Efficacy, Safety, and Quality of Life (Qol) Data from the Eortc 18071 Phase III Trial of Ipilimumab (Ipi) Versus Placebo After Complete Resection of Stage III Melanoma

Abstract

ABSTRACT Aim: Ipi, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses, is an approved treatment for advanced melanoma. We report primary efficacy data and ongoing analyses from a phase III trial to evaluate Ipi as an adjuvant therapy for resected stage III melanoma at high risk of recurrence. Methods: In this randomized, double-blind trial, eligible patients (pts) included those ≥18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to Ipi 10 mg/kg (n = 475) or placebo (Pbo, n = 476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included safety and health-related QoL. Results: Overall, 20%/44%/36% of pts had stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. At a median follow-up of 2.7 yrs, Ipi significantly improved RFS vs Pbo (234/475 vs 294/476 events): median RFS 26.1 mos for Ipi vs 17.1 mos for Pbo (HR 0.75, 0.64–0.90; log-rank P = 0.0013). 3-yr RFS rates were 46.5% and 34.8%, respectively. RFS benefit was consistent across subgroups (e.g., stage IIIB or IIIC, ulcerated primary). Most common grade 3/4 immune-related adverse events (irAEs) in the Ipi and Pbo arms were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Most irAEs were managed and resolved using established algorithms. Of 471 pts who started Ipi, 245 (52%) discontinued treatment due to AEs (182 [38.6%] within 12 weeks); 5 (1.1%) died due to drug-related AEs. RFS analyses adjusted for prognostic factors and key HRQoL data will be presented. Conclusions: In this phase III trial, Ipi as adjuvant therapy provided a clinically and statistically significant improvement in RFS vs Pbo for pts with stage III melanoma at high risk of recurrence. AE profile was generally consistent with that observed in advanced melanoma, although with a higher incidence of endocrinopathies. Disclosure: A.M.M. Eggermont: Financial interest: Advisory boards for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, MedImmune, and MSD; V. Chiarion-Sileni: Advisory board participation: Bristol-Myers Squibb, GlaxoSmithKline, and Roche; J.-. Grob: Consultant or advisory role: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck; honoraria: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck; R. Dummer: Consultant or advisory role, honoraria, and research funding: AstraZeneca, Novartis, Cephalon, MSD, Bristol-Myers Squibb, GlaxoSmithKline, Roche, Amgen, Bayer; J.D. Wolchok: Grants and personal fees: Bristol-Myers Squibb, during conduct of the study; grants and personal fees from Medimmune, Glaxo SmithKline; personal fees: Merck Sharpe and Dohme, EMDSerono, Johnson and Johnson; H. Schmidt: Advisory board: Roche; speakers' bureau: Bristol-Myers Squibb; O. Hamid: Consultant or advisory role: Bristol-Myers Squibb; speakers' bureau: Bristol-Myers Squibb; research funding from Bristol-Myers Squibb to The Angeles Clinic; C. Robert: Consultant or advisory role: Bristol-Myers Squibb, GlaxoSmithKline, Roche, MSD; honoraria: Bristol-Myers Squibb, GlaxoSmithKline, Roche; P.A. Ascierto: Consultant or advisory role: Bristol-Myers Squibb, Roche-Genentech, MSD, GlaxoSmithKline, Novartis, Ventana; honoraria: Bristol-Myers Squibb, Roche-Genentech, GlaxoSmithKline; research funding: Bristol-Myers Squibb, Ventana; J.M. Richards: Stock ownership: Bristol-Myers Squibb; C. Lebbe: Advisory boards: Bristol-Myers Squibb, Roche, Novartis, GlaxoSmithKline, Amgen.; M. Smylie: Consultant or advisory role: Bristol-Myers Squibb; honoraria: Bristol-Myers Squibb; J.S. Weber: Advisory boards: Bristol-Myers Squibb (less than 10,000 USD annually for advisory boards); grants from Bristol-Myers Squibb to Moffitt for the conduct of the trial in question; M. Maio: Consultant or advisory role: Bristol-Myers Squibb; honoraria: Bristol-Myers Squibb; research funding: Bristol-Myers Squibb; C. Konto: Employee of Bristol-Myers Squibb; V. De Pril: Employee of Bristol-Myers Squibb; stock ownership: Bristol-Myers Squibb; A. Testori: Consultant or advisory role: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Amgen, Celgene; honoraria: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.