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

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.

Keywords: MET dysregulation; NSCLC; capmatinib; detection; tyrosine kinase inhibitor.

Figure 1

MET signaling pathway and blockade by MET inhibitors. In cancer, the MET proto-oncogene is abnormally activated and stimulates other signaling pathways in tumor cells, notably PI3K/AKT, JAK/STAT, Ras/MAPK, SRC, and Wnt/beta-catenin [11]. Type 1a inhibitor crizotinib blocks ATP binding to prevent the phosphorylation of the receptor, whereas type 1b inhibitors such as capmatinib are more specific and bind to a pocket adjacent to the ATP binding site. This figure was generated by BioRender.

Figure 2

Chemical structure of capmatinib; the asterisk (*) represents the chiral carbons that are part of the chemical structure.. The chemical name for capmatinib is 2-Fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2 b][1,2,4]triazin-2-yl]benzamide—hydrogen chloride—water (1/2/1). The molecular formula for capmatinib hydrochloride is C₂₃H₂₁Cl₂FN₆O₂ [38].