Abstract LB_C09: QTX3034, a potent and selective multi-KRAS inhibitor, synergizes with EGFR inhibitors and enhances anti-tumor activity

Abstract KRAS, one of the most frequently mutated oncogenes in cancer, was considered undruggable until the development of covalent KRASG12C inhibitors. While these KRASG12C-targeted therapies exhibit clinical benefit, they do not address the most common KRAS mutant variants. QTX3034 is a potent, highly selective, orally bioavailable allosteric multi-KRAS inhibitor that is efficacious against a broad spectrum of the more common KRASG12D- and KRASG12V-mutated cancers in vitro and in vivo. In an effort to enhance anti-tumor activity of QTX3034 and to minimize the development of possible resistance mechanisms, we explored the potential synergy of combining QTX3034 with EGFR inhibitors in multiple KRAS-mutated tumor models. Cell viability assays over a 7-day period revealed that QTX3034 synergized with three different EGFR inhibitors (afatinib, cetuximab, erlotinib) to profoundly inhibit proliferation across multiple KRASG12D, KRASG12V, and KRASWT Amp mutant cell lines with strong ZIP synergy scores (>10). Combination of QTX3034 and afatinib exhibited a markedly greater inhibitory effect on KRAS-mutant colony formation compared to the respective single agents. Analysis of RAS downstream signaling revealed that the combination of QTX3034 and afatinib produced a more potent suppression of the MAPK pathway than either single agent alone in KRAS-mutant cells. Moreover, QTX3034 monotherapy induced a dose-dependent increase in EGFR phosphorylation in the KRASG12D-mutated cell line GP2D, while co-administration with afatinib robustly inhibited this EGFR activation. Combining QTX3034 and cetuximab elicited durable tumor regressions in KRASG12D-mutant cell line-derived xenograft models. Furthermore, tumor regressions in these combination studies were obtained using meaningfully lower doses of QTX3034 than needed to achieve tumor regression by monotherapy. Similar combinations improved QTX3034 anti-tumor activity in patient-derived xenograft models that exceeded monotherapy with either agent. Taken together, these data support the rationale to co-administer QTX3034 and EGFR inhibitors to optimize therapeutic benefit for patients with KRAS-mutated cancers. Citation Format: Yang J. Zhang, Jillian M. Silva, Yang W. Zhang, Elizabeth Donohue Vo, John M. Micozzi, Douglas Krauth, Arghyotri Sinha, Ben Reid, Brooke McDonough, Gregory M. Lee, Christopher C. Pan, Audrey Hospital, Juan I. Luengo, Cameron Pitt, Hong Lin. QTX3034, a potent and selective multi-KRAS inhibitor, synergizes with EGFR inhibitors and enhances anti-tumor activity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C09.