Advanced Renal Cell Carcinoma, Metastatic Renal Cell Carcinoma
Conditions
Brief summary
The purpose of this study is to compare the objective response rate, progression free survival and the overall survival of Nivolumab combined with Ipilimumab to Sunitinib monotherapy in patients with previously untreated Renal Cell Cancer.
Interventions
BIOLOGICALNivolumab
BIOLOGICALIpilimumab
DRUGSunitinib
Sponsors
Bristol-Myers Squibb
Ono Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Histological confirmation of renal cell carcinoma (RCC) with a clear-cell component * Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC * No prior systemic therapy for RCC with the following exception: 1. One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets vascular endothelial growth factor (VEGF) or VEGF receptors and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy * Karnofsky Performance Status (KPS) of at least 70% * Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * Tumor tissue \[formalin-fixed paraffin-embedded (FFPE) archival or recent acquisition\] must be received by the central vendor (block or unstained slides) in order to randomize a subject to study treatment. (Note: Fine Needle Aspiration \[FNA\] and bone metastases samples are not acceptable for submission)
Exclusion criteria
* Any history of or current central nervous system (CNS) metastases. Baseline imaging of the brain is required within 28 days prior to randomization * Prior systemic treatment with VEGF or VEGF receptor targeted therapy (including, but not limited to, Sunitinib, Pazopanib, Axitinib, Tivozanib, and Bevacizumab) * Prior treatment with an anti-programmed death (PD)-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways * Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (\>10 mg daily Prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll * Any condition requiring systemic treatment with corticosteroids (\>10 mg daily Prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses \>10 mg daily Prednisone equivalents are permitted in the absence of active autoimmune disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) in Intermediate/Poor Risk Participants Per Independent Radiology Review Committee (IRRC) Using RECIST v1.1 | From first dose until date of documented disease progression or subsequent therapy, whichever occurs first (assessed up to June 2017, approximately 31 months) | ORR was defined as the proportion of randomized subjects who achieved a best response of complete response (CR) or partial response (PR) using the RECIST v1.1 criteria based on Independent Radiology Review Committee (IRRC) assessment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), greater than or equal to 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
| Overall Survival (OS) in Intermediate/Poor-Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | From the date of randomization to the date of death (assessed up to June 2017, approximately 31 months) | OS was defined as the time from randomization to the date of death from any cause. Survival time was censored at the date of last contact ("last known alive date") for subjects who were alive. |
| Progression-Free Survival (PFS) in Intermediate/Poor-Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | From date of first dose to date of documented disease progression or death due to any cause, whichever occurs first (assessed up to June 2017, approximately 31 months) | PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the IRRC (as per RECIST 1.1 criteria), or death due to any cause, whichever occurred first. Subsequent therapy included anticancer therapy, tumor directed radiotherapy, or tumor directed surgery. Subjects who died without a reported progression were considered to have progressed on the date of their death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed Objective Response Rate(ORR) in Any Risk Participants Per IRRC Using RECIST v1.1 | From the date of randomization until date of documented disease progression or subsequent therapy, whichever occurs first (assessed up to approximately 125 months and 6 days) | ORR was defined as the proportion of randomized subjects who achieved a best response of complete response (CR) or partial response (PR) using the RECIST v1.1 criteria based on IRRC assessment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), greater than or equal to 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
| Overall Survival (OS) in Any Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | From the date of randomization to the date of death (assessed up to approximately 125 months and 6 days) | Overall survival is defined as the time from randomization to the date of death from any cause. For subjects that are alive, their survival time will be censored at the date of last contact ("last known alive date"). Overall survival will be censored for subjects at the date of randomization if they were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after subject's off-treatment date. |
| Progression-Free Survival (PFS) in Any Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | From the date of randomization to date of documented disease progression or death due to any cause, whichever occurs first (assessed up to approximately 125 months and 6 days) | PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the IRRC (as per RECIST 1.1 criteria), or death due to any cause, whichever occurred first. Subsequent therapy included anticancer therapy, tumor directed radiotherapy, or tumor directed surgery. Subjects who died without a reported progression were considered to have progressed on the date of their death. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Czechia, Denmark, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Mexico, Netherlands, Poland, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORBristol-Myers Squibb
Bristol-Myers Squibb
Participant flow
Pre-assignment details
A total of 1096 participants were randomized, with 550 assigned to the Nivolumab + Ipilimumab group and 546 assigned to the Sunitinib group. Of these, 1082 participants received at least one dose of study treatment, including 547 in the Nivolumab + Ipilimumab group and 535 in the Sunitinib group.
Participants by arm
| Arm | Count |
|---|---|
| Nivolumab + Ipilimumab Nivolumab 3 mg/kg combined with Ipilimumab 1 mg/kg solutions intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solutions intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends | 550 |
| Sunitinib Sunitinib 50 mg capsules by mouth once daily for 4 weeks then 2 weeks off, continuously until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends After completion of final analysis eligible participants may switch from receiving Sunitinib to receiving Nivolumab 3 mg/kg IV combined with Ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then Nivolumab 240mg flat dose IV every 2 weeks | 546 |
| Total | 1,096 |
Baseline characteristics
| Characteristic | Total | Nivolumab + Ipilimumab | Sunitinib |
|---|---|---|---|
| Age, Continuous | 60.9 Years STANDARD_DEVIATION 9.93 | 61.1 Years STANDARD_DEVIATION 9.76 | 60.7 Years STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 29 Participants | 12 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 517 Participants | 264 Participants | 253 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 550 Participants | 274 Participants | 276 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 93 Participants | 46 Participants | 47 Participants |
| Race/Ethnicity, Customized Black or African American | 13 Participants | 7 Participants | 6 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 20 Participants | 10 Participants | 10 Participants |
| Race/Ethnicity, Customized White | 969 Participants | 486 Participants | 483 Participants |
| Sex: Female, Male Female | 288 Participants | 137 Participants | 151 Participants |
| Sex: Female, Male Male | 808 Participants | 413 Participants | 395 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 367 / 550 | 417 / 546 | 11 / 25 |
| other Total, other adverse events | 534 / 547 | 523 / 535 | 25 / 25 |
| serious Total, serious adverse events | 367 / 547 | 277 / 535 | 6 / 25 |
Outcome results
Primary
Investigator-assessed Objective Response Rate(ORR) in Intermediate/Poor Risk Participants Per IRRC Using RECIST v1.1
ORR was defined as the proportion of randomized subjects who achieved a best response of complete response (CR) or partial response (PR) using the RECIST v1.1 criteria based on IRRC assessment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), greater than or equal to 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: From first dose until date of documented disease progression or subsequent therapy, whichever occurs first (assessed up to June 2017, approximately 31 months)
Population: All Intermediate/Poor-Risk Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab + Ipilimumab | Investigator-assessed Objective Response Rate(ORR) in Intermediate/Poor Risk Participants Per IRRC Using RECIST v1.1 | 41.6 percentage of participants |
| Sunitinib | Investigator-assessed Objective Response Rate(ORR) in Intermediate/Poor Risk Participants Per IRRC Using RECIST v1.1 | 26.5 percentage of participants |
p-value: <0.000195% CI: [9.8, 22.2]DerSimonian and Laird Test
Primary
Overall Survival (OS) in Intermediate/Poor-Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC)
OS was defined as the time from randomization to the date of death from any cause. Survival time was censored at the date of last contact (last known alive date) for subjects who were alive.
Time frame: From the date of randomization to the date of death (assessed up to June 2017, approximately 31 months)
Population: All Intermediate/Poor-Risk Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Ipilimumab | Overall Survival (OS) in Intermediate/Poor-Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | NA months |
| Sunitinib | Overall Survival (OS) in Intermediate/Poor-Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | 25.95 months |
p-value: <0.000199.8% CI: [0.44, 0.89]Log Rank
Primary
Progression-Free Survival (PFS) in Intermediate/Poor-Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC)
PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the IRRC (as per RECIST 1.1 criteria), or death due to any cause, whichever occurred first. Subsequent therapy included anticancer therapy, tumor directed radiotherapy, or tumor directed surgery. Subjects who died without a reported progression were considered to have progressed on the date of their death.
Time frame: From date of first dose to date of documented disease progression or death due to any cause, whichever occurs first (assessed up to June 2017, approximately 31 months)
Population: All Intermediate/Poor-Risk Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Ipilimumab | Progression-Free Survival (PFS) in Intermediate/Poor-Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | 11.56 months |
| Sunitinib | Progression-Free Survival (PFS) in Intermediate/Poor-Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | 8.38 months |
p-value: 0.033199.1% CI: [0.64, 1.05]Log Rank
Secondary
Investigator-assessed Objective Response Rate(ORR) in Any Risk Participants Per IRRC Using RECIST v1.1
ORR was defined as the proportion of randomized subjects who achieved a best response of complete response (CR) or partial response (PR) using the RECIST v1.1 criteria based on IRRC assessment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), greater than or equal to 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: From first dose until date of documented disease progression or subsequent therapy, whichever occurs first (assessed up to June 2017, approximately 31 months)
Population: All Randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab + Ipilimumab | Investigator-assessed Objective Response Rate(ORR) in Any Risk Participants Per IRRC Using RECIST v1.1 | 38.7 percentage of participants |
| Sunitinib | Investigator-assessed Objective Response Rate(ORR) in Any Risk Participants Per IRRC Using RECIST v1.1 | 32.2 percentage of participants |
p-value: 0.019195% CI: [1.8, 12.7]DerSimonian and Laird Test
Secondary
Overall Survival (OS) in Any Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC)
Overall survival is defined as the time from randomization to the date of death from any cause. For subjects that are alive, their survival time will be censored at the date of last contact (last known alive date). Overall survival will be censored for subjects at the date of randomization if they were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after subject's off-treatment date.
Time frame: From the date of randomization to the date of death (assessed up to June 2017, approximately 31 months)
Population: All Randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Ipilimumab | Overall Survival (OS) in Any Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | NA months |
| Sunitinib | Overall Survival (OS) in Any Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | 32.92 months |
p-value: 0.000399.8% CI: [0.49, 0.95]Log Rank
Secondary
Progression-Free Survival (PFS) in Any Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC)
PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the IRRC (as per RECIST 1.1 criteria), or death due to any cause, whichever occurred first. Subsequent therapy included anticancer therapy, tumor directed radiotherapy, or tumor directed surgery. Subjects who died without a reported progression were considered to have progressed on the date of their death.
Time frame: From date of first dose to date of documented disease progression or death due to any cause, whichever occurs first (assessed up to June 2017, approximately 31 months)
Population: All Randomized
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Ipilimumab | Progression-Free Survival (PFS) in Any Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | 12.42 months |
| Sunitinib | Progression-Free Survival (PFS) in Any Risk Participants With Previously Untreated Metastatic Renal Cell Carcinoma (mRCC) | 12.32 months |
p-value: 0.849899.1% CI: [0.79, 1.23]Log Rank