Abstract B068: A Novel, wild-type sparing pan-EGFR Inhibitor (ZE77-0273) with Broad Activity Against Resistance Mutations in EGFR-Mutant NSCLC

Abstract Background Lung cancer is the most common cause of cancer death globally, with non-small cell lung cancer representing 87% of the cases. Activating mutations in the kinase domain of EGFR (epidermal growth factor receptor) are a key driver in a subset of NSCLC, accounting for up to 50% of newly diagnosed lung adenocarcinoma in Asian patients and 15-20% in Western countries. The most common EGFR mutations are deletions in exon 19 and the L858R point mutation in exon 21. While multiple generations of EGFR inhibitors have effectively targeted these alterations there remains a critical challenge to target additional mutations like C797S and atypical variants such as exon 20 insertions. There is a clear need for a reversible, broad-spectrum EGFR inhibitor to address this gap. We describe herein, ZE77-0273, a novel, reversible, panEGFR inhibitor that wild-type–sparing of EGFR, with potent in vitro and in vivo activity. Methods ZE77-0273 was developed using a rational structure-guided, approach that incorporated AI-enabled modeling, virtual screening, and medicinal chemistry optimization from Expert Systems. The compound’s potency was evaluated against mutant EGFR kinases in biochemical assays, and its cytotoxicity assessed in engineered and patient-derived cell lines. Pharmacokinetic (PK) properties were characterized in rodents and dogs. Antitumor efficacy was tested in an EGFR-driven patient-derived xenograft (PDX) model in mice. Results ZE77-0273 exhibited sub-nanomolar inhibition of EGFR mutants in vitro, including atypical or PACC mutations, such as L792H/C797S/L858R (0.4 nM), L718Q (0.8 nM), G719C (0.4 nM), S768I (0.04 nM). Cell-based assays showed potent cytotoxicity in Ba/F3 and Rat1 cells expressing various EGFR mutations, including C797S triple mutants (EGFR L861Q 3.3 nM, EGFR (G719S) 43 nM, EGFR (T790M/L858R/C797S) 17 nM), compared to 100 nM for wild type EGFR. ZE77-0273 demonstrated strong oral bioavailability with preferential to lung and brain penetration. In patient-derived NSCLC cells harboring EGFR exon 20 insertions, CC50 values were 44 nM and 60 nM. In vivo, ZE77-0273 induced tumor regression in a PDX model, with durable tumor control across multiple dosing regimens. Conclusions ZE77-0273 is a promising, AI-designed, reversible pan-EGFR inhibitor with broad activity across classical, atypical, and resistance EGFR mutations. Its favorable PK profile, preclinical efficacy, and broad mutational coverage support its advancement toward clinical development in EGFR-mutant NSCLC. Citation Format: Alexander Khvat, Ruben Karapetian, Alexey Rjahovskiy, Elena Bulanova, Vladislav Parchinsky, Nikolay Savchuk, Amy Burd, Iain Dukes. A Novel, wild-type sparing pan-EGFR Inhibitor (ZE77-0273) with Broad Activity Against Resistance Mutations in EGFR-Mutant NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B068.