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

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 & resistance seen clinically. Combination therapy with AMG 193 overcame sotorasib resistance in KRAS G12C LUAD models. Other drug combinations will be evaluated in primary or acquired resistance models. Acute dosing studies are underway to further characterize response to AMG 193 in these models. Summary of 7 MTAP-deleted PDX models PDX model Drug Activity† Doubling time in weeks, from linear mixed-effects modeling (N.R. = not reached due to complete response) KRAS G12C LUAD#239 Sotorasib monotherapy: resistant. AMG 193 monotherapy: sensitive. Sotorasib + AMG 193: sensitive with accelerated deep response On-treatment (d10-21) , Vehicle 2.3 vs. Sotorasib 3.6 P =0.20, AMG 193 N.R. P< 0.001 ***, Combo N.R. P< 0.001 ***. KRAS G12C LUAD#256 Sotorasib monotherapy: resistant. AMG 193 monotherapy: partial sensitivity. Sotorasib + AMG 193: sensitive with accelerated deep response On-treatment (d0-45) , Combo N.R. vs. Sotorasib 5.9 P =0.04*, AMG 193 5.3 P= 0.04 *. KRAS WT LUAD#196 AMG 193: partial resistance On-treatment (d0-24) , Vehicle 1.8 vs. AMG 193 2.3 P= 0.04 * LUSC#410 AMG 193: sensitive (d0-48) with eventual acquired resistance (d49-91) On-treatment (d0-15) , Vehicle 0.9 vs. AMG 193 19.3 P< 0.001 *** LUSC#470 AMG 193: sensitive On-treatment (d0-20) , Vehicle 1.1 vs. AMG 193 2.8 P< 0.001 *** MESO#7 AMG 193: sensitive On-treatment (d0-49) , Vehicle 3.4 vs. AMG 193 N.R. P< 0.001 *** MESO#18 AMG 193: partial resistance On-treatment (d0-24) , Vehicle 1.8 vs. AMG 193 2.9 P =0.003 ** † Drug activity assessed based upon tumor growth curve kinetics and doubling time.