CheckMate 915: An Investigational Immuno-therapy Study of Nivolumab Combined With Ipilimumab Compared to Nivolumab by Itself After Complete Surgical Removal of Stage IIIb/c/d or Stage IV Melanoma

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03068455
• Collaborator: (none)
• Enrollment: 1,844
• Locations: 124
• Arms: 2
• Actual Duration (Months): 45.8
• Patients Per Site: 14.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether an investigational immunotherapy Nivolumab, when combined with Ipilimumab, is more effective than Nivolumab by itself, in delaying the return of cancer in patients who have had a complete surgical removal of stage IIIb/c/d or stage IV Melanoma

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Biological: nivolumab; Biological: ipilimumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1844 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized Study of Adjuvant Immunotherapy With Nivolumab Combined With Ipilimumab Versus Nivolumab Monotherapy After Complete Resection of Stage IIIb/c/d or Stage IV Melanoma
• Actual Study Start Date: Apr 11, 2017
• Actual Primary Completion Date: Jun 12, 2020
• Actual Study Completion Date: Feb 2, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: nivolumab + ipilimumab Specified Dose on Specified Days	Biological: nivolumab; Specified Dose on Specified Days; Other Names: Opdivo BMS-936558 ; Biological: ipilimumab; Specified Dose on Specified Days; Other Names: Yervoy BMS-734016
Experimental: nivolumab Specified Dose on Specified Days	Biological: nivolumab; Specified Dose on Specified Days; Other Names: Opdivo BMS-936558

Outcome Measures

Primary Outcome Measures

1. Recurrence-free Survival (RFS) - All Randomized Participants [From randomization to Primary Completion Date (up to approximately 3 years)]

   RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median values based on Kaplan-Meier Estimates.

2. Recurrence-free Survival (RFS) - All Randomized Participants With PD-L1 Expression Level < 1% [From randomization to Primary Completion Date (up to approximately 3 years)]

   RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates.

Secondary Outcome Measures

1. Overall Survival (OS) - All Randomized Participants [From randomization to date of death (up to approximately 45 months)]

   OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates.

2. Overall Survival (OS) - All Randomized Participants With PD-L1 Expression Level < 1% [From randomization to date of death (up to approximately 45 months)]

   OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates.

3. Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression [From randomization to Study Completion Date (up to approximately 45 months)]

   RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates.

4. Time to Next-Line Therapies - All Randomized Participants [From randomization to start of next therapy or second next therapy (up to approximately 45 months)]

   Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date.

5. Time to Next-Line Therapies - All Randomized Participants With PD-L1 Expression Level < 1% [From randomization to start of next therapy or second next therapy (up to approximately 45 months)]

   Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date

6. Time From Next Therapy to Second Next Therapy - All Randomized Participants [From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months)]

   Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment.

7. Time From Next Therapy to Second Next Therapy - All Randomized Participants With PD-L1 Expression Level < 1% [From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months)]

   Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment.

8. Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants [From randomization to progression event (up to approximately 45 months)]

   PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death.

9. Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants With PD-L1 Expression Level < 1% [From randomization to progression event (up to approximately 45 months)]

   PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Completely surgically resected stage IIIb/c/d or stage IV melanoma within 12 weeks of participation in study.

• Must have full activity or, if limited, must be able to walk and carry out activities such as light house work or office work

• No prior anti-cancer treatment for melanoma (except surgery for the melanoma lesion(s) and/or except for adjuvant radiation therapy (RT) after neurosurgical resection for central nervous system (CNS) lesions)

Exclusion Criteria:

• History of uveal melanoma

• Patients with active, known or suspected autoimmune disease

• Prior treatment with interferon (if complete < 6 months prior to participation in study), anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways

Other protocol defined inclusion/exclusion criteria could apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona Cancer Center	Tucson	Arizona	United States	85724
2	The Angeles Clinic & Research Institute	Los Angeles	California	United States	90025
3	California Pacific Medical Center	San Francisco	California	United States	94115
4	University Of Colorado	Aurora	Colorado	United States	80045
5	Georgetown University Med Ctr	Washington	District of Columbia	United States	20007
6	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida	United States	33140
7	UF Health Cancer Center at Orlando Health	Orlando	Florida	United States	32806
8	H. Lee Moffitt Cancer Center	Tampa	Florida	United States	33612
9	Winship Cancer Institute	Atlanta	Georgia	United States	30322
10	University Of Chicago	Chicago	Illinois	United States	19123
11	Northwestern University	Chicago	Illinois	United States	60611
12	Oncology Specialists, S.C.	Park Ridge	Illinois	United States	60068
13	Mass General Hospital	Boston	Massachusetts	United States	02114
14	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
15	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
16	University Of Michigan Health System	Ann Arbor	Michigan	United States	48109-5848
17	Virginia Piper Cancer Institute	Minneapolis	Minnesota	United States	55407
18	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
19	Washington University School Of Medicine	Saint Louis	Missouri	United States	63110
20	NYU Langone Medical Center	New York	New York	United States	10016
21	Memorial Sloan Kettering Nassau	New York	New York	United States	10065
22	Carolinas Med Ctr	Charlotte	North Carolina	United States	28204
23	Duke University Medical Center	Durham	North Carolina	United States	27710
24	Providence Cancer Center Oncology And Hematology Care	Portland	Oregon	United States	97213
25	Oregon Health & Science University	Portland	Oregon	United States	97239
26	St. Luke's University Health Network	Easton	Pennsylvania	United States	18045
27	Local Institution	Nashville	Tennessee	United States	37232
28	Texas Oncology Sammons Cancer Center	Dallas	Texas	United States	75246
29	Md Anderson Can Cnt	Houston	Texas	United States	77030-4009
30	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
31	University Of Virginia Health System	Charlottesville	Virginia	United States	22908
32	Inova Melanoma and Skin Cancer Center	Fairfax	Virginia	United States	55905
33	University Of Washington Cancer Care Alliance	Seattle	Washington	United States	98109-1023
34	Local Institution	North Sydney	New South Wales	Australia	2060
35	Local Institution	Waratah	New South Wales	Australia	2298
36	Local Institution	Westmead	New South Wales	Australia	2145
37	Local Institution	Greenslopes	Queensland	Australia	4120
38	Local Institution	Southport	Queensland	Australia	4215
39	Local Institution	Woolloongabba	Queensland	Australia	4120
40	Local Institution	Adelaide	South Australia	Australia	5000
41	Local Institution	Box Hill	Victoria	Australia	3128
42	Local Institution	Melbourne	Victoria	Australia	3000
43	Local Institution	Melbourne	Victoria	Australia	3004
44	Local Institution	Nedlands	Western Australia	Australia	6009
45	Local Institution	Subiaco	Western Australia	Australia	6008
46	Local Institution	Graz		Austria	8036
47	Local Institution	Wien		Austria	1090
48	Local Institution	Brussels		Belgium	1090
49	Local Institution	Bruxelles		Belgium	1200
50	Local Institution	Gent		Belgium	B-9000
51	Local Institution	Liege		Belgium	4000
52	Local Institution	Salvador	Bahia	Brazil	41950-610
53	Local Institution	Belo Horizonte	Minas Gerais	Brazil	30130-090
54	Local Institution	Ijui	RIO Grande DO SUL	Brazil	98700-000
55	Local Institution	Porto Alegre	RIO Grande DO SUL	Brazil	90610-000
56	Local Institution	Florianópolis	Santa Catarina	Brazil	88034-000
57	Local Institution	Barretos	Sao Paulo	Brazil	14780-070
58	Local Institution	Sao Jose do Rio Preto	SAO Paulo	Brazil	15090-000
59	Local Institution	Rio De Janeiro		Brazil	20220-410
60	Local Institution	Rio de Janeiro		Brazil	22793-080
61	Local Institution	Sao Paulo		Brazil	01246-000
62	Local Institution	Edmonton	Alberta	Canada	T6G 1Z2
63	Local Institution	Vancouver	British Columbia	Canada	V5Z 4E6
64	Local Institution	Ottawa	Ontario	Canada	K1H 8L6
65	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
66	Local Institution	Montreal	Quebec	Canada	H2L 4M1
67	Local Institution	Montreal	Quebec	Canada	H3T 1E2
68	CHU de Quebec - Universite Laval	Quebec		Canada	G1R 2J6
69	Klinika komplexni onkologicke pece	Brno		Czechia	656 53
70	Klinika onkologie a radioterapie	Hradec Kralove		Czechia	500 05
71	Dermatovenerologicka klinika 3. LF UK a FNKV	Praha 10		Czechia	100 34
72	Dermatovenerologicka klinika VFN a 1. LF UK	Praha 2		Czechia	128 08
73	Centre Hospitalier Universitaire Dijon Bocage	Dijon		France	21079
74	Hopital Claude Huriez	LILLE Cedex		France	59037
75	Hopital De La Timone	Marseille Cedex 5		France	13385
76	Chu Nantes	Nantes		France	44093
77	Hopital Saint Louis	Paris		France	75475
78	Centre Hospitalier Lyon Sud	Pierre Benite Cedex		France	69495
79	Institut Claudius Regaud	Toulouse Cedex 9		France	31059
80	Institut Gustave Roussy	Villejuif		France	94805
81	Local Institution	Berlin		Germany	10117
82	Local Institution	Buxtehude		Germany	21614
83	Local Institution	Essen		Germany	45147
84	Local Institution	Gera		Germany	07548
85	Local Institution	Hannover		Germany	30625
86	Local Institution	Heidelberg		Germany	69120
87	Local Institution	Luebeck		Germany	23538
88	Local Institution	Muenchen		Germany	80337
89	Local Institution	Tuebingen		Germany	72076
90	Laiko Hospital	Athens		Greece	11527
91	Metropolitan Hospital	Athens		Greece	18547
92	Local Institution	Haifa		Israel	3109601
93	Local Institution	Jerusalem		Israel	91120
94	Local Institution	Tel Hashomer		Israel	52621
95	ASST Papa Giovanni XXIII	Bergamo		Italy	24127
96	Ospedale Policlinico San Martino	Genova		Italy	16132
97	IRCCS Istituto Nazionale Tumori Milano	Milano		Italy	20133
98	Istituto Nazionale Tumori Fondazione Pascale	Napoli		Italy	80131
99	Istituto Oncologico Veneto IOV	Padova		Italy	35128
100	Azienda Ospedaliera Universitaria Senese	Siena		Italy	53100
101	Local Institution	Tauranga	BAY OF Plenty	New Zealand	3143
102	Local Institution	Christchurch		New Zealand
103	Local Institution	Dunedin		New Zealand	9001
104	Klinika Nowotworow Ukladowych i Uogolnionych	Krakow		Poland	31-115
105	Klinika Nowotworow Tkanek Miekkich, Kosci i Czerniakow	Warszawa		Poland	02-781
106	Institute Of Oncology "Prof.Dr.Alexandru Trestioreanu" Bucha	Bucharest		Romania	022328
107	Sf. Nectarie Oncology Center	Craiova		Romania	200347
108	Local Institution	Krasnodar		Russian Federation	350040
109	Local Institution	Krasnoyarsk		Russian Federation	660133
110	Local Institution	Moscow		Russian Federation	115478
111	Hospital Universitari Germans Trias I Pujol	Badalona-barcelona		Spain	08916
112	H. Univ. Vall dHebron	Barcelona		Spain	08035
113	Hospital Clinic I Provincial	Barcelona		Spain	08036
114	Hospital Gral. Univ. Gregorio Maranon	Madrid		Spain	28007
115	Hospital Regional Universitario De Malaga	Malaga		Spain	29010
116	Hosp Univ Virgen Macarena	Sevilla		Spain	41009
117	Hospital Universitario Y Politecnico La Fe	Valencia		Spain	46026
118	Local Institution	Lausanne		Switzerland	1011
119	Local Institution	Zuerich		Switzerland	8091
120	Local Institution	Oxford	Oxfordshire	United Kingdom	OX3 7LJ
121	The Beatson West Of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN
122	The Royal Marsden Hospital	London		United Kingdom	SW3 6JJ
123	Christie Hospital Nhs Trust	Manchester		United Kingdom	M20 4BX
124	Royal Marsden Hospital - Surrey	Sutton.		United Kingdom	SM25PT

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Mar 11, 2019
• Statistical Analysis Plan - Aug 23, 2019

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT03068455
• Other Study ID Numbers: CA209-915; 2016-003729-41
• First Posted: Mar 1, 2017
• Last Update Posted: Sep 20, 2021
• Last Verified: Aug 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Melanoma; Nivolumab; Ipilimumab

Study Results

Participant Flow

Pre-assignment Detail	1844 participants randomized and 1833 treated. Reasons not treated: 1 disease progression; 2 participants withdrew consent; 1 poor/non-compliance; 4 participants no longer met study criteria; 3 not reported

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Period Title: Pre-treatment Period
STARTED	920	924
COMPLETED	916	917
NOT COMPLETED	4	7
Period Title: Pre-treatment Period
STARTED	916	917
COMPLETED	364	561
NOT COMPLETED	552	356

Baseline Characteristics

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo	Total
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49	Total of all reporting groups
Overall Participants	920	924	1844
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.8 (14.6)	54.6 (13.7)	54.2 (14.2)
Sex: Female, Male (Count of Participants)
Female	405 44%	387 41.9%	792 43%
Male	515 56%	537 58.1%	1052 57%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	22 2.4%	22 2.4%	44 2.4%
Not Hispanic or Latino	359 39%	376 40.7%	735 39.9%
Unknown or Not Reported	539 58.6%	526 56.9%	1065 57.8%
Race/Ethnicity, Customized (Count of Participants)
White	907 98.6%	911 98.6%	1818 98.6%
Black or African American	4 0.4%	1 0.1%	5 0.3%
American Indian or Alaska Native	0 0%	1 0.1%	1 0.1%
Asian	3 0.3%	5 0.5%	8 0.4%
Other	6 0.7%	6 0.6%	12 0.7%

Outcome Measures

1. Primary Outcome

Title	Recurrence-free Survival (RFS) - All Randomized Participants
Description	RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median values based on Kaplan-Meier Estimates.
Time Frame	From randomization to Primary Completion Date (up to approximately 3 years)

Outcome Measure Data

Analysis Population Description

All randomized participants with completely resected stage IIIb/c/d or stage IV no evidence of disease (NED) melanoma

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	918	922
Median (95% Confidence Interval) [Months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivo + Ipi, Arm B: Nivo
	Comments
	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	0.90
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified Cox proportional hazard model. Hazard Ratio is Nivolumab + Ipilimumab over Nivolumab

2. Primary Outcome

Title	Recurrence-free Survival (RFS) - All Randomized Participants With PD-L1 Expression Level < 1%
Description	RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates.
Time Frame	From randomization to Primary Completion Date (up to approximately 3 years)

Outcome Measure Data

Analysis Population Description

All randomized participants with PD-L1 expression level < 1% and with completely resected stage IIIb/c/d or stage IV no evidence of disease (NED) melanoma. PD-L1 expression levels based on Interactive Response Technology (IRT)

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	347	350
Median (95% Confidence Interval) [Months]	33.15	27.63

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivo + Ipi, Arm B: Nivo
	Comments
	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%; 0.75 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified Cox proportional hazard model. Hazard Ratio is Nivolumab + Ipilimumab over Nivolumab

3. Secondary Outcome

Title	Overall Survival (OS) - All Randomized Participants
Description	OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates.
Time Frame	From randomization to date of death (up to approximately 45 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with completely resected stage IIIb/c/d or stage IV no evidence of disease (NED) melanoma

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	918	922
Median (95% Confidence Interval) [Months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivo + Ipi, Arm B: Nivo
	Comments
	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	1.03
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified Cox proportional hazard model. Hazard Ratio is Nivolumab + Ipilimumab over Nivolumab.

4. Secondary Outcome

Title	Overall Survival (OS) - All Randomized Participants With PD-L1 Expression Level < 1%
Description	OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates.
Time Frame	From randomization to date of death (up to approximately 45 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with PD-L1 expression level < 1% and with completely resected stage IIIb/c/d or stage IV no evidence of disease (NED) melanoma

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	347	350
Median (95% Confidence Interval) [Months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivo + Ipi, Arm B: Nivo
	Comments
	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	1.22
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.73
	Parameter Dispersion	Type: Value:
	Estimation Comments	Stratified Cox proportional hazard model. Hazard Ratio is Nivolumab + Ipilimumab over Nivolumab.

5. Secondary Outcome

Title	Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression
Description	RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates.
Time Frame	From randomization to Study Completion Date (up to approximately 45 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with variable PD-L1 expression levels (see data table for details). PD-L1 expression levels based on clinical database.

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	920	924
< 1% Tumor PD-L1 Expression	33.18	25.33
≥ 1% Tumor PD-L1 Expression	NA	NA
≥ 5% Tumor PD-L1 Expression	NA	NA
< 5% Tumor PD-L1 Expression	NA	NA
Non-quantifiable Tumor PD-L1 Expression	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivo + Ipi, Arm B: Nivo
	Comments
	Type of Statistical Test	Superiority
	Comments	< 1% Tumor PD-L1 Expression
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratisfied HR, Nivolumab over Ipilimumab

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivo + Ipi, Arm B: Nivo
	Comments
	Type of Statistical Test	Superiority
	Comments	>= 1% Tumor PD-L1 Expression
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratisfied HR, Nivolumab over ipilimumab

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivo + Ipi, Arm B: Nivo
	Comments
	Type of Statistical Test	Superiority
	Comments	>= 5% Tumor PD-L1 Expression
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratisfied HR, Nivolumab over ipilimumab

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivo + Ipi, Arm B: Nivo
	Comments
	Type of Statistical Test	Superiority
	Comments	< 5% Tumor PD-L1 Expression
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%; 0.77 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratisfied HR, Nivolumab over ipilimumab

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Arm A: Nivo + Ipi, Arm B: Nivo
	Comments
	Type of Statistical Test	Superiority
	Comments	Non-quantifiable Tumor PD-L1 Expression
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%; 0.38 to 1.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratisfied HR, Nivolumab over ipilimumab

6. Secondary Outcome

Title	Time to Next-Line Therapies - All Randomized Participants
Description	Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date.
Time Frame	From randomization to start of next therapy or second next therapy (up to approximately 45 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	920	924
Time to next therapy	NA	NA
Time to second next therapy	NA	NA

7. Secondary Outcome

Title	Time to Next-Line Therapies - All Randomized Participants With PD-L1 Expression Level < 1%
Description	Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date
Time Frame	From randomization to start of next therapy or second next therapy (up to approximately 45 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with PD-L1 expression level < 1%

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	349	351
Time to next therapy	NA	NA
Time to second next therapy	NA	NA

8. Secondary Outcome

Title	Time From Next Therapy to Second Next Therapy - All Randomized Participants
Description	Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment.
Time Frame	From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months)

Outcome Measure Data

Analysis Population Description

All randomized participants who received first and second next systemic therapy

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	81	81
Median (Full Range) [Months]	4.60	4.80

9. Secondary Outcome

Title	Time From Next Therapy to Second Next Therapy - All Randomized Participants With PD-L1 Expression Level < 1%
Description	Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment.
Time Frame	From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with PD-L1 expression level < 1% who received first and second next therapy

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	35	46
Median (Full Range) [Months]	4.44	5.04

10. Secondary Outcome

Title	Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants
Description	PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death.
Time Frame	From randomization to progression event (up to approximately 45 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	920	924
Median (95% Confidence Interval) [Months]	NA	NA

11. Secondary Outcome

Title	Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants With PD-L1 Expression Level < 1%
Description	PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death.
Time Frame	From randomization to progression event (up to approximately 45 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with PD-L1 expression level < 1%.

Arm/Group Title	Arm A: Nivo + Ipi	Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)	Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
Measure Participants	349	351
Median (95% Confidence Interval) [Months]	NA	NA

Adverse Events

Time Frame	All-cause mortality was assessed from first dose to study completion date (up to approximately 45 months). Serious Adverse Events and Non Serious Adverse Events above 5% were assessed from first dose to 100 days post last dose (up to approximately 15 months)
Arm/Group Title	Arm A: Nivo + Ipi		Arm B: Nivo
Arm/Group Description	Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)		Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
All Cause Mortality
	Arm A: Nivo + Ipi		Arm B: Nivo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	122/916 (13.3%)		121/917 (13.2%)
Serious Adverse Events
	Arm A: Nivo + Ipi		Arm B: Nivo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	374/916 (40.8%)		242/917 (26.4%)
Blood and lymphatic system disorders
Anaemia	2/916 (0.2%)		2/917 (0.2%)
Haemolytic anaemia	1/916 (0.1%)		0/917 (0%)
Lymphadenopathy	0/916 (0%)		3/917 (0.3%)
Lymphadenopathy mediastinal	2/916 (0.2%)		0/917 (0%)
Neutropenia	2/916 (0.2%)		0/917 (0%)
Splenic lesion	0/916 (0%)		1/917 (0.1%)
Thrombocytopenia	2/916 (0.2%)		1/917 (0.1%)
Cardiac disorders
Acute coronary syndrome	1/916 (0.1%)		0/917 (0%)
Acute myocardial infarction	1/916 (0.1%)		1/917 (0.1%)
Atrial fibrillation	4/916 (0.4%)		0/917 (0%)
Atrial flutter	1/916 (0.1%)		1/917 (0.1%)
Cardiac failure	0/916 (0%)		1/917 (0.1%)
Cardio-respiratory distress	1/916 (0.1%)		0/917 (0%)
Cardiomegaly	1/916 (0.1%)		0/917 (0%)
Myocardial infarction	0/916 (0%)		1/917 (0.1%)
Myocarditis	3/916 (0.3%)		0/917 (0%)
Palpitations	1/916 (0.1%)		0/917 (0%)
Pericardial effusion	1/916 (0.1%)		0/917 (0%)
Pericarditis	1/916 (0.1%)		0/917 (0%)
Tachycardia	1/916 (0.1%)		0/917 (0%)
Endocrine disorders
Addison's disease	1/916 (0.1%)		0/917 (0%)
Adrenal insufficiency	10/916 (1.1%)		2/917 (0.2%)
Adrenocortical insufficiency acute	0/916 (0%)		1/917 (0.1%)
Adrenocorticotropic hormone deficiency	0/916 (0%)		1/917 (0.1%)
Goitre	0/916 (0%)		1/917 (0.1%)
Hyperparathyroidism	0/916 (0%)		1/917 (0.1%)
Hyperparathyroidism primary	0/916 (0%)		1/917 (0.1%)
Hyperthyroidism	5/916 (0.5%)		0/917 (0%)
Hypophysitis	24/916 (2.6%)		9/917 (1%)
Hypothyroidism	2/916 (0.2%)		1/917 (0.1%)
Lymphocytic hypophysitis	3/916 (0.3%)		0/917 (0%)
Primary adrenal insufficiency	1/916 (0.1%)		0/917 (0%)
Thyroiditis	2/916 (0.2%)		1/917 (0.1%)
Thyroiditis acute	1/916 (0.1%)		1/917 (0.1%)
Thyrotoxic crisis	1/916 (0.1%)		0/917 (0%)
Eye disorders
Orbital myositis	1/916 (0.1%)		1/917 (0.1%)
Papilloedema	0/916 (0%)		2/917 (0.2%)
Retinal detachment	0/916 (0%)		1/917 (0.1%)
Retinal tear	1/916 (0.1%)		0/917 (0%)
Gastrointestinal disorders
Abdominal pain	1/916 (0.1%)		1/917 (0.1%)
Abdominal pain upper	0/916 (0%)		1/917 (0.1%)
Ascites	0/916 (0%)		1/917 (0.1%)
Autoimmune colitis	8/916 (0.9%)		2/917 (0.2%)
Autoimmune pancreatitis	1/916 (0.1%)		0/917 (0%)
Colitis	29/916 (3.2%)		7/917 (0.8%)
Colitis microscopic	1/916 (0.1%)		0/917 (0%)
Colitis ulcerative	1/916 (0.1%)		0/917 (0%)
Constipation	1/916 (0.1%)		0/917 (0%)
Diarrhoea	18/916 (2%)		7/917 (0.8%)
Duodenitis	1/916 (0.1%)		1/917 (0.1%)
Enteritis	1/916 (0.1%)		1/917 (0.1%)
Enterocolitis	2/916 (0.2%)		0/917 (0%)
Epigastric discomfort	0/916 (0%)		1/917 (0.1%)
Gastric ulcer	2/916 (0.2%)		0/917 (0%)
Gastritis	4/916 (0.4%)		1/917 (0.1%)
Gastrooesophageal reflux disease	0/916 (0%)		1/917 (0.1%)
Ileus	0/916 (0%)		1/917 (0.1%)
Immune-mediated enterocolitis	16/916 (1.7%)		7/917 (0.8%)
Impaired gastric emptying	0/916 (0%)		1/917 (0.1%)
Inguinal hernia	1/916 (0.1%)		0/917 (0%)
Mallory-Weiss syndrome	1/916 (0.1%)		0/917 (0%)
Melaena	0/916 (0%)		1/917 (0.1%)
Nausea	2/916 (0.2%)		0/917 (0%)
Oesophageal obstruction	1/916 (0.1%)		0/917 (0%)
Oesophageal spasm	1/916 (0.1%)		0/917 (0%)
Pancreatic cyst	1/916 (0.1%)		0/917 (0%)
Pancreatitis	2/916 (0.2%)		4/917 (0.4%)
Pneumatosis intestinalis	0/916 (0%)		1/917 (0.1%)
Retroperitoneal fibrosis	1/916 (0.1%)		0/917 (0%)
Small intestinal obstruction	0/916 (0%)		1/917 (0.1%)
Small intestinal perforation	1/916 (0.1%)		0/917 (0%)
Ulcerative gastritis	1/916 (0.1%)		0/917 (0%)
Umbilical hernia	1/916 (0.1%)		0/917 (0%)
Upper gastrointestinal haemorrhage	2/916 (0.2%)		0/917 (0%)
Vomiting	1/916 (0.1%)		0/917 (0%)
General disorders
Asthenia	1/916 (0.1%)		0/917 (0%)
Chills	1/916 (0.1%)		0/917 (0%)
Complication associated with device	0/916 (0%)		1/917 (0.1%)
Fatigue	6/916 (0.7%)		0/917 (0%)
Gait disturbance	0/916 (0%)		1/917 (0.1%)
General physical health deterioration	1/916 (0.1%)		0/917 (0%)
Granuloma	1/916 (0.1%)		0/917 (0%)
Lithiasis	0/916 (0%)		1/917 (0.1%)
Malaise	1/916 (0.1%)		0/917 (0%)
Mass	1/916 (0.1%)		0/917 (0%)
Nodule	0/916 (0%)		1/917 (0.1%)
Non-cardiac chest pain	1/916 (0.1%)		0/917 (0%)
Polyserositis	0/916 (0%)		1/917 (0.1%)
Pyrexia	12/916 (1.3%)		5/917 (0.5%)
Hepatobiliary disorders
Autoimmune hepatitis	14/916 (1.5%)		1/917 (0.1%)
Cholangitis sclerosing	1/916 (0.1%)		0/917 (0%)
Cholecystitis	2/916 (0.2%)		0/917 (0%)
Cholelithiasis	1/916 (0.1%)		0/917 (0%)
Hepatic function abnormal	0/916 (0%)		1/917 (0.1%)
Hepatitis	6/916 (0.7%)		4/917 (0.4%)
Hepatotoxicity	4/916 (0.4%)		0/917 (0%)
Hypertransaminasaemia	0/916 (0%)		1/917 (0.1%)
Immune-mediated hepatitis	6/916 (0.7%)		0/917 (0%)
Liver disorder	2/916 (0.2%)		1/917 (0.1%)
Nodular regenerative hyperplasia	1/916 (0.1%)		0/917 (0%)
Venoocclusive liver disease	1/916 (0.1%)		0/917 (0%)
Immune system disorders
Autoimmune disorder	0/916 (0%)		1/917 (0.1%)
Drug hypersensitivity	1/916 (0.1%)		0/917 (0%)
Sarcoidosis	7/916 (0.8%)		1/917 (0.1%)
Infections and infestations
Adrenalitis	1/916 (0.1%)		2/917 (0.2%)
Arthritis bacterial	0/916 (0%)		1/917 (0.1%)
Atypical pneumonia	3/916 (0.3%)		0/917 (0%)
Bacterial infection	1/916 (0.1%)		0/917 (0%)
Bronchiolitis	0/916 (0%)		1/917 (0.1%)
Bronchitis	2/916 (0.2%)		2/917 (0.2%)
Bronchitis viral	1/916 (0.1%)		0/917 (0%)
Bursitis infective	2/916 (0.2%)		0/917 (0%)
Campylobacter colitis	1/916 (0.1%)		1/917 (0.1%)
Cellulitis	4/916 (0.4%)		5/917 (0.5%)
Chronic sinusitis	0/916 (0%)		1/917 (0.1%)
Clostridium difficile colitis	1/916 (0.1%)		0/917 (0%)
Cystitis	1/916 (0.1%)		0/917 (0%)
Cytomegalovirus infection reactivation	0/916 (0%)		1/917 (0.1%)
Dengue fever	0/916 (0%)		1/917 (0.1%)
Device related infection	1/916 (0.1%)		0/917 (0%)
Diarrhoea infectious	1/916 (0.1%)		0/917 (0%)
Encephalitis	4/916 (0.4%)		2/917 (0.2%)
Endocarditis enterococcal	1/916 (0.1%)		0/917 (0%)
Enterovirus infection	1/916 (0.1%)		0/917 (0%)
Erysipelas	5/916 (0.5%)		3/917 (0.3%)
Fournier's gangrene	1/916 (0.1%)		0/917 (0%)
Gastroenteritis	2/916 (0.2%)		1/917 (0.1%)
Gastrointestinal infection	0/916 (0%)		1/917 (0.1%)
Groin abscess	1/916 (0.1%)		0/917 (0%)
Haematoma infection	0/916 (0%)		1/917 (0.1%)
Herpes oesophagitis	1/916 (0.1%)		0/917 (0%)
Infected bite	1/916 (0.1%)		0/917 (0%)
Infection	1/916 (0.1%)		0/917 (0%)
Localised infection	0/916 (0%)		1/917 (0.1%)
Lower respiratory tract infection	3/916 (0.3%)		1/917 (0.1%)
Meningitis	2/916 (0.2%)		0/917 (0%)
Meningitis aseptic	2/916 (0.2%)		0/917 (0%)
Myelitis	1/916 (0.1%)		0/917 (0%)
Pharyngitis	0/916 (0%)		1/917 (0.1%)
Picornavirus infection	0/916 (0%)		1/917 (0.1%)
Pneumonia	11/916 (1.2%)		2/917 (0.2%)
Pneumonia klebsiella	1/916 (0.1%)		0/917 (0%)
Postoperative wound infection	1/916 (0.1%)		0/917 (0%)
Respiratory tract infection	1/916 (0.1%)		1/917 (0.1%)
Sepsis	3/916 (0.3%)		0/917 (0%)
Septic shock	2/916 (0.2%)		1/917 (0.1%)
Sinusitis	1/916 (0.1%)		1/917 (0.1%)
Skin infection	1/916 (0.1%)		0/917 (0%)
Subcutaneous abscess	0/916 (0%)		2/917 (0.2%)
Tonsillitis	1/916 (0.1%)		0/917 (0%)
Tracheitis	1/916 (0.1%)		0/917 (0%)
Urinary tract infection	2/916 (0.2%)		1/917 (0.1%)
Urosepsis	3/916 (0.3%)		0/917 (0%)
Varicella zoster virus infection	0/916 (0%)		1/917 (0.1%)
Vascular device infection	1/916 (0.1%)		1/917 (0.1%)
Vestibular neuronitis	0/916 (0%)		1/917 (0.1%)
Viral infection	1/916 (0.1%)		0/917 (0%)
Wound infection	0/916 (0%)		1/917 (0.1%)
Injury, poisoning and procedural complications
Clavicle fracture	1/916 (0.1%)		0/917 (0%)
Facial bones fracture	0/916 (0%)		1/917 (0.1%)
Fall	0/916 (0%)		1/917 (0.1%)
Fracture	1/916 (0.1%)		0/917 (0%)
Graft complication	1/916 (0.1%)		0/917 (0%)
Head injury	1/916 (0.1%)		0/917 (0%)
Infusion related reaction	2/916 (0.2%)		3/917 (0.3%)
Joint dislocation	1/916 (0.1%)		0/917 (0%)
Joint injury	1/916 (0.1%)		0/917 (0%)
Lower limb fracture	0/916 (0%)		1/917 (0.1%)
Meniscus injury	0/916 (0%)		1/917 (0.1%)
Overdose	0/916 (0%)		1/917 (0.1%)
Patella fracture	1/916 (0.1%)		0/917 (0%)
Post lumbar puncture syndrome	0/916 (0%)		1/917 (0.1%)
Post procedural haematoma	0/916 (0%)		1/917 (0.1%)
Procedural pneumothorax	0/916 (0%)		1/917 (0.1%)
Road traffic accident	1/916 (0.1%)		0/917 (0%)
Skin laceration	0/916 (0%)		1/917 (0.1%)
Spinal fracture	1/916 (0.1%)		0/917 (0%)
Subdural haematoma	1/916 (0.1%)		0/917 (0%)
Tendon rupture	1/916 (0.1%)		0/917 (0%)
Traumatic liver injury	1/916 (0.1%)		0/917 (0%)
Wound complication	0/916 (0%)		2/917 (0.2%)
Wound dehiscence	0/916 (0%)		1/917 (0.1%)
Investigations
Alanine aminotransferase increased	2/916 (0.2%)		0/917 (0%)
Amylase increased	1/916 (0.1%)		0/917 (0%)
Blood creatine phosphokinase increased	1/916 (0.1%)		0/917 (0%)
Blood creatinine increased	1/916 (0.1%)		0/917 (0%)
Electrocardiogram abnormal	1/916 (0.1%)		0/917 (0%)
General physical condition abnormal	1/916 (0.1%)		1/917 (0.1%)
Hepatic enzyme increased	1/916 (0.1%)		0/917 (0%)
Lipase increased	1/916 (0.1%)		0/917 (0%)
Transaminases increased	2/916 (0.2%)		1/917 (0.1%)
Troponin I increased	1/916 (0.1%)		0/917 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/916 (0.1%)		0/917 (0%)
Dehydration	1/916 (0.1%)		1/917 (0.1%)
Diabetes mellitus	1/916 (0.1%)		2/917 (0.2%)
Diabetes mellitus inadequate control	1/916 (0.1%)		0/917 (0%)
Diabetic ketoacidosis	1/916 (0.1%)		1/917 (0.1%)
Diabetic metabolic decompensation	1/916 (0.1%)		0/917 (0%)
Fulminant type 1 diabetes mellitus	0/916 (0%)		1/917 (0.1%)
Hyperglycaemia	4/916 (0.4%)		4/917 (0.4%)
Hypoglycaemia	1/916 (0.1%)		0/917 (0%)
Hypokalaemia	2/916 (0.2%)		0/917 (0%)
Hyponatraemia	1/916 (0.1%)		2/917 (0.2%)
Steroid diabetes	4/916 (0.4%)		0/917 (0%)
Type 1 diabetes mellitus	2/916 (0.2%)		2/917 (0.2%)
Type 2 diabetes mellitus	1/916 (0.1%)		0/917 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/916 (0.1%)		2/917 (0.2%)
Arthritis	1/916 (0.1%)		1/917 (0.1%)
Back pain	0/916 (0%)		1/917 (0.1%)
Muscular weakness	1/916 (0.1%)		0/917 (0%)
Musculoskeletal chest pain	1/916 (0.1%)		0/917 (0%)
Musculoskeletal pain	1/916 (0.1%)		0/917 (0%)
Myopathy	0/916 (0%)		1/917 (0.1%)
Myositis	2/916 (0.2%)		2/917 (0.2%)
Myositis-like syndrome	1/916 (0.1%)		0/917 (0%)
Osteoarthritis	1/916 (0.1%)		2/917 (0.2%)
Polyarthritis	0/916 (0%)		1/917 (0.1%)
Polymyalgia rheumatica	2/916 (0.2%)		0/917 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	0/916 (0%)		1/917 (0.1%)
Basal cell carcinoma	14/916 (1.5%)		23/917 (2.5%)
Bowen's disease	3/916 (0.3%)		1/917 (0.1%)
Malignant melanoma	3/916 (0.3%)		7/917 (0.8%)
Malignant melanoma in situ	1/916 (0.1%)		0/917 (0%)
Malignant neoplasm progression	15/916 (1.6%)		10/917 (1.1%)
Marginal zone lymphoma	1/916 (0.1%)		0/917 (0%)
Melanoma recurrent	6/916 (0.7%)		1/917 (0.1%)
Metastases to breast	0/916 (0%)		1/917 (0.1%)
Metastases to central nervous system	0/916 (0%)		1/917 (0.1%)
Metastases to liver	0/916 (0%)		1/917 (0.1%)
Metastases to lymph nodes	4/916 (0.4%)		1/917 (0.1%)
Metastases to meninges	1/916 (0.1%)		0/917 (0%)
Metastasis	4/916 (0.4%)		1/917 (0.1%)
Metastatic malignant melanoma	3/916 (0.3%)		2/917 (0.2%)
Neoplasm malignant	2/916 (0.2%)		0/917 (0%)
Neoplasm progression	0/916 (0%)		1/917 (0.1%)
Oesophageal carcinoma	1/916 (0.1%)		0/917 (0%)
Oesophageal squamous cell carcinoma	0/916 (0%)		1/917 (0.1%)
Oncocytoma	0/916 (0%)		1/917 (0.1%)
Papilloma	0/916 (0%)		1/917 (0.1%)
Plasma cell myeloma	0/916 (0%)		1/917 (0.1%)
Plasmacytoma	0/916 (0%)		1/917 (0.1%)
Prostate cancer	1/916 (0.1%)		3/917 (0.3%)
Recurrent cancer	1/916 (0.1%)		0/917 (0%)
Schwannoma	0/916 (0%)		1/917 (0.1%)
Skin cancer	1/916 (0.1%)		0/917 (0%)
Squamous cell carcinoma	8/916 (0.9%)		12/917 (1.3%)
Squamous cell carcinoma of skin	2/916 (0.2%)		2/917 (0.2%)
Transitional cell carcinoma	1/916 (0.1%)		0/917 (0%)
Tumour haemorrhage	0/916 (0%)		1/917 (0.1%)
Uterine leiomyoma	0/916 (0%)		1/917 (0.1%)
Nervous system disorders
Acute disseminated encephalomyelitis	1/916 (0.1%)		0/917 (0%)
Amnesia	1/916 (0.1%)		0/917 (0%)
Autoimmune neuropathy	1/916 (0.1%)		0/917 (0%)
Carotid artery dissection	1/916 (0.1%)		0/917 (0%)
Cerebral infarction	0/916 (0%)		1/917 (0.1%)
Cerebrovascular accident	0/916 (0%)		1/917 (0.1%)
Encephalitis autoimmune	1/916 (0.1%)		0/917 (0%)
Encephalopathy	2/916 (0.2%)		0/917 (0%)
Epilepsy	0/916 (0%)		1/917 (0.1%)
Facial paresis	1/916 (0.1%)		0/917 (0%)
Guillain-Barre syndrome	0/916 (0%)		1/917 (0.1%)
Haemorrhage intracranial	0/916 (0%)		1/917 (0.1%)
Headache	2/916 (0.2%)		4/917 (0.4%)
Hypertensive encephalopathy	1/916 (0.1%)		0/917 (0%)
Intracranial aneurysm	0/916 (0%)		1/917 (0.1%)
Intracranial pressure increased	1/916 (0.1%)		0/917 (0%)
Meningism	0/916 (0%)		1/917 (0.1%)
Miller Fisher syndrome	1/916 (0.1%)		0/917 (0%)
Monoparesis	1/916 (0.1%)		0/917 (0%)
Myasthenia gravis	2/916 (0.2%)		0/917 (0%)
Myasthenic syndrome	0/916 (0%)		1/917 (0.1%)
Myelitis transverse	1/916 (0.1%)		0/917 (0%)
Neuropathy peripheral	0/916 (0%)		1/917 (0.1%)
Optic neuritis	1/916 (0.1%)		0/917 (0%)
Paraesthesia	0/916 (0%)		1/917 (0.1%)
Peripheral motor neuropathy	0/916 (0%)		1/917 (0.1%)
Peripheral sensory neuropathy	1/916 (0.1%)		0/917 (0%)
Polyneuropathy	1/916 (0.1%)		0/917 (0%)
Radiculopathy	1/916 (0.1%)		0/917 (0%)
Seizure	1/916 (0.1%)		0/917 (0%)
Spinal cord compression	0/916 (0%)		1/917 (0.1%)
Syncope	2/916 (0.2%)		0/917 (0%)
Transient ischaemic attack	2/916 (0.2%)		0/917 (0%)
Psychiatric disorders
Anxiety	0/916 (0%)		1/917 (0.1%)
Completed suicide	1/916 (0.1%)		0/917 (0%)
Delirium	1/916 (0.1%)		0/917 (0%)
Depression	2/916 (0.2%)		3/917 (0.3%)
Mania	1/916 (0.1%)		0/917 (0%)
Mental disorder	1/916 (0.1%)		0/917 (0%)
Renal and urinary disorders
Acute kidney injury	4/916 (0.4%)		4/917 (0.4%)
Autoimmune nephritis	0/916 (0%)		2/917 (0.2%)
Calculus bladder	0/916 (0%)		1/917 (0.1%)
Calculus urinary	0/916 (0%)		1/917 (0.1%)
Haematuria	0/916 (0%)		1/917 (0.1%)
Nephritis	1/916 (0.1%)		3/917 (0.3%)
Nephrolithiasis	2/916 (0.2%)		0/917 (0%)
Renal colic	0/916 (0%)		1/917 (0.1%)
Renal failure	2/916 (0.2%)		0/917 (0%)
Renal impairment	0/916 (0%)		1/917 (0.1%)
Tubulointerstitial nephritis	0/916 (0%)		1/917 (0.1%)
Ureterolithiasis	1/916 (0.1%)		1/917 (0.1%)
Urinary retention	1/916 (0.1%)		0/917 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/916 (0%)		1/917 (0.1%)
Prostatitis	1/916 (0.1%)		0/917 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/916 (0.1%)		0/917 (0%)
Asthma	0/916 (0%)		1/917 (0.1%)
Bronchitis chronic	1/916 (0.1%)		0/917 (0%)
Cough	1/916 (0.1%)		0/917 (0%)
Diaphragmatic spasm	0/916 (0%)		1/917 (0.1%)
Dyspnoea	2/916 (0.2%)		0/917 (0%)
Epistaxis	0/916 (0%)		1/917 (0.1%)
Immune-mediated pneumonitis	4/916 (0.4%)		0/917 (0%)
Interstitial lung disease	0/916 (0%)		1/917 (0.1%)
Laryngeal oedema	1/916 (0.1%)		0/917 (0%)
Lung disorder	1/916 (0.1%)		0/917 (0%)
Organising pneumonia	0/916 (0%)		1/917 (0.1%)
Pleural effusion	2/916 (0.2%)		0/917 (0%)
Pneumonitis	9/916 (1%)		3/917 (0.3%)
Pulmonary embolism	4/916 (0.4%)		0/917 (0%)
Pulmonary mass	1/916 (0.1%)		0/917 (0%)
Pulmonary sarcoidosis	1/916 (0.1%)		0/917 (0%)
Respiratory disorder	0/916 (0%)		1/917 (0.1%)
Respiratory failure	0/916 (0%)		1/917 (0.1%)
Skin and subcutaneous tissue disorders
Angioedema	0/916 (0%)		1/917 (0.1%)
Dermatitis allergic	0/916 (0%)		1/917 (0.1%)
Drug eruption	1/916 (0.1%)		1/917 (0.1%)
Drug reaction with eosinophilia and systemic symptoms	1/916 (0.1%)		0/917 (0%)
Pemphigoid	0/916 (0%)		2/917 (0.2%)
Psoriasis	0/916 (0%)		1/917 (0.1%)
Rash	3/916 (0.3%)		2/917 (0.2%)
Rash maculo-papular	1/916 (0.1%)		1/917 (0.1%)
Subcutaneous emphysema	0/916 (0%)		1/917 (0.1%)
Toxic skin eruption	2/916 (0.2%)		1/917 (0.1%)
Vascular disorders
Capillary leak syndrome	1/916 (0.1%)		0/917 (0%)
Deep vein thrombosis	2/916 (0.2%)		1/917 (0.1%)
Hypertension	2/916 (0.2%)		1/917 (0.1%)
Lymphoedema	0/916 (0%)		1/917 (0.1%)
Orthostatic hypotension	1/916 (0.1%)		0/917 (0%)
Shock	0/916 (0%)		1/917 (0.1%)
Other (Not Including Serious) Adverse Events
	Arm A: Nivo + Ipi		Arm B: Nivo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	868/916 (94.8%)		844/917 (92%)
Endocrine disorders
Adrenal insufficiency	56/916 (6.1%)		7/917 (0.8%)
Hyperthyroidism	180/916 (19.7%)		98/917 (10.7%)
Hypophysitis	92/916 (10%)		11/917 (1.2%)
Hypothyroidism	219/916 (23.9%)		139/917 (15.2%)
Gastrointestinal disorders
Abdominal pain	102/916 (11.1%)		84/917 (9.2%)
Abdominal pain upper	57/916 (6.2%)		37/917 (4%)
Constipation	108/916 (11.8%)		89/917 (9.7%)
Diarrhoea	338/916 (36.9%)		304/917 (33.2%)
Dry mouth	99/916 (10.8%)		90/917 (9.8%)
Nausea	218/916 (23.8%)		187/917 (20.4%)
Vomiting	100/916 (10.9%)		77/917 (8.4%)
General disorders
Asthenia	165/916 (18%)		147/917 (16%)
Fatigue	348/916 (38%)		338/917 (36.9%)
Influenza like illness	58/916 (6.3%)		47/917 (5.1%)
Pyrexia	118/916 (12.9%)		84/917 (9.2%)
Infections and infestations
Nasopharyngitis	109/916 (11.9%)		101/917 (11%)
Upper respiratory tract infection	69/916 (7.5%)		86/917 (9.4%)
Injury, poisoning and procedural complications
Infusion related reaction	56/916 (6.1%)		46/917 (5%)
Investigations
Alanine aminotransferase increased	134/916 (14.6%)		86/917 (9.4%)
Amylase increased	85/916 (9.3%)		37/917 (4%)
Aspartate aminotransferase increased	110/916 (12%)		70/917 (7.6%)
Blood creatine phosphokinase increased	56/916 (6.1%)		50/917 (5.5%)
Lipase increased	120/916 (13.1%)		58/917 (6.3%)
Metabolism and nutrition disorders
Decreased appetite	106/916 (11.6%)		63/917 (6.9%)
Hyperglycaemia	51/916 (5.6%)		49/917 (5.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	168/916 (18.3%)		213/917 (23.2%)
Back pain	94/916 (10.3%)		96/917 (10.5%)
Myalgia	99/916 (10.8%)		81/917 (8.8%)
Pain in extremity	47/916 (5.1%)		52/917 (5.7%)
Nervous system disorders
Dizziness	67/916 (7.3%)		64/917 (7%)
Headache	270/916 (29.5%)		214/917 (23.3%)
Psychiatric disorders
Anxiety	32/916 (3.5%)		47/917 (5.1%)
Insomnia	88/916 (9.6%)		75/917 (8.2%)
Respiratory, thoracic and mediastinal disorders
Cough	162/916 (17.7%)		168/917 (18.3%)
Dyspnoea	73/916 (8%)		74/917 (8.1%)
Oropharyngeal pain	52/916 (5.7%)		43/917 (4.7%)
Skin and subcutaneous tissue disorders
Pruritus	339/916 (37%)		238/917 (26%)
Rash	258/916 (28.2%)		234/917 (25.5%)
Vitiligo	49/916 (5.3%)		56/917 (6.1%)
Vascular disorders
Hypertension	42/916 (4.6%)		47/917 (5.1%)

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.