GenFleet Therapeutics (2595.HK), a commercial-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, announced the initiation of registrational phase III study (GFH375X1301) for GFH375, an oral KRAS G12D (ON/OFF) inhibitor, in patients with pretreated KRAS G12D-mutated metastatic pancreatic cancer. The trial has been initiated at Peking University Cancer Hospital, building on GFH375’s position as one of the fastest advancing oral KRAS G12D inhibitors in clinical development.
Multiple trials evaluating GFH375 (known as VS-7375 outside of China) as monotherapy and in combination regimens are currently underway by GenFleet in China and by GenFleet’s partner Verastem Oncology outside of China; these include a China-based trial investigating GFH375 in combination with chemotherapy (albumin-bound paclitaxel and gemcitabine, AG) as first-line treatment of advanced pancreatic ductal adenocarcinoma (PDAC). In addition, GFH375/VS-7375 has been granted Fast Track Designation by the U.S. FDA for locally advanced and metastatic KRAS G12D-mutated PDAC across all lines of settings.
This multicenter, open-label, randomized and controlled study (GFH375X1301) will be conducted across about 40 sites and plans to enroll approximately 320 metastatic pancreatic cancer patients who had received at least one prior standard systemic therapy.
According to Frost & Sullivan, the global incidence of pancreatic cancer is projected to exceed 770,000 new cases in 2037, highlighting the disease as an aggressive malignancy with a five-year survival rate below 10%. Current standard-of-care relies largely on chemotherapy, with objective response rates of only 10–20% in second- and third-line settings and no established standard regimen beyond third line. Nearly 40% of pancreatic cancer patients harbor KRAS G12D mutation, yet no targeted therapy for this mutation has been approved worldwide. KRAS G12D is an independent prognostic biomarker associated with poor response rate and overall survival in PDAC; the KRAS mutation also plays a vital role in regulatory T-cell (Treg) conversion, potentially contributing to an immune-suppressive tumor microenvironment and reducing the response to immune checkpoint inhibitors.
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.
With a focus on cutting-edge therapies, GenFleet Therapeutics is dedicated to serving significant unmet medical needs globally in oncology and immunology. Leveraging its deep understanding of disease biology and translational medicine, GenFleet has established a proprietary and fully integrated R&D system that yields a robust pipeline of multiple cutting-edge products with novel mechanisms and global IP.
Since its inception in 2017, GenFleet has built up industry-leading capabilities and expertise in developing novel drug candidates spanning small molecules and biologics. Its pipeline comprises numerous programs that have advanced to later-stage or pivotal clinical trials across China, the United States and Europe.
The company has set up a highly differentiated RAS-targeted matrix including selective and pan-RAS inhibitors of diverse molecular types, with most assets leading their categories in clinical progress in China or globally. In addition, the company has pioneered a series of first-in-class combination therapies based on dual-target synergistic mechanisms. By integrating clinical needs and insights, GenFleet is dedicated to expanding its portfolio into major therapeutic areas including pancreatic cancer, NSCLC, and cachexia. Furthermore, it's strengthening its commercial collaborative network through strategic out-licensing agreements or clinical cooperations with prestigious listed companies across the world.
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