BRAF kinase inhibitors for treatment of melanoma: developments from early-stage animal studies to Phase II clinical trials

ABSTRACT

Introduction: Approximately, 30.4–66.0% of cutaneous melanomas possess a mutation in the BRAF gene that activates downstream signaling through the mitogen-activated protein (MAP) kinase pathway; this provides an attractive target for the treatment of advanced melanoma. Although BRAF inhibitors rapidly suppress melanoma growth, median progression-free survival remains unsatisfactory. Recent clinical trials have investigated drugs that can optimally enhance and prolong the anti-melanoma effects of BRAF inhibitors.

Area covered: This review discusses the development of BRAF inhibitor-based combination therapies for BRAF-mutant advanced melanoma.

Expert opinion: Future strategies for the treatment of advanced melanoma include novel combination therapies using BRAF/MEK inhibitors and immune checkpoints inhibitors or histone deacetylase inhibitors. These combination therapies might enhance antitumor responses against melanoma, prolonging survival in advanced melanoma patients. Further clinical studies are needed to optimize these novel combination therapies.

KEYWORDS:

• BRAF-mutant metastatic melanoma
• BRAF inhibitors
• MEK inhibitors
• immune checkpoints inhibitors
• HDAC inhibitors
• BRAF resistance

Article Highlights

• BRAF inhibitors in combination with MEK inhibitors rapidly suppress melanoma growth, but median PFS remains unsatisfactory, suggesting the necessity to improve long-acting antitumor effects against melanoma.

• According to recent pre-clinical studies, combination therapy with BRAF inhibitors and immune checkpoints inhibitors could provide a highly useful therapy for advanced melanoma.

• Encorafenib administration might be superior to approved BRAF inhibitors from the perspective of anti-tumor effects and incidence of SAE, because of the immunomodulatory effects.

• HDAC inhibitor is effective for the treatment of BRAF inhibitor-resistant advanced melanoma.

• Next-generation therapy for BRAF-mutant advanced melanoma may involve BRAF/MEK inhibitor-based combination therapy with additional drugs to prolong overall and PFSs in patients with BRAF-mutant advanced melanoma.

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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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This grant is funded by Japan Society for the Promotion of Science (JSPS) and by a Grant-in-Aid for scientific research from the Japan Society for the Promotion of Science [16K10143].