Development

Genfleet becomes first to test oral KRAS G12D inhibitor in Phase III for NSCLC

Edited by Robert McTiernan··2 min read
Genfleet becomes first to test oral KRAS G12D inhibitor in Phase III for NSCLC

China-based GenFleet Therapeutics (Shanghai) Inc. (HKEX: 02595) announced on August 10 that the first patient has been dosed in Kylin-Flight 01, a multicenter, open-label, randomized Phase III study comparing GFH375 monotherapy against docetaxel in patients with KRAS G12D-mutant locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) who have failed standard-of-care therapy. The trial, enrolling across more than 40 sites in China, is described by the company as the first registrational Phase III study of an oral KRAS G12D inhibitor in NSCLC.

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, 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 NSCLC trial is GenFleet's second registrational study for GFH375. The Kylin-Wings 01 Phase III study in previously treated KRAS G12D-mutant metastatic pancreatic cancer, initiated in 2025, is described by the company as progressing on track. GFH375 has received China's first two Breakthrough Therapy Designations (BTD) for a KRAS G12D inhibitor — one for NSCLC and one for pancreatic cancer. Its ex-China rights 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.

The clinical rationale for pursuing NSCLC specifically is supported by a series of Phase I/II readouts. 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. Updated NSCLC monotherapy data are scheduled for oral presentation at the 2026 WCLC. GenFleet said the company designed the Kylin-Flight 01 trial based on product profile, trial progress, and clinical imperatives, with docetaxel as the comparator.

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The KRAS G12D mutation accounts for approximately 26% of all KRAS mutations and occurs in roughly 5% of NSCLC cases. GenFleet noted that KRAS G12D-mutant NSCLC has been associated with lower PD-L1 expression and reduced sensitivity to chemotherapy and immune checkpoint inhibitors compared with some other KRAS subtypes. Current second-line and later options — including immunotherapy, chemotherapy, and anti-angiogenic regimens — produce modest objective response rates in this population.

The competitive landscape for KRAS G12D 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. No KRAS G12D-targeted therapy is currently approved. 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 give GenFleet an early position in the emerging class.

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