Preclinical evaluation of GFH276 monotherapy and combination therapy for RAS-mutant tumors
Presenter: Feng Yan, PhD Session: Novel Antitumor Agents 2 Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Feng Yan , Jichen Zhao , Jingyang Zhang , Siyuan Le , Fusheng Zhou , Jiong Lan , Qiang Lu Genfleet Therapeutics, Shanghai, China
Abstract
Background: RAS mutations are found in 90% PDAC, 50% CRC, 30% NSCLC, 27% cholangiocarcinomas, 20% uterine corpus endometrial carcinomas and some other types of tumors. KRAS G12C was the first RAS mutant clinically conquered, yet targeting other isoforms remains unresolved. GFH276, an investigational molecular-glue panRAS(ON) inhibitor currently being evaluated in a Phase 1 trial (NCT07198321), has previously shown potent activity across RAS-mutant models and demonstrated MOA-derived superiority to SIIP-based KRAS inhibitors and dose-level advantage over the competitor compound. Here we present a further pre-clinical assessment of GFH276 monotherapy and its rational combination with distinct therapeutic agents. Methods: BULB/c nude mice bearing CDX tumors harboring different KRAS mutations were used to determine the anti-tumor efficacy of GFH276 monotherapy or its combination with Cetuximab. BULB/c mice bearing CT-26 tumors engineered to harbor KRAS G12C mutation were used to compare GFH276 monotherapy with its combination with an anti-mouse PD-1 mAb. Results: Across a serial of NSCLC, CRC and PDAC CDX models, daily oral administration of 3 mg/kg of GFH276 drove significant anti-tumor efficacy. In a cholangiocarcinoma and an endometrial tumor models, GFH276 also inhibited tumor growth in a dose-dependent manner. Considering the validated synergism between KRAS G12C inhibitors and EGFR mAbs in clinic, combination therapy of GFH276 plus Cetuximab was also investigated and the result showed that co-administration with Cetuximab enhanced the efficacy of GFH276 significantly. Coordination between GFH276 and immunotherapy was also explored in the syngeneic CT26-KRAS G12C mouse model. In this model, 21-day treatment with 0.3-3 mg/kg of GFH276 elicited significant anti-tumor effect and all animals from the 3 mg/kg group were tumor free. Co-treatment with an anti-mouse PD-1 antibody not only synergized with GFH276 dosing , but also helped maintain the tumor free status after GFH276 dosing was stopped for another 79 days. Conclusions: GFH276 monotherapy was effective in mouse models harboring tumors originating from most common RAS-mutant cancers. GFH276 also showed synergistic effects with anti-EGFR mAb and immunotherapy. These results depict the promising therapeutic potential of GFH276 in broad indications via different application strategies.
Disclosure
F. Yan, Genfleet Therapeutics Employment. J. Zhao, Genfleet Therapeutics Employment. J. Zhang, Genfleet Therapeutics Employment. S. Le, Genfleet Therapeutics Employment. F. Zhou, Genfleet Therapeutics Employment. J. Lan, Genfleet Therapeutics Employment. Q. Lu, Genfleet Therapeutics Employment.
Cited in
Control: 3321 · Presentation Id: 8823 · Meeting 21436