Abstract 7134: Developing drug combinations with AMG 193, a novel MTA-cooperative PRMT5 inhibitor, using patient-derived xenograft models of MTAP -deleted non-small cell lung cancer and mesothelioma

Abstract BACKGROUND: AMG 193 is an MTA-cooperative PRMT5 inhibitor designed for preferential selectivity against MTAP-del tumor cells. AMG 193 is currently being investigated in phase I-II clinical trials in MTAP-del solid tumors (MTAPESTRY-101,104, 201). In vivo testing in patient-derived xenograft (PDX) models has significant potential to inform focused clinical development of AMG 193. OBJECTIVES: Using MTAP-del PDX models from our institutional biobank, we sought to: (i) identify promising drug combination partners for AMG 193 across lung adenocarcinomas (LUAD), lung squamous cell carcinomas (LUSC), and mesotheliomas (MESO); and (ii) investigate mechanisms of primary or acquired resistance to AMG 193. METHODS: We identified 21 PDX models with MTAP deep deletion by SNP array or MTAP loss by immunohistochemistry - including 7 LUAD (including 2 KRAS G12C; 1 EGFR L858R + MET amp), 10 LUSC, and 6 MESO. In vivo AMG 193 activity was characterized in 7 models subcutaneously implanted in NOD SCID or NSG mice (n=5-7 per group). RESULTS: Four models (2 KRAS G12C LUAD; 1 LUSC; 1 MESO) showed sustained sensitivity to AMG 193. Two models (1 KRAS-wildtype LUAD; 1 MESO) exhibited primary resistance to AMG 193. One LUSC model showed acquired resistance to AMG 193 after initial sensitivity. Interestingly, the two KRAS G12C LUAD models demonstrated additive/synergistic activity with AMG 193+sotorasib despite exhibiting resistance to sotorasib monotherapy. CONCLUSIONS: A spectrum of AMG 193 activity was demonstrated across MTAP-del LUAD, LUSC, MESO PDX models, recapitulating the range of response Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7134.