Data from Preclinical Study of a Biparatopic METxMET Antibody–Drug Conjugate, REGN5093-M114, Overcomes MET-driven Acquired Resistance to EGFR TKIs in EGFR-mutant NSCLC

Abstract

<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>

Advancing non-small cell lung cancer treatment: the power of combination immunotherapies

“…A study discussed the prevalence of MET amplification causing resistance to EGFR TKIs in EGFR -mutated NSCLC patients ( 208 ). To tackle this resistance, researchers have explored combined treatment with EGFR TKIs and MET TKIs, but the emergence of acquired resistance limits durable responses.…”

“…The antibody–drug conjugate proves effective across various genetic backgrounds, showcasing its adaptability in overcoming resistance. These findings suggest that REGN5093-M114 could be a valuable addition to the treatment options for patients encountering challenges associated with functional MET pathway blockade ( 208 ).…”