Abstract 4565: Preclinical evaluation of GFH276 monotherapy and combination therapy for RAS-mutant tumors

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-KRASG12C 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. Citation Format: Feng Yan, Jichen Zhao, Jingyang Zhang, Siyuan Le, Fusheng Zhou, Jiong Lan, Qiang Lu. Preclinical evaluation of GFH276 monotherapy and combination therapy for RAS-mutant tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4565.