Background: Approximately 50% of metastatic melanoma are activating BRAF mutation-positive, most commonly in codon V600. Vemurafenib (VEM), an inhibitor of oncogenic BRAF kinase, has been shown to improve progression-free survival (PFS) and overall survival (OS) in pts with advanced V600E-mutated melanoma (Chapman et al, 2011; NEJM). An open-label phase II trial (NCT01586195) is being conducted to determine the activity and safety of VEM in previously treated or untreated stage IIIC or IV melanoma pts with measurable disease and an activating, non-V600E BRAF mutation at exon 15 detected by centralized DNA sequencing. Methods: Eligible pts received oral VEM (960 mg bid) until disease progression, unmanageable toxicity, pt request for discontinuation, or other protocol-specified criteria. Tumor responses were evaluated per RECIST v1.1. The primary endpoint was investigator-assessed objective response rate. Time to response, duration of response, PFS and OS, 6- and 12-month survival rates, and safety were additional endpoints. Results: As of October 2013, 10 US sites had enrolled 29 pts: 12 with V600K (cohort 1) and 17 with non-V600K mutations (cohort 2 [7 V600R, 3 L597S, 7 others]). Median (range) age was 61 (33-88) years, 86% were male, 45% were stage M1c and 17% unresectable stage IIIC, 28% had brain metastases, and 10% had ECOG PS 2 (the remainder were ECOG PS 0-1). 7% of pts were treatment naive. In pts who had prior therapy for advanced disease, the median (range) number of therapies was 2 (1-6). At this interim analysis, 12/29 pts (41%) had an unconfirmed response (5 V600K, 3 V600R, 4 other). Confirmed responses were observed in 3 pts (all PRs; V600K, V600R, and D594G); there were no CRs. Overall toxicity profile is consistent with the reported experience in melanoma, with the following AEs reported most frequently: fatigue (52%), rash (48%), and arthralgia (38%). 11 pts had ≥1 grade 3-5 AEs, irrespective of causality. We plan to present an updated data cut at ASCO. Conclusions: Preliminary results show objective responses in this population of advanced melanoma pts with rarer non-V600E BRAF mutations; however, additional follow-up is required. Clinical trial information: NCT01586195.