The Current Landscape for METex14 Skipping Mutations in Non–Small Cell Lung Cancer

Abstract

Capmatinib and tepotinib received US Food and Drug Administration (FDA) approval for mesenchymal-epithelial transition (<i>MET</i>) exon 14 (<i>MET</i>ex14) skipping alteration in 2020 and 2021, respectively. Capmatinib was FDA approved in May 2020 under accelerated approval for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to <i>MET</i>ex14 skipping. Accelerated approval was based on overall response rate and response duration to capmatinib, and it was granted orphan drug and breakthrough therapy designation. Capmatinib is a potent selective kinase inhibitor of the MET receptor, crosses the blood-brain barrier, and has shown low-grade adverse events. Based on phase II data, capmatinib demonstrated an overall response rate (ORR) of 41% and a median duration of response (DOR) of 9.7 months in those who previously received one or two lines of therapy. In treatment-naive patients, capmatinib demonstrated a 68% ORR with a median DOR of 12.6 months. The FDA also granted accelerated approval to tepotinib for adult patients with metastatic NSCLC harboring <i>MET</i>ex14 skipping alteration. Accelerated approval for tepotinib was based on an ORR of 43% with a median DOR of 10.8 months in treatment-naive patients. Among previously treated patients, the ORR was 43% with a median DOR of 11.1 months. Continued approval for capmatinib and tepotinib is contingent upon confirmatory trials. Both agents are now considered first-line therapy or a subsequent therapy option in patients with metastatic NSCLC who are positive for <i>MET</i>ex14 skipping alterations.