GenFleet Therapeutics, a commercial-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, announced preliminary data from the first-in-human study of GFH375 in a rapid oral presentation at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. 

GFH375X1101 is an open label, multicenter study evaluating GFH375 monotherapy in advanced solid tumor patients harboring KRAS G12D mutation. Preliminary phase I data demonstrated good oral bioavailability and anti-tumor activities of GFH375, with encouraging efficacy in treating multiple tumor types including pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Following the IND approval for a phase I/II study in China in June 2024, GFH375/VS-7375 has advanced into phase II in China while a phase I/IIa trial was initiated in the U.S. by GenFleet's partner Verastem Oncology. 

A first-in-human phase I/II study of GFH375, a highly selective and potent oral KRAS G12D inhibitor in patients with KRAS G12D mutant advanced solid tumors（Abstract. No.: 3013）

So far 62 patients were enrolled in phase I trial: 98% of patients in the study had metastatic diseases (all stage IV), with involvement primarily in the liver (53%) and bone (21%); 75% of patients had received ≥2 prior lines of therapy (40% with 2 lines, 35% with ≥3 lines). Among all trial participants, PDAC patients accounted for 53% (33/62) and NSCLC cases comprised 26% (16/62); the median time on treatment was 11.8 weeks and 36 patients remain on treatment.

Target dose levels

As of the data cutoff date, among 49 patients orally administered at daily dosages of 400 or 600 mg: 43 patients who received at least one post-treatment tumor assessment achieved an objective response rate (ORR) of 42% and a disease control rate (DCR) of 91%; the ORR was 52% and DCR was 100% among 23 efficacy-evaluable PDAC patients, and the ORR was 42% and DCR was 83% among 12 efficacy-evaluable NSCLC patients. Pharmacokinetic analysis revealed the dose levels of 400 mg and 600 mg QD were able to achieve average trough concentrations that were three times above the IC90 value for p-ERK inhibition in AsPC-1 cells. Moreover, 600 mg QD has been recommended as the phase II dose (RP2D) for the phase II portion which started in February 2025.

All dose levels

As of the data cutoff date, among the 52 patients across all dose levels and indications who received at least one post-treatment tumor assessment (efficacy evaluable): the overall ORR was 38% and DCR was 90%; 38 patients exhibited reduction in target lesion, and 20 patients achieved partial response. With good oral bioavailability, GFH375 demonstrated antitumor activities among patients of major cancer types like PDAC and those who had experienced disease progression following multiple lines of prior treatments.Initial data demonstrated that GFH375 was tolerable with a manageable safety profile. Anti-tumor activity was observed starting from the 100 mg QD dose level, and no dose-limiting toxicities (DLTs) were observed across all dose levels (100-900 mg QD). The treatment-related adverse events (TRAEs) were mostly graded 1-2; the most common TRAEs occurring in at least 20% of patients were diarrhea, nausea, vomiting and anemia. TRAEs ≥grade 3 consisted mainly of decreased neutrophil count (8%) and diarrhea (5%). No TRAE-related deaths were reported. The rapid oral presentation at ASCO was delivered by Dr. Xinghao Ai from Dept. of Medical Oncology, Shanghai Chest Hospital. 

"We are delighted at the encouraging efficacy of GFH375 in treatment of cancer types including PDAC and NSCLC. G12D represents the most prevalent KRAS mutation subtype across multiple solid tumors, and we were impressed by the significant unmet medical needs in patients. We anticipate more positive results from this study that may lead to a life-saving treatment.”stated Prof. Shun Lu, Dept. of Medical OncologyShanghai Chest Hospital.

“Leveraging our expertise from developing fulzerasib (a KRAS G12C inhibitor), the first marketed product in GenFleet’s pipeline, we are expanding the diversity of therapeutic targets and modalities in our RAS-targeted matrix. GFH375 is the second selective inhibitor in the matrix to reach clinical stage. Preliminary data exhibited its promising efficacy in treating PDAC, NSCLC and other tumor types; notably, advanced PDAC represents a crucial medical need, with limited options of targeted therapies available to patients. We look forward to the potential of GFH375 addressing diverse malignancies with KRAS G12D mutation." stated Yu Wang, M.D.,Ph.D. Chief Medical Officer of GenFleet.

About GFH375/VS-7375

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.