Abstract 1329: Preclinical development of EFTX-G12V, a first-in-class EGFR-directed KRAS G12V selective inhibitor.

Abstract The KRAS proto-oncogene encodes a small GTPase that is crucial for the activation of intracellular signaling pathways that control cell proliferation, survival and differentiation. KRAS is frequently mutated in cancer resulting in its constitutive activation and dysregulation of downstream signaling pathways that drive oncogenic transformation. KRAS G12V is the second most common KRAS mutation in cancer, and occurs frequently in lung, colon and pancreatic cancers. However, while significant advancements have been made in developing KRAS G12C, G12D and pan-KRAS inhibitors, there remain no direct KRAS G12V inhibitors in the clinic. Previously, we developed EFTX-G12V, a fully-modified, mutant-selective, ligand-conjugated siRNA that shows significant anti-tumor activity in multiple cancer models. EFTX-G12V inhibits KRAS G12V expression at both the mRNA and protein level while completely sparing KRAS WT. Further, EFTX-G12V significantly inhibited cancer cell growth in vitro and displays no concerning off-target effects. Importantly, our approach takes advantage of high tumor expression of EFGR where our siRNA is conjugated to an EGFR linear ligand that enables high tumor-to-normal tissue payload delivery in models with varying levels of EGFR expression. EFTX-G12V significantly inhibited KRAS G12V mRNA and protein in vivo and showed significant anti-tumor activity in lung, colon and pancreatic xenograft models. Critically, EFTX-G12V showed no off-target effects on WT KRAS in somatic tissues. Unexpectedly, we found that EFTX-G12V showed improved efficacy in comparison to a pan-KRAS siRNA which we found is due to increased inhibition of tumor angiogenesis in EFTX-G12V treated groups. Here, we describe further preclinical evaluation of EFTX-G12V including pharmacokinetics in mouse xenograft models and the efficacy and safety profile in an immunocompetent mouse model. We performed a pharmacokinetic evaluation of the antisense strand of EFTX-G12V in plasma, tumors, skin, kidney and liver tissue following a single injection. We observed clearance of the siRNA from the plasma within four hours and uptake of a therapeutic dose level in tumor tissue through 96 hours post injection, with limited exposure to somatic tissues. We evaluated EFTX-G12V in an immunocompetent mouse model and observed significant tumor reduction and a robust anti-tumor immune response that was not a result of a systemic inflammatory response and displayed no concerning toxicities. Lastly, we recently completed non-GLP safety studies in rat and mini-pig models and observed no test article related clinical observations, no injection site reactions and initial gross pathology detected no visible lesions across all tissues. Together these data indicate that EFTX-G12V has therapeutic efficacy in multiple cancer models, is delivered to tumor tissue with minimal somatic tissue exposure, and may be well tolerated. Citation Format: Lyla J. Stanland, Hayden Huggins, Snehasudha S. Sahoo, Alessandro Porrello, Yogitha Chareddy, Salma Azam, Jillian Perry, Pradeep S. Pallan, Kristina Whately, Lincy Edatt, William D. Green, Matthew C. Fleming, Jonah Im, Christina Gutierrez-Ford, Imani Simmons, Alyaa Dawoud, Katherine I. Zhou, Vandanaa Jayaprakash, Rani Sellers, Gabriela de la Cruz, Albert Wielgus, Justin Milner, Martin Egli, Albert A. Bowers, Chad V. Pecot. Preclinical development of EFTX-G12V, a first-in-class EGFR-directed KRAS G12V selective inhibitor [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 1329.