Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

The hepatocyte growth factor receptor (MET) is a potential therapeutic target in a number of cancers, including NSCLC. In NSCLC, MET pathway activation is thought to occur through a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggests a role for MET activation as both a primary oncogenic driver in subsets of lung cancer and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. In this review, we explore the biology and clinical significance behind MET proto-oncogene receptor tyrosine kinase (MET) exon 14 alterations and MET amplification in NSCLC, the role of MET amplification in the setting of acquired resistance to EGFR tyrosine kinase inhibitor therapy in EGFR-mutant NSCLC, and the history of MET pathway inhibitor drug development in NSCLC, highlighting current strategies that enrich for biomarkers likely to be predictive of response. Whereas previous trials that focused on MET pathway–directed targeted therapy in unselected or MET-overexpressing NSCLC yielded largely negative results, more recent investigations focusing on MET exon 14 alterations and MET amplification have been notable for meaningful clinical responses to MET inhibitor therapy in a substantial proportion of patients.