Data from The Preclinical Pharmacology of Tepotinib—A Highly Selective MET Inhibitor with Activity in Tumors Harboring <i>MET</i> Alterations

Abstract

<div>Abstract<p>The mesenchymal–epithelial transition factor (<i>MET</i>) proto-oncogene encodes the MET receptor tyrosine kinase. <i>MET</i> aberrations drive tumorigenesis in several cancer types through a variety of molecular mechanisms, including <i>MET</i> mutations, gene amplification, rearrangement, and overexpression. Therefore, MET is a therapeutic target and the selective type Ib MET inhibitor, tepotinib, was designed to potently inhibit MET kinase activity. <i>In vitro</i>, tepotinib inhibits MET in a concentration-dependent manner irrespective of the mode of MET activation, and <i>in vivo</i>, tepotinib exhibits marked, dose-dependent antitumor activity in MET-dependent tumor models of various cancer indications. Tepotinib penetrates the blood–brain barrier and demonstrates strong antitumor activity in subcutaneous and orthotopic brain metastasis models, in-line with clinical activity observed in patients. <i>MET</i> amplification is an established mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI), and preclinical studies show that tepotinib in combination with EGFR TKIs can overcome this resistance. Tepotinib is currently approved for the treatment of adult patients with advanced or metastatic non–small cell lung cancer harboring <i>MET</i> exon 14 skipping alterations. This review focuses on the pharmacology of tepotinib in preclinical cancer models harboring <i>MET</i> alterations and demonstrates that strong adherence to the principles of the Pharmacological Audit Trail may result in a successful discovery and development of a precision medicine.</p></div>