Abstract PR007: Anti-tumor efficacy of the selective oral KRAS G12D dual ON/OFF inhibitor VS-7375 as a single agent and in combination with targeted agents

Abstract KRAS G12D is the most prevalent KRAS mutation in human cancers, mutated in 40%, 15%, and 5% of pancreatic, colorectal and lung cancers, respectively. 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. In KRAS G12D-mutated (mt) xenograft models representing pancreatic, colorectal and lung cancers, VS-7375 has shown potent single agent anti-tumor efficacy with oral dosing. To assess potential benefits of dual ON/OFF inhibition relative to ON-only RAS inhibitors, we compared VS-7375 relative to the KRAS G12D-ON inhibitor zoldonrasib (RMC-9805) in tumor cell signaling assays. In KRAS G12D mt cells in vitro, VS-7375 strongly reduced pERK at concentrations as low as 1 nM at 4 hours and was durable through 48 hours. In contrast, substantial inhibition of pERK by the KRAS G12D-ON inhibitor zoldonrasib (RMC-9805) was not evident until 24 hours and required 30-fold higher concentration. Additionally, 1 nM of VS-7375 durably suppressed pAKT, pS6 and MYC signaling, while suppression of these markers by zoldonrasib required higher concentrations. We further compared efficacy of VS-7375 relative to zoldonrasib and the pan-RAS ON-only inhibitor daraxonrasib (RMC-6236) in KRAS G12D mt in vivo models. In the KP4 KRAS G12D mt pancreatic cancer model, VS-7375 showed similar initial tumor regression relative to zoldonrasib and daraxonrasib. However, by approximately 20 days of dosing with continuous dosing of all agents, zoldonrasib and daraxonrasib progressively lost 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 ERK, 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. Additionally, we assessed combination of VS-7375 with other targeted agents. In KRAS G12D mt colorectal models, the combination of VS-7375 with cetuximab induced strong tumor growth inhibition. Furthermore, in the KP4 pancreatic cancer model (KRAS G12D mt; MTAP deleted), while VS-7375 single agent induced strong tumor regression lasting through day 40, the combination of VS-7375 with a PRMT5 inhibitor induced strong tumor regression lasting through 100 days of dosing. VS-7375 is currently undergoing clinical evaluation as monotherapy and in combination with cetuximab, chemotherapy, or chemotherapy + pembrolizumab for patients with KRAS G12D-mutated cancers in the US (VS-7375-101; NCT07020221) and in China (NCT06500676). Citation Format: Silvia Coma, Brandon L. Mouery, Ryan D. Mouery, Clint A. Stalnecker, Fusheng Zhou, Adrienne D. Cox, Channing J. Der, Jonathan A. Pachter. Anti-tumor efficacy of the selective oral KRAS G12D dual ON/OFF inhibitor VS-7375 as a single agent and in combination with targeted agents [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr PR007.