Adjuvant nivolumab (Opdivo) remains superior to ipilimumab (Yervoy) on both recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at 4 years in patients with completely resected stage III/IV melanoma with a high risk for recurrence. Four-year data from the phase 3 CheckMate-238 clinical trial, presented at the European Society for Medical Oncology Virtual Congress 2020, showed similar overall survival (OS) between the 2 study arms.
CheckMate-238 included 906 patients with completely resected stage IIIB-IIIC or IV melanoma. Patients were randomized into equal groups to treatment with either nivolumab (3 mg/kg every 2 weeks and every 12 weeks thereafter) or ipilimumab (10 mg/kg every 3 weeks for 4 doses and every 12 weeks thereafter) for a maximum of 1 year or until disease recurrence or unacceptable toxicity. Approximately 40% of patients in each arm had a BRAF mutation.
The previous update from CheckMate-238, at 36 months of follow-up, showed that nivolumab improved RFS in patients with resected stage IIIB-IIIC/IV melanoma and was associated with less toxicity and significantly fewer grade 3/4 treatment-related adverse events compared with ipilimumab (14.4% vs 45.9%, respectively).
After 48 months of follow-up, median RFS was 52.4 months in the nivolumab arm versus 24.1 months in the ipilimumab arm (hazard ratio [HR], 0.71; P = .0003), reported Jeffrey S. Weber, MD, PhD, Deputy Director, Perlmutter Cancer Center, and Co-Director, Melanoma Research Program, New York University Langone Perlmutter Cancer Center, New York City.
In the 4-year analysis, when stratified by cancer stage, median RFS in patients with stage IIIB-IIIC cancer treated with nivolumab was significantly greater than in those treated with ipilimumab (52.4 vs 25.5 months; HR, 0.71; 95% confidence interval [CI], 0.58-0.88). In patients with stage IV disease, 48-month median RFS was also significantly higher in the nivolumab arm compared with the ipilimumab arm (47.4 vs 16.8 months; HR, 0.74; 95% CI, 0.49-1.11). A similar advantage to nivolumab versus ipilimumab on 48-month RFS was observed in patients with in-transit metastases without nodal involvement (46.8 vs 19.1 months) and in those with BRAF-mutant disease (not reached vs 25.5 months) and BRAF wild-type disease (46.8 vs 16.6 months). DMFS was an exploratory end point. In all patients with stage IIIB-IIIC disease, median DMFS was not reached in the nivolumab group compared with 52.9 months in the ipilimumab group (HR, 0.79; P = .045).
The presentation was the first in which OS results were reported, and showed fewer than expected survival events (211 vs 302 expected events), and comparable OS rates in both the nivolumab- and ipilimumab-treated patients (78% vs 77%, respectively; HR, 0.87; 95% CI, 0.66-1.14; P = .3148). The rate of subsequent systemic treatment for recurrence was similar in patients treated with ipilimumab compared with nivolumab (70% vs 69%, respectively). Subsequent immunotherapy was used in 57% of the ipilimumab group compared with 49% of the nivolumab group.
No new safety concerns were reported, and the rate of late-emergent treatment-related adverse events was low in both groups.
Dr Weber concluded that at 4 years, nivolumab continues to be an effective adjuvant therapy for patients with resected high-risk melanoma, with sustained RFS and DMFS benefit compared with ipilimumab.