Abstract A076: VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with superior anti-tumor efficacy relative to ON-only KRAS inhibitors

Abstract KRAS G12D is the most prevalent KRAS mutation in human cancers, present in 37%, 12.5%, and 4.9% of pancreatic, colorectal and lung cancers, respectively. Currently, there are no FDA-approved RAS inhibitors effective for patients with KRAS G12D mutant cancers. VS-7375 (GFH375) is an orally available KRAS G12D inhibitor (G12Di) currently being evaluated in patients with KRAS G12D mutant solid tumors. In 3D proliferation assays among a panel of human tumor cell lines, VS-7375 showed improved KRAS G12D potency and selectivity relative to the G12Di RMC-9805 and MRTX1133. In contrast to ON-only RAS inhibitors, VS-7375 potently blocks KRAS G12D in both the active (ON; GTP-bound) and inactive (OFF; GDP-bound) states. Additionally, VS-7375 was more potent than RMC-9805 and MRTX1133 in reducing the level of RAF1-bound active KRAS G12D-GTP (ON) and inhibiting cell proliferation in mouse embryonic fibroblasts expressing human KRAS G12D. VS-7375 also reduced pERK and pCRAF more potently than these other KRAS G12D inhibitors corresponding with greater increase in pro-apoptotic BIM. To assess potential benefits of dual ON/OFF inhibition in KRAS G12D in vivo models, we compared efficacy relative to the ON-only inhibitors RMC-9805 (G12Di) and RMC-6236 (pan-RAS inhibitor). In the LS513 KRAS G12D colorectal cancer xenograft model, VS-7375 showed tumor regression, whereas the ON-only inhibitors RMC-9805 and RMC-6236 showed tumor growth inhibition, but not tumor regression. In the KP4 KRAS G12D pancreatic cancer model, VS-7375 (50 mg/kg twice daily orally) showed similar initial tumor regression relative to the ON-only inhibitors RMC-9805 (100 mg/kg once daily orally) and RMC-6236 (25 mg/kg once daily orally). However, after approximately 2 weeks of dosing, tumors continually treated with RMC-9805 or RMC-6236 began to grow (mean tumor volume >850 mm3 by day 30) in contrast to those treated with the ON/OFF inhibitor VS-7375 which showed sustained tumor regression (mean tumor volume ∼80 mm3 by day 30). Combination of VS-7375 with the anti-EGFR antibody cetuximab induced complete responses in all mice in a colorectal cancer xenograft model, and cetuximab also augmented the antitumor efficacy of VS-7375 in pancreatic and lung cancer models. Additional combinations with VS-7375 are also being explored in preclinical models. In an ongoing phase 1/2 trial in patients with KRAS G12D mutant solid tumors in China (NCT06500676), VS-7375 monotherapy exhibited compelling initial overall response rates (confirmed and unconfirmed) of 52% (12/23) and 42% (5/12) in patients with pancreatic and lung cancers, respectively, with a manageable safety profile. VS-7375 is now being evaluated as monotherapy and in combinations in the US (NCT07020221). Altogether, these results demonstrate that the dual ON/OFF profile of VS-7375 corresponds with strong preclinical anti-tumor efficacy in KRAS G12D mutant cell lines and animal models, along with promising initial response rates for patients with KRAS G12D mutant solid tumors. Citation Format: Silvia Coma, Cristina Caffarra Malvezzi, Feng Yan, Fusheng Zhou, Yu Wang, Nathan Sanburn, Chiara Ambrogio, Jonathan A. Pachter. VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with superior anti-tumor efficacy relative to ON-only KRAS inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A076.