Abstract PO3-26-02: Identification of a novel, brain penetrant, EGFR sparing, ErbB2 inhibitor with activity against oncogenic ErbB2 mutations

Abstract Alterations in ErbB2 have an established role as oncogenic drivers in many solid tumors, including gastric and breast cancer. While ErbB2 amplification is well recognized, activating ErbB2 mutations including exon 20 YVMA insertions, S310F/Y, L755S, V777L, and V842I, have emerged as mutually exclusive oncogenic drivers. ErbB2 mutations are present in ~3-4% of breast cancers and are now recognized as known mechanisms of acquired resistance to ErbB2 targeted therapies. These alterations can also be found in metastastic breast cancer that has advanced to the brain, a major clinical challenge with few therapeutic options. Unfortunately, many approved ErbB2 inhibitors are limited in their utility due to the inhibition of wild type EGFR resulting in severe rash and diarrhea. Herein, we describe preclinical data on a brain penetrant, wild type EGFR sparing, ErbB2 inhibitor with activity against prevalent mutations including exon 20 YVMA insertions. Citation Format: Mark J. Chicarelli, Ben Arwood-Levine, Tanna Bettendorf, Karyn Bouhana, Richard Brizendine, LouAnn Cable, Michelle Crow, Brad Fell, John Fischer, Jennifer Fulton, Anna Guarnieri, Madison Hillman, Ravi Jalluri, Daniel Krischlunas, Keith Koch, Vijay Kumar, Cori Malinky, Rob Rieger, John Robinson, Lee Stunkard, Francis Sullivan, Roy Turton, Logan Vine, Shannon Winski, Yeyun Zhou. Identification of a novel, brain penetrant, EGFR sparing, ErbB2 inhibitor with activity against oncogenic ErbB2 mutations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-26-02.