Abstract 4375: LY4066434, an oral small molecule pan-KRAS inhibitor, demonstrates robust anti-tumor activity in KRAS-mutant models, including in the CNS

Abstract KRAS is altered in ∼16% of all cancers and is an oncogenic driver in NSCLC, pancreatic, colorectal, and other cancers. Next generation KRAS inhibitors, designed to target multiple oncogenic KRAS mutations, have the potential to improve outcomes for the large burden of KRAS-mutated disease. Importantly, preclinical data suggest that a pan-KRAS approach that spares wildtype HRAS and NRAS may avoid the skin toxicities associated with pan-RAS inhibition.1 This is particularly important in the context of treating KRAS-mutated colorectal cancer in combination with EGFR inhibition, which also carries skin toxicity. Next generation KRAS inhibitors could treat a wide range of patients including the approximately 35% of those with NSCLC who are at increased risk of developing CNS metastases. LY4066434 is an orally bioavailable, highly potent pan-KRAS inhibitor that has high selectivity over HRAS and NRAS.2 Here, we report the antitumor activity of LY4066434 in patient-derived xenograft (PDX) and intracranial cancer models. We evaluated the activity of LY4066434 in PDX models harboring different KRAS mutations (both common and less frequent) and representing diverse histologies. LY4066434 showed robust anti-tumor activity, ranging from significant tumor growth inhibition to strong regression, in KRAS-driven PDX models of NSCLC, pancreatic, colorectal, and gastric cancers. Furthermore, we analyzed the activity of LY4066434 in combination with standard-of-care therapies. LY4066434 when combined with cetuximab showed enhanced antitumor activity in PDX models of NSCLC, pancreatic, and colorectal cancers with various KRAS mutations. Additionally, the combination of LY4066434 with chemotherapies also demonstrated greater efficacy in KRAS-mutant PDX models of endometrial and ovarian cancers. Finally, evaluation of LY4066434 activity in two KRAS-mutant orthotopic brain tumor models of NSCLC showed that LY4066434 inhibited tumor growth and promoted survival in these brain tumor models. Taken together, these results demonstrate the potential of LY4066434 as a promising therapeutic option for a range of cancer types driven by KRAS mutations including NSCLC, pancreatic, and colorectal cancers. LY4066434 is currently being investigated clinically (NCT06607185). 1. Manousaridis I. et al. 2013. J Eur Acad Dermatol and Venereol, 27: 11-18. 2. 2. Prieto L. et al. AACR-NCI-EORTC. Oct 11-15, 2023. Boston, MA. Citation Format: Hong Gao, Youyan Zhang, Chun Ping Yu, Wei Guo Xu, Binghui Li, Huimin Bian, Manuj Tandon, Tao Wang, Trent R. Stewart, Mark H. Bender, Wenyu Ming, Megan A. Johnson, Lisa M. Kays, Madeleine Leonard, Mark A. Castanares, Andrew Capen, Arthur Xintian You, Wen Ting Bian, Lourdes Prieto, Timothy Kercher, Laurie LeBrun, Anke Klippel, Chandrasekar Iyer, Xueqian Gong. LY4066434, an oral small molecule pan-KRAS inhibitor, demonstrates robust anti-tumor activity in KRAS-mutant models, including in the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4375.