Overall survival (OS) and safety results from a phase 3 trial of ipilimumab (IPI) at 3 mg/kg vs 10 mg/kg in patients with metastatic melanoma (MEL)

In phase 3 trials, IPI demonstrated an OS benefit at 3 mg/kg as monotherapy in previously treated patients (pts) and at 10 mg/kg in combination with DTIC in untreated pts with MEL. Results of a dose-ranging phase 2 trial suggested longer OS, but a higher incidence of treatment-related grade 3-4 adverse events (AEs), with IPI 10 mg/kg vs. 3 mg/kg. We report the primary results of a randomized, double-blind, phase 3 trial that directly compared the benefit-risk profile of IPI 10 mg/kg vs. 3 mg/kg in MEL pts. Pts (N = 727) with untreated or previously treated unresectable stage III or IV melanoma, who had not received prior BRAF or immune checkpoint inhibitors, were randomly assigned 1:1 to IPI 3 mg/kg Q3W x 4 or IPI 10 mg/kg Q3W x 4. Pts were stratified by M substage, prior treatment, and ECOG performance status. Upon disease progression, pts who experienced clinical benefit could be re-induced with IPI at the same dose and schedule. The primary endpoint was OS. Safety was evaluated in all treated pts. Baseline patient characteristics were balanced between dose groups. Overall, 56.5% of pts received prior systemic therapy. At a minimum follow-up of ∼43 months, IPI 10 mg/kg improved OS vs. IPI 3 mg/kg (Table). Among 726 treated patients, IPI 10 mg/kg vs. 3 mg/kg was associated with higher rates of treatment-related grade 3-5 AEs (34.3% vs. 18.5%), grade 3-5 AEs leading to discontinuation (26.1% vs. 16.0%), and grade 3-5 immune-mediated adverse reactions (33.5% vs. 17.4%). There were 4 (1.1%) deaths in the IPI 10 mg/kg group and 2 (0.6%) in the 3 mg/kg group attributed to study drug toxicity.Tabled 1IPI 10 mg/kg (N = 365)IPI 3 mg/kg (N = 362)Median OS, months (95% CI)15.7 (11.6–17.8)11.5 (9.9–13.3)HR (95% CI)0.84 (0.70–0.99)P = 0.041–Year OS rate (95% CI)54.3 (49.0–59.3)47.6 (42.4–52.7)2–Year OS rate (95% CI)38.5 (33.4–43.5)31.0 (26.2–35.8)3–Year OS rate (95% CI)31.2 (26.4–36.0)23.2 (18.9–27.7) Open table in a new tab In the first phase 3 trial to directly compare IPI 10 mg/kg with 3 mg/kg in MEL pts who had not received prior BRAF or immune checkpoint inhibitors, IPI 10 mg/kg demonstrated improved OS vs IPI 3 mg/kg, and higher incidence of treatment-related AEs, AEs leading to discontinuation, and immune-mediated adverse reactions.