Management of patients with lymph node-positive (high-risk) stage III melanoma is a clinical challenge today. In Europe, high-dose interferon alpha-2b is approved for use in this setting. In the United States, both high-dose interferon alpha-2b and pegylated interferon alpha-2b are registered for patients with high-risk stage III melanoma.1,2 Because these agents can be challenging for patients in light of adverse events and administration, alternative treatments are desired.3
Eggermont and colleagues presented final data from EORTC 18071, a randomized, double-blind, placebo-controlled phase 3 study designed to assess the impact of ipilimumab (IPI), an anti-CTLA antibody, on relapse-free survival (RFS) by an independent review committee (ASCO 2014; Abstract LBA9008). This study is the first to assess an immune checkpoint inhibitor in the adjuvant melanoma setting.
A total of 951 patients with surgically treated stage III cutaneous melanoma were randomly assigned to receive IPI or placebo in this protocol. None had received prior systemic therapy for melanoma. Patients were selected to have disease features correlated with a high likelihood of melanoma recurrence, including positive lymph nodes. Patients receiving IPI were dosed at 10 mg/kg every 3 weeks x 4, followed by 10 mg/kg every 12 weeks for up to 3 years. Placebo was given in a double-blind fashion using the same schedule.
After a median follow-up of 2.7 years, IPI reduced the relative risk of melanoma recurrence by 25% compared with placebo. The 3-year RFS rates were 46.5% and 35% in the IPI and placebo groups, respectively. Subgroup analysis showed a 33% reduction in relapse risk among stage III melanoma patients with microscopic disease in lymph nodes and a 17% reduction in relapse risk among patients with macroscopic disease. In contrast, the EORTC 18991 trial that supported the approval of pegylated interferon alpha-2b did not show a significant RFS benefit in patients with positive lymph nodes.4
Side effects were observed with IPI, including 5 treatment-related deaths, on the study. Over half (52%) of the patients discontinued IPI secondary to adverse events (AEs), most often during the first 12 to 16 weeks of treatment. AEs were consistent with those observed with IPI in the treatment of metastatic melanoma, and included colitis, endocrinopathies, and skin rash.
Dr Eggermont stated that these phase 3 data justify consideration of adjuvant use of IPI for patients with high-risk stage III melanoma. More study is needed to fully assess the balance of benefits and risks associated with this treatment, including longer follow-up to assess the extent to which IPI affects overall survival. An ongoing phase 3 study, known as ECOG 1609, is comparing 2 different doses (3 mg/kg and 10 mg/kg) of adjuvant IPI with single-agent high-dose interferon.
