MET amplification + MET overexpression

The combination of targeted therapy with MET or SHP2 inhibitors was found to overcome MET-mediated resistance in both in vitro and in vivo assays. This study highlights the importance of considering MET overexpression as a resistance driver to NSCLC targeted therapies to better identify patients who could potentially benefit from combination approaches with MET or SHP2 inhibitors.

Together, these findings indicated a significant correlation between MET overexpression and MET amplification in NSCLC patients but no correlation to prognosis.

Antitumor activity of savolitinib in combination with osimertinib is very promising as first-line therapy of patients with advanced EGFR-mutated NSCLC, initially with MET expression. The safety profile of savolitinib as monotherapy and in combination with osimertinib or gefitinib is so favorable in all available studies that this drug has become a very promising therapeutic option and is being intensively investigated in ongoing clinical trials.

In conclusion, the four plasma protein signature (MYH9, GNB1, ALOX12B, and HSD17B4 proteins) might play a substitutable or complementary role to conventional MET FISH or IHC tests. This exploration will help select patients who may benefit from MET inhibitors.

MET exon 14 skipping mutation (METex14) was established as a strong predictor of response to selective MET tyrosine kinase inhibitors (TKIs), and clinical trial results in patients with non-small cell lung cancer (NSCLC) harboring METex14 led to the approval of capmatinib and tepotinib by regulatory agencies worldwide. This review summarizes the current methods used for the detection of METex14, MET amplification and MET overexpression, and discusses the evidence for the use of MET-TKIs in patients with NSCLC with MET dysregulation. We discuss the practical challenges that impact the use of METex14 in the clinic and the evidence gaps that need to be addressed to validate additional genomic markers for MET-dependent cancers.