Abstract 1440: Identification of a novel EGFR sparing brain penetrant ErbB2 inhibitor with activity against oncogenic ErbB2 mutations

Abstract

Abstract Oncogenic driver mutations in ErbB2 (e.g., S310F/Y, L755S, V777L, V842I) are present in a variety of tumor types including gastric, uterine, urothelial carcinoma, non-small cell lung, breast, and colorectal, some of which are also known to metastasize to the CNS. These mutations can also emerge as mechanisms of acquired resistance to targeted therapies and as such represent a novel and actionable target mutation set across solid tumor indications. Current therapies that target ErbB2 have poor potency against these mutations or are limited in their utility due to inhibition of wild type epidermal growth factor receptors (WT EGFR). The inhibition of WT EGFR is associated with debilitating clinical effects that include diarrhea, stomatitis, and hepatotoxicity. Additionally, treatment of CNS metastases is especially challenging since the potential therapy must also cross the blood brain barrier to have a therapeutic effect. Next generation ErbB2 inhibitors that are active against ErbB2 mutations, spare WT EGFR, and that can penetrate the brain would provide improved target coverage with the potential for fewer off target side effects compared to current therapies and as well as the potential to exhibit superior clinical efficacy. Herein, we describe the pre-clinical in vitro and in vivo activity of a novel, brain penetrant ErbB2 inhibitor which retains potency against prevalent mutations while sparing WT EGFR. Citation Format: Mark J Chicarelli, Karyn Bouhana, Richard K. Brizendine, LouAnn Cable, Michelle Crow, Brad Fell, John Fischer, Jennifer Fulton, Anna Guarnieri, Ravi Jalluri, Hailey Knox, Keith A. Koch, Rob Rieger, John Robinson, Lee M. Stunkard, Francis Sullivan, Roy Turton, Shannon Winski, Yeyun Zhou. Identification of a novel EGFR sparing brain penetrant ErbB2 inhibitor with activity against oncogenic ErbB2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1440.