Dabrafenib Active in BRAF-600E/K Mutant Metastatic Melanoma
In a phase II study (BREAK-2) reported in Journal of Clinical Oncology, Paolo A. Ascierto, MD, of Istituto Nazionale Tumori Fondazione G. Pascale, and colleagues assessed the activity of the mutated BRAF kinase inhibitor dabrafenib (Tafinlar) in patients with BRAF-V600E/K mutant metastatic melanoma. They found a high response rate among patients with BRAF-V600E mutation.
In the single-arm multicenter study, 76 patients with BRAF-V600E and 16 patients with BRAF-V600K mutant stage IV melanoma received oral dabrafenib, 150 mg twice daily, until disease progression, death, or unacceptable toxicity. The primary endpoint was overall response rate in BRAF-V600E mutant patients. The study also assessed the ability of tumor-specific circulating cell-free DNA (cfDNA) to predict outcome.
Response Rates
In the BRAF-V600E group, 45 patients (59%) had a confirmed response (95% confidence interval [CI] = 48.2%–70.3%), including five patients (7%) with complete response. Two patients (13%) in the BRAF-V600K group had a confirmed partial response (95% CI = 0%–28.7%).
Median progression-free survival was 6.3 months in the BRAF-V600E group and 4.5 months in the BRAF-V600K group, and median overall survival was 13.1 months and 12.9 months, respectively. The authors noted that there is no clear explanation for the difference in response rate between patients with BRAF-V600E and those with BRAF-V600K mutation–positive melanoma.
cfDNA Assay Predicts Response in BRAF-V600E Group
The overall agreement between tumor tissue and cfDNA was 84% for BRAF-V600E mutation status and 97% for BRAF-V600K mutation status. Assay sensitivity was 79% and 89% for BRAF-V600E and BRAF-V600K, respectively, and specificity was 100% and 99%, respectively. There was a positive correlation between baseline tumor burden and levels of BRAF-V600E cfDNA (correlation coefficient = 0.73; P < .001, n = 60).
There was also a significant association between baseline cfDNA BRAF-V600E mutation fraction and overall response rate (hazard ratio [HR] = 0.83, P = .0134, n = 46) and between cfDNA BRAF-V600E mutation fraction and progression-free survival (HR = 1.09, P = .0006, n = 46), indicating that as the BRAF-V600E mutation fraction increased, overall response rate and progression-free survival decreased. There was no correlation between the BRAF-V600K mutation fraction and any efficacy endpoint.
The most common adverse events were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious adverse event and 9 patients (10%) developed squamous cell carcinoma.
The investigators concluded, “Dabrafenib was well tolerated and clinically active in patients with BRAF-V600E/K mutation–positive metastatic melanoma. cfDNA may be a useful prognostic and response marker in future studies.” Two phase III studies (NCT01597908 and NCT01584648) are underway to examine the combination of dabrafenib and the MEK inhibitor trametinib (Mekinist) in metastatic melanoma.
The study was supported by GlaxoSmithKline.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
