Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations

ABSTRACT

Introduction

Combination treatment with a BRAF inhibitor and MEK inhibitor is the standard of care for patients with advanced BRAF^V600 mutation-positive melanoma. With the currently available combinations of dabrafenib plus trametinib and vemurafenib plus cobimetinib, median progression-free survival (PFS) of over 12 months has been achieved. However, treatment resistance and disease recurrence remain a clinical challenge.

Areas covered

Encorafenib in combination with bimetinib offers a new approach that may offer benefits over existing BRAF/MEK inhibitor combinations.

Expert opinion

While other BRAF/MEK inhibitor combinations have achieved a median overall survival (OS) of 22 months, patients with advanced BRAF mutation-positive melanoma treated with encorafenib plus binimetinib achieved a median OS of 33.6 months in the phase III COLUMBUS trial. PFS also appears to be improved with encorafenib plus binimetinib. This improved efficacy may be related to the distinct pharmacokinetics of encorafenib, with prolonged binding to the target molecule providing greater BRAF inhibition and increased potency compared with other drugs in the same class. Increased specificity of encorafenib may also result in better tolerability with less off-target effects, including reduced occurrence of pyrexia and photosensitivity. Encorafenib plus binimetinib seems likely to emerge as a valuable therapeutic alternative to established BRAF/MEK inhibitor combinations.

KEYWORDS:

• Binimetinib
• BRAF inhibitor
• encorafenib
• MEK inhibitor
• melanoma
• targeted therapy

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Article highlights

• Encorafenib plus binimetinib combination is the third combination of a BRAF and MEK inhibitors.

• The combination of encorafenib plus binimetinib increased median survival of about 16.9 months in comparison to vemurafenib monotherapy.

• Moreover, encorafenib monotherapy showed, in a direct comparison, a better efficacy than vemurafenib alone, and can be considered the most powerful BRAF inhibitor.

• The safety profile of encorafenib and binimetinib showed a similar incidence of grade 3–4 adverse events compared to the other BRAF/MEK inhibitors combinations, but with less pyrexia and photosensitivity reaction.

• Encorafenib and binimetinib is a valuable BRAF/MEK inhibitor combination.

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Acknowledgments

The authors would like to thank Fondazione Melanoma Onlus and Alessandra Trocino for providing excellent bibliography service and assistance.

Declaration of interest

PA Ascierto has/had advisory/consultant role for BMS, Roche-Genentech, MSD, Array, Novartis, Amgen, Merck Serono, Incyte, Pierre Fabre, Genmab, NewLink Genetics, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs; he received also research funds from BMS, Roche-Genenetch, Array and travel support from MSD. 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.

Reviewer disclosures

A reviewer on this manuscript has disclosed they have received honoraria for lectures and Advisory Boards from Novartis, Roche, BMS, MSD, Amgen, Pierre Fabre. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.