At the planned interim analysis, the Data and Safety Monitoring Board determined that both the OS and PFS endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib. A total of 675 patients were evaluated for OS; although the median survival had not yet been reached for vemurafenib and the data were immature for reliable Kaplan-Meier estimates of survival curves, the OS in the vemurafenib arm was clearly superior to that in the dacarbazine arm. The HR for death in the vemurafenib group was 0.37 (95% CI, 0.26–0.55; P < .001). The survival benefit in the vemurafenib group was observed in each prespecified subgroup, for example, age, sex, ECOG PS, tumor-stage lactic dehydrogenase, and geographic region. The HR for tumor progression in the vemurafenib arm was 0.26 (95% CI, 0.20–0.33; P < .001). The estimated median PFS was 5.3 months versus 1.6 months in the vemurafenib and dacarbazine arms, respectively.
Twenty patients had non-V600E mutations: 19 with V600K and 1 with V600D. Four patients with a BRAF V600K mutation had a response to vemurafenib.
AEs required dose modification or interruption in 38% of patients receiving vemurafenib and 16% of those receiving dacarbazine. The most common AEs with vemurafenib were cutaneous events, arthralgia, and fatigue. Cutaneous squamous cell carcinoma (SCC), keratoacanthoma, or both, developed in 18% of patients and were treated by simple excision. The most common AEs with dacarbazine were fatigue, nausea, vomiting, and neutropenia.
Previously treated patients. A total of 132 patients with a BRAF V600E or BRAF V600K mutation were enrolled in a multicenter phase II trial of vemurafenib, which was administered as 960 mg orally twice daily. Of the enrolled patients, 61% percent had stage M1c disease, and 49% had an elevated lactate dehydrogenase level. All patients had received one or more prior therapies for advanced disease. Median follow-up was 12.9 months. An Independent Review Committee (IRC) reported a 53% response rate (95% CI, 44–62) with eight patients (6%) achieving CR. Median duration of response per IRC assessment was 6.7 months (95% CI, 5.6–8.6). Most responses were evident at the first radiologic assessment at 6 weeks; however, some patients did not respond until they received therapy for more than 6 months.[Level of evidence: 3iiiDiv]
Dabrafenib is an orally available, small molecule, selective BRAF inhibitor that has been compared with DTIC in an international, multicenter trial (BREAK-3 [NCT01227889]). A total of 250 patients with unresectable stage III or IV melanoma and BRAF V600E mutations were randomly assigned in a 3:1 ratio (dabrafenib 150 mg orally twice a day or DTIC 1000 mg/m2 IV every 3 weeks). IL-2 was allowed as prior treatment for advanced disease. The primary endpoint was PFS; patients could cross over at the time of progressive disease after confirmation by a blinded IRC.