ADJUVANT IPILIMUMAB FOR MELANOMA-NOT READY FOR PRIME TIME

In the phase III EORTC 18071 trial reported in The Lancet Oncology, Eggermont et al found that adjuvant ipilimumab (Yervoy) significantly improved recurrence-free survival vs placebo in patients with completely resected stage III melanoma at high risk of disease recurrence. Ipilimumab was associated with a high rate of immune-related adverse events.

Study Details

In this double-blind trial, 951 patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤ 1 mm or in-transit metastasis) with adequate resection of lymph nodes who had not received previous systemic therapy were enrolled at 91 hospitals in 19 countries and randomly assigned between July 2008 and August 2011 to receive ipilimumab (n = 475) or placebo (n = 476). The study drug was given as an intravenous infusion of 10 mg/kg every 3 weeks for four doses and then every 3 months for up to 3 years. The primary endpoint was recurrence-free survival on independent review in the intention-to-treat population.

Recurrence-Free Survival

After median follow-up of 2.74 years, median recurrence-free survival was 26.1 months (95% confidence interval [CI] = 19.3–39.3 months) in the ipilimumab group vs 17.1 months (95% CI = 13.4–21.6 months) in the placebo group (hazard ratio [HR] = 0.75, P = .0013). One-, 2-, and 3-year recurrence-free survival rates were 63.5% vs 56.1%, 51.5% vs 43.8%, and 46.5% vs 34.8%. Three-year recurrence-free survival was 57.6% vs 39.2% among 210 vs 193 patients with microscopic stage III disease (HR = 0.65, P = .004) and 37.8% vs 31.7% among 265 vs 283 patients with palpable nodes (HR = 0.81, P = .06).

Adverse Events

Grade 3 or 4 adverse events occurred in 54% vs 25% of patients, and grade 3 or 4 immune-related adverse events occurred in 43% vs 2%. The most common grade 3 or 4 immune-related adverse events in the ipilimumab group were gastrointestinal (16% vs < 1% in the placebo group), hepatic (11% vs < 1%), and endocrine (8% vs 0%). Adverse events led to discontinuation of treatment in 52% of ipilimumab patients, including in 39% during the initial treatment period, vs 4% of placebo patients. Five patients (1%) died of drug-related adverse events in the ipilimumab group, including three from colitis (two with gastrointestinal perforation), one from myocarditis, and one from multiorgan failure with Guillain-Barre syndrome. No treatment-related deaths were reported in the placebo group.

The investigators concluded: “Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value.”

Alexander M. M. Eggermont, MD, of Gustave Roussy Cancer Campus Grand Paris and University Paris-Sud, is the corresponding author of The Lancet Oncology article.

The trial was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com.