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This month, a third agent joined vemurafenib and trametinib as a highly effective treatment for BRAF-mutated melanomas. In a prospective, randomized phase III study, the selective BRAF inhibitor dabrafenib was found to improve the survival of stage IV melanoma patients.
The investigators randomly assigned 187 patients to receive dabrafenib and 63 patients to receive dacarbazine. Median progression-free survival (the primary endpoint) was 5.1 months with dabrafenib and 2.7 months with dacarbazine, a significant improvement (P<0.0001). Cutaneous lesions were the most common adverse effect of dabrafenib; hyperkeratoses (acanthoma, acrochordon, actinic keratosis, hyperkeratosis, keratosis pilaris, lichenoid keratosis, papilloma, seborrheic keratosis, and skin papilloma) developed in 12% of recipients, and 6% developed squamous cell carcinoma/keratoacanthomas.
Hauschild A et al. Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012 Jun 25; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(12)60868-X)
Comment
These results are similar to results with vemurafenib. Although genotyping assays differed slightly in trials of each drug, studies of both included only tumors bearing V600E mutations. Because progression-free survival was the primary endpoint in this trial, patients on dacarbazine were allowed to cross over to dabrafenib at the time of progression. This procedure allowed all patients access to the drug, and median follow-up for patients on dabrafenib was only 5 months, so it is difficult to interpret overall survival data at this juncture. Furthermore, with combination trials emerging, single-agent BRAF inhibition may represent a brief historical milestone in the long run.