CHICAGO—Ipilimumab in combination with dacarbazine significantly improved overall survival (OS) in metastatic melanoma compared with dacarabazine alone, according to data presented at the American Society of Clinical Oncology’s 2011 Annual Meeting.
In a previous Phase 3 study, ipilimumab monotherapy improved OS in previously treated, unresectable or metastatic melanoma. Jedd Wolchok, MD, from Memorial Sloan-Kettering Cancer Center, New York, and colleagues sought to evaluate ipilimumab in combination with dacarbazine (a global standard of care) as first-line therapy for metastatic melanoma. In this Phase 3, double-blind study, patients ≥18 years with metastatic melanoma, ECOG performance status 0/1, who had received no prior therapy for advanced disease, were randomized 1:1 to receive ipilimumab 10mg/kg + dacarbazine 850mg/m2 or placebo + dacarbazine 850mg/m2 at Weeks 1, 4, 7, and 10, followed by dacarbazine every 3 weeks through Week 22 (induction). Eligible patients then received ipilimumab or placebo every 12 weeks (maintenance). The primary endpoint was OS; 2-sided log-rank test was performed, stratified by baseline M stage and ECOG PS. Patients were eligible for enrollment regardless of b-raf mutation status, HLA type, or lactate dehydrogenase (LDH) levels. Baseline characteristics were comparable between both treatment arms.
Of 502 patients, 56% had M1c disease, 40% elevated LDH, and 26% had received adjuvant therapy. A total of four induction doses were administered in 37% of patients in the ipilimumab + dacarbazine arm and 65% in the placebo + dacarbazine arm. A significant improvement was observed for overall survival (HR 0.72; P=0.0009) and higher estimated 1-, 2-, and 3-year survival rates were see with ipilimumab + dacarbazine. See Table. The best overall response rate was comparable between the two treatment arms, though response favored the ipilimumab + dacarbazine arm (15% vs. 10%; complete response (2% vs. 1%), partial response (14% vs. 10%), stable disease (18% vs. 20%, and progressive disease (44% vs. 52%).
Grade 3/4 adverse events (AEs) were observed in 56% of patients in the ipilimumab + dacarbazine arm (n=247) and 27% in the placebo + dacarbazine arm (n=251) and included elevated ALT (22% vs. 1%), diarrhea (4% vs. 0%), and rash (1% vs. 0%). No intestinal perforations or hypophysitis were noted. One drug-related death occurred due to gastrointestinal (GI) hemorrhage in the placebo + dacarbazine arm; none occurred in the ipilimumab + dacarbazine arm. Dr. Wolchok noted that the rates of high-grade AEs differed from the results from previous Phase 2 trials: a higher incidence of liver toxicities and a lower incidence of gastrointestinal toxicities were observed.
Dr. Wolchok et al concluded that ipilimumab 10mg/kg in combination with dacarbazine significantly improved OS as first-line therapy in treatment-naïve metastatic melanoma, regardless of b-raf mutation status or HLA-type. Additionally, durable survival of approximately 3 years and objective responses were observed in about 21% of patients after follow-up for up to 4 years. The types of AEs observed were consistent with those from previous ipilimumab studies, though frequencies of some AEs differed with a higher transaminitis and lower diarrhea/colitis/GI perforation rates than expected.