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

Abstract

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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.</p>Results:<p>Capmatinib was found to be highly selective for MET over other kinases. It was active against cancer models that are characterized by <i>MET</i> amplification, marked <i>MET</i> overexpression, <i>MET</i> exon 14 skipping mutations, or MET activation via expression of the ligand hepatocyte growth factor (HGF). In cancer models where <i>MET</i> 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 <i>MET</i> activation co-occurred with other oncogenic drivers, for example <i>EGFR</i> activating mutations.</p>Conclusions:<p>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.</p></div>