Abstract LB515A: A MET targeting biparatopic antibody-drug conjugates (ADC), REGN5093-M114, has an antitumor efficacy in NSCLC harboring MET gene alterations
Authors: Oh Seung Yeon , Lim Sun Min , Lee You Won , Lee Eun Ji , Kim Jae Hwan , Heo Seong Gu , Yu Mi Ra , Hong Min Hee , Kim Hye Ryun , DaSilva John , Daly Christopher , Yun Mi Ran , Cho Byoung Chul 
Published: June 2022

Abstract
Introduction: Aberrations in MET occurs frequently in non-small cell lung cancer (NSCLC), via MET amplification or MET exon 14 skipping (METex14) mutation. Small-molecule tyrosine kinase inhibitors (TKIs) targeting MET have been developed, but durable response is invariably limited by the emergence of acquired resistance. In this study, we examined the preclinical activity of a MET x MET biparatopic antibody to a novel maytansinoid payload, REGN5093-M114, in MET-driven patient-derived models.
Experimental Design: We had previously established patient-derived models from EGFR-TKIs resistant patients with MET-amplified or -overexpressed EGFR-mutant NSCLC. Patient-derived organoids (PDOs), patient-derived cells (PDCs), or ATCC cell lines were used for cell viability, apoptosis assay and western blots to investigate the activity of REGN5093-M114. In order to explore the predictive biomarker correlates of REGN5093-M114 and MET status, we investigated whole MET expression, surface MET expression by flow cytometry, MET amplification by copy number analysis. We evaluated the antitumor activity of REGN5093-M114 in patient-derived tumor xenograft (PDX) models from EGFR-mutant NSCLC patients with acquired resistance to osimertinib plus savolitinib, including acquired MET p.Y1230C mutation. Finally, we determined whether REGN5093-M114 is able to overcome acquired resistance to the MET-TKI, tepotinib, using PDC from METex14 mutant NSCLC patients.
Result: In acquired MET-amplified EGFR-TKI resistant PDCs, PDOs, ATCC cell lines and PDX models, REGN5093-M114 alone exhibited a significant antitumor efficacy compared to MET-TKI or the MET x MET biparatopic antibody (REGN5093), but had no effect on some models with same MET copy number as the sensitive models. On the other hand, regardless of MET CNV, MET-overexpressed TKI-naïve EGFR mutant NSCLC cells showed a sensitive response to REGN5093-M114. Thus, we calculated the area under the curve plot for REGN5093-M114 by quantifying whole MET expression, surface MET expression, and MET CNV values for each cell line. As a result, the surface MET expression had the most predictive power on determining the efficacy of the REGN5093-M114. Notably, REGN5093-M114 potently reduced tumor growth of EGFR mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior TATTON study. Furthermore, we demonstrated that the combined treatment of MET-TKI and REGN5093-M114 shows synergistic antitumor efficacy with a marked reduction of MET downstream signals and increased apoptotic proteins in the METex14 mutant NSCLC. Altogether, REGN5093-M114 is a potent candidate to overcome the current challenges faced in targeting MET pathway.
Conclusion: REGN5093-M114 has the potential to be a novel therapeutic option in NSCLC harboring MET genetic alterations, and further clinical application is highly warranted.
Citation Format: Seung Yeon Oh, Sun Min Lim, You Won Lee, Eun Ji Lee, Jae Hwan Kim, Seong Gu Heo, Mi Ra Yu, Min Hee Hong, Hye Ryun Kim, John DaSilva, Christopher Daly, Mi Ran Yun, Byoung Chul Cho. A MET targeting biparatopic antibody-drug conjugates (ADC), REGN5093-M114, has an antitumor efficacy in NSCLC harboring MET gene alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB515A.