Melanoma
Conditions
Keywords
Melanoma, Relatlimab, Nivolumab, Opdivo
Brief summary
The purpose of this study is to assess nivolumab plus relatlimab fixed-dose combination (FDC) versus nivolumab alone in participants with completely resected stage III-IV melanoma.
Interventions
BIOLOGICALNivolumab
Specified dose on specified days
BIOLOGICALNivolumab + Relatlimab Fixed Dose Combination
Specified dose on specified days
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must have been diagnosed with either Stage IIIA (\> 1 mm tumor in lymph node)/B/C/D or Stage IV melanoma by American Joint Committee on Cancer (AJCC) v8 and have histologically confirmed melanoma that is completely surgically resected (free of disease) with negative margins in order to be eligible * Participants ≥ 18 years of age must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1. Adolescent participants between 12 and \< 18 years of age must have a Lansky/Karnofsky performance score ≥ 80% * Complete resection must be performed within 90 days prior to randomization * All participants must have disease-free status documented by a complete physical examination within 14 days prior to randomization and imaging studies within 35 days prior to randomization * Tumor tissue must be provided for biomarker analyses
Exclusion criteria
* History of ocular melanoma * Untreated/unresected CNS metastases or leptomeningeal metastases * Active, known, or suspected autoimmune disease * Participants with serious or uncontrolled medical disorder * Prior immunotherapy treatment for any prior malignancy: No prior immunotherapies are permitted * Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 4 weeks prior to screening * History of myocarditis, regardless of etiology. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence Free Survival (RFS) | Approximately 27.5 Months | RFS is defined as the time between the date of randomization and the first date of documented recurrence (local, regional, distant, new primary melanoma) or death due to any cause, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Distant Metastasis Free Survival (DMFS) | Approximately 27.5 Months | DMFS is defined as the time between the date of randomization and the date of first distant metastasis or date of death due to any cause, whichever occurs first. |
| Progression Free Survival on Next-Line Systemic Therapy (PFS2) | Approximately 27.5 Months | PFS2 defined as time from randomization to second recurrence/objective disease progression on next-line systemic therapy per investigator, or death from any cause, whichever occurs first. |
| Number of Participants With Safety Related Events | Approximately 27.5 Months | Safety related events encompass the following measures: Adverse events (AEs), Serious AEs, AEs leading to discontinuation, Drug-Related AEs and Deaths. An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment that does not necessarily have a causal relationship with this treatment. An SAE is an AE which: * Results in death * Is life threatening * Requires hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Is an important medical event |
| Overall Survival (OS) | Approximately 27.5 Months | OS is defined as the time between the date of randomization and the date of death due to any cause. |
| Number of Participants With Endocrine Related Immune Mediated AEs | Approximately 27.5 Months | Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology which were exacerbated by the induction of autoimmunity. |
| Number of Participants With Non-endocrine Related Immune Mediated AEs | Approximately 27.5 Months | Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology which were exacerbated by the induction of autoimmunity. |
| Laboratory Abnormalities for Specific Thyroid Tests | Approximately 27.5 Months | Number of participants with laboratory abnormalities in specific thyroid tests. |
| Number of Participants With Select AEs | Approximately 27.5 Months | Select AEs will be reported as AEs per organ class. Organ classes which will be reported: * Gastrointestinal * Hepatic * Pulmonary * Renal * Skin * Hypersensitivity/Infusion reaction |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Czechia, Denmark, Finland, France, Germany, Greece, Israel, Italy, Mexico, Norway, Portugal, Romania, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
1093 participants randomized and 1088 treated.
Participants by arm
| Arm | Count |
|---|---|
| Treatment 1 nivolumab 480 mg and relatlimab 160 mg IV every 4 weeks (Q4W) | 547 |
| Treatment 2 nivolumab 480 mg IV Q4W | 546 |
| Total | 1,093 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow Up | Death | 78 | 69 |
| Follow Up | Lost to Follow-up | 3 | 3 |
| Follow Up | Other Reasons | 444 | 452 |
| Follow Up | Withdrew consent | 17 | 16 |
| Randomized | AE unrelated to study drug | 1 | 0 |
| Randomized | No longer meets study criteria | 0 | 1 |
| Randomized | Withdrew Consent | 3 | 0 |
| Treatment Period | AE unrelated to study drug | 6 | 12 |
| Treatment Period | Death | 1 | 1 |
| Treatment Period | Disease Recurrence | 102 | 128 |
| Treatment Period | Other Reasons | 4 | 7 |
| Treatment Period | Requested to Discontinue | 26 | 5 |
| Treatment Period | Study Drug Toxicity | 114 | 64 |
| Treatment Period | Withdrew Consent | 7 | 1 |
Baseline characteristics
| Characteristic | Treatment 2 | Total | Treatment 1 |
|---|---|---|---|
| Age, Continuous | 57.6 Years STANDARD_DEVIATION 13.34 | 57.4 Years STANDARD_DEVIATION 13.75 | 57.3 Years STANDARD_DEVIATION 14.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 39 Participants | 85 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 269 Participants | 549 Participants | 280 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 238 Participants | 459 Participants | 221 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 37 Participants | 76 Participants | 39 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 24 Participants | 14 Participants |
| Race (NIH/OMB) White | 497 Participants | 988 Participants | 491 Participants |
| Sex: Female, Male Female | 231 Participants | 451 Participants | 220 Participants |
| Sex: Female, Male Male | 315 Participants | 642 Participants | 327 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 86 / 547 | 76 / 546 |
| other Total, other adverse events | 489 / 543 | 473 / 545 |
| serious Total, serious adverse events | 174 / 543 | 121 / 545 |
Outcome results
Primary
Recurrence Free Survival (RFS)
RFS is defined as the time between the date of randomization and the first date of documented recurrence (local, regional, distant, new primary melanoma) or death due to any cause, whichever occurs first.
Time frame: Approximately 27.5 Months
Population: All Randomized Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment 1 | Recurrence Free Survival (RFS) | NA Months |
| Treatment 2 | Recurrence Free Survival (RFS) | 33.84 Months |
Secondary
Distant Metastasis Free Survival (DMFS)
DMFS is defined as the time between the date of randomization and the date of first distant metastasis or date of death due to any cause, whichever occurs first.
Time frame: Approximately 27.5 Months
Population: All Randomized Participants with Resected Stage 3/4a/4b Melanoma at study entry
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment 1 | Distant Metastasis Free Survival (DMFS) | NA Months |
| Treatment 2 | Distant Metastasis Free Survival (DMFS) | NA Months |
Secondary
Laboratory Abnormalities for Specific Thyroid Tests
Number of participants with laboratory abnormalities in specific thyroid tests.
Time frame: Approximately 27.5 Months
Population: All Treated Participants with at least one on treatment TSH measurement
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment 1 | Laboratory Abnormalities for Specific Thyroid Tests | TSH > ULN | 229 Participants |
| Treatment 1 | Laboratory Abnormalities for Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 193 Participants |
| Treatment 1 | Laboratory Abnormalities for Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 148 Participants |
| Treatment 1 | Laboratory Abnormalities for Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 168 Participants |
| Treatment 1 | Laboratory Abnormalities for Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 52 Participants |
| Treatment 1 | Laboratory Abnormalities for Specific Thyroid Tests | TSH < LLN | 198 Participants |
| Treatment 1 | Laboratory Abnormalities for Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 180 Participants |
| Treatment 1 | Laboratory Abnormalities for Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 119 Participants |
| Treatment 1 | Laboratory Abnormalities for Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 117 Participants |
| Treatment 1 | Laboratory Abnormalities for Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 27 Participants |
| Treatment 2 | Laboratory Abnormalities for Specific Thyroid Tests | TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN | 72 Participants |
| Treatment 2 | Laboratory Abnormalities for Specific Thyroid Tests | TSH > ULN | 159 Participants |
| Treatment 2 | Laboratory Abnormalities for Specific Thyroid Tests | TSH > ULN WITH FT3/FT4 TEST MISSING | 28 Participants |
| Treatment 2 | Laboratory Abnormalities for Specific Thyroid Tests | TSH < LLN | 131 Participants |
| Treatment 2 | Laboratory Abnormalities for Specific Thyroid Tests | TSH > ULN WITH TSH ≤ ULN AT BASELINE | 124 Participants |
| Treatment 2 | Laboratory Abnormalities for Specific Thyroid Tests | TSH < LLN WITH FT3/FT4 TEST MISSING | 19 Participants |
| Treatment 2 | Laboratory Abnormalities for Specific Thyroid Tests | TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN | 74 Participants |
| Treatment 2 | Laboratory Abnormalities for Specific Thyroid Tests | TSH <LLN WITH TSH ≥ LLN AT BASELINE | 123 Participants |
| Treatment 2 | Laboratory Abnormalities for Specific Thyroid Tests | TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN | 124 Participants |
| Treatment 2 | Laboratory Abnormalities for Specific Thyroid Tests | TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN | 85 Participants |
Secondary
Number of Participants With Endocrine Related Immune Mediated AEs
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology which were exacerbated by the induction of autoimmunity.
Time frame: Approximately 27.5 Months
Population: All Treated Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment 1 | Number of Participants With Endocrine Related Immune Mediated AEs | Thyroiditis | 18 Participants |
| Treatment 1 | Number of Participants With Endocrine Related Immune Mediated AEs | Diabetes Melitus | 11 Participants |
| Treatment 1 | Number of Participants With Endocrine Related Immune Mediated AEs | Hypothyroidism/Thyroiditis | 158 Participants |
| Treatment 1 | Number of Participants With Endocrine Related Immune Mediated AEs | Hyperthyroidism | 96 Participants |
| Treatment 1 | Number of Participants With Endocrine Related Immune Mediated AEs | Adrenal Insufficiency | 33 Participants |
| Treatment 1 | Number of Participants With Endocrine Related Immune Mediated AEs | Hypophysitis | 51 Participants |
| Treatment 1 | Number of Participants With Endocrine Related Immune Mediated AEs | Hypothyroidism | 152 Participants |
| Treatment 2 | Number of Participants With Endocrine Related Immune Mediated AEs | Hypophysitis | 13 Participants |
| Treatment 2 | Number of Participants With Endocrine Related Immune Mediated AEs | Adrenal Insufficiency | 9 Participants |
| Treatment 2 | Number of Participants With Endocrine Related Immune Mediated AEs | Hypothyroidism/Thyroiditis | 93 Participants |
| Treatment 2 | Number of Participants With Endocrine Related Immune Mediated AEs | Thyroiditis | 14 Participants |
| Treatment 2 | Number of Participants With Endocrine Related Immune Mediated AEs | Diabetes Melitus | 8 Participants |
| Treatment 2 | Number of Participants With Endocrine Related Immune Mediated AEs | Hyperthyroidism | 56 Participants |
| Treatment 2 | Number of Participants With Endocrine Related Immune Mediated AEs | Hypothyroidism | 82 Participants |
Secondary
Number of Participants With Non-endocrine Related Immune Mediated AEs
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology which were exacerbated by the induction of autoimmunity.
Time frame: Approximately 27.5 Months
Population: All Treated Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment 1 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Hypersensitivity | 12 Participants |
| Treatment 1 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Pneumonitis | 8 Participants |
| Treatment 1 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Diarrhea/colitis | 28 Participants |
| Treatment 1 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Hepatitis | 26 Participants |
| Treatment 1 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Nephritis and Renal Dysfunction | 3 Participants |
| Treatment 1 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Rash | 49 Participants |
| Treatment 2 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Nephritis and Renal Dysfunction | 3 Participants |
| Treatment 2 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Hypersensitivity | 2 Participants |
| Treatment 2 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Hepatitis | 17 Participants |
| Treatment 2 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Pneumonitis | 10 Participants |
| Treatment 2 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Rash | 40 Participants |
| Treatment 2 | Number of Participants With Non-endocrine Related Immune Mediated AEs | Diarrhea/colitis | 21 Participants |
Secondary
Number of Participants With Safety Related Events
Safety related events encompass the following measures: Adverse events (AEs), Serious AEs, AEs leading to discontinuation, Drug-Related AEs and Deaths. An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment that does not necessarily have a causal relationship with this treatment. An SAE is an AE which: * Results in death * Is life threatening * Requires hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Is an important medical event
Time frame: Approximately 27.5 Months
Population: All Treated Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment 1 | Number of Participants With Safety Related Events | Drug-Related AEs | 483 Participants |
| Treatment 1 | Number of Participants With Safety Related Events | AEs leading to discontinuation | 102 Participants |
| Treatment 1 | Number of Participants With Safety Related Events | Serious AEs | 132 Participants |
| Treatment 1 | Number of Participants With Safety Related Events | Deaths | 83 Participants |
| Treatment 1 | Number of Participants With Safety Related Events | AEs | 522 Participants |
| Treatment 2 | Number of Participants With Safety Related Events | Deaths | 76 Participants |
| Treatment 2 | Number of Participants With Safety Related Events | AEs | 520 Participants |
| Treatment 2 | Number of Participants With Safety Related Events | Drug-Related AEs | 438 Participants |
| Treatment 2 | Number of Participants With Safety Related Events | Serious AEs | 78 Participants |
| Treatment 2 | Number of Participants With Safety Related Events | AEs leading to discontinuation | 65 Participants |
Secondary
Number of Participants With Select AEs
Select AEs will be reported as AEs per organ class. Organ classes which will be reported: * Gastrointestinal * Hepatic * Pulmonary * Renal * Skin * Hypersensitivity/Infusion reaction
Time frame: Approximately 27.5 Months
Population: All Treated Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment 1 | Number of Participants With Select AEs | Gastrointestinal | 115 Participants |
| Treatment 1 | Number of Participants With Select AEs | Hepatic | 108 Participants |
| Treatment 1 | Number of Participants With Select AEs | Pulmonary | 11 Participants |
| Treatment 1 | Number of Participants With Select AEs | Renal | 33 Participants |
| Treatment 1 | Number of Participants With Select AEs | Skin | 244 Participants |
| Treatment 1 | Number of Participants With Select AEs | Hypersensitivity/Infusion Reaction | 37 Participants |
| Treatment 2 | Number of Participants With Select AEs | Pulmonary | 13 Participants |
| Treatment 2 | Number of Participants With Select AEs | Hypersensitivity/Infusion Reaction | 26 Participants |
| Treatment 2 | Number of Participants With Select AEs | Gastrointestinal | 120 Participants |
| Treatment 2 | Number of Participants With Select AEs | Skin | 240 Participants |
| Treatment 2 | Number of Participants With Select AEs | Hepatic | 86 Participants |
| Treatment 2 | Number of Participants With Select AEs | Renal | 21 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time between the date of randomization and the date of death due to any cause.
Time frame: Approximately 27.5 Months
Population: All Randomized Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment 1 | Overall Survival (OS) | NA Months |
| Treatment 2 | Overall Survival (OS) | NA Months |
Secondary
Progression Free Survival on Next-Line Systemic Therapy (PFS2)
PFS2 defined as time from randomization to second recurrence/objective disease progression on next-line systemic therapy per investigator, or death from any cause, whichever occurs first.
Time frame: Approximately 27.5 Months
Population: All Randomized Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment 1 | Progression Free Survival on Next-Line Systemic Therapy (PFS2) | NA Months |
| Treatment 2 | Progression Free Survival on Next-Line Systemic Therapy (PFS2) | NA Months |