Vemurafenib Plus Dacarbazine Improves Survival in Metastatic Melanoma Patients

Chicago—A phase 3 study presented in the plenary session at the ASCO meeting showed that patients with previously untreated metastatic melanoma who received vemurafenib plus dacarbazine (a chemotherapy agent) had prolonged survival compared with those taking placebo plus dacarbazine. Patients who took vemurafenib also had higher estimated 1-, 2-, and 3-year survival rates and longer durable responses. Results were simultaneously published online in the New England Journal of Medicine [10.1056/NEJMoa1104621]. Ipilimumab is a human monoclonal antibody and an immunotherapeutic agent that earlier this year became the first drug approved by the US Food and Drug Administration (FDA) that demonstrated improved survival in patients with advanced melanoma. Jedd Wolchok, MD, the study’s lead author, said it was the first time that a combination of immunotherapy and chemotherapy was found to be safe and effective for patients with metastatic melanoma. Dr. Wolchok said patients with previously untreated metastatic melanoma typically have a 1-year survival rate after treatment initiation of approximately 25% and a 2-year survival rate after treatment initiation of approximately 10%. “There’s an urgent need for the development of new medicines that are highly effective and capable of durable disease control,” Dr. Wolchok said. In the double-blind study, 502 patients ≥18 years of age with previously untreated metastatic melanoma were treated in 24 countries between August 2006 and January 2008. They were randomized in a 1:1 ratio to receive 850 mg/m2 of dacarbazine once every 3 weeks with 10 mg/kg of ipilimumab or placebo. They received the treatment through week 12 and then underwent a tumor assessment. If patients had stable disease or objective response and no evidence of dose-limiting toxicities, they could receive 4 additional doses of dacarbazine alone until week 24. If imaging at week 24 showed sustained response and lack of dose-limiting toxicities, patients could continue to receive blinded ipilimumab or placebo once every 12 weeks. Inclusion criteria included stage IIIC or IV melanoma and an Eastern Cooperative Oncology Group performance status score of 0 or 1. There were no restrictions on lactate dehydrogenase level, BRAF mutation status, or human leukocyte antigen type. Exclusion criteria included radiographically detected brain metastases at baseline or a history of symptomatic autoimmune disease. The primary analysis, performed in March 2011, found that patients in the ipilimumab cohort had a median overall survival of 11.2 months compared with 9.1 months for the placebo cohort (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.59-0.87; P=.0009). At 1 year, 47.3% of patients taking ipilimumab had survived compared with 36.3% of patients taking placebo; at 2 years, 28.5% of patients taking ipilimumab had survived compared with 17.9% of patients taking placebo; and at 3 years, 20.8% of patients taking ipilimumab had survived compared with 12.2% of patients taking placebo. The median progression-free survival in the ipilimumab group was 2.8 months compared with 2.6 months in the placebo group (HR, 0.76; 95% CI, 0.63-0.93; P=.006). The disease control rate (the sum of stable disease, partial response, and complete response) was 33.2% in the ipilimumab group and 30.2% in the placebo group, while the best overall response rate (the sum of partial response and complete response) was 15.2% in the ipilimumab group and 10.3% in the placebo group. The median duration of response was 19.3 months for patients taking ipilimumab and 8.1 months for patients receiving placebo. More patients had grade 3 or 4 adverse events (AEs) in the ipilimumab group (56.3% vs 27.5%), and most AEs were drug-related, according to Dr. Wolchok. He said the AEs associated with ipilimumab primarily affected the skin, gastrointestinal tract, liver, and endocrine system.