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Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF V600 Mutation

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Abstract

The BRAF inhibitor dabrafenib (Tafinlar®) and the MEK inhibitor trametinib (Mekinist®) are indicated, as monotherapy or in combination with each other, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. This article reviews the therapeutic efficacy and tolerability of combination treatment with dabrafenib and trametinib in this indication and summarizes relevant pharmacological data. Dabrafenib plus trametinib significantly prolonged progression-free survival (PFS) and overall survival (OS), improved objective response rates (ORRs) and preserved health-related quality of life (HR-QOL) to a greater extent than dabrafenib (in the double-blind COMBI-d study) and vemurafenib (in the open-label COMBI-v study) in two large, randomized, phase III studies in treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E/K mutation. Limited treatment benefit with the combination was also seen in patients who had progressed on prior BRAF inhibitor therapy, as indicated by ORRs of ≤ 15 % and stable disease in ≤ 50 % of patients in small phase I and II studies. Combination therapy did not increase overall toxicity relative to dabrafenib or vemurafenib monotherapy, with most adverse events (AEs) mild or moderate in severity and generally manageable. Fewer skin-related AEs (e.g. cutaneous malignancies, hyperkeratinosis and hand-foot syndrome) were reported with combination therapy than with dabrafenib or vemurafenib, probably because of reduced paradoxical activation of the MAPK pathway. Thus, dabrafenib plus trametinib provides an important treatment option for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

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Acknowledgments

During the peer review process, the manufacturer of dabrafenib and trametinib was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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    Sohita Dhillon

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  1. Sohita Dhillon
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Correspondence to Sohita Dhillon.

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The preparation of this review was not supported by any external funding.

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Sohita Dhillon is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

Additional information

The manuscript was reviewed by: M. A. Davies, Department of Melanoma Medical Oncology, Department of Systems Biology, Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston (TX), USA; F. Grange, Department of Dermatology, Robert Debré University Hospital, Reims, France; P. Hersey, Sydney Medical School, University of Sydney, Sydney, Australia; P. Rutkowski, Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; R. J. Sullivan, Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston (MA), USA.

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Dhillon, S. Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF V600 Mutation. Targ Oncol 11, 417–428 (2016). https://doi.org/10.1007/s11523-016-0443-8

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