GenFleet Therapeutics (2595.HK) announced that GFH375 has entered a phase II study for first-line treatment of patients with advanced, KRAS G12D-mutant non-small cell lung cancer (NSCLC). The multicenter, open-label, randomized trial features three arms including GFH375 monotherapy and two combination regimens pairing GFH375 with the EGFR antibody (cetuximab) or with chemotherapy (pemetrexed). The study will be conducted in dozens of clinical sites across China, with Guangdong Provincial People’s Hospital as the leading site. GFH375 (also known as VS-7375 outside of China) stands as the first KRAS G12D inhibitor that received Breakthrough Therapy Designation (BTD) in China for NSCLC and has also been granted with the U.S. FDA’s Fast Track designation (FTD) for locally advanced unresectable or metastatic KRAS G12D-mutant NSCLC.
Current first-line standard of care for KRAS G12D-mutant patients follows the treatment paradigm for oncogene-negative NSCLC, yielding only modest survival benefits. Moreover, effective therapeutic options after frontline progression remain scarce. Multiple real-world studies show that patients with KRAS G12D mutations experience significantly poorer outcomes under first-line chemotherapy - with or without immunotherapy - compared to KRAS wild-type or non-KRAS G12D-mutant patients. GFH375 has already entered the world’s first registrational phase III study of an oral KRAS G12D inhibitor in patients with NSCLC, and GFH375 demonstrated best-in-class efficacy in NSCLC patients according to publicly available data of KRAS G12D inhibitor monotherapies. Notably, updated phase I/II GFH375 monotherapy data in NSCLC patients (abstract No. 2333) have been selected for an oral presentation at this year’s World Conference on Lung Cancer (WCLC) to be held in Seoul, and the presentation will take place in the section Beyond KRAS: Emerging Targets, Smart Therapies on Sept. 14.
On the combination front, preclinical data presented at this year’s American Association for Cancer Research (AACR) Annual Meeting demonstrated that in KRAS G12D-mutant NSCLC models, the combination of GFH375 with cetuximab delivered markedly superior antitumor activity compared with either agent alone. Moreover, GFH375 advanced into a phase Ib/II trial last year evaluating combinations with chemotherapy or cetuximab across multiple solid tumors; early data indicated a favorable safety and tolerability profile with no obvious overlapping toxicities. The data from the GFH375/cetuximab combination treating RAS-mutant solid tumors have been granted the eligibility for full submission of a Late-Breaking Abstract (LBA) at the European Society for Medical Oncology (ESMO) Annual Meeting in 2026.
"Driven by the monotherapy efficacy of GFH375 in NSCLC and the active progression of multiple combination studies, we are confident in moving GFH375-based lung cancer therapies from late-line to the first-line setting. Over the past two years, multiple clinical programs for GFH375 have advanced efficiently, with clinical data across various tumor types consecutively selected for LBAs or oral presentations at major international academic conferences. Meanwhile, we deeply recognize the urgent need of KRAS G12D-mutant patients for innovative targeted therapies and look forward to more of our innovative therapies reaching patients." 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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