GenFleet Therapeutics, a commercial-stage biopharmaceutical company focusing on cutting-edge therapies in oncology and immunology, today unveiled the latest preclinical findings of GFH375/VS-7375, an oral KRAS G12D (ON/OFF) inhibitor, at the poster presentation of the 2025 American Association for Cancer Research (AACR) Annual Meeting.
Through extensive preclinical research, the poster highlights the anti-tumor activity of GFH375, as well as its mechanistic advantage in dual ON/OFF inhibition of KRAS G12D. Specifically, cell-based assays demonstrated GFH375’s superior selective inhibition of the target protein; in the comparative studies of animal models, GFH375 induced significant tumor responses that outperformed the efficacy of multiple other RAS-inhibiting therapeutics and chemotherapy. Furthermore, the combination of GFH375 with cetuximab enhanced anti-tumor activity to exceed either agent alone and achieved remarkable tumor responses in colorectal and pancreatic cancer models.
GenFleet has started the phase II trial of GFH375 in China, and GenFleet’s partner Verastem Oncology (Nasdaq: VSTM) is expected to initiate a phase I/IIa study in the US around mid-2025.
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 No.：4394）
Animal studies for GFH375 monotherapy exhibited dose-dependent anti-tumor activity, and superior tumor regression compared to multiple other RAS-targeted therapies and chemotherapy
In a comparative study of a colorectal cancer model, the mice orally dosed with GFH375 for 2 weeks were observed to achieve substantial tumor regression, with 7 in 8 reaching partial response (≥30% reduction from baseline); the mice orally treated with RMC-9805 at daily equivalent dosage were observed with varying disease progression. Besides, the mice dosed with RMC-6236 at 25 mg/kg QD achieved 1 partial response.
In a comparative research using two models of colorectal and pancreatic cancers respectively, oral administration of GFH375 for 4 weeks were observed to induce significant tumor regression in both models, with 7 in 8 reaching partial response in each model. In contrast, the mice exhibited varying disease progression both in the colorectal model after receiving maximum tolerated dose of irinotecan via intraperitoneal injection and in the pancreatic cancer model after receiving a combination of gemcitabine and paclitaxel via intravenous injection at maximum tolerated dose. Additionally, all chemotherapy-treated mice in the pancreatic cancer model demonstrated over 200% tumor growth from baseline.
The oral administration from a low dosage of GFH375 elicited dose-dependent anti-tumor activity across multiple models of pancreatic and colorectal cancers, and a notable ratio of partial response occurred following two weeks of continuous administration at medium dosage. Moreover, anti-tumor activity was observed in intracranial tumor models, suggesting therapeutic potential of GFH375 for patients with brain metastases.
Cell-based assays for GFH375 monotherapy indicated dual ON/OFF inhibition of target protein with selectivity and potency surpassing singular ON or OFF inhibition
GFH375 is a potent dual inhibitor of KRAS G12D ON (active) and OFF (inactive); for the active state, GFH375 inhibits the GTP-bound protein while also blocking its interaction with downstream effectors such as RAF1 or disrupt the activation process of KRAS G12D from GDP-bound to GTP-bound.
In vivo efficacy data displayed better potency and selectivity of GFH375 obstructing the G12D-mutant cell proliferation relative to other G12D-targeted therapies including RMC-9805 (ON inhibitor) and MRTX1133 (OFF inhibitor): the IC50 level of GFH375 was lower in G12D-mutant cell lines and considerably higher than RMC-9805 in most cell lines of wild-type KRAS or bearing non-G12D KRAS mutations (G12C, G12V, G12S, G13D). In addition, GFH375 is more potent reducing active KRAS G12D-GTP (ON), pERK and pCRAF in RAS-less MEFs expressing KRAS G12D.
Animal testing for GFH375-cetuximab combination presented favorable response rates in animal models
The combinational regimen in animal models presented augmented anti-tumor activity over either single-agent therapy and revealed crucial tumor response when dosed with GFH375 in combinatin with cetuximab; the combination enabled complete responses in all mice in a colorectal cancer model and partial responses in all mice in a pancreatic cancer model. Besides, animal testing for the combination of GFH375 and avutometinib (RAF/MEK clamp) also showed enhanced activity over GFH375 monotherapy in models of pancreatic and lung cancers.
About KRAS G12D Mutation and GFH375/VS-7375
RAS proteins, in active GTP-bound or inactive GDP-bound form, are binary molecular switches controlling cellular responses in signaling pathways including RAS-RAF-MEK-ERK and PI3K/AKT/mTOR. Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS), and KRAS is the most frequently mutated oncogene in humans. Among KRAS mutations, G12D, G12V, and G12C represent the top three most frequently mutated alleles. KRAS G12D mutation is commonly found in pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma.
A large percentage of patients harboring KRAS G12D mutation are found without smoking history and with poor response to PD-1 inhibitors. Mutant-selective G12D inhibitors hold promise to benefit large segments of KRAS-driven PDAC patients since KRAS G12D alterations are the most frequently occurring somatic change in PDAC patients (about 40%) who are reported to have an overall 5-year survival rate lower than 10%.
GFH375 is an orally active, potent, highly selective small-molecule KRAS G12D (ON/OFF) inhibitor designed to target the GTP/GDP exchange, thereby disrupting the activation of downstream pathways and effectively inhibiting tumor cell proliferation. Preclinical studies demonstrated dose-dependent inhibition in models bearing KRAS G12D mutation; GFH375 also demonstrated low off-target risk in kinase selectivity and safety target assays.GenFleet entered into a discovery and development collaboration with Verastem Oncology (Nasdaq: VSTM) to advance three novel oncology discovery programs related to RAS/MAPK pathway-driven cancers. The collaboration provides Verastem with an exclusive option to obtain a license for each of the three compounds in the collaboration after the successful completion of pre-determined milestones in a Phase I trial. Verastem selected GFH375/VS-7375, an oral KRAS G12D (ON/OFF) inhibitor, as its lead program from the collaboration, in December 2023 and the license for GFH375 that was exercised in January 2025 is the first one from this collaboration. The licenses would give Verastem development and commercialization rights outside of China while GenFleet would retain rights inside of China.
