Dabrafenib in combination with trametinib for the treatment of metastatic melanoma

Abstract

Oncogenic BRAF mutations are present in approximately 40–50% of patients with metastatic melanoma. Targeting BRAF mutations with either small molecule inhibitors of BRAF or one of the downstream mediators of oncogenic BRAF – MEK – is associated with improved outcomes compared with chemotherapy and has led to the US FDA approval of two BRAF inhibitors – vemurafenib and dabrafenib – and the MEK inhibitor trametinib. Further, the combination of dabrafenib and trametinib is well tolerated and associated with higher responses and improved survival compared with single-agent BRAF inhibitors.

Keywords:

• BRAF
• MEK
• melanoma
• resistance
• targeted therapy

Financial & competing interests disclosure

RJ Sullivan has acted as a consultant for Astex Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Dabrafenib is a small molecule inhibitor of BRAF that is highly specific for the BRAF V600, oncogenic form of BRAF. It has been proven safe and effective for the treatment of BRAF-mutant melanoma and was the second BRAF inhibitor approved by the FDA.

• Trametinib is a potent small molecule inhibitor of MEK1/2 that has been proven safe and effective for the treatment of BRAF-mutant melanoma. It was the first MEK inhibitor approved by the FDA.

• The combination of dabrafenib and trametinib is the first novel small molecule inhibitor combination to receive regulatory approval. This combination is well tolerated at the FDA-approved doses of the two individual agents, is associated with high response rates and appears to be associated with improved survival compared with single-agent BRAF inhibitor therapy.

Notes