Anti-Tumor Activity Of Tepotinib In Orthotopic Models Of Lung Cancer Patient-Derived Brain Metastases With Met Amplification

Background Patients with advanced non-small cell lung cancer (NSCLC) harboring oncogenic MET alterations, such as MET exon 14 skipping or MET amplification (MET amp), benefit from MET tyrosine kinase inhibitor (TKI) treatment. Brain metastases are common in patients with advanced NSCLC. In preclinical studies in rats, tepotinib had relatively high binding to brain tissue (fu br=0.4%, fu pl=4%) and free tepotinib concentrations in brain were 25% of the concentrations found in plasma (Kp u,u=0.25). In this study we investigated the efficacy of the MET TKIs tepotinib, capmatinib, savolitinib and crizotinib in mice implanted orthotopically with MET-dependent tumor explants derived from human NSCLC brain metastases. Methods The antitumor activity of tepotinib (30 mg/kg qd) was investigated in a screen of 21 subcutaneous lung cancer patient-derived xenograft (PDX) models of brain metastases grown in NOD-SCID mice (n=1/model). 20 of these tumors were retrospectively analyzed for cancer-specific mutations, gene copy number (GCN) and gene expression by Nanostring. 2 responding models, both found to harbor MET amp, were tested again subcutaneously in NOD-SCID mice treated with vehicle or tepotinib (125 mg/kg qd; n=5). Both models were orthotopically implanted into brains of NOD-SCID mice and tumor growth was monitored by MRI. Established tumors were treated with MET TKIs (n=10) tepotinib (125 mg/kg qd), capmatinib (30 mg/kg bid), savolitinib (60 mg/kg qd) or crizotinib (50 mg/kg qd). Results 2 of 21 subcutaneous PDX tumors (LU5406 and LU5349) regressed in response to tepotinib treatment. When implanted subcutaneously again into mice, both models regressed completely upon treatment with tepotinib. Molecular profiles revealed that these were the only tumors of the 20 models investigated by Nanostring that had MET amp (high-level increase in MET GCN of \u003e10). Both models grew orthotopically when implanted into brains of mice. Contrast-weighted MRI indicated regions with intact and disrupted blood–brain barrier (BBB) in all implanted tumors. Tumor regression of orthotopic LU5406 tumors was observed with all MET TKIs (% median tumor volume changes [%TV]: tepotinib, –63%; capmatinib, –24%; savolitinib, –38%; crizotinib, –27%). In the orthotopic LU5349 tumors, treatment with crizotinib or savolitinib led to growth inhibition (%TV: +88% and –13%, respectively), whereas tepotinib and capmatinib induced tumor regression (%TV: –84% and –63%, respectively). Conclusions The heterogenous pattern of regions with intact and disrupted BBB in the orthotopic brain metastases models is thought to mirror the clinical situation. Tepotinib was efficacious in the two MET-driven orthotopic brain metastases PDX tumors characterized by pronounced tumor regression and may be relevant to patients with brain metastases. Relationships between efficacy and BBB leakiness will be discussed. Citation Format: Manja Friese-Hamim, Anderson Clark, Lindsey Crowley, Christof Reusch, Olga Bogatyrova, Claudia Wilm, Hong Zhang, Timothy Crandall, Jing Lin, Jianguo Ma, David Bachner, Jurgen Schmidt, Martin Schaefer, Christopher Stroh. Anti-tumor activity of tepotinib in orthotopic models of lung cancer patient-derived brain metastases with MET amplification [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3407.