Adjuvant Therapy for Stage III Melanoma

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The two standard adjuvant therapies for patients with stage III melanoma are interferon alfa-2b and peginterferon alfa-2b, explains Jeffrey A. Sosman, MD. Clinical studies have demonstrated that both treatments improve recurrence-free survival (RFS), with anecdotal evidence from meta-analyses suggesting they also improve overall survival, Sosman notes.

Randomized trials are currently exploring BRAF inhibitors alone or in combination with MEK inhibitors for patients with BRAF-mutated high-risk melanoma, explains Sosman. Additionally, trials are exploring the checkpoint inhibitors, namely those targeting CTLA-4 and PD-1. The ongoing phase III ECOG 1609 study is comparing adjuvant treatment with high-dose interferon with 3-mg/kg and 10-mg/kg doses of ipilimumab, Sosman notes.

Recently, the phase III EORTC 18701 study demonstrated that adjuvant ipilimumab reduced the risk of recurrence compared with placebo for patients with stage III node-positive melanoma, notes Sosman. In this study, ipilimumab was administered at 10 mg/kg. At a median follow-up of 2.7 years, RFS rates were 46.5% with ipilimumab versus 34.8% with placebo. The median RFS was 26.1 versus 17.1 months for ipilimumab and placebo, respectively (HR=0.75, P = .0013).

Treatment with ipilimumab in this study resulted in high rates of toxicity, including hypophysitis and colitis, notes Sosman. The most common grade 3/4 immune-related adverse events (irAEs) for ipilimumab compared with placebo were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Approximately half of ipilimumab-treated patients discontinued treatment (52%) and 1.1% died as a result of treatment-related side effects.

The 10-mg/kg dose used in this trial is not approved in the United States. Moreover, the costs associated with this large of a dose in the adjuvant setting would be astronomical, Sosman states. However, this study does provide evidence that checkpoint inhibition is successful in the adjuvant setting. This sets the stage for trials exploring newer checkpoint inhibitors, Sosman notes.