China-based GenFleet Therapeutics has launched a Phase III clinical trial for oral KRAS G12D inhibitor GFH375 in 320 patients with pretreated metastatic pancreatic cancer, following Phase I/II data showing 41% objective response rate (ORR) and 97% disease control rate (DCR). The multicentre open-label randomised study compares GFH375 monotherapy against investigator's choice chemotherapy, with co-primary endpoints of progression-free survival (PFS) and overall survival (OS) supporting a potential registration pathway. The small-molecule inhibitor binds non-covalently to both active and inactive KRAS G12D conformations preventing downstream pathway activation, with low off-target risk demonstrated in kinase selectivity profiling.

GenFleet partnered with Verastem Oncology in a 2023 agreement covering three RAS pathway targets, with Verastem exercising an option for ex-China rights to GFH375 in January 2025 following promising early clinical data. The programme represents the second KRAS G12D inhibitor to reach Phase III development globally after Hengrui's HRS-4642. Safety data from 66 patients showed 30% grade-3 treatment-related adverse events incidence, with manageable gastrointestinal and haematological toxicities supporting continued development in the advanced pancreatic ductal adenocarcinoma population.

PharmCube's NextBiopharm® database lists 183 active KRAS G12D programs globally, including 33 in the clinic. Click here to request a free trial for NextBiopharm®.