Nivolumab

In a multinational double-blind trial (CheckMate 238 [NCT02388906]), patients with stage IIIB, IIIC, or IV melanoma who underwent complete resection were randomly assigned (1:1) to receive either nivolumab or ipilimumab.[24][Level of evidence B1] The primary end point was RFS and was defined as time from randomization until the date of the first recurrence, new primary melanoma, or death from any cause. Patients who were excluded included those with resection occurring more than 12 weeks before randomization, autoimmune disease, use of systemic glucocorticoids, previous systemic therapy for melanoma, and an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score higher than 1. Nivolumab (3 mg/kg) was given IV every 2 weeks and ipilimumab (10 mg/kg) was given every 3 weeks for four doses, then every 3 months for up to 1 year or until disease recurrence, along with corresponding placebo. A total of 906 patients were randomly assigned: 453 patients to nivolumab and 453 patients to ipilimumab. Baseline characteristics were balanced in the two treatment groups. Approximately 81% of patients had stage III disease, 32% had ulcerated primary melanoma, 48% had macroscopic lymph node involvement, 62% had less than a 5% PD-L1 expression, and 42% had BRAF pathogenic variants.

In a multinational double-blind trial (CheckMate 238 [NCT02388906]), patients with stage IIIB, IIIC, or IV melanoma who underwent complete resection were randomly assigned (1:1) to receive either nivolumab or ipilimumab.[24][Level of evidence B1] The primary end point was RFS and was defined as time from randomization until the date of the first recurrence, new primary melanoma, or death from any cause. Patients who were excluded included those with resection occurring more than 12 weeks before randomization, autoimmune disease, use of systemic glucocorticoids, previous systemic therapy for melanoma, and an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score higher than 1. Nivolumab (3 mg/kg) was given IV every 2 weeks and ipilimumab (10 mg/kg) was given every 3 weeks for four doses, then every 3 months for up to 1 year or until disease recurrence, along with corresponding placebo. A total of 906 patients were randomly assigned: 453 patients to nivolumab and 453 patients to ipilimumab. Baseline characteristics were balanced in the two treatment groups. Approximately 81% of patients had stage III disease, 32% had ulcerated primary melanoma, 48% had macroscopic lymph node involvement, 62% had less than a 5% PD-L1 expression, and 42% had BRAF pathogenic variants.

The European Organisation for Research and Treatment of Cancer (EORTC) Independent Data Monitoring Committee stopped the study at the protocol-specified interim analysis, when all patients had a minimum follow-up of 18 months, at which time there were 360 events of RFS. The median RFS has not been reached in either treatment group. At 12 months, the RFS rate was 70.5% (95% CI, 66.1%–74.0%) for patients treated with nivolumab versus 60.8% (95% CI, 56.0%–65.2%) for patients treated with ipilimumab. Recurrence or death occurred in 34% (154 of 453) of patients treated with nivolumab versus 45.5% (206 of 453) of patients treated with ipilimumab (hazard ratio [HR] recurrence or death, 0.65; 97.56% CI, 0.51–0.83; P < .001). Subgroup analyses of RFS favored nivolumab regardless of PD-L1 expression or the presence of a BRAF V600 pathogenic variant.

In a multinational double-blind trial (CheckMate 238 [NCT02388906]), patients with stage IIIB, IIIC, or IV melanoma who underwent complete resection were randomly assigned (1:1) to receive either nivolumab or ipilimumab.[24][Level of evidence B1] The primary end point was RFS and was defined as time from randomization until the date of the first recurrence, new primary melanoma, or death from any cause. Patients who were excluded included those with resection occurring more than 12 weeks before randomization, autoimmune disease, use of systemic glucocorticoids, previous systemic therapy for melanoma, and an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score higher than 1. Nivolumab (3 mg/kg) was given IV every 2 weeks and ipilimumab (10 mg/kg) was given every 3 weeks for four doses, then every 3 months for up to 1 year or until disease recurrence, along with corresponding placebo. A total of 906 patients were randomly assigned: 453 patients to nivolumab and 453 patients to ipilimumab. Baseline characteristics were balanced in the two treatment groups. Approximately 81% of patients had stage III disease, 32% had ulcerated primary melanoma, 48% had macroscopic lymph node involvement, 62% had less than a 5% PD-L1 expression, and 42% had BRAF pathogenic variants.

Patients treated with nivolumab had fewer adverse events, including grade 3 to 4 serious adverse events and death. Adverse events led to treatment discontinuation in 9.7% of patients assigned to nivolumab and 42.6% of patients assigned to ipilimumab. Two treatment-related deaths occurred among patients treated with ipilimumab (e.g., marrow aplasia and colitis) and none occurred among the patients treated with nivolumab. The adverse event profile was like the type of checkpoint inhibitor toxicities seen in the metastatic setting, with immune-related events most commonly seen in the gastrointestinal system, hepatic system, and skin. Grade 3 or 4 adverse events occurred in 14% of patients treated with nivolumab and in 46% of patients treated with ipilimumab.

In a multinational double-blind trial (CheckMate 238 [NCT02388906]), patients with stage IIIB, IIIC, or IV melanoma who underwent complete resection were randomly assigned (1:1) to receive either nivolumab or ipilimumab.[24][Level of evidence B1] The primary end point was RFS and was defined as time from randomization until the date of the first recurrence, new primary melanoma, or death from any cause. Patients who were excluded included those with resection occurring more than 12 weeks before randomization, autoimmune disease, use of systemic glucocorticoids, previous systemic therapy for melanoma, and an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score higher than 1. Nivolumab (3 mg/kg) was given IV every 2 weeks and ipilimumab (10 mg/kg) was given every 3 weeks for four doses, then every 3 months for up to 1 year or until disease recurrence, along with corresponding placebo. A total of 906 patients were randomly assigned: 453 patients to nivolumab and 453 patients to ipilimumab. Baseline characteristics were balanced in the two treatment groups. Approximately 81% of patients had stage III disease, 32% had ulcerated primary melanoma, 48% had macroscopic lymph node involvement, 62% had less than a 5% PD-L1 expression, and 42% had BRAF pathogenic variants.

An updated analysis, after a minimum of 4 years of follow-up, showed an RFS rate of 51.7% (95% CI, 46.8%–56.3%) for patients who received nivolumab versus 41.2% (95% CI, 36.4%–45.9%) for patients who received ipilimumab (HR relapse or death, 0.71; 95% CI, 0.60–0.86; P = .0003). Median OS has not been reached in either group.[28]