Study of Nivolumab (BMS-936558) Compared With Dacarbazine in Untreated, Unresectable, or Metastatic Melanoma (CheckMate 066)

• ClinicalTrials.gov Identifier: NCT01721772
• Recruitment Status: Completed
• First Posted: November 6, 2012
• Results First Posted: February 25, 2016
• Last Update Posted: July 12, 2022
• Sponsor: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Melanoma
• Interventions: Biological: BMS-936558 (Nivolumab); Biological: Placebo matching BMS-936558 (Nivolumab); Drug: Dacarbazine; Drug: Placebo matching Dacarbazine
• Enrollment: 418

Participant Flow

Recruitment Details
Pre-assignment Details	418 were randomized (210 to nivolumab, 208 to dacarbazine) and 411 received treatment (206 with nivolumab, 205 with dacarbazine).

Arm/Group Title	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description	Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
Period Title: Pre-Treatment
Started [1]	210	208
Completed [2]	206	205
Not Completed	4	3
Reason Not Completed
Participant no longer meets study criteria	3	1
Poor/non-compliance	0	1
Participant withdrew consent	0	1
Adverse event unrelated to study drug	1	0
[1] Randomized; [2] Moving to the treatment period
Period Title: Treatment
Started [1]	206	205
Completed	0	0
Not Completed	206	205
Reason Not Completed
Disease progression	119	168
Study drug toxicity	19	10
Adverse event unrelated to study drug	7	7
Maximum clinical benefit	16	4
Other	19	2
Participant withdrew consent	2	5
Participant request to discontinue study treatment	21	8
Death	1	0
Not reported	1	0
Poor/non-compliance	1	0
Lost to Follow-up	0	1
[1] Treated

Baseline Characteristics

Arm/Group Title		Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab	Total
Arm/Group Description		Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Total of all reporting groups
Overall Number of Baseline Participants		210	208	418
Baseline Analysis Population Description		All participants randomized to receive treatment
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	210 participants	208 participants	418 participants
		61.6 (13.00)	63.7 (12.60)	62.7 (12.83)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	210 participants	208 participants	418 participants
	Younger than 65 years	105 50.0%	94 45.2%	199 47.6%
	65 to younger than 75 years	78 37.1%	74 35.6%	152 36.4%
	75 years and older	27 12.9%	40 19.2%	67 16.0%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	210 participants	208 participants	418 participants
	Female	89 42.4%	83 39.9%	172 41.1%
	Male	121 57.6%	125 60.1%	246 58.9%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	210 participants	208 participants	418 participants
	White	209 99.5%	207 99.5%	416 99.5%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	1 0.5%	1 0.2%
	American Indian or Alaskan native	0 0.0%	0 0.0%	0 0.0%
	Other	1 0.5%	0 0.0%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time between the date of randomization and the date of death or the last date the participant was known to be alive.
Time Frame	From date of randomization to date of death. For those without documentation of death, to the last date the participant was known to be alive, assessed up to 17 months.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description:	Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
Overall Number of Participants Analyzed	210	208
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	10.84; (9.33 to 12.09)

[1]

NA due to insufficient number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine, Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
	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) 95%; 0.30 to 0.60
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Overall Survival (OS) Rate
Description	OS rate is calculated as the percentage of participants alive at the indicated timepoints
Time Frame	From randomization to 6 months and or to 12 months

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description:	Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
Overall Number of Participants Analyzed	210	208
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
At 6 months	84.1; (78.3 to 88.5)	71.8; (64.9 to 77.6)
At 12 months	72.9; (65.5 to 78.9)	42.1; (33.0 to 50.9)

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Investigator-assessed PFS is defined as the time from randomization to the date of the first documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Patients who died without progressing were considered to have progressed on the date of their death. Those who did not progress or die were documented on the date of their last evaluable tumor assessment. Patients who did not have any on-study tumor assessments and did not die were documented on their date of randomization. Those who started any subsequent anticancer therapy without a prior reported progression were documented on the date of their last evaluable tumor assessment prior to initiation of subsequent anticancer therapy.
Time Frame	From date of randomization up to date of disease progression or death, up to approximately 84 months

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description:	Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
Overall Number of Participants Analyzed	210	208
Median (95% Confidence Interval); Unit of Measure: Months
	5.06; (3.52 to 12.16)	2.17; (2.10 to 2.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine, Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
	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	0.44
	Confidence Interval	(2-Sided) 95%; 0.34 to 0.56
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Progression-free Survival (PFS) Rate
Description	The PFS rate at a time point is the estimated percentage of patients who have not progressed and are alive at that time point following randomization and is estimated using the Kaplan-Meier methodology.
Time Frame	From randomization to the specified timepoints, up to 84 months

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description:	Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
Overall Number of Participants Analyzed	210	208
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
At 6 months	48.2; (41.0 to 55.0)	20.0; (14.6 to 26.1)
At 12 months	43.3; (36.3 to 50.2)	7.4; (3.9 to 12.4)
At 18 months	40.5; (33.5 to 47.4)	5.2; (2.2 to 10.2)
At 24 months	35.8; (29.0 to 42.6)	5.2; (2.2 to 10.2)
At 36 months	32.8; (26.1 to 39.6)	3.9; (1.3 to 8.9)
At 48 months	29.7; (23.2 to 36.5)	3.9; (1.3 to 8.9)
At 60 months	28.4; (22.0 to 35.2)	3.9; (1.3 to 8.9)
At 72 months	27.8; (21.4 to 34.5)	3.9; (1.3 to 8.9)
At 84 months	25.9; (19.5 to 32.7)	3.9; (1.3 to 8.9)

5. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	ORR is defined as the percentage of participants with a best overall response of Response Evaluation Criteria in Solid Tumors (RECIST) defined complete response (CR) or partial response (PR). RECIST, volume 1.1 for target lesions: CR=disappearance of all target lesions; PR=at least a 30% decrease in the sum of the longest dimension (LD) of target lesions, taking as reference the baseline sum LD; stable disease=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started; PD=at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, and the sum LD must have an absolute increase of ≥5 mm.
Time Frame	Tumor assessments beginning at 9 weeks following randomization and continuing every 6 weeks for the first year, then every 12 weeks thereafter until disease progression or death, assessed to 94 months

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description:	Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
Overall Number of Participants Analyzed	210	208
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	42.4; (35.6 to 49.4)	14.4; (9.9 to 19.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine, Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
	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	4.43
	Confidence Interval	(2-Sided) 95%; 2.75 to 7.13
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Overall Survival by Programmed Cell Death Ligand 1 (PD-L1) Expression Level
Description	Overall Survival is defined as the time between the date of randomization and the date of death or the last date the participant was known to be alive. PD-L1 expression level is defined as the percent of tumor cells demonstrating plasma membrane PD-L1-staining in a minimum of 100 evaluable tumor cells per a Dako PD-L1 IHC (immunohistochemistry) assay (referred to as quantifiable PD-L1 expression). Assessment of OS by PD-L1 expression as measured by a validated assay and comparing OS in patients with tumor PD-L1 expression ≥5% (PD-L1 positive) versus patients with tumor PD-L1 expression <5% (PD-L1 negative). Tumor tissue samples for PD-L1 testing were collected at screening from metastatic or unresectable sites prior to randomization.
Time Frame	From date of randomization to date of disease progression or death, up to approximately 94 months

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title		Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description:		Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
Overall Number of Participants Analyzed		210	208
Median (95% Confidence Interval); Unit of Measure: Months
PD-L1 positive participants (cutoff=5%)	Number Analyzed	74 participants	74 participants
		53.36 [1]; (31.47 to NA)	12.39; (9.33 to 18.99)
PD-L1 negative/indeterminate participants (cutoff=5%)	Number Analyzed	136 participants	134 participants
		26.97; (16.36 to 39.79)	10.84; (8.38 to 12.25)

[1]

Upper limit not reached due to insufficient number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine, Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Unstratified Hazard Ratio
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95%; 0.24 to 0.56
	Estimation Comments	PD-L1 positive group

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine, Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Unstratified Hazard Ratio
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.80
	Estimation Comments	PD-L1 negative group

7. Secondary Outcome

Title	Change From Baseline in Health-related Quality of Life (HRQoL) Scores
Description	HRQoL is evaluated by mean changes from baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/quality of life composite scale in all randomized patients. The QLQ-30 is a cancer-specific, self-administered questionnaire that contains 30 questions, covering global, functional, and symptom scales. Scores range from 0 to 100. Higher scores on global and functional scales indicate better quality of life (QoL), while higher scores on the symptom scales indicate declining QoL.
Time Frame	At baseline and every 6 weeks for 12 months and at follow-up visits 1 and 2, assessed up to 93 months

Outcome Measure Data

Analysis Population Description

All randomized participants with available measurements

Arm/Group Title		Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description:		Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
Overall Number of Participants Analyzed		210	208
Mean (Standard Deviation); Unit of Measure: Units on a scale
Week 7	Number Analyzed	126 participants	115 participants
		1.39 (19.46)	2.32 (20.52)
Week 13	Number Analyzed	95 participants	59 participants
		1.49 (18.91)	3.81 (16.33)
Week 19	Number Analyzed	87 participants	37 participants
		3.07 (16.58)	3.15 (17.16)
Week 25	Number Analyzed	71 participants	33 participants
		3.52 (20.25)	-0.76 (21.28)
Week 31	Number Analyzed	66 participants	20 participants
		2.53 (20.46)	4.17 (17.83)
Week 37	Number Analyzed	64 participants	14 participants
		3.26 (17.61)	7.14 (18.45)
Week 43	Number Analyzed	69 participants	8 participants
		1.69 (20.24)	-1.04 (18.06)
Week 49	Number Analyzed	60 participants	5 participants
		4.31 (18.95)	3.33 (13.94)
Week 55	Number Analyzed	57 participants	6 participants
		2.92 (18.26)	12.50 (23.42)
Week 61	Number Analyzed	56 participants	3 participants
		1.79 (18.72)	13.89 (17.35)
Week 67	Number Analyzed	56 participants	2 participants
		2.08 (21.92)	8.33 (11.79)
Week 73	Number Analyzed	48 participants	2 participants
		4.69 (17.10)	12.50 (5.89)
Week 79	Number Analyzed	46 participants	2 participants
		5.62 (18.84)	8.33 (11.79)
Week 85	Number Analyzed	41 participants	2 participants
		3.05 (19.43)	12.50 (5.89)
Week 91	Number Analyzed	41 participants	2 participants
		3.66 (20.92)	16.67 (0.00)
Week 97	Number Analyzed	39 participants	2 participants
		4.27 (19.48)	8.33 (11.79)
Week 103	Number Analyzed	39 participants	1 participants
		6.20 (19.56)	0.00 (0.00)
Week 109	Number Analyzed	37 participants	2 participants
		3.83 (20.75)	8.33 (11.79)
Week 115	Number Analyzed	34 participants	1 participants
		4.17 (21.15)	0.00 (0.00)
Week 121	Number Analyzed	34 participants	1 participants
		1.47 (20.25)	0.00 (0.00)
Week 127	Number Analyzed	32 participants	0 participants
		-0.26 (19.91)
Week 133	Number Analyzed	29 participants	1 participants
		3.16 (22.09)	16.67 [1] (NA)
Week 139	Number Analyzed	30 participants	1 participants
		1.11 (21.86)	16.67 [1] (NA)
Week 145	Number Analyzed	32 participants	1 participants
		4.69 (20.07)	16.67 [1] (NA)
Week 151	Number Analyzed	30 participants	1 participants
		1.67 (20.34)	16.67 [1] (NA)
Week 157	Number Analyzed	26 participants	1 participants
		3.53 (22.99)	33.33 [1] (NA)
Week 163	Number Analyzed	21 participants	1 participants
		7.94 (20.83)	16.67 [1] (NA)
Week 169	Number Analyzed	20 participants	1 participants
		13.33 (17.61)	33.33 [1] (NA)
Week 175	Number Analyzed	17 participants	1 participants
		7.84 (23.66)	50.00 [1] (NA)
Week 181	Number Analyzed	20 participants	0 participants
		5.42 (21.16)
Week 187	Number Analyzed	18 participants	1 participants
		1.85 (22.06)	33.33 [1] (NA)
Week 193	Number Analyzed	20 participants	1 participants
		2.50 (20.96)	16.67 [1] (NA)
Week 199	Number Analyzed	16 participants	1 participants
		6.77 (21.13)	33.33 [1] (NA)
Week 205	Number Analyzed	18 participants	1 participants
		0.93 (24.07)	33.33 [1] (NA)
Week 211	Number Analyzed	17 participants	0 participants
		0.49 (18.97)
Week 217	Number Analyzed	21 participants	1 participants
		1.19 (23.32)	33.33 [1] (NA)
Week 223	Number Analyzed	19 participants	1 participants
		5.26 (25.49)	33.33 [1] (NA)
Week 229	Number Analyzed	21 participants	1 participants
		5.56 (23.77)	16.67 [1] (NA)
Week 235	Number Analyzed	17 participants	0 participants
		5.39 (24.82)
Week 241	Number Analyzed	18 participants	0 participants
		2.78 (25.72)
Week 247	Number Analyzed	14 participants	1 participants
		5.36 (25.45)	16.67 [1] (NA)
Week 253	Number Analyzed	15 participants	1 participants
		3.89 (26.89)	16.67 [1] (NA)
Week 259	Number Analyzed	13 participants	1 participants
		7.05 (24.26)	25.00 [1] (NA)
Week 265	Number Analyzed	14 participants	1 participants
		8.93 (21.55)	33.33 [1] (NA)
Week 271	Number Analyzed	12 participants	0 participants
		6.25 (21.94)
Week 277	Number Analyzed	14 participants	1 participants
		4.17 (21.12)	25.00 [1] (NA)
Week 283	Number Analyzed	12 participants	1 participants
		5.56 (21.42)	33.33 [1] (NA)
Week 289	Number Analyzed	14 participants	1 participants
		3.57 (20.86)	33.33 [1] (NA)
Week 295	Number Analyzed	12 participants	1 participants
		3.47 (23.15)	16.67 [1] (NA)
Week 301	Number Analyzed	12 participants	1 participants
		2.78 (23.92)	16.67 [1] (NA)
Week 307	Number Analyzed	11 participants	1 participants
		1.52 (24.95)	33.33 [1] (NA)
Week 313	Number Analyzed	10 participants	0 participants
		9.17 (24.04)
Week 319	Number Analyzed	10 participants	1 participants
		3.33 (26.70)	33.33 [1] (NA)
Week 325	Number Analyzed	8 participants	0 participants
		9.38 (25.37)
Week 331	Number Analyzed	7 participants	1 participants
		10.71 (27.09)	33.33 [1] (NA)
Week 337	Number Analyzed	7 participants	0 participants
		11.90 (26.29)
Week 343	Number Analyzed	6 participants	0 participants
		16.67 (26.35)
Week 349	Number Analyzed	7 participants	0 participants
		9.52 (26.54)
Week 355	Number Analyzed	5 participants	0 participants
		0 (10.21)
Week 361	Number Analyzed	4 participants	0 participants
		20.83 (30.81)
Week 367	Number Analyzed	3 participants	0 participants
		25.00 (36.32)
Week 373	Number Analyzed	3 participants	0 participants
		25.00 (36.32)
Week 379	Number Analyzed	1 participants	0 participants
		8.33 [1] (NA)
Week 385	Number Analyzed	1 participants	0 participants
		8.33 [1] (NA)
Week 391	Number Analyzed	1 participants	0 participants
		8.33 [1] (NA)
Week 397	Number Analyzed	1 participants	0 participants
		8.33 [1] (NA)
Week 403	Number Analyzed	1 participants	0 participants
		8.33 [1] (NA)

[1]

Insufficient number of participants to calculate standard deviation

8. Post-Hoc Outcome

Title	Overall Survival (OS) Extended
Description	OS is defined as the time between the date of randomization and the date of death. For those without documentation of death, OS will be censored on the last date the participant was known to be alive. OS data for this endpoint was collected after the primary completion date up until study completion.
Time Frame	From date of randomization to date of death. For those without documentation of death, to the last date the participant was known to be alive, assessed up to 94 months.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description:	Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
Overall Number of Participants Analyzed	210	208
Median (95% Confidence Interval); Unit of Measure: Months
	37.29; (25.40 to 51.55)	11.17; (9.56 to 12.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine, Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.41 to 0.65
	Estimation Comments	[Not Specified]

9. Post-Hoc Outcome

Title	Overall Survival (OS) Rate Extended
Description	OS rate is calculated as the percentage of participants alive at the indicated timepoints. Data for this endpoint was collected after the primary completion date up until study completion. The OS rate for the 6 month and 12 month timepoints reflect updated data that was collected after the primary completion date.
Time Frame	From randomization to the specified timepoints, up to 84 months

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description:	Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
Overall Number of Participants Analyzed	210	208
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
6 months	48.2; (41.0 to 55.0)	20.0; (14.6 to 26.1)
12 months	43.3; (36.3 to 50.2)	7.4; (3.9 to 12.4)
18 months	63.8; (56.8 to 70.0)	36.7; (30.0 to 43.3)
24 months	57.8; (50.7 to 64.2)	26.3; (20.4 to 32.6)
36 months	50.8; (43.7 to 57.5)	21.6; (16.1 to 27.6)
48 months	43.8; (36.9 to 50.5)	17.9; (12.9 to 23.6)
60 months	39.3; (32.6 to 46.0)	17.4; (12.4 to 23.0)
72 months	37.3; (30.7 to 43.9)	16.9; (12.0 to 22.5)
84 months	36.2; (29.5 to 42.8)	16.9; (12.0 to 22.5)

Adverse Events

Time Frame	All-cause mortality was assessed from date of randomization to study completion (up to approximately 99 months). Serious Adverse events and other adverse events were assessed from date of first dose to 100 days following date of last dose (up to approximately 97 months).
Adverse Event Reporting Description	All-Cause Mortality = all randomized participants SAEs and NSAEs (Other Adverse Events) = all treated participants
Arm/Group Title	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
Arm/Group Description	Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion	Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
All-Cause Mortality
	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	126/210 (60.00%)	165/208 (79.33%)
Serious Adverse Events
	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	125/206 (60.68%)	119/205 (58.05%)
Blood and lymphatic system disorders
Anaemia † 1	1/206 (0.49%)	2/205 (0.98%)
Lymphadenopathy † 1	1/206 (0.49%)	1/205 (0.49%)
Neutropenia † 1	0/206 (0.00%)	2/205 (0.98%)
Pancytopenia † 1	0/206 (0.00%)	4/205 (1.95%)
Thrombocytopenia † 1	0/206 (0.00%)	4/205 (1.95%)
Cardiac disorders
Angina pectoris † 1	0/206 (0.00%)	1/205 (0.49%)
Atrial fibrillation † 1	1/206 (0.49%)	1/205 (0.49%)
Atrial flutter † 1	1/206 (0.49%)	0/205 (0.00%)
Cardiac failure † 1	1/206 (0.49%)	0/205 (0.00%)
Tachycardia † 1	0/206 (0.00%)	1/205 (0.49%)
Ear and labyrinth disorders
Deafness unilateral † 1	1/206 (0.49%)	0/205 (0.00%)
Vertigo † 1	1/206 (0.49%)	0/205 (0.00%)
Endocrine disorders
Hypophysitis † 1	2/206 (0.97%)	0/205 (0.00%)
Hypopituitarism † 1	1/206 (0.49%)	0/205 (0.00%)
Hypothyroidism † 1	1/206 (0.49%)	0/205 (0.00%)
Eye disorders
Diplopia † 1	0/206 (0.00%)	1/205 (0.49%)
Eyelid retraction † 1	0/206 (0.00%)	1/205 (0.49%)
Retinal vein thrombosis † 1	1/206 (0.49%)	0/205 (0.00%)
Uveitis † 1	1/206 (0.49%)	0/205 (0.00%)
Visual acuity reduced † 1	0/206 (0.00%)	2/205 (0.98%)
Gastrointestinal disorders
Abdominal distension † 1	1/206 (0.49%)	0/205 (0.00%)
Abdominal pain † 1	2/206 (0.97%)	4/205 (1.95%)
Ascites † 1	3/206 (1.46%)	1/205 (0.49%)
Colitis † 1	4/206 (1.94%)	1/205 (0.49%)
Constipation † 1	1/206 (0.49%)	0/205 (0.00%)
Diarrhoea † 1	6/206 (2.91%)	4/205 (1.95%)
Enterocolitis † 1	0/206 (0.00%)	2/205 (0.98%)
Gastric haemorrhage † 1	0/206 (0.00%)	1/205 (0.49%)
Gastric mucosal lesion † 1	0/206 (0.00%)	1/205 (0.49%)
Gastric ulcer † 1	0/206 (0.00%)	1/205 (0.49%)
Gastrointestinal disorder † 1	0/206 (0.00%)	1/205 (0.49%)
Gastrointestinal haemorrhage † 1	0/206 (0.00%)	1/205 (0.49%)
Intestinal obstruction † 1	1/206 (0.49%)	1/205 (0.49%)
Lower gastrointestinal haemorrhage † 1	0/206 (0.00%)	1/205 (0.49%)
Pancreatitis † 1	1/206 (0.49%)	0/205 (0.00%)
Pneumatosis intestinalis † 1	0/206 (0.00%)	1/205 (0.49%)
Upper gastrointestinal haemorrhage † 1	1/206 (0.49%)	0/205 (0.00%)
Vomiting † 1	2/206 (0.97%)	2/205 (0.98%)
General disorders
Chills † 1	0/206 (0.00%)	1/205 (0.49%)
Death † 1	1/206 (0.49%)	1/205 (0.49%)
Fatigue † 1	2/206 (0.97%)	3/205 (1.46%)
General physical health deterioration † 1	6/206 (2.91%)	6/205 (2.93%)
Infusion site reaction † 1	0/206 (0.00%)	1/205 (0.49%)
Injection site reaction † 1	0/206 (0.00%)	1/205 (0.49%)
Multiple organ dysfunction syndrome † 1	1/206 (0.49%)	0/205 (0.00%)
Non-cardiac chest pain † 1	0/206 (0.00%)	1/205 (0.49%)
Oedema peripheral † 1	0/206 (0.00%)	1/205 (0.49%)
Pain † 1	2/206 (0.97%)	6/205 (2.93%)
Pyrexia † 1	4/206 (1.94%)	2/205 (0.98%)
Hepatobiliary disorders
Cholecystitis acute † 1	1/206 (0.49%)	0/205 (0.00%)
Cholecystitis chronic † 1	1/206 (0.49%)	0/205 (0.00%)
Cholelithiasis † 1	1/206 (0.49%)	0/205 (0.00%)
Hepatic function abnormal † 1	0/206 (0.00%)	1/205 (0.49%)
Hepatitis † 1	3/206 (1.46%)	0/205 (0.00%)
Jaundice † 1	1/206 (0.49%)	0/205 (0.00%)
Immune system disorders
Hypersensitivity † 1	2/206 (0.97%)	0/205 (0.00%)
Infections and infestations
Bronchopulmonary aspergillosis allergic † 1	1/206 (0.49%)	0/205 (0.00%)
Cellulitis † 1	3/206 (1.46%)	2/205 (0.98%)
Coronavirus infection † 1	1/206 (0.49%)	0/205 (0.00%)
Device related sepsis † 1	0/206 (0.00%)	1/205 (0.49%)
Erysipelas † 1	1/206 (0.49%)	2/205 (0.98%)
Infected cyst † 1	1/206 (0.49%)	0/205 (0.00%)
Infection † 1	0/206 (0.00%)	1/205 (0.49%)
Infusion site infection † 1	0/206 (0.00%)	1/205 (0.49%)
Klebsiella infection † 1	0/206 (0.00%)	1/205 (0.49%)
Lower respiratory tract infection † 1	2/206 (0.97%)	0/205 (0.00%)
Pneumocystis jirovecii pneumonia † 1	1/206 (0.49%)	0/205 (0.00%)
Pneumonia † 1	2/206 (0.97%)	1/205 (0.49%)
Pyelonephritis † 1	1/206 (0.49%)	0/205 (0.00%)
Sepsis † 1	1/206 (0.49%)	0/205 (0.00%)
Skin infection † 1	1/206 (0.49%)	0/205 (0.00%)
Urinary tract infection † 1	1/206 (0.49%)	2/205 (0.98%)
Injury, poisoning and procedural complications
Arthropod sting † 1	0/206 (0.00%)	1/205 (0.49%)
Femoral neck fracture † 1	1/206 (0.49%)	0/205 (0.00%)
Fracture † 1	0/206 (0.00%)	1/205 (0.49%)
Hip fracture † 1	1/206 (0.49%)	0/205 (0.00%)
Infusion related reaction † 1	2/206 (0.97%)	0/205 (0.00%)
Lumbar vertebral fracture † 1	1/206 (0.49%)	0/205 (0.00%)
Post procedural complication † 1	0/206 (0.00%)	1/205 (0.49%)
Post procedural inflammation † 1	1/206 (0.49%)	0/205 (0.00%)
Radiation skin injury † 1	0/206 (0.00%)	1/205 (0.49%)
Spinal column injury † 1	1/206 (0.49%)	0/205 (0.00%)
Investigations
Blood calcium decreased † 1	0/206 (0.00%)	1/205 (0.49%)
General physical condition abnormal † 1	2/206 (0.97%)	0/205 (0.00%)
Oxygen saturation decreased † 1	0/206 (0.00%)	1/205 (0.49%)
Pancreatic enzymes abnormal † 1	1/206 (0.49%)	0/205 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	0/206 (0.00%)	1/205 (0.49%)
Diabetic ketoacidosis † 1	1/206 (0.49%)	0/205 (0.00%)
Hypercalcaemia † 1	1/206 (0.49%)	0/205 (0.00%)
Hyperglycaemia † 1	2/206 (0.97%)	1/205 (0.49%)
Hyponatraemia † 1	1/206 (0.49%)	1/205 (0.49%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	2/206 (0.97%)	0/205 (0.00%)
Back pain † 1	2/206 (0.97%)	2/205 (0.98%)
Bone pain † 1	1/206 (0.49%)	2/205 (0.98%)
Muscular weakness † 1	0/206 (0.00%)	1/205 (0.49%)
Osteoarthritis † 1	2/206 (0.97%)	0/205 (0.00%)
Pain in extremity † 1	0/206 (0.00%)	1/205 (0.49%)
Pathological fracture † 1	2/206 (0.97%)	0/205 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon † 1	1/206 (0.49%)	0/205 (0.00%)
Basal cell carcinoma † 1	8/206 (3.88%)	0/205 (0.00%)
Bowen's disease † 1	1/206 (0.49%)	1/205 (0.49%)
Brain neoplasm † 1	0/206 (0.00%)	1/205 (0.49%)
Breast cancer † 1	1/206 (0.49%)	0/205 (0.00%)
Breast cancer recurrent † 1	1/206 (0.49%)	0/205 (0.00%)
Cancer pain † 1	1/206 (0.49%)	0/205 (0.00%)
Gastrointestinal adenocarcinoma † 1	1/206 (0.49%)	0/205 (0.00%)
Malignant melanoma † 1	2/206 (0.97%)	1/205 (0.49%)
Malignant neoplasm progression † 1	32/206 (15.53%)	69/205 (33.66%)
Melanoma recurrent † 1	1/206 (0.49%)	0/205 (0.00%)
Metastases to central nervous system † 1	3/206 (1.46%)	1/205 (0.49%)
Metastases to liver † 1	0/206 (0.00%)	1/205 (0.49%)
Metastases to lymph nodes † 1	2/206 (0.97%)	0/205 (0.00%)
Metastatic malignant melanoma † 1	2/206 (0.97%)	3/205 (1.46%)
Neoplasm † 1	0/206 (0.00%)	1/205 (0.49%)
Nodular melanoma † 1	1/206 (0.49%)	0/205 (0.00%)
Skin neoplasm bleeding † 1	0/206 (0.00%)	1/205 (0.49%)
Squamous cell carcinoma † 1	1/206 (0.49%)	2/205 (0.98%)
Squamous cell carcinoma of skin † 1	1/206 (0.49%)	0/205 (0.00%)
Thyroid neoplasm † 1	1/206 (0.49%)	0/205 (0.00%)
Tumour pain † 1	0/206 (0.00%)	1/205 (0.49%)
Nervous system disorders
Cerebral haemorrhage † 1	1/206 (0.49%)	0/205 (0.00%)
Cerebrovascular accident † 1	0/206 (0.00%)	1/205 (0.49%)
Cognitive disorder † 1	0/206 (0.00%)	1/205 (0.49%)
Disturbance in attention † 1	0/206 (0.00%)	1/205 (0.49%)
Dizziness † 1	1/206 (0.49%)	0/205 (0.00%)
Epilepsy † 1	1/206 (0.49%)	1/205 (0.49%)
Facial paresis † 1	1/206 (0.49%)	0/205 (0.00%)
Guillain-Barre syndrome † 1	1/206 (0.49%)	1/205 (0.49%)
Ischaemic stroke † 1	1/206 (0.49%)	0/205 (0.00%)
Nerve compression † 1	1/206 (0.49%)	0/205 (0.00%)
Neurological decompensation † 1	0/206 (0.00%)	1/205 (0.49%)
Presyncope † 1	1/206 (0.49%)	1/205 (0.49%)
Seizure † 1	2/206 (0.97%)	2/205 (0.98%)
Somnolence † 1	0/206 (0.00%)	1/205 (0.49%)
Spinal cord compression † 1	2/206 (0.97%)	2/205 (0.98%)
Subarachnoid haemorrhage † 1	1/206 (0.49%)	0/205 (0.00%)
Transient ischaemic attack † 1	1/206 (0.49%)	0/205 (0.00%)
Pregnancy, puerperium and perinatal conditions
Ectopic pregnancy † 1	1/206 (0.49%)	0/205 (0.00%)
Product Issues
Device dislocation † 1	1/206 (0.49%)	0/205 (0.00%)
Device occlusion † 1	0/206 (0.00%)	1/205 (0.49%)
Psychiatric disorders
Confusional state † 1	2/206 (0.97%)	4/205 (1.95%)
Disorientation † 1	1/206 (0.49%)	0/205 (0.00%)
Mania † 1	0/206 (0.00%)	1/205 (0.49%)
Psychotic disorder † 1	1/206 (0.49%)	0/205 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	1/206 (0.49%)	2/205 (0.98%)
Haematuria † 1	1/206 (0.49%)	1/205 (0.49%)
Nephrolithiasis † 1	1/206 (0.49%)	1/205 (0.49%)
Renal failure † 1	0/206 (0.00%)	1/205 (0.49%)
Renal injury † 1	1/206 (0.49%)	0/205 (0.00%)
Ureterolithiasis † 1	1/206 (0.49%)	0/205 (0.00%)
Reproductive system and breast disorders
Endometriosis † 1	1/206 (0.49%)	0/205 (0.00%)
Genital haemorrhage † 1	1/206 (0.49%)	0/205 (0.00%)
Ovarian cyst † 1	0/206 (0.00%)	1/205 (0.49%)
Vaginal haemorrhage † 1	1/206 (0.49%)	0/205 (0.00%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	1/206 (0.49%)	0/205 (0.00%)
Dyspnoea † 1	4/206 (1.94%)	0/205 (0.00%)
Epistaxis † 1	0/206 (0.00%)	1/205 (0.49%)
Haemoptysis † 1	1/206 (0.49%)	0/205 (0.00%)
Hypoxia † 1	0/206 (0.00%)	1/205 (0.49%)
Lung disorder † 1	1/206 (0.49%)	1/205 (0.49%)
Pleural effusion † 1	1/206 (0.49%)	7/205 (3.41%)
Pneumonitis † 1	2/206 (0.97%)	0/205 (0.00%)
Pulmonary embolism † 1	0/206 (0.00%)	7/205 (3.41%)
Pulmonary oedema † 1	1/206 (0.49%)	0/205 (0.00%)
Respiratory distress † 1	0/206 (0.00%)	1/205 (0.49%)
Respiratory failure † 1	0/206 (0.00%)	2/205 (0.98%)
Skin and subcutaneous tissue disorders
Rash † 1	2/206 (0.97%)	0/205 (0.00%)
Rash maculo-papular † 1	1/206 (0.49%)	0/205 (0.00%)
Rash papular † 1	1/206 (0.49%)	0/205 (0.00%)
Sarcoid-like reaction † 1	1/206 (0.49%)	0/205 (0.00%)
Skin lesion † 1	1/206 (0.49%)	1/205 (0.49%)
Vascular disorders
Embolism † 1	0/206 (0.00%)	1/205 (0.49%)
Haematoma † 1	1/206 (0.49%)	0/205 (0.00%)
Haemorrhage † 1	1/206 (0.49%)	0/205 (0.00%)
Hypertension † 1	0/206 (0.00%)	1/205 (0.49%)
Hypotension † 1	0/206 (0.00%)	1/205 (0.49%)
Pelvic venous thrombosis † 1	0/206 (0.00%)	1/205 (0.49%)
Thrombosis † 1	1/206 (0.49%)	1/205 (0.49%)
1 Term from vocabulary, 24.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Nivolumab, 3 mg/kg + Placebo-matching Dacarbazine	Dacarbazine, 1000 mg/m^2 + Placebo-matching Nivolumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	191/206 (92.72%)	187/205 (91.22%)
Blood and lymphatic system disorders
Anaemia † 1	26/206 (12.62%)	24/205 (11.71%)
Neutropenia † 1	1/206 (0.49%)	26/205 (12.68%)
Thrombocytopenia † 1	2/206 (0.97%)	22/205 (10.73%)
Endocrine disorders
Hyperthyroidism † 1	11/206 (5.34%)	3/205 (1.46%)
Hypothyroidism † 1	20/206 (9.71%)	8/205 (3.90%)
Gastrointestinal disorders
Abdominal pain † 1	30/206 (14.56%)	21/205 (10.24%)
Abdominal pain upper † 1	17/206 (8.25%)	12/205 (5.85%)
Constipation † 1	57/206 (27.67%)	57/205 (27.80%)
Diarrhoea † 1	75/206 (36.41%)	58/205 (28.29%)
Dyspepsia † 1	11/206 (5.34%)	7/205 (3.41%)
Nausea † 1	59/206 (28.64%)	104/205 (50.73%)
Vomiting † 1	34/206 (16.50%)	54/205 (26.34%)
General disorders
Asthenia † 1	43/206 (20.87%)	38/205 (18.54%)
Fatigue † 1	77/206 (37.38%)	60/205 (29.27%)
Influenza like illness † 1	13/206 (6.31%)	4/205 (1.95%)
Oedema peripheral † 1	26/206 (12.62%)	11/205 (5.37%)
Pain † 1	13/206 (6.31%)	13/205 (6.34%)
Pyrexia † 1	36/206 (17.48%)	29/205 (14.15%)
Infections and infestations
Bronchitis † 1	12/206 (5.83%)	4/205 (1.95%)
Influenza † 1	15/206 (7.28%)	3/205 (1.46%)
Nasopharyngitis † 1	34/206 (16.50%)	10/205 (4.88%)
Rhinitis † 1	12/206 (5.83%)	3/205 (1.46%)
Upper respiratory tract infection † 1	20/206 (9.71%)	13/205 (6.34%)
Urinary tract infection † 1	13/206 (6.31%)	11/205 (5.37%)
Investigations
Alanine aminotransferase increased † 1	17/206 (8.25%)	7/205 (3.41%)
Aspartate aminotransferase increased † 1	12/206 (5.83%)	8/205 (3.90%)
Blood alkaline phosphatase increased † 1	12/206 (5.83%)	7/205 (3.41%)
Blood creatinine increased † 1	12/206 (5.83%)	6/205 (2.93%)
Gamma-glutamyltransferase increased † 1	13/206 (6.31%)	6/205 (2.93%)
Platelet count decreased † 1	0/206 (0.00%)	11/205 (5.37%)
Metabolism and nutrition disorders
Decreased appetite † 1	40/206 (19.42%)	37/205 (18.05%)
Hyperglycaemia † 1	14/206 (6.80%)	0/205 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	46/206 (22.33%)	29/205 (14.15%)
Back pain † 1	39/206 (18.93%)	23/205 (11.22%)
Myalgia † 1	18/206 (8.74%)	13/205 (6.34%)
Pain in extremity † 1	34/206 (16.50%)	20/205 (9.76%)
Nervous system disorders
Dizziness † 1	14/206 (6.80%)	15/205 (7.32%)
Headache † 1	45/206 (21.84%)	32/205 (15.61%)
Psychiatric disorders
Anxiety † 1	16/206 (7.77%)	12/205 (5.85%)
Insomnia † 1	15/206 (7.28%)	9/205 (4.39%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	40/206 (19.42%)	29/205 (14.15%)
Dyspnoea † 1	25/206 (12.14%)	25/205 (12.20%)
Oropharyngeal pain † 1	11/206 (5.34%)	4/205 (1.95%)
Skin and subcutaneous tissue disorders
Actinic keratosis † 1	14/206 (6.80%)	1/205 (0.49%)
Dry skin † 1	21/206 (10.19%)	5/205 (2.44%)
Erythema † 1	29/206 (14.08%)	7/205 (3.41%)
Photosensitivity reaction † 1	5/206 (2.43%)	12/205 (5.85%)
Pruritus † 1	64/206 (31.07%)	40/205 (19.51%)
Rash † 1	63/206 (30.58%)	29/205 (14.15%)
Vitiligo † 1	37/206 (17.96%)	3/205 (1.46%)
Vascular disorders
Hypertension † 1	22/206 (10.68%)	5/205 (2.44%)
Hypotension † 1	5/206 (2.43%)	11/205 (5.37%)
1 Term from vocabulary, 24.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

An independent data monitoring committee (DMC) found that data from a DMC-requested database lock showed clear survival benefit with nivolumab and thus recommended unblinding the study and switching patients randomized to dacarbazine to nivolumab.

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
• Phone: Please email
• EMail: Clinical.Trials@bms.com

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

Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Rutkowski P, Hassel JC, McNeil CM, Kalinka EA, Lebbe C, Charles J, Hernberg MM, Savage KJ, Chiarion-Sileni V, Mihalcioiu C, Mauch C, Arance A, Cognetti F, Ny L, Schmidt H, Schadendorf D, Gogas H, Zoco J, Re S, Ascierto PA, Atkinson V. Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma. J Clin Oncol. 2020 Nov 20;38(33):3937-3946. doi: 10.1200/JCO.20.00995. Epub 2020 Sep 30.

Ascierto PA, Long GV, Robert C, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Ny L, Arance A, Svane IM, Schadendorf D, Gogas H, Saci A, Jiang J, Rizzo J, Atkinson V. Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial. JAMA Oncol. 2019 Feb 1;5(2):187-194. doi: 10.1001/jamaoncol.2018.4514. Erratum In: JAMA Oncol. 2019 Feb 1;5(2):271.

Long GV, Tykodi SS, Schneider JG, Garbe C, Gravis G, Rashford M, Agrawal S, Grigoryeva E, Bello A, Roy A, Rollin L, Zhao X. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer. Ann Oncol. 2018 Nov 1;29(11):2208-2213. doi: 10.1093/annonc/mdy408.

Long GV, Weber JS, Larkin J, Atkinson V, Grob JJ, Schadendorf D, Dummer R, Robert C, Marquez-Rodas I, McNeil C, Schmidt H, Briscoe K, Baurain JF, Hodi FS, Wolchok JD. Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. JAMA Oncol. 2017 Nov 1;3(11):1511-1519. doi: 10.1001/jamaoncol.2017.1588.

Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. doi: 10.1056/NEJMoa1412082. Epub 2014 Nov 16.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT01721772
• Other Study ID Numbers: CA209-066; 2012-003718-16 ( EudraCT Number )
• First Submitted: November 2, 2012
• First Posted: November 6, 2012
• Results First Submitted: November 20, 2015
• Results First Posted: February 25, 2016
• Last Update Posted: July 12, 2022