Melanoma
Conditions
Brief summary
The purpose of this study is to determine whether an investigational immunotherapy Nivolumab, when combined with Ipilimumab, is more effective than Nivolumab by itself, in delaying the return of cancer in patients who have had a complete surgical removal of stage IIIb/c/d or stage IV Melanoma
Interventions
BIOLOGICALnivolumab
Specified Dose on Specified Days
BIOLOGICALipilimumab
Specified Dose on Specified Days
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Completely surgically resected stage IIIb/c/d or stage IV melanoma within 12 weeks of participation in study. * Must have full activity or, if limited, must be able to walk and carry out activities such as light house work or office work * No prior anti-cancer treatment for melanoma (except surgery for the melanoma lesion(s) and/or except for adjuvant radiation therapy (RT) after neurosurgical resection for central nervous system (CNS) lesions)
Exclusion criteria
* History of uveal melanoma * Patients with active, known or suspected autoimmune disease * Prior treatment with interferon (if complete \< 6 months prior to participation in study), anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-free Survival (RFS) - All Randomized Participants | From randomization to Primary Completion Date (up to approximately 3 years) | RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median values based on Kaplan-Meier Estimates. |
| Recurrence-free Survival (RFS) - All Randomized Participants With PD-L1 Expression Level < 1% | From randomization to Primary Completion Date (up to approximately 3 years) | RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | From randomization to Study Completion Date (up to approximately 45 months) | RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates. |
| Time to Next-Line Therapies - All Randomized Participants | From randomization to start of next therapy or second next therapy (up to approximately 45 months) | Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date. |
| Time to Next-Line Therapies - All Randomized Participants With PD-L1 Expression Level < 1% | From randomization to start of next therapy or second next therapy (up to approximately 45 months) | Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date |
| Overall Survival (OS) - All Randomized Participants | From randomization to date of death (up to approximately 45 months) | OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates. |
| Time From Next Therapy to Second Next Therapy - All Randomized Participants With PD-L1 Expression Level < 1% | From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months) | Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment. |
| Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants | From randomization to progression event (up to approximately 45 months) | PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death. |
| Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants With PD-L1 Expression Level < 1% | From randomization to progression event (up to approximately 45 months) | PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death. |
| Time From Next Therapy to Second Next Therapy - All Randomized Participants | From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months) | Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment. |
| Overall Survival (OS) - All Randomized Participants With PD-L1 Expression Level < 1% | From randomization to date of death (up to approximately 45 months) | OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates. |
Countries
Australia, Austria, Belgium, Brazil, Canada, Czechia, France, Germany, Greece, Israel, Italy, New Zealand, Poland, Romania, Russia, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
1844 participants randomized and 1833 treated. Reasons not treated: 1 disease progression; 2 participants withdrew consent; 1 poor/non-compliance; 4 participants no longer met study criteria; 3 not reported
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Nivo + Ipi Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment) | 920 |
| Arm B: Nivo Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49 | 924 |
| Total | 1,844 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Pre-treatment Period | Disease progression | 0 | 1 |
| Pre-treatment Period | Not reported | 2 | 1 |
| Pre-treatment Period | Participant no longer meets study criteria | 1 | 3 |
| Pre-treatment Period | Participant withdrew consent | 1 | 1 |
| Pre-treatment Period | Poor/non-compliance | 0 | 1 |
| Treatment Period | Adverse Event unrelated to study drug | 15 | 7 |
| Treatment Period | Disease progression | 166 | 208 |
| Treatment Period | Other reasons | 12 | 4 |
| Treatment Period | Participant no longer meets study criteria | 1 | 3 |
| Treatment Period | Participant request to stop therapy | 33 | 20 |
| Treatment Period | Participant withdrew consent | 5 | 10 |
| Treatment Period | Poor/non-compliance | 3 | 0 |
| Treatment Period | Study drug toxicity | 317 | 104 |
Baseline characteristics
| Characteristic | Arm A: Nivo + Ipi | Arm B: Nivo | Total |
|---|---|---|---|
| Age, Continuous | 53.8 Years STANDARD_DEVIATION 14.6 | 54.6 Years STANDARD_DEVIATION 13.7 | 54.2 Years STANDARD_DEVIATION 14.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 22 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 359 Participants | 376 Participants | 735 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 539 Participants | 526 Participants | 1065 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Black or African American | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Other | 6 Participants | 6 Participants | 12 Participants |
| Race/Ethnicity, Customized Race White | 907 Participants | 911 Participants | 1818 Participants |
| Sex: Female, Male Female | 405 Participants | 387 Participants | 792 Participants |
| Sex: Female, Male Male | 515 Participants | 537 Participants | 1052 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 122 / 916 | 121 / 917 |
| other Total, other adverse events | 868 / 916 | 844 / 917 |
| serious Total, serious adverse events | 374 / 916 | 242 / 917 |
Outcome results
Primary
Recurrence-free Survival (RFS) - All Randomized Participants
RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median values based on Kaplan-Meier Estimates.
Time frame: From randomization to Primary Completion Date (up to approximately 3 years)
Population: All randomized participants with completely resected stage IIIb/c/d or stage IV no evidence of disease (NED) melanoma
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivo + Ipi | Recurrence-free Survival (RFS) - All Randomized Participants | NA Months |
| Arm B: Nivo | Recurrence-free Survival (RFS) - All Randomized Participants | NA Months |
95% CI: [0.78, 1.04]
Primary
Recurrence-free Survival (RFS) - All Randomized Participants With PD-L1 Expression Level < 1%
RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates.
Time frame: From randomization to Primary Completion Date (up to approximately 3 years)
Population: All randomized participants with PD-L1 expression level \< 1% and with completely resected stage IIIb/c/d or stage IV no evidence of disease (NED) melanoma. PD-L1 expression levels based on Interactive Response Technology (IRT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivo + Ipi | Recurrence-free Survival (RFS) - All Randomized Participants With PD-L1 Expression Level < 1% | 33.15 Months |
| Arm B: Nivo | Recurrence-free Survival (RFS) - All Randomized Participants With PD-L1 Expression Level < 1% | 27.63 Months |
95% CI: [0.75, 1.14]
Secondary
Overall Survival (OS) - All Randomized Participants
OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates.
Time frame: From randomization to date of death (up to approximately 45 months)
Population: All randomized participants with completely resected stage IIIb/c/d or stage IV no evidence of disease (NED) melanoma
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivo + Ipi | Overall Survival (OS) - All Randomized Participants | NA Months |
| Arm B: Nivo | Overall Survival (OS) - All Randomized Participants | NA Months |
95% CI: [0.8, 1.32]
Secondary
Overall Survival (OS) - All Randomized Participants With PD-L1 Expression Level < 1%
OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates.
Time frame: From randomization to date of death (up to approximately 45 months)
Population: All randomized participants with PD-L1 expression level \< 1% and with completely resected stage IIIb/c/d or stage IV no evidence of disease (NED) melanoma
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivo + Ipi | Overall Survival (OS) - All Randomized Participants With PD-L1 Expression Level < 1% | NA Months |
| Arm B: Nivo | Overall Survival (OS) - All Randomized Participants With PD-L1 Expression Level < 1% | NA Months |
95% CI: [0.85, 1.73]
Secondary
Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants
PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death.
Time frame: From randomization to progression event (up to approximately 45 months)
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivo + Ipi | Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants | NA Months |
| Arm B: Nivo | Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants | NA Months |
Secondary
Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants With PD-L1 Expression Level < 1%
PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death.
Time frame: From randomization to progression event (up to approximately 45 months)
Population: All randomized participants with PD-L1 expression level \< 1%.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivo + Ipi | Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants With PD-L1 Expression Level < 1% | NA Months |
| Arm B: Nivo | Progression-free Survival (PFS) on Next-line Therapy - All Randomized Participants With PD-L1 Expression Level < 1% | NA Months |
Secondary
Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression
RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates.
Time frame: From randomization to Study Completion Date (up to approximately 45 months)
Population: All randomized participants with variable PD-L1 expression levels (see data table for details). PD-L1 expression levels based on clinical database.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm A: Nivo + Ipi | Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | ≥ 1% Tumor PD-L1 Expression | NA Months |
| Arm A: Nivo + Ipi | Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | < 5% Tumor PD-L1 Expression | NA Months |
| Arm A: Nivo + Ipi | Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | ≥ 5% Tumor PD-L1 Expression | NA Months |
| Arm A: Nivo + Ipi | Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | Non-quantifiable Tumor PD-L1 Expression | NA Months |
| Arm A: Nivo + Ipi | Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | < 1% Tumor PD-L1 Expression | 33.18 Months |
| Arm B: Nivo | Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | Non-quantifiable Tumor PD-L1 Expression | NA Months |
| Arm B: Nivo | Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | < 1% Tumor PD-L1 Expression | 25.33 Months |
| Arm B: Nivo | Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | ≥ 1% Tumor PD-L1 Expression | NA Months |
| Arm B: Nivo | Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | ≥ 5% Tumor PD-L1 Expression | NA Months |
| Arm B: Nivo | Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression | < 5% Tumor PD-L1 Expression | NA Months |
95% CI: [0.73, 1.14]
95% CI: [0.76, 1.18]
95% CI: [0.71, 1.34]
95% CI: [0.77, 1.1]
95% CI: [0.38, 1.51]
Secondary
Time From Next Therapy to Second Next Therapy - All Randomized Participants
Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment.
Time frame: From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months)
Population: All randomized participants who received first and second next systemic therapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivo + Ipi | Time From Next Therapy to Second Next Therapy - All Randomized Participants | 4.60 Months |
| Arm B: Nivo | Time From Next Therapy to Second Next Therapy - All Randomized Participants | 4.80 Months |
Secondary
Time From Next Therapy to Second Next Therapy - All Randomized Participants With PD-L1 Expression Level < 1%
Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment.
Time frame: From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months)
Population: All randomized participants with PD-L1 expression level \< 1% who received first and second next therapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Nivo + Ipi | Time From Next Therapy to Second Next Therapy - All Randomized Participants With PD-L1 Expression Level < 1% | 4.44 Months |
| Arm B: Nivo | Time From Next Therapy to Second Next Therapy - All Randomized Participants With PD-L1 Expression Level < 1% | 5.04 Months |
Secondary
Time to Next-Line Therapies - All Randomized Participants
Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date.
Time frame: From randomization to start of next therapy or second next therapy (up to approximately 45 months)
Population: All randomized participants
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm A: Nivo + Ipi | Time to Next-Line Therapies - All Randomized Participants | Time to next therapy | NA Months |
| Arm A: Nivo + Ipi | Time to Next-Line Therapies - All Randomized Participants | Time to second next therapy | NA Months |
| Arm B: Nivo | Time to Next-Line Therapies - All Randomized Participants | Time to next therapy | NA Months |
| Arm B: Nivo | Time to Next-Line Therapies - All Randomized Participants | Time to second next therapy | NA Months |
Secondary
Time to Next-Line Therapies - All Randomized Participants With PD-L1 Expression Level < 1%
Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date
Time frame: From randomization to start of next therapy or second next therapy (up to approximately 45 months)
Population: All randomized participants with PD-L1 expression level \< 1%
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm A: Nivo + Ipi | Time to Next-Line Therapies - All Randomized Participants With PD-L1 Expression Level < 1% | Time to next therapy | NA Months |
| Arm A: Nivo + Ipi | Time to Next-Line Therapies - All Randomized Participants With PD-L1 Expression Level < 1% | Time to second next therapy | NA Months |
| Arm B: Nivo | Time to Next-Line Therapies - All Randomized Participants With PD-L1 Expression Level < 1% | Time to next therapy | NA Months |
| Arm B: Nivo | Time to Next-Line Therapies - All Randomized Participants With PD-L1 Expression Level < 1% | Time to second next therapy | NA Months |