Research in context
Evidence before this study
We searched PubMed and congress abstracts, including the annual meetings of the American Society of Clinical Oncology, the European Society for Medical Oncology, and the Society for Melanoma Research, for articles published in English up to May 31, 2020. We searched for studies that evaluated immune checkpoint inhibitors or targeted therapies approved for the adjuvant treatment of advanced melanoma, in which recurrence-free survival was a study endpoint, with particular attention to studies that also reported overall survival. We used the search terms “adjuvant melanoma treatment” and the US Food and Drug Administration-approved therapies of “nivolumab”, “pembrolizumab”, “ipilimumab”, “dabrafenib”, and “trametinib”. Before the current report, recurrence-free survival results were reported for nivolumab and pembrolizumab at a follow-up of 3 years, ipilimumab at 5 years, and dabrafenib plus trametinib at 5 years. In these reports, pembrolizumab, ipilimumab, and dabrafenib plus trametinib showed a recurrence-free survival benefit compared with placebo, and nivolumab showed a benefit compared with the active agent, ipilimumab. Among checkpoint inhibitors, an overall survival benefit was reported for ipilimumab 10 mg/kg compared with placebo (European Organisation for Research and Treatment of Cancer 18071) and ipilimumab 3 mg/kg compared with high-dose interferon (E1609). In addition, an improvement in overall survival was reported for dabrafenib plus trametinib compared with placebo at an interim overall survival analysis, but the improvement did not cross the prespecified threshold for significance.
Added value of this study
To our knowledge, this is the first report of overall survival results for a PD-1 inhibitor in the adjuvant melanoma setting. In addition, compared with longer-term reports published for recurrence-free survival in this setting, this report includes data on patients with American Joint Committee on Cancer (7th edition) stage IIIB–C melanoma with in-transit metastases, as well as patients with resected stage IV melanoma. Moreover, we provide a recurrence-free survival analysis of patients with BRAF-mutated stage IIIB and IIIC disease, a population that resembles one treated with the approved targeted therapy dabrafenib plus trametinib. Voluntary reports of late-emergent treatment-related adverse events were few in number.
Implications of all the available evidence
Updated recurrence-free survival and distant metastasis-free survival results with longer follow-up show that nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, including multiple patient subgroups and, notably, patients with in-transit metastases who have traditionally not been enrolled in such trials. Additional support for the continued use of nivolumab in this patient population is derived from the high 4-year overall survival observed in patients in the nivolumab group, albeit not significant when compared with patients in the ipilimumab group, who received effective approved subsequent therapies; comparison of these results with a watch-and-wait strategy is warranted.