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

aberrations, including <i>MET</i> 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 <i>ALK</i> fusion. <i>MET</i> amplification also occurs as an acquired resistance mechanism in <i>EGFR</i>-mutated NSCLC after EGFR tyrosine kinase inhibitors (TKI) treatment failure. Therefore, the development of therapies for activated MET is urgently needed. This review summarizes (1) the mechanisms and frequencies of <i>MET</i> 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. 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.