Abstract 7100: VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with potent anti-tumor activity as a single agent and in combination with other agents

Abstract KRAS G12D is the most prevalent KRAS mutation in human cancers, present in 40%, 15%, and 5% of pancreatic, colorectal and lung cancers, respectively. Currently, there are no FDA-approved RAS inhibitors for patients with KRAS G12D-mutated (mt) cancers. VS-7375 (GFH375) is an oral, selective KRAS G12D dual ON/OFF inhibitor exhibiting extremely high affinity (KD = 12-18 pM) and long residence time (18-24 hours) for the ON and OFF states of human KRAS G12D. VS-7375 has shown potent single agent anti-tumor efficacy with oral dosing across multiple KRAS G12D mt xenograft models representing pancreatic, colorectal and lung cancers. To assess potential benefits of dual ON/OFF inhibition relative to ON-only RAS inhibitors, we compared efficacy in KRAS G12D mt in vivo models relative to the KRAS G12D ON-only inhibitor zoldonrasib (RMC-9805) and the pan-RAS ON-only inhibitor daraxonrasib (RMC-6236). In the KP4 KRAS G12D pancreatic cancer model, VS-7375 (50 mg/kg twice daily orally) showed similar initial tumor regression (through day 9) relative to zoldonrasib (100 mg/kg once daily orally) and daraxonrasib (25 mg/kg once daily orally). However, by approximately 20 days of dosing, zoldonrasib and daraxonrasib progressively lose their anti-tumor activity with associated tumor outgrowth (mean tumor volume 850 mm3 by day 30) in contrast to those treated with VS-7375 which showed sustained tumor regression (mean tumor volume ∼80 mm3 by day 30). Accordingly, pharmacodynamic analysis with pathway-specific gene signatures showed that whereas all three KRAS inhibitors inhibited MAPK, MYC and PI3K signaling at day 6, only the G12D ON/OFF inhibitor VS-7375 maintained inhibition of these signaling pathways by day 20. VS-7375 also showed deeper tumor regression compared to these RAS ON-only inhibitors in KRAS G12D mt lung and colorectal xenograft models. Currently, we are assessing the anti-tumor efficacy of VS-7375 in combination with other anti-cancer agents including EGFR, PRMT5 and FAK inhibitors. Briefly, the combination of the anti-EGFR antibody cetuximab with VS-7375 induced strong tumor growth inhibition in KRAS G12D mt cancer models. Furthermore, addition of a PRMT5 inhibitor with VS-7375 increased duration of tumor regression in KRAS G12D mt;MTAP-deleted pancreatic cancer models. Lastly, addition of a FAK inhibitor with VS-7375 increased duration of tumor regression in KRAS G12D mt cancer models, altogether supporting the potential clinical evaluation of novel combination strategies with VS-7375 in patients with KRAS G12D mt cancers for maximal anti-tumor efficacy and durability. VS-7375 is currently in phase 1/2 clinical evaluation in the US (VS-7375-101; NCT07020221) and in advanced clinical evaluation in China (NCT06500676) as monotherapy and in combination with cetuximab or chemotherapy ± pembrolizumab for patients with KRAS G12D mt cancers. Citation Format: Silvia Coma, Ian Smith, Cristina Caffarra Malvezzi, Clint A. Stalnecker, Emilia Berardelli, Enrico Patrucco, Fusheng Zhou, Channing Der, Chiara Ambrogio, David G. DeNardo, Jonathan A. Pachter. VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with potent anti-tumor activity as a single agent and in combination with other agents abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7100.