Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab— which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100(gp100) peptide vaccinewas compared with gp100 alonein patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumabplus gp100 (403 patients), ipilimumab alone(137), or gp100 alone(136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumabplus gp100, as compared with 6.4 months among patients receiving gp100 alone( hazard ratiofor death, 0.68; P<0.001). The median overall survival with ipilimumab alonewas 10.1 months ( hazard ratiofor death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumabgroups ( hazard ratiowith ipilimumabplus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumaband in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-MyersSquibb; ClinicalTrials.gov number, NCT00094653.)