsequent tumor assessments are scheduled every 6 weeks (± 1 week) up to Week 
48, then every 12 weeks (± 1 week) until BICR assessed disease progression.
4.1.2.1
Primary Definition of Progression-Free Survival (Accounting for 
Subsequent Therapy)
The primary definition of PFS (PFS truncated at subsequent therapy) is defined as the time between 
the date of randomization and the date of first documented tumor progression, based on BICR
assessments (per RECIST v1.1 criteria), or death due to any cause, whichever occurs first.
Subjects who die without a reported progression will be considered to have progressed on the date 
of their death. The following censoring rules will be applied for the primary definition of PFS:
•
Subjects who did not progress or die will be censored on the date of their last evaluable tumor 
assessment.
•
Subjects who did not have any on study tumor assessments and did not die will be censored on 
their date of randomization.
•
Subjects who receive subsequent anti-cancer therapy prior to documented progression will be 
censored at the date of the last evaluable tumor assessment conducted on or prior to the date 
of initiation of the subsequent anti-cancer therapy.
•
Subjects who did not have a documented progression and received subsequent anti-cancer 
therapy will be censored at the date of the last evaluable tumor assessment conducted on or 
prior to the initiation of the subsequent anti-cancer therapy.
Censoring rules for the primary definition of PFS (PFS truncated at subsequent therapy) are 
presented as follows and in Table 4.1.2.1-1.
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Figure 4.1.2.1-1:
PFS Primary Definition
Table 4.1.2.1-1:
Censoring Scheme used in Primary Definition of PFS
Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments*
Date of randomization
Censored 
No on study tumor assessments and 
no death*
Date of randomization
Censored
Subsequent anti-cancer therapy 
started without death or progression 
per RECIST v1.1 reported prior or 
on the same day
Date of last evaluable tumor 
assessment prior to or on the date of 
initiation of the subsequent anti-
cancer therapy
Censored 
Documented progression per 
RECIST v1.1 and no new anti-
cancer started before
Date of the first documented 
progression per RECIST v1.1
(excludes clinical progression)
Progressed 
No progression and no death, and 
no new anti-cancer therapy started
Date of last evaluable tumor 
assessment 
Censored 
Death without progression per 
RECIST v1.1 and no new anti-
cancer started before
Date of death 
Progressed 
* Tumor assessments and death if any, occurring after start of subsequent anti-cancer therapy are not considered.
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4.1.2.2
Secondary Definition of Progression Free Survival (Irrespective of 
Subsequent Therapy)
The secondary definition of PFS (ITT definition) is defined as the time between the date of 
randomization and the date of first documented tumor progression, based on BICR assessments 
(per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. 
Subjects who die without a reported progression will be considered to have progressed on the date 
of their death. The following censoring rules will be applied for the secondary definition of PFS:
•
Subjects who did not progress or die will be censored on the date of their last evaluable tumor 
assessment.
•
Subjects who did not have any on study tumor assessments and did not die will be censored on 
their date of randomization.
Censoring rules for the secondary definition of PFS (ITT definition) are presented as follows and 
in Table 4.1.2.2-1.
Figure 4.1.2.2-1:
PFS Secondary Definition
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Table 4.1.2.2-1:
Censoring Scheme for Secondary definition of PFS
Situation
Date of Progression of Censoring
Outcome
No baseline tumor assessment
Date of randomization
Censored
No on-study tumor assessments and 
no death
Date of randomization
Censored
Documented progression per 
RECIST v1.1 
Date of first documented 
progression per RECIST v1.1 
criteria (excludes clinical 
progression)
Progressed
No progression and no death
Date of last evaluable tumor 
assessment
Censored
Death without progression per 
RECIST v1.1
Date of death
Progressed
4.1.3
Objective Response Rate
Objective Response Rate (ORR) is defined as the number of randomized subjects who achieve a 
best response of confirmed complete response (CR) or confirmed partial response (PR) based on 
BICR assessments (using RECIST v1.1 criteria) divided by the number of all randomized subjects. 
Best Overall Response (BOR) is defined as the best response, as determined by the BICR, recorded 
between the date of randomization and the date of objectively documented progression per 
RECIST v1.1 criteria or the date of initiation of palliative local therapy or the date of subsequent 
therapy, whichever occurs first. For subjects without documented progression or palliative local 
therapy or subsequent therapy, all available response designations will contribute to the BOR 
determination. Confirmation of response is required at least 4 weeks after the initial response.
Further characterization of the response will include time to response and depth of response 
(maximum tumor shrinkage in target lesions).
4.1.3.1
Time to Response
Time to Response (TTR) is defined as the time from randomization to the date of the first 
confirmed documented response (CR or PR), as assessed by the BICR. TTR will be evaluated for 
responders (confirmed CR or PR) only.
4.1.3.2
Duration of Response
Duration of Response (DOR) is defined as the time between the date of first confirmed documented 
response (CR or PR) to the date of the first documented tumor progression as determined by the 
BICR (per RECIST v1.1 criteria), or death due to any cause, whichever occurs first. Subjects who 
start subsequent therapy (including palliative local therapy) without a prior reported progression 
will be censored at the last evaluable tumor assessments prior to initiation of the subsequent 
anticancer therapy (including palliative local therapy). Subjects who die without a reported prior 
progression will be considered to have progressed on the date of their death. Subjects who neither 
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progress nor die, DOR will be censored on the date of their last evaluable tumor assessment. DOR 
will be evaluated for responders (confirmed CR or PR) only.
4.1.4
PFS2
PFS on next-line therapy (PFS2) is defined as the time from randomization to objectively 
documented progression after the next line of therapy, per investigator assessment, or to death 
from any cause, whichever occurs first. Subjects who were alive and without progression after the 
next line of therapy will be censored at last known alive date. 
The following censoring rules will be applied for PFS2:
•
Subjects who did not receive subsequent anti-cancer therapy (i.e. second-line therapy):
−
Subjects who died, the death date is the event date;
−
Else the subject’s PFS2 is censored at his last known alive date.
•
Subjects who received subsequent anti-cancer therapy (i.e. second-line therapy):
−
Subjects who had a disease progression after the start of subsequent anti-cancer therapy, 
this disease progression date is the event date;
−
Else if a subject died or discontinued subsequent anti-cancer therapy, the date of min 
(death, discontinuation of subsequent anti-cancer therapy) is the event date;
−
Else the subject’s PFS2 is censored at his last known alive date.
Figure 4.1.4-1:
PFS2 Definition
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4.2
Safety endpoints
The assessment of safety will be based on the incidence of adverse events (AEs), serious adverse 
events (SAEs), adverse events leading to discontinuation, adverse events leading to dose 
modification, select adverse events (select AEs) for EU/ROW Submissions, immune-mediated 
AEs (IMAEs) for US Submission, other events of special interest (OEOSI), and deaths. The use 
of immune modulating concomitant medication will be also summarized. In addition clinical 
laboratory tests, and immunogenicity (i.e. development of anti-drug antibody) will be analyzed.
 
 
 
 
4.3.2.1
PD-L1 Expression
PD-L1 expression is defined as the percent of tumor cells membrane staining in a minimum of 100 
evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is 
referred to as quantifiable PD-L1 expression. If the PD-L1 staining could not be quantified, it is 
further classified as:
1) Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology 
of the tumor tissue sample and not because of improper sample preparation or handling.
2) Not evaluable: Tumor tissue sample was not optimally collected or prepared and PD-L1 
expression is neither quantifiable nor indeterminate. Not evaluable can be determined from 
H&E process before the tumor biopsy specimen is sent for PD-L1 evaluation or from the H&E 
process during PD-L1 evaluation.
Subjects with missing PD-L1 expression are subjects with no tumor tissue sample available for 
evaluation.
PD-L1 expression will be collected in the IRT as well as in the clinical database. Statistical analysis 
using PD-L1 expression will be solely based on PD-L1 expression data from clinical database.
4.3.2.2
Tumor Mutation Burden (TMB)
Tumor Tissue TMB
Tumor tissue will be evaluated by targeted and/or whole exome sequencing for potential 
association with clinical outcomes. Gene expression signatures such as but not limited to those 
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associated with inflammatory processes and/or immune related signaling may also be evaluated 
by targeted and/or whole transcriptome RNA sequencing for potential association with clinical 
outcomes.
Blood TMB using Plasma Cell Free DNA (cfDNA)
Cell free DNA (cfDNA) are small fragments of DNA that are shed from tumor and from non-
malignant cells and can be found circulating in the peripheral bloodstream. cfDNA derived from 
malignant cells can be isolated and analyzed from blood-derived plasma for genetic features 
including, but not limited to somatic mutations using targeted sequencing-based methods (eg, Next 
Generation sequencing). To complement the planned genomics analyses outlined for tumor 
assessments, plasma will be collected at baseline and on-treatment to isolate cfDNA baseline and 
on-treatment changes in mutational burden (either global, or individual genes) will be evaluated 
for association with treatment outcomes.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5
SAMPLE SIZE AND POWER
The sample size is based on the comparison of the primary endpoint of OS between nivolumab 
and ipilimumab plus chemotherapy and chemotherapy alone, with a two-sided overall alpha of 
0.05. The number of events was estimated assuming an exponential distribution of OS for the 
chemotherapy arm and a piecewise exponential distribution with a 3 month delayed treatment 
effect for the nivolumab + ipilimumab + chemotherapy arm2345.
Approximately 700 participants will be randomized to treatment arm and control arm in a 1:1 ratio. 
Approximately 402 events (ie, deaths), observed among the 700 randomized participants, provides 
81% power to detect an average hazard ratio (HR) of 0.75 with a type 1 error of 0.05 (two-sided). 
The average HR of 0.75 resulted from an assumed targeted hazard ratio of 1 for the initial 3 months 
from randomization and a targeted hazard ratio of 0.68 for the time beyond 3 months from 
randomization and corresponds to a 33% increase in the median OS, assuming a median OS of 
13.93 months for chemotherapy alone and 18.57 months for nivolumab and ipilimumab plus 
chemotherapy respectively.
There is one planned interim analysis of OS for superiority at approximately 80% of total events, 
ie, 322. The stopping boundaries at the interim and final analyses will be based on the actual 
number of OS events at the time of the analysis using Lan-DeMets alpha spending function with 
O’Brien-Fleming boundaries. It is estimated that it will take approximately 24/29 months from the 
randomization of the first participant to observe the required number of events for the interim and 
the final OS analysis, with approximately 15 months of accrual to reach 700 randomized 
participants, assuming a piecewise accrual rate (5 for the first 2 months, 23 for the next 3 months, 
47 for the next 3 months, and 70/month starting from the eighth month).
Comparison of PFS per BICR is one of the key secondary objectives. 596 events provides 
approximately 94% power to detect a hazard ratio (HR) of 0.75 with a type 1 error of 0.05 (two-
sided). The HR of 0.75 corresponds to a 33% increase in the median PFS per BICR, assuming a 
median PFS per BICR of 6 months for chemotherapy alone and 8 months for nivolumab and 
ipilimumab plus chemotherapy respectively. One interim analysis of PFS per BICR is planned at 
the time of the interim analysis of the primary analysis of OS. This formal interim comparison of 
PFS per BICR would be conducted in a hierarchical manner, i.e. if the formal comparison of OS 
is statistically significant then the formal comparison of PFS per BICR would be conducted (see 
Section 7.5). The stopping boundaries at the interim and final analyses will be based on the actual 
number of PFS per BICR events at the time of the analysis using Lan-DeMets alpha spending 
function with O’Brien-Fleming boundaries. At the final analysis time of OS, 596 PFS per BICR 
events are expected. Approximately 524 out of 596 (88%) PFS per BICR are expected at the time 
of the interim analysis. If the interim analysis is performed exactly at 524 events, then PFS per 
BICR would be considered statistically significant if the p-value is ≤ 0.034, providing 
approximately 88% power. The type 1 error to be used for the final analysis of PFS per BICR 
would then be 0.041.
This study includes a sub-study to allow enrollment of patients from China (site-specific protocol 
Amendment 02). Data from these additional subjects will be reported separately. Subjects from 
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China randomized on or before the end of global study accrual will be included in the population 
used for the primary analysis clinical study report. The required number of deaths for the interim 
and final OS analyses are based on the global study population.
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
•
Baseline period:
−
Baseline evaluations or pre-treatment events will be defined as evaluations or events that 
occur before the date and time of the first dose of study treatment. Evaluations (laboratory 
tests, pulse oximetry, vital signs, and biomarkers) on the same date and time of the first 
dose of study treatment will be considered as baseline evaluations. Events (AEs) on the 
same date and time of the first dose of study treatment will not be considered as pre-
treatment events.
−
In cases where the time (onset time of event or evaluation time and dosing time) is missing 
or not collected, the following definitions will apply:
♦Pre-treatment AEs will be defined as AEs with an onset date prior to but not including 
the day of the first dose of study treatment;
♦Baseline evaluations (laboratory tests, pulse oximetry, vital signs, and biomarkers) will 
be defined as evaluations with a date on or prior to the day of first dose of study 
treatment.
−
If there are multiple valid observations on or prior to the first dose of study treatment then 
the latest non missing observation on or before first dose date (and time if collected) will 
be used as the baseline in the analyses. If multiple observations exist on the latest collection 
date (and time if collected), the record with the latest data entry date and time will be used. 
If multiple observations exist on the latest collection date (and time if collected) and data 
entry date and time, then the first observation is used as baseline, unless otherwise 
specified.
♦For PD-L1, non-missing is identified as those with quantifiable test result. After 
applying the rule above, if there are no records with a quantifiable test result, then select 
those with indeterminate result (“INDETERMINATE”). If there are no records with 
indeterminate test result, then select those with unavailable result (“NOT 
EVALUABLE”). If there are no records with unavailable test result, then select those 
which are not reported or not available result (all other records).
♦For Anti-Drug Antibody (ADA), the record related to the most recent assessment 
among those records where date (and time if collected) of Nivolumab/Ipilimumab 
immunoglobulin (IMG) assessment is less than the date (and time if collected) of the 
first Nivolumab/Ipilimumab dose date.
•
Post baseline period:
−
On-treatment AEs will be defined as AEs with an onset date and time on or after the date 
and time of the first dose of study treatment (or with an onset date on or after the day of 
first dose of study treatment if time is not collected or is missing). For subjects who are off 
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study treatment, AEs will be included if event occurred within a safety window of 30 days 
(or 100 days depending on the analysis) after the last dose of study treatment. No 
“subtracting rule” will be applied when an AE occurs both pre-treatment and post-
treatment with the same preferred term and grade.
−
On-treatment evaluations (such as laboratory tests, pulse oximetry, vital signs, etc.) will be 
defined as evaluations taken after the day (and time, if collected and not missing) of first 
dose of study treatment. For subjects who are off study treatment, evaluations should be 
within a safety window of 30 days (or 100 days depending on the analysis) after the last 
dose of study treatment.
•
Late-emergent drug-related AEs will be defined as drug-related AEs with an onset date greater 
than 100 days after the last dose of study treatment in subjects who are off study treatment
6.2
Treatment Regimens
Treatment group “as randomized” corresponds to the treatment group assigned by the Interactive 
Response Technology (IRT) system.
The treatment group “as treated” will be same as the treatment group “as randomized” by IRT 
unless a subject received the incorrect study treatment for the entire period of treatment, in which 
case the subject’s treatment group “as treated” will be defined as the incorrect study treatment.
Unless otherwise specified, the safety analysis will be based on the treatment group “as treated”.
Unless otherwise specified, the efficacy analysis will be based on the treatment group “as 
randomized”.
6.3
Populations for Analyses
•
Global study population: all subjects enrolled during the global accrual window (from first 
patient first consent date to last patient outside of China’s consent date). Any patient from 
China enrolled during the global accrual window will be included.
•
Enrolled subjects: All subjects who signed the informed consent form and obtained a subject
number during the global enrollment period.
•
Randomized subjects: All subjects from the global study population who were randomized 
through the IRT.
•
Treated subjects: All randomized subjects from the global study population who received at 
least one dose of any study treatment.
•
Response evaluable subjects: All randomized subjects from the global study population with 
baseline and at least one on-study tumor assessment. This population is used for analysis of 
tumor burden changes over the time.
•
Tumor Tissue TMB evaluable subjects: All randomized subjects from the global study 
population with baseline evaluable tumor tissue TMB (non-missing numeric).
•
Blood TMB evaluable subjects: All randomized subjects from the global study population with 
baseline evaluable blood TMB (non-missing numeric).
•
China Cohort: Subjects enrolled from China Mainland.
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The primary population of analysis of analysis is the global study population.
Unless otherwise specified, the safety analyses will include all treated subjects, global study 
population.
Unless otherwise specified, the efficacy analyses will include all randomized subjects, global study 
population.
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, discrete variables will be tabulated by the frequency and proportion of 
subjects falling into each category, grouped by treatment. Percentages given in these tables will be 
rounded to the first decimal and, therefore, may not always sum to 100%. Percentages less than 
0.1 will be indicated as ‘< 0.1’. Continuous variables will be summarized by treatment group using 
the mean, standard deviation, median, minimum, and maximum values.
Time-to-event variables (e.g. time-to resolution) will be analyzed using the Kaplan-Meier 
technique. When specified, the median will be reported along with 95% CI using Brookmeyer and 
Crowley method10 (using log-log transformation for constructing the confidence intervals11).
The conventions to be used for imputing missing and partial dates for analyses requiring dates are 
described in Section 8.
7.1.1
Adverse Events, Serious Adverse Events, Multiple events, Select 
Adverse Events, Other Events of Special Interest and Immune-Mediated 
Adverse Events
Drug-related AEs are those events with relationship to study drug “Related”, as recorded on the 
CRF. If the relationship to study drug is missing, the AE will be considered as drug-related. 
Serious adverse events consist of AEs deemed serious by the Investigator and flagged accordingly 
in the CRF and clinical database.
Adverse events leading to study drug discontinuation are AEs with action taken regarding study 
drug(s) = “Drug was discontinued”. 
Adverse events leading to dose delay are AEs with action taken regarding study drug(s) = “Drug
was delayed”.
Adverse events leading to dose reduction are AEs with action taken regarding study drug(s) = 
“Dose was reduced”.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
and the most recent version of the dictionary at the time of the database lock will be used. Adverse 
events results will be graded for severity using NCI Common Terminology Criteria for Adverse 
Events (CTCAE) and the most recent version of the criteria at the time of the database lock will 
be used.
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In the AE summary tables, unless otherwise specified, subjects will be counted only once at the 
Preferred Term (PT), only once at the System Organ Class (SOC), and only once at subject level 
for the counting of total number of subjects with an AE. The AE tables will be sorted by the SOCs 
and then PTs. SOC will be ordered by descending frequency overall and then alphabetically. PTs 
will be ordered within SOC by descending frequency overall and then alphabetically. The sorting 
will be done based on the ‘Any Grade’ column of the experimental arm when arms are presented 
side-by-side.
Unless otherwise specified, the AE summary tables will be restricted to on-treatment events 
regardless of the causality.
Analyses that take into account the multiple occurrences of a given adverse event will be conducted 
(see Section 7.6.9). To prepare these analyses, the CRF data will be processed according to 
standard BMS algorithms12 in order to collapse adverse event records into unique records based 
on the preferred term. These data will be presented as the rate per 100 person-years of exposure. 
These analyses will take into account all on-treatment events (allowing more than 1 event per 
subject) and the total exposure time. The person-year exposure will be computed as the sum over 
the subjects’ exposure expressed in years where the exposure time is defined as 
•
(Date of last dose of study treatment - date of first dose of study treatment + 31 days (or 
101 days, depending on the analysis))/365.25, for subject who are off study treatment and were 
followed for at least 30 days (or 100 days, depending on the analysis) after last dose of study 
treatment.
•
(Last known alive date - date of first dose of study treatment +1)/365.25, for subjects who are 
still on-treatment or who are off study treatment and were followed less than 30 days (or 
100 days depending on the analysis) after last dose of study treatment.
7.1.1.1
Select Adverse Events (EU/ROW Submissions)
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific 
category (e.g. pulmonary events, gastrointestinal events categories, etc.). AEs that may differ from 
or be more severe than AEs caused by non-immunotherapies and AEs whose early recognition and 
management may mitigate severe toxicity are included as select AEs. Categories of select AEs 
may include subcategories (e.g. adrenal disorders, diabetes, pituitary disorders, and thyroid 
disorders are subcategories of the endocrine event category). 
The list of MedDRA preferred terms used to identify select adverse events is revisited quarterly 
and updated accordingly. The preferred terms used for the selection at the time of the database 
lock will be provided by categories/subcategories.
In addition to the frequency and worst severity of select AEs, time-to onset, time-to resolution,
and time-to resolution where immune modulating medication was initiated will be analyzed for 
each specific category/subcategory of drug-related select AEs when applicable.
Further details on the definitions time-to onset and time-to resolution are described in APPENDIX 
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7.1.1.2
Other Events of Special Interest
Other events of special interest (OEOSI) consist of a list of preferred terms grouped by specific 
category (e.g. Myositis Event, Myocarditis Event, Demyelination Event, Guillain-Barre 
Syndrome, Pancreatitis Event, Uveitis Event, Encephalitis Event, Myasthenic Syndrome, 
Rhabdomyolysis Event, Graft Versus Host Disease). The list of MedDRA preferred terms used to 
identify OEOSI is revisited quarterly and updated accordingly. The preferred terms used for the 
selection at the time of the database lock by categories will be provided.
 
 
 
 
 
 
 
 
 
 
 
 
 
7.1.2
Laboratory Tests
Clinical laboratory parameters (hematology, serum chemistry and electrolytes) will be evaluated.
Laboratory tests will be graded using the NCI Common Terminology Criteria, and the most recent 
version of the criteria at the time of the database lock will be used.
Clinical laboratory data will be first analyzed using International System of Units (SI).
Analyses will be repeated using US conventional units.
In the laboratory summary tables, unless otherwise specified, subjects will be counted only once 
for each lab parameter according to their worst on treatment CTC grade (worst being the highest 
CTC grade). The laboratory tables and listings will be sorted by laboratory category, laboratory 
subcategory and laboratory test code sequence number.
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7.2
Study Conduct
The following programmable deviations will be considered as relevant protocol deviations.
Eligibility:
•
Subjects with misclassified PD-L1 stratification level (IRT vs clinical database)
•
Subjects who do not have measurable disease at baseline per investigator
On-study:
•
Subjects receiving concurrent anti-cancer therapy
•
Subjects treated differently than as randomized (subjects who received the wrong treatment for 
the entire treatment period, excluding the never treated)
The Relevant Protocol Deviations will be summarized and listed based on all randomized subjects, 
by treatment group and overall. 
Enrollment by country and site, and enrollment by month will be summarized and listed for all 
enrolled subjects.
A by-subject listing of batch numbers for all treated subjects will be provided.
7.3
Study Population
Analyses in this section will be tabulated for all randomized subjects by treatment group as 
randomized, unless otherwise specified.
7.3.1
Subject Disposition
The total number of subjects enrolled (randomized or not randomized) will be presented along 
with the reason for not being randomized. This analysis will be performed on the all enrolled 
subjects population only.
Number of subjects randomized but not treated along with the reason for not being treated will be 
tabulated by treatment group as randomized.
Number of subjects who discontinued study treatment along with corresponding reason will be 
tabulated by treatment group as treated. Reason for discontinuation will be derived from subject 
status CRF page. This analysis will be performed only on the all treated subjects population.
A by-subject listing for all treated subjects will be provided showing the subject’s off treatment 
date and whether the subject continue in the treatment period/study along with the reason for going 
off treatment period/study. A by-subject listing for all enrolled subjects will also be provided,
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showing whether the subject was randomized/treated along with the reason for not being 
randomized/treated.
7.3.2
Demographics and Other Baseline Disease Characteristics
The following demographic and baseline disease characteristics will be summarized and listed by 
treatment group as randomized:
•
Age (continuous)
•
Age categorization (< 65, ≥65 and < 75, ≥75 and < 85, ≥85, ≥75, ≥65)
•
Sex (Male vs. Female)
•
Race (White, Black or African American, Asian, American Indian, or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other, Asian Indian, Chinese, Japanese, Asian Other)
•
Ethnicity (Hispanic/Latino and Not Hispanic/Latino)
•
Country by geographic region
•
ECOG performance status (0, 1, >1)
•
Baseline weight (kg) (continuous)
•
Tumor histology (Squamous vs. Non-squamous)
•
Prior surgery related to cancer (Yes vs. No)
•
Prior radiotherapy (Yes vs. No)
•
Time from initial disease diagnosis to randomization (< 1 year, ≥1 year, 1 - < 2 years, 
2 - < 3 years, 3 - < 4 years, 4 - < 5 years, ≥5 years)
•
Disease stage (Stage IV vs. Recurrent to Metastatic Disease)
•
Smoking status (Current/Former, Never Smoked, Unknown)
•
Region (Europe, North America, Rest of the World, Asia)
•
Baseline PD-L1+ status based on a 1% cut off (≥1% vs. < 1% or indeterminate)
•
PD-L1 expression subgroups (<1%, ≥1%, 1-49%, ≥50%)
•
CNS Metastasis (Yes vs. No)
•
Liver Metastasis (Yes vs. No)
•
Bone Metastasis (Yes vs. No)
•
Sites of diseases (all lesions)
•
Number of disease sites per subject (all lesions)
•
Tumor burden: sum of the diameters of target lesions at baseline
•
Pre-treatment tumor assessments (per investigator)
Summary table (cross-tabulation) by treatment group for stratification factors (PD-L1 status, 
histology, sex) will be provided to show any discrepancies between what was reported through 
IRT vs. CRF data or clinical database at baseline. This summary will be performed based on all
randomized subjects.
A listing of randomization scheme presenting randomized treatment group and as treated treatment 
group will be provided for all randomized subjects.
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7.3.3
Medical History
A by-subject listing of general medical history for all randomized subjects will be provided.
7.3.4
Prior Therapy Agents
Prior cancer therapy will be summarized by treatment group and overall.
Prior systemic cancer therapy will be summarized by treatment group and overall and listed by 
subject.
Prior radiotherapy and prior surgery related to cancer will be listed by subject.
7.3.5
Physical Examinations
Subjects with abnormal baseline physical examination will be listed by subject.
7.3.6
Baseline Physical Measurements
Baseline physical measurements will be listed by subject.
7.4
Extent of Exposure
Listings will include all available exposure data. Analyses will be performed by treatment group 
“as treated” in all treated subjects, unless otherwise specified.
7.4.1
Administration of Study Therapy 
The following parameters will be summarized (descriptive statistics) by study therapy and
treatment group:
•
Number of doses received
•
Cumulative dose
•
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 
90 - < 110%; ≥110%
Duration of study therapy will be summarized (descriptive statistics) by treatment group. Duration 
of combination treatment is the last dosing date of any drug component minus the first dosing date 
of any drug component plus one during the treatment phase.
A by-subject listing of dosing of study medication (record of study medication, infusion details,
and dose changes) will be also provided. 
Table 7.4.1-1:
Administration of study therapy -
Nivolumab and Ipilimumab
nivolumab
Iplimumab
Dosing schedule per protocol
360 mg every 3 weeks 
1 mg/kg every 6 weeks
Dose
Dose (mg/kg) is defined as Total Dose 
administered (mg). Dose administered in 
Dose (mg/kg) is defined as Total 
Dose administered (mg)/Most 
recent weight (kg). Dose 
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Table 7.4.1-1:
Administration of study therapy -
Nivolumab and Ipilimumab
nivolumab
Iplimumab
mg at each dosing date is collected on 
the CRF.
administered in mg at each dosing 
date and weight are collected on the 
CRF.
Cumulative Dose
Cum dose (mg) is sum of the doses (mg) 
administered to a subject during the 
treatment period.
Cum dose (mg/kg) is sum of the 
doses (mg/kg) administered to a 
subject during the treatment period.
Relative dose intensity (%)
[Cum dose (mg)/((Last Nivolumab dose 
date - Nivolumab Start dose date + 21) x 
360 / 21)] x 100
[Cum dose (mg/kg)/((Last dose date 
- Start dose date + 42) x 1 / 42)] x 
100
Duration of study therapy
Last Nivolumab dose date - Nivolumab 
Start dose date +1
(Start dose date of the combination is 
the first dose date among the first dose 
dates of all drugs of the combination 
and last dose date of the combination is 
the last date among the last dose dates 
of all drugs of the combination)
Last Ipilimumab dose date -
Ipilimumab Start dose date +1
Table 7.4.1-2:
Administration of study therapy - Carboplatin/Paclitaxel
Carboplatin
Paclitaxel
Dosing schedule per protocol
AUC 6 every 3 weeks
200 mg/m2 every 3 weeks
Dose
Dose (AUC) is defined as Total Dose 
administered (mg)/(creatinine clearance + 
25). Dose administered in mg at each 
dosing date is collected on the CRF and 
creatinine clearance derived from the CRF 
data.
Dose (mg/kg) is defined as Total 
Dose administered (mg)/Most 
recent BSA (m2). Dose 
administered in mg at each dosing 
date is collected on the CRF and 
BSA is derived from most recent 
weight and baseline height also 
collected on the CRF.
Cumulative Dose
Cum Dose (AUC) is the sum of the doses 
(AUC) administered to a subject.
Cum dose (mg/m2) is sum of the 
doses (mg/m2) administered to a 
subject during the treatment 
period.
Relative dose intensity (%)
Cum dose (AUC)/((Last dose date of Carbo 
- Start dose date of Carbo + 21) x 6 / 21) x 
100
[Cum dose (mg/m2)/((Last 
paclitaxel dose date - paclitaxel 
Start dose date + 21) x 200 / 21)] x 
100
Duration of study therapy
Last dose date - Start dose date + 1
(Start dose date of the combination is the 
first dose date between the first dose dates 
of the two drugs of the combination and 
Last dose date - Start dose date + 1
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Table 7.4.1-3:
Administration of study therapy - Carboplatin and Pemetrexed
Carboplatin
Pemetrexed
Dosing schedule per protocol
AUC 6 every 3 weeks
500 mg/m2 every 3 weeks
Dose
Dose (AUC) is defined as Total Dose 
administered (mg)/(creatinine clearance + 
25). Dose administered in mg at each 
dosing date is collected on the CRF and 
creatinine clearance derived from the CRF 
data.
Dose (mg/kg) is defined as Total 
Dose administered (mg)/Most 
recent BSA (m2). Dose 
administered in mg at each dosing 
date is collected on the CRF and 
BSA is derived from most recent 
weight and baseline height also 
collected on the CRF.
Cumulative Dose
Cum Dose (AUC) is the sum of the doses 
(AUC) administered to a subject.
Cum dose (mg/m2) is sum of the 
doses (mg/m2) administered to a 
subject during the treatment 
period.
Relative dose intensity (%)
Cum dose (AUC)/((Last dose date of Carbo 
- Start dose date of Carbo + 21) x 6 / 21) x 
100
[Cum dose (mg/m2)/((Last 
pemetrexed dose date - pemetrexed 
Start dose date + 21) x 500 / 21)] x 
100
Duration of study therapy
Last dose date - Start dose date + 1
(Start dose date of the combination is the 
first dose date between the first dose dates 
of the two drugs of the combination and 
last dose date of the combination is the last 
date between the last dose dates of the two 
drugs of the combination)
Last dose date - Start dose date + 1
Table 7.4.1-4:
Administration of study therapy - Cisplatin/Pemetrexed
Cisplatin
Pemetrexed
Dosing schedule per protocol
75 mg/m2 every 3 weeks
500 mg/m2 every 3 weeks
Dose
Dose (mg/kg) is defined as Total Dose 
administered (mg)/Most recent BSA (m2). 
Dose administered in mg at each dosing 
date is collected on the CRF and BSA is 
derived from most recent weight and 
baseline height also collected on the CRF.
Dose (mg/kg) is defined as Total 
Dose administered (mg)/Most 
recent BSA (m2). Dose 
administered in mg at each dosing 
date is collected on the CRF and 
BSA is derived from most recent 
last dose date of the combination is the last 
date between the last dose dates of the two 
drugs of the combination)
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Table 7.4.1-4:
Administration of study therapy - Cisplatin/Pemetrexed
Cisplatin
Pemetrexed
weight and baseline height also 
collected on the CRF.
Cumulative Dose
Cum dose (mg/m2) is sum of the doses 
(mg/m2) administered to a subject during 
the treatment period.
Cum dose (mg/m2) is sum of the 
doses (mg/m2) administered to a 
subject during the treatment period.
Relative dose intensity (%)
[Cum dose (mg/m2)/((Last pemetrexed 
dose date - pemetrexed Start dose date + 
21) x 75 / 21)] x 100
[Cum dose (mg/m2)/((Last 
pemetrexed dose date - pemetrexed 
Start dose date + 21) x 500 / 21)] x 
100
Duration of study therapy
Last dose date - Start dose date + 1
(Start dose date of the combination is the 
first dose date between the first dose dates 
of the two drugs of the combination and 
last dose date of the combination is the
last date between the last dose dates of the 
two drugs of the combination)
Last dose date - Start dose date + 1
Creatinine clearance will be calculated using the Crokroft-Gault formula, defined as:
ܥݎܥܮሺ݈݉/݉݅݊ሻൌ
ሺ140 െܽ݃݁ሺ݅݊ݕ݁ܽݎݏሻሻ∗ݓ݄݁݅݃ݐሺ݅݊݇݃ሻ
72 ∗ݏ݁ݎݑ݉ܿݎ݁ܽݐ݅݊݅݊݁ሺ݅݊݉݃/݀ܮሻ
for males, and
ܥݎܥܮሺ݈݉/݉݅݊ሻൌ
ሺ140 െܽ݃݁ሺ݅݊ݕ݁ܽݎݏሻሻ∗ݓ݄݁݅݃ݐሺ݅݊݇݃ሻ
72 ∗ݏ݁ݎݑ݉ܿݎ݁ܽݐ݅݊݅݊݁ሺ݅݊݉݃/݀ܮሻ
∗0.85
for females. The most recent weight will be used. If the computed creatinine clearance is more 
than 125 ml/min, then the creatinine clearance value should be capped at 125 ml/min for dose 
exposure computations.
7.4.2
Modifications of Study Therapy
7.4.2.1
Dose Delays
Each study medication (nivolumab, ipilimumab, and chemotherapy drugs) infusion may be 
delayed. A dose will be considered as actually delayed if the delay is exceeding 3 days (i.e. greater 
than or equal to 4 days from scheduled dosing date) for nivolumab, ipilimumab, and chemotherapy 
drugs. All study drugs must be delayed until treatment can resume. Reason for dose delay will be
retrieved from CRF dosing pages.
The following parameters will be summarized by treatment group:
•
Number of subjects with at least one dose delayed, the number of dose delays per subject, the 
reason for dose delay and the length of dose delay.
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7.4.2.2
Infusion Interruptions and Rate Changes
Each nivolumab, ipilimumab, or chemotherapy drug infusion can be interrupted and/or the IV 
infusion rate can be reduced. This information will be retrieved from CRF dosing pages.
The following parameters will be summarized by treatment group:
•
Number of subjects with at least one dose infusion interruption, the reason for interruption, 
and the number of infusion interruptions per subject.
•
Number of subjects with at least one IV infusion rate reduction, the reason for reduction and 
the number of infusion with IV rate reduction per subject.
7.4.2.3
Dose Escalations
Dose escalations (within subject) are not permitted for either nivolumab or ipilimumab.
7.4.2.4
Dose Reductions
Dose reductions (within subject) are not permitted for either nivolumab or ipilimumab.
Dose reductions of chemotherapy may be modified for toxicity. Dose levels of chemotherapy are 
defined in the protocol as follows:
Table 7.4.2.4-1:
Dose Modifications of Chemotherapeutic Agents
Dose Level
Carboplatin
Pemetrexed
Paclitaxel
Cisplatin
Starting dose
AUC 6 or AUC 5
500 mg/m2
200 mg/m2
75 mg/m2
First dose reduction
AUC 5 (if starting dose is 
AUC 6) or AUC 4 (if 
starting dose is AUC 5)
375 mg/m2
150 mg/m2
56 mg/m2
Second dose reduction
AUC 4 (if starting dose is 
AUC 6) or AUC 3 (if 
starting dose is AUC 5)
250 mg/m2
100 mg/m2
38 mg/m2
Third dose reduction
Discontinue
Discontinue
Discontinue
Discontinue
Source: Table 7.4.2.2-1 in CA2099LA Protocol
For any cycle, it will be defined as a dose reduction if the observed dose level (based on calculated 
administered dose) is below protocol specified dose level. Dose ranges for dose levels of platinum 
doublet chemotherapy are defined in Table 7.4.2.4-2.
The reason for dose reduction as reported by the investigator will be tabulated for all instances of 
dose reductions based on the CRF page. A category “Not Reported” will be defined for all 
reductions with no reason reported by the investigator.
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Table 7.4.2.4-2:
Calculated Dose Ranges and Related Dose Levels
Dose Level
Carboplatin (AUC)
Pemetrexed
(mg/m2)
Paclitaxel
(mg/m2)
Cisplatin
(mg/m2)
Level 0
With pemetrexed:
≥ 5.5 (start of AUC 6) or 
≥ 4.5 (start of AUC 5)
With Paclitaxel:
≥ 5.5
≥ 437.5
With Carboplatin:
≥ 175
≥ 65.5
Level -1
With pemetrexed:
< 5.5 and ≥ 4.5 (start of AUC 6) or 
< 4.5 and ≥ 3.5 (start of AUC 5)
With Paclitaxel:
< 5.5 and ≥ 4.5
< 437.5 and ≥ 312.5
With Carboplatin:
< 175 and ≥ 125
< 65.5 and ≥ 47
Level -2
With pemetrexed:
< 4.5 (start of AUC 6) or 
< 3.5 (start of AUC 5)
With Paclitaxel:
≥ 5.5
< 312.5
With Carboplatin:
< 125
< 47
The following will be summarized:
•
Number and percentage of subjects with at least one dose reduction, the reason of dose 
reduction, and the number of dose reductions per subject.
7.4.2.5
Partial Discontinuation of Ipilimumab
Subjects treated with nivolumab and ipilimumab may discontinue ipilimumab and continue to 
receive nivolumab (ie, partial discontinuation). Continuation of ipilimumab after discontinuation 
of nivolumab is not allowed on study.
The following will be summarized for subjects receiving the combination of nivolumab and 
ipilimumab:
•
Number and percentage of subjects who had partial discontinuation of ipilimumab
•
Reason for partial discontinuation
Reason for partial discontinuation will be retrieved from the dosing CRF pages.
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the UMC WHO Drug Global Dictionary.
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The following summary table will be provided: 
•
Concomitant medications (subjects with any concomitant medication, subjects by medication 
class and generic term) 
Prior medications, defined as non-study medications with a start date before consent date, and 
current medications, defined as non-study medications with a start date before the first date of 
study medication and stop date after consent date, will be coded using the UMC WHO Drug Global 
Dictionary. 
The following summary table will be provided: 
•
Prior/current medications (subjects with any prior/current medication, subjects by medication 
class and generic term) 
By-subject listings will accompany the tables.
7.4.3.1
Immune modulating medication 
Immune modulating concomitant medications are medications entered on an immune modulating 
medication form or available from the most current pre-defined list of immune modulating 
medications. The list of anatomic class, therapeutic class and generic name used for the selection 
at the time of the database lock will be provided.
The percentage of subjects who received immune modulating concomitant medication for
•
management of adverse event 
•
premedication 
•
other use
•
any use
•
management of drug-related select adverse event (any grade, grade 3-5) by select AE category/ 
subcategory (EU/ROW Submissions)
•
management of IMAEs (any grade, grade 3-5) by IMAE category (US Submission)
will be reported separately for each treatment group (percentages of treated subjects by medication 
class and generic term).
For each category/subcategory of drug-related select AEs (any grade, grade 3-5) and IMAEs (any 
grade, grade 3-5), the following will be reported for each treatment group:
•
The total immune modulating medication treatment duration (excluding overlaps), duration of 
high dose of corticosteroid, initial dose of corticosteroid, and tapering duration (summary 
statistics)
Duration represents the total duration the subject received the concomitant medication of interest. 
If the subject took the medication periodically, then DURATION in the summation of all use. 
Initial dose represents the dose of the concomitant medication of interest received at the start of 
the event. In the case multiple medications started on the same date, the highest equivalent dose is 
chosen and converted to mg/kg by dividing by the subject’s recent weight.
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These analyses, except the ones related to IMAEs will be conducted using the 30-day safety 
window. The analyses related to IMAEs will be conducted using the 100-day safety window.
7.4.3.2
Subsequent Cancer Therapy
Number and percentage of subjects receiving subsequent cancer therapies will be summarized for 
all randomized subjects. Categories include:
•
Subsequent systemic therapy
−
Immunotherapy including commercial Nivolumab (anti-PD1 agents, anti-PD-L1 agents, 
anti-CTLA-4 agents and others) by drug name
−
Other anti-cancer agents excluding all immunotherapy (approved and investigational) by 
drug name
−
Palliative local therapy (including on-treatment)
•
Subsequent surgery (limited to: tumor resection, curative; tumor resection, palliative; 
incisional biopsy; excisional biopsy towards censoring for progression free survival per 
primary definition) for treatment of tumors 
•
Subsequent radiotherapy for treatment of tumors
•
Any combination of the above
A by-subject listing of subsequent cancer therapy will also be produced for all randomized 
subjects.
7.5
Efficacy
Principal analyses of progression free survival (PFS) and objective response rate (ORR) will be 
based on the Blinded Independent Central Review (BICR) evaluation, unless noted otherwise.
Analyses in this section will be tabulated for all randomized subjects by treatment group as 
randomized, unless otherwise specified.
Unless stated otherwise, whenever a stratified analysis is specified, the following stratifications 
factors (recorded at randomization as per IRT) will be used:
•
Histology (Squamous vs. Non-squamous)
•
Sex (Male vs. Female)
•
PD-L1 Level (≥ 1% vs. < 1% or not quantifiable)
For assessing the secondary objectives of this study, a hierarchical testing procedure13 will be used 
so that the overall experiment-wise Type I error rate is two-sided 0.05.
A separate group sequential spending function will be used to adjust for the overall Type I error at 
the interim and final analysis for each of the formal comparisons. The actual level of significance 
which each objective is assessed will be determined based on the individual group sequential 
spending function and the amount of information spent at the time of the analysis. The significance 
level for ORR per BICR will be pre-specified as α=0.025 for the interim analysis as an equal 
Bonferroni splitting of the two-sided alpha=0.05.
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The hierarchical ordering of the key secondary endpoints is as follows:
1) Progression Free Survival per BICR
2) Objective Response Rate per BICR
The statistical testing will be carried out using the following sequential procedure:
1) The primary endpoint of OS will be tested first.
2) If the p-value of OS is not statistically significant either at the interim or the final analysis, then 
no further statistical testing regarding the secondary endpoints will be conducted. However, 
estimates, along with their 95% CI, will be provided for those (i.e., medians and HR, rates and 
odds ratios) at the time of the final analysis.
3) If the p-value of OS is statistically significant either at the interim or the final analysis, PFS 
per BICR will be tested. If the p-value of PFS per BICR is statistically significant, ORR per 
BICR will be tested and the p-value will be provided. If the p-value of PFS is not statistically 
significant, then no statistical testing of ORR per BICR will be conducted. For ORR per BICR, 
estimates (rates and odds ratios) and associated 95% CI will be provided, regardless of the 
outcome of PFS per BICR testing.
Confidence intervals (CI) for primary and secondary endpoint analyses included in hierarchy will 
be based on nominal significance level adjusted for primary endpoints and interim analyses to 
preserve overall type one error rate.
Alpha (ߙሻfor the CI will be the same as nominal significance level for hypothesis testing. CIs for 
other endpoints will be at the two-sided 95% level. All p-values reported will be two-sided. P-
values will be rounded to the fourth decimal place. Point estimates and confidence bounds for 
efficacy variables will be rounded to the second decimal place.
A by-subject listing of efficacy results will be presented including treatment group, treatment 
duration, BICR progression date, overall survival, death date, etc.
7.5.1
Analysis of Overall Survival
The primary objective of the study is to compare the overall survival between treatment groups in 
all randomized subjects.
Overall survival will be compared between the treatment groups (nivolumab and ipilimumab plus 
chemotherapy versus chemotherapy alone) at the interim and final analyses, using stratified log-
rank test. The stratification factors will be histology (squamous vs. non-squamous), sex (male vs. 
female), and PD-L1 level (≥ 1% vs. < 1% or not quantifiable). A Lan DeMets α-spending function 
with O’Brien and Fleming type of boundary will be employed to determine the nominal 
significance levels for the interim and final analyses. The stratified hazard ratio between the 
treatment groups will be presented along with 100*(1- α)% CI (adjusted for interim). In addition, 
two-sided p-value will also be reported for the analysis of OS.
OS will be estimated using the KM techniques. A two-sided 95% CI for median OS in each 
treatment group will be computed via the log-log transformation method. OS rates at fixed time 
points (e.g. 6 months, depending on the minimum follow-up) will be presented along with their 
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associated 95% CIs. These estimates will be derived from the Kaplan Meier estimate and 
corresponding CIs will be derived based on Greenwood formula for variance derivation and on 
log-log transformation applied on the survivor function.
The status of subjects who are censored in the OS KM analysis will be tabulated for each treatment 
group using the following categories:
•
On-study (on-treatment, in follow-up)
•
Off-study (lost to follow-up, withdraw consent, never treated)
A by-subject listing will be presented including treatment group, first and last dose date, whether 
the subject died, and if censored, the reason, event/censored date and OS duration.
7.5.2
Supportive Analyses of Overall Survival
The following OS sensitivity analyses will be conducted in all randomized subjects:
1) Delayed effect of immunotherapy interventions may cause a late separation in the OS KM 
curves and non-proportional hazards. OS will be compared between treatment groups via two-
sided 0.05 stratified weighted log-rank test among subjects. The two-sided stratified weighted 
log-rank p-value will be reported using G (rho = 0, gamma = 1) weights, in the terminology of 
Fleming and Harrington14. 
The Fleming Harrington test can be unstable, so it is possible, though uncommon, that the p-
value for this trial will not be estimable. 
The estimate of the OS hazard ratio in the period before and following 3 months will be 
calculated using a stratified time-dependent Cox model with effects for treatment and period-
by-treatment interaction. In this model, period is a binary variable indicating pre- vs. post-
3 months. Ties will be handled using the exact method. A two-sided 95% CI for the hazard 
ratio will also be presented.
2) Stratified log-rank test in the All Treated Subjects population, using arm as treated. This 
analysis will be performed only if the proportion of randomized but never treated subjects 
exceeds 10%.
3) A multivariate Cox regression model will be used in order to estimate the treatment effect after 
adjustment for possible imbalances in known or potential prognostic factors. The factors used 
in the randomization, which, by definition, will be balanced across treatment groups, will still 
be included in the model as stratification factors. However, all additional factors will be 
incorporated as covariates. The additional factors, which are all measured at baseline, will 
include:
a) ECOG performance status (0, ≥1)
b) Baseline histology (squamous, non-squamous) (only for randomized subjects)
c) Sex (male, female)
d) PD-L1 subgroups (≥ 1% vs <1%)
The level of the covariate normally associated with the worst prognosis will be coded as the 
reference level. The hazard ratio associated with treatment and with each of the baseline 
covariates will be presented along with associated 95% CIs.
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4) OS using stratification factors as obtained from the baseline CRF pages (instead of IRT). The 
hazard ratio associated with treatment will be presented along with the associated two-sided 
95% CIs. This analysis will be performed only if at least one stratification variable/factor at 
randomization (as per IRT) and baseline are not concordant for at least 10% of the randomized 
subjects.
5) OS using an un-stratified log rank test. The hazard ratio associated with treatment will be 
presented along with the associated two-sided 95% CIs.
6) OS for subjects with no relevant protocol deviations. This analysis will be conducted only if 
there are more than 10% subjects with relevant protocol deviations. The hazard ratio associated 
with treatment will be presented along with the associated two-sided 95% CIs.
7) The method of Gail and Simon15 will be used to test for a qualitative interaction between 
treatment and strata. This test will be conducted at α= 0.10 level. The p-value reported from 
this specific analysis is for descriptive purposes alone.
8) To examine the assumption of proportional hazards in the Cox regression model, in addition 
to treatment, a time-dependent variable defined by treatment by time interaction will be added 
into the model. A two-sided Wald Chi-square p-value of less than 0.1 may indicate a potential 
nonconstant treatment effect. In that case, additional exploratory analyses may be performed.
7.5.3
Subset Analyses of Overall Survival
The influence of baseline and demographic characteristics on the treatment effect among all 
randomized subjects will be explored via exploratory subset analyses. The median OS based on 
KM product-limit method along with two-sided 95% CIs will be produced for the following 
subgroups:
•
Age categorization (<65, ≥65 and <75, ≥75 and <85, ≥85, ≥75, and ≥65)
•
Sex (male vs. female)
•
Race (white, black, asian, other)
•
Region (Europe, North America, Rest of World, Asia)
•
ECOG performance (0, ≥1)
•
Baseline histology (squamous, non-squamous)
•
Smoking status (current/former, never smoked, unknown)
•
PD-L1 subgroups (<1%, ≥1%, 1-49%, ≥50%)
•
Disease stage (stage IV, recurrent to metastatic disease)
•
CNS Metastasis (yes vs. no)
•
Liver Metastasis (yes vs. no)
•
Bone Metastasis (yes vs. no)
•
Tumor Tissue TMB Evaluable (≥10 Mut/MB, < 10 Mut/MB, Overall)
•
Tumor Tissue TMB Not Evaluable
•
Blood TMB Evaluable (≥16 Mut/MB, < 16 Mut/MB, ≥20 Mut/MB and < 20 Mut/MB, Overall)
•
Blood TMB Not Evaluable
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A forest plot of the OS hazard ratios (along with the 95% CIs) will be produced for each level of 
the subgroups listed above. The analysis comparing treatment (i.e., Hazard Ratio) will be 
conducted if the number of subjects in the subgroup category is more than 10.
7.5.4
Interim Analysis of Overall Survival
An independent statistician external to BMS will perform the analysis. In addition to the formal 
planned interim analysis for OS, the Data Monitoring Committee (DMC) will have access to 
periodic un-blinded interim reports of efficacy and safety to allow a risk/benefit assessment. 
Details are included in the DMC charter.
One interim analysis of OS is planned. The interim analysis is scheduled when 322 events 
(approximately 80% of the targeted OS events) have been observed among randomized subjects.
This formal comparison of OS will allow for early stopping for superiority, and the boundaries for 
declaring superiority will be derived based on the actual number of events using Lan-DeMets 
spending function with O’Brien and Fleming type of boundary. If the interim analysis is performed 
exactly at 322 events, the boundary in terms of statistical significance for declaring superiority 
would be 0.024 (HR boundary of 0.78). The boundary for declaring superiority in terms of 
statistical significance for the final analysis after 402 events would be 0.042 (HR boundary of 
0.82).
The DMC will review the safety and efficacy data from the informal interim analyses and will 
determine if the study should continue with or without changes or if accrual should be stopped. 
Subject enrollment will continue while waiting for the DMC’s decisions.
The chair of the DMC and the sponsor can call an unscheduled review of the safety data.
At the time of the formal interim analysis for superiority of OS, the DMC may recommend 
continuing or stopping the trial. If the trial continues beyond the formal interim analysis, the 
nominal critical point for the final OS analysis will be determined using the recalculated 
information fraction at the time of the interim analysis, as described aboveThe final OS hazard 
ratio and corresponding confidence interval will be reported whereby the confidence interval will 
be adjusted accordingly (i.e. using the recalculated nominal α level at the final analysis). 
If the trial is stopped for superiority of OS at the interim, the p-value from the interim stratified 
log-rank test will be considered the final primary analysis result.
7.5.5
Analysis of Progression-Free Survival
One of the secondary objectives of the study is to compare the progression-free survival (as 
determined by BICR) between treatment groups in all randomized subjects.
Hierarchical testing of PFS (as determined by BICR) will be performed upon demonstration of 
superiority in OS at OS at interim or final analyses for all randomized subjects (see Section 7.5). 
P-values will not be presented for PFS if the primary endpoint OS was not statistically significant. 
In this case, descriptive analysis and treatment difference estimations for PFS will still be 
presented.
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PFS will be compared between the treatment groups via stratified log-rank test among all 
randomized subjects. The stratification factors will be histology (squamous vs. non-squamous), 
sex (male vs. female), and PD-L1 level (≥ 1% vs. < 1% or not quantifiable).
The primary definition of PFS adjusting for subsequent anticancer therapy will be used in this 
analysis. The two-sided log-rank p-value will be reported.
The estimate of the PFS hazard ratio between treatment groups will be calculated using a stratified
Cox proportional hazards model, with treatment as the sole covariate. Ties will be handled using 
the exact method. The 100*(1-α)% CI (adjusted for multiplicity, see Section 7.5) will be provided. 
For descriptive purposes, a two-sided 95% CI for the hazard ratio will also be presented.
The PFS function for each treatment group will be estimated using the KM product limit method 
and will be displayed graphically. A two-sided 95% CI for median PFS in each treatment group 
will be computed via the log-log transformation method. PFS rates at fixed time points (e.g. 6 
months, depending on the minimum follow-up) will be presented along with their associated 95% 
CIs. These estimates will be derived from the Kaplan Meier estimate and corresponding CIs will 
be derived based on Greenwood16 formula for variance derivation and on log-log transformation 
applied on the survivor function17.
Analyses of PFS will also be conducted based on the secondary definition of PFS. These analyses 
will be the same as those specified above.
The source of PFS event (progression or death) will be summarized by treatment group. The status 
of subjects who are censored (as per primary definition of PFS) in the PFS KM analysis will be 
tabulated for each treatment group including the following categories:
•
On-study (on-treatment, in follow-up)
•
Off-study (lost to follow-up, withdraw consent, never treated)
•
No baseline tumor assessment
•
No on-study tumor assessment and no death
•
Received subsequent anticancer therapy
A by-subject listing will be presented including treatment group, PFS duration under the primary 
definition, PFS duration on the ITT definition, whether the subject was censored under the primary 
definition, and if censored, the reason, and whether the subject was censored under the ITT 
definition, and if censored, the reason.
A by-subject listing of lesion evaluations per BICR will be presented.
7.5.6
Supportive Analyses of Progression-Free Survival
Unless otherwise specified, the following sensitivity analyses will be conducted using both the 
primary and the secondary definition of PFS in all randomized subjects:
1) PFS using stratification factors as obtained from the baseline CRF pages (instead of IRT). The 
hazard ratio associated with treatment will be presented along with the associated two-sided 
95% CIs. This analysis will be performed only if at least one stratification variable/factor at 
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randomization (as per IRT) and baseline are not concordant for at least 10% of the randomized 
subjects.
2) PFS using the investigator’s assessment. The hazard ratio associated with treatment and 
median PFS will be presented along with the associated two-sided 95% CIs.
A cross tabulation of PFS assessment by BICR versus PFS assessment by investigator will be 
presented, by treatment group. Concordance Rate of event will be computed as the frequency 
with which investigator and BICR agree on classification of a subject as event vs censored as 
a proportion of the total number of randomized subjects assessed by both the investigator and 
BICR.
3) PFS per BICR account for missing tumor assessment prior to PFS event (progression or death). 
This analysis will be performed only if at least 20% of events have missing prior tumor 
assessment within the primary efficacy analysis population. It will apply the following 
restriction to the primary definition: if the elapsed time between the PFS event and the last on-
study assessment immediately prior to the event (or randomization date if no on-study scan) is 
two or more missed visits (more than 12 weeks + 10 days), the subject will be censored at
his/her last tumor assessment prior to the PFS event (or randomization date if no on-study 
scan).
A by-subject listing of PFS assessment per BICR and investigator will be presented.
7.5.7
Subset Analyses of Progression-Free Survival
The influence of baseline and demographic characteristics on the treatment effect among all 
randomized subjects will be explored via exploratory subset analyses. The median PFS based on 
KM product-limit method along with two-sided 95% CIs will be produced for the following 
subgroups:
•
Age categorization (<65, ≥65 and <75, ≥75 and <85, ≥85, ≥75, and ≥65)
•
Sex (male vs. female)
•
Race (white, black, asian, other)
•
Region (Europe, North America, Rest of World, Asia)
•
ECOG performance (0, ≥1)
•
Baseline histology (squamous, non-squamous)
•
Smoking status (current/former, never smoked, unknown)
•
PD-L1 subgroups (<1%, ≥1%, 1-49%, ≥50%)
•
Disease stage (stage IV, recurrent to metastatic disease)
•
CNS Metastasis (yes vs. no)
•
Liver Metastasis (yes vs. no)
•
Bone Metastasis (yes vs. no)
•
Tumor Tissue TMB Evaluable (≥10 Mut/MB, < 10 Mut/MB, Overall)
•
Tumor Tissue TMB Not Evaluable
•
Blood TMB Evaluable (≥16 Mut/MB, < 16 Mut/MB, ≥20 Mut/MB and < 20 Mut/MB, Overall)
•
Blood TMB Not Evaluable
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A forest plot of the PFS hazard ratios (along with the 95% CIs) will be produced for each level of 
the subgroups listed above. The analysis comparing treatment (i.e., Hazard Ratio) will be 
conducted if the number of subjects in the subgroup category is more than 10.
7.5.8
Current Status of PFS and OS Follow-up
The extent of follow-up for survival, defined as the time between randomization date and last 
known alive date (for subjects who are alive) or death date (for subjects who died), will be 
summarized descriptively (median, min, max, etc.) in months for all randomized subjects.
The currentness of follow-up for survival, defined as the time between last OS contact (i.e., last 
known alive date or death date) and cutoff date (defined by last patient last visit date), will be 
summarized in months for all randomized subjects. Subjects who died and subjects with last known 
alive date on or after data cut-off date will have zero value for currentness of follow-up.
Minimum follow-up for OS for all randomized subjects, defined as the time from cutoff date to 
last subject’s randomization date, will be summarized in months for all randomized subjects.
Time from last evaluable tumor assessment to cutoff date in months will be summarized by 
treatment group and overall for all randomized subjects. Subjects who have a PFS event will be 
considered as current for this analysis. The secondary definition of PFS will be used for this 
summary. 
In addition, time to treatment discontinuation will be summarized and presented by treatment 
group 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 study therapy and associated 95% CI will 
be provided. Subjects who are still on study therapy will be censored on their last dose date.
A by-subject listing will also be produced to accompany the subject time from last evaluable tumor 
assessment.
7.5.9
Analysis of Objective Response Rate
One of the secondary objectives of the study is to estimate the ORR per BICR in the treatment 
groups among all randomized subjects.
Hierarchical testing of ORR will be performed upon demonstration of superiority in OS and 
superiority in PFS per BICR at OS interim or final analyses for all randomized subjects (see 
Section 7.5).
The number and percentage of subjects in each category of BOR per BICR (complete response 
[CR], partial response [PR], stable disease [SD], progressive disease [PD], or unable to determine 
[UTD]) will be presented, by treatment group. Estimates of response rate, along with its exact two-
sided 95% CI by Clopper and Pearson18 will be presented, by treatment group. An estimate of the 
difference in response rates between the treatment groups along with the corresponding two sided 
CI will also be computed using the following Cochran-Mantel-Haenszel (CMH) method of 
weighting, adjusting for stratification factors19. The formula is
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ߠ෠ൌ
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௜
∑ݓ௜
௜
~ܰ
ۏ
ێ
ێ
ێ
ۍ
ߠ,
∑ݓ௜
ଶ
௜
ቈ݌௜௫ሺ1 െ݌௜௫ሻ
݊௜௫െ1
൅݌௜௬൫1 െ݌௜௬൯
݊௜௬െ1
቉
ሺ∑ݓ௜
௜
ሻଶ
ے
ۑ
ۑ
ۑ
ې
where ߠ෠ൌ݌௜௫െ݌௜௬is the difference in rates in the ith stratum, ݓ௜ൌ
௡೔ೣ௡೔೤
௡೔ೣା௡೔೤, and ݊௜௫and ݊௜௬are 
the number of subjects randomized to treatments x and y, respectively, in the ith stratum. 
Stratification factors will be PD-L1 level, histology, and sex, as entered into the IRT.
A two sided 95% CI for odds ratio of response between the treatment groups will also be computed.
Similar analyses will be repeated based on the investigator’s assessment of ORR. A cross 
tabulation of BICR best response versus the investigator best response will be presented, by 
treatment group and by response categories. Concordance Rate of Responders will be computed 
as the frequency with which investigator and BICR agree on classification of a subject as responder 
vs. non responder/UTD as a proportion of the total number of randomized subjects assessed by 
both the investigator and BICR.
The following subject-level graphics will also be provided:
•
For the responders only, time courses of the following events of interest will be graphically 
displayed: tumor response, progression, last dose received, and death.
•
For response evaluable subjects (randomized subjects with baseline and at least one on-study 
tumor assessment), 
−
A bar plot showing the best % reduction from baseline in sum of diameter of target lesions 
based on BICR assessment for each subject will be produced (excluding assessments after 
PD and assessments after start of subsequent anti-cancer therapy).
−
A plot of individual time course of tumor burden change per BICR assessment will be 
produced. 
A by-subject listing of best overall response will be presented including treatment group, best 
overall response per BICR and dates of CR/PR/progression.
A by-subject listing of per time point tumor response per BICR will be presented. 
7.5.10
Subset Analyses of Objective Response
The influence of baseline and demographic characteristics on the treatment effect will be explored 
via exploratory subset analysis. BICR assessment of ORR will be summarized for the following 
subgroups:
•
Age categorization (<65, ≥65 and <75, ≥75 and <85, ≥85, ≥75, and ≥65)
•
Sex (male vs. female)
•
Race (white, black, asian, other)
•
Region (Europe, North America, Rest of World, Asia)
•
ECOG performance (0, ≥1)
•
Baseline histology (squamous, non-squamous)
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•
Smoking status (current/former, never smoked, unknown)
•
PD-L1 subgroups (<1%, ≥1%, 1-49%, ≥50%)
•
Disease stage (stage IV, recurrent to metastatic disease)
•
CNS Metastasis (yes vs. no)
•
Liver Metastasis (yes vs. no)
•
Bone Metastasis (yes vs. no)
•
Tumor Tissue TMB Evaluable (≥10 Mut/MB, < 10 Mut/MB, Overall)
•
Tumor Tissue TMB Not Evaluable
•
Blood TMB Evaluable (≥16 Mut/MB, < 16 Mut/MB, ≥20 Mut/MB and < 20 Mut/MB, Overall)
•
Blood TMB Not Evaluable
A forest plot of treatment effect on ORR per BICR in the above subgroups will be produced. The 
un-weighted differences in ORR between the two treatment groups and corresponding 95% two-
sided CI using the method of Newcombe20,21 will be provided. The analysis comparing treatment 
(i.e., ORR difference) will be conducted if the number of subjects in the subgroup category is more 
than 10.
7.5.11
Time to Tumor Response and Duration of Response
Duration of response (DOR) and time to response (TTR) will also be evaluated for subjects who 
achieved confirmed PR or CR. The DOR for each treatment group will be estimated using the 
Kaplan-Meier (KM) product limit method and will be displayed graphically. A table will be 
produced presenting number of events, number of subjects involved, medians, and 95% CIs for 
the medians. Median values of DOR, along with two-sided 95% CI in each treatment group will 
be computed based on a log-log transformation method.
The status of subjects who are censored in the DOR KM analysis will be tabulated for each 
treatment group including the following categories:
•
Ongoing follow-up (current [last scan within adequate window vs cutoff date], not current)
•
Off-study (lost to follow-up, withdraw consent, never treated)
•
Received subsequent anticancer therapy.
TTR, which does not involve censoring, will be summarized by treatment group in all responders 
using descriptive statistics. 
Cumulative Response Rates will be tabulated for Week 6, Month 3, 6, 8, and 12, and overall 
response rate will be provided.
A by-subject listing will be presented including treatment group, best response, time to response, 
duration of response, whether the subject was censored for duration of response, and, if so, the 
reason.
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7.5.12
PFS2
One of the exploratory objectives of the study is to compare PFS2 between treatment groups in all 
randomized subjects.
PFS2 will be analyzed similarly to PFS:
•
Median values based on KM method, along with two-sided 95% CI using Brookmeyer and 
Crowley method will be calculated. The estimate of standard error will be calculated using the 
Greenwood formula;
•
PFS2 will be graphically displayed along with the median and 95% CI. 
A by-subject listing of PFS and PFS2 will be provided.
7.6
Safety
Analyses in this section will be tabulated for all treated subjects by treatment group as treated,
unless otherwise specified.
7.6.1
Deaths
Deaths will be summarized by treatment group:
•
All deaths, reasons for death.
•
Deaths within 30 days of last dose received, reasons for death.
•
Deaths within 100 days of last dose received, reasons for death.
A by-subject listing of deaths will be provided for the all enrolled subjects population.
7.6.2
Serious Adverse Events
Serious adverse events will be summarized by treatment group:
•
Overall summary of SAEs by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
SOC/PT.
•
Overall summary of drug-related SAEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT.
All analyses will be conducted using the 30-day safety window. 
A by-subject SAE listing will be provided for the “enrolled subjects” population.
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
AEs leading to discontinuation will be summarized by treatment group:
•
Overall summary of AEs leading to discontinuation by worst CTC grade (any grade, grade 
3-4, grade 5) presented by SOC/PT.
•
Overall summary of drug-related AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT.
The analyses will be conducted using the 30-day safety window.
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A by-subject AEs leading to discontinuation listing will be provided.
7.6.4
Adverse Events Leading to Dose Modification
AEs leading to dose delay/reduction will be summarized by treatment group:
•
Overall summary of AEs leading to dose delay/reduction by worst CTC grade (any grade, 
grade 3-4, grade 5) presented by SOC/PT.
•
Overall summary of related AEs leading to dose delay/reduction by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by SOC/PT.
The analysis will be conducted using the 30-day safety window.
A by-subject AEs leading to dose delay/reduction listing will be provided.
7.6.5
Adverse Events
Adverse events will be summarized by treatment group.
The following analyses will be conducted using the 30 days safety window only:
•
Overall summary of any AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) presented 
by SOC/PT.
•
Overall summary of any AEs presented by worst CTC grade (any grade, grade 3-4, grade 5) 
by SOC/PT. This table will be restricted to events with an incidence greater or equal to 5% in 
any treatment group.
•
Overall summary of any non-serious AEs presented by SOC/PT. This table will be restricted 
to events with an incidence greater or equal to 5% in any treatment group.
•
Overall summary of any AEs that required immune modulating medication by worst CTC 
grade (any grade, grade 3-4, grade 5) presented by SOC/PT.
•
Overall summary of drug-related AEs by worst CTC grade (1, 2, 3, 4, 5, not reported, total) 
presented by SOC/PT. 
The following analyses will be conducted using the 30 days safety window and repeated using the 
100 days safety window:
•
Overall summary of drug-related AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by SOC/PT.
A by-subject AE listing will be provided. A by-subject listing of any AE requiring immune 
modulating medications will also be provided.
7.6.6
Select Adverse Events (EU/ROW Submissions)
Unless otherwise specified, analyses will be performed by select AE category. Analyses will also 
be repeated by subcategory of endocrine events.
7.6.6.1
Incidence of Select AE
Select AEs will be summarized by treatment group for each category/subcategory. 
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The following analyses will be conducted using the 30-day safety window only:
•
Overall summaries of any select AEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category or Subcategory/PT.
•
Overall summaries of any drug-related select AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by Category or Subcategory/PT.
•
Overall summaries of any serious select AEs by worst CTC grade (any grade, grade 3-4, grade 
5) presented by Category or Subcategory /PT.
•
Overall summaries of drug-related serious select AEs by worst CTC grade (any grade, grade 
3-4, grade 5) presented by Category or Subcategory /PT.
•
Overall summaries of any select AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category or Subcategory /PT.
•
Overall summaries of drug-related select AEs leading to discontinuation by worst CTC grade
(any grade, grade 3-4, grade 5) presented by Category or Subcategory /PT.
•
Summary of frequency of unique select AEs by Category.
A by-subject select AE listing will be provided.
7.6.6.2
Time-to Onset of Select AE
Time-to onset of drug-related select AEs (any grade, grade 3-5) will be summarized for each 
category/subcategory by treatment group.
Time-to onset analyses are restricted to treated subjects who experienced at least one drug-related 
select AE in the category/subcategory. The analyses will be conducted using the 30-day safety 
window.
Additional details regarding the time-to onset definition are described in time-to onset definition
subsection of APPENDIX 1.
7.6.6.3
Time-to Resolution of Select AE
Time-to resolution of the following specific events will be summarized separately for each 
category/subcategory.
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) by treatment group
•
Time-to resolution of drug-related select AE (any grade, grade 3-5) where immune modulating 
medication was initiated, by treatment group
Time-to resolution analyses are restricted to treated subjects who experienced the specific events. 
Time-to resolution where immune modulating medication was initiated analyses are restricted to 
treated subjects who experienced the specific events and who received immune modulating 
medication during the longest select AE.
The analyses will be conducted using the 30-day safety window.
The following summary statistics will be reported: percentage of subjects with resolution of the 
longest select AE, median time-to resolution along with 95% CI (derived from Kaplan-Meier 
estimation) and ranges.
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See time-to resolution definition subsection of APPENDIX 1 for additional details.
7.6.7
Immune-Mediated Adverse Events (US Submission)
IMAEs will be summarized by treatment group for each immune-mediated category / PT using the 
100-day safety window:
•
Overall summary of non-endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 
5) where immune modulating medication was initiated presented by Category / PT.
•
Overall summary of endocrine IMAEs by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT.
•
Overall summary of non-endocrine IMAEs leading to discontinuation by worst CTC grade 
(any grade, grade 3-4, grade 5) where immune modulating medication was initiated presented 
by Category / PT.
•
Overall summary of endocrine IMAEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category / PT.
•
Overall summary of non-endocrine IMAEs leading to dose delay or reduction by worst CTC 
grade (any grade, grade 3-4, grade 5) where immune modulating medication was initiated 
presented by Category / PT
•
Overall summary of endocrine IMAEs leading to dose delay or reduction by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by Category / PT.
•
Summaries of time-to onset and time-to resolution of non-endocrine IMAEs where immune 
modulating medication was initiated presented by Category.
•
Summaries of time-to onset and time-to resolution of endocrine IMAEs presented by Category.
A by-subject listing of IMAEs will be provided. By-subject listings of time-to resolution for 
longest IMAEs cluster (any grade and grade 3-5 in separate summaries) will also be provided. For 
new studies which collect investigator assessment of potential IMAE data, a by-subject listing of 
AEs considered as immune-mediated events per investigator but not qualified for IMAEs 
definition will also be provided.
In addition, for all nivolumab or ipilimumab treated subjects who experienced at least one IMAE, 
the following data presentation will be provided:
•
Summary of subjects who were re-challenged with nivolumab or ipilimumab by IMAE
category, with extended follow-up
•
Summary of subjects who were re-challenged with nivolumab or ipilimumab by IMAE 
category, with extended follow-up
For these, re-challenge is considered to have occurred when last nivolumab and/or ipilimumab 
infusion was administered after the onset of an IMAE.
7.6.8
Other Events of Special Interest
OEOSI will be summarized by treatment group for each category.
The following analyses will be conducted using the 100-day safety window:
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•
Overall summary of OEOSI by worst CTC grade (any grade, grade 3-4, grade 5) presented by 
Category / PT
•
Overall summary of drug-related OEOSI by worst CTC grade (any grade, grade 3-4, grade 5)
presented by Category / PT
A by-subject listing of OEOSI will be provided.
7.6.9
Multiple Events
The following summary tables will be provided:
•
A table showing the total number and rate (exposure adjusted) of occurrences for all AEs. 
•
A table showing the total number and rate (exposure adjusted) of occurrences for AEs 
occurring in at least 5% of subjects in any treatment group. 
In addition, the rate (exposure adjusted) and its 95% CI evaluated for different time intervals will 
be displayed graphically for each treatment group. This analysis will be limited to the rate of all 
AEs and all drug-related AEs. The analyses will be conducted using the 30-day safety window.
A listing displaying the unique instances of all AEs, i.e., after duplicates have been eliminated and 
overlapping and contiguous occurrences of the same event (i.e. same PT) have been collapsed will 
be provided. No formal comparisons will be made between treatment groups.
7.6.10
Laboratory Parameters
The analysis population for each laboratory test is restricted to treated subjects who underwent that 
laboratory test. Laboratory tests (in addition to the tests specified below) with CTC criteria 
collected in the specific studies may also be included in the summaries.
A by-subject listing of differences in categorization of SI and US laboratory test results will be 
provided.
7.6.10.1
Hematology
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: hemoglobin (HB), platelets, white blood counts (WBC), absolute neutrophils count (ANC) 
and lymphocyte count (LYMPH).
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.10.2
Serum Chemistry
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: ALT, AST, alkaline phosphatase (ALP), total bilirubin and creatinine.
The analyses will be conducted using the 30-day safety window.
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A by-subject listing of these laboratory parameters will be provided.
7.6.10.3
Electrolytes
The following will be summarized by treatment group as worst CTC grade on-treatment per 
subject and as shift table of worst on-treatment CTC grade compared to baseline CTC grade per 
subject: sodium (high and low), potassium (high and low), calcium (high and low), magnesium 
(high and low), and Glucose Serum (fasting hyperglycemia and hypoglycemia regardless of fasting 
status).
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these laboratory parameters will be provided.
7.6.10.4
Additional Analyses
In addition, further analyses on specific laboratory parameters will be performed by treatment 
group:
Abnormal Hepatic Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
•
ALT or AST > 3 x ULN, > 5 x ULN, > 10 x ULN and > 20 x ULN
•
Total bilirubin > 2 x ULN
•
ALP > 1.5 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
•
Concurrent (within 1 day) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
•
Concurrent (within 30 days) ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these specific abnormalities will be provided.
Abnormal Thyroid Function Test
The number of subjects with the following laboratory abnormalities from on-treatment evaluations 
will be summarized by treatment group:
•
TSH value > ULN and
−
with baseline TSH value ≤ULN
−
with at least one FT3/FT4 test value < LLN within 2-week window after the abnormal TSH 
test
−
with all FT3/FT4 test values ≥ LLN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test.
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•
TSH < LLN and
−
with baseline TSH value ≥LLN
−
with at least one FT3/FT4 test value > ULN within 2-week window after the abnormal 
TSH test
−
with all FT3/FT4 test values ≤ ULN within 2-week window after the abnormal TSH test
−
with FT3/FT4 missing within 2-week window after the abnormal TSH test
The analyses will be conducted using the 30-day safety window.
A by-subject listing of these specific abnormalities will be provided.
7.6.11
Vital Signs and Pulse Oximetry
Vital signs and pulse oximetry (i.e. % oxygen saturation) collected on the CRF will be provided 
in separate listings.
7.6.12
Physical Measurements
Physical measurements will be listed by subject.
7.6.13
Non-Protocol Medical Procedures
Non-protocol medical procedures will be listed by subject.
 
 
 
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7.6.15
Pregnancy
A by-subject listing of pregnancy tests results will be provided for randomized female subjects.
7.6.16
Adverse Events By Subgroup
Overall summary of any AEs and drug-related AEs by worst CTC grade (any grade, grade 3-4, 
grade 5) presented by SOC/PT and for each treatment group for the following subgroups:
•
Sex (Male vs. Female)
•
Race
•
Age (< 65 vs. 65 - < 75 vs. 75 - < 85 vs. ≥85 vs. ≥75 vs. ≥65)
•
Region (Europe, North America, Rest of World, Asia)
These analyses will be conducted using the 30-day safety window only.
 
 
 
 
 
 
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7.8.1
Distribution of PD-L1 Expression
Descriptive statistics of PD-L1 expression:
•
Listing of all PD-L1 IHC data, all randomized subjects.
•
Summary of tumor specimen acquisition and characteristics, all randomized subjects.
•
Summary statistics of PD-L1 expression in all randomized subjects with quantifiable PD-L1 
expression.
•
Summary of BOR and ORR by baseline PD-L1 expression in all randomized subjects.
•
Cumulative distribution plot of baseline PD-L1 expression versus population percentile in all 
randomized subjects with quantifiable PD-L1 expression.
•
Box plots of PD-L1 expression versus Response Status (BICR assessment) in all randomized
subjects with quantifiable PD-L1 expression. 
•
Waterfall plot of Individual PD-L1 expression in all randomized subjects with quantifiable 
PD-L1 expression.
7.8.2
Tumor Mutation Burden (TMB)
7.8.2.1
Tumor Tissue TMB
The analyses are based on tumor tissue TMB evaluable subjects, defined as subjects with tissue 
TMB data available. It is known that not all subjects will provide tumor tissue TMB data, due to 
factors such as available remaining tissue and inherent failure rates of the TMB process.
The descriptive analyses of tumor tissue TMB at baseline will be conducted:
•
Listing of all tumor tissue TMB data.
•
Summary of tumor specimen characteristics
•
Cumulative distribution plot of TMB at baseline versus population percentile in all subjects 
with evaluable tumor tissue TMB.
In addition, the joint distribution of PD-L1 and tumor tissue TMB among both PD-L1 and tumor 
tissue TMB-evaluable subjects will be examined.
The pre-specified tumor tissue TMB thresholds (≥10 Mut/MB, < 10 Mut/MB) will be used to 
categorize subjects in subgroups. The following descriptive analyses of efficacy endpoints (OS, 
PFS per BICR, and ORR) among tumor tissue TMB-evaluable subjects will be presented 
separately by treatment group.
A summary of OS/PFS per BICR by tumor tissue TMB subgroups (high, low) will be presented 
according to TMB cutpoints (10 Mut/MB). OS/PFS function for each tumor tissue TMB subgroup 
will be estimated using the KM product limit method for each treatment arm and will be displayed 
graphically. A two-sided 95% CI for median OS/PFS in each arm will be computed via log-log 
transformation method. Hazard ratios of OS/PFS and corresponding two-sided 95% CIs will be 
estimated using an unstratified Cox proportional hazards model, with treatment group as a single 
covariate.
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The comparison of ORR per BICR by tumor tissue TMB subgroups (high, low) will be conducted. 
An estimate of the difference in ORRs and corresponding 95% CI will be calculated using 
unstratified CMH methodology.
The number and percentage of subjects in each category of BOR per BICR will presented by tumor 
tissue TMB subgroups, by treatment group. A summary of DOR (as determined per BICR) by 
tumor tissue TMB subgroups will also be presented. A two-sided 95% CI for median DOR in each 
arm will be computed via the log-log transformation method.
7.8.2.2
Blood TMB
The analyses are based on blood TMB evaluable subjects, defined as subjects with blood TMB 
data available. It is known that not all subjects will provide blood TMB data, due to inherent failure 
rates of the TMB process.
The descriptive analyses of blood TMB at baseline will be conducted:
•
Listing of all blood TMB data.
•
Cumulative distribution plot of TMB at baseline versus population percentile in all subjects 
with evaluable blood TMB.
In addition, the joint distribution of PD-L1 and blood TMB among both PD-L1 and blood TMB-
evaluable subjects will be examined.
The pre-specified blood TMB thresholds (≥16 Mut/MB and < 16 Mut/MB; ≥20 Mut/MB and < 20 
Mut/MB) will be used to categorize subjects in subgroups. The following descriptive analyses of 
efficacy endpoints (OS, PFS per BICR, and ORR) among blood TMB-evaluable subjects will be 
presented separately by treatment group.
A summary of OS/PFS per BICR by blood TMB subgroups (high, low) will be presented according 
to TMB cutpoints (16 Mut/MB and 20 Mut/MB). OS/PFS function for each tumor tissue TMB 
subgroup will be estimated using the KM product limit method for each treatment arm and will be 
displayed graphically. A two-sided 95% CI for median OS/PFS in each arm will be computed via 
log-log transformation method. Hazard ratios of OS/PFS and corresponding two-sided 95% CIs 
will be estimated using an unstratified Cox proportional hazards model, with treatment group as a 
single covariate.
The comparison of ORR per BICR by blood TMB subgroups (high, low) will be conducted. An 
estimate of the difference in ORRs and corresponding 95% CI will be calculated using unstratified
CMH methodology.
The number and percentage of subjects in each category of BOR per BICR will presented by blood
TMB subgroups, by treatment group. A summary of DOR (as determined per BICR) by blood
TMB subgroups will also be presented. A two-sided 95% CI for median DOR in each arm will be 
computed via the log-log transformation method.
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7.8.2.3
Correlation between Tissue TMB and Blood TMB
As an exploratory analysis, the correlation between baseline tumor tissue TMB and blood TMB 
will be assessed using Spearman correlation based on rank order. The 95% CI for Spearman 
correlation will be provided based on Fisher transformation.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates: 
•
For missing and partial adverse event onset dates, imputation will be performed using the 
Adverse Event Domain Requirements Specification22
•
For missing and partial adverse event resolution dates, imputation will be performed as 
follows:
−
If only the day of the month is missing, the last day of the month will be used to replace 
the missing day. If the imputed date is after the death date or the last known alive date, then 
the latest known alive date or death date is considered as the resolution date. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
•
Missing and partial non-study medication domain dates will be imputed using the derivation 
algorithm described in 4.1.3 of BMS Non-Study Medication Domain Requirements 
Specification23.
•
Missing and partial radiotherapy and surgery dates will be imputed using algorithm described 
in APPENDIX 2.
•
For death dates, the following conventions will be used for imputing partial dates:
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known alive date and the 
maximum will be considered as the death date. 
−
If the month or the year is missing, the death date will be imputed as the last known alive 
date. 
−
If the date is completely missing but the reason for death is present, the death date will be 
imputed as the last known date alive. 
•
For date of progression after start of study therapy, the following conventions will be used for 
imputing partial dates: 
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. In case of the date of death is present and complete, the imputed progression 
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. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing. 
•
For date of progression to prior therapies, the following conventions will be used for imputing 
partial dates: 
−
If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. 
−
If the day and month are missing or a date is completely missing, it will be considered as 
missing. 
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•
For other partial/missing dates, the following conventions were used: 
−
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day. 
−
If both the day and the month are missing, “July 1” will be used to replace the missing 
information. 
−
If a date is completely missing, it will be considered as missing. 
The following conversion factors will be used to convert days to months or years: 
1 month = 30.4375 days and 1 year = 365.25 days.
Duration (e.g. time-to onset, time-to resolution) will be calculated as follows:
Duration = (Last date - first date + 1)
Last known alive date will be defined based on all appropriate dates collected on the CRF.
All statistical analyses will be carried out using SAS (Statistical Analysis System software, SAS 
Institute, North Carolina, USA) unless otherwise noted.
9
CONTENT OF REPORTS
The analyses described in this SAP will be included in the study-specific CSR(s). Refer to the Data 
Presentation Plan for mock-ups of all tables and listings.
10
DOCUMENT HISTORY
Table 10-1:
Document History
Version 
Number
Author(s)
Description
1
Stephanie Meadows-
Shropshire
Initial version.
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