Abstract 4713: Elucidating the mechanism of clinical Teliso-v (cMet-MMAE ADC) and osimertinib combination: A CAV1 and EGFR multi-protein complex controls endolysosomal trafficking of Teliso-V

Abstract Introduction: Telisotuzumab Vedotin (Teliso-V), a first-in-class c-Met-MMAE antibody-drug conjugate (ADC), achieved FDA breakthrough therapy designation in c-Met overexpressing (OE), 2nd Line+ EGFR wild-type, non-squamous, non-small cell lung cancer (NSCLC) patients. In addition, in a phase 1/1b trial, Teliso-V demonstrated 50% response in combination with the EGFR inhibitor, osimertinib, in EGFR mutant (EGFR-MT) NSCLC patients who had progressed on osimertinib. Here, we present mechanistic insights into the combinatorial effects of Teliso-V with osimertinib in this patient population. Methods: EGFR-MT NSCLC cell lines were exposed to osimertinib and subjected to RNA expression, mutation, EGFR-interactome, and ADC intracellular localization and endolysosomal (EL) trafficking analysis. Results: While no mutation gains or losses were detected, chronic and acute treatment with osimertinib enhanced Teliso-V sensitivity in EGFR-MT NSCLC cells. In addition to enhanced Teliso-V cytotoxicity, we observed enhanced accumulation of Teliso-V in a low pH intracellular compartment, consistent with increased endolysosome (EL) trafficking. Chronic osimertinib exposure induced gene expression changes related to increased lysosomal membranes, lytic vacuole membranes, and endoplasmic reticulum as well as reduced EGFR signaling. In addition to osimertinib, other EGFR inhibitors including erlotinib, gefitnib, or afatinib also enhanced Teliso-V EL trafficking which is consistent with the effect of EGFR-MT signaling in suppressing c-Met ADC EL trafficking. Cells harboring EGFR-MT are known to form large multimeric protein complexes to regulate EGFR trafficking and cell survival. EGFR-MT immunoprecipitation, followed by mass spectrometry analysis identified 84 proteins associated with an osimertinib-sensitive complex including c-Met, and caveolin-1 (CAV-1), a structural protein involved in signaling and trafficking. Confocal microscopy imaging showed that osimertinib treatment altered the subcellular localization of these proteins and their interaction with CAV-1. CAV-1 knockdown disrupted the multimeric protein complex, suppressed EGFR and c-Met activation, reduced downstream AKT/ERK signaling, and enhanced Teliso-V-associated EL trafficking, phenocopying osimertinib effect. Conclusions: Chronic and acute treatment with osimertinib displaces EGFR/c-Met/CAV-1 multimeric signaling complexes leading to improved lysosomal processing of c-Met-targeted ADCs and enhanced tumor cytotoxicity. This study provides mechanistic insights into the combination of Teliso-V and osimertnib in 2L+ EGFRMT NSCLC patients in the clinic. Citation Format: Izhar Batth, Ronald Pandoy, Lisa Roberts-Rapp, Athan Vasilopoulos, Peter Ansell, Vincent Blot, Gregory K. Potts, Janice Y. Lee, Hua Tang, Jon D. Williams, Tamar Uziel, PK Epling-Burnette. Elucidating the mechanism of clinical Teliso-v (cMet-MMAE ADC) and osimertinib combination: A CAV1 and EGFR multi-protein complex controls endolysosomal trafficking of Teliso-V [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4713.