Dabrafenib in the treatment of metastatic or unresectable melanoma

Abstract

Dabrafenib is a potent inhibitor of mutant BRAF. Trials to date have shown it to be well tolerated, with significant activity in unresectable stage III or IV metastatic melanoma. Overall response rates of approximately 50% were seen in addition to improved progression-free and overall survival of 6 and 18 months, respectively. Preclinical studies suggested that combining BRAF and MEK inhibition would increase response rates and decrease toxicity. Clinical trials with the combination of dabrafenib and trametinib have improved progression-free and overall survival in interim analyses. Future improvements in responses and outcomes will depend on additional combination strategies, possibly employing immunotherapy.

Keywords:

• BRAF
• dabrafenib
• efficacy
• metastatic melanoma
• toxicity
• trametinib

Financial & competing interests disclosure

D Hogg serves on Advisory Boards for Roche, Merck, GlaxoSmithKline, Bristol-Myers Squibb and Novartis. L Khoja received fellowship funding from the Canadian Institute of Health Research and the Guiletti Family Fellowship Fund. 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.

Key issues

• Dabrafenib is an oral BRAF inhibitor which demonstrated activity in a Phase I study in a variety of tumors including metastatic melanoma.

• Subsequent Phase II–III studies demonstrated significant single-agent activity in metastatic and unresectable melanoma, with an acceptable toxicity profile, leading to FDA approval in 2013.

• Combination trials of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) have demonstrated superior progression-free survival over dabrafenib alone. One open-label study has reported superior overall survival and mature data are awaited from double-blinded studies.

• The combination of dabrafenib and trametinib was granted FDA approval in 2014 and further combination strategies with immunotherapy in particular are under evaluation in a number of trials. These are likely to lead to further improvements in responses and outcomes if they are found to be safe.

• Other carcinomas that harbor BRAF mutations are likely to respond to dabrafenib so that the indications for this medication will expand, FDA breakthrough status was recently granted for non-small cell lung cancer.