CheckMate 069: Study of Nivolumab (BMS-936558) Plus Ipilimumab Compared With Ipilimumab Alone in the Treatment of Previously Untreated, Unresectable, or Metastatic Melanoma

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01927419
• Collaborator: (none)
• Enrollment: 142
• Locations: 21
• Arms: 2
• Actual Duration (Months): 90.2
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary purpose of this study is to compare the objective response rate, as determined by investigators, of Nivolumab combined with Ipilimumab versus Ipilimumab monotherapy in patients with untreated, unresectable, or metastatic melanoma

Condition or Disease	Intervention/Treatment	Phase
Unresectable Melanoma; Metastatic Melanoma	Drug: Nivolumab; Drug: Ipilimumab; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 142 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 2, Randomized, Double Blinded, Study of Nivolumab (BMS-936558) in Combination With Ipilimumab vs Ipilimumab Alone in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma
• Actual Study Start Date: Aug 23, 2013
• Actual Primary Completion Date: Jul 24, 2014
• Actual Study Completion Date: Feb 26, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nivolumab + Ipilimumab Participants received (Part 1) 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then (Part 2) 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.	Drug: Nivolumab; Other Names: Opdivo, BMS-936558 ; Drug: Ipilimumab; Other Names: Yervoy
Experimental: Placebo + Ipilimumab Participants received (Part 1) placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then (Part 2) placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.	Drug: Ipilimumab; Other Names: Yervoy ; Drug: Placebo; Matching nivolumab

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) - BRAF Wild-type (WT) Participants [From 12 weeks after Randomization, assessed every 6 weeks up to Week 49 of study treatment and then every 12 weeks until disease progression (up to approximately 76 months)]

   Objective Response Rate is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), assessed by the investigator by using RECIST 1.1 criteria. CR=all target and nontarget lesions have disappeared. Lymph nodes selected must have returned to normal size (<10 mm). PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) - BRAF Wild-type (WT) Participants [From randomization to progression or death (up to approximately 88 months)]

   PFS is defined as the time between the date of randomization and the first date of documented progression, as assessed by the investigator, or death due to any cause, whichever occurs 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 died were censored on the date of their last evaluable tumor assessment. PFS values are based on Kaplan-Meier Estimates.

2. Objective Response Rate (ORR) - BRAF Mutant Participants [From 12 weeks after Randomization, assessed every 6 weeks up to Week 49 of study treatment and then every 12 weeks until disease progression (up to approximately 76 months)]

   Objective Response Rate is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), assessed by the investigator by using RECIST 1.1 criteria. CR=all target and nontarget lesions have disappeared. Lymph nodes selected must have returned to normal size (<10 mm). PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.

3. Progression-Free Survival (PFS) - BRAF Mutant Participants [From randomization to progression or death (up to approximately 88 months)]

   PFS is defined as the time between the date of randomization and the first date of documented progression, as assessed by the investigator, or death due to any cause, whichever occurs 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 died were censored on the date of their last evaluable tumor assessment. PFS values are based on Kaplan-Meier Estimates.

4. Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Overall Quality of Life (QOL) C30 Score [From Baseline (prior to start of study treatment) to Week 25 after first dose]

   The EORTC QLQ-C30 version 3 is a questionnaire developed to assess the QOL of cancer patients. The questionnaire is a 30-item tool, and it comprises 6 functional subscales (physical functioning, role functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as 9 symptom subscales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Scores for each subscale range from 0 to 100. For the 6 functional subscales, a higher score represents a better level of functioning/health status. For the 9 symptom subscales, a lower score represents a better outcome (low level of symptomatology). Scores for the 15 subscales are presented individually.

Eligibility Criteria

Criteria

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

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Key Inclusion Criteria:

• Eastern Cooperative Oncology Group performance status of 0 or 1

• Histologically confirmed unresectable Stage III or Stage IV melanoma

• No prior systemic anticancer therapy for unresectable or metastatic melanoma. Note that prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed at least 6 weeks prior to date of first dose, and all related adverse events have either returned to baseline or stabilized

• Tumor tissue obtained in the metastatic setting or from an unresectable site must be provided for biomarker analyses and sent to the central laboratory. Biopsy should be excisional, incisional punch, or core needle. Fine needle aspirates or other cytology samples are insufficient

• Known BRAF V600 mutation status as determined by an FDA-approved test. Patients with either V600 wild-type or V600 mutation-positive melanoma are eligible.

Key Exclusion Criteria:

• Active brain metastases or leptomeningeal metastases. Patients with treated brain metastases are eligible if there is no evidence of progression on magnetic resonance imaging scan for at least 8 weeks after completion of treatment and within 28 days prior to first dose of study drug administration. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (>10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration

• Ocular melanoma

• Patients with active, known, or suspected autoimmune disease. Those with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	San Francisco Oncology Associates	San Francisco	California	United States	94115
2	Orlando Health Inc	Orlando	Florida	United States	32806
3	University Of Louisville Medical Center, Inc., Dba	Louisville	Kentucky	United States	40202
4	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
5	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02215
7	Washington University School Of Medicine	Saint Louis	Missouri	United States	63110
8	Comprehensive Cancer Centers Of Nevada	Las Vegas	Nevada	United States	89148
9	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
10	University Of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87131
11	NYU Clinical Cancer Center	New York	New York	United States	10016
12	Memorial Sloan Kettering Nassau	New York	New York	United States	10065
13	Duke University Medical Center	Durham	North Carolina	United States	27710
14	The Christ Hospital	Cincinnati	Ohio	United States	45219
15	Oregon Health & Science University	Portland	Oregon	United States	97239
16	St. Luke's Hospital	Easton	Pennsylvania	United States	18045
17	GHS Cancer Institute	Greenville	South Carolina	United States	29615
18	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
19	University Of Wisconsin Paul P Carbone Comprehensive Ca Ctr	Madison	Wisconsin	United States	53792
20	Hopital Larrey	Toulouse		France	31059
21	Institut Gustave Roussy	Villejuif		France	94805

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT01927419
• Other Study ID Numbers: CA209-069; 2013-002018-11
• First Posted: Aug 22, 2013
• Last Update Posted: Mar 18, 2022
• Last Verified: Feb 1, 2022

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

Study Results

Participant Flow

Pre-assignment Detail	142 participants were randomized, and 140 participants received treatment.

Arm/Group Title	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description	Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.	Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
Period Title: Pre-Treatment Period
STARTED	95	47
COMPLETED	94	46
NOT COMPLETED	1	1
Period Title: Pre-Treatment Period
STARTED	94	46
COMPLETED	0	0
NOT COMPLETED	94	46

Baseline Characteristics

Arm/Group Title	Nivolumab + Ipilimumab	Ipilimumab	Total
Arm/Group Description	Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.	Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.	Total of all reporting groups
Overall Participants	95	47	142
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.3 (11.0)	64.5 (10.2)	63.7 (10.7)
Age, Customized (Count of Participants)
Younger than 65 years	48 50.5%	20 42.6%	68 47.9%
65 years and older to younger than 75 years	35 36.8%	22 46.8%	57 40.1%
75 years and older	12 12.6%	5 10.6%	17 12%
Sex: Female, Male (Count of Participants)
Female	32 33.7%	15 31.9%	47 33.1%
Male	63 66.3%	32 68.1%	95 66.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.1%	0 0%	1 0.7%
Not Hispanic or Latino	82 86.3%	43 91.5%	125 88%
Unknown or Not Reported	12 12.6%	4 8.5%	16 11.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.1%	0 0%	1 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	92 96.8%	47 100%	139 97.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 2.1%	0 0%	2 1.4%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR) - BRAF Wild-type (WT) Participants
Description	Objective Response Rate is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), assessed by the investigator by using RECIST 1.1 criteria. CR=all target and nontarget lesions have disappeared. Lymph nodes selected must have returned to normal size (<10 mm). PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Time Frame	From 12 weeks after Randomization, assessed every 6 weeks up to Week 49 of study treatment and then every 12 weeks until disease progression (up to approximately 76 months)

Outcome Measure Data

Analysis Population Description

All randomized BRAF wild-type participants .

Arm/Group Title	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description	Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.	Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
Measure Participants	73	37
Number (95% Confidence Interval) [Percentage of participants]	60.3 63.5%	10.8 23%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	49.5
	Confidence Interval	(2-Sided) 95%; 31.4 to 61.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of ORR
Other Statistical Analysis		Exact 95% CI for difference in ORR uses Newcombe's method

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	12.52
	Confidence Interval	(2-Sided) 95%; 3.79 to 52.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-Free Survival (PFS) - BRAF Wild-type (WT) Participants
Description	PFS is defined as the time between the date of randomization and the first date of documented progression, as assessed by the investigator, or death due to any cause, whichever occurs 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 died were censored on the date of their last evaluable tumor assessment. PFS values are based on Kaplan-Meier Estimates.
Time Frame	From randomization to progression or death (up to approximately 88 months)

Outcome Measure Data

Analysis Population Description

All randomized BRAF wild-type participants

Arm/Group Title	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description	Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.	Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
Measure Participants	73	37
Median (95% Confidence Interval) [Months]	58.41	4.30

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.21 to 0.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	Nivolumab + Ipilimumab over Ipilimumab

3. Secondary Outcome

Title	Objective Response Rate (ORR) - BRAF Mutant Participants
Description	Objective Response Rate is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), assessed by the investigator by using RECIST 1.1 criteria. CR=all target and nontarget lesions have disappeared. Lymph nodes selected must have returned to normal size (<10 mm). PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Time Frame	From 12 weeks after Randomization, assessed every 6 weeks up to Week 49 of study treatment and then every 12 weeks until disease progression (up to approximately 76 months)

Outcome Measure Data

Analysis Population Description

All randomized BRAF mutant participants

Arm/Group Title	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description	Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.	Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
Measure Participants	22	10
Number (95% Confidence Interval) [Percentage of participants]	54.5 57.4%	10.0 21.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	44.5
	Confidence Interval	(2-Sided) 95%; 8.2 to 64.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of ORR
Other Statistical Analysis		Exact 95% CI for difference in ORR uses Newcombe's method

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	10.80
	Confidence Interval	(2-Sided) 95%; 1.07 to 511.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Progression-Free Survival (PFS) - BRAF Mutant Participants
Description	PFS is defined as the time between the date of randomization and the first date of documented progression, as assessed by the investigator, or death due to any cause, whichever occurs 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 died were censored on the date of their last evaluable tumor assessment. PFS values are based on Kaplan-Meier Estimates.
Time Frame	From randomization to progression or death (up to approximately 88 months)

Outcome Measure Data

Analysis Population Description

All randomized BRAF mutant participants

Arm/Group Title	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description	Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.	Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
Measure Participants	22	10
Median (95% Confidence Interval) [Months]	8.61	2.73

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nivolumab + Ipilimumab, Ipilimumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.14 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Nivolumab + Ipilimumab over Ipilimumab

5. Secondary Outcome

Title	Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Overall Quality of Life (QOL) C30 Score
Description	The EORTC QLQ-C30 version 3 is a questionnaire developed to assess the QOL of cancer patients. The questionnaire is a 30-item tool, and it comprises 6 functional subscales (physical functioning, role functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as 9 symptom subscales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Scores for each subscale range from 0 to 100. For the 6 functional subscales, a higher score represents a better level of functioning/health status. For the 9 symptom subscales, a lower score represents a better outcome (low level of symptomatology). Scores for the 15 subscales are presented individually.
Time Frame	From Baseline (prior to start of study treatment) to Week 25 after first dose

Outcome Measure Data

Analysis Population Description

All randomized participants with available measurements at baseline and week 25

Arm/Group Title	Nivolumab + Ipilimumab	Ipilimumab
Arm/Group Description	Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.	Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
Measure Participants	22	13
Physical Functioning	2.12 (17.625)	1.03 (9.367)
Role Functioning	-1.52 (22.950)	5.13 (21.926)
Emotional Functioning	8.33 (10.603)	10.26 (17.063)
Cognitive Functioning	-1.52 (15.352)	-2.56 (11.479)
Social Functioning	2.27 (22.593)	0.00 (16.667)
Global Health Status	3.79 (11.422)	-0.64 (29.357)
Fatigue	-3.54 (21.520)	-0.85 (17.836)
Nausea and Vomiting	-3.03 (12.211)	-2.56 (6.259)
Pain	-2.27 (12.905)	-8.97 (21.099)
Dyspnea	-9.09 (23.417)	-7.69 (27.735)
Insomnia	-12.12 (31.782)	-12.82 (16.879)
Appetite Loss	-13.64 (30.271)	-2.56 (16.452)
Constipation	-3.03 (20.339)	0.00 (13.608)
Diarrhea	-3.03 (14.213)	5.13 (12.518)
Financial Difficulties	-3.03 (22.792)	-2.78 (22.285)

Adverse Events

Time Frame	All-cause mortality was assessed from date of first dose to study completion (up to approximately 90 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 86 months).
Adverse Event Reporting Description	All treated participants
Arm/Group Title	Nivolumab + Ipilimumab		Ipilimumab
Arm/Group Description	Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.		Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
All Cause Mortality
	Nivolumab + Ipilimumab		Ipilimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/94 (46.8%)		29/46 (63%)
Serious Adverse Events
	Nivolumab + Ipilimumab		Ipilimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	69/94 (73.4%)		27/46 (58.7%)
Blood and lymphatic system disorders
Febrile neutropenia	1/94 (1.1%)		0/46 (0%)
Haemolysis	1/94 (1.1%)		0/46 (0%)
Leukocytosis	0/94 (0%)		1/46 (2.2%)
Thrombocytopenia	2/94 (2.1%)		0/46 (0%)
Cardiac disorders
Angina pectoris	0/94 (0%)		1/46 (2.2%)
Atrial fibrillation	2/94 (2.1%)		1/46 (2.2%)
Cardiac failure	1/94 (1.1%)		0/46 (0%)
Myocardial infarction	2/94 (2.1%)		0/46 (0%)
Supraventricular tachycardia	1/94 (1.1%)		0/46 (0%)
Ventricular arrhythmia	1/94 (1.1%)		0/46 (0%)
Endocrine disorders
Adrenal insufficiency	3/94 (3.2%)		0/46 (0%)
Adrenocortical insufficiency acute	1/94 (1.1%)		0/46 (0%)
Autoimmune thyroiditis	1/94 (1.1%)		0/46 (0%)
Endocrine disorder	1/94 (1.1%)		0/46 (0%)
Hypercalcaemia of malignancy	0/94 (0%)		1/46 (2.2%)
Hypophysitis	2/94 (2.1%)		1/46 (2.2%)
Hypopituitarism	1/94 (1.1%)		0/46 (0%)
Gastrointestinal disorders
Abdominal pain	1/94 (1.1%)		0/46 (0%)
Abdominal pain lower	0/94 (0%)		1/46 (2.2%)
Ascites	1/94 (1.1%)		0/46 (0%)
Autoimmune colitis	3/94 (3.2%)		2/46 (4.3%)
Colitis	13/94 (13.8%)		2/46 (4.3%)
Constipation	2/94 (2.1%)		0/46 (0%)
Diarrhoea	10/94 (10.6%)		5/46 (10.9%)
Diarrhoea haemorrhagic	1/94 (1.1%)		0/46 (0%)
Enterocolitis	1/94 (1.1%)		0/46 (0%)
Gastrointestinal haemorrhage	0/94 (0%)		1/46 (2.2%)
Immune-mediated enterocolitis	1/94 (1.1%)		0/46 (0%)
Large intestine perforation	1/94 (1.1%)		0/46 (0%)
Nausea	0/94 (0%)		2/46 (4.3%)
Oesophageal pain	1/94 (1.1%)		0/46 (0%)
Pancreatitis	2/94 (2.1%)		0/46 (0%)
Small intestinal obstruction	2/94 (2.1%)		0/46 (0%)
Upper gastrointestinal haemorrhage	1/94 (1.1%)		0/46 (0%)
Vomiting	1/94 (1.1%)		2/46 (4.3%)
General disorders
Chills	0/94 (0%)		1/46 (2.2%)
Generalised oedema	0/94 (0%)		1/46 (2.2%)
Non-cardiac chest pain	2/94 (2.1%)		0/46 (0%)
Pain	0/94 (0%)		1/46 (2.2%)
Pyrexia	6/94 (6.4%)		4/46 (8.7%)
Hepatobiliary disorders
Hepatitis	3/94 (3.2%)		0/46 (0%)
Hepatocellular injury	1/94 (1.1%)		0/46 (0%)
Infections and infestations
Abdominal abscess	1/94 (1.1%)		0/46 (0%)
Abscess	1/94 (1.1%)		0/46 (0%)
Cellulitis	1/94 (1.1%)		0/46 (0%)
Diverticulitis	1/94 (1.1%)		0/46 (0%)
Encephalitis	0/94 (0%)		1/46 (2.2%)
Enterococcal bacteraemia	1/94 (1.1%)		0/46 (0%)
Epididymitis	1/94 (1.1%)		0/46 (0%)
Gastroenteritis viral	1/94 (1.1%)		0/46 (0%)
Necrotising fasciitis	1/94 (1.1%)		0/46 (0%)
Oral candidiasis	1/94 (1.1%)		0/46 (0%)
Periorbital cellulitis	1/94 (1.1%)		0/46 (0%)
Pneumonia	4/94 (4.3%)		3/46 (6.5%)
Sepsis	3/94 (3.2%)		0/46 (0%)
Septic shock	2/94 (2.1%)		0/46 (0%)
Investigations
Alanine aminotransferase increased	3/94 (3.2%)		0/46 (0%)
Amylase increased	2/94 (2.1%)		0/46 (0%)
Aspartate aminotransferase increased	1/94 (1.1%)		0/46 (0%)
Blood creatinine increased	2/94 (2.1%)		0/46 (0%)
Lipase increased	2/94 (2.1%)		1/46 (2.2%)
Transaminases increased	2/94 (2.1%)		0/46 (0%)
Metabolism and nutrition disorders
Dehydration	2/94 (2.1%)		1/46 (2.2%)
Diabetic ketoacidosis	2/94 (2.1%)		0/46 (0%)
Hypercalcaemia	2/94 (2.1%)		0/46 (0%)
Hyperglycaemia	1/94 (1.1%)		0/46 (0%)
Hyperkalaemia	0/94 (0%)		1/46 (2.2%)
Hyponatraemia	2/94 (2.1%)		0/46 (0%)
Hypophosphataemia	0/94 (0%)		1/46 (2.2%)
Type 1 diabetes mellitus	1/94 (1.1%)		0/46 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/94 (0%)		1/46 (2.2%)
Back pain	0/94 (0%)		1/46 (2.2%)
Myalgia	0/94 (0%)		1/46 (2.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/94 (1.1%)		0/46 (0%)
Malignant neoplasm progression	10/94 (10.6%)		8/46 (17.4%)
Metastatic malignant melanoma	1/94 (1.1%)		0/46 (0%)
Squamous cell carcinoma	1/94 (1.1%)		1/46 (2.2%)
Nervous system disorders
Dizziness	1/94 (1.1%)		0/46 (0%)
Embolic stroke	1/94 (1.1%)		0/46 (0%)
Guillain-Barre syndrome	1/94 (1.1%)		0/46 (0%)
Haemorrhagic stroke	0/94 (0%)		1/46 (2.2%)
Meningoradiculitis	1/94 (1.1%)		0/46 (0%)
Neuralgia	1/94 (1.1%)		0/46 (0%)
Seizure	0/94 (0%)		2/46 (4.3%)
Spinal cord compression	0/94 (0%)		1/46 (2.2%)
Syncope	0/94 (0%)		1/46 (2.2%)
Tremor	1/94 (1.1%)		0/46 (0%)
Renal and urinary disorders
Acute kidney injury	0/94 (0%)		1/46 (2.2%)
Haematuria	0/94 (0%)		1/46 (2.2%)
Urinary tract obstruction	1/94 (1.1%)		0/46 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/94 (1.1%)		0/46 (0%)
Bronchial obstruction	0/94 (0%)		1/46 (2.2%)
Dyspnoea	3/94 (3.2%)		1/46 (2.2%)
Hypoxia	0/94 (0%)		2/46 (4.3%)
Pleural effusion	1/94 (1.1%)		1/46 (2.2%)
Pleuritic pain	1/94 (1.1%)		0/46 (0%)
Pneumonia aspiration	1/94 (1.1%)		0/46 (0%)
Pneumonitis	7/94 (7.4%)		2/46 (4.3%)
Pulmonary embolism	3/94 (3.2%)		0/46 (0%)
Respiratory failure	1/94 (1.1%)		1/46 (2.2%)
Skin and subcutaneous tissue disorders
Rash	1/94 (1.1%)		0/46 (0%)
Vascular disorders
Deep vein thrombosis	3/94 (3.2%)		0/46 (0%)
Embolism	0/94 (0%)		1/46 (2.2%)
Hypertension	0/94 (0%)		1/46 (2.2%)
Hypotension	0/94 (0%)		2/46 (4.3%)
Other (Not Including Serious) Adverse Events
	Nivolumab + Ipilimumab		Ipilimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/94 (95.7%)		45/46 (97.8%)
Blood and lymphatic system disorders
Anaemia	24/94 (25.5%)		15/46 (32.6%)
Cardiac disorders
Atrial fibrillation	6/94 (6.4%)		3/46 (6.5%)
Sinus tachycardia	4/94 (4.3%)		3/46 (6.5%)
Tachycardia	5/94 (5.3%)		5/46 (10.9%)
Ear and labyrinth disorders
Ear pain	5/94 (5.3%)		1/46 (2.2%)
Endocrine disorders
Adrenal insufficiency	7/94 (7.4%)		3/46 (6.5%)
Hypophysitis	10/94 (10.6%)		2/46 (4.3%)
Hypothyroidism	18/94 (19.1%)		7/46 (15.2%)
Eye disorders
Vision blurred	15/94 (16%)		0/46 (0%)
Gastrointestinal disorders
Abdominal discomfort	4/94 (4.3%)		3/46 (6.5%)
Abdominal distension	9/94 (9.6%)		3/46 (6.5%)
Abdominal pain	20/94 (21.3%)		12/46 (26.1%)
Abdominal pain upper	9/94 (9.6%)		3/46 (6.5%)
Colitis	9/94 (9.6%)		4/46 (8.7%)
Constipation	32/94 (34%)		14/46 (30.4%)
Diarrhoea	54/94 (57.4%)		24/46 (52.2%)
Dry mouth	9/94 (9.6%)		6/46 (13%)
Dyspepsia	7/94 (7.4%)		3/46 (6.5%)
Flatulence	4/94 (4.3%)		4/46 (8.7%)
Gastrooesophageal reflux disease	5/94 (5.3%)		2/46 (4.3%)
Nausea	40/94 (42.6%)		25/46 (54.3%)
Rectal haemorrhage	1/94 (1.1%)		4/46 (8.7%)
Vomiting	29/94 (30.9%)		11/46 (23.9%)
General disorders
Asthenia	17/94 (18.1%)		11/46 (23.9%)
Chills	21/94 (22.3%)		8/46 (17.4%)
Fatigue	57/94 (60.6%)		34/46 (73.9%)
Influenza like illness	5/94 (5.3%)		6/46 (13%)
Malaise	2/94 (2.1%)		3/46 (6.5%)
Mucosal inflammation	3/94 (3.2%)		5/46 (10.9%)
Non-cardiac chest pain	5/94 (5.3%)		4/46 (8.7%)
Oedema peripheral	26/94 (27.7%)		10/46 (21.7%)
Pain	14/94 (14.9%)		10/46 (21.7%)
Peripheral swelling	3/94 (3.2%)		3/46 (6.5%)
Pyrexia	32/94 (34%)		17/46 (37%)
Infections and infestations
Pneumonia	2/94 (2.1%)		5/46 (10.9%)
Upper respiratory tract infection	7/94 (7.4%)		5/46 (10.9%)
Urinary tract infection	9/94 (9.6%)		2/46 (4.3%)
Investigations
Alanine aminotransferase increased	30/94 (31.9%)		7/46 (15.2%)
Amylase increased	14/94 (14.9%)		3/46 (6.5%)
Aspartate aminotransferase increased	31/94 (33%)		7/46 (15.2%)
Blood alkaline phosphatase increased	13/94 (13.8%)		7/46 (15.2%)
Blood bilirubin increased	12/94 (12.8%)		1/46 (2.2%)
Blood creatinine increased	10/94 (10.6%)		4/46 (8.7%)
Blood thyroid stimulating hormone decreased	7/94 (7.4%)		1/46 (2.2%)
Blood thyroid stimulating hormone increased	8/94 (8.5%)		0/46 (0%)
Lipase increased	22/94 (23.4%)		6/46 (13%)
Platelet count decreased	5/94 (5.3%)		0/46 (0%)
Weight decreased	16/94 (17%)		2/46 (4.3%)
Weight increased	5/94 (5.3%)		3/46 (6.5%)
Metabolism and nutrition disorders
Decreased appetite	26/94 (27.7%)		17/46 (37%)
Dehydration	22/94 (23.4%)		4/46 (8.7%)
Hyperglycaemia	13/94 (13.8%)		3/46 (6.5%)
Hyperkalaemia	8/94 (8.5%)		2/46 (4.3%)
Hypoalbuminaemia	11/94 (11.7%)		6/46 (13%)
Hypocalcaemia	5/94 (5.3%)		2/46 (4.3%)
Hypokalaemia	15/94 (16%)		5/46 (10.9%)
Hypomagnesaemia	11/94 (11.7%)		3/46 (6.5%)
Hyponatraemia	22/94 (23.4%)		6/46 (13%)
Musculoskeletal and connective tissue disorders
Arthralgia	26/94 (27.7%)		11/46 (23.9%)
Back pain	19/94 (20.2%)		7/46 (15.2%)
Muscle spasms	6/94 (6.4%)		2/46 (4.3%)
Muscular weakness	12/94 (12.8%)		2/46 (4.3%)
Myalgia	14/94 (14.9%)		13/46 (28.3%)
Pain in extremity	10/94 (10.6%)		9/46 (19.6%)
Nervous system disorders
Dizziness	17/94 (18.1%)		5/46 (10.9%)
Dysgeusia	6/94 (6.4%)		1/46 (2.2%)
Headache	35/94 (37.2%)		11/46 (23.9%)
Paraesthesia	9/94 (9.6%)		0/46 (0%)
Peripheral sensory neuropathy	4/94 (4.3%)		4/46 (8.7%)
Taste disorder	5/94 (5.3%)		0/46 (0%)
Psychiatric disorders
Anxiety	7/94 (7.4%)		4/46 (8.7%)
Depression	4/94 (4.3%)		4/46 (8.7%)
Insomnia	20/94 (21.3%)		11/46 (23.9%)
Renal and urinary disorders
Pollakiuria	5/94 (5.3%)		1/46 (2.2%)
Reproductive system and breast disorders
Vaginal haemorrhage	0/94 (0%)		3/46 (6.5%)
Respiratory, thoracic and mediastinal disorders
Cough	30/94 (31.9%)		20/46 (43.5%)
Dysphonia	7/94 (7.4%)		3/46 (6.5%)
Dyspnoea	28/94 (29.8%)		14/46 (30.4%)
Epistaxis	5/94 (5.3%)		1/46 (2.2%)
Nasal congestion	9/94 (9.6%)		5/46 (10.9%)
Oropharyngeal pain	9/94 (9.6%)		5/46 (10.9%)
Pleural effusion	5/94 (5.3%)		4/46 (8.7%)
Pneumonitis	5/94 (5.3%)		2/46 (4.3%)
Productive cough	3/94 (3.2%)		4/46 (8.7%)
Rhinorrhoea	2/94 (2.1%)		3/46 (6.5%)
Skin and subcutaneous tissue disorders
Dry skin	9/94 (9.6%)		5/46 (10.9%)
Erythema	10/94 (10.6%)		1/46 (2.2%)
Night sweats	8/94 (8.5%)		1/46 (2.2%)
Pruritus	47/94 (50%)		17/46 (37%)
Rash	45/94 (47.9%)		17/46 (37%)
Rash erythematous	2/94 (2.1%)		4/46 (8.7%)
Rash maculo-papular	16/94 (17%)		8/46 (17.4%)
Rash pruritic	3/94 (3.2%)		4/46 (8.7%)
Skin hypopigmentation	5/94 (5.3%)		0/46 (0%)
Vitiligo	11/94 (11.7%)		4/46 (8.7%)
Vascular disorders
Flushing	5/94 (5.3%)		1/46 (2.2%)
Hot flush	1/94 (1.1%)		3/46 (6.5%)
Hypertension	12/94 (12.8%)		4/46 (8.7%)
Hypotension	11/94 (11.7%)		5/46 (10.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.