Dabrafenib therapy for advanced melanoma

Objective: To summarize the clinical development of dabrafenib and to highlight the clinically relevant distinct characteristics of dabrafenib in contrast to vemurafenib.

Data source: An English-language literature search of MEDLINE/PubMed (1966-June 2013), using the keywords GSK2118436, dabrafenib, vemurafenib, selective BRAF inhibitor, and advanced melanoma, was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries.

Study selection and data extraction: All relevant published articles on dabrafenib and vemurafenib were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing studies.

Data synthesis: BRAF(V600E) mutation confers constitutive BRAK kinase activation in melanoma cells, promoting tumor growth. This discovery led to the development of BRAF kinase inhibitors like vemurafenib and dabrafenib. Dabrafenib has been approved to treat patients with BRAF(V600E)-positive unresectable or metastatic melanoma based on its clinical benefit demonstrated in a randomized phase III study. It has also been shown to be safe and effective in patients with BRAF mutant advanced melanoma involving the brain. Dabrafenib is well tolerated, with the most common adverse effects being hyperkeratosis, headache, pyrexia, and arthralgia. Currently, there is no evidence to suggest that one BRAF inhibitor is superior to the other. With similar efficacy, therapy selection will likely be influenced by differential tolerability and cost.

Conclusions: Dabrafenib joins vemurafenib to confirm the superior clinical outcome of the BRAF inhibitors when compared with dacarbazine in patients with BRAF(V600E)-positive advanced melanoma. Active research is ongoing to expand its utility into the adjuvant setting and to circumvent rapid emergence of drug resistance.