Abstract 5779: RCZY-869: A highly potent, selective, and orally bioavailable covalent KRASG12D (ON-state) inhibitor with robust antitumor activity in preclinical models of KRASG12D-driven solid tumors

Abstract KRASG12D is the most prevalent oncogenic mutation in the RAS family. Among common solid tumors, it drives approximately 40% of pancreatic ductal adenocarcinoma (PDAC), 15% of colorectal cancer (CRC), and 5% of non-small cell lung cancer (NSCLC) cases, underscoring a significant unmet clinical need for targeted therapies. To date, no direct KRASG12D inhibitors have received global regulatory approval, highlighting the pressing demand for effective agents. In KRASG12D, the G12D substitution reduces RAS-bound GTP hydrolysis rate by ∼2-fold compared to wild-type KRAS (and even more relative to KRASG12C), resulting in a higher proportion of KRASG12D existing in the GTP-bound conformation within cancer cells. This makes the “ON” state the dominant, therapeutically relevant form driving oncogenesis. Inhibiting this active, GTP-bound pool directly disrupts the core signaling activity, potentially yielding greater efficacy than targeting the transient “OFF” state. This mechanism supports targeting the GTP-bound conformation as a strategy with high clinical benefit potential. Emerging KRASG12D inhibitors target OFF, ON, or both states. Phase 1/1b data show ON-state inhibitor RMC-9805 and ON/OFF inhibitor VS-7375 (GFH375) have comparable objective response rates (ORR) and disease control rates (DCR) in NSCLC at their respective recommended Phase 2 doses (RP2D). In PDAC, VS-7375 had marginally higher ORR/DCR (52%/100% vs. 30%/80% for RMC-9805), but RMC-9805 had superior safety: low dose modification rates, no grade 4/5 TRAEs (predominantly grade 1 toxicities), and no DLTs. VS-7375 had a ∼4-fold higher discontinuation rate, with 27.5% of patients experiencing grade 3/4 TRAEs. To address these challenges, Rongchang Pharmaceuticals has developed RCZY-869, a highly potent, selective, and orally bioavailable covalent tri-complex inhibitor that specifically targets the GTP-bound (ON) state of KRASG12D. It engages cyclophilin A (CypA) to form a stable ternary complex with KRASG12D(ON), blocking downstream effectors and suppressing MAPK signaling. RCZY-869 exhibits significantly greater in vitro antiproliferative activity than RMC-9805 across KRASG12D-mutant cell lines, favorable ADME properties, and superior oral PK in preclinical species. In KRASG12D xenograft models, it delivers dose-dependent antitumor effects at well-tolerated doses, achieving tumor growth inhibition (TGI) comparable to RMC-9805 but at substantially lower exposures. These findings position RCZY-869 as a novel ON-state-selective KRASG12D inhibitor with compelling preclinical potency and efficacy. Ongoing characterization advances its candidate package to support clinical development. Citation Format: Xiaojing (Celia) Chen, Lin Wang, Xiaohong Liu, Dan Wang, Jianming Bao, . RCZY-869: A highly potent, selective, and orally bioavailable covalent KRASG12D (ON-state) inhibitor with robust antitumor activity in preclinical models of KRASG12D-driven solid 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 5779.