GenFleet's Oral KRAS G12D Inhibitor GFH375 Enters Registrational Phase III Trial in NSCLC, First of Its Kind Globally
核心洞察
GenFleet Therapeutics (搜索) has dosed the first patient in Kylin-Flight 01, the first registrational Phase III study of an oral KRAS G12D (搜索) inhibitor in non-small cell lung cancer (搜索).
The multicenter, open-label, randomized trial will compare GFH375 monotherapy against docetaxel in KRAS G12D (搜索)-mutant NSCLC patients who have failed standard therapy across over 40 sites in China.
Phase I/II data presented at WCLC 2025 showed a 68.8% overall response rate at the recommended Phase II dose of 600 mg once daily, with a disease control rate of 93.8%.
GenFleet Therapeutics (搜索) (Shanghai) Inc. (HKEX: 02595) has officially launched Kylin-Flight 01, a registrational Phase III clinical study evaluating its oral KRAS G12D (搜索) inhibitor GFH375 as monotherapy in patients with KRAS G12D-mutant non-small cell lung cancer (搜索) (NSCLC). The first patient was recently enrolled at Nanjing Drum Tower Hospital, marking what the company describes as the first registrational Phase III study of an oral KRAS G12D inhibitor in NSCLC globally.
The multicenter, open-label, randomized controlled trial is expected to be conducted at over 40 research centers across China. It will directly compare GFH375 against the chemotherapy drug docetaxel for the treatment of patients with locally advanced, unresectable, or metastatic NSCLC harboring a KRAS G12D (搜索) mutation who have failed standard-of-care therapy.
A Dual-Mechanism Oral Inhibitor with No Approved Competitor
GFH375 is an orally active, non-covalent small-molecule inhibitor targeting both the GTP-bound (ON) and GDP-bound (OFF) states of mutant KRAS G12D (搜索), thereby blocking downstream RAS/MAPK pathway signaling and inhibiting tumor cell proliferation. No targeted therapy is currently approved globally for KRAS G12D-mutant cancers in any indication.
The KRAS G12D (搜索) mutation accounts for approximately 26% of all KRAS mutations and occurs in roughly 5% of NSCLC cases. Currently, first-line standard treatment for this patient population still relies on regimens designed for driver-gene-negative NSCLC. However, previous studies indicate that NSCLC patients with KRAS mutations exhibit lower sensitivity to chemotherapy and, due to epigenetic regulatory mechanisms, are prone to developing rapid resistance. Furthermore, PD-L1 expression levels in KRAS G12D patients are generally low, resulting in a lower response rate to PD-1/L1 inhibitor monotherapy compared to other KRAS mutation subtypes.
In second-line and later-line settings, whether using immunotherapy, chemotherapy, or chemotherapy combined with anti-angiogenic agents, the objective response rate and overall survival benefit remain quite limited, making KRAS G12D (搜索)-mutated NSCLC a field with a massive unmet medical need.
Compelling Early Efficacy Data
Data presented at the 2025 World Conference on Lung Cancer (WCLC) reported an overall response rate of 68.8% at the recommended Phase II dose of 600 mg once daily in 16 evaluable NSCLC patients, with a disease control rate of 93.8%. Across all dose levels, 26 evaluable NSCLC patients achieved a 57.7% overall response rate.
Wang Yu, Chief Medical Officer of GenFleet, noted that since entering clinical trials in 2024, GFH375 has demonstrated excellent efficacy potential in treating NSCLC, with related research data consistently selected for oral presentations or breakthrough research abstracts at international academic conferences. Updated NSCLC monotherapy data are scheduled for oral presentation at the 2026 WCLC.
Regulatory Recognition and Dual-Indication Strategy
GFH375 became the first drug in China to receive two breakthrough therapy designations for the single-agent treatment of KRAS G12D (搜索)-mutated NSCLC and pancreatic cancer (搜索), highlighting regulatory recognition of its potential clinical value.
The NSCLC trial is GenFleet's second registrational study for GFH375. The Kylin-Wings 01 Phase III study in previously treated KRAS G12D (搜索)-mutant metastatic pancreatic cancer (搜索), initiated in 2025, is described by the company as progressing on track. With the launch of the lung cancer study, GFH375 becomes one of the very few oral KRAS G12D inhibitors simultaneously advancing registrational clinical trials in two different solid tumors.
Competitive Landscape
The competitive landscape for KRAS G12D (搜索) inhibition remains early but increasingly active. Revolution Medicines' zoldonrasib (RMC-9805), a RAS(ON) G12D-selective inhibitor, is in clinical development across KRAS G12D-mutant solid tumors, including NSCLC, while several other companies are pursuing G12D-selective approaches. GFH375's reported ability to inhibit both ON- and OFF-state KRAS G12D and its advancement into registrational studies in both NSCLC and pancreatic cancer (搜索) give GenFleet an early position in the emerging class.
The ex-China rights for GFH375 are held by Verastem Oncology (Nasdaq: VSTM), which licensed the compound as VS-7375 in January 2025 and has an active Phase I/II study underway in the US. GenFleet stated that the company designed the Kylin-Flight 01 trial based on product profile, trial progress, and clinical imperatives, with docetaxel as the comparator.