MET in Non-Small-Cell Lung Cancer (NSCLC): Cross 'a Long and Winding Road' Looking for a Target

Simple Summary Around 3% of patients with Non-Small-Cell Lung Cancer (NSCLC) harbour a MET exon 14 skipping mutation (METex14). Early mutation identification is important for accurate treatment of these patients because they receive more benefit from chemotherapy than from immune checkpoint inhibitors (ICIs). Moreover, the treatment landscape of this disease has radically changed in recent years thanks to the introduction of new selective and potent MET inhibitors (MET-Is). The aim of our review was to summarize the historical milestones since the discovery of the MET pathway through studies investigating the role of MET in the prognosis of NSCLC patients harbouring MET alterations to the discovery of MET exon 14 skipping mutation, the real target of this pathway in NSCLC. Moreover, we focused on the results from pivotal clinical trials of MET inhibitors and on mechanisms of resistance to these drugs. The last section of this review is dedicated to future developments.Abstract Non-Small-Cell Lung Cancer (NSCLC) can harbour different MET alterations, such as MET overexpression (MET OE), MET gene amplification (MET AMP), or MET gene mutations. Retrospective studies of surgical series of patients with MET-dysregulated NSCLC have shown worse clinical outcomes irrespective of the type of specific MET gene alteration. On the other hand, earlier attempts failed to identify the 'druggable' molecular gene driver until the discovery of MET exon 14 skipping mutations (METex14). METex14 are rare and amount to around 3% of all NSCLCs. Patients with METex14 NSCLC attain modest results when they are treated with immune checkpoint inhibitors (ICIs). New selective MET inhibitors (MET-Is) showed a long-lasting clinical benefit in patients with METex14 NSCLC and modest activity in patients with MET AMP NSCLC. Ongoing clinical trials are investigating new small molecule tyrosine kinase inhibitors, bispecific antibodies, or antibodies drug conjugate (ADCs). This review focuses on the prognostic role of MET, the summary of pivotal clinical trials of selective MET-Is with a focus on resistance mechanisms. The last section is addressed to future developments and challenges.