• Sabrina Baltschukat, Barbara Schacher Engstler, Alan Huang, Huai-Xiang Hao, Angela Tam, Hui Qin Wang, Jinsheng Liang, Matthew T DiMare, Hyo-Eun Carrie Bhang, Youzhen Wang, Pascal Furet, William R Sellers, Francesco Hofmann, Joseph Schoepfer, and Ralph Tiedt.
• Novartis Institutes for BioMedical Research, Oncology Disease Area, Basel, Switzerland.
• Clin Cancer Res. 2019 May 15; 25 (10): 3164-3175.

PurposeThe 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 DesignThe 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.ResultsCapmatinib 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 co-occurred with other oncogenic drivers, for example EGFR activating mutations.ConclusionsActivity 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.©2019 American Association for Cancer Research.

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