GenFleet Therapeutics, a commercial-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, announced the dosing of the first subject in the phase II portion of the phase I/II trial evaluating the efficacy, safety and pharmacokinetic characteristics of GFH375, an oral KRAS G12D (ON/OFF) inhibitor. This multi-center, open-label (~20 sites in China) trial enrolls patients with advanced G12D-mutant solid tumors, including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC)—three cancer types with high prevalence of G12D mutations.
GenFleet received approval from China’s National Medical Products Administration (NMPA) in June last year for GFH375 (VS-7375) to advance into a phase I/II study treating advanced solid tumor patients with KRAS G12D mutation. The phase I portion of the study demonstrated a favorable safety and tolerability profile, with the latest findings set to be presented at global academic meetings later this year. Data unveiled at the 2024 AACR Annual Meeting highlighted GFH375's oral bioavailability and potent efficacy across preclinical models; additionally, the drug candidate exhibited anti-tumor activity in an intracranial CDX tumor model, suggesting its potential as a treatment for G12D mutant cancers with brain metastases.
"G12D is the most prevalent type of KRAS mutation in solid tumors. We are highly encouraged by the progress of GFH375 in its clinical development and look forward to posting the phase I trial results at global academic meetings later this year. We eagerly anticipate this novel G12D inhibitor has the potential to emerge as an important treatment option for KRAS G12D cancers." stated Yu Wang, M.D.,Ph.D., Chief Medical Officer of GenFleet.
About KRAS G12D Mutation and GFH375
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 collaboratinon, 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.
