Phase 3 Study of Nivolumab or Nivolumab Plus Ipilimumab Versus Ipilimumab Alone in Previously Untreated Advanced Melanoma (CheckMate 067)

• ClinicalTrials.gov Identifier: NCT01844505
• Recruitment Status: Active, not recruiting
• First Posted: May 1, 2013
• Results First Posted: September 26, 2017
• Last Update Posted: January 10, 2024
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Unresectable or Metastatic Melanoma
• Interventions: Biological: Nivolumab; Biological: Ipilimumab; Biological: Placebo for Nivolumab; Biological: Placebo for Ipilimumab
• Enrollment: 1296

Participant Flow

Recruitment Details
Pre-assignment Details	1296 participants were enrolled; 945 were randomized to a treatment group; 937 received at least one dose of study drug.

Arm/Group Title	Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description	Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Period Title: Overall Study
Started	313	313	311
Completed	64 [1]	44 [1]	16 [1]
Not Completed	249	269	295
Reason Not Completed
Disease progression	170	88	224
Study drug toxicity	40	131	50
Death	1	3	1
Adverse event unrelated to study drug	7	15	6
Subject request discontinue treatment	17	14	8
Withdrawal by Subject	0	3	0
Lost to Follow-up	1	0	0
Maximum clinical benefit	8	11	2
Poor/non-compliance	1	1	1
Subject no longer meets criteria	0	1	0
Other Reasons	4	2	2
Not Reported	0	0	1
[1] Completed = Number of subjects continuing in the treatment period

Baseline Characteristics

Arm/Group Title		Nivolumab	Nivolumab + Ipilimumab	Ipilimumab	Total
Arm/Group Description		Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses	Total of all reporting groups
Overall Number of Baseline Participants		316	314	315	945
Baseline Analysis Population Description		All randomized participants
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	316 participants	314 participants	315 participants	945 participants
		58.7 (13.92)	59.3 (13.86)	60.8 (13.23)	59.6 (13.69)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	316 participants	314 participants	315 participants	945 participants
< 65 years		198 62.7%	185 58.9%	182 57.8%	565 59.8%
>= 65 and < 75 years		79 25.0%	94 29.9%	89 28.3%	262 27.7%
>=75 years		39 12.3%	35 11.1%	44 14.0%	118 12.5%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	316 participants	314 participants	315 participants	945 participants
	Female	114 36.1%	108 34.4%	113 35.9%	335 35.4%
	Male	202 63.9%	206 65.6%	202 64.1%	610 64.6%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	316 participants	314 participants	315 participants	945 participants
WHITE		308 97.5%	310 98.7%	303 96.2%	921 97.5%
BLACK OR AFRICAN AMERICAN		0 0.0%	0 0.0%	0 0.0%	0 0.0%
ASIAN		2 0.6%	2 0.6%	6 1.9%	10 1.1%
AMERICAN INDIAN OR ALASKA NATIVE		1 0.3%	0 0.0%	0 0.0%	1 0.1%
NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER		1 0.3%	0 0.0%	0 0.0%	1 0.1%
OTHER		4 1.3%	2 0.6%	5 1.6%	11 1.2%
NOT REPORTED		0 0.0%	0 0.0%	1 0.3%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the Investigator, or death due to any cause, whichever occurred first. Progression is defined, using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm. Participants who died without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. Participants who started anti-cancer therapy without prior reported progression were censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy.
Time Frame	From randomization until disease progression or death, whichever occurred first (assessed up to February 2015, approximately 20 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:	Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed	316	314	315
Median (95% Confidence Interval); Unit of Measure: months
	6.87; (4.34 to 9.46)	11.50; (8.90 to 16.72)	2.89; (2.79 to 3.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log Rank test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 99.5%; 0.43 to 0.76
	Estimation Comments	Stratified Cox proportional hazard model. Ratio of Nivolumab over Ipilimumab.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log Rank test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 99.5%; 0.31 to 0.57
	Estimation Comments	Stratified Cox proportional hazard model. Ratio of Nivolumab+Ipilimumab over Ipilimumab.

2. Primary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive.
Time Frame	From randomization to date of death (Assessed up to September 2016, approximately 39 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:	Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed	316	314	315
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (29.08 to NA)	NA [1]; (NA to NA)	19.98; (17.08 to 24.61)

[1]

Median OS was not reached

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Log-rank Test stratified by PD-L1 status, BRAF status, and M stage at screening as entered into the Interactive Voice Response System (IVRS).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 98%; 0.50 to 0.78
	Estimation Comments	Stratified Cox proportional hazard model. Ratio of Nivolumab over Ipilimumab.
Other Statistical Analysis		Median survival for the nivolumab arm was not estimable because the lower confidence limits for the survivor function are above 0.50. The p-value is calculated from a stratified log rank statistic which compares the survival distributions between the two treatment arms.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Log-rank Test stratified by PD-L1 status, BRAF status, and M stage at screening as entered into the IVRS.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 98%; 0.42 to 0.72
	Estimation Comments	Stratified Cox proportional hazard model. Ratio of Nivolumab+Ipilimumab over Ipilimumab.
Other Statistical Analysis		Median survival for the nivolumab arm was not estimable because the lower confidence limits for the survivor function are above 0.50. The p-value is calculated from a stratified log rank statistic which compares the survival distributions between the two treatment arms.

3. Primary Outcome

Title	Rate of Overall Survival
Description	OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive. The overall survival rate at time T (6, 12, or 24 months) was defined as the probability that a participant was alive at time T following randomization.
Time Frame	6, 12, and 24 months

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:	Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed	316	314	315
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Probability of survival at Time T
Rate of OS at 6 months	0.85; (0.81 to 0.89)	0.86; (0.81 to 0.89)	0.82; (0.78 to 0.86)
Rate of OS at 12 months	0.74; (0.69 to 0.79)	0.73; (0.68 to 0.78)	0.67; (0.61 to 0.72)
Rate of OS at 24 months	0.59; (0.53 to 0.64)	0.64; (0.59 to 0.69)	0.45; (0.39 to 0.50)

4. Primary Outcome

Title	Rate of Progression-Free Survival
Description	PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the Investigator, or death due to any cause, whichever occurred first. Participants who died without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. Participants treated beyond progression were considered to have progressive disease at the time of the initial progression event regardless of subsequent tumor response. Participants who started anti-cancer therapy without a prior reported progression were censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy.
Time Frame	6, 12, and 24 months

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:	Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed	316	314	315
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
Rate at 6 months	0.52; (0.46 to 0.58)	0.63; (0.57 to 0.68)	0.28; (0.23 to 0.33)
Rate at 12 months	0.43; (0.37 to 0.49)	0.50; (0.44 to 0.55)	0.18; (0.14 to 0.22)
Rate at 24 months	0.37; (0.31 to 0.43)	0.43; (0.37 to 0.48)	0.12; (0.09 to 0.17)

5. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS data is presented as it was in Primary Outcome Measure #1. The statistical analysis following this outcome measure (#5) reports on a secondary objective comparing PFS between the Nivolumab and Nivolumab + Ipilimumab arms.
Time Frame	From randomization until disease progression or death, whichever occurred first (assessed up to February 2015, approximately 20 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:	Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed	316	314	315
Median (95% Confidence Interval); Unit of Measure: months
	6.87; (4.34 to 9.46)	11.50; (8.90 to 16.72)	2.89; (2.79 to 3.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.60 to 0.92
	Estimation Comments	Stratified Cox proportional hazard model. Hazard Ratio is Nivolumab + Ipilimumab over Nivolumab.

6. Secondary Outcome

Title	Overall Survival (OS)
Description	OS data is presented as it was in Primary Outcome Measure #2. The statistical analysis following this outcome measure (#6) reports on a secondary objective comparing OS between the Nivolumab and Nivolumab + Ipilimumab arms.
Time Frame	From randomization to date of death (Assessed up to September 2016, approximately 39 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:	Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed	316	314	315
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (29.08 to NA)	NA [2]; (NA to NA)	19.98; (17.08 to 24.61)

[1]

Median OS and Upper 95% CI were not reached

[2]

Median OS was not reached

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.12
	Estimation Comments	Stratified Cox proportional hazard model. Hazard Ratio is Nivolumab + Ipilimumab over Nivolumab.
Other Statistical Analysis		Median survival for the nivolumab arm was not estimable because the lower confidence limits for the survivor function are above 0.50. The p-value is calculated from a stratified log rank statistic which compares the survival distributions between the two treatment arms.

7. Secondary Outcome

Title	Objective Response Rate (ORR) Per Investigator Assessment
Description	The ORR was defined as the number of participants with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each arm. The BOR was defined as the best response designation, as determined by the Investigator, recorded between the date of randomization and the date of progression, as assessed by the Investigator per RECIST 1.1 or the date of subsequent anticancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurred first. For participants without evidence of RECIST 1.1 progression or subsequent anticancer therapy, all available response designations contributed to the BOR assessment. CR= Disappearance of all evidence of disease, confirmed by PET scan; PR= Regression of measureable disease and no new sites; Stable Disease (SD)= Failure to attain CR/PR or PD; Progressive Disease (PD)= Any new lesion or increase by >=50% of previously involved sites from nadir.
Time Frame	From randomization until date of disease progression or the date of subsequent anti-cancer therapy, whichever occurs first (Assessed up to February 2015, approximately 20 months)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:	Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed	316	314	315
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	43.7; (38.1 to 49.3)	57.6; (52.0 to 63.2)	19.0; (14.9 to 23.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.40
	Confidence Interval	(2-Sided) 99.5%; 2.02 to 5.72
	Estimation Comments	Cochran-Mantel-Haenszel Test Stratified by PD-L1 Status, BRAF Status and M stage at screening as entered into the IVRS. Ratio of Nivolumab over Ipilimumab.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	6.11
	Confidence Interval	(2-Sided) 99.5%; 3.59 to 10.38
	Estimation Comments	Cochran-Mantel-Haenszel Test Stratified by PD-L1 Status, BRAF Status and M stage at screening as entered into the IVRS. Ratio of Nivolumab + Ipilimumab over Ipilimumab.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference of Objective Response Rates
	Estimated Value	24.7
	Confidence Interval	(2-Sided) 95%; 17.9 to 31.5
	Estimation Comments	Difference in ORR and corresponding 95% CI is based on Cochran-Mantel-Haenszel (CMH) method of weighting, adjusting for PD-L1 Status, BRAF Mutation Status and M-stage at screening as entered into the IVRS. Difference of Nivolumab - Ipilimumab.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference of Objective Response Rates
	Estimated Value	38.4
	Confidence Interval	(2-Sided) 95%; 31.5 to 45.2
	Estimation Comments	Difference in ORR and corresponding 95% CI is based on CMH method of weighting, adjusting for PD-L1 Status, BRAF Mutation Status and M-stage at screening as entered into the IVRS. Difference of Nivolumab and Ipilimumab - Ipilimumab.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.80
	Confidence Interval	(2-Sided) 95%; 1.30 to 2.49
	Estimation Comments	Cochran-Mantel-Haenszel Test Stratified by PD-L1 Status, BRAF Status and M stage at screening as entered into the IVRS. Ratio of Nivolumab + Ipilimumab over Nivolumab

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference of Objective Response Rates
	Estimated Value	13.8
	Confidence Interval	(2-Sided) 95%; 6.3 to 21.3
	Estimation Comments	Difference in ORR and corresponding 95% CI is based on CMH method of weighting, adjusting for PD-L1 Status, BRAF Mutation Status and M-stage at screening as entered into the IVRS. Difference of Nivolumab and Ipilimumab - Nivolumab.

8. Secondary Outcome

Title	Progression-Free Survival Based on PD-L1 Expression Level
Description	PD-L1 expression was defined as the percent of tumor cells demonstrating plasma membrane PD-L1 staining of any intensity using an IHC assay. Tumor biopsy specimens without measurable PD-L1 expression were classified as indeterminate if the staining was hampered for reasons attributed to the biology of the specimen and not because of improper specimen preparation or handling. Missing specimens, specimens that were not optimally collected (ie not evaluable), and all other specimens were classified as unknown. Participants must have been classified as PD-L1 >=5% or PD-L1 <5% per a verified IHC assay, or as indeterminate (ie not unknown), in order to be randomized.
Time Frame	From randomization until disease progression or death from any cause, whichever occurs first (Assessed up to September 2016, approximately 39 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable PD-L1 expression level at baseline

Arm/Group Title		Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:		Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed		316	314	315
Median (95% Confidence Interval); Unit of Measure: months
PD-L1 < 1%	Number Analyzed	117 participants	123 participants	113 participants
		2.83; (2.76 to 5.39)	11.17; (6.93 to 26.68)	2.76; (2.66 to 2.86)
PD-L1 >= 1%	Number Analyzed	171 participants	155 participants	164 participants
		16.20; (8.11 to 27.66)	16.72 [1]; (9.72 to NA)	3.48; (2.83 to 4.17)
PD-L1 < 5%	Number Analyzed	208 participants	210 participants	202 participants
		5.32; (2.96 to 6.87)	11.17; (8.31 to 22.18)	2.83; (2.76 to 3.02)
PD-L1 >= 5%	Number Analyzed	80 participants	68 participants	75 participants
		22.34 [1]; (9.46 to NA)	22.11 [1]; (9.72 to NA)	3.94; (2.79 to 4.21)
PD-L1 < 10%	Number Analyzed	229 participants	232 participants	223 participants
		5.62; (3.09 to 8.87)	11.10; (8.02 to 18.14)	2.83; (2.76 to 3.02)
PD-L1 >= 10%	Number Analyzed	59 participants	46 participants	54 participants
		21.98 [1]; (9.07 to NA)	NA [2]; (13.96 to NA)	4.11; (2.79 to 5.59)
PD-L1 Indeterminate/ Not Evaluable	Number Analyzed	28 participants	36 participants	38 participants
		2.99; (2.66 to 6.93)	6.93; (2.79 to 20.04)	2.83; (2.60 to 6.41)

[1]

Upper 95% Confidence Interval was not reached.

[2]

Median and upper 95% Confidence Interval were not reached.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.46 to 0.85
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression < 1%

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; 0.28 to 0.54
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression < 1%

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.87
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression < 1%

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.34 to 0.59
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression >= 1%

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.30 to 0.53
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression >= 1%

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.21
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression >= 1%

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.71
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression < 5%

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95%; 0.33 to 0.53
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression < 5%

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.57 to 0.94
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression < 5%

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.27 to 0.60
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression >= 5%

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.54
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression >= 5%

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.54 to 1.38
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression >= 5%

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.43 to 0.67
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression < 10%

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95%; 0.34 to 0.54
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression < 10%

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.63 to 1.01
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression < 10%

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.28 to 0.73
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression >= 10%

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; 0.16 to 0.49
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression >= 10%

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.34 to 1.09
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression >= 10%

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.52
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression not evaluable at baseline

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.30 to 0.89
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression not evaluable at baseline

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.33 to 1.09
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression not evaluable at baseline

9. Secondary Outcome

Title	Overall Survival Based on PD-L1 Expression Level
Description	OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive.
Time Frame	From randomization until date of death (Assessed up to September 2016, approximately 39 months)

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable PD-L1 expression level at baseline

Arm/Group Title		Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:		Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed		316	314	315
Median (95% Confidence Interval); Unit of Measure: months
PD-L1 < 1%	Number Analyzed	117 participants	123 participants	113 participants
		23.46 [1]; (13.01 to NA)	NA [1]; (26.45 to NA)	18.56; (13.67 to 23.20)
PD-L1 >= 1%	Number Analyzed	171 participants	155 participants	164 participants
		NA [2]; (NA to NA)	NA [2]; (NA to NA)	22.11; (17.08 to 29.67)
PD-L1 < 5%	Number Analyzed	208 participants	210 participants	202 participants
		NA [3]; (23.06 to NA)	NA [3]; (31.84 to NA)	18.50; (13.70 to 22.51)
PD-L1 >= 5%	Number Analyzed	80 participants	68 participants	75 participants
		NA [2]; (NA to NA)	NA [2]; (NA to NA)	28.88 [1]; (18.10 to NA)
PD-L1 < 10%	Number Analyzed	229 participants	232 participants	223 participants
		NA [3]; (23.46 to NA)	NA [3]; (32.72 to NA)	18.56; (14.98 to 23.03)
PD-L1 >= 10%	Number Analyzed	59 participants	46 participants	54 participants
		NA [3]; (31.24 to NA)	NA [2]; (NA to NA)	29.08 [1]; (17.91 to NA)
PD-L1 Indeterminate/ Not Evaluable	Number Analyzed	28 participants	36 participants	38 participants
		23.89 [1]; (11.76 to NA)	NA [3]; (21.39 to NA)	18.73; (8.41 to 30.00)

[1]

Upper 95% Confidence Interval was not reached

[2]

Median, Lower, and Upper 95% Confidence Intervals were not reached

[3]

Median and Upper 95% Confidence Interval were not reached

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.12
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression < 1%

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.84
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression < 1%

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	95%; 0.52 to 1.06
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression < 1%

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.38 to 0.71
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression >= 1%

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; 0.38 to 0.74
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression >= 1%

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.48
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression >= 1%

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.50 to 0.85
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression < 5%

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.72
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression < 5%

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.63 to 1.12
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression < 5%

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.35 to 0.92
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression >= 5%

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.36 to 1.00
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression >= 5%

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.83
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression >= 5%

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.50 to 0.82
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression < 10%

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.74
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression < 10%

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.17
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression < 10%

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.35 to 1.05
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression >= 10%

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; 0.29 to 0.99
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression >= 10%

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.71
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression >= 10%

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.37 to 1.34
	Estimation Comments	HR of Nivolumab vs. Ipilimumab in participants with PD-L1 expression not evaluable at baseline

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.48
	Confidence Interval	(2-Sided) 95%; 0.26 to 0.91
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Ipilimumab in participants with PD-L1 expression not evaluable at baseline

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, Nivolumab + Ipilimumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.34 to 1.39
	Estimation Comments	HR of Nivolumab+Ipilimumab vs. Nivolumab in participants with PD-L1 expression not evaluable at baseline

10. Secondary Outcome

Title	Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status
Description	Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline. The mean score for all participants in an arm at a given week was subtracted from the mean score of the participants in that arm at baseline. Mean changes from baseline score is presented for all participants in an arm that remained on treatment and completed the EORTC-QLQ-C30 questionnaire at that time point.
Time Frame	Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable EORTC scores at baseline and specified time point

Arm/Group Title		Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:		Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed		316	314	315
Mean (Standard Deviation); Unit of Measure: Points on EORTC scale
Week 5	Number Analyzed	233 participants	183 participants	221 participants
		-2.8 (15.74)	-4.3 (21.38)	-3.1 (17.24)
Week 7	Number Analyzed	239 participants	183 participants	218 participants
		-2.6 (16.89)	-5.0 (20.60)	-4.3 (18.07)
Week 11	Number Analyzed	201 participants	112 participants	163 participants
		-2.0 (18.10)	-2.4 (21.99)	-6.2 (18.73)
Week 13	Number Analyzed	195 participants	106 participants	130 participants
		-1.9 (16.44)	-3.8 (21.21)	-5.5 (20.27)
Week 17	Number Analyzed	158 participants	84 participants	104 participants
		-1.6 (19.73)	-6.0 (22.01)	-6.1 (16.80)
Week 19	Number Analyzed	164 participants	96 participants	98 participants
		-0.8 (18.30)	-0.8 (21.70)	-5.4 (19.52)
Week 23	Number Analyzed	134 participants	86 participants	75 participants
		-2.8 (19.44)	-2.6 (22.00)	-3.7 (16.28)
Week 25	Number Analyzed	144 participants	97 participants	75 participants
		1.3 (17.39)	-3.3 (17.70)	-4.2 (16.52)
Week 31	Number Analyzed	123 participants	92 participants	51 participants
		2.5 (17.40)	1.5 (21.47)	2.0 (15.51)
Week 37	Number Analyzed	116 participants	88 participants	48 participants
		3.2 (18.44)	-0.2 (21.18)	-1.9 (15.11)
Week 43	Number Analyzed	103 participants	74 participants	44 participants
		3.5 (18.28)	-0.5 (23.04)	-0.9 (15.59)
Week 49	Number Analyzed	97 participants	70 participants	40 participants
		2.7 (16.52)	0.6 (21.95)	-0.4 (15.78)
Week 55	Number Analyzed	86 participants	66 participants	34 participants
		1.8 (14.26)	-2.4 (22.01)	0.7 (13.03)
Week 61	Number Analyzed	85 participants	61 participants	31 participants
		1.6 (16.29)	-3.6 (20.78)	0.8 (11.25)
Week 67	Number Analyzed	76 participants	61 participants	29 participants
		2.1 (17.49)	-2.9 (21.35)	-6.6 (15.17)
Week 73	Number Analyzed	67 participants	54 participants	19 participants
		0.1 (19.11)	-4.5 (21.76)	-3.5 (16.97)
Week 79	Number Analyzed	67 participants	54 participants	21 participants
		-0.1 (14.40)	-4.8 (20.51)	-0.8 (14.65)
Week 85	Number Analyzed	68 participants	51 participants	18 participants
		2.8 (16.64)	-3.3 (22.37)	0.0 (10.69)
Week 91	Number Analyzed	62 participants	53 participants	16 participants
		0.9 (17.08)	-3.9 (20.78)	0.5 (12.72)
Week 97	Number Analyzed	58 participants	49 participants	17 participants
		0.9 (17.01)	-5.1 (23.06)	-2.9 (12.13)
Week 103	Number Analyzed	53 participants	46 participants	17 participants
		2.2 (17.61)	-9.8 (19.03)	0.0 (13.50)
Week 109	Number Analyzed	44 participants	39 participants	14 participants
		2.8 (16.56)	-3.8 (23.17)	-2.4 (14.03)
Week 115	Number Analyzed	44 participants	36 participants	17 participants
		0.6 (15.50)	-6.9 (22.76)	-0.5 (11.59)
Week 121	Number Analyzed	44 participants	39 participants	16 participants
		1.1 (19.90)	-1.5 (19.20)	-3.1 (15.18)
Week 127	Number Analyzed	47 participants	36 participants	17 participants
		0.9 (20.06)	-1.9 (22.37)	1.5 (12.92)
Week 133	Number Analyzed	29 participants	31 participants	11 participants
		3.2 (20.70)	-2.4 (25.11)	3.8 (13.10)
Week 139	Number Analyzed	20 participants	19 participants	6 participants
		0.0 (18.73)	-4.4 (17.43)	5.6 (15.52)
Week 145	Number Analyzed	14 participants	14 participants	6 participants
		0.6 (25.42)	-8.9 (8.93)	-4.2 (17.28)
Week 151	Number Analyzed	7 participants	7 participants	1 participants
		3.6 (9.45)	-13.1 (9.45)	8.3 [1] (NA)
Week 157	Number Analyzed	1 participants	3 participants	0 participants
		0.0 [1] (NA)	-16.7 (8.33)

[1]

No SD calculated; only one patient analyzed

11. Secondary Outcome

Title	Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Social Functioning
Description	Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
Time Frame	Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable EORTC scores at baseline and specified time point

Arm/Group Title		Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:		Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed		316	314	315
Mean (Standard Deviation); Unit of Measure: Points on EORTC scale
Week 5	Number Analyzed	233 participants	183 participants	221 participants
		-1.2 (21.99)	-4.6 (21.76)	-1.6 (21.59)
Week 7	Number Analyzed	239 participants	183 participants	218 participants
		-0.1 (20.58)	-5.8 (21.81)	-0.2 (21.79)
Week 11	Number Analyzed	201 participants	112 participants	163 participants
		-0.6 (22.32)	-5.1 (22.02)	-3.4 (21.53)
Week 13	Number Analyzed	195 participants	106 participants	130 participants
		0.6 (22.73)	-3.6 (20.57)	-2.2 (24.41)
Week 17	Number Analyzed	158 participants	84 participants	104 participants
		-0.9 (22.28)	-4.4 (25.10)	-2.9 (18.06)
Week 19	Number Analyzed	164 participants	96 participants	98 participants
		1.4 (21.40)	-1.7 (23.13)	-1.3 (24.71)
Week 23	Number Analyzed	134 participants	86 participants	75 participants
		-0.1 (19.87)	-1.2 (23.40)	-4.2 (21.94)
Week 25	Number Analyzed	144 participants	97 participants	75 participants
		1.2 (19.77)	-3.4 (21.37)	-1.3 (25.23)
Week 31	Number Analyzed	123 participants	92 participants	51 participants
		3.5 (16.84)	0.2 (20.30)	3.6 (22.68)
Week 37	Number Analyzed	116 participants	88 participants	48 participants
		1.6 (18.12)	1.1 (22.71)	3.1 (18.40)
Week 43	Number Analyzed	103 participants	74 participants	44 participants
		-0.2 (20.68)	2.9 (21.43)	4.2 (22.77)
Week 49	Number Analyzed	97 participants	70 participants	40 participants
		2.4 (17.35)	3.1 (19.92)	6.3 (18.37)
Week 55	Number Analyzed	86 participants	66 participants	34 participants
		0.6 (19.21)	0.0 (21.68)	5.9 (17.83)
Week 61	Number Analyzed	85 participants	61 participants	31 participants
		2.7 (16.44)	-0.5 (22.76)	5.9 (17.51)
Week 67	Number Analyzed	76 participants	61 participants	29 participants
		1.8 (16.46)	-0.8 (24.80)	-2.3 (17.66)
Week 73	Number Analyzed	67 participants	54 participants	19 participants
		1.5 (17.58)	-2.5 (17.85)	-8.8 (18.73)
Week 79	Number Analyzed	67 participants	54 participants	21 participants
		1.2 (14.01)	-3.4 (24.31)	0.8 (3.64)
Week 85	Number Analyzed	68 participants	51 participants	18 participants
		1.0 (13.77)	-7.5 (21.68)	-1.9 (7.86)
Week 91	Number Analyzed	62 participants	53 participants	16 participants
		-0.8 (17.96)	-5.7 (24.23)	1.0 (4.17)
Week 97	Number Analyzed	58 participants	49 participants	17 participants
		-0.3 (16.95)	-2.7 (22.14)	0.0 (0.00)
Week 103	Number Analyzed	53 participants	46 participants	17 participants
		-0.6 (17.28)	-4.3 (22.62)	-1.0 (4.04)
Week 109	Number Analyzed	44 participants	39 participants	14 participants
		4.2 (15.72)	-2.6 (20.43)	-3.6 (9.65)
Week 115	Number Analyzed	44 participants	36 participants	17 participants
		3.8 (18.63)	-2.3 (25.56)	0.0 (5.89)
Week 121	Number Analyzed	44 participants	39 participants	16 participants
		3.4 (19.88)	-3.0 (25.33)	-1.0 (4.17)
Week 127	Number Analyzed	47 participants	36 participants	17 participants
		3.5 (18.37)	-2.3 (22.24)	2.0 (5.54)
Week 133	Number Analyzed	29 participants	31 participants	11 participants
		0.6 (15.74)	-2.2 (26.44)	3.0 (10.05)
Week 139	Number Analyzed	20 participants	19 participants	6 participants
		4.2 (10.64)	-4.4 (19.12)	2.8 (16.39)
Week 145	Number Analyzed	14 participants	14 participants	6 participants
		-8.3 (26.75)	-11.9 (16.57)	2.8 (16.39)
Week 151	Number Analyzed	7 participants	7 participants	1 participants
		7.1 (23.29)	-9.5 (16.27)	0 [1] (NA)
Week 157	Number Analyzed	1 participants	3 participants	0 participants
		0.0 [1] (NA)	-22.2 (19.25)

[1]

No SD calculated; only one patient analyzed

12. Secondary Outcome

Title	Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Cognitive Functioning
Description	Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
Time Frame	Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable EORTC scores at baseline and specified time point

Arm/Group Title		Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:		Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed		316	314	315
Mean (Standard Deviation); Unit of Measure: Points on EORTC scale
Week 5	Number Analyzed	233 participants	183 participants	221 participants
		0.1 (12.28)	-2.1 (16.49)	-0.2 (13.99)
Week 7	Number Analyzed	239 participants	183 participants	218 participants
		-1.7 (12.80)	-3.6 (16.26)	-1.5 (13.36)
Week 11	Number Analyzed	201 participants	112 participants	163 participants
		-1.7 (13.27)	-0.1 (16.67)	-4.7 (15.33)
Week 13	Number Analyzed	195 participants	106 participants	130 participants
		-0.9 (13.45)	-0.3 (14.36)	-2.3 (14.64)
Week 17	Number Analyzed	158 participants	84 participants	104 participants
		-0.9 (12.79)	-3.6 (19.37)	-2.4 (13.43)
Week 19	Number Analyzed	164 participants	96 participants	98 participants
		-1.9 (13.99)	-1.0 (17.07)	-2.2 (13.39)
Week 23	Number Analyzed	134 participants	86 participants	75 participants
		-0.6 (13.31)	-4.5 (21.61)	-5.6 (14.58)
Week 25	Number Analyzed	144 participants	97 participants	75 participants
		-1.2 (12.72)	-4.8 (20.26)	-2.4 (12.46)
Week 31	Number Analyzed	123 participants	92 participants	51 participants
		1.1 (12.40)	-1.6 (17.13)	-3.3 (12.48)
Week 37	Number Analyzed	116 participants	88 participants	48 participants
		1.6 (11.42)	-2.8 (17.91)	-5.6 (15.88)
Week 43	Number Analyzed	103 participants	74 participants	44 participants
		-1.6 (15.40)	-2.9 (13.89)	0.0 (11.37)
Week 49	Number Analyzed	97 participants	70 participants	40 participants
		-1.2 (12.32)	-1.2 (15.10)	0.4 (12.22)
Week 55	Number Analyzed	86 participants	66 participants	34 participants
		0.4 (13.52)	-2.8 (14.79)	-2.5 (12.40)
Week 61	Number Analyzed	85 participants	61 participants	31 participants
		0.0 (14.09)	-1.6 (15.12)	-3.2 (15.76)
Week 67	Number Analyzed	76 participants	61 participants	29 participants
		-1.3 (13.27)	-3.0 (17.35)	-7.5 (16.42)
Week 73	Number Analyzed	67 participants	54 participants	19 participants
		-2.2 (11.20)	-4.9 (19.86)	-6.1 (11.40)
Week 79	Number Analyzed	67 participants	54 participants	21 participants
		-0.2 (12.48)	-4.6 (20.58)	-4.8 (13.06)
Week 85	Number Analyzed	68 participants	51 participants	18 participants
		-1.5 (12.79)	-4.2 (17.90)	-2.8 (13.10)
Week 91	Number Analyzed	62 participants	53 participants	16 participants
		-0.5 (12.06)	-4.7 (19.44)	-1.0 (9.56)
Week 97	Number Analyzed	58 participants	49 participants	17 participants
		-3.2 (14.12)	-3.7 (13.72)	-2.0 (10.00)
Week 103	Number Analyzed	53 participants	46 participants	17 participants
		-2.5 (15.81)	-5.8 (23.63)	-5.9 (15.52)
Week 109	Number Analyzed	44 participants	39 participants	14 participants
		1.1 (10.42)	-3.8 (19.29)	-1.2 (7.91)
Week 115	Number Analyzed	44 participants	36 participants	17 participants
		0.4 (9.84)	-3.7 (15.49)	-2.0 (10.00)
Week 121	Number Analyzed	44 participants	39 participants	16 participants
		-1.1 (14.56)	-7.7 (15.22)	-1.0 (9.56)
Week 127	Number Analyzed	47 participants	36 participants	17 participants
		-2.8 (17.83)	-3.2 (13.10)	-1.0 (13.78)
Week 133	Number Analyzed	29 participants	31 participants	11 participants
		-4.6 (22.67)	-3.8 (13.41)	1.5 (8.99)
Week 139	Number Analyzed	20 participants	19 participants	6 participants
		-3.3 (6.84)	-6.1 (11.40)	5.6 (8.61)
Week 145	Number Analyzed	14 participants	14 participants	6 participants
		-11.9 (29.55)	-4.8 (12.10)	-5.6 (17.21)
Week 151	Number Analyzed	7 participants	7 participants	1 participants
		-2.4 (11.50)	-7.1 (13.11)	16.7 [1] (NA)
Week 157	Number Analyzed	1 participants	3 participants	0 participants
		0.0 [1] (NA)	-11.1 (9.62)

[1]

No SD calculated; only one patient analyzed

13. Secondary Outcome

Title	Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Emotional Functioning
Description	Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
Time Frame	Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable EORTC scores at baseline and specified time point

Arm/Group Title		Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:		Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed		316	314	315
Mean (Standard Deviation); Unit of Measure: Points on EORTC scale
Week 5	Number Analyzed	233 participants	183 participants	221 participants
		4.6 (15.91)	2.5 (16.44)	3.7 (17.21)
Week 7	Number Analyzed	239 participants	183 participants	218 participants
		4.0 (16.82)	2.0 (18.10)	3.1 (17.39)
Week 11	Number Analyzed	201 participants	112 participants	163 participants
		5.3 (14.84)	3.7 (15.57)	2.0 (18.89)
Week 13	Number Analyzed	195 participants	106 participants	130 participants
		3.8 (15.99)	4.3 (17.53)	2.9 (18.03)
Week 17	Number Analyzed	158 participants	84 participants	104 participants
		5.6 (16.54)	4.2 (18.81)	4.9 (15.86)
Week 19	Number Analyzed	164 participants	96 participants	98 participants
		5.8 (16.26)	6.2 (19.01)	6.5 (18.27)
Week 23	Number Analyzed	134 participants	86 participants	75 participants
		6.1 (17.04)	4.5 (20.20)	3.7 (18.85)
Week 25	Number Analyzed	144 participants	97 participants	75 participants
		6.6 (16.31)	2.1 (19.69)	5.9 (17.15)
Week 31	Number Analyzed	123 participants	92 participants	51 participants
		8.3 (15.57)	4.7 (15.64)	9.2 (16.69)
Week 37	Number Analyzed	116 participants	88 participants	48 participants
		9.6 (15.60)	6.8 (17.98)	5.9 (16.75)
Week 43	Number Analyzed	103 participants	74 participants	44 participants
		6.7 (18.89)	7.5 (18.36)	6.1 (14.86)
Week 49	Number Analyzed	97 participants	70 participants	40 participants
		5.8 (18.61)	7.1 (19.67)	8.1 (15.50)
Week 55	Number Analyzed	86 participants	66 participants	34 participants
		8.1 (18.57)	8.3 (16.79)	12.3 (15.11)
Week 61	Number Analyzed	85 participants	61 participants	31 participants
		7.9 (18.54)	7.9 (22.69)	9.9 (14.82)
Week 67	Number Analyzed	76 participants	61 participants	29 participants
		7.8 (19.97)	7.1 (20.52)	3.7 (15.36)
Week 73	Number Analyzed	67 participants	54 participants	19 participants
		8.0 (18.66)	4.5 (18.29)	4.8 (10.51)
Week 79	Number Analyzed	67 participants	54 participants	21 participants
		7.6 (19.56)	2.9 (23.36)	6.7 (10.41)
Week 85	Number Analyzed	68 participants	51 participants	18 participants
		6.4 (16.55)	3.3 (21.09)	7.9 (12.61)
Week 91	Number Analyzed	62 participants	53 participants	16 participants
		9.1 (17.77)	4.7 (20.25)	3.6 (12.53)
Week 97	Number Analyzed	58 participants	49 participants	17 participants
		5.3 (17.78)	3.9 (21.05)	3.9 (14.47)
Week 103	Number Analyzed	53 participants	46 participants	17 participants
		6.6 (19.50)	1.4 (23.46)	4.4 (12.88)
Week 109	Number Analyzed	44 participants	39 participants	14 participants
		8.3 (17.33)	4.1 (22.61)	12.5 (11.20)
Week 115	Number Analyzed	44 participants	36 participants	17 participants
		8.1 (21.15)	6.0 (21.23)	10.3 (10.84)
Week 121	Number Analyzed	44 participants	39 participants	16 participants
		8.3 (20.01)	4.5 (21.36)	9.4 (7.98)
Week 127	Number Analyzed	47 participants	36 participants	17 participants
		10.6 (17.61)	7.2 (21.19)	8.3 (13.50)
Week 133	Number Analyzed	29 participants	31 participants	11 participants
		7.5 (19.46)	8.3 (19.48)	9.1 (7.87)
Week 139	Number Analyzed	20 participants	19 participants	6 participants
		9.6 (11.87)	9.2 (16.87)	11.1 (10.09)
Week 145	Number Analyzed	14 participants	14 participants	6 participants
		2.4 (18.32)	6.0 (15.82)	11.1 (10.09)
Week 151	Number Analyzed	7 participants	7 participants	1 participants
		17.9 (16.27)	-2.4 (22.93)	16.7 [1] (NA)
Week 157	Number Analyzed	1 participants	3 participants	0 participants
		16.7 [1] (NA)	-11.1 (17.35)

[1]

No SD calculated; only one patient analyzed

14. Secondary Outcome

Title	Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Role Functioning
Description	Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
Time Frame	Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable EORTC scores at baseline and specified time point

Arm/Group Title		Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:		Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed		316	314	315
Mean (Standard Deviation); Unit of Measure: Points on EORTC scale
Week 5	Number Analyzed	233 participants	183 participants	221 participants
		-4.1 (23.71)	-6.8 (24.90)	-4.4 (21.18)
Week 7	Number Analyzed	239 participants	183 participants	218 participants
		-3.6 (24.21)	-11.6 (28.25)	-4.9 (22.44)
Week 11	Number Analyzed	201 participants	112 participants	163 participants
		-3.2 (24.46)	-9.7 (28.97)	-6.1 (24.56)
Week 13	Number Analyzed	195 participants	106 participants	130 participants
		-3.1 (24.15)	-8.3 (25.33)	-6.9 (25.65)
Week 17	Number Analyzed	158 participants	84 participants	104 participants
		-3.2 (26.14)	-11.1 (27.05)	-6.3 (20.27)
Week 19	Number Analyzed	164 participants	96 participants	98 participants
		-1.3 (24.56)	-4.3 (25.04)	-6.1 (24.80)
Week 23	Number Analyzed	134 participants	86 participants	75 participants
		-2.6 (25.76)	-6.4 (24.14)	-8.4 (24.56)
Week 25	Number Analyzed	144 participants	97 participants	75 participants
		0.7 (21.13)	-7.7 (23.70)	-7.8 (23.78)
Week 31	Number Analyzed	123 participants	92 participants	51 participants
		-0.7 (21.38)	-3.1 (24.82)	-3.9 (23.24)
Week 37	Number Analyzed	116 participants	88 participants	48 participants
		1.6 (22.94)	-3.2 (26.37)	-3.1 (21.92)
Week 43	Number Analyzed	103 participants	74 participants	44 participants
		1.0 (20.85)	-3.4 (26.46)	-1.1 (19.49)
Week 49	Number Analyzed	97 participants	70 participants	40 participants
		1.7 (20.62)	-1.2 (21.67)	-2.1 (21.08)
Week 55	Number Analyzed	86 participants	66 participants	34 participants
		1.6 (20.07)	-4.8 (21.03)	1.0 (16.89)
Week 61	Number Analyzed	85 participants	61 participants	31 participants
		0.4 (19.58)	-3.0 (24.82)	1.1 (21.05)
Week 67	Number Analyzed	76 participants	61 participants	29 participants
		0.7 (19.33)	-4.6 (25.84)	-1.7 (17.45)
Week 73	Number Analyzed	67 participants	54 participants	19 participants
		0.5 (19.24)	-5.6 (26.70)	-0.9 (17.10)
Week 79	Number Analyzed	67 participants	54 participants	21 participants
		-0.7 (18.45)	-8.3 (27.99)	-2.4 (12.12)
Week 85	Number Analyzed	68 participants	51 participants	18 participants
		-2.2 (16.26)	-9.8 (28.90)	0.9 (12.09)
Week 91	Number Analyzed	62 participants	53 participants	16 participants
		1.1 (22.76)	-10.7 (29.25)	2.1 (13.44)
Week 97	Number Analyzed	58 participants	49 participants	17 participants
		0.6 (23.77)	-7.5 (26.80)	0.0 (13.18)
Week 103	Number Analyzed	53 participants	46 participants	17 participants
		-0.6 (26.95)	-9.8 (23.46)	2.0 (10.00)
Week 109	Number Analyzed	44 participants	39 participants	14 participants
		1.1 (21.98)	-5.6 (22.73)	4.8 (10.19)
Week 115	Number Analyzed	44 participants	36 participants	17 participants
		1.1 (22.27)	-10.6 (28.77)	2.0 (11.61)
Week 121	Number Analyzed	44 participants	39 participants	16 participants
		0.4 (28.41)	-8.1 (26.73)	2.1 (14.75)
Week 127	Number Analyzed	47 participants	36 participants	17 participants
		1.4 (24.03)	-6.0 (26.17)	1.0 (7.15)
Week 133	Number Analyzed	29 participants	31 participants	11 participants
		1.1 (34.48)	-4.3 (24.33)	-1.5 (11.68)
Week 139	Number Analyzed	20 participants	19 participants	6 participants
		-5.8 (9.79)	-8.8 (18.73)	8.3 (13.94)
Week 145	Number Analyzed	14 participants	14 participants	6 participants
		-6.0 (34.96)	-10.7 (16.80)	0.0 (23.57)
Week 151	Number Analyzed	7 participants	7 participants	1 participants
		7.1 (26.97)	-14.3 (17.82)	0.0 [1] (NA)
Week 157	Number Analyzed	1 participants	3 participants	0 participants
		0.0 [1] (NA)	-11.1 (19.25)

[1]

No SD calculated; only one patient analyzed

15. Secondary Outcome

Title	Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Physical Functioning
Description	Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
Time Frame	Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation

Outcome Measure Data

Analysis Population Description

All randomized participants with evaluable EORTC scores at baseline and specified time point

Arm/Group Title		Nivolumab	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description:		Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
Overall Number of Participants Analyzed		316	314	315
Mean (Standard Deviation); Unit of Measure: Points on EORTC scale
Week 5	Number Analyzed	233 participants	183 participants	221 participants
		-2.6 (13.62)	-4.9 (14.52)	-5.2 (14.09)
Week 7	Number Analyzed	239 participants	183 participants	218 participants
		-2.4 (14.53)	-5.3 (14.92)	-5.1 (14.69)
Week 11	Number Analyzed	201 participants	112 participants	163 participants
		-2.4 (16.14)	-5.6 (13.76)	-6.3 (14.72)
Week 13	Number Analyzed	195 participants	106 participants	130 participants
		-1.7 (15.79)	-4.3 (14.11)	-5.0 (17.47)
Week 17	Number Analyzed	158 participants	84 participants	104 participants
		-1.4 (15.82)	-6.7 (17.27)	-3.7 (13.46)
Week 19	Number Analyzed	164 participants	96 participants	98 participants
		0.4 (14.14)	-3.7 (14.34)	-4.3 (17.70)
Week 23	Number Analyzed	134 participants	86 participants	75 participants
		0.9 (13.87)	-4.0 (15.59)	-5.5 (15.04)
Week 25	Number Analyzed	144 participants	97 participants	75 participants
		1.4 (11.02)	-4.2 (14.28)	-3.6 (16.19)
Week 31	Number Analyzed	123 participants	92 participants	51 participants
		1.9 (11.60)	-2.4 (12.91)	-2.9 (14.62)
Week 37	Number Analyzed	116 participants	88 participants	48 participants
		2.1 (13.57)	-0.8 (13.00)	-2.2 (13.71)
Week 43	Number Analyzed	103 participants	74 participants	44 participants
		1.9 (13.16)	-0.5 (13.55)	-1.7 (12.71)
Week 49	Number Analyzed	97 participants	70 participants	40 participants
		1.3 (12.08)	-0.1 (12.97)	0.2 (12.31)
Week 55	Number Analyzed	86 participants	66 participants	34 participants
		1.8 (11.68)	-2.9 (13.24)	0.2 (10.57)
Week 61	Number Analyzed	85 participants	61 participants	31 participants
		0.2 (11.65)	-2.1 (13.91)	-0.2 (11.35)
Week 67	Number Analyzed	76 participants	61 participants	29 participants
		0.9 (12.44)	-1.7 (13.22)	-3.9 (10.62)
Week 73	Number Analyzed	67 participants	54 participants	19 participants
		0.5 (14.38)	-3.5 (11.27)	-3.9 (7.80)
Week 79	Number Analyzed	67 participants	54 participants	21 participants
		-1.7 (7.99)	-4.3 (17.09)	-1.3 (6.54)
Week 85	Number Analyzed	68 participants	51 participants	18 participants
		-1.6 (12.86)	-3.5 (12.88)	-2.6 (6.11)
Week 91	Number Analyzed	62 participants	53 participants	16 participants
		-0.4 (13.27)	-4.2 (14.45)	0.0 (0.00)
Week 97	Number Analyzed	58 participants	49 participants	17 participants
		-0.4 (13.79)	-4.4 (16.53)	-0.8 (4.00)
Week 103	Number Analyzed	53 participants	46 participants	17 participants
		-1.5 (17.18)	-5.4 (15.63)	-2.4 (7.05)
Week 109	Number Analyzed	44 participants	39 participants	14 participants
		1.7 (14.74)	-1.2 (13.92)	-1.0 (3.56)
Week 115	Number Analyzed	44 participants	36 participants	17 participants
		0.2 (14.20)	-2.0 (15.10)	-0.8 (3.23)
Week 121	Number Analyzed	44 participants	39 participants	16 participants
		-0.3 (15.77)	-3.4 (13.58)	-2.5 (5.37)
Week 127	Number Analyzed	47 participants	36 participants	17 participants
		1.2 (17.21)	-3.0 (16.75)	-2.4 (5.75)
Week 133	Number Analyzed	29 participants	31 participants	11 participants
		0.2 (23.33)	0.4 (14.40)	-2.4 (6.16)
Week 139	Number Analyzed	20 participants	19 participants	6 participants
		0.4 (7.94)	-3.9 (11.40)	-3.3 (5.58)
Week 145	Number Analyzed	14 participants	14 participants	6 participants
		-1.4 (27.94)	-6.7 (9.06)	-6.7 (8.43)
Week 151	Number Analyzed	7 participants	7 participants	1 participants
		8.6 (17.52)	-9.5 (12.68)	0.0 [1] (NA)
Week 157	Number Analyzed	1 participants	3 participants	0 participants
		0.0 [1] (NA)	-17.8 (25.24)

[1]

No SD calculated; only one patient analyzed

Adverse Events

Time Frame	From first dose to last dose plus 30 days (Assessed up to September 2016, approximately 39 months)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	NIVOLUMAB	NIVOLUMAB+IPILIMUMAB	IPILIMUMAB
Arm/Group Description	Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity	Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity	Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
All-Cause Mortality
	NIVOLUMAB	NIVOLUMAB+IPILIMUMAB	IPILIMUMAB
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	NIVOLUMAB	NIVOLUMAB+IPILIMUMAB	IPILIMUMAB
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	133/313 (42.49%)	223/313 (71.25%)	171/311 (54.98%)
Blood and lymphatic system disorders
Anaemia † 1	4/313 (1.28%)	3/313 (0.96%)	4/311 (1.29%)
Anaemia of chronic disease † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Febrile neutropenia † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Haemolytic anaemia † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Lymphadenitis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Microcytic anaemia † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Neutropenia † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Normochromic normocytic anaemia † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Thrombocytopenia † 1	1/313 (0.32%)	1/313 (0.32%)	0/311 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Atrial fibrillation † 1	0/313 (0.00%)	4/313 (1.28%)	0/311 (0.00%)
Atrial flutter † 1	1/313 (0.32%)	1/313 (0.32%)	1/311 (0.32%)
Atrioventricular block † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Bradycardia † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Cardiac arrest † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Cardiac failure † 1	0/313 (0.00%)	1/313 (0.32%)	1/311 (0.32%)
Cardiac failure congestive † 1	0/313 (0.00%)	0/313 (0.00%)	2/311 (0.64%)
Cardiac tamponade † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Cardiac ventricular thrombosis † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Myocardial infarction † 1	0/313 (0.00%)	1/313 (0.32%)	1/311 (0.32%)
Sinus tachycardia † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Endocrine disorders
Adrenal insufficiency † 1	2/313 (0.64%)	7/313 (2.24%)	1/311 (0.32%)
Adrenocortical insufficiency acute † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Goitre † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Hyperparathyroidism † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Hyperthyroidism † 1	0/313 (0.00%)	6/313 (1.92%)	0/311 (0.00%)
Hypophysitis † 1	2/313 (0.64%)	8/313 (2.56%)	8/311 (2.57%)
Hypopituitarism † 1	1/313 (0.32%)	2/313 (0.64%)	2/311 (0.64%)
Hypothyroidism † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Inappropriate antidiuretic hormone secretion † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Lymphocytic hypophysitis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Thyroiditis † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Eye disorders
Diplopia † 1	1/313 (0.32%)	1/313 (0.32%)	0/311 (0.00%)
Uveitis † 1	0/313 (0.00%)	1/313 (0.32%)	1/311 (0.32%)
Gastrointestinal disorders
Abdominal distension † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Abdominal pain † 1	4/313 (1.28%)	5/313 (1.60%)	5/311 (1.61%)
Abdominal pain lower † 1	0/313 (0.00%)	0/313 (0.00%)	3/311 (0.96%)
Abdominal pain upper † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Anal fistula † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Ascites † 1	2/313 (0.64%)	2/313 (0.64%)	1/311 (0.32%)
Autoimmune colitis † 1	1/313 (0.32%)	1/313 (0.32%)	2/311 (0.64%)
Autoimmune pancreatitis † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Chronic gastritis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Colitis † 1	3/313 (0.96%)	31/313 (9.90%)	26/311 (8.36%)
Colonic pseudo-obstruction † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Constipation † 1	2/313 (0.64%)	2/313 (0.64%)	3/311 (0.96%)
Diarrhoea † 1	6/313 (1.92%)	33/313 (10.54%)	25/311 (8.04%)
Diarrhoea haemorrhagic † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Diverticular perforation † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Dysphagia † 1	2/313 (0.64%)	0/313 (0.00%)	0/311 (0.00%)
Enteritis † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Enterocolitis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Gastric haemorrhage † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Gastritis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Gastritis haemorrhagic † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Gastrointestinal disorder † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Gastrointestinal haemorrhage † 1	3/313 (0.96%)	1/313 (0.32%)	1/311 (0.32%)
Ileus paralytic † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Intestinal obstruction † 1	0/313 (0.00%)	0/313 (0.00%)	2/311 (0.64%)
Intestinal perforation † 1	0/313 (0.00%)	1/313 (0.32%)	1/311 (0.32%)
Intussusception † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Large intestine perforation † 1	0/313 (0.00%)	1/313 (0.32%)	1/311 (0.32%)
Lymphangiectasia intestinal † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Nausea † 1	2/313 (0.64%)	9/313 (2.88%)	1/311 (0.32%)
Pancreatitis † 1	1/313 (0.32%)	2/313 (0.64%)	1/311 (0.32%)
Pancreatitis acute † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Rectal haemorrhage † 1	0/313 (0.00%)	1/313 (0.32%)	1/311 (0.32%)
Rectal prolapse † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Retroperitoneal haemorrhage † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Small intestinal obstruction † 1	2/313 (0.64%)	2/313 (0.64%)	3/311 (0.96%)
Small intestinal perforation † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Subileus † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Upper gastrointestinal haemorrhage † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Volvulus † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Vomiting † 1	3/313 (0.96%)	10/313 (3.19%)	3/311 (0.96%)
General disorders
Asthenia † 1	0/313 (0.00%)	1/313 (0.32%)	3/311 (0.96%)
Catheter site discharge † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Chest pain † 1	3/313 (0.96%)	0/313 (0.00%)	0/311 (0.00%)
Chills † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Death † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Fatigue † 1	2/313 (0.64%)	5/313 (1.60%)	1/311 (0.32%)
General physical health deterioration † 1	3/313 (0.96%)	8/313 (2.56%)	2/311 (0.64%)
Hyperthermia † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Implant site reaction † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Influenza like illness † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Malaise † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Mucosal inflammation † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Nodule † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Non-cardiac chest pain † 1	1/313 (0.32%)	0/313 (0.00%)	1/311 (0.32%)
Pain † 1	1/313 (0.32%)	4/313 (1.28%)	2/311 (0.64%)
Performance status decreased † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Pyrexia † 1	2/313 (0.64%)	26/313 (8.31%)	10/311 (3.22%)
Sudden cardiac death † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Sudden death † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Hepatobiliary disorders
Autoimmune hepatitis † 1	2/313 (0.64%)	6/313 (1.92%)	1/311 (0.32%)
Bile duct obstruction † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Cholecystitis † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Cholecystitis acute † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Cholecystitis chronic † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Cholelithiasis † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Hepatitis † 1	0/313 (0.00%)	4/313 (1.28%)	0/311 (0.00%)
Hepatitis acute † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Hepatocellular injury † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Hepatorenal failure † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Hepatotoxicity † 1	1/313 (0.32%)	5/313 (1.60%)	0/311 (0.00%)
Hypertransaminasaemia † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Portal hypertension † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Infections and infestations
Anal abscess † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Appendicitis † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Bacteraemia † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Biliary sepsis † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Bronchitis † 1	0/313 (0.00%)	2/313 (0.64%)	1/311 (0.32%)
Cellulitis † 1	2/313 (0.64%)	2/313 (0.64%)	3/311 (0.96%)
Clostridium bacteraemia † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Clostridium difficile colitis † 1	1/313 (0.32%)	2/313 (0.64%)	0/311 (0.00%)
Clostridium difficile infection † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Device related infection † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Diverticulitis † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Encephalitis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Erysipelas † 1	2/313 (0.64%)	0/313 (0.00%)	2/311 (0.64%)
Febrile infection † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Gastroenteritis † 1	0/313 (0.00%)	3/313 (0.96%)	1/311 (0.32%)
Gastroenteritis viral † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Gastrointestinal infection † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Groin abscess † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
H1n1 influenza † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Herpes zoster † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Infection † 1	0/313 (0.00%)	2/313 (0.64%)	1/311 (0.32%)
Infective exacerbation of chronic obstructive airways disease † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Lower respiratory tract infection † 1	0/313 (0.00%)	2/313 (0.64%)	1/311 (0.32%)
Lung infection † 1	2/313 (0.64%)	1/313 (0.32%)	0/311 (0.00%)
Meningitis † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Oral candidiasis † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Peritonitis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Peritonitis bacterial † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Pneumocystis jirovecii pneumonia † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Pneumonia † 1	0/313 (0.00%)	6/313 (1.92%)	2/311 (0.64%)
Pneumonia streptococcal † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Respiratory syncytial virus infection † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Respiratory tract infection † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Sepsis † 1	3/313 (0.96%)	3/313 (0.96%)	0/311 (0.00%)
Septic shock † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Tonsillitis † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Urinary tract infection † 1	1/313 (0.32%)	2/313 (0.64%)	3/311 (0.96%)
Viral infection † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Wound infection † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Injury, poisoning and procedural complications
Ankle fracture † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Concussion † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Fall † 1	0/313 (0.00%)	0/313 (0.00%)	2/311 (0.64%)
Femoral neck fracture † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Hip fracture † 1	0/313 (0.00%)	1/313 (0.32%)	2/311 (0.64%)
Humerus fracture † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Infusion related reaction † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Laceration † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Multiple fractures † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Osteoradionecrosis † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Post procedural complication † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Procedural pneumothorax † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Radius fracture † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Skull fracture † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Spinal compression fracture † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Spinal fracture † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Tibia fracture † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Urinary retention postoperative † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Investigations
Alanine aminotransferase increased † 1	0/313 (0.00%)	3/313 (0.96%)	1/311 (0.32%)
Aspartate aminotransferase increased † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Blood cortisol decreased † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Blood creatine phosphokinase increased † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Gamma-glutamyltransferase increased † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Hepatic enzyme increased † 1	0/313 (0.00%)	3/313 (0.96%)	0/311 (0.00%)
Lipase increased † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Liver function test increased † 1	1/313 (0.32%)	1/313 (0.32%)	0/311 (0.00%)
Transaminases increased † 1	1/313 (0.32%)	8/313 (2.56%)	0/311 (0.00%)
Weight decreased † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Metabolism and nutrition disorders
Decreased appetite † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Dehydration † 1	0/313 (0.00%)	8/313 (2.56%)	3/311 (0.96%)
Diabetes mellitus † 1	1/313 (0.32%)	1/313 (0.32%)	0/311 (0.00%)
Diabetes mellitus inadequate control † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Diabetic ketoacidosis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Hyperglycaemia † 1	1/313 (0.32%)	5/313 (1.60%)	1/311 (0.32%)
Hyperkalaemia † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Hypocalcaemia † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Hypokalaemia † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Hyponatraemia † 1	0/313 (0.00%)	2/313 (0.64%)	1/311 (0.32%)
Metabolic acidosis † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Arthritis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Arthropathy † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Back pain † 1	2/313 (0.64%)	2/313 (0.64%)	2/311 (0.64%)
Bone pain † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Chondrocalcinosis pyrophosphate † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Fibromyalgia † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Flank pain † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Groin pain † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Intervertebral disc disorder † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Intervertebral disc protrusion † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Muscular weakness † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Musculoskeletal chest pain † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Musculoskeletal stiffness † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Myalgia † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Osteoarthritis † 1	2/313 (0.64%)	0/313 (0.00%)	0/311 (0.00%)
Pain in extremity † 1	1/313 (0.32%)	1/313 (0.32%)	0/311 (0.00%)
Pathological fracture † 1	1/313 (0.32%)	0/313 (0.00%)	1/311 (0.32%)
Polymyositis † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Rotator cuff syndrome † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Spinal pain † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenoid cystic carcinoma of salivary gland † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Basal cell carcinoma † 1	7/313 (2.24%)	2/313 (0.64%)	3/311 (0.96%)
Bowen's disease † 1	1/313 (0.32%)	1/313 (0.32%)	0/311 (0.00%)
Diffuse large b-cell lymphoma † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Fibromatosis † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Infected neoplasm † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Intracranial tumour haemorrhage † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Malignant melanoma † 1	4/313 (1.28%)	0/313 (0.00%)	1/311 (0.32%)
Malignant melanoma in situ † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Malignant neoplasm progression † 1	25/313 (7.99%)	16/313 (5.11%)	33/311 (10.61%)
Malignant pleural effusion † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Metastases to bone † 1	1/313 (0.32%)	1/313 (0.32%)	0/311 (0.00%)
Metastases to central nervous system † 1	2/313 (0.64%)	0/313 (0.00%)	4/311 (1.29%)
Metastases to gastrointestinal tract † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Metastases to meninges † 1	1/313 (0.32%)	1/313 (0.32%)	0/311 (0.00%)
Metastatic malignant melanoma † 1	0/313 (0.00%)	0/313 (0.00%)	2/311 (0.64%)
Prostate cancer † 1	2/313 (0.64%)	0/313 (0.00%)	0/311 (0.00%)
Squamous cell carcinoma † 1	8/313 (2.56%)	1/313 (0.32%)	0/311 (0.00%)
Tumour haemorrhage † 1	1/313 (0.32%)	0/313 (0.00%)	2/311 (0.64%)
Tumour pain † 1	1/313 (0.32%)	2/313 (0.64%)	0/311 (0.00%)
Nervous system disorders
Ataxia † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Diabetic coma † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Epilepsy † 1	0/313 (0.00%)	1/313 (0.32%)	1/311 (0.32%)
Facial paralysis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Guillain-barre syndrome † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Haemorrhage intracranial † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Haemorrhagic stroke † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Headache † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Intraventricular haemorrhage † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Ischaemic stroke † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Lethargy † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Nerve compression † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Nervous system disorder † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Neuralgia † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Neuropathy peripheral † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Paraparesis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Peripheral motor neuropathy † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Polyneuropathy † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Seizure † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Somnolence † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Spinal claudication † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Spinal cord compression † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Subarachnoid haemorrhage † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Syncope † 1	1/313 (0.32%)	1/313 (0.32%)	2/311 (0.64%)
Transient ischaemic attack † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Product Issues
Device breakage † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Device loosening † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Device malfunction † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Psychiatric disorders
Anxiety † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Confusional state † 1	0/313 (0.00%)	3/313 (0.96%)	1/311 (0.32%)
Delirium † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Delusion † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Mental status changes † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Psychotic disorder † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	1/313 (0.32%)	7/313 (2.24%)	3/311 (0.96%)
Autoimmune nephritis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Dysuria † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Glomerulonephritis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Nephrolithiasis † 1	1/313 (0.32%)	0/313 (0.00%)	1/311 (0.32%)
Nephropathy toxic † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Prerenal failure † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Renal colic † 1	1/313 (0.32%)	0/313 (0.00%)	1/311 (0.32%)
Renal failure † 1	2/313 (0.64%)	3/313 (0.96%)	0/311 (0.00%)
Renal impairment † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Tubulointerstitial nephritis † 1	0/313 (0.00%)	1/313 (0.32%)	1/311 (0.32%)
Urinary retention † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Reproductive system and breast disorders
Ejaculation failure † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Asthma † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Atelectasis † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Cough † 1	1/313 (0.32%)	1/313 (0.32%)	2/311 (0.64%)
Dyspnoea † 1	3/313 (0.96%)	6/313 (1.92%)	3/311 (0.96%)
Haemoptysis † 1	1/313 (0.32%)	1/313 (0.32%)	0/311 (0.00%)
Hepatic hydrothorax † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Hypoxia † 1	1/313 (0.32%)	0/313 (0.00%)	1/311 (0.32%)
Interstitial lung disease † 1	0/313 (0.00%)	2/313 (0.64%)	0/311 (0.00%)
Lung disorder † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Lung infiltration † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Pleural effusion † 1	3/313 (0.96%)	3/313 (0.96%)	3/311 (0.96%)
Pneumonitis † 1	2/313 (0.64%)	6/313 (1.92%)	2/311 (0.64%)
Pneumothorax † 1	1/313 (0.32%)	1/313 (0.32%)	0/311 (0.00%)
Pulmonary embolism † 1	2/313 (0.64%)	8/313 (2.56%)	2/311 (0.64%)
Pulmonary oedema † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Respiratory failure † 1	1/313 (0.32%)	3/313 (0.96%)	0/311 (0.00%)
Skin and subcutaneous tissue disorders
Dermatitis exfoliative † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Pemphigoid † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Pruritus † 1	0/313 (0.00%)	1/313 (0.32%)	1/311 (0.32%)
Rash † 1	1/313 (0.32%)	0/313 (0.00%)	1/311 (0.32%)
Rash generalised † 1	0/313 (0.00%)	2/313 (0.64%)	1/311 (0.32%)
Rash maculo-papular † 1	1/313 (0.32%)	0/313 (0.00%)	1/311 (0.32%)
Rash pruritic † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Skin burning sensation † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Skin lesion † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Skin oedema † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Toxic skin eruption † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Vasculitic ulcer † 1	0/313 (0.00%)	0/313 (0.00%)	1/311 (0.32%)
Surgical and medical procedures
Excision of lesion of tissue of parietal lobe of brain † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Vascular disorders
Deep vein thrombosis † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Embolism † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Haematoma † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Hypertension † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Hypotension † 1	1/313 (0.32%)	2/313 (0.64%)	1/311 (0.32%)
Inferior vena caval occlusion † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Lymphorrhoea † 1	1/313 (0.32%)	0/313 (0.00%)	0/311 (0.00%)
Orthostatic hypotension † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
Superior vena cava syndrome † 1	0/313 (0.00%)	1/313 (0.32%)	0/311 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 19.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	NIVOLUMAB	NIVOLUMAB+IPILIMUMAB	IPILIMUMAB
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	300/313 (95.85%)	301/313 (96.17%)	301/311 (96.78%)
Blood and lymphatic system disorders
Anaemia † 1	31/313 (9.90%)	33/313 (10.54%)	38/311 (12.22%)
Cardiac disorders
Tachycardia † 1	4/313 (1.28%)	16/313 (5.11%)	10/311 (3.22%)
Endocrine disorders
Hyperthyroidism † 1	19/313 (6.07%)	29/313 (9.27%)	3/311 (0.96%)
Hypophysitis † 1	2/313 (0.64%)	18/313 (5.75%)	8/311 (2.57%)
Hypothyroidism † 1	34/313 (10.86%)	58/313 (18.53%)	16/311 (5.14%)
Gastrointestinal disorders
Abdominal pain † 1	51/313 (16.29%)	56/313 (17.89%)	61/311 (19.61%)
Abdominal pain upper † 1	21/313 (6.71%)	21/313 (6.71%)	21/311 (6.75%)
Colitis † 1	6/313 (1.92%)	19/313 (6.07%)	13/311 (4.18%)
Constipation † 1	66/313 (21.09%)	58/313 (18.53%)	69/311 (22.19%)
Diarrhoea † 1	109/313 (34.82%)	164/313 (52.40%)	141/311 (45.34%)
Dry mouth † 1	24/313 (7.67%)	32/313 (10.22%)	17/311 (5.47%)
Dyspepsia † 1	16/313 (5.11%)	11/313 (3.51%)	7/311 (2.25%)
Gastrooesophageal reflux disease † 1	17/313 (5.43%)	13/313 (4.15%)	12/311 (3.86%)
Nausea † 1	95/313 (30.35%)	132/313 (42.17%)	95/311 (30.55%)
Stomatitis † 1	6/313 (1.92%)	16/313 (5.11%)	8/311 (2.57%)
Vomiting † 1	63/313 (20.13%)	95/313 (30.35%)	52/311 (16.72%)
General disorders
Asthenia † 1	46/313 (14.70%)	48/313 (15.34%)	30/311 (9.65%)
Chest pain † 1	22/313 (7.03%)	12/313 (3.83%)	13/311 (4.18%)
Chills † 1	20/313 (6.39%)	32/313 (10.22%)	18/311 (5.79%)
Fatigue † 1	150/313 (47.92%)	161/313 (51.44%)	133/311 (42.77%)
Influenza like illness † 1	29/313 (9.27%)	25/313 (7.99%)	25/311 (8.04%)
Oedema peripheral † 1	33/313 (10.54%)	35/313 (11.18%)	34/311 (10.93%)
Pain † 1	17/313 (5.43%)	20/313 (6.39%)	27/311 (8.68%)
Pyrexia † 1	50/313 (15.97%)	116/313 (37.06%)	51/311 (16.40%)
Infections and infestations
Nasopharyngitis † 1	38/313 (12.14%)	30/313 (9.58%)	28/311 (9.00%)
Rhinitis † 1	17/313 (5.43%)	23/313 (7.35%)	9/311 (2.89%)
Upper respiratory tract infection † 1	24/313 (7.67%)	25/313 (7.99%)	16/311 (5.14%)
Urinary tract infection † 1	11/313 (3.51%)	17/313 (5.43%)	8/311 (2.57%)
Investigations
Alanine aminotransferase increased † 1	24/313 (7.67%)	64/313 (20.45%)	15/311 (4.82%)
Amylase increased † 1	18/313 (5.75%)	28/313 (8.95%)	17/311 (5.47%)
Aspartate aminotransferase increased † 1	23/313 (7.35%)	57/313 (18.21%)	17/311 (5.47%)
Blood alkaline phosphatase increased † 1	14/313 (4.47%)	18/313 (5.75%)	8/311 (2.57%)
Blood creatinine increased † 1	6/313 (1.92%)	21/313 (6.71%)	10/311 (3.22%)
Lipase increased † 1	27/313 (8.63%)	49/313 (15.65%)	21/311 (6.75%)
Weight decreased † 1	23/313 (7.35%)	38/313 (12.14%)	21/311 (6.75%)
Metabolism and nutrition disorders
Decreased appetite † 1	70/313 (22.36%)	91/313 (29.07%)	73/311 (23.47%)
Dehydration † 1	3/313 (0.96%)	22/313 (7.03%)	12/311 (3.86%)
Hyperglycaemia † 1	9/313 (2.88%)	16/313 (5.11%)	13/311 (4.18%)
Hypokalaemia † 1	9/313 (2.88%)	32/313 (10.22%)	11/311 (3.54%)
Hyponatraemia † 1	5/313 (1.60%)	22/313 (7.03%)	11/311 (3.54%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	66/313 (21.09%)	66/313 (21.09%)	51/311 (16.40%)
Back pain † 1	53/313 (16.93%)	37/313 (11.82%)	46/311 (14.79%)
Muscle spasms † 1	19/313 (6.07%)	13/313 (4.15%)	13/311 (4.18%)
Muscular weakness † 1	11/313 (3.51%)	16/313 (5.11%)	12/311 (3.86%)
Musculoskeletal pain † 1	28/313 (8.95%)	21/313 (6.71%)	31/311 (9.97%)
Myalgia † 1	30/313 (9.58%)	34/313 (10.86%)	22/311 (7.07%)
Pain in extremity † 1	43/313 (13.74%)	31/313 (9.90%)	36/311 (11.58%)
Nervous system disorders
Dizziness † 1	28/313 (8.95%)	38/313 (12.14%)	28/311 (9.00%)
Dysgeusia † 1	27/313 (8.63%)	21/313 (6.71%)	13/311 (4.18%)
Headache † 1	69/313 (22.04%)	80/313 (25.56%)	75/311 (24.12%)
Paraesthesia † 1	20/313 (6.39%)	16/313 (5.11%)	17/311 (5.47%)
Psychiatric disorders
Anxiety † 1	11/313 (3.51%)	19/313 (6.07%)	17/311 (5.47%)
Depression † 1	11/313 (3.51%)	18/313 (5.75%)	7/311 (2.25%)
Insomnia † 1	41/313 (13.10%)	45/313 (14.38%)	39/311 (12.54%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	86/313 (27.48%)	76/313 (24.28%)	65/311 (20.90%)
Dyspnoea † 1	44/313 (14.06%)	69/313 (22.04%)	40/311 (12.86%)
Dyspnoea exertional † 1	18/313 (5.75%)	7/313 (2.24%)	12/311 (3.86%)
Nasal congestion † 1	19/313 (6.07%)	15/313 (4.79%)	8/311 (2.57%)
Oropharyngeal pain † 1	18/313 (5.75%)	20/313 (6.39%)	14/311 (4.50%)
Skin and subcutaneous tissue disorders
Dry skin † 1	24/313 (7.67%)	27/313 (8.63%)	16/311 (5.14%)
Erythema † 1	22/313 (7.03%)	13/313 (4.15%)	12/311 (3.86%)
Hyperhidrosis † 1	10/313 (3.19%)	22/313 (7.03%)	10/311 (3.22%)
Pruritus † 1	83/313 (26.52%)	122/313 (38.98%)	124/311 (39.87%)
Rash † 1	93/313 (29.71%)	103/313 (32.91%)	80/311 (25.72%)
Rash maculo-papular † 1	18/313 (5.75%)	43/313 (13.74%)	42/311 (13.50%)
Vitiligo † 1	32/313 (10.22%)	28/313 (8.95%)	16/311 (5.14%)
Vascular disorders
Hypertension † 1	32/313 (10.22%)	22/313 (7.03%)	27/311 (8.68%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 19.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

Results Point of Contact

• Name/Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb
• EMail: Clinical.Trials@bms.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mantia CM, Werner L, Stwalley B, Ritchings C, Tarhini AA, Atkins MB, McDermott DF, Regan MM. Sensitivity of treatment-free survival to subgroup analyses in patients with advanced melanoma treated with immune checkpoint inhibitors. Melanoma Res. 2022 Feb 1;32(1):35-44. doi: 10.1097/CMR.0000000000000793.

Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Butler MO, Hill A, Marquez-Rodas I, Haanen JBAG, Guidoboni M, Maio M, Schoffski P, Carlino MS, Lebbe C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bas T, Ritchings C, Larkin J, Hodi FS. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022 Jan 10;40(2):127-137. doi: 10.1200/JCO.21.02229. Epub 2021 Nov 24.

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• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT01844505
• Other Study ID Numbers: CA209-067; 2012-005371-13 ( EudraCT Number )
• First Submitted: April 29, 2013
• First Posted: May 1, 2013
• Results First Submitted: July 14, 2017
• Results First Posted: September 26, 2017
• Last Update Posted: January 10, 2024