This protocol has been superseded due to the availability of superior alternatives. The preferred regimen is ID 3635 Melanoma adjuvant nivolumab (flat dosing).
The evidence supporting this protocol is provided by a prespecified interim analysis of a phase III multicentre international randomised trial (CheckMate 238) comparing nivolumab alone with ipilimumab alone as adjuvant therapy after complete resection of stage IIIB, IIIC or IV malignant melanoma.r
Between March 2015 and November 2015, 906 patients were recruited. All had undergone complete resection of stage IIIB, IIIC or IV malignant melanoma within 12 weeks of randomisation. Patients were randomised 1:1 to receive nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for 4 doses then every 12 weeks. Treatment was continued for up to 12 months or until disease recurrence, unacceptable toxicity or consent withdrawal. Patients were included regardless of BRAF mutation status. Uveal melanoma was excluded but acral and mucosal melanomas were included. Patients with resected brain metastases were included.
The primary end point was recurrence-free survival (RFS) and secondary end points were overall survival (OS), safety, RFS according to PD-L1 expression and health-related quality of life.
Efficacy
After a median follow up of 51.5 months, the median RFS was 52.4 months (95% CI 42.5-not reached) in the nivolumab arm and 24.1 months (95% CI 16.6-35.1) in the ipilimumab arm. The 12-month RFS was 70.5% (95% CI 66.1-74.5) in the nivolumab arm and 60.8% (95% CI 56.0-65.2) in the ipilimumab arm. The 4-year RFS was 51.7% (95% CI 46.8-56.3) and 41.2% (95% CI 36.4-45.9) respectively. OS data is not yet mature. 4-year OS was 77.9% (95% CI 73.7-81.5) in the nivolumab arm and 76.6% (95% CI 72.2-80.3) in the ipilumumab arm.rr
Prespecified subgroup analyses showed improvement in RFS with nivolumab over ipilimumab regardless of PD-L1 expression, stage or BRAF mutation status. The subgroups with hazard ratios for RFS which did not favour nivolumab over ipilimumab included patients with mucosal or acral melanoma and those with resected visceral metastases (M1c disease).
Quality of life scores did not differ between the groups.
Kaplan-Meier curves of recurrence-free survival (A), distant metastasis-free survival (B) and overall survival (C) in the intention to treat populationr
© Lancet Oncol 2020
Forest plot of hazard ratios for disease recurrence or death among prespecified subgroups of patientsr
© N Engl J Med 2017
Toxicity
Adverse events were reported in 96.9% of patients in the nivolumab arm and 98.5% in the ipilimumab arm. Grade 3 or 4 events were reported in 14.4% and 45.9% respectively. Adverse events leading to discontinuation of the trial drug occurred in 9.7% of the nivolumab group and 42.6% of the ipilimumab group. The spectrum of adverse events was similar to that observed in other trials of ipilimumab or nivolumab. There were two treatment-related deaths in the ipilimumab group, due to colitis and marrow aplasia, both more than 100 days after the last dose. There were no treatment-related deaths in the nivolumab arm.r
Any-grade late-emergent treatment-related adverse events were reported in 4% of patients, and grade 3 or 4 events in 1% of patients in the nivolumab group, compared with 6% and 2% of patients respectively in the ipilimumab group.r
Adverse eventsr
© N Engl J Med 2017