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|Ref Type||Journal Article|
|Authors||Baltschukat S, Engstler BS, Huang A, Hao HX, Tam A, Wang HQ, Liang J, DiMare MT, Bhang HC, Wang Y, Furet P, Sellers WR, Hofmann F, Schoepfer J, Tiedt R|
|Title||Capmatinib (INC280) Is Active Against Models of Non-Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2019 05 15|
|Abstract Text||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.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.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 co-occurred with other oncogenic drivers, for example EGFR activating mutations.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||stomach cancer||not applicable||Capmatinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Tabrecta (capmatinib) did not induce tumor regression, however, inhibited tumor growth in an autocrine cell line xenograft model of gastric cancer overexpressing HGF (PMID: 30674502).||30674502|
|ERBB2 amp||lung cancer||sensitive||Lapatinib||Preclinical - Cell culture||Actionable||In a preclinical study, Tykerb (lapatinib) treatment reduced viability of a lung cancer cell line harboring an ERBB2 (HER2) amplification in culture (PMID: 30674502).||30674502|