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Summary Tepotinib is an oral MET inhibitor approved for metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations. Examining treatment-naive or tepotinib-resistant cells with MET amplification or METex14 skipping mutations identifies other receptor tyrosine kinases (RTKs) that co-exist in cells prior to tepotinib exposure and become more prominent upon tepotinib resistance. In a small cohort of patients with lung cancer with MET genetic alterations treated with tepotinib, gene copy number gains of other RTKs were found at baseline and affected treatment outcome. An Src homology 2 domain-containing phosphatase 2 (SHP2) inhibitor delayed the emergence of tepotinib resistance and synergized with tepotinib in treatment-naive and tepotinib-resistant cells as well as in xenograft models. Alternative signaling pathways potentially diminish the effect of tepotinib monotherapy, and the combination of tepotinib with an SHP2 inhibitor enables the control of tumor growth in cells with MET genetic alterations.

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Background: Therapeutic antibodies can attack tumor cells by functionally interfering with the target and/or by employing immune effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). The objective of this study was to analyze the anti-EGFR therapeutic antibodies cetuximab, panitumumab and matuzumab with regard to both modes of action: Interference with EGFR signaling and immune effector functions. Methods: EGFR binding and inhibition of EGFR signal transduction were characterized for the individual antibodies and antibody combinations in various tumor cell lines. The ability of single antibodies or antibody combinations to kill tumor cells via ADCC or CDC was analyzed in ex vivo assays using human immune effector cell isolates from blood or human serum, respectively. Results: In cellular assays (FACS and binding assays with 125I-labeled antibodies) cetuximab, panitumumab and matuzumab showed similar EGFR binding affinities. All three antibodies were capable of blocking EGFR signal transduction (phospho-EGFR, phospho-ERK1/2, phospho-Akt, phospho-STAT3 and inhibition of VEGF production) with cetuximab and panitumumab being slightly more potent than matuzumab. Using peripheral blood mononuclear cells (PBMCs) as effector cells, cetuximab and matuzumab mediated a marked, dose-dependent ADCC response, while no or only marginal ADCC was observed with panitumumab. Natural killer (NK) cells were the main effector cells of the PBMC fraction. Comparable results were obtained in assays using whole blood indicating no or only marginal contribution of polymorphonuclear leukocytes to the ADCC activity. No CDC activity was detected with either antibody alone. Overlapping EGFR binding epitopes for cetuximab and panitumumab that are distinct from the binding site for matuzumab have been reported. However, in cellular binding assays only cetuximab and matuzumab (but not panitumumab and matuzumab) were able to bind simultaneously to EGFR. The combination of cetuximab and matuzumab led to a strong internalization and degradation of EGFR and to an increased inhibition of EGFR signaling. Interestingly, while the cetuximab-matuzumab combination did not result in enhanced ADCC we observed a strong increase in CDC activity and recruitment of complement factors. Conclusions: Cetuximab, panitumumab and matuzumab have different characteristics with regard to EGFR binding and immune effector functions. The non-competitive, simultaneous binding of cetuximab and matuzumab resulted in superior interference with EGFR function and enhanced CDC activity of the combination. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-316.

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 >10). 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, Jürgen 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.