The Preclinical Pharmacology of Tepotinib—A Highly Selective MET Inhibitor with Activity in Tumors Harboring MET Alterations

Abstract

The mesenchymal–epithelial transition factor (MET) proto-oncogene encodes the MET receptor tyrosine kinase. MET aberrations drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET 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. In vitro, tepotinib inhibits MET in a concentration-dependent manner irrespective of the mode of MET activation, and in vivo, 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 anti-tumor activity in subcutaneous and orthotopic brain metastasis models, in-line with clinical activity observed in patients. MET amplification is an established mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) 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 METex14 skipping alterations. This review focuses on the pharmacology of tepotinib in preclinical cancer models harboring MET 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.

Comprehensive NGS profiling to enable detection of ALK gene rearrangements and MET amplifications in non-small cell lung cancer

“…As opposed to gains or polysomy, amplification is thought to represent a state of true biologic selection for MET activation as an oncogenic driver (16). In published results of clinical trials in response to MET inhibitors, clinical benefit was only observed in patients with the so-called "true" amplification (18,19,50).…”

Real-World Data on Combined EGFR-TKI and Crizotinib Treatment for Acquired and De Novo MET Amplification in Patients with Metastatic EGFR-Mutated NSCLC

“…Given the availability of the above-mentioned anti-MET drugs and their proven effect in preclinical models and phase I-II trials, MET amplification as a mechanism of resistance to EGFR-TKIs is clinically actionable in a combination approach attempting concomitant inhibition of EGFR and MET signaling [7,11,12,[22][23][24][25]. However, until now, none of the available anti-MET drugs have been approved in this setting [26].…”