Dabrafenib for the treatment of melanoma.
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
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.
The University of Texas MD Anderson Cancer Center, Department of Melanoma Medical Oncology , Unit 430, 1515 Holcombe Blvd, Houston, TX 77030 , USA.
Rodabe N
RN
Amaria
Kevin B
KB
Kim
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D004341:Drug Evaluation; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D010091:Oximes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib