The discovery and development of binimetinib for the treatment of melanoma

ABSTRACT

Introduction

Binimetinib is an uncompetitive, small-molecule inhibitor of selective mitogen-activated protein kinase (MEK1/2) and was recently approved in 2018 in combination with encorafenib for the treatment of metastatic melanomas. Preclinical and clinical trial data on the drug demonstrate its potent efficacy in cancers, especially melanomas with BRAF and NRAS mutations.

Areas covered

The authors review the preclinical as well as clinical Phase 1, 2 and 3 trial data leading to its FDA approval in 2018 for metastatic melanoma. Phase 3 data in combination with encorafenib demonstrated double the PFS (14.9 months) compared to vemurafenib alone (7.3 months) in patients with BRAF-mutated metastatic melanoma.

Expert opinion

No longer-term data is available yet to demonstrate any durable complete responses to therapy with binimetinib or improvements in overall survival compared to other FDA-approved therapies including immunotherapy or vemurafenib. Treatment approaches to patients with BRAF-mutated metastatic melanoma should be individualized and binimetinib in combination with encorafenib is a reasonable oral strategy with a reasonably tolerated toxicity profile. The cost of treatment and durability of response should be incorporated into the discussion as part of the overall medical decision-making.

KEYWORDS:

• Binimetinib
• metastatic melanoma
• MEK inhibitor
• combination therapy
• targeted therapy

Declaration of Interest

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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article Highlights

• Binimetinib (Mektovi®) is an uncompetitive, small-molecule inhibitor of selective mitogen-activated protein kinase (MEK1/2).

• Binimetinib is highly potent in BRAF- and NRAS-mutated melanomas, has 50% oral bioavailability, and its maximum recommended dose is 45 mg twice daily.

• Binimetinib demonstrated safety and early efficacy in metastatic melanomas in Phase 1 and II trials at a dose of 45 mg BID and was shown in combination with encorafenib to be superior to vemurafenib in the COLUMBUS Phase III trial.

• Binimetinib has currently been evaluated in over 70 clinical trials in a variety of cancers and was FDA approved in 2018 in combination with encorafenib for the treatment of metastatic melanomas where it demonstrated double the progression-free survival (14.9 months) compared to vemurafenib alone (7.3 months) in patients with BRAF-mutated metastatic melanoma.

• Factors including binimetinib side effects, high cost, and limited durable tumor benefits must be considered in clinical decision-making as no durable complete responses have yet been observed with binimetinib combination therapy in melanoma compared to immunotherapy regimens.

Additional information

Funding

The authors are supported by funds from the University of Michigan Comprehensive Cancer Center, the University of Michigan Department of Surgery, and the National Institute of Health (Grants # R01 CA120458, R01 CA213566, and R01 CA216919).