GenFleet Therapeutics today announced that the recap of phase I data for GFH375, its oral KRAS G12D (ON/OFF) inhibitor, in advanced solid tumors were featured in a recent publication in Nature Medicine (IMF 52.5). Across different dose levels (100-900 mg QD) in the early-stage clincal development, GFH375 had demonstrated encouraging antitumor activity with a manageable safety and tolerability profile in heavily pretreated patients across tumor types including pancreatic cancer and non-small cell lung cancer (NSCLC). GFH375 has now entered the world's first registrational phase III trials of an oral KRAS G12D inhibitor in metastatic pancreatic cancer as well as in pretreated NSCLC. It is also the first KRAS G12D inhibitor in China to have received Breakthrough Therapy Designation (BTD) for monotherapy in pancreatic cancer and NSCLC.

This multicenter, open-label phase I trial dosed the first patient in July 2024 and enrolled over 70 patients with KRAS G12D-mutant advanced solid tumors. In these heavily pretreated patients, the study showed encouraging preliminary efficacy with a manageable safety profile. Patients received oral GFH375 at daily dose levels ranging from 100 mg to 900 mg, and the recommended Phase II dose (RP2D) for the study in China was established at 600 mg QD. Pharmacokinetic analyses indicated that GFH375 is rapidly absorbed following oral administration, with a steady-state trough concentration at 600 mg QD approximately three times the level required for >90% target inhibition in tumor cells, providing ample exposure to support clinical efficacy.

Initial data from the phase I study were selected for an oral presentation at the 2025 ASCO Annual Meeting. Since then, phase I/II data of GFH375 as monotherapy in pancreatic cancer, NSCLC, and other tumor types have been consecutively selected for oral presentations and late-breaking abstracts (LBAs) at major international congresses, including ASCO, WCLC, and ESMO. According to the latest 2026 WCLC oral presentation of GFH375's phase II data for heavily pretreated NSCLC patients, as of the data cutoff date, 71 patients had undergone at least one post-treatment evaluation, with an objective response rate (ORR) of 59.2%, a confirmed objective response rate (cORR) of 52.1% and a disease control rate (DCR) of 93%. In addition, the median progression-free survival (mPFS) reached 9.6 months (with median follow-up time of 11 months) among taxane-naïve patients, and the 12-month overall survival rate (OS rate) was 77% (with median follow-up time of 11.2 months) among all patients.

"This publication offers a comprehensive review of GFH375's early clinical data, demonstrating clinical benefit across multiple tumor types in heavily pretreated patients and validating the product's favorable pharmaceutical properties and oral bioavailability along with its unique dual ON/OFF inhibition advantage through promising efficacy results. The product is now being evaluated in multiple mid- to late-stage trials, both as a monotherapy and in combination regimens, across KRAS G12D-mutant tumor types and from first-line to later-line settings. These include globally innovative combination approaches, such as co-administration with a cachexia-targeting agent. We look forward to further favorable data publications in academic journals and will accelerate the advancement of GFH375's mid- to late-stage clinical trials  for patients with KRAS G12D-mutant tumors." 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. In the U.S., GenFleet’s partner Verastem Oncology is evaluating VS-7375 in TARGET-D 202, a registration-directed study in NSCLC.

GenFleet received the Breakthrough Therapy Designations granted by China’s CDE in 2026 for GFH375 in pretreated KRAS G12D-mutant NSCLC and metastatic pancreatic cancer respectively; Verastem received the Fast Track Designations granted by U.S. FDA for VS-7375 treating KRAS G12D-mutant pancreatic ductal adenocarcinoma across all lines of therapy in 2025, and treating locally advanced unresectable or metastatic KRAS G12D-mutant NSCLC in 2026.

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