Emerging MET tyrosine kinase inhibitors for the treatment of non-small cell lung cancer

ABSTRACT

Introduction

MET

aberrations, including MET exon 14 skipping mutation and amplification, are present in ~5% of non-small cell lung cancer (NSCLC) cases, and these levels are comparable to the frequency of ALK fusion. MET amplification also occurs as an acquired resistance mechanism in EGFR-mutated NSCLC after EGFR tyrosine kinase inhibitors (TKI) treatment failure. Therefore, the development of therapies for activated MET is urgently needed.

Areas covered

This review summarizes (1) the mechanisms and frequencies of MET aberrations in NSCLC, (2) the efficacies and toxicities of MET-TKIs under clinical development and (3) the mechanisms of inherent and acquired resistance to MET-TKIs.

Expert opinion

Type Ia, Ib and II MET-TKIs are currently under clinical development, and phase I/II studies have shown the potent activities of tepotinib, capmatinib and savolitinib; in fact, tepotinib and capmatinib were approved for use by health authorities. However, inherent and acquired resistance through on- and off-target mechanisms has been detected, and strategies to overcome this resistance are being developed.

KEYWORDS:

• MET exon 14 skipping mutation
• MET amplification
• MET fusion
• NSCLC
• resistance mechanisms

Declaration of interest

Dr. Fujino has received research funding from Apollomics. Dr. Suda has received an honorarium from Boehringer Ingelheim, has been on the advisory board of AstraZeneca, and has received research funding from Boehringer Ingelheim and Rain Therapeutics. Dr. Mitsudomi has received lecture fees from AstraZeneca, Boehringer Ingelheim, Chugai, and Pfizer and research funding from Astra Zeneca, Boehringer Ingelheim, and Chugai; in addition, he has been on the advisory board of Novartis and received lecture fees from Bristol-Myers Squibb, Eli Lilly, Merck Sharp and Dohme. Dr. Mitsudomi has also received research funding from Daiichi Sankyo, Taiho, and Ono Pharmaceutical for studies not described inthis paper.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received institutional grant funding from Novartis and AstraZeneca. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

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