Half of patients with previously treated metastatic melanoma responded to the targeted agent vemurafenib (Zelboraf), data from a phase II trial showed. Treatment with the BRAF inhibitor was associated with a median progression-free survival of 6.8 months and a median overall survival of 16 months. The results corroborated those from a phase I trial and were consistent with results from a phase III study that showed a high response rate in previously treated metastatic melanoma. \"Most responses were rapid, with less than 15% of patients having had disease progression at their first evaluation,\" Jeffrey A. Sosman, MD, of Vanderbilt University in Nashville, Tenn., and co-authors wrote in conclusion in the Feb. 23 issue of the New England Journal of Medicine. \"Therefore this trial shows that vemurafenib has clinically evident antitumor activity in metastatic melanoma and that response rates are higher than those associated with previously used treatments.\" \"The long follow-up period in our study provides critical information on long-term overall survival, not yet shown in the phase III trial comparing vemurafenib and dacarbazine,\" they added. A decade ago, laboratory studies showed that more than 60% of melanomas had the BRAF V600E mutation, which activated the MAP kinase pathway to promote cell proliferation and inhibit apoptosis (Nature 2002; 417: 949-954, Nature 2007; 445: 851-857). Those observations led to development of vemurafenib, a tyrosine kinase inhibitor that targets the BRAF V600E mutation in cancer cells. A phase I clinical study showed that 26 of 32 patients with previously-treated melanoma had responses to vemurafenib, including 18 confirmed responses (N Engl J Med 2010; 363: 809-819). The encouraging results of the phase I trial led to the phase II investigation by Sosman and colleagues. The study involved patients with histologically confirmed stage IV melanoma that had progressed after one or more prior systemic therapies for advanced disease. The final analysis included 132 patients who had a median age of 52. Men accounted for 61% of the total population. Half the patients had received one prior regimen for advanced melanoma, 27% had received two, and 22% had received three or more. Patients underwent baseline tumor imaging, and follow-up assessments occurred every six weeks and at final visit. A blinded independent review committee assessed response to therapy. All patients received vemurafenib daily until disease progression or unacceptable toxicity. The primary endpoint was overall response rate. The study population had a median follow-up of 12.9 months at the cutoff for efficacy data, and follow-up for the entire cohort ranged from 0.6 to 20.1 months. By independent review, eight patients (6%) had a complete response to vemurafenib, and 47% had a partial response, resulting in an overall response rate of 53%. Investigator assessment showed an overall response rate of 57% (5% complete response rate). The 70 patients with confirmed responses had a median response duration of 6.7 months. Although most responses occurred by the time of the first follow-up imaging assessment at six weeks, some occurred after more than six months of treatment. At efficacy cutoff, 62 patients remained alive and the median overall survival was 15.9 months. The authors noted that 32 (24%) patients received ipilimumab (Yervoy) after disease progressed. An unplanned post hoc analysis showed that median overall survival remained at 15.9 months after exclusion of the 32 patients. Providing context for the results, the authors wrote that metastatic melanoma has a median overall survival of six to 10 months and that, historically, few patients have responded to systemic therapy. Trials of ipilimumab, also approved for treatment of metastatic melanoma, showed an overall survival of 10.1 months in treated patients and 11.2 months in untreated patients. Experience with vemurafenib has shown that non-melanoma skin cancer is a potential side effect of treatment. In the phase trial, 26% of patients developed cutaneous squamous-cell carcinoma or keratoacanthoma. \"Lesions usually manifested in the first eight to 12 weeks of treatment and were effectively managed with simple resection without discontinuation of vemurafenib,\" the authors wrote. \"This suggests differential effects of vemurafenib on cells without oncogenic BRAF.\" Adverse effects occurred in most patients but usually were mild or moderate in severity, the authors reported. In addition to skin cancer, the most common events were arthralgia (59%), rash (52%), photosensitivity (52%), fatigue (42%), alopecia (36%), pruritus (29%), skin papilloma (29%), nausea (17%), peripheral neuropathy (10%), and hand-foot syndrome (10%). From: medpage today