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Study of Nivolumab (BMS-936558) vs. Everolimus in Pre-Treated Advanced or Metastatic Clear-cell Renal Cell Carcinoma (CheckMate 025)

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ClinicalTrials.gov Identifier: NCT01668784
Recruitment Status : Completed
First Posted : August 20, 2012
Results First Posted : April 29, 2016
Last Update Posted : August 9, 2022
Sponsor:
Collaborator:
Ono Pharmaceutical Co. Ltd
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Advanced or Metastatic (Medically or Surgically Unresectable) Clear-cell Renal Cell Carcinoma
Interventions Biological: Nivolumab
Drug: Everolimus
Enrollment 821
Recruitment Details  
Pre-assignment Details 803 Participants Treated
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends. Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Period Title: Randomized (Pre-treatment)
Started 410 411
Completed 406 397
Not Completed 4 14
Reason Not Completed
Disease Progression             0             1
Request to Discontinue Study Treatment             0             3
Withdrawal by Subject             1             8
Poor/Non-Compliance             1             0
No Longer Meets Study Criteria             2             1
participant requested to be treated a local facility             0             1
Period Title: Treatment Period
Started 406 397
Completed 0 0
Not Completed 406 397
Reason Not Completed
Disease Progression             316             293
Study Drug Toxicity             46             53
Death             1             1
Adverse Event Unrelated to Study Drug             14             14
Request to Discontinue Study Treatment             14             21
Withdrawal by Subject             5             3
Maximal Clinical Benefit             3             3
Other             2             8
Administrative Reason by Sponsor             5             1
Arm/Group Title Nivolumab Everolimus Total
Hide Arm/Group Description Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends. Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends. Total of all reporting groups
Overall Number of Baseline Participants 410 411 821
Hide Baseline Analysis Population Description
All randomized participants; any participant that was randomized to any treatment group in the study.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 410 participants 411 participants 821 participants
60.6  (10.87) 61.9  (10.43) 61.3  (10.66)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 410 participants 411 participants 821 participants
Female
95
  23.2%
107
  26.0%
202
  24.6%
Male
315
  76.8%
304
  74.0%
619
  75.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 410 participants 411 participants 821 participants
American Indian or Alaska Native
1
   0.2%
0
   0.0%
1
   0.1%
Asian
42
  10.2%
32
   7.8%
74
   9.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
1
   0.2%
1
   0.1%
Black or African American
1
   0.2%
4
   1.0%
5
   0.6%
White
353
  86.1%
367
  89.3%
720
  87.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
13
   3.2%
7
   1.7%
20
   2.4%
1.Primary Outcome
Title Overall Survival (OS) at Primary Endpoint
Hide Description Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Interim analysis for the Primary Endpoint occurred after 398 deaths (70% of the total OS events needed for final analysis). At that time the data monitoring committee noted that the pre-specified boundary for OS (nominal significance level p < 0.0148) was crossed while no new safety signals that would affect continuation of the study were found. The study was stopped early by the Sponsor, Bristol-Myers Squibb (BMS) and the interim analysis became the final analysis. As a result, participants in the everolimus groups could be assessed for a crossover to nivolumab treatment if they met all inclusion criteria.
Time Frame Randomization until 398 deaths, up to May 2015 (approximately 30 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants; any participants that was randomized to any treatment group in the study.
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description:
Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 410 411
Median (95% Confidence Interval)
Unit of Measure: months
25.00 [1] 
(21.75 to NA)
19.55
(17.64 to 23.06)
[1]
N.A.: Not Available: Too few events to estimate the upper limit of the confidence interval
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab, Everolimus
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0018
Comments The boundary for statistical significance required the p-value to be less than 0.0148 at the interim analyses.
Method Log Rank
Comments Log-rank Test stratified by the Memorial Sloan-Kettering Cancer Center risk group, number of prior anti-angiogenic therapies, and the region.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.73
Confidence Interval (2-Sided) 98.52%
0.57 to 0.93
Estimation Comments Stratified Cox proportional hazard model. Hazard ratio (HR) was Nivolumab over Everolimus.
2.Secondary Outcome
Title Investigator-assessed Objective Response Rate (ORR)
Hide Description ORR is defined as Percentage of participants with a best response of complete response (CR) or partial response (PR) divided by number of randomized participants. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference. Tumor assessments began at 8 weeks following randomization and continued every 8 weeks for the first year, then every 12 weeks thereafter until disease progression or death. CIs used Clopper and Pearson.
Time Frame from randomization up to disease progression or death (approximately up to 105 Months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants; any participants that was randomized to any treatment group in the study.
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description:
Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 410 411
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
25.9
(21.7 to 30.4)
6.1
(4.0 to 8.8)
3.Secondary Outcome
Title Investigator-assessed Duration of Objective Response
Hide Description Duration of objective response is defined as the time from study start date to response, CR or partial response, PR) to the date of the first documented tumor progression as determined by the investigator (per RECIST 1.1 criteria or clinical) or death due to any cause, whichever occurred first. For participants who neither progress nor die, the duration of objective response were censored at the same time they were censored for the primary definition. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference. Based on Kaplan-Meier Estimates.
Time Frame From randomization to date of disease progression or death or censoring if no progression or death occurred (approximately 105 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a response; any participants that were randomized to any treatment group in the study and that had a response.
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description:
Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 106 25
Median (95% Confidence Interval)
Unit of Measure: months
13.11
(9.26 to 19.75)
10.18
(5.39 to 18.73)
4.Secondary Outcome
Title Investigator-assessed Time to Objective Response
Hide Description Time to objective response is defined as the time from randomization to first response (complete response, CR or partial response, PR). CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference.
Time Frame Randomization to date of first response (approximately 105 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with a response; any participants that was randomized to any treatment group in the study and that had a response.
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description:
Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 106 25
Median (Full Range)
Unit of Measure: months
3.55
(1.4 to 24.8)
3.71
(1.5 to 68.9)
5.Secondary Outcome
Title Investigator-assessed Time of Progression-free Survival (PFS)
Hide Description PFS=time from randomization to date of first documented tumor progression as determined by investigator (per RECIST 1.1 criteria or clinical) or death due to any cause, whichever occurred first. Participants who die without a reported prior progression and without subsequent anti-cancer therapy 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 the date they were randomized. Participants who received any subsequent anti-cancer therapy without a prior reported progression were censored at the last evaluable tumor assessment prior to or on initiation date of the subsequent anti-cancer therapy. Progressive disease: >=20% increase in sum of target lesion diameters and sum must show absolute increase of >=5mm; smallest sum on study as reference. Based on Kaplan-Meier Estimates.
Time Frame from randomization up to disease progression or death (approximately up to 105 Months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants; any participants that was randomized to any treatment group in the study.
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description:
Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 410 411
Median (95% Confidence Interval)
Unit of Measure: months
4.21
(3.68 to 5.36)
4.50
(3.71 to 5.52)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab, Everolimus
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0340
Comments [Not Specified]
Method Log Rank
Comments Log-rank Test stratified by the Memorial Sloan-Kettering Cancer Center (MSKCC) risk group, number of prior anti-angiogenic therapies, and the region.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.72 to 0.99
Estimation Comments Stratified Cox proportional hazard model. Hazard ratio is nivolumab over everolimus.
6.Secondary Outcome
Title Overall Survival (OS) by Programmed Death-Ligand 1 (PD-L1) Expression Level
Hide Description Quantifiable PD-L1 expression=percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per Dako PD-L1 IHC assay. If the PD-L1 staining could not be quantified it was classified as: indeterminate=tumor cell membrane staining hampered for reasons attributed to biology of tumor biopsy specimen and not due to improper sample preparation or handling; not evaluable=tumor biopsy specimen was not optimally collected or prepared. Not evaluable determined from H&E process before the tumor biopsy specimen was sent for evaluation or from H&E process during PD-L1 evaluation; baseline PD-L1 expression=if more than one tumor biopsy specimen was available, the most recently collected specimen with a quantifiable result. If all specimens for a given participant are either indeterminate or not evaluable, then the PD-L1 expression was considered indeterminate as long as at least one specimen is indeterminate. Otherwise, PD-L1 expression was considered not evaluable.
Time Frame Randomization to date of death or date of last contact for patients without documentation of death, up to May 2015 (approximately 30 months)
Hide Outcome Measure Data
Hide Analysis Population Description
PD-L1 quantifiable participants; All randomized participants with quantifiable PD-L1 expression at baseline
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description:
Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 370 386
Median (95% Confidence Interval)
Unit of Measure: months
Participant PD-L1 expression >=1% Number Analyzed 94 participants 87 participants
5.36
(2.04 to 7.46)
4.17
(3.09 to 5.52)
Participant PD-L1 expression <1% Number Analyzed 276 participants 299 participants
3.94
(3.68 to 5.36)
4.67
(3.71 to 5.72)
7.Secondary Outcome
Title Number of Participants With Serious Adverse Events, Death, Discontinuation Due to Adverse Events
Hide Description Adverse event (AE) defined: any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious adverse event (SAE) defined: a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
Time Frame Day of first dose to 30 days post study completion (approximately 106 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants; all participants who received at least one dose of nivolumab or everolimus
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description:
Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 406 397
Measure Type: Count of Participants
Unit of Measure: Participants
Deaths
324
  79.8%
342
  86.1%
SAEs
211
  52.0%
177
  44.6%
Drug related SAEs
51
  12.6%
55
  13.9%
Drug related AEs
327
  80.5%
353
  88.9%
Discontinued due to Drug-related AEs
40
   9.9%
51
  12.8%
Discontinued due to AEs
85
  20.9%
82
  20.7%
Adverse Events
398
  98.0%
387
  97.5%
8.Secondary Outcome
Title Percentage of Participants With Disease-related Symptom Progression (DRSP)
Hide Description Disease-related symptom progression rate (DRSPR)=a decrease of two points in the Functional Assessment of Cancer Therapy-Kidney Symptom Index - Disease Related Symptoms (FKSI-DRS) questionnaire relative to the participant's baseline FKSI-DRS score with no later increase above this threshold observed during the course of the study. The 9 items of the FKSI-DRS were summarized into a symptom scale ranging in score from 0 to 36, with 0 being the worst possible score and 36 being the best possible score. A single measure reporting a decrease of at least 2 units was considered disease-related symptom progression only if it was the last one available for the participant. In order to consider a questionnaire received as valid, over 50% of the items were to be completed. Calculated by the Clopper-Pearson method for each treatment group.
Time Frame from randomization up to disease progression or death (approximately up to 105 Months)
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants; any participants that was randomized to any treatment group in the study.
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description:
Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 410 411
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Disease-related Symptom Progression Rate (DRSPR)
44.6
(39.0 to 50.3)
54.6
(49.2 to 60.0)
DRSPR Including Death and Investigator Progression
95.5
(92.6 to 97.5)
99.4
(97.9 to 99.9)
9.Secondary Outcome
Title Number of Participants Meeting Marked Laboratory Abnormality Criteria in Specific Liver and Thyroid Tests
Hide Description Aspartate aminotransferase, AST. Alanine aminotransaminase, ALT. Total bilirubin, tBIL. Thyroid stimulating hormone, TSH. Upper limit of normal (ULN). Units per Liter (U/L). Results reported in International System of Units (SI).
Time Frame Day 1 to 30 days post study completion (approximately 106 months)
Hide Outcome Measure Data
Hide Analysis Population Description
To all treated participants with evaluable measurements
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description:
Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 406 397
Measure Type: Count of Participants
Unit of Measure: Participants
ALT or AST > 3.0*ULN Number Analyzed 401 participants 377 participants
32
   8.0%
15
   4.0%
ALT or AST > 5.0*ULN Number Analyzed 401 participants 377 participants
20
   5.0%
7
   1.9%
ALT or AST > 10.0*ULN Number Analyzed 401 participants 377 participants
9
   2.2%
1
   0.3%
ALT or AST > 20.0*ULN Number Analyzed 401 participants 377 participants
2
   0.5%
0
   0.0%
Total Bilirubin > 2.0*ULN Number Analyzed 401 participants 376 participants
6
   1.5%
2
   0.5%
ALT or AST>3.0*ULN, tBIL>2.0 ULN, 1day Number Analyzed 401 participants 376 participants
3
   0.7%
0
   0.0%
ALT or AST>3.0*ULN, tBIL>2.0 ULN,30day Number Analyzed 401 participants 376 participants
4
   1.0%
1
   0.3%
TSH > ULN Number Analyzed 382 participants 361 participants
159
  41.6%
78
  21.6%
TSH < LLN Number Analyzed 382 participants 361 participants
60
  15.7%
60
  16.6%
10.Secondary Outcome
Title Number of Participants With Abnormal Hematology and Serum Chemistry Laboratory Parameters by Worse CTC Grade - SI Units
Hide Description Common Terminology Criteria (CTC) version 4.0 in International System of Units (SI); Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Hematology parameters=Hemoglobin (Gr 3: < 8.0 g/dL), Platelet Count (Gr 3: 25.0 -< 50.0*10^9 c/L; Gr 4: < 25.0*10^9 c/L), Leukocyte Count (Gr 3: 1.0 -< 2.0*10^3 c/µL; Gr4: < 1.0*10^3 c/µL), Absolute Lymphocyte Count (Gr 3: 0.2 -< 0.5*10^3 c/µL; Gr 4: < 0.2*10^3 c/µL), Absolute Neutrophil Count (Gr 3: 0.5 - < 1.0*10^3 c/µL; Gr 4: < 0.5*10^3 c/µL). Liver Function parameters=Alkaline Phosphatase (Gr 3: > 5.0 - 20.0 U/L * ULN; Gr 4: > 20.0 U/L * ULN), AST (Gr 3: > 5.0 - 20.0 U/L * ULN; Gr 4: > 20.0 U/L * ULN), ALT (Gr 3: > 5.0 - 20.0 U/L * ULN; Gr 4: > 20.0 U/L * ULN), tBIL (Gr 3: > 3.0 - 10.0 mg/dL * ULN; Gr 4: > 10.0 mg/dL * ULN). Renal parameter=Creatinine (Grade: Gr3: > 3.0 - 6.0 mg/dL *ULN; Gr4: > 6.0 mg/dL *ULN). Cells per microliter (c/µL). Cells per Liter (c/L). Grams per deciliter (g/dL). Milligrams per deciliter (mg/dL).
Time Frame Day 1 to 30 days post study completion (approximately 106 months)
Hide Outcome Measure Data
Hide Analysis Population Description
To all treated participants with evaluable measurements
Arm/Group Title Nivolumab Everolimus
Hide Arm/Group Description:
Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 406 397
Measure Type: Count of Participants
Unit of Measure: Participants
Hemoglobin, Grade 3 Number Analyzed 395 participants 383 participants
33
   8.4%
61
  15.9%
Platelet Count, Grade 3 Number Analyzed 391 participants 379 participants
1
   0.3%
6
   1.6%
Platelet Count, Grade 4 Number Analyzed 391 participants 379 participants
0
   0.0%
1
   0.3%
Leukocytes, Grade 3 Number Analyzed 394 participants 380 participants
0
   0.0%
1
   0.3%
Leukocytes, Grade 4 Number Analyzed 394 participants 380 participants
1
   0.3%
0
   0.0%
Lymphocytes (absolute), Grade 3 Number Analyzed 391 participants 377 participants
28
   7.2%
43
  11.4%
Lymphocytes (absolute), Grade 4 Number Analyzed 391 participants 377 participants
3
   0.8%
6
   1.6%
Absolute Neutrophil Count, Grade 3 Number Analyzed 392 participants 378 participants
0
   0.0%
2
   0.5%
Absolute Neutrophil Count, Grade 4 Number Analyzed 392 participants 378 participants
0
   0.0%
1
   0.3%
Alkaline Phosphatase, Grade 3 Number Analyzed 400 participants 374 participants
11
   2.8%
3
   0.8%
Aspartate Aminotransferase, Grade 3 Number Analyzed 400 participants 375 participants
9
   2.3%
6
   1.6%
Aspartate Aminotransferase, Grade 4 Number Analyzed 400 participants 375 participants
2
   0.5%
0
   0.0%
Alanine Aminotransferase, Grade 3 Number Analyzed 401 participants 376 participants
12
   3.0%
3
   0.8%
Alanine Aminotransferase, Grade 4 Number Analyzed 401 participants 376 participants
1
   0.2%
0
   0.0%
Bilirubin Total, Grade 3 Number Analyzed 401 participants 376 participants
3
   0.7%
2
   0.5%
Creatinine, Grade 3 Number Analyzed 398 participants 379 participants
5
   1.3%
5
   1.3%
Creatinine, Grade 4 Number Analyzed 398 participants 379 participants
3
   0.8%
1
   0.3%
Hypercalcemia, Grade 3 Number Analyzed 339 participants 315 participants
7
   2.1%
1
   0.3%
Hypercalcemia, Grade 4 Number Analyzed 339 participants 315 participants
4
   1.2%
1
   0.3%
Hypocalcemia, Grade 3 Number Analyzed 339 participants 315 participants
2
   0.6%
4
   1.3%
Hypocalcemia, Grade 4 Number Analyzed 339 participants 315 participants
1
   0.3%
0
   0.0%
Hyperkalemia, Grade 3 Number Analyzed 352 participants 332 participants
11
   3.1%
7
   2.1%
Hyperkalemia, Grade 4 Number Analyzed 352 participants 332 participants
3
   0.9%
0
   0.0%
Hypokalemia, Grade 3 Number Analyzed 352 participants 332 participants
5
   1.4%
3
   0.9%
Hypermagnesmia, Grade 3 Number Analyzed 196 participants 174 participants
3
   1.5%
0
   0.0%
Hypomagnesmia, Grade 3 Number Analyzed 196 participants 174 participants
1
   0.5%
0
   0.0%
Hyponatremia, Grade 3 Number Analyzed 353 participants 332 participants
26
   7.4%
22
   6.6%
Hyponatremia, Grade 4 Number Analyzed 353 participants 332 participants
1
   0.3%
1
   0.3%
11.Post-Hoc Outcome
Title Extended Collection to Post Hoc Overall Survival (OS)
Hide Description

Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Interim analysis for the Primary Endpoint occurred after 398 deaths (70% of the total OS events needed for final analysis). At that time the data monitoring committee noted that the pre-specified boundary for OS (nominal significance level p < 0.0148) was crossed while no new safety signals that would affect continuation of the study were found. The study was stopped early by the Sponsor, Bristol-Myers Squibb (BMS) and the interim analysis became the final analysis. As a result, participants in the everolimus groups could be assessed for a crossover to nivolumab treatment if they met all inclusion criteria.

This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date.
Time Frame from randomization up to disease progression or death (approximately up to 105 months)
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Hide Analysis Population Description
All Randomized Participants
Arm/Group Title Nivolumab Everolimus
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Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
Overall Number of Participants Analyzed 410 411
Median (95% Confidence Interval)
Unit of Measure: Months
25.82
(22.21 to 29.77)
19.55
(17.64 to 21.88)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nivolumab, Everolimus
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Stratified Cox Proportional hazard Model
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.63 to 0.86
Estimation Comments [Not Specified]
Time Frame All-cause mortality was assessed from first dose to study completion (up to 105 months). SAEs and Other AEs were assessed from first dose to 100 days following last dose (approximately up to 107 months)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title NIVOLUMAB EVEROLIMUS
Hide Arm/Group Description Nivolumab at 3 mg/kg solution provided intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends. Everolimus provided in 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends.
All-Cause Mortality
NIVOLUMAB EVEROLIMUS
Affected / at Risk (%) Affected / at Risk (%)
Total   324/406 (79.80%)   342/397 (86.15%) 
Hide Serious Adverse Events
NIVOLUMAB EVEROLIMUS
Affected / at Risk (%) Affected / at Risk (%)
Total   248/406 (61.08%)   243/397 (61.21%) 
Blood and lymphatic system disorders     
Anaemia † 1  9/406 (2.22%)  15/397 (3.78%) 
Febrile neutropenia † 1  1/406 (0.25%)  0/397 (0.00%) 
Methaemoglobinaemia † 1  0/406 (0.00%)  1/397 (0.25%) 
Pancytopenia † 1  1/406 (0.25%)  0/397 (0.00%) 
Cardiac disorders     
Acute coronary syndrome † 1  3/406 (0.74%)  1/397 (0.25%) 
Acute myocardial infarction † 1  1/406 (0.25%)  1/397 (0.25%) 
Angina pectoris † 1  3/406 (0.74%)  0/397 (0.00%) 
Arrhythmia † 1  1/406 (0.25%)  0/397 (0.00%) 
Atrial fibrillation † 1  2/406 (0.49%)  3/397 (0.76%) 
Atrial flutter † 1  1/406 (0.25%)  1/397 (0.25%) 
Atrioventricular block † 1  1/406 (0.25%)  0/397 (0.00%) 
Cardiac arrest † 1  0/406 (0.00%)  1/397 (0.25%) 
Cardiac failure † 1  4/406 (0.99%)  1/397 (0.25%) 
Cardiac failure chronic † 1  0/406 (0.00%)  1/397 (0.25%) 
Cardiac failure congestive † 1  0/406 (0.00%)  3/397 (0.76%) 
Cardiac ventricular thrombosis † 1  1/406 (0.25%)  0/397 (0.00%) 
Cardio-respiratory arrest † 1  1/406 (0.25%)  0/397 (0.00%) 
Left ventricular dysfunction † 1  1/406 (0.25%)  1/397 (0.25%) 
Myocardial infarction † 1  7/406 (1.72%)  2/397 (0.50%) 
Pericardial effusion † 1  0/406 (0.00%)  2/397 (0.50%) 
Supraventricular tachycardia † 1  0/406 (0.00%)  1/397 (0.25%) 
Congenital, familial and genetic disorders     
Pancreas divisum † 1  1/406 (0.25%)  0/397 (0.00%) 
Ear and labyrinth disorders     
Tympanic membrane perforation † 1  1/406 (0.25%)  0/397 (0.00%) 
Endocrine disorders     
Adrenal insufficiency † 1  3/406 (0.74%)  1/397 (0.25%) 
Hypercalcaemia of malignancy † 1  1/406 (0.25%)  0/397 (0.00%) 
Hypopituitarism † 1  1/406 (0.25%)  0/397 (0.00%) 
Eye disorders     
Corneal disorder † 1  1/406 (0.25%)  0/397 (0.00%) 
Retinal detachment † 1  0/406 (0.00%)  1/397 (0.25%) 
Visual impairment † 1  1/406 (0.25%)  0/397 (0.00%) 
Gastrointestinal disorders     
Abdominal pain † 1  5/406 (1.23%)  4/397 (1.01%) 
Abdominal pain upper † 1  0/406 (0.00%)  1/397 (0.25%) 
Ascites † 1  1/406 (0.25%)  3/397 (0.76%) 
Autoimmune colitis † 1  0/406 (0.00%)  1/397 (0.25%) 
Colitis † 1  3/406 (0.74%)  0/397 (0.00%) 
Constipation † 1  5/406 (1.23%)  2/397 (0.50%) 
Diabetic gastroparesis † 1  1/406 (0.25%)  0/397 (0.00%) 
Diarrhoea † 1  8/406 (1.97%)  3/397 (0.76%) 
Enterocolitis † 1  1/406 (0.25%)  1/397 (0.25%) 
Food poisoning † 1  0/406 (0.00%)  1/397 (0.25%) 
Gastrointestinal haemorrhage † 1  0/406 (0.00%)  1/397 (0.25%) 
Haemoperitoneum † 1  0/406 (0.00%)  1/397 (0.25%) 
Ileus † 1  1/406 (0.25%)  0/397 (0.00%) 
Immune-mediated enterocolitis † 1  0/406 (0.00%)  1/397 (0.25%) 
Intestinal ischaemia † 1  0/406 (0.00%)  1/397 (0.25%) 
Intestinal obstruction † 1  1/406 (0.25%)  1/397 (0.25%) 
Intra-abdominal haemorrhage † 1  0/406 (0.00%)  1/397 (0.25%) 
Large intestinal haemorrhage † 1  1/406 (0.25%)  0/397 (0.00%) 
Large intestinal obstruction † 1  1/406 (0.25%)  0/397 (0.00%) 
Large intestine perforation † 1  2/406 (0.49%)  0/397 (0.00%) 
Lower gastrointestinal haemorrhage † 1  1/406 (0.25%)  0/397 (0.00%) 
Melaena † 1  2/406 (0.49%)  0/397 (0.00%) 
Nausea † 1  3/406 (0.74%)  2/397 (0.50%) 
Oesophageal obstruction † 1  1/406 (0.25%)  0/397 (0.00%) 
Pancreatitis † 1  2/406 (0.49%)  0/397 (0.00%) 
Pneumoperitoneum † 1  0/406 (0.00%)  1/397 (0.25%) 
Rectal haemorrhage † 1  2/406 (0.49%)  1/397 (0.25%) 
Small intestinal obstruction † 1  1/406 (0.25%)  6/397 (1.51%) 
Small intestinal perforation † 1  0/406 (0.00%)  1/397 (0.25%) 
Stomatitis † 1  0/406 (0.00%)  1/397 (0.25%) 
Umbilical hernia † 1  1/406 (0.25%)  0/397 (0.00%) 
Upper gastrointestinal haemorrhage † 1  0/406 (0.00%)  1/397 (0.25%) 
Vomiting † 1  3/406 (0.74%)  0/397 (0.00%) 
General disorders     
Asthenia † 1  1/406 (0.25%)  0/397 (0.00%) 
Chest pain † 1  1/406 (0.25%)  0/397 (0.00%) 
Chills † 1  0/406 (0.00%)  1/397 (0.25%) 
Disease progression † 1  1/406 (0.25%)  2/397 (0.50%) 
Fatigue † 1  2/406 (0.49%)  3/397 (0.76%) 
Gait disturbance † 1  1/406 (0.25%)  0/397 (0.00%) 
General physical health deterioration † 1  4/406 (0.99%)  5/397 (1.26%) 
Hernia † 1  0/406 (0.00%)  1/397 (0.25%) 
Hernia pain † 1  0/406 (0.00%)  1/397 (0.25%) 
Hyperpyrexia † 1  1/406 (0.25%)  0/397 (0.00%) 
Inadequate analgesia † 1  2/406 (0.49%)  0/397 (0.00%) 
Influenza like illness † 1  1/406 (0.25%)  0/397 (0.00%) 
Multiple organ dysfunction syndrome † 1  1/406 (0.25%)  1/397 (0.25%) 
Non-cardiac chest pain † 1  2/406 (0.49%)  2/397 (0.50%) 
Oedema peripheral † 1  2/406 (0.49%)  2/397 (0.50%) 
Pain † 1  4/406 (0.99%)  3/397 (0.76%) 
Performance status decreased † 1  0/406 (0.00%)  1/397 (0.25%) 
Peripheral swelling † 1  1/406 (0.25%)  0/397 (0.00%) 
Polyp † 1  0/406 (0.00%)  1/397 (0.25%) 
Pyrexia † 1  7/406 (1.72%)  6/397 (1.51%) 
Systemic inflammatory response syndrome † 1  1/406 (0.25%)  0/397 (0.00%) 
Hepatobiliary disorders     
Biliary colic † 1  1/406 (0.25%)  1/397 (0.25%) 
Biliary obstruction † 1  0/406 (0.00%)  2/397 (0.50%) 
Cholecystitis † 1  1/406 (0.25%)  1/397 (0.25%) 
Hepatic cytolysis † 1  1/406 (0.25%)  0/397 (0.00%) 
Hepatic function abnormal † 1  1/406 (0.25%)  0/397 (0.00%) 
Hepatic pain † 1  1/406 (0.25%)  0/397 (0.00%) 
Hepatitis acute † 1  1/406 (0.25%)  1/397 (0.25%) 
Hepatorenal failure † 1  1/406 (0.25%)  0/397 (0.00%) 
Immune-mediated hepatitis † 1  1/406 (0.25%)  0/397 (0.00%) 
Jaundice cholestatic † 1  1/406 (0.25%)  0/397 (0.00%) 
Immune system disorders     
Anaphylactic reaction † 1  1/406 (0.25%)  0/397 (0.00%) 
Hypersensitivity † 1  0/406 (0.00%)  1/397 (0.25%) 
Infections and infestations     
Abdominal infection † 1  0/406 (0.00%)  1/397 (0.25%) 
Anal abscess † 1  1/406 (0.25%)  0/397 (0.00%) 
Appendicitis † 1  1/406 (0.25%)  1/397 (0.25%) 
Brain abscess † 1  1/406 (0.25%)  0/397 (0.00%) 
Bronchiolitis † 1  1/406 (0.25%)  0/397 (0.00%) 
Bronchitis † 1  2/406 (0.49%)  0/397 (0.00%) 
Cellulitis † 1  2/406 (0.49%)  2/397 (0.50%) 
Cystitis † 1  1/406 (0.25%)  0/397 (0.00%) 
Device related sepsis † 1  0/406 (0.00%)  2/397 (0.50%) 
Escherichia infection † 1  0/406 (0.00%)  1/397 (0.25%) 
Febrile infection † 1  1/406 (0.25%)  0/397 (0.00%) 
Gastroenteritis † 1  1/406 (0.25%)  2/397 (0.50%) 
Gastroenteritis viral † 1  1/406 (0.25%)  0/397 (0.00%) 
Genital infection fungal † 1  1/406 (0.25%)  0/397 (0.00%) 
Groin infection † 1  0/406 (0.00%)  1/397 (0.25%) 
Herpes zoster † 1  0/406 (0.00%)  1/397 (0.25%) 
Infection † 1  1/406 (0.25%)  1/397 (0.25%) 
Infective exacerbation of chronic obstructive airways disease † 1  1/406 (0.25%)  0/397 (0.00%) 
Influenza † 1  2/406 (0.49%)  1/397 (0.25%) 
Lower respiratory tract infection † 1  0/406 (0.00%)  2/397 (0.50%) 
Lymphangitis † 1  0/406 (0.00%)  1/397 (0.25%) 
Meningitis † 1  0/406 (0.00%)  1/397 (0.25%) 
Periorbital cellulitis † 1  1/406 (0.25%)  0/397 (0.00%) 
Peritonitis bacterial † 1  0/406 (0.00%)  1/397 (0.25%) 
Pneumocystis jirovecii pneumonia † 1  0/406 (0.00%)  1/397 (0.25%) 
Pneumonia † 1  19/406 (4.68%)  25/397 (6.30%) 
Pneumonia mycoplasmal † 1  0/406 (0.00%)  1/397 (0.25%) 
Psoas abscess † 1  1/406 (0.25%)  0/397 (0.00%) 
Respiratory tract infection † 1  1/406 (0.25%)  0/397 (0.00%) 
Sepsis † 1  9/406 (2.22%)  3/397 (0.76%) 
Septic shock † 1  0/406 (0.00%)  1/397 (0.25%) 
Skin infection † 1  1/406 (0.25%)  1/397 (0.25%) 
Soft tissue infection † 1  1/406 (0.25%)  0/397 (0.00%) 
Spinal cord infection † 1  2/406 (0.49%)  0/397 (0.00%) 
Splenic infection † 1  0/406 (0.00%)  1/397 (0.25%) 
Staphylococcal bacteraemia † 1  1/406 (0.25%)  0/397 (0.00%) 
Upper respiratory tract infection † 1  0/406 (0.00%)  1/397 (0.25%) 
Urinary tract infection † 1  3/406 (0.74%)  5/397 (1.26%) 
Urosepsis † 1  4/406 (0.99%)  0/397 (0.00%) 
Wound infection † 1  1/406 (0.25%)  0/397 (0.00%) 
Injury, poisoning and procedural complications     
Cervical vertebral fracture † 1  0/406 (0.00%)  1/397 (0.25%) 
Clavicle fracture † 1  1/406 (0.25%)  0/397 (0.00%) 
Contusion † 1  0/406 (0.00%)  1/397 (0.25%) 
Fall † 1  1/406 (0.25%)  1/397 (0.25%) 
Femur fracture † 1  1/406 (0.25%)  2/397 (0.50%) 
Humerus fracture † 1  3/406 (0.74%)  1/397 (0.25%) 
Incision site impaired healing † 1  0/406 (0.00%)  1/397 (0.25%) 
Incisional hernia † 1  0/406 (0.00%)  1/397 (0.25%) 
Ligament sprain † 1  0/406 (0.00%)  1/397 (0.25%) 
Overdose † 1  0/406 (0.00%)  1/397 (0.25%) 
Post procedural complication † 1  1/406 (0.25%)  0/397 (0.00%) 
Post procedural swelling † 1  0/406 (0.00%)  1/397 (0.25%) 
Procedural pain † 1  0/406 (0.00%)  1/397 (0.25%) 
Product administration error † 1  1/406 (0.25%)  0/397 (0.00%) 
Spinal compression fracture † 1  1/406 (0.25%)  1/397 (0.25%) 
Spinal fracture † 1  0/406 (0.00%)  1/397 (0.25%) 
Toxicity to various agents † 1  1/406 (0.25%)  0/397 (0.00%) 
Wound complication † 1  1/406 (0.25%)  0/397 (0.00%) 
Investigations     
Alanine aminotransferase increased † 1  2/406 (0.49%)  0/397 (0.00%) 
Aspartate aminotransferase increased † 1  2/406 (0.49%)  0/397 (0.00%) 
Blood bilirubin increased † 1  1/406 (0.25%)  0/397 (0.00%) 
Blood creatinine increased † 1  2/406 (0.49%)  3/397 (0.76%) 
Blood culture positive † 1  1/406 (0.25%)  0/397 (0.00%) 
Blood glucose increased † 1  1/406 (0.25%)  0/397 (0.00%) 
Blood potassium increased † 1  0/406 (0.00%)  1/397 (0.25%) 
Gamma-glutamyltransferase increased † 1  1/406 (0.25%)  0/397 (0.00%) 
General physical condition abnormal † 1  1/406 (0.25%)  2/397 (0.50%) 
Haemoglobin decreased † 1  2/406 (0.49%)  0/397 (0.00%) 
Lipase increased † 1  1/406 (0.25%)  0/397 (0.00%) 
Pancreatic enzymes increased † 1  0/406 (0.00%)  1/397 (0.25%) 
Transaminases increased † 1  1/406 (0.25%)  0/397 (0.00%) 
Viral test positive † 1  1/406 (0.25%)  0/397 (0.00%) 
Metabolism and nutrition disorders     
Cachexia † 1  0/406 (0.00%)  1/397 (0.25%) 
Decreased appetite † 1  3/406 (0.74%)  0/397 (0.00%) 
Dehydration † 1  0/406 (0.00%)  5/397 (1.26%) 
Diabetes mellitus † 1  1/406 (0.25%)  1/397 (0.25%) 
Diabetes mellitus inadequate control † 1  0/406 (0.00%)  2/397 (0.50%) 
Diabetic ketoacidosis † 1  1/406 (0.25%)  1/397 (0.25%) 
Glucose tolerance impaired † 1  0/406 (0.00%)  1/397 (0.25%) 
Hypercalcaemia † 1  10/406 (2.46%)  5/397 (1.26%) 
Hyperglycaemia † 1  5/406 (1.23%)  5/397 (1.26%) 
Hyperkalaemia † 1  1/406 (0.25%)  1/397 (0.25%) 
Hypoglycaemia † 1  0/406 (0.00%)  1/397 (0.25%) 
Hyponatraemia † 1  3/406 (0.74%)  4/397 (1.01%) 
Type 2 diabetes mellitus † 1  0/406 (0.00%)  1/397 (0.25%) 
Musculoskeletal and connective tissue disorders     
Arthralgia † 1  4/406 (0.99%)  2/397 (0.50%) 
Back disorder † 1  0/406 (0.00%)  1/397 (0.25%) 
Back pain † 1  9/406 (2.22%)  7/397 (1.76%) 
Bone disorder † 1  1/406 (0.25%)  0/397 (0.00%) 
Bone lesion † 1  0/406 (0.00%)  1/397 (0.25%) 
Bone pain † 1  3/406 (0.74%)  1/397 (0.25%) 
Flank pain † 1  1/406 (0.25%)  0/397 (0.00%) 
Muscular weakness † 1  1/406 (0.25%)  3/397 (0.76%) 
Musculoskeletal chest pain † 1  1/406 (0.25%)  2/397 (0.50%) 
Musculoskeletal stiffness † 1  1/406 (0.25%)  0/397 (0.00%) 
Neck pain † 1  2/406 (0.49%)  1/397 (0.25%) 
Osteitis † 1  1/406 (0.25%)  0/397 (0.00%) 
Osteolysis † 1  2/406 (0.49%)  1/397 (0.25%) 
Osteonecrosis † 1  1/406 (0.25%)  0/397 (0.00%) 
Osteonecrosis of jaw † 1  3/406 (0.74%)  0/397 (0.00%) 
Osteoporosis † 1  1/406 (0.25%)  0/397 (0.00%) 
Pain in extremity † 1  3/406 (0.74%)  1/397 (0.25%) 
Pathological fracture † 1  5/406 (1.23%)  4/397 (1.01%) 
Soft tissue necrosis † 1  1/406 (0.25%)  0/397 (0.00%) 
Spinal pain † 1  1/406 (0.25%)  0/397 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Acoustic neuroma † 1  0/406 (0.00%)  1/397 (0.25%) 
Acute lymphocytic leukaemia † 1  1/406 (0.25%)  0/397 (0.00%) 
Basal cell carcinoma † 1  3/406 (0.74%)  1/397 (0.25%) 
Breast cancer † 1  0/406 (0.00%)  1/397 (0.25%) 
Cancer pain † 1  4/406 (0.99%)  0/397 (0.00%) 
Duodenal neoplasm † 1  0/406 (0.00%)  1/397 (0.25%) 
Intracranial tumour haemorrhage † 1  1/406 (0.25%)  0/397 (0.00%) 
Lung adenocarcinoma † 1  1/406 (0.25%)  0/397 (0.00%) 
Lung neoplasm malignant † 1  1/406 (0.25%)  0/397 (0.00%) 
Lymphangiosis carcinomatosa † 1  0/406 (0.00%)  1/397 (0.25%) 
Malignant melanoma † 1  1/406 (0.25%)  1/397 (0.25%) 
Malignant melanoma in situ † 1  1/406 (0.25%)  0/397 (0.00%) 
Malignant neoplasm progression † 1  64/406 (15.76%)  85/397 (21.41%) 
Metastases to abdominal cavity † 1  0/406 (0.00%)  1/397 (0.25%) 
Metastases to adrenals † 1  1/406 (0.25%)  0/397 (0.00%) 
Metastases to bone † 1  2/406 (0.49%)  2/397 (0.50%) 
Metastases to central nervous system † 1  7/406 (1.72%)  1/397 (0.25%) 
Metastases to lung † 1  3/406 (0.74%)  3/397 (0.76%) 
Metastases to pancreas † 1  2/406 (0.49%)  1/397 (0.25%) 
Metastases to peritoneum † 1  0/406 (0.00%)  1/397 (0.25%) 
Metastases to spine † 1  0/406 (0.00%)  1/397 (0.25%) 
Metastases to thyroid † 1  0/406 (0.00%)  1/397 (0.25%) 
Metastatic neoplasm † 1  0/406 (0.00%)  1/397 (0.25%) 
Metastatic renal cell carcinoma † 1  4/406 (0.99%)  1/397 (0.25%) 
Neoplasm † 1  0/406 (0.00%)  1/397 (0.25%) 
Neoplasm malignant † 1  1/406 (0.25%)  0/397 (0.00%) 
Oesophageal adenocarcinoma † 1  0/406 (0.00%)  1/397 (0.25%) 
Renal cell carcinoma recurrent † 1  0/406 (0.00%)  1/397 (0.25%) 
Skin cancer metastatic † 1  0/406 (0.00%)  1/397 (0.25%) 
Squamous cell carcinoma † 1  2/406 (0.49%)  1/397 (0.25%) 
Tumour pain † 1  3/406 (0.74%)  2/397 (0.50%) 
Nervous system disorders     
Central nervous system haemorrhage † 1  1/406 (0.25%)  0/397 (0.00%) 
Cerebral haemorrhage † 1  2/406 (0.49%)  1/397 (0.25%) 
Cerebral ischaemia † 1  2/406 (0.49%)  0/397 (0.00%) 
Cerebrovascular accident † 1  3/406 (0.74%)  6/397 (1.51%) 
Dizziness † 1  1/406 (0.25%)  0/397 (0.00%) 
Dural arteriovenous fistula † 1  1/406 (0.25%)  0/397 (0.00%) 
Encephalopathy † 1  1/406 (0.25%)  0/397 (0.00%) 
Epilepsy † 1  0/406 (0.00%)  1/397 (0.25%) 
Facial spasm † 1  0/406 (0.00%)  1/397 (0.25%) 
Haemorrhage intracranial † 1  2/406 (0.49%)  0/397 (0.00%) 
Hyperammonaemic encephalopathy † 1  0/406 (0.00%)  1/397 (0.25%) 
Immune-mediated encephalitis † 1  0/406 (0.00%)  1/397 (0.25%) 
Intracranial pressure increased † 1  0/406 (0.00%)  1/397 (0.25%) 
Intraventricular haemorrhage † 1  1/406 (0.25%)  0/397 (0.00%) 
Memory impairment † 1  1/406 (0.25%)  0/397 (0.00%) 
Nerve compression † 1  0/406 (0.00%)  1/397 (0.25%) 
Nervous system disorder † 1  1/406 (0.25%)  0/397 (0.00%) 
Seizure † 1  0/406 (0.00%)  2/397 (0.50%) 
Somnolence † 1  1/406 (0.25%)  0/397 (0.00%) 
Spinal cord compression † 1  9/406 (2.22%)  1/397 (0.25%) 
Syncope † 1  2/406 (0.49%)  0/397 (0.00%) 
Thalamus haemorrhage † 1  0/406 (0.00%)  1/397 (0.25%) 
Transient ischaemic attack † 1  0/406 (0.00%)  1/397 (0.25%) 
Vasogenic cerebral oedema † 1  1/406 (0.25%)  0/397 (0.00%) 
Product Issues     
Device loosening † 1  0/406 (0.00%)  1/397 (0.25%) 
Psychiatric disorders     
Completed suicide † 1  1/406 (0.25%)  1/397 (0.25%) 
Confusional state † 1  3/406 (0.74%)  1/397 (0.25%) 
Delirium † 1  0/406 (0.00%)  1/397 (0.25%) 
Mental disorder † 1  1/406 (0.25%)  0/397 (0.00%) 
Mental status changes † 1  1/406 (0.25%)  0/397 (0.00%) 
Renal and urinary disorders     
Acute kidney injury † 1  12/406 (2.96%)  6/397 (1.51%) 
Dysuria † 1  0/406 (0.00%)  1/397 (0.25%) 
Haematuria † 1  0/406 (0.00%)  3/397 (0.76%) 
Nephrolithiasis † 1  1/406 (0.25%)  2/397 (0.50%) 
Renal colic † 1  0/406 (0.00%)  1/397 (0.25%) 
Renal failure † 1  7/406 (1.72%)  6/397 (1.51%) 
Renal impairment † 1  2/406 (0.49%)  1/397 (0.25%) 
Renal mass † 1  1/406 (0.25%)  1/397 (0.25%) 
Renal tubular necrosis † 1  0/406 (0.00%)  1/397 (0.25%) 
Tubulointerstitial nephritis † 1  1/406 (0.25%)  0/397 (0.00%) 
Urinary incontinence † 1  0/406 (0.00%)  1/397 (0.25%) 
Urinary tract obstruction † 1  2/406 (0.49%)  0/397 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema † 1  0/406 (0.00%)  1/397 (0.25%) 
Acute respiratory failure † 1  1/406 (0.25%)  2/397 (0.50%) 
Asthma † 1  1/406 (0.25%)  0/397 (0.00%) 
Atelectasis † 1  0/406 (0.00%)  1/397 (0.25%) 
Bronchial obstruction † 1  1/406 (0.25%)  1/397 (0.25%) 
Chronic obstructive pulmonary disease † 1  1/406 (0.25%)  1/397 (0.25%) 
Cough † 1  1/406 (0.25%)  1/397 (0.25%) 
Dyspnoea † 1  9/406 (2.22%)  8/397 (2.02%) 
Haemoptysis † 1  4/406 (0.99%)  4/397 (1.01%) 
Hypoxia † 1  2/406 (0.49%)  2/397 (0.50%) 
Interstitial lung disease † 1  0/406 (0.00%)  3/397 (0.76%) 
Lung disorder † 1  0/406 (0.00%)  1/397 (0.25%) 
Organising pneumonia † 1  1/406 (0.25%)  0/397 (0.00%) 
Pleural effusion † 1  16/406 (3.94%)  19/397 (4.79%) 
Pleurisy † 1  1/406 (0.25%)  0/397 (0.00%) 
Pneumonitis † 1  10/406 (2.46%)  13/397 (3.27%) 
Pneumothorax † 1  1/406 (0.25%)  0/397 (0.00%) 
Pneumothorax spontaneous † 1  0/406 (0.00%)  1/397 (0.25%) 
Pulmonary embolism † 1  4/406 (0.99%)  8/397 (2.02%) 
Pulmonary haemorrhage † 1  2/406 (0.49%)  1/397 (0.25%) 
Pulmonary infarction † 1  0/406 (0.00%)  1/397 (0.25%) 
Pulmonary mass † 1  1/406 (0.25%)  0/397 (0.00%) 
Pulmonary oedema † 1  1/406 (0.25%)  0/397 (0.00%) 
Respiratory distress † 1  0/406 (0.00%)  1/397 (0.25%) 
Respiratory failure † 1  0/406 (0.00%)  3/397 (0.76%) 
Skin and subcutaneous tissue disorders     
Acute febrile neutrophilic dermatosis † 1  0/406 (0.00%)  1/397 (0.25%) 
Angioedema † 1  0/406 (0.00%)  2/397 (0.50%) 
Erythema multiforme † 1  1/406 (0.25%)  1/397 (0.25%) 
Rash † 1  1/406 (0.25%)  0/397 (0.00%) 
Rash maculo-papular † 1  2/406 (0.49%)  0/397 (0.00%) 
Skin lesion † 1  1/406 (0.25%)  0/397 (0.00%) 
Vascular disorders     
Aortic dissection † 1  1/406 (0.25%)  0/397 (0.00%) 
Circulatory collapse † 1  0/406 (0.00%)  1/397 (0.25%) 
Hypertension † 1  1/406 (0.25%)  1/397 (0.25%) 
Hypertensive crisis † 1  1/406 (0.25%)  0/397 (0.00%) 
Hypotension † 1  3/406 (0.74%)  1/397 (0.25%) 
Lymphoedema † 1  0/406 (0.00%)  1/397 (0.25%) 
Orthostatic hypotension † 1  1/406 (0.25%)  0/397 (0.00%) 
Thrombosis † 1  0/406 (0.00%)  1/397 (0.25%) 
Venous thrombosis † 1  1/406 (0.25%)  0/397 (0.00%) 
1
Term from vocabulary, 24.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
NIVOLUMAB EVEROLIMUS
Affected / at Risk (%) Affected / at Risk (%)
Total   392/406 (96.55%)   379/397 (95.47%) 
Blood and lymphatic system disorders     
Anaemia † 1  93/406 (22.91%)  149/397 (37.53%) 
Endocrine disorders     
Hypothyroidism † 1  39/406 (9.61%)  15/397 (3.78%) 
Gastrointestinal disorders     
Abdominal pain † 1  46/406 (11.33%)  44/397 (11.08%) 
Abdominal pain upper † 1  27/406 (6.65%)  22/397 (5.54%) 
Constipation † 1  110/406 (27.09%)  93/397 (23.43%) 
Diarrhoea † 1  122/406 (30.05%)  141/397 (35.52%) 
Dry mouth † 1  30/406 (7.39%)  25/397 (6.30%) 
Dyspepsia † 1  15/406 (3.69%)  20/397 (5.04%) 
Nausea † 1  135/406 (33.25%)  139/397 (35.01%) 
Stomatitis † 1  29/406 (7.14%)  125/397 (31.49%) 
Vomiting † 1  77/406 (18.97%)  80/397 (20.15%) 
General disorders     
Asthenia † 1  44/406 (10.84%)  71/397 (17.88%) 
Chills † 1  32/406 (7.88%)  30/397 (7.56%) 
Fatigue † 1  215/406 (52.96%)  196/397 (49.37%) 
Malaise † 1  22/406 (5.42%)  14/397 (3.53%) 
Mucosal inflammation † 1  21/406 (5.17%)  89/397 (22.42%) 
Oedema peripheral † 1  73/406 (17.98%)  110/397 (27.71%) 
Pain † 1  21/406 (5.17%)  26/397 (6.55%) 
Pyrexia † 1  81/406 (19.95%)  84/397 (21.16%) 
Infections and infestations     
Nasopharyngitis † 1  43/406 (10.59%)  25/397 (6.30%) 
Pneumonia † 1  11/406 (2.71%)  29/397 (7.30%) 
Sinusitis † 1  10/406 (2.46%)  22/397 (5.54%) 
Upper respiratory tract infection † 1  34/406 (8.37%)  26/397 (6.55%) 
Urinary tract infection † 1  24/406 (5.91%)  25/397 (6.30%) 
Investigations     
Alanine aminotransferase increased † 1  29/406 (7.14%)  30/397 (7.56%) 
Aspartate aminotransferase increased † 1  34/406 (8.37%)  33/397 (8.31%) 
Blood alkaline phosphatase increased † 1  29/406 (7.14%)  18/397 (4.53%) 
Blood cholesterol increased † 1  8/406 (1.97%)  31/397 (7.81%) 
Blood creatinine increased † 1  62/406 (15.27%)  61/397 (15.37%) 
Platelet count decreased † 1  11/406 (2.71%)  21/397 (5.29%) 
Weight decreased † 1  58/406 (14.29%)  67/397 (16.88%) 
Metabolism and nutrition disorders     
Decreased appetite † 1  109/406 (26.85%)  145/397 (36.52%) 
Hypercalcaemia † 1  27/406 (6.65%)  17/397 (4.28%) 
Hypercholesterolaemia † 1  3/406 (0.74%)  38/397 (9.57%) 
Hyperglycaemia † 1  38/406 (9.36%)  66/397 (16.62%) 
Hyperkalaemia † 1  27/406 (6.65%)  20/397 (5.04%) 
Hypertriglyceridaemia † 1  24/406 (5.91%)  77/397 (19.40%) 
Hyponatraemia † 1  27/406 (6.65%)  24/397 (6.05%) 
Musculoskeletal and connective tissue disorders     
Arthralgia † 1  120/406 (29.56%)  79/397 (19.90%) 
Back pain † 1  99/406 (24.38%)  77/397 (19.40%) 
Bone pain † 1  19/406 (4.68%)  22/397 (5.54%) 
Flank pain † 1  22/406 (5.42%)  18/397 (4.53%) 
Muscle spasms † 1  23/406 (5.67%)  18/397 (4.53%) 
Musculoskeletal chest pain † 1  32/406 (7.88%)  22/397 (5.54%) 
Myalgia † 1  40/406 (9.85%)  24/397 (6.05%) 
Pain in extremity † 1  60/406 (14.78%)  45/397 (11.34%) 
Nervous system disorders     
Dizziness † 1  40/406 (9.85%)  37/397 (9.32%) 
Dysgeusia † 1  9/406 (2.22%)  40/397 (10.08%) 
Headache † 1  65/406 (16.01%)  66/397 (16.62%) 
Taste disorder † 1  9/406 (2.22%)  21/397 (5.29%) 
Psychiatric disorders     
Anxiety † 1  33/406 (8.13%)  25/397 (6.30%) 
Depression † 1  25/406 (6.16%)  14/397 (3.53%) 
Insomnia † 1  40/406 (9.85%)  38/397 (9.57%) 
Renal and urinary disorders     
Pollakiuria † 1  21/406 (5.17%)  15/397 (3.78%) 
Respiratory, thoracic and mediastinal disorders     
Cough † 1  146/406 (35.96%)  152/397 (38.29%) 
Dysphonia † 1  36/406 (8.87%)  32/397 (8.06%) 
Dyspnoea † 1  101/406 (24.88%)  114/397 (28.72%) 
Dyspnoea exertional † 1  26/406 (6.40%)  28/397 (7.05%) 
Epistaxis † 1  19/406 (4.68%)  66/397 (16.62%) 
Haemoptysis † 1  22/406 (5.42%)  17/397 (4.28%) 
Nasal congestion † 1  24/406 (5.91%)  15/397 (3.78%) 
Oropharyngeal pain † 1  21/406 (5.17%)  27/397 (6.80%) 
Pleural effusion † 1  13/406 (3.20%)  22/397 (5.54%) 
Pneumonitis † 1  24/406 (5.91%)  56/397 (14.11%) 
Productive cough † 1  23/406 (5.67%)  25/397 (6.30%) 
Skin and subcutaneous tissue disorders     
Dermatitis acneiform † 1  14/406 (3.45%)  24/397 (6.05%) 
Dry skin † 1  50/406 (12.32%)  50/397 (12.59%) 
Palmar-plantar erythrodysaesthesia syndrome † 1  22/406 (5.42%)  38/397 (9.57%) 
Pruritus † 1  92/406 (22.66%)  64/397 (16.12%) 
Rash † 1  86/406 (21.18%)  101/397 (25.44%) 
Rash maculo-papular † 1  21/406 (5.17%)  24/397 (6.05%) 
Vascular disorders     
Hypertension † 1  49/406 (12.07%)  47/397 (11.84%) 
Hypotension † 1  24/406 (5.91%)  11/397 (2.77%) 
1
Term from vocabulary, 24.0
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
EMail: Clinical.Trials@bms.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01668784    
Other Study ID Numbers: CA209-025
2011-005132-26 ( EudraCT Number )
First Submitted: August 16, 2012
First Posted: August 20, 2012
Results First Submitted: March 28, 2016
Results First Posted: April 29, 2016
Last Update Posted: August 9, 2022