Dabrafenib for the treatment of melanoma

Abstract

Introduction: Approximately 50% of patients with cutaneous melanoma have an activating mutation in BRAF kinase, leading to constitutive activation of the mitogen-activated protein kinase pathway and unregulated cell growth. Selective inhibitors of the mutated BRAF kinase produce response rates of approximately 50% with median progression-free survival of 6 – 7 months. BRAF-blocking therapies work rapidly, with responses seen within 2 weeks after therapy initiation, and they are associated with generally mild toxicities. The BRAF inhibitor dabrafenib recently was approved for use in patients with BRAF V600-mutated metastatic melanoma.

Areas covered: This article discusses the mechanisms of action and pharmacokinetic and pharmacodynamic changes as well as clinical efficacy and safety of dabrafenib for treatment of patients with advanced melanoma including unresectable stage IIIc and stage IV patients who harbor a BRAF V600 mutation. Clinical trial data are reviewed, and efficacy of dabrafenib in patients with brain metastases and in combination with the MEK inhibitor trametinib is discussed.

Expert opinion: Despite rapid and significant tumor reduction in a majority of patients with BRAF-mutant metastatic melanoma who are treated with dabrafenib, this drug’s use as a single agent is limited because of its relatively short duration of response. Various combinations with drug(s) inhibiting other target kinases and/or with immunomodulating agent(s) will likely be the standard in the near future.

Keywords::

• BRAF mutation
• dabrafenib
• melanoma
• resistance
• targeted therapy

Notes