GENFLEET-B: The first patient has been dosed in the Phase Ib/II study of KRAS G12D inhibitor GFH375 in combination with cetuximab or chemotherapy for the treatment of advanced solid tumors

According to the Zhitong Finance APP, GENFLEET-B (02595) announced that the first patient in the Phase Ib/II study of the GFH375 combination therapy for treating KRAS G12D mutant advanced solid tumors has been enrolled at Peking University Cancer Hospital. This study (GFH375X1202) received clinical trial approval from the National Medical Products Administration in September and includes two combination therapies: GFH375 (an oral KRAS G12D inhibitor) combined with cetuximab or chemotherapy; among them, the GFH375 combined with chemotherapy regimen is a first-line treatment for pancreatic ductal adenocarcinoma (PDAC).

The Phase Ib trial will initially be conducted at approximately 15 centers, including Peking University Cancer Hospital, with the main research objective of assessing the safety/tolerability, efficacy, and pharmacokinetic characteristics of GFH375 combined with cetuximab or chemotherapy in patients with solid tumors. In the Phase II trial, the GFH375 combined with chemotherapy (albumin-bound paclitaxel and gemcitabine) regimen will treat first-line advanced PDAC patients, while the GFH375 combined with cetuximab (EGFR monoclonal antibody) regimen will treat advanced PDAC and colorectal cancer (CRC) patients.

Dr. Yu Wang, Chief Medical Officer of GENFLEET, stated: "We are pleased that the GFH375 combination therapy regimens have entered the clinical stage, especially the first-line PDAC treatment, which will push the clinical development of GFH375 from later lines to the front line. The research data on GFH375 monotherapy for PDAC and non-small cell lung cancer (NSCLC) have recently been presented as breakthrough research abstracts and oral reports at ESMO and WCLC, respectively, indicating excellent efficacy and the potential of this product to treat multiple tumor types. We look forward to the rapid advancement of several domestic and international studies based on this product, benefiting patients as soon as possible."

The GFH375 monotherapy was approved by the National Medical Products Administration to enter Phase I/II trials in June 2024, and GFH375/VS-7375 has received FDA Fast Track designation this year for use in first-line and later-line treatment of locally advanced, metastatic KRAS G12D mutant PDAC patients.

GFH375 is an orally administered, highly active, and highly selective small molecule KRAS G12D (ON/OFF) inhibitor that binds non-covalently to the KRAS G12D protein, inhibiting its interaction with downstream effector proteins, thereby disrupting the sustained activation of downstream pathways by KRAS G12D in cells, ultimately leading to efficient inhibition of tumor cell proliferation. Preclinical studies have shown that the inhibitory effect of GFH375 monotherapy on tumor growth increases with the dosage and duration of administration, and it has demonstrated low off-target risk in kinase selectivity and safety target testing.

GENFLEET has reached a licensing and early collaboration agreement with Verastem regarding three products related to RAS/MAPK-driven cancers developed by GENFLEET. This collaboration grants Verastem exclusive options to obtain licenses for these three products after successfully achieving pre-defined milestones in Phase I clinical trials. In December 2023, Verastem selected GFH375/VS-7375 (an oral KRAS G12D (ON/OFF) inhibitor) as its lead project for collaboration, with the license obtained for GFH375 being the first license resulting from this collaboration These licenses will grant Verastem the development and commercialization rights outside of Greater China, while GENFLEET retains those rights within China