CheckMate 451: An Investigational Immuno-therapy Study of Nivolumab, or Nivolumab in Combination With Ipilimumab, or Placebo in Patients With Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) After Completion of Platinum-based Chemotherapy

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02538666
• Collaborator: Ono Pharmaceutical Co. Ltd (Industry)
• Enrollment: 1,212
• Locations: 196
• Arms: 3
• Actual Duration (Months): 73
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

In this study, all patients must have already completed first-line chemotherapy to treat extensive-stage disease small cell lung cancer. The purpose of this study is to show that nivolumab, or nivolumab plus ipilimumab followed by nivolumab by itself, will prolong overall survival when administered as consolidation treatment in patients that are stable or responding after chemotherapy. Patients receiving treatment will be compared with patients taking placebo.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Biological: Nivolumab; Biological: Ipilimumab; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1212 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Multicenter, Double-Blind, Phase 3 Study of Nivolumab, Nivolumab in Combination With Ipilimumab, or Placebo as Maintenance Therapy in Subjects With Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) After Completion of Platinum-based First Line Chemotherapy (CheckMate 451: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 451)
• Actual Study Start Date: Oct 13, 2015
• Actual Primary Completion Date: Oct 1, 2018
• Actual Study Completion Date: Nov 11, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nivolumab monotherapy Nivolumab intravenous fusion	Biological: Nivolumab; Other Names: Opdivo
Experimental: Nivolumab and ipilimumab combination therapy Nivolumab and ipilimumab intravenous fusion	Biological: Nivolumab; Other Names: Opdivo ; Biological: Ipilimumab; Other Names: Yervoy
Placebo Comparator: Placebo Placebo	Other: Placebo

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) of Nivo + Ipi vs Placebo [Approximately 37 months after the first subject is randomized]

   OS was defined as the time from randomization to the date of death. A participant who had not died was censored at last known alive date. OS was followed up during the blinded study drug treatment and every 3 months via in-person or phone contact after participant discontinued the blinded study drug

Secondary Outcome Measures

1. Overall Survival (OS) [Approximately 37 months after the first subject is randomized]

   OS was defined as the time from randomization to the date of death. A participant who had not died was censored at last known alive date. OS was followed up during the blinded study drug treatment and every 3 months via in-person or phone contact after participant discontinued the blinded study drug

2. Progression Free Survival (PFS) [Approximately 37 months after the first subject is randomized]

   PFS (primary definition) was defined as the time between the date of randomization and the first date of documented progression as determined by Blind Independent Central Review (BICR) or death due to any cause, whichever occurred first. Participants who died with no reported progression were considered to have progressed on the date of death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on study tumor assessments and did not die (or died after initiation of the subsequent anti- cancer therapy) were censored on their date of randomization. Participants who started any subsequent anti- cancer therapy without a prior reported Progressive Disease (PD) per BICR were censored at the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.

3. OS in TMB High and Low Subgroups by TMB Cutoff [Approximately 37 Months]

   OS in TMB by the following cutoff points: ≥10 mutations/mb, < 10 mutations/mb, ≥13 mutations/mb, <13 mutations/mb

4. PFS in TMB High and Low Subgroups by TMB Cutoff [Approximately 37 Months]

   PFS in TMB by the following cutoff points: ≥10 mutations/mb, < 10 mutations/mb, ≥13 mutations/mb, <13 mutations/mb

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects with histologically or cytologically confirmed extensive stage disease SCLC

• Ongoing response of stable disease or better following 4 cycles of platinum-based first line chemotherapy

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

• Subjects with symptomatic Central Nervous System (CNS) metastases

• Subjects receiving consolidative chest radiation

• Subjects with active, known, or suspected autoimmune disease are excluded

• All side effects attributed to prior anti-cancer therapy must have resolved to Grade 1 or baseline

Other protocol-defined inclusion/exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sutter Cancer Center	Sacramento	California	United States	95816
2	Yale University	New Haven	Connecticut	United States	06520
3	Florida Cancer Specialists S.	Fort Myers	Florida	United States	33901
4	Cancer Specialists of North FL	Jacksonville	Florida	United States	32256
5	Florida Cancer Specialists	Saint Petersburg	Florida	United States	33705
6	Winship Cancer Institute.	Atlanta	Georgia	United States	30322
7	Franciscan St. Francis Health	Indianapolis	Indiana	United States	46237
8	University of Kansas Cancer Center - Clinical Research Center	Fairway	Kansas	United States	66205
9	Cancer Center Of Kansas	Wichita	Kansas	United States	67214
10	Baptist Health Lexington	Lexington	Kentucky	United States	40503
11	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287
12	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
13	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
14	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
15	Memorial Sloan Kettering Nassau	New York	New York	United States	10065
16	Duke University	Durham	North Carolina	United States	27710
17	Novant Health Oncology Specialists	Winston-Salem	North Carolina	United States	27103
18	Sanford Health	Fargo	North Dakota	United States	58102
19	Oncology Hematology Care, Inc.	Cincinnati	Ohio	United States	45242
20	Ohio State University	Columbus	Ohio	United States	43210
21	Providence Portland Medical Center	Portland	Oregon	United States	97213
22	Oregon Health & Science University	Portland	Oregon	United States	97239
23	Lehigh Valley Health Network	Allentown	Pennsylvania	United States	18103
24	Donald Guthrie Foundation	Sayre	Pennsylvania	United States	18840
25	Medical University Of South Carolina	Charleston	South Carolina	United States	29425
26	Sanford Health	Sioux Falls	South Dakota	United States	57104
27	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
28	Virginia Cancer Institute	Richmond	Virginia	United States	23226
29	Local Institution	Berazategui	Buenos Aires	Argentina	1880
30	Local Institution	Capital Federal	Buenos Aires	Argentina	1426
31	Local Institution	Ciudad Autonoma De Buenos Aire	Buenos Aires	Argentina	1181
32	Local Institution	Cordoba		Argentina	5004
33	Local Institution	Tucuman		Argentina	4000
34	Local Institution	Kogarah	New South Wales	Australia
35	Local Institution	Wollongong	New South Wales	Australia	2500
36	Local Institution	Birtinya	Queensland	Australia	4575
37	Princess Alexandra Hospital	Brisbane	Queensland	Australia	4102
38	Local Institution	Adelaide	South Australia	Australia	5000
39	Local Institution	East Melbourne	Victoria	Australia	3165
40	Local Institution	Innsbruck		Austria	6020
41	Local Institution	Salzburg		Austria	5020
42	Local Institution	Wien		Austria	1130
43	Local Institution	Brussels		Belgium	1090
44	Local Institution	Charleroi		Belgium	6000
45	Local Institution	Roeselare		Belgium	8800
46	Local Institution	Fortaleza	Ceara	Brazil	60430-230
47	Local Institution	Belo Horizonte	Minas Gerais	Brazil	30110-022
48	Local Institution	Ijui	RIO Grande DO SUL	Brazil	98700-000
49	Local Institution	Porto Alegre	RIO Grande DO SUL	Brazil	90610-000
50	Local Institution	Itajai	Santa Catarina	Brazil	88301-220
51	Local Institution	Barretos	Sao Paulo	Brazil	14784-400
52	Local Institution	Rio de Janeiro		Brazil	22793-080
53	Local Institution	Salvador		Brazil	40170-110
54	Local Institution	Edmonton	Alberta	Canada	T6G 1Z2
55	Local Institution	Moncton	New Brunswick	Canada	E1C 6Z8
56	Local Institution	Oshawa	Ontario	Canada	L1G 2B9
57	Local Institution	Sudbury	Ontario	Canada	P3E 5J1
58	Local Institution	Windsor	Ontario	Canada	N8W 2X3
59	Local Institution	Hefei	Anhui	China	230001
60	Local Institution	Hefei	Anhui	China	230022
61	Local Institution	Beijing	Beijing	China	100001
62	Local Institution	Beijing	Beijing	China	100142
63	Local Institution	Harbin	Heilongjiang	China	155040
64	Local Institution	Wuhang	Hubei	China	430030
65	Local Institution	Nantong	Jiangsu	China	226361
66	Local Institution	Nanchang	Jiangxi	China	330006
67	Local Institution	Changchun	Jilin	China	130021
68	Local Institution	Shenyang	Liaoning	China	110046
69	Local Institution	Shanghai	Shanghai	China	200030
70	Local Institution	Shanghai	Shanghai	China	200032
71	Local Institution	Shanghai	Shanghai	China	200433
72	Local Institution	Kunming	Yunnan	China	650118
73	Local Institution	Hangzhou	Zhejiang	China	310003
74	Local Institution	Hangzhou	Zhejiang	China	310016
75	Local Institution	Wenzhou	Zhejiang	China	325000
76	Local Institution	Changsha		China
77	Local Institution	Guangzhou		China	510515
78	Local Institution	Monteria	Cordoba	Colombia
79	Local Institution	Bogota		Colombia
80	Local Institution	Medellin		Colombia	MEDELLIN
81	Local Institution	Oulu		Finland	90029
82	Local Institution	Tampere		Finland	33521
83	Local Institution	Turku		Finland	FIN-20521
84	Local Institution	Vaasa		Finland	65130
85	Local Institution	Avignon Cedes 9		France	84918
86	Local Institution	Lyon Cedex 08		France	69373
87	Local Institution	Marseille Cedex 20		France	13915
88	Local Institution	Paris Cedex 20		France	75970
89	Local Institution	Pierre Benite		France	69495
90	Local Institution	Rennes Cedex 9		France	35033
91	Local Institution	Saint Herblain		France	44805
92	Nouvel Hopital Civil Chru De Strasbourg	Strasbourg		France	67090
93	Local Institution	Toulouse		France	31059
94	Local Institution	Augsburg		Germany	86156
95	Local Institution	Bad Berka		Germany	99437
96	Local Institution	Berlin		Germany	14165
97	Local Institution	Bochum		Germany	44791
98	Local Institution	Gauting		Germany	82131
99	Local Institution	Grosshansdorf		Germany	22927
100	Local Institution	Immenhausen		Germany	34376
101	Local Institution	Tuebingen		Germany	72076
102	General Oncology Hospital of Kifissia Agioi Anargyroi	N.Kifissia		Greece	14564
103	Interbalkan European Medical Center	Thessaloniki		Greece	57001
104	Local Institution	Hong Kong		Hong Kong
105	Local Institution	Wilton	Cork	Ireland
106	Local Institution	Dublin		Ireland	24
107	Local Institution	Dublin		Ireland	4
108	Local Institution	Galway		Ireland	ST4 6QG
109	Local Institution	Limerick		Ireland
110	Local Institution	Haifa		Israel	31096
111	Local Institution	Jerusalem		Israel	91031
112	Local Institution	Petach Tikva		Israel	49100
113	Local Institution	Tel Aviv		Israel	64239
114	Local Institution	Zerifin		Israel	70300
115	Local Institution	Avellino		Italy	83100
116	Local Institution	Bologna		Italy	40138
117	Local Institution	Messina		Italy	98158
118	Local Institution	Milan		Italy	20141
119	Local Institution	Perugia		Italy	06132
120	Local Institution	Kashiwa-shi	Chiba	Japan	2778577
121	Local Institution	Matsuyama-shi	Ehime	Japan	7910280
122	Local Institution	Fukuoka-shi	Fukuoka	Japan	8128582
123	Local Institution	Kurume-shi	Fukuoka	Japan	8300011
124	Local Institution	Gifu-shi	Gifu	Japan	5008513
125	Local Institution	Sapporo-shi	Hokkaido	Japan	0608648
126	Local Institution	Kobe-shi	Hyogo	Japan	6500047
127	Local Institution	Kanazawa-shi	Ishikawa	Japan	9208641
128	Local Institution	Yokohama-shi	Kanagawa	Japan	2408555
129	Local Institution	Sendai-shi	Miyagi	Japan	9800873
130	Local Institution	Sendai-shi	Miyagi	Japan	9808574
131	Local Institution	Kurashiki-shi	Okayama	Japan	7108602
132	Local Institution	Hirakata-shi	Osaka	Japan	5731191
133	Local Institution	Osaka-sayama-shi	Osaka	Japan	5898511
134	Local Institution	Osaka-shi	Osaka	Japan	5340021
135	Local Institution	Takatsuki-shi	Osaka	Japan	5698686
136	Local Institution	Hidaka-shi	Saitama	Japan	3501298
137	Local Institution	Bunkyo-ku	Tokyo	Japan	1130022
138	Local Institution	Chuo-ku	Tokyo	Japan	1040045
139	Local Institution	Koto-ku	Tokyo	Japan	1358550
140	Local Institution	Shinjuku-ku	Tokyo	Japan	1600023
141	Local Institution	Wakayama-shi	Wakayama	Japan	6418510
142	Local Institution	Seongnam-si	Gyeonggi-do	Korea, Republic of	13620
143	Local Institution	Suwon-si	Gyeonggi-do	Korea, Republic of	16499
144	Local Institution	Seoul		Korea, Republic of	03722
145	Local Institution	Seoul		Korea, Republic of	05505
146	Local Institution	Seoul		Korea, Republic of	06351
147	Local Institution	Mexico	Distrito Federal	Mexico	14050
148	Local Institution	Leon de los Aldama	Guanajuato	Mexico	37000
149	Local Institution	Monterrey	Nuevo Leon	Mexico	64000
150	Local Institution	Queretaro		Mexico	76090
151	Local Institution	's-Hertogenbosch		Netherlands	5223 GZ
152	Local Institution	Eindhoven		Netherlands	5623 EJ
153	Local Institution	Rotterdam		Netherlands	3000 CA
154	Local Institution	Miraflores	Lima	Peru	18
155	Local Institution	Lima		Peru	27
156	Local Institution	Lima		Peru	34
157	Local Institution	Gdansk		Poland	80-19
158	Local Institution	Gdynia		Poland	81-519
159	Local Institution	Olsztyn		Poland	10-357
160	Local Institution	Warszawa		Poland	02-781
161	Local Institution	Bucharest		Romania	010991
162	Local Institution	Bucharest		Romania	020122
163	Local Institution	Craiova		Romania	200347
164	Local Institution	Lasi		Romania	700106
165	Local Institution	Romania		Romania	400015
166	Local Institution	Timisoara, Timis		Romania	300239
167	Local Institution	Moscow		Russian Federation	105229
168	Local Institution	Moscow		Russian Federation	115478
169	Local Institution	Moscow		Russian Federation	121309
170	Local Institution	St Petersburg		Russian Federation	197758
171	Local Institution	St Petersburg		Russian Federation	198255
172	Local Institution	St. Petersburg		Russian Federation	194291
173	Local Institution	Singapore		Singapore	169610
174	Local Institution	Sandton	Gauteng	South Africa	2199
175	Local Institution	Cape Town	Western Cape	South Africa	7570
176	Local Institution	Cape Town	Western CAPE	South Africa	7700
177	Local Institution	George	Western CAPE	South Africa	6530
178	Local Institution	Barcelona		Spain	08035
179	Local Institution	Barcelona		Spain	08036
180	Local Institution	Madrid		Spain	28040
181	Local Institution	Malaga		Spain	29011
182	Local Institution	Sevilla		Spain	41013
183	Local Institution	Lund		Sweden	221 85
184	Local Institution	Uppsala		Sweden	751 85
185	Local Institution	Aarau		Switzerland	5001
186	Local Institution	Geneve		Switzerland	1205
187	Local Institution	St. Gallen		Switzerland	9007
188	Local Institution	Tainan		Taiwan	704
189	Local Institution	Taoyuan		Taiwan	333
190	Local Institution	Truro	Cornwall	United Kingdom	TR1 3LJ
191	Local Institution	London	Greater London	United Kingdom	NW1 2PG
192	Local Institution	London	Greater London	United Kingdom	SW3 6JJ
193	Local Institution	Oxford	Oxfordshire	United Kingdom	OX3 7LJ
194	Local Institution	Sutton	Surrey	United Kingdom	SM2 5PT
195	Local Institution	Sheffield		United Kingdom	S10 2SJ
196	Local Institution	Wirral		United Kingdom	CH63 4JY

Sponsors and Collaborators

• Bristol-Myers Squibb
• Ono Pharmaceutical Co. Ltd

Investigators

• Study Director: Bristol Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

• Study Protocol - Sep 20, 2018
• Statistical Analysis Plan - Oct 4, 2018

More Information

Additional Information:

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• Investigator Inquiry Form
• FDA Safety Alerts and Recalls

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT02538666
• Other Study ID Numbers: CA209-451; 2015-002441-61
• First Posted: Sep 2, 2015
• Last Update Posted: Feb 2, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma; Nivolumab; Ipilimumab

Study Results

Participant Flow

Pre-assignment Detail	1212 participants enrolled; 834 randomized. 378 Not Randomized. Reasons not randomized: 2 Adverse events, 31 withdrew consent, 2 lost to follow up, 3 poor/non-compliant, 334 no longer met study criteria, 5 not reported, 1 other therapy was proposed

Arm/Group Title	Placebo (Pbo)	Nivolumab	Nivolumab + Ipilimumab
Arm/Group Description	Nivo pbo: 100 mL and Ipi pbo: 100 mL	nivolumab 240mg Q2W IV infusion	nivolumab 1mg/kg IV + ipilimumab 3mg/kg IV Q3W for Four (4) doses followed by nivolumab 240mg Q2W
Period Title: Overall Study
STARTED	275	280	279
COMPLETED	273	279	278
NOT COMPLETED	2	1	1

Baseline Characteristics

Arm/Group Title	Placebo (Pbo)	Nivolumab	Nivolumab + Ipilimumab	Total
Arm/Group Description	Nivo pbo: 100 mL and Ipi pbo: 100 mL	nivolumab 240mg Q2W IV infusion	nivolumab 1mg/kg IV + ipilimumab 3mg/kg IV Q3W for Four (4) doses followed by nivolumab 240mg Q2W	Total of all reporting groups
Overall Participants	275	280	279	834
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.2 (8.1)	64.6 (8.6)	63.9 (8.8)	63.9 (8.5)
Sex: Female, Male (Count of Participants)
Female	100 36.4%	103 36.8%	99 35.5%	302 36.2%
Male	175 63.6%	177 63.2%	180 64.5%	532 63.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	14 5.1%	11 3.9%	15 5.4%	40 4.8%
Not Hispanic or Latino	151 54.9%	159 56.8%	164 58.8%	474 56.8%
Unknown or Not Reported	110 40%	110 39.3%	100 35.8%	320 38.4%
Race/Ethnicity, Customized (Number) [Number]
Asian	69 25.1%	58 20.7%	58 20.8%	185 22.2%
Black or African American	2 0.7%	6 2.1%	1 0.4%	9 1.1%
White	198 72%	213 76.1%	216 77.4%	627 75.2%
Other	6 2.2%	3 1.1%	3 1.1%	12 1.4%
Not Reported	0 0%	0 0%	1 0.4%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS) of Nivo + Ipi vs Placebo
Description	OS was defined as the time from randomization to the date of death. A participant who had not died was censored at last known alive date. OS was followed up during the blinded study drug treatment and every 3 months via in-person or phone contact after participant discontinued the blinded study drug
Time Frame	Approximately 37 months after the first subject is randomized

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Nivolumab + Ipilimumab
Arm/Group Description	Nivo pbo: 100 mL and Ipi pbo: 100 mL	nivolumab 1mg/kg IV + ipilimumab 3mg/kg IV Q3W for Four (4) doses followed by nivolumab 240mg Q2W
Measure Participants	275	279
Median (95% Confidence Interval) [Months]	9.56	9.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab
	Comments	nivo + ipi over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3693
	Comments
	Method	Stratified Log Rank
	Comments	Stratified by response to ECOG PS (0vs1), gender (MvF), irradiation following chemotherapy (YorN) as entered in IVRS
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	based on stratified 3-arms Cox proportional hazard model

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to the date of death. A participant who had not died was censored at last known alive date. OS was followed up during the blinded study drug treatment and every 3 months via in-person or phone contact after participant discontinued the blinded study drug
Time Frame	Approximately 37 months after the first subject is randomized

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Nivolumab	Nivolumab + Ipilimumab
Arm/Group Description	Nivo pbo: 100 mL and Ipi pbo: 100 mL	nivolumab 240mg Q2W IV infusion	nivolumab 1mg/kg IV + ipilimumab 3mg/kg IV Q3W for Four (4) doses followed by nivolumab 240mg Q2W
Measure Participants	275	280	279
Median (95% Confidence Interval) [Months]	9.56	10.41	9.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab
	Comments	nivo over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	based on stratified 3-arms Cox proportional hazard model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Nivolumab + Ipilimumab
	Comments	nivo + ipi over nivo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratios are based on stratified 3-arms Cox proportional hazard model.

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS (primary definition) was defined as the time between the date of randomization and the first date of documented progression as determined by Blind Independent Central Review (BICR) or death due to any cause, whichever occurred first. Participants who died with no reported progression were considered to have progressed on the date of death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on study tumor assessments and did not die (or died after initiation of the subsequent anti- cancer therapy) were censored on their date of randomization. Participants who started any subsequent anti- cancer therapy without a prior reported Progressive Disease (PD) per BICR were censored at the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.
Time Frame	Approximately 37 months after the first subject is randomized

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Nivolumab	Nivolumab + Ipilimumab
Arm/Group Description	Nivo pbo: 100 mL and Ipi pbo: 100 mL	nivolumab 240mg Q2W IV infusion	nivolumab 1mg/kg IV + ipilimumab 3mg/kg IV Q3W for Four (4) doses followed by nivolumab 240mg Q2W
Measure Participants	275	280	279
Median (95% Confidence Interval) [Months]	1.45	1.87	1.74

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab
	Comments	nivo + ipi over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.60 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratios based on stratified 3-arms Cox proportional hazard model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab
	Comments	nivo over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.56 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratios based on stratified 3-arms Cox proportional hazard model

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Nivolumab + Ipilimumab
	Comments	nivo+ ipi over nivo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratios are based on stratified 3-arms Cox proportional hazard model.

4. Secondary Outcome

Title	OS in TMB High and Low Subgroups by TMB Cutoff
Description	OS in TMB by the following cutoff points: ≥10 mutations/mb, < 10 mutations/mb, ≥13 mutations/mb, <13 mutations/mb
Time Frame	Approximately 37 Months

Outcome Measure Data

Analysis Population Description

All TMB Evaluable Participants, Global Population

Arm/Group Title	Placebo	Nivolumab	Nivolumab + Ipilimumab
Arm/Group Description	Nivo pbo: 100 mL and Ipi pbo: 100 mL	nivolumab 240mg Q2W IV infusion	nivolumab 1mg/kg IV + ipilimumab 3mg/kg IV Q3W for Four (4) doses followed by nivolumab 240mg Q2W
Measure Participants	192	196	192
≥10 mutations/mb	11.50	12.98	10.55
< 10 mutations/mb	9.20	9.89	8.11
≥13 mutations/mb	9.53	13.24	13.47
<13 mutations/mb	10.02	10.09	7.85

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff ≥10 mutations/mb: Nivo+Ipi over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.55 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff ≥10 mutations/mb: Nivo over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.54 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff ≥13 mutations/mb: Nivo+Ipi over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff ≥13 mutations/mb: Nivo over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff <10 mutations/mb: Nivo+Ipi over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff <10 mutations/mb: Nivo over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff <13 mutations/mb: Nivo+Ipi over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff <13 mutations/mb: Nivo over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

5. Secondary Outcome

Title	PFS in TMB High and Low Subgroups by TMB Cutoff
Description	PFS in TMB by the following cutoff points: ≥10 mutations/mb, < 10 mutations/mb, ≥13 mutations/mb, <13 mutations/mb
Time Frame	Approximately 37 Months

Outcome Measure Data

Analysis Population Description

All TMB Evaluable Participants, Global Population

Arm/Group Title	Placebo	Nivolumab	Nivolumab + Ipilimumab
Arm/Group Description	Nivo pbo: 100 mL and Ipi pbo: 100 mL	nivolumab 240mg Q2W IV infusion	nivolumab 1mg/kg IV + ipilimumab 3mg/kg IV Q3W for Four (4) doses followed by nivolumab 240mg Q2W
Measure Participants	192	196	192
≥10 mutations/mb	1.58	2.79	2.33
< 10 mutations/mb	1.41	1.61	1.48
≥13 mutations/mb	1.58	2.76	2.66
<13 mutations/mb	1.41	1.61	1.48

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff ≥10 mutations/mb: Nivo+Ipi over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff ≥10 mutations/mb: Nivo over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.51 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff ≥13 mutations/mb: Nivo+Ipi over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.47 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff ≥13 mutations/mb: Nivo over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.47 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff <10 mutations/mb: Nivo+Ipi over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff <10 mutations/mb: Nivo over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.50 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff <13 mutations/mb: Nivo+Ipi over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.60 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nivolumab + Ipilimumab
	Comments	TMB cutoff <13 mutations/mb: Nivo over placebo
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified Cox proportional hazard model. Hazard Ratios are experimental treatment group over placebo.

Adverse Events

Time Frame	Reporting Adverse Events (AEs) include events reported between first dose and 30 days after last dose of study therapy
Arm/Group Title	Placebo		Nivolumab 240 mg		Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
Arm/Group Description	Nivo pbo: 100 mL and Ipi pbo: 100 mL		nivolumab 240mg Q2W IV infusion		nivolumab 1mg/kg IV + ipilimumab 3mg/kg IV Q3W for Four (4) doses followed by nivolumab 240mg Q2W
All Cause Mortality
	Placebo		Nivolumab 240 mg		Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	210/273 (76.9%)		194/279 (69.5%)		189/278 (68%)
Serious Adverse Events
	Placebo		Nivolumab 240 mg		Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/273 (27.8%)		93/279 (33.3%)		165/278 (59.4%)
Blood and lymphatic system disorders
Anaemia	0/273 (0%)		2/279 (0.7%)		0/278 (0%)
Febrile neutropenia	3/273 (1.1%)		2/279 (0.7%)		4/278 (1.4%)
Immune thrombocytopenic purpura	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Neutropenia	0/273 (0%)		1/279 (0.4%)		1/278 (0.4%)
Thrombocytopenia	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Cardiac disorders
Atrial fibrillation	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Atrial flutter	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Cardiac failure	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Cardiac failure acute	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Myocardial infarction	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Myocarditis	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Ear and labyrinth disorders
Vertigo positional	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Endocrine disorders
Addison's disease	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Adrenal insufficiency	0/273 (0%)		0/279 (0%)		4/278 (1.4%)
Adrenocortical insufficiency acute	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Basedow's disease	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Cushing's syndrome	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Hyperthyroidism	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Hypopituitarism	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Inappropriate antidiuretic hormone secretion	0/273 (0%)		1/279 (0.4%)		2/278 (0.7%)
Eye disorders
Eyelid ptosis	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Papilloedema	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Rhegmatogenous retinal detachment	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Vision blurred	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Gastrointestinal disorders
Abdominal pain	0/273 (0%)		1/279 (0.4%)		1/278 (0.4%)
Anal fistula	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Autoimmune colitis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Colitis	0/273 (0%)		1/279 (0.4%)		19/278 (6.8%)
Colitis ischaemic	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Colitis ulcerative	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Diarrhoea	0/273 (0%)		1/279 (0.4%)		14/278 (5%)
Dysphagia	0/273 (0%)		0/279 (0%)		3/278 (1.1%)
Enterocolitis haemorrhagic	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Gastrointestinal haemorrhage	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Impaired gastric emptying	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Intestinal perforation	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Nausea	1/273 (0.4%)		0/279 (0%)		1/278 (0.4%)
Pancreatic mass	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Proctitis ulcerative	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Small intestinal obstruction	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Stomatitis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Upper gastrointestinal haemorrhage	0/273 (0%)		1/279 (0.4%)		1/278 (0.4%)
Vomiting	2/273 (0.7%)		2/279 (0.7%)		5/278 (1.8%)
General disorders
Asthenia	2/273 (0.7%)		0/279 (0%)		3/278 (1.1%)
Chest discomfort	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Chest pain	2/273 (0.7%)		3/279 (1.1%)		0/278 (0%)
Death	0/273 (0%)		1/279 (0.4%)		1/278 (0.4%)
Disease progression	1/273 (0.4%)		2/279 (0.7%)		0/278 (0%)
Facial pain	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Fatigue	1/273 (0.4%)		1/279 (0.4%)		6/278 (2.2%)
General physical health deterioration	0/273 (0%)		2/279 (0.7%)		1/278 (0.4%)
Influenza like illness	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Non-cardiac chest pain	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Pain	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Performance status decreased	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Pyrexia	3/273 (1.1%)		2/279 (0.7%)		7/278 (2.5%)
Sudden death	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Hepatobiliary disorders
Autoimmune hepatitis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Drug-induced liver injury	1/273 (0.4%)		0/279 (0%)		1/278 (0.4%)
Hepatic failure	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Hepatic function abnormal	0/273 (0%)		1/279 (0.4%)		1/278 (0.4%)
Hepatitis	0/273 (0%)		0/279 (0%)		4/278 (1.4%)
Hepatotoxicity	0/273 (0%)		1/279 (0.4%)		2/278 (0.7%)
Immune-mediated hepatitis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Infections and infestations
Abdominal abscess	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Bronchitis	1/273 (0.4%)		0/279 (0%)		2/278 (0.7%)
Clostridium difficile colitis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Clostridium difficile infection	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Diverticulitis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Encephalitis	0/273 (0%)		1/279 (0.4%)		3/278 (1.1%)
Gastric infection	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Infective thrombosis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Influenza	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Lower respiratory tract infection	0/273 (0%)		1/279 (0.4%)		2/278 (0.7%)
Lung infection	1/273 (0.4%)		2/279 (0.7%)		4/278 (1.4%)
Periodontitis	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Pneumonia	8/273 (2.9%)		4/279 (1.4%)		9/278 (3.2%)
Pneumonia legionella	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Respiratory tract infection	1/273 (0.4%)		2/279 (0.7%)		1/278 (0.4%)
Sepsis	3/273 (1.1%)		2/279 (0.7%)		8/278 (2.9%)
Soft tissue infection	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Staphylococcal infection	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Urinary tract infection	2/273 (0.7%)		2/279 (0.7%)		1/278 (0.4%)
Vascular device infection	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Injury, poisoning and procedural complications
Fall	2/273 (0.7%)		1/279 (0.4%)		1/278 (0.4%)
Femoral neck fracture	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Fracture	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Hip fracture	2/273 (0.7%)		0/279 (0%)		0/278 (0%)
Infusion related reaction	0/273 (0%)		1/279 (0.4%)		1/278 (0.4%)
Spinal compression fracture	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Tendon rupture	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Investigations
Amylase increased	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Hepatic enzyme increased	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Lipase increased	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Neutrophil count decreased	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Platelet count decreased	0/273 (0%)		1/279 (0.4%)		2/278 (0.7%)
Transaminases increased	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Metabolism and nutrition disorders
Appetite disorder	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Decreased appetite	2/273 (0.7%)		1/279 (0.4%)		3/278 (1.1%)
Dehydration	1/273 (0.4%)		0/279 (0%)		6/278 (2.2%)
Diabetes mellitus inadequate control	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Diabetic ketoacidosis	0/273 (0%)		1/279 (0.4%)		1/278 (0.4%)
Failure to thrive	1/273 (0.4%)		1/279 (0.4%)		0/278 (0%)
Hyperglycaemia	1/273 (0.4%)		1/279 (0.4%)		2/278 (0.7%)
Hypokalaemia	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Hyponatraemia	5/273 (1.8%)		7/279 (2.5%)		9/278 (3.2%)
Type 1 diabetes mellitus	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Arthritis	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Back pain	0/273 (0%)		2/279 (0.7%)		2/278 (0.7%)
Bone pain	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Mobility decreased	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Muscular weakness	2/273 (0.7%)		1/279 (0.4%)		2/278 (0.7%)
Musculoskeletal pain	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Myalgia	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Myositis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Rhabdomyolysis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Spinal disorder	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Spinal pain	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Malignant neoplasm progression	23/273 (8.4%)		21/279 (7.5%)		19/278 (6.8%)
Metastases to central nervous system	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Metastases to spinal cord	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Neoplasm progression	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Tumour pain	2/273 (0.7%)		1/279 (0.4%)		0/278 (0%)
Nervous system disorders
Cauda equina syndrome	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Cerebral infarction	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Cognitive disorder	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Dizziness	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Dysarthria	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Encephalitis autoimmune	0/273 (0%)		1/279 (0.4%)		1/278 (0.4%)
Encephalopathy	1/273 (0.4%)		0/279 (0%)		1/278 (0.4%)
Guillain-Barre syndrome	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Hemiparesis	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Lethargy	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Limbic encephalitis	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Myasthenia gravis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Neurological symptom	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Occipital neuralgia	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Paraesthesia	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Paraparesis	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Seizure	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Spinal cord compression	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Subarachnoid haemorrhage	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Transient ischaemic attack	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Tremor	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Psychiatric disorders
Insomnia	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Renal and urinary disorders
Acute kidney injury	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Bladder mass	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Renal failure	1/273 (0.4%)		1/279 (0.4%)		3/278 (1.1%)
Renal tubular disorder	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Respiratory, thoracic and mediastinal disorders
Alveolitis allergic	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Bronchial haemorrhage	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Bronchospasm	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Chronic obstructive pulmonary disease	1/273 (0.4%)		5/279 (1.8%)		1/278 (0.4%)
Cough	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Dyspnoea	5/273 (1.8%)		7/279 (2.5%)		2/278 (0.7%)
Dyspnoea exertional	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Haemoptysis	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Interstitial lung disease	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Pleural effusion	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Pleurisy	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Pneumonia aspiration	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Pneumonitis	1/273 (0.4%)		7/279 (2.5%)		15/278 (5.4%)
Productive cough	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Pulmonary embolism	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Pulmonary haemorrhage	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Respiratory failure	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Skin and subcutaneous tissue disorders
Dermatitis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Pruritus	1/273 (0.4%)		0/279 (0%)		0/278 (0%)
Rash maculo-papular	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Skin toxicity	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Subcutaneous emphysema	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Vascular disorders
Circulatory collapse	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Deep vein thrombosis	1/273 (0.4%)		1/279 (0.4%)		0/278 (0%)
Hypertension	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Hypotension	1/273 (0.4%)		0/279 (0%)		1/278 (0.4%)
Shock	0/273 (0%)		0/279 (0%)		2/278 (0.7%)
Superior vena cava stenosis	0/273 (0%)		1/279 (0.4%)		0/278 (0%)
Superior vena cava syndrome	1/273 (0.4%)		4/279 (1.4%)		1/278 (0.4%)
Venous thrombosis	0/273 (0%)		0/279 (0%)		1/278 (0.4%)
Other (Not Including Serious) Adverse Events
	Placebo		Nivolumab 240 mg		Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	218/273 (79.9%)		235/279 (84.2%)		260/278 (93.5%)
Blood and lymphatic system disorders
Anaemia	17/273 (6.2%)		25/279 (9%)		22/278 (7.9%)
Endocrine disorders
Hyperthyroidism	6/273 (2.2%)		18/279 (6.5%)		27/278 (9.7%)
Hypothyroidism	3/273 (1.1%)		19/279 (6.8%)		20/278 (7.2%)
Gastrointestinal disorders
Abdominal pain	10/273 (3.7%)		13/279 (4.7%)		20/278 (7.2%)
Abdominal pain upper	14/273 (5.1%)		10/279 (3.6%)		10/278 (3.6%)
Constipation	28/273 (10.3%)		26/279 (9.3%)		41/278 (14.7%)
Diarrhoea	43/273 (15.8%)		56/279 (20.1%)		83/278 (29.9%)
Nausea	57/273 (20.9%)		59/279 (21.1%)		69/278 (24.8%)
Vomiting	17/273 (6.2%)		23/279 (8.2%)		46/278 (16.5%)
General disorders
Asthenia	32/273 (11.7%)		37/279 (13.3%)		46/278 (16.5%)
Chest pain	15/273 (5.5%)		13/279 (4.7%)		16/278 (5.8%)
Fatigue	62/273 (22.7%)		83/279 (29.7%)		84/278 (30.2%)
Pyrexia	8/273 (2.9%)		18/279 (6.5%)		39/278 (14%)
Investigations
Alanine aminotransferase increased	9/273 (3.3%)		18/279 (6.5%)		40/278 (14.4%)
Amylase increased	8/273 (2.9%)		8/279 (2.9%)		17/278 (6.1%)
Aspartate aminotransferase increased	7/273 (2.6%)		17/279 (6.1%)		37/278 (13.3%)
Blood creatinine increased	6/273 (2.2%)		11/279 (3.9%)		18/278 (6.5%)
Lipase increased	11/273 (4%)		11/279 (3.9%)		27/278 (9.7%)
Weight decreased	11/273 (4%)		13/279 (4.7%)		26/278 (9.4%)
Metabolism and nutrition disorders
Decreased appetite	53/273 (19.4%)		63/279 (22.6%)		96/278 (34.5%)
Dehydration	6/273 (2.2%)		8/279 (2.9%)		16/278 (5.8%)
Hyperglycaemia	11/273 (4%)		12/279 (4.3%)		16/278 (5.8%)
Hypokalaemia	6/273 (2.2%)		8/279 (2.9%)		17/278 (6.1%)
Hypomagnesaemia	7/273 (2.6%)		10/279 (3.6%)		15/278 (5.4%)
Hyponatraemia	13/273 (4.8%)		19/279 (6.8%)		33/278 (11.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	24/273 (8.8%)		27/279 (9.7%)		27/278 (9.7%)
Back pain	22/273 (8.1%)		27/279 (9.7%)		16/278 (5.8%)
Musculoskeletal pain	7/273 (2.6%)		17/279 (6.1%)		5/278 (1.8%)
Myalgia	13/273 (4.8%)		26/279 (9.3%)		21/278 (7.6%)
Nervous system disorders
Dizziness	22/273 (8.1%)		26/279 (9.3%)		27/278 (9.7%)
Headache	23/273 (8.4%)		31/279 (11.1%)		44/278 (15.8%)
Psychiatric disorders
Insomnia	15/273 (5.5%)		17/279 (6.1%)		20/278 (7.2%)
Respiratory, thoracic and mediastinal disorders
Cough	44/273 (16.1%)		51/279 (18.3%)		49/278 (17.6%)
Dyspnoea	37/273 (13.6%)		59/279 (21.1%)		45/278 (16.2%)
Productive cough	7/273 (2.6%)		15/279 (5.4%)		10/278 (3.6%)
Skin and subcutaneous tissue disorders
Dry skin	14/273 (5.1%)		10/279 (3.6%)		16/278 (5.8%)
Pruritus	31/273 (11.4%)		36/279 (12.9%)		73/278 (26.3%)
Rash	14/273 (5.1%)		18/279 (6.5%)		67/278 (24.1%)
Rash maculo-papular	5/273 (1.8%)		9/279 (3.2%)		25/278 (9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.