MEK inhibitors under development for treatment of non-small-cell lung cancer

ABSTRACT

Introduction: The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC.

Areas covered: In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents.

Expert opinion: Trametinib in combination with the BRAF inhibitor dabrafenib represents the first MEK1/2 inhibitor containing regimen that is approved for advanced BRAF^V600E-mutant NSCLC. Other MEK1/2 inhibitors that are also in advanced stages of clinical development include selumetinib, cobimetinib, and binimetinib. Several studies of MEK inhibitor combination therapies are underway, including trials using combined MEK inhibition and immune checkpoint blockade. Further research aimed at discovering biomarkers of response and resistance to MEK1/2 inhibitors will be needed to develop rational combination strategies for the treatment of NSCLC driven by aberrant MAPK signaling.

KEYWORDS:

• MEK inhibitor
• KRAS
• BRAF
• MAPK
• non-small-cell lung cancer

Article highlights

• The approval of trametinib in combination with dabrafenib represents a major step forward in precision medicine in oncology.

• Evaluation of BRAF mutations has become an essential part of diagnostic work-up for patients with NSCLC, especially for those with adenocarcinoma.

• Patients with MEK1 mutations, BRAF-fusion, or non-V600E BRAF mutations may benefit from MEK inhibitor therapy and further clinical research should be pursued in these patients.

• Therapeutic strategies using MEK inhibition have largely been unsuccessful in patients with KRAS-mutant NSCLC. MEK inhibitor monotherapy does not have sufficient activity in this patient population, underscoring the need for developing effective combination therapies.

• Several combination approaches are being assessed for patients with NSCLC and MAPK pathway aberrations, including combined MEK inhibition and immune checkpoint blockade.

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Declaration of Interest

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

Additional information

Funding

This paper was not funded.