Abstract 5623: Identification of CGT4255 an EGFR sparing, pan-mutant HER2 clinical development candidate with potential best-in-class brain penetration

Abstract HER2 alterations such as amplification, overexpression, insertions, and point mutations, are established oncogenic drivers in many solid tumors. Activating HER2 mutations are found in 2-4% of advanced lung cancers and have emerged as mechanisms of acquired resistance to targeted therapies. Patients with HER2 mutant lung tumors develop more brain metastasis during treatment than patients with any other oncogenic drivers in lung cancer. Addressing brain metastasis in this group of patients remains a clinical challenge with limited therapeutic options. Approved HER2 tyrosine kinase inhibitors have inferior potency against key mutations and lack sufficient brain penetration to be an impactful treatment option for patients with brain metastasis. Herein, we describe advanced preclinical profiling of an EGFR-sparing, HER2 inhibitor clinical development candidate CGT4255 with potential best-in-class brain penetrance and potent activity across prevalent point mutations and exon 20 YVMA insertions. CGT4255 demonstrates robust efficacy in intracranial tumor growth inhibition studies and shows an additive effect on intracranial tumor shrinkage when combined with a HER2 ADC. Pre-clinical studies with the CGT4255 and T-DXd combination demonstrate enhancement of ADC internalization, thus highlighting a biological rationale for combination therapy. Citation Format: Mark J. Chicarelli, Tanna Bettendorf, Abiezer Blandon, Karyn Bouhana, Richard K. Brizendine, LouAnn Cable, Michelle Crow, Brad Fell, John Fischer, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Maddie Hillman, Ravi Jalluri, Vijay Kumar, Cori A. Malinky, Rob Rieger, John Robinson, Lee Stunkard, Francis Sullivan, John I. Trujillo, Logan E. Vine, Shannon Winski, Yeyun Zhou. Identification of CGT4255 an EGFR sparing, pan-mutant HER2 clinical development candidate with potential best-in-class brain penetration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5623.