Abstract LB430: QTX3544, a potent and selective G12V-preferring KRAS inhibitor, synergizes with EGFR inhibitors for enhanced anti-tumor activity

Abstract The KRAS G12V variant mutation is the second most prevalent oncogenic alteration in KRAS-driven cancers that leads to aberrant activation of the mitogen-activated protein kinase (MAPK) pathway and promotes tumorigenesis and metastasis. Although recent advancements in KRAS-targeted therapies have led to the approval of KRASG12C inhibitors and the clinical investigation of KRASG12D-selective and multi-KRAS inhibitors, there are no current strategies specifically targeting KRAS G12V-driven cancers. QTX3544 is a potent, selective, non-covalent, and orally bioavailable KRASG12V-preferring multi-KRAS inhibitor. QTX3544 inhibited both the “ON-state” (active) and “OFF-state” (inactive) KRAS activity in both biochemical and cellular assays with the most potent activity against KRASG12V and high selectivity over NRAS and HRAS. We examined the potential synergy between QTX3544 and EGFR inhibitors (afatinib and cetuximab) in KRAS G12V-driven cancer cell lines and tumor models. Cell viability assays showed that QTX3544 synergized with EGFR inhibitors and potently inhibited KRAS G12V-mutant cell proliferation. Combined treatment of QTX3544 with afatinib led to a deeper suppression of MAPK signaling and enhanced inhibition of colony formation in KRAS G12V-driven cancer cells compared to single-agent treatment. Co-administration of QTX3544 and cetuximab significantly enhanced anti-tumor efficacy and elicited greater tumor regressions in the Capan-2 pancreatic and SW-403 colorectal KRAS G12V-mutant cell line-derived xenograft models (CDX), as well as in a patient-derived colorectal tumor xenograft model (PDX), compared to monotherapy. Taken together, these preclinical data support the clinical strategy to combine QTX3544 and cetuximab to enhance the depth and breadth of therapeutic activity against KRAS G12V-driven cancers. Citation Format: Yang J. Zhang, Jillian M. Silva, Yang W. Zhang, Elizabeth D. Vo, John M. Micozzi, Arghyotri Sinha, Ben Reid, Brook McDonough, Boyang Zhao, Gregory M. Lee, Christopher C. Pan, Rajsi Thaker, Jennifer Barry, Cameron Pitt, Hong Lin. QTX3544, a potent and selective G12V-preferring KRAS inhibitor, synergizes with EGFR inhibitors for enhanced anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB430.