GenFleet Therapeutics (2595.HK) announced that GFH375, an oral KRAS G12D (ON/OFF) inhibitor, has received its third Breakthrough Therapy Designation (BTD) from China’s National Medical Products Administration (NMPA), in combination with cetuximab (an anti-EGFR antibody) among patients with KRAS G12D-mutant metastatic colorectal cancer (CRC) who had failed prior chemotherapy regimens (oxaliplatin, fluoropyrimidine and irinotecan-based). GFH375 was the first oral KRAS G12D inhibitor in China to have been granted BTDs for pretreated non-small cell lung cancer (NSCLC) and pancreatic cancer, and has entered two registrational phase III studies evaluating monotherapy in pretreated pancreatic cancer and NSCLC. Preliminary data from the study of GFH375 in combination with cetuximab in solid tumors will be released via an online investor call in October.
According to data from the International Agency for Research on Cancer (IARC) and Frost & Sullivan, over 2 million new CRC cases were diagnosed worldwide in 2024, with KRAS mutations occurring in approximately 40% of CRC cases and KRAS G12D mutations in over 10%. Currently, both first-line and second-line CRC regimens rely primarily on chemotherapy with limited options of subsequent targeted therapies upon chemotherapy resistance. Meanwhile, monotherapy trials of KRAS G12D inhibitors in global landscape have demonstrated lower efficacy in CRC than in pancreatic cancer and NSCLC populations. Compensatory activation of the EGFR pathway is identified as one of the resistance mechanisms for KRAS inhibitors. Sotorasib, a marketed KRAS G12C inhibitor, in combination with panitumumab (an anti-EGFR antibody) has been approved in the United States for later-line CRC treatment, demonstrating an objective response rate (ORR) substantially superior to sotorasib monotherapy (30.2% vs 9.7%) and providing clinical validation for combination strategies in KRAS-mutant CRC.
According to a poster presentation at this year’s AACR annual meeting, GFH375 (switch II pocket/SIIP inhibitor) in combination with cetuximab demonstrated superior anti-tumor activity over monotherapy across animal models with multiple KRAS G12D-mutant solid tumors, and the most notable tumor inhibition was observed in CRC models. In addition, data from two fulzerasib (a KRAS G12C inhibitor) combination regimens – fulzerasib, also a SIIP inhibitor, plus cetuximabβ in second-line CRC (investigator-initiated trial data released at 2026 CSCO) and fulzerasib plus cetuximab in first-line NSCLC (GenFleet's KROCUS data published in Lancet Oncology in 2026) – both demonstrated efficacy and safety profiles markedly superior to monotherapy, providing insights for GenFleet’s subsequent clinical development of SIIP inhibitors in combination with anti-EGFR antibodies.
“GFH375 monotherapy has demonstrated encouraging efficacy in various tumor types, underpinning multiple BTDs granted to this asset and its advancement into late-stage clinical trials across indications. KRAS G12D-mutant CRC represents a substantial patient population, but KRAS G12D inhibitor monotherapy has shown limited success in CRC trials. Leveraging industry experience with KRAS inhibitor combination trials and from our own KROCUS study, we aim to address unmet needs through chemo-free combination and bring innovative options to patients awaiting breakthroughs in CRC targeted therapy.”stated Yu Wang, M.D., Ph.D., Chief Medical Officer of GenFleet.
References:
1. Global cancer statistics 2024: GLOBOCAN estimates of incidence and mortality worldwide for 34 cancers in 186 countries, GLOBOCAN
2. Fulzerasib plus cetuximab in first-line KRAS G12C mutated non-small-cell lung cancer (KROCUS): a single-arm, multicentre, phase Ib/2 trial, 2026 Lancet Oncology
3. Efficacy and safety of fulzerasib plus cetuximabβ with or without FOLFIRI in first- and second-line treatment of KRAS G12C-mutant mCRC (CRUCIAL study), 2026 CSCO
4. VS-7375: An oral, selective KRAS G12D dual ON/OFF inhibitor with potent anti-tumor activity as a single agent and in combination with other agents, 2026 AACR
5. Overall Survival Analysis of the Phase III CodeBreaK 300 Study of Sotorasib Plus Panitumumab Versus Investigator’s Choice in Chemorefractory KRAS G12C Colorectal Cancer, 2025 ASCO
6. Sotorasib for previously treated colorectal cancers with KRAS G12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial, 2022 Lancet Oncology
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 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. Outside of China, GenFleet’s partner Verastem Oncology is evaluating VS-7375 in TARGET-D 202, a registration-directed phase 2 study in NSCLC.
GenFleet received the Breakthrough Therapy Designations granted by China’s CDE in 2026 for GFH375 in pretreated KRAS G12D-mutant NSCLC and metastatic pancreatic cancer respectively; Verastem received the Fast Track Designations granted by U.S. FDA for VS-7375 treating KRAS G12D-mutant pancreatic ductal adenocarcinoma across all lines of therapy in 2025, and treating locally advanced unresectable or metastatic KRAS G12D-mutant NSCLC in 2026.
Forward-looking Statements
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