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

Toshio Fujino, Kenichi Suda, Tetsuya Mitsudomi Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, JapanCorrespondence: Tetsuya MitsudomiKindai University Faculty of Medicine, Division of Thoracic Surgery, Department of Surgery, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, JapanTel +81 72 366 0221Fax +81 72 365 7161Email mitsudom@med.kindai.ac.jpAbstract: 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