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

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ClinicalTrials.gov Identifier: NCT01844505
Recruitment Status : Active, not recruiting
First Posted : May 1, 2013
Results First Posted : September 26, 2017
Last Update Posted : March 16, 2018
Sponsor:
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
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
Hide 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
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab Total
Hide 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
Hide 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%
1.Primary Outcome
Title Progression Free Survival (PFS)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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.
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with evaluable PD-L1 expression level at baseline
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 11 Hide Statistical Analysis 11
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 12 Hide Statistical Analysis 12
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 13 Hide Statistical Analysis 13
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 14 Hide Statistical Analysis 14
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 15 Hide Statistical Analysis 15
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 16 Hide Statistical Analysis 16
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 17 Hide Statistical Analysis 17
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 18 Hide Statistical Analysis 18
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 19 Hide Statistical Analysis 19
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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
Show Statistical Analysis 20 Hide Statistical Analysis 20
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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
Show Statistical Analysis 21 Hide Statistical Analysis 21
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with evaluable PD-L1 expression level at baseline
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 11 Hide Statistical Analysis 11
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 12 Hide Statistical Analysis 12
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 13 Hide Statistical Analysis 13
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 14 Hide Statistical Analysis 14
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 15 Hide Statistical Analysis 15
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 16 Hide Statistical Analysis 16
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 17 Hide Statistical Analysis 17
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 18 Hide Statistical Analysis 18
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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%
Show Statistical Analysis 19 Hide Statistical Analysis 19
Statistical Analysis Overview Comparison Group Selection Nivolumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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
Show Statistical Analysis 20 Hide Statistical Analysis 20
Statistical Analysis Overview Comparison Group Selection Nivolumab + Ipilimumab, Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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
Show Statistical Analysis 21 Hide Statistical Analysis 21
Statistical Analysis Overview Comparison Group Selection Nivolumab, Nivolumab + Ipilimumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with evaluable EORTC scores at baseline and specified time point
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with evaluable EORTC scores at baseline and specified time point
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with evaluable EORTC scores at baseline and specified time point
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with evaluable EORTC scores at baseline and specified time point
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with evaluable EORTC scores at baseline and specified time point
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with evaluable EORTC scores at baseline and specified time point
Arm/Group Title Nivolumab Nivolumab + Ipilimumab Ipilimumab
Hide 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
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
Hide 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   --/--   --/--   --/-- 
Show Serious Adverse Events Hide 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