LARGER DOSE OF IPILIMUMAB MORE TOXIC BUT ALSO MORE EFFECTIVE

In a phase III trial reported by Ascierto et al in The Lancet Oncology, treatment with ipilimumab (Yervoy) at 10 mg/kg vs 3 mg/kg resulted in improved overall survival in patients with advanced unresectable or metastatic melanoma. As noted by the investigators, although options for first-line treatment in this setting have changed since the start of the trial, which excluded patients with prior BRAF or immune checkpoint inhibitor therapy, use of ipilimumab monotherapy in patients with programmed cell death ligand 1 (PD-1) inhibitor–refractory disease might warrant further assessment.

Study Details

In the double-blind trial, 727 patients from 87 sites in 21 countries were randomized between February and July 2012 to receive ipilimumab at 10 mg/kg (n = 365) or ipilimumab at 3 mg/kg (n = 362) via 90-minute infusion every 3 weeks for 4 doses. Patients had untreated or previously treated unresectable stage III or IV disease. The primary endpoint was overall survival in the intent-to-treat population.

Overall Survival

Median follow-up was 14.5 months in the 10-mg/kg group and 11.2 months in the 3-mg/kg group. Median overall survival was 15.7 months vs 11.5 months (hazard ratio = 0.84, P = .04). Median progression-free survival was 2.8 months vs 2.8 months. Subsequent therapy was received by 36% in the 10-mg/kg group, including immunotherapy in 16% and targeted therapy in 10%, compared with 38% in the 3-mg/kg group, including immunotherapy in 14% and targeted therapy in 13%. Median time from randomization to first subsequent therapy was 216 days vs 190 days.

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 34% of the 10-mg/kg group vs 18% of the 3-mg/kg group, with the most common being diarrhea (10% vs 6%), colitis (5% vs 2%), increased alanine transaminase (3% vs 1%), and hypophysitis (3% vs2%). Treatment-related serious adverse events were reported in 37% vs 18%. Discontinuation of treatment due to treatment-related adverse events occurred in 24% vs 10%. Four (1%) vs two (< 1%) patients died of treatment-related adverse events.

The investigators concluded: “In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment.”

The study was funded by Bristol-Myers Squibb.

Paolo A. Ascierto, MD, of the Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione Pascale, is the corresponding author of The Lancet Oncology article.