GenFleet launches world’s first Phase 3 study of an oral KRAS G12D inhibitor for the treatment of NSCLC
GenFleet Therapeutics today held a national investigator conference for its Phase III registrational clinical trial of GFH375 (an oral KRAS G12D inhibitor) as monotherapy for non-small cell lung cancer (NSCLC) (“Kylin-Flight 01”). “Kylin-Flight 01” is a multicenter, open-label, randomized controlled Phase III study evaluating GFH375 against docetaxel in patients with KRAS G12D-mutant, locally advanced, unresectable, or metastatic NSCLC who have failed standard treatment. The study will be conducted at over 40 research centers nationwide, and the first patient was recently enrolled at Nanjing Drum Tower Hospital. Previously, GFH375 entered the world’s first Phase III registrational clinical trial of an oral KRAS G12D inhibitor for pancreatic cancer last year (“Kylin-Wings 01”). This year, GFH375 has become the first in China to receive Breakthrough Therapy Designation for monotherapy in both KRAS G12D-mutant NSCLC and pancreatic cancer.
Professor Shun Lu, the leading PI of this study from Shanghai Chest Hospital, stated in his presentation: “Targeted therapy for lung cancer has advanced rapidly over the past 20 years, but there remains a huge unmet need for treatment of KRAS G12D-mutant NSCLC, and currently no relevant targeted drugs have been approved globally. GFH375 is among the world’s leading clinical explorers in this indication. The preliminary data presented in oral presentations at last year’s American Society of Clinical Oncology (ASCO) and the World Congress on Lung Cancer (WCLC) were encouraging and gave us sufficient confidence to initiate a registrational clinical trial. We have developed the most feasible and efficient clinical protocol by combining product characteristics, research progress, and clinical needs, hoping to change the treatment landscape for KRAS G12D-mutant NSCLC.”
Dr. Qiang Lu, Chairman of GenFleet, stated, “We focus on the RAS (Rapid Assay) field with innovative products in various molecular forms, and fully leverage China’s industrial chain advantages to form a leading product matrix in the RAS field. We have also launched several first-in-class combination therapies with synergistic mechanisms. GFH375 has shown promising clinical development prospects in three major RAS-mutant tumor types: NSCLC, pancreatic cancer, and colorectal cancer. We will select the most suitable treatment strategies in terms of molecular form, target, and regimen for different indications, and expedite the mid-to-late stage clinical projects for various major tumor types, practicing our corporate spirit of ‘soaring against the wind and waves, adhering to principles and fulfilling our mission.’”
Currently, there are no targeted therapies available globally for patients with KRAS G12D mutations. The first-line standard of care for this patient population follows the treatment regimen for driver gene-negative NSCLC. However, previous studies have shown that KRAS-mutant NSCLC patients have lower sensitivity to chemotherapy and are prone to developing resistance to chemotherapy relatively quickly due to epigenetic regulatory mechanisms. Furthermore, KRAS G12D patients have lower PD-L1 expression, resulting in lower single-agent response rates to PD-1/L1 inhibitors compared to other KRAS mutation subtypes. The objective response rates and overall survival benefits of second-line and later-line immunotherapy, chemotherapy ± anti-angiogenic drugs are also limited. GFH375 has demonstrated potentially best-in-class efficacy in treating NSCLC among global KRAS G12D inhibitors, and the latest data on its single-agent second-line treatment of NSCLC will be presented orally at this year’s WCLC Congress.
Dr. Yu Wang, Chief Medical Officer of GenFleet, stated, “We are delighted that GFH375 has entered its second registrational Phase III clinical trial. Since entering clinical trials in 2024, GFH375 has demonstrated excellent efficacy in treating NSCLC, and related research data has consistently been presented in oral presentations or Breakthrough Abstracts (LBAs) at multiple international academic conferences. Based on the efficacy of Phase I/II monotherapy and the current landscape of NSCLC treatment, we are confident in rapidly advancing various trials of GFH375 for NSCLC. Furthermore, the registrational Phase III study of GFH375 for pancreatic cancer, initiated last year, has also progressed as expected. We look forward to the early availability of various monotherapy and combination regimens of this KRAS G12D inhibitor, providing patients with new targeted therapy options.”
At the conference, the clinical team from Jingfang introduced the protocol design, inclusion criteria, and efficacy assessment of the “Kylin-Flight 01” study. Professor Ziming Li from Shanghai Chest Hospital and Director Sanxing Guo from the First Affiliated Hospital of Zhengzhou University respectively introduced the key points of the “Kylin-Flight 01” study implementation and safety management, and shared the positive efficacy of GFH375 in patients with different tumor types during clinical research. Attendees discussed the product’s mechanism of action, the progress planning of this study, and communication and collaboration. They expressed their anticipation for the rapid advancement of the “Kylin-Flight 01” study and for more GFH375 treatment options to move from secondary to primary care in the future for patients.
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 previously 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.
Source/Top Image: GenFleet Therapeutics
