Patients with Metastatic Melanoma Benefit from Vemurafenib

Chicago—Patients with untreated metastatic melanoma who took vemurafenib had significant improvements in overall and progression-free survival compared with a group that took dacarbazine, according to a phase 3 trial presented in a plenary session at the ASCO meeting. Results were simultaneously published online in the New England Journal of Medicine [10.1056/NEJMoa1103782]. Paul Chapman, MD, the study’s lead author, said that vemurafenib is the first melanoma agent to prove superior to any standard chemotherapy regimen (in this case, dacarbazine) in terms of improved response proportion, progression-free survival, and overall survival. Vemurafenib is an oral therapy that targets the V600E mutations in the BRAF gene. Dr. Chapman said patients with metastatic melanoma have poor prognosis and few treatment options. Approved by the US Food and Drug Administration (FDA) in 1975, dacarbazine is still used worldwide, but Dr. Chapman said it is uncommon for dacarbazine to be associated with prolonged survival. He added that the response rate to dacarbazine is between 7% and 12%, and the median overall survival from the time patients began dacarbazine treatment is <8 months. The open-label BRIM3 (BRAF Inhibitor in Melanoma) study enrolled 675 patients at 104 centers in 12 countries between January 2010 and December 2010 who had not received treatment for unresectable stage IIIC or stage IV melanoma and tested positive for BRAF V600E mutation. Other inclusion criteria included an Eastern Cooperative Oncology Group performance status score of 0 or 1 and no active central nervous system metastases. Patients were randomized in a 1:1 ratio to receive 960 mg of vemurafenib twice daily or 1000 mg/m2 of dacarbazine intravenously every 3 weeks. Crossover between the groups was not allowed, according to Dr. Chapman. However, Dr. Chapman said that based on evolving phase 2 data the researchers in the BRIM3 study found they had underestimated the treatment effect, so they reached out to the FDA and revised the statistical plan in October 2010. The interim analysis included all events as of December 30, 2010. In January 2011, an independent data and safety monitoring board reviewed the data and found there was “compelling evidence that there was a benefit to vemurafenib,” according to Dr. Chapman. The board recommended that patients in the dacarbazine arm be allowed to cross over to the vemurafenib arm. At the planned interim analysis, patients who took vemurafenib had a median progression-free survival of 5.3 months compared with a median of 1.6 months in the dacarbazine group (hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.20-0.33; P<.0001). Dr. Chapman said the researchers could not provide median overall survival because not enough deaths occurred. However, he said that an estimated 84% of patients in the vemurafenib group survived at 6 months compared with 64% in the dacarbazine cohort (HR, 0.37; 95% CI, 0.26-0.55; P<.0001). The vemurafenib group also showed a 74% decrease in the risk of tumor progression or death compared with patients who took dacarbazine (P<.0001). Among the 65% of patients who could be evaluated for response rate, 48.4% of patients taking vemurafenib had a response compared with 5.5% taking dacarbazine. The most common adverse events (AEs) in patients who received vemurafenib were cutaneous squamous cell carcinoma, rash, an increase in liver enzymes, and keratoacanthoma. In the vemurafenib group, 6% of patients discontinued treatment because of AEs compared with 4% in the dacarbazine group.