Update on BRAF and MEK inhibition for treatment of melanoma in metastatic, unresectable, and adjuvant settings

ABSTRACT

Introduction: Selective inhibition of the MAPK pathway with BRAF and MEK inhibitors has emerged as a key component of the treatment of BRAF-mutant unresectable/locally advanced metastatic melanoma.

Areas covered: Current data are presented on the efficacy and safety of BRAFi + MEKi combination therapy (dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib) from phase I, II, and III trials in the unresectable/locally advanced metastatic setting, as well as neoadjuvant and adjuvant applications. The theoretical basis, pre-clinical findings, clinical trial results and current ongoing clinical studies of combined BRAF/MEK inhibition with immunotherapy, also known as ‘triplet therapy,’ are also explored.

Expert opinion: Combination therapy with BRAF and MEK inhibitors dramatically improves response rates, progression-free survival and overall survival in patients with BRAF-mutant metastatic melanoma compared to historical treatments such as chemotherapy. Some serious adverse effects, including cutaneous squamous cell carcinoma, are attenuated with combination therapy, while less severe and reversible effects including pyrexia, left ventricular dysfunction, and ocular events can be more common with combination therapy. Existing data are insufficient to recommend triplet therapy, or a particular treatment sequence, with respect to BRAF and MEK inhibitors and immune therapies, though results from multiple ongoing trials are anticipated.

Trial registration: ClinicalTrials.gov identifier: NCT02231775.

Trial registration: ClinicalTrials.gov identifier: NCT01940809.

Trial registration: ClinicalTrials.gov identifier: NCT02902042.

Trial registration: ClinicalTrials.gov identifier: NCT02967692.

Trial registration: ClinicalTrials.gov identifier: NCT02858921.

Trial registration: ClinicalTrials.gov identifier: NCT02130466.

Trial registration: ClinicalTrials.gov identifier: NCT02902029.

Trial registration: ClinicalTrials.gov identifier: NCT02631447.

Trial registration: ClinicalTrials.gov identifier: NCT02968303.

Trial registration: ClinicalTrials.gov identifier: NCT02910700.

Trial registration: ClinicalTrials.gov identifier: NCT02908672.

Trial registration: ClinicalTrials.gov identifier: NCT3149029.

KEYWORDS:

• BRAF
• MEK
• MAPK
• melanoma
• targeted therapy
• triplet therapy
• encorafenib
• binimetinib
• dabrafenib
• trametinib

Article highlights

• MAPK pathway inhibition with combination BRAF plus MEK inhibition is a key component of the treatment of BRAF-mutant metastatic melanoma, with additional potential applications in adjuvant and neoadjuvant settings

• Treatment resistance and adverse events associated with single-agent BRAF inhibitors are the results of reactivation of the MAPK pathway which can be attenuated with MEK inhibition

• Combination BRAF/MEK therapy improves response rates and progression-free survival

• Results of ongoing investigations of BRAF/MEK therapy in combination with immune therapy could further improve outcomes for patients with advanced melanoma

This box summarizes key points contained in the article.

Declaration of interest

J Zager and Z Eroglu receive research funding from Novartis and serve on the Advisory Board for Array Biopharma. J Zager also serves on the Speakers Bureau for Array Biopharma. Z Eroglu is a consultant for Regeneron. 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 peer reviewer on this manuscript has received honoraria for lectures from, and has served on advisory boards for, Novartis, Roche, BMS, MSD, Amgen, Pfizer and Pierre Fabre. All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.