Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges

Abstract: MET exon 14 skipping mutation ( MET ∆ex14) is present about 3% of non-small cell lung cancers (NSCLCs). NSCLC patients with MET ∆ex14 are characterized by an average age of over 70 years at diagnosis, a smoking history and a higher frequency in pleomorphic carcinoma and adenosquamous cell carcinoma than in adenocarcinoma. It has also been reported that NSCLCs with MET ∆ex14 often have codriver alterations such as EGFR amplification (6– 28%), FGFR1 alterations (5– 17%), KRAS alterations (∼ 8%), BRAF alterations (∼ 21%), or PIK3CA mutation/amplification (∼ 14%). In 2020, the approval of two MET-tyrosine kinase inhibitors (TKIs), capmatinib and tepotinib, for NSCLCs carrying MET ∆ex14 dawned a new era for MET-targeted therapy. These drugs yielded progression-free survival of 5.4− 12.4 months in clinical trials; however, it has also been reported that one-third to half of patients show inherent resistance to MET-TKIs. In addition, the emergence of acquired resistance to MET-TKIs is inevitable. In this review, we summarize the clinical and molecular characteristics of NSCLCs with MET ∆ex14, the efficacy and safety of capmatinib and tepotinib, the inherent and acquired resistance mechanisms to MET-TKIs, and new treatment strategies for NSCLCs with MET ∆ex14 in the near future. Keywords: non-small cell lung cancer, MET exon 14 skipping, capmatinib, tepotinib, resistance mechanisms, immune checkpoint inhibitors