Abstract 5869: Preclinical characterization of CGT4255, an EGFR sparing, pan-mutant HER2 clinical development candidate with potential best-in-class brain penetration

Abstract HER2 alterations including amplification, overexpression, insertions, and point mutations are established oncogenic drivers across various solid tumor types. HER2 is amplified or overexpressed in 15-20% of breast cancer patients. In contrast, activating mutations are found in approximately 4% of cases with the L755S mutation commonly associated with drug resistance. Up to 50% of patients with HER2+ metastatic breast cancer may develop brain metastasis over the course of the disease, highlighting a critical need for brain penetrant HER2-directed therapies. In lung cancer, activating HER2 mutations occur in 2-4% of advanced cases and are linked to increased incidence of brain metastasis. The risk is especially high in patients whose tumors harbor an exon 20 YVMA insertion. Treating brain metastasis in this group of patients remains a clinical challenge, as most therapeutic options have limited CNS penetration. Herein, we describe the advanced preclinical profiling of CGT4255, an investigational drug targeting mutant and wild type HER2, which spares EGFR and demonstrates potential best-in-class brain penetrance. CGT4255 shows potent activity against commonly occurring point mutations such as L755S and exon 20 YVMA insertions. In vitro assays confirmed that CGT4255 is not a substrate of the P-gp or BCRP efflux transporters at the blood-brain barrier. In vivo pharmacokinetic studies with CGT4255 in mice and monkeys showed high drug levels in the CNS, predicting high human brain exposure. CGT4255 demonstrated robust efficacy in HER2 overexpressed and HER2 YVMA intracranial models. The CGT4255 and T-DXd combination demonstrated enhancement of ADC internalization, thus highlighting a biological rationale for combination therapy. In HER2-overexpressed, L755S, YVMA, and T-DXd resistant subcutaneous xenografts, CGT4255 demonstrated dose dependent TGI with tumor regressions observed at dose levels as low as 30 mg/kg. Citation Format: Paul Larsen, Tanna Bettendorf, Abiezer Blandon, Karyn Bouhana, Richard K. Brizendine, Eric Brown, LouAnn Cable, Mark J. Chicarelli, Michelle Crow, Brad Fell, John Fischer, Jennifer Fulton, Anna Guarnieri, Jackie Harrison, Leyla Haygood, Ravi Jalluri, Vijay Kumar, Cori A. Malinky, Maralee McVean, Rob Rieger, John Robinson, Lee Stunkard, Francis Sullivan, John I. Trujillo, Logan E. Vine, Shannon Winski, Yeyun Zhou, . Preclinical characterization 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 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5869.