The Development and Role of Capmatinib in the Treatment of MET-Dysregulated Non-Small Cell Lung Cancer—A Narrative Review

SIMPLE SUMMARY: In this narrative review, we discuss the development of capmatinib, a reversible MET tyrosine kinase inhibitor that received approval for advanced non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutation. Capmatinib was first discovered in 2011 and has been shown to have promising antitumor activity. Early-phase trials identified a recommended dose of 400 mg twice daily in tablet formulation. The GEOMETRY mono-1 trial showed efficacy in MET exon 14 skipping mutation, leading to FDA approval for capmatinib. Currently, ongoing clinical trials evaluating combination therapy with capmatinib, including amivantamab, trametinib, and immunotherapy, are being conducted to improve efficacy and broaden indications of capmatinib with new drug agents such as antibody–drug conjugates being developed to treat MET dysregulated NSCLC. ABSTRACT: Non-small cell lung cancer (NSCLC) is a leading cause of death, but over the past decade, there has been tremendous progress in the field with new targeted therapies. The mesenchymal–epithelial transition factor (MET) proto-oncogene has been implicated in multiple solid tumors, including NSCLC, and dysregulation in NSCLC from MET can present most notably as MET exon 14 skipping mutation and amplification. From this, MET tyrosine kinase inhibitors (TKIs) have been developed to treat this dysregulation despite challenges with efficacy and reliable biomarkers. Capmatinib is a Type Ib MET TKI first discovered in 2011 and was FDA approved in August 2022 for advanced NSCLC with MET exon 14 skipping mutation. In this narrative review, we discuss preclinical and early-phase studies that led to the GEOMETRY mono-1 study, which showed beneficial efficacy in MET exon 14 skipping mutations, leading to FDA approval of capmatinib along with Foundation One CDx assay as its companion diagnostic assay. Current and future directions of capmatinib are focused on improving the efficacy, overcoming the resistance of capmatinib, and finding approaches for new indications of capmatinib such as acquired MET amplification from epidermal growth factor receptor (EGFR) TKI resistance. Clinical trials now involve combination therapy with capmatinib, including amivantamab, trametinib, and immunotherapy. Furthermore, new drug agents, particularly antibody–drug conjugates, are being developed to help treat patients with acquired resistance from capmatinib and other TKIs.