The EORTC 18071 Trial: Comparing Adjuvant Ipilimumab Treatment and Placebo in Patients with Stage III Melanoma
The adjuvant treatment options for patients with locally advanced melanoma that are at high risk for relapse are limited, underscoring the need for effective agents in this setting. The monoclonal antibody ipilimumab that is directed against an immune checkpoint molecule cytotoxic T-lymphocyte antigen (CTLA)-4 to augment antitumor immune responses is currently approved for patients with advanced melanoma. At ESMO 2014, Eggermont and colleagues presented results of the large, randomized, double-blind EORTC 18071 clinical trial that sought to test ipilimumab in the adjuvant setting (Eggermont et al. ESMO 2014: Abstract 1087O).
In this trial, 951 patients who had undergone complete resection of stage III cutaneous melanoma were randomized to receive ipilimumab 10 mg/kg (n = 475) or placebo (n = 476) every 3 weeks for 4 doses (ie, induction therapy), then every 3 months for up to 3 years, until completion, disease recurrence, or unacceptable toxicity (ie, maintenance therapy). The primary end point was recurrence-free survival (RFS); secondary end points included overall survival and distant metastasis-free survival.
At a median follow-up of 2.7 years, ipilimumab therapy resulted in a significant prolongation of RFS compared with placebo (26.1 vs 17.1 months), with a 25% reduction in risk of recurrence (hazard ratio, 0.75; P = .0013). The 3-year RFS rates were 46.5% and 34.8%, respectively, for the ipilimumab and the placebo cohorts. The RFS benefit extended to all patient subgroups assessed, including stage IIIA, IIIB, or IIIC, microscopic or macroscopic lymph nodes, and with or without an ulcerated primary lesion. In particular, post-hoc analysis showed that the RFS benefit was higher for patients with microscopic disease and for those with ulceration of the primary disease.
A higher incidence of grade 3 or 4 immune-related adverse events was reported in the ipilimumab-treated group compared with placebo (42% vs 2.5%, respectively). Common immune-related adverse events were gastrointestinal (16% vs 0.8%), hepatic (10.7% vs 0.2%), and endocrine (8.5% vs 0%) in nature. There were 5 treatment-related deaths (1.1%), including 3 patients with colitis, 2 with gastrointestinal perforations, 1 with myocarditis, and 1 with Guillain-Barre syndrome. Treatment discontinuation because of adverse events was 52%, of which 38.6% discontinued within 12 weeks.
Health-related quality-of-life assessment showed no clinically significant differences between treatment arms in mean scores for global health status at any time. The researchers concluded that ipilimumab as adjuvant therapy provided a significant improvement in RFS compared with placebo for patients with stage III melanoma at high risk for recurrence. Although the safety profile was consistent with that observed with ipilimumab therapy in advanced disease, the investigators pointed out that its use in the adjuvant setting was associated with a higher incidence of endocrinopathies.