Abstract 4394: GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy as single agent and in combination with other anticancer therapies in preclinical models

Abstract KRAS G12D is the most prevalent KRAS mutation in human cancers, present in 37%, 12.5%, 8% and 4.9% of pancreatic, colorectal, endometrial and lung cancers, respectively. Currently there are no FDA approved KRAS G12D-selective inhibitors and thus, cancers with KRAS G12D mutations represent a significant unmet medical need. GFH375 (also known as VS-7375) is an orally available KRAS G12D-selective small molecule inhibitor that binds KRAS G12D in the active (ON; GTP-bound) and inactive (OFF; GDP-bound) states. By blocking the activities of the ON and OFF states of KRAS G12D, GFH375 has the potential to inhibit KRAS G12D signaling and tumor growth more completely than compounds that block KRAS G12D only in the OFF state or only in the ON state. Here we show that among a panel of human cancer cell lines, GFH375 potently and selectively inhibited proliferation of tumor cells bearing a KRAS G12D mutation relative to cell lines bearing wild-type KRAS or non-G12D KRAS mutations. Similarly, in a panel of mouse embryonic fibroblasts (MEFs) engineered to express various human KRAS mutation variants, GFH375 selectively inhibited proliferation of KRAS G12D mutant MEFs relative to MEFs expressing other KRAS G12X or Q61X mutations. Furthermore, GFH375 was more potent than other KRAS G12D inhibitors (e.g. RMC-9805, MRTX1133) in reducing the level of RAF1-bound active KRAS G12D-GTP (ON) and inhibiting cell proliferation in MEFs expressing human KRAS G12D. GFH375 also reduced pERK and pCRAF more potently than these other KRAS G12D inhibitors corresponding with greater increase in pro-apoptotic BIM. In vivo, oral administration of GFH375 single agent induced strong tumor regressions in multiple KRAS G12D colorectal and pancreatic cancer tumor models, including xenograft models and a transplanted pancreatic cancer model derived from KPC genetically engineered mice. GFH375 also demonstrated potent anti-tumor activity in an intracranial GP2D tumor model, suggesting potential to use for treatment of brain metastases. Combination of GFH375 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 GFH375 in pancreatic and lung cancer models. Combination with the RAF/MEK clamp avutometinib also enhanced the anti-tumor efficacy of GFH375. Additional combinations with GFH375 are currently being explored. Altogether, GFH375 is a potent and selective orally active inhibitor of KRAS G12D (ON/OFF) and demonstrated promising anti-tumor activity in multiple KRAS G12D tumor models in vivo as single agent and in combination with other anticancer therapies including cetuximab. These results support the ongoing clinical evaluation of GFH375 for treatment of patients with KRAS G12D mutant cancers (NCT06500676). Citation Format: Jonathan A. Pachter, Feng Yan, Silvia Coma, Cristina Caffarra Malvezzi, Xiuting Liu, Emilia Berardelli, Tao Jiang, Siyuan Le, Nathan Sanburn, Fusheng Zhou, Jiong Lan, David G. DeNardo, Chiara Ambrogio, Qiang Lu. GFH375 (VS-7375): An oral, selective KRAS G12D (ON/OFF) inhibitor with potent anti-tumor efficacy as single agent and in combination with other anticancer therapies in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4394.