Purpose: MET amplification is a frequent mechanism of resistance to epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC patients, and combined treatment with EGFR TKIs and MET TKIs has been explored as a strategy to overcome resistance. However, durable response is invariably limited by the emergence of acquired resistance. Here, we investigated the preclinical activity of REGN5093-M114, a novel antibody-drug conjugate (ADC) targeting MET in MET driven patient-derived models. Experimental Design: Patient-derived organoids (PDOs), patient-derived cells (PDCs), or ATCC cell lines were used to investigate the in vitro/in vivo activity of REGN5093-M114. Results: REGN5093- M114 exhibited significant antitumor efficacy compared to MET TKI or unconjugated METxMET biparatopic antibody (REGN5093). Regardless of MET gene copy number, MET-overexpressed TKI-naïve EGFR mutant NSCLC cells responded to REGN5093-M114 treatment. Cell surface MET expression had the most predictive power in determining the efficacy of REGN5093-M114. REGN5093-M114 potently reduced tumor growth of EGFR-mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior osimertinib and savolitinib treatment. Conclusions: Altogether, REGN5093-M114 is a promising candidate to overcome the challenges facing functional MET pathway blockade.

<p>(A-B) Cells were incubated with the REGN5093-M114, IgG4 control-M114, osimertinib for 5 days, capmatinib for 3 days. Cell viability was analyzed via CellTiter-Glo. The curved graphs show the cell viability results for a single drug, and the bar-graphs show the cell viability for the combination of two drugs.</p>

<p>(A-B) Apoptosis level was measured after incubated with drugs for 48 hours. YU1089 and HCC827 AR cells were treated with osimertinib, capmatinib or tepotinib at a concentration of 100nM, Control Ab-M114 at 1 µg/ml or REGN5093-M114 at 1 µg/ml.</p>

<div>AbstractPurpose:<p>MET amplification is a frequent mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non–small cell lung cancer (NSCLC), and combined treatment with EGFR TKIs and MET TKIs has been explored as a strategy to overcome resistance. However, durable response is invariably limited by the emergence of acquired resistance. Here, we investigated the preclinical activity of REGN5093-M114, a novel antibody–drug conjugate targeting MET in MET-driven patient-derived models.</p>Experimental Design:<p>Patient-derived organoids, patient-derived cells, or ATCC cell lines were used to investigate the <i>in vitro</i>/<i>in vivo</i> activity of REGN5093-M114.</p>Results:<p>REGN5093-M114 exhibited significant antitumor efficacy compared with MET TKI or unconjugated METxMET biparatopic antibody (REGN5093). Regardless of MET gene copy number, MET-overexpressed TKI-naïve EGFR-mutant NSCLC cells responded to REGN5093-M114 treatment. Cell surface MET expression had the most predictive power in determining the efficacy of REGN5093-M114. REGN5093-M114 potently reduced tumor growth of EGFR-mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior osimertinib and savolitinib treatment.</p>Conclusions:<p>Altogether, REGN5093-M114 is a promising candidate to overcome the challenges facing functional MET pathway blockade.</p></div>

<div>AbstractPurpose:<p>MET amplification is a frequent mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non–small cell lung cancer (NSCLC), and combined treatment with EGFR TKIs and MET TKIs has been explored as a strategy to overcome resistance. However, durable response is invariably limited by the emergence of acquired resistance. Here, we investigated the preclinical activity of REGN5093-M114, a novel antibody–drug conjugate targeting MET in MET-driven patient-derived models.</p>Experimental Design:<p>Patient-derived organoids, patient-derived cells, or ATCC cell lines were used to investigate the <i>in vitro</i>/<i>in vivo</i> activity of REGN5093-M114.</p>Results:<p>REGN5093-M114 exhibited significant antitumor efficacy compared with MET TKI or unconjugated METxMET biparatopic antibody (REGN5093). Regardless of MET gene copy number, MET-overexpressed TKI-naïve EGFR-mutant NSCLC cells responded to REGN5093-M114 treatment. Cell surface MET expression had the most predictive power in determining the efficacy of REGN5093-M114. REGN5093-M114 potently reduced tumor growth of EGFR-mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior osimertinib and savolitinib treatment.</p>Conclusions:<p>Altogether, REGN5093-M114 is a promising candidate to overcome the challenges facing functional MET pathway blockade.</p></div>