Capmatinib (INC280) Is Active Against Models of Non–Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation

Abstract

Purpose: The selective MET inhibitor capmatinib is being investigated in multiple clinical trials, both as a single agent and in combination. Here, we describe the preclinical data of capmatinib, which supported the clinical biomarker strategy for rational patient selection. Experimental Design: The selectivity and cellular activity of capmatinib were assessed in large cellular screening panels. Antitumor efficacy was quantified in a large set of cell line-or patient-derived xenograft models, testing single-agent or combination treatment depending on the genomic profile of the respective models. Results: Capmatinib was found to be highly selective for MET over other kinases. It was active against cancer models that are characterized by MET amplification, marked MET overexpression, MET exon 14 skipping mutations, or MET activation via expression of the ligand hepatocyte growth factor (HGF). In cancer models where MET is the dominant oncogenic driver, anticancer activity could be further enhanced by combination treatments, for example, by the addition of apoptosis-inducing BH3 mimetics. The combinations of capmatinib and other kinase inhibitors resulted in enhanced anticancer activity against models where MET activation cooccurred with other oncogenic drivers, for example EGFR activating mutations. Conclusions: Activity of capmatinib in preclinical models is associated with a small number of plausible genomic features. The low fraction of cancer models that respond to capmatinib as a single agent suggests that the implementation of patient selection strategies based on these biomarkers is critical for clinical development. Capmatinib is also a rational combination partner for other kinase inhibitors to combat MET-driven resistance.

Development and full validation of an LC–MS/MS methodology to quantify capmatinib (INC280) following intragastric administration to rats

“…A plethora of preclinical and clinical observations spanning several decades has established the receptor tyrosine kinase mesenchymal–epithelial transition factor (c‐Met, cMET or c‐MET) as an oncogene and attractive therapeutic target for cancer therapy. It is a member of a distinct subfamily of heterodimeric receptor tyrosine kinases and encodes the high‐affinity receptor for hepatocyte growth factor (Baltschukat et al, ; Shaker, Ashamallah, & El‐Mesery, ). Dysregulation of MET signaling results in activation of downstream pathways, including the RAS/MAPK, PI3K/AkT and Rac/Rho pathways, which promote cell proliferation, survival and metastasis (Kim et al, ; Lara et al, ).…”

Phase 1 study of capmatinib in MET‐positive solid tumor patients: Dose escalation and expansion of selected cohorts

“…Type III inhibitors bind to allosteric sites different from the ATP binding site . Capmatinib (INC280) is an oral, ATP‐competitive and highly potent type 1b MET inhibitor in biochemical (IC 50 0.13 nmol/L) and cellular (IC 50 ~ 1 nmol/L) assays and has proven to be highly selective versus other kinases in large panels of biochemical and binding assays . Capmatinib caused regression of MET‐dependent tumors at tolerable doses in animal models across a range of tumor types, including NSCLC, HCC, and GBM .…”

“…Capmatinib (INC280) is an oral, ATP‐competitive and highly potent type 1b MET inhibitor in biochemical (IC 50 0.13 nmol/L) and cellular (IC 50 ~ 1 nmol/L) assays and has proven to be highly selective versus other kinases in large panels of biochemical and binding assays . Capmatinib caused regression of MET‐dependent tumors at tolerable doses in animal models across a range of tumor types, including NSCLC, HCC, and GBM . MET dependency in such responsive tumor models was associated with MET gene amplification (NSCLC, HCC), MET exon 14 skipping mutation (NSCLC), marked MET overexpression without amplification (NSCLC), or coexpression of MET and its ligand HGF (GBM).…”

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…It interacts with MET through the Y1230 residue. A salt bridge between D1246 and Y1248 further stabilizes the inhibitor [149]. Resistance mutations to capmatinib arise that disrupt the interaction of the drug with the kinase.…”