Abstract 1146: Tepotinib treatment inhibits tumor growth and affects tumor permeability in an intracranial PDX model of MET-amplified NSCLC brain metastasis
Authors: Clark Anderson , Albers Joachim , McConville Patrick , Stopka Sylwia A. , Regan Michael S. , DiPiazza Marina , Agar Nathalie Y.R. 
Published: June 2023

Abstract
Background: Tepotinib is approved to treat patients with NSCLC harboring MET exon 14 skipping. We previously provided preclinical proof of concept for tepotinib to treat NSCLC metastasized to the brain (Friese-Hamim M, et al. Lung Cancer 2022;163:77-86). Here, we report a detailed analysis of the effects of high-dose tepotinib in preclinical models of MET-amplified NSCLC brain metastases. Experimental methods: Using the previously reported intracranial MET-amplified patient-derived xenograft (PDX) models (LU5349 and LU5406), we measured the effects of tepotinib at the clinically relevant dose of 125 mg/kg QD and above (300 mg/kg QD) or a vehicle control on plasma concentrations, tumor growth (by T2-weighted MRI), intra-tumoral compound distribution (by MALDI MSI) and tumor vasculature (by DCE-MRI for Ktrans, a measure of tumor permeability), as well as biomarkers in tumor tissue (pMET, pAKT, Ki67, endoglin, caspase-3, and MoIgG). For model LU5349, animals were imaged on the day before euthanasia at Day (D) 0, 6 and 16 of treatment (n=10 per time point). Results: Plasma concentrations of tepotinib 2 hours after the final administration at each time point were not proportional by dose, indicating a limited absorption at the higher dose. By D16, tumor measurements (±SD) in tepotinib-treated mice (5.5 ± 3.4 mm3) were approximately 20-fold smaller than those in control mice (109.3 ± 50.1 mm3). At the lower dosing level, concentrations of tepotinib within the tumor regions decreased from 12 ± 6.4 µM (D0) to 3.2 ± 2.7 µM (D6) and then increased to 4.6 ± 1.2 µM (D16). In the higher dose group, concentrations of tepotinib in tumor regions decreased from 15.1 ± 8.7 µM (D0) to 6.8 ± 2.9 µM (D6) and then to 4.5 ± 3.6 µM (D16). Concentrations of tepotinib were below the limit of detection in non-tumor regions. Ktrans of the tumor was also affected by tepotinib treatment. While there was an apparent decline in mean Ktrans over time in control tumors (7.4 ± 3.0 × 10−2 s−1 [D0], 6.4 ± 2.8 × 10−2 s−1 [D6], 5.6 ± 3.5 × 10−2 s−1 [D16]), tepotinib treatment caused a further reduction at both the lower (7.8 ± 3.2 × 10−2 s−1 [D0], 2.9 ± 1.3 × 10−2 s−1 [D6], 2.7 ± 1.4 × 10−2 s−1 [D16]) and higher dose (8.0 ± 3.0 × 10−2 s−1 [D0], 2.7 ± 1.1 × 10−2 s−1 [D6], 2.9 ± 1.2 × 10−2 s−1 [D16]), indicating potential anti-vascular effects in the tumor. Conclusions: These preclinical analyses of tepotinib treatment of MET-amplified NSCLC brain metastases provide new insights, considering the observed tumor regression, the compound’s distribution to tumor versus non-tumor brain tissue and anti-vascular effects (via DCE-MRI), which may provide a predictive biomarker of response and patient survival. A possible causal association between reduced vascular permeability and the restricted distribution of tepotinib to tumor regions may exist. Analyses of the second PDX model and tumor biomarkers are ongoing and will be presented.
Citation Format: Anderson Clark, Joachim Albers, Patrick McConville, Sylwia A. Stopka, Michael S. Regan, Marina DiPiazza, Nathalie Y.R. Agar. Tepotinib treatment inhibits tumor growth and affects tumor permeability in an intracranial PDX model of MET-amplified NSCLC brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1146.