Results of the CheckMate 238 trial presented at ESMO 2017 and simultaneously published in the New England Journal of Medicine demonstrate that adjuvant nivolumab is superior to ipilimumab in patients with surgically resected stage III/IV melanoma who are at high risk of relapse. In this study nivolumab was associated with a statistically longer relapse-free survival (RFS) (p< 0.0001) and a better safety profile than ipilimumab.
Nivolumab and ipilimumab are 2 immune checkpoint inhibitors that are approved for the treatment of metastatic melanoma. Ipilimumab is also FDA-approved as standard of care adjuvant therapy for resected stage III melanoma in the US. This is however not the case in Europe. In a pilot study of 33 patients with resected stage IIIC and IV melanoma, nivolumab was well-tolerated and showed promising survival results in the adjuvant setting. These data formed the basis for CheckMate 238, a randomised, double-blind, phase III trial comparing adjuvant treatment with nivolumab versus standard of care ipilimumab. The trial included 906 patients with stages IIIB, IIIC, and IV resected melanoma who had a greater than 50% risk of relapse over 5 years. Patients were randomised (1:1) to nivolumab 3mg/kg (N = 453) every 2 weeks or ipilimumab 10mg/kg (N = 453) every 3 weeks for 4 doses, then every 12 weeks for up to 1 year, disease recurrence, or unacceptable toxicity. The primary endpoint of the study was RFS, with overall survival (OS) as a secondary objective.
The trial was stopped early by the data safety monitoring committee due to clear evidence of benefit for nivolumab. The planned interim analysis, which occurred at a minimum follow-up of 18 months, demonstrated that the rate of RFS was significantly improved with nivolumab (66.4%) compared to ipilimumab (52.7%), with a hazard ratio of 0.65 (95%CI: 0.51-0.83; p < 0.0001). The median RFS was not reached in either of the study arms. The benefit of nivolumab over ipilimumab in terms of RFS was observed across all prespecified subgroups. In addition to the superior efficacy, there were also fewer treatment-related, clinically relevant adverse events (grade 3/4) in the group of patients treated with nivolumab (14%) compared to those treated with ipilimumab (46%). Adverse events of any grade led to discontinuation in 10% of patients treated with nivolumab and in 43% of patients treated with ipilimumab. Organ systems with the highest frequency of treatment-related, grade 3/4 immune-related adverse events in the nivolumab and ipilimumab arms were gastrointestinal (2.0% versus 16.8%), hepatic (1.8% versus 10.8%), and skin (1.1% versus 6.0%). No deaths due to study drug toxicity were reported for nivolumab, but 2 (0.4%) fatalities were reported with ipilimumab (colitis and medullary aplasia).
An adjuvant trial presented at the ESMO 2016 Congress showed that ipilimumab gave an OS advantage over placebo but it was highly toxic. CheckMate 238 shows that nivolumab is superior to ipilimumab, so extrapolating these results, nivolumab is far better than no adjuvant treatment for high-risk melanoma. Based on the presented results, nivolumab appears to be a superior adjuvant melanoma regimen compared to ipilimumab from every angle: it leads to a better relapse-free survival, has fewer adverse events, and is well-tolerated. Data on OS were still immature at the time of the analysis.
Weber J, Mandala M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238). Presented at ESMO 2017; abstract LBA8_PR.