Background: Most agents tested in large phase II trials in patients (pts) with metastatic melanoma have response rates of 10-20%. Approximately 50% of melanomas harbor a V600E activating mutation in the BRAF gene, which can now be targeted with specific inhibitors. In a Phase I study, treatment with vemurafenib (V), an orally available inhibitor of mutant BRAF, led to a high incidence of tumor regressions in BRAF-mutant melanoma (Flaherty et al. NEJM 2010). Here we report the results of BRIM-2, a pivotal Phase II trial of V in previously treated pts with BRAF-mutant melanoma.
Methods: The primary endpoint was best overall response rate (BORR), with a target of 30% and a lower boundary of the exact 95% CI of at least 20% by independent review committee (IRC). BRAF mutation status was determined using a PCR-based investigational, companion diagnostic assay (cobas 4800 BRAF V600 Mutation Test, Roche Molecular Systems). Pts without active CNS metastasis who had received at least one prior line of therapy for metastatic melanoma received V (960 mg po twice daily) until progressive disease, unacceptable toxicity, or death.
Results: 132 pts were enrolled (Oct 2009-Mar 2010), median age 51.5 yr, 54% ECOG PS 1, 61% M1c, 49% elevated LDH, and 49% >1 line of prior therapy. At the time of analysis (Sept 27, 2010, median follow-up 7 mo), BORR was 52.3% (95% CI: 43–61%; 2.3% CR, 50% PR) by IRC, with 29.5% SD and only 13.6% PD. Median duration of response was 6.8 mo (95% CI: 5.6-NR), and median PFS was 6.2 mo (95% CI: 5.6–6.8%). Median OS had not been reached. Most common adverse events (AEs; ≥25% pts, mostly Grade 1-2) were arthralgia, rash, photosensitivity, fatigue, alopecia, pruritis, and skin papilloma. The most common Grade 3 AE was cutaneous squamous cell carcinoma (24.2%), the majority centrally reviewed as keratoacanthoma-type. AEs were generally reversible with dose modification or interruption. 42% of pts required dose reductions, most commonly for rash, arthralgia and LFT abnormalities.
Conclusions: BRIM2 met its primary endpoint based on BORR, confirming that V is an active agent in pts with BRAF mutation-positive melanoma who have completed prior first-line therapy.