Adjuvant Ipilimumab Increases Recurrence-Free Survival After Complete Resection of High-Risk Stage III Melanoma

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Alexander M.M. Eggermont, MD, PhD

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, PhD, and colleagues

In the phase III European Organisation for Research and Treatment of Cancer (EORTC) 18071 trial reported in The Lancet Oncology, Alexander M.M. Eggermont, MD, PhD, Director General of the Gustave Roussy Cancer Center in Villejuif, France, and colleagues found that adjuvant therapy with the immune checkpoint inhibitor ipilimumab (Yervoy) significantly improved recurrence-free survival vs placebo in patients with completely resected stage III melanoma (ie, with regional lymph node involvement) at high risk of recurrence.1 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) and 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.

The ipilimumab and placebo groups were generally balanced for age (median, 51 and 52 years, 17% and 18% ≥ 65 years), sex (62% male in both), stage provided at randomization (IIIA in 21% in both, IIIB in 38% in both, IIIC with 1–3 positive nodes in 15% and 17%, IIIC with ≥ 4 positive nodes in 15% and 16%), American Joint Committee on Cancer 2002 stage (IIIA in 21% and 18%), microscopic (44% and 41%) and macroscopic (56% and 59%) nodal involvement, number of nodes positive on pathology (1 in 46% in both, 2–3 in 34% and 33%, ≥ 4 in 20% and 21%), and ulceration (no in 54% and 51%, yes in 41% and 43%, unknown in 4% and 6%).

Recurrence-Free Survival

The median number of study medication doses was four in the ipilimumab group and eight in the placebo group, with 42% vs 70% receiving at least one maintenance dose and 29% vs 57% receiving at least seven doses (ie, approximately 1 year of treatment).

After a 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] stratified by stage indicated at randomization = 0.75, 95% CI = 0.64–0.90, P = .0013). The effect of ipilimumab was consistent across subgroups, including benefit irrespective of number of positive nodes. The 1-, 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%.

Outcomes by Nodal Involvement and Ulceration

Three-year recurrence-free survival was 57.6% vs 39.2% among patients with microscopic stage III disease (HR = 0.65, 99% CI = 0.45–0.96, P = .004) and 37.8% vs 31.7% among patients with palpable nodes (HR = 0.81, 99% CI = 0.61–1.08, P = .06).

A post hoc analysis of outcome by nodal involvement and ulceration status showed hazard ratios of 0.64 (99% CI = 0.46–0.90) among all patients with ulcerated primary tumor and 0.84 (99% CI = 0.60–1.17) among all with nonulcerated primaries, 0.58 (99% CI = 0.34–0.97) and 0.75 (99% CI = 0.41–1.37) among patients with microscopic nodal involvement with ulcerated and nonulcerated primaries, and 0.70 (99% CI = 0.45–1.08) and 0.86 (99% CI = 0.57–1.27) among patients with macroscopic nodal involvement with ulcerated and nonulcerated primaries.

Adverse Events

Grade 3 or 4 adverse events occurred in 54% of ipilimumab recipients vs 25% of placebo recipients, 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%).

Median time to onset of grade ≥ 2 immune-related adverse events ranged from 4.3 weeks for skin events to 13.1 weeks for neurologic events. Grade 2 to 4 immune-related adverse events other than endocrine events resolved to baseline or grade 1 with use of established management protocols in 82% to 95% of cases, with median time to resolution of 4 to 8 weeks. Endocrine events resolved in 56% of patients, with median time to resolution of 31 weeks.

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 from drug-related adverse events in the ipilimumab group. 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. ■

Disclosure: The trial was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit


1. Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncol 16:522-530, 2015.


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