Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma

Purpose Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAF V600E/K mutation–positive metastatic melanoma (mut + MM). Patients and Methods Histologically confirmed patients with stage IV BRAF V600E/K mut + MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAF V600E mut + MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome. Results Seventy-six patients with BRAF V600E and 16 patients with BRAF V600K mut + MM were enrolled onto the study. In the BRAF V600E group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAF V600K mut + MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAF V600E and BRAF V600K groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAF V600E mut + MM patients. Conclusion Dabrafenib was well tolerated and clinically active in patients with BRAF V600E/K mut + MM. cfDNA may be a useful prognostic and response marker in future studies.