Identifying the optimum first-line therapy in BRAF-mutant metastatic melanoma

ABSTRACT

Introduction: The emergence of molecularly targeted agents and immune checkpoint inhibitors has positively revolutionized the management and prognosis of BRAF-mutant metastatic melanoma. However, the availability of both therapeutic options, with their pros and cons, rationally triggered clinical considerations for the optimum frontline and subsequent treatment decisions.

Areas covered: Here, we debate all approved therapies in patients with BRAF-mutant metastatic melanoma evaluating their efficacy and safety based on their pivotal trials. With prospective randomized data pending, retrospective comparisons of BRAF/MEK versus immune checkpoint inhibitors are reviewed to recognize any advantage between these two alternatives and to optimize their implementation. Preclinical and early clinical results of combining concurrently or sequentially targeted therapy and immunotherapy are also discussed.

Expert opinion: BRAF/MEK inhibitors produce rapid and deep responses and should be included in first-line approaches, particularly in cases with aggressive and bulky disease, while single or double checkpoint inhibition lead to more durable responses and could be involved either in frontline treatment of BRAF-mutant melanoma with less unfavorable characteristics or in maintenance after initial targeted induction or in future immune/targeted regimens for high-risk groups. Data from ongoing trials directly comparing or combining these strategies are expected to update their role in a more individualized basis.

KEYWORDS:

• First-line
• metastatic melanoma
• BRAF/MEK inhibitors
• targeted therapy
• immunotherapy

Article highlights

• Novel available agents, such as BRAF/MEK inhibitors and PD-1 and CTLA-4 blocking antibodies have significantly improved outcomes of patients with metastatic BRAF-mutant melanoma but in parallel made more complicated their therapeutic management.

• These treatment options have not been directly compared in the frontline setting and in current practice there is no clear choice between BRAF/MEK inhibitors or immunotherapy for those with previously untreated metastatic BRAF-mutant disease.

• According to the results from phase III clinical trials that established these treatments, BRAF/MEK inhibitors produce a high-response rate and rapid onset and thus should be included in the first-line approach, particularly in cases with symptomatic disease, while single or double checkpoint inhibition lead to more late but durable responses and should be considered as a reasonable frontline option in BRAF-mutant melanoma with less unfavorable characteristics.

• Many ongoing trials are expected this year to identify whether an immune/targeted regimen is superior over BRAF/MEK inhibition and if not, which is the best sequence of targeted agents and immunotherapy in BRAF-mutant unresectable melanoma.

• Decisions of first-line therapy should include many considerations of disease extent, baseline characteristics of melanoma, patient preferences, performance status, clinical comorbidities, and available options provided by the national regulatory affairs.

Declaration of interest

Helen Gogas has received grants and personal fees from Roche, BMS, MSD, Novartis, and personal fees by Amgen and Pierre Fabre. 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.

Additional information

Funding

This paper received no funding.