C-MET inhibitors for advanced non-small cell lung cancer

ABSTRACT

Introduction: The role of the c-mesenchymal-epithelial transition factor (c-MET) signaling pathway in tumor progression and invasion has been extensively studied. C-MET inhibitors have shown anti-tumor activity in NSCLC both in preclinical and in clinical trials. However, given the molecular heterogeneity of NSCLC, it is likely that only a specific subset of NSCLC patients will benefit from c-MET inhibitors. Emerging data also suggest that MET inhibitors in combination with EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) may have a role in therapy for both EGFR-TKI resistant and EGFR-TKI naïve patients. The challenges ahead are in the identification of the molecular subtypes that benefit most.

Areas covered: This review summarizes the current understanding of c-MET biology in relation to studies evaluating c-MET inhibitors in the treatment of NSCLC.

Expert opinion: MET inhibitors have the potential to benefit subsets of NSCLC patients with specific genetic alterations. Exon-14 skipping mutations appear so far to be the most promising molecular subset that is sensitive to MET inhibitors, whereas overexpression, amplification and point mutations of MET seem more challenging subgroups to target. Combination with other target agents, such as EGFR inhibitors, may represent a promising therapeutic strategy in specific areas (e.g. EGFR-TKI resistance).

KEYWORDS:

• MET pathway
• non-small cell lung cancer
• target therapy
• c-MET inhibitors
• epidermal growth factor receptor tyrosine kinase inhibitors

Article Highlights

• Mechanisms of activation of MET that have been detected in NSCLC may be through a variety of alterations, such as protein overexpression, gene amplification and MET exon 14 skip mutation.

• Patients with MET alterations may benefit from MET inhibitors therapy; several MET inhibitors have been evaluated in phase III trials, but to date the results of clinical studies have been negative.

• More recently small molecule inhibitors such as tivantinib, crizotinib and savolitinib exhibited some promising activity, suggesting the need of proper selection of patients.

• Dysregulation of the MET pathway is known to confer primary or secondary resistance against EGFR TKIs. Based on this rationale the combinations of savolitinib with osimertinib or gefitinib showed clinical activity in patients with EGFR mutation-positive NSCLC with MET-amplification who had progressed following prior treatment with an EGFR inhibitor.

Further studies are warranted to select candidates for MET inhibitors in NSCLC based on robust biomarkers.

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Declaration of interest

G Giaccone has received research grants from Karyopharm and Eli-Lilli; G Giaccone has also served in advisory boards for Bristol-Myers Squibb, Astra-Zeneca, and G1 Therapeutics. 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper is not funded.