GenFleet Therapeutics, a commercial-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, announced US Food and Drug Administration (FDA) cleared the investigational new drug (IND) application of GFH375/VS-7375, an oral KRAS G12D (ON/OFF) inhibitor, for clinical trial treating advanced solid tumor patients harboring KRAS G12D mutation. The study is planned to be initiated by GenFleet’s partner Verastem Oncology (Nasdaq: VSTM) in the US around mid-2025. The first-in-human study of GFH375 initiated by GenFleet in China has progressed into phase II and the preliminary efficacy & safety data of this study were selected into the rapid oral presentation at the upcoming 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.
The phase I/IIa study in the US will be sponsored and led by Verastem to evaluate the safety and efficacy of GFH375 across various dose levels, with reference to the safety and efficacy data in GenFleet’s study. In the phase IIa portion, the study will further assess the efficacy and safety of GFH375 both as a single agent and in combination therapies among patients with advanced KRAS G12D-mutant solid tumors, including pancreatic, colorectal and non-small cell lung cancers.
GenFleet received China’s IND approval in Jun. 2024, for GFH375 to move into a phase I/II study treating KRAS G12D-mutant advanced solid tumors. The first patient was dosed in phase II portion in Feb. 2025. The study demonstrated favorable efficacy and safety data, with no dose-limiting toxicities observed across all tested dose levels and with partial responses achieved among patients of different tumor types including pancreatic and lung cancers, well positioning GFH375 at the forefront of oral KRAS G12D inhibitor development.
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 promises 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.
