Abstract 4712: ELVN-002; a potent, selective HER2 inhibitor with a differentiated binding mode conferring the potential for enhanced efficacy in combination with HER2-targeting antibody-drug conjugates

Abstract Overexpression, amplification or mutation of human epidermal growth factor receptor 2 (HER2) is observed in up to 30% of solid tumors resulting in increased downstream signaling and oncogenic transformation. While trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate (ADC) recently approved for HER2 altered cancer types, has resulted in improved outcomes there remains a substantial unmet need for patients who either progress on T-DXd or discontinue treatment due to adverse events. The advent of small molecule HER2 inhibitors represents an opportunity to provide meaningful therapeutic benefit to these patients either as a single agent or in combination. However, given the structural similarities between EGFR and HER2, most small molecule HER2 kinase inhibitors are dual EGFR/HER2 inhibitors. These inhibitors often face significant dose-limiting toxicities related to EGFR, which hinder their clinical utility. ELVN-002 is a potent irreversible HER2 inhibitor with > 100-fold selectivity over EGFR currently undergoing clinical evaluation in patients with HER2 alterations both alone and in combination with approved standard of care therapies. We evaluated the effect of ELVN-002 and other clinically-relevant HER2 small molecule inhibitors on HER2 cell surface expression and internalization in HER2 positive cell lines derived from patients with either gastric cancer or breast cancer. We determined that ELVN-002 reduces HER2 expression on the cell surface but had no effect in total HER2 expression. Further, HER2 degradation was quantified by measuring ubiquitinated HER2. We discovered that upon ELVN-002 treatment, HER2 ubiquitination and internalization was significantly increased compared to control cells. In contrast, treatment with other clinically-relevant HER2 inhibitors did not increase HER2 internalization. Reduced cell surface HER2, in conjunction with enhanced HER2 degradation suggest that ELVN-002 induces greater HER2 receptor flux at the cell surface. ADCs bind their target and are subsequently degraded in the lysosome, resulting in the intracellular release of their toxic payload. However, some intact ADCs escape degradation via endocytic recycling. The increase in ubiquitinylated HER2 upon treatment with ELVN-002 suggests ELVN-002 enhances the amount of HER2 targeted to the lysosome and would therefore increase the amount of payload released relative to untreated cells. In contrast, treatment with other HER2 inhibitors results in increased cell surface HER2 retention and decreased internalization suggesting a decrease in cytotoxic payload deposition if combined with an ADC. The differentiated profile and mechanism of ELVN-002 has the potential to be a superior treatment in HER2 expressing cancers in combination with ADCs, other modalities, and as a single agent. Citation Format: Amanda J. Broad, Monette Aujay, Stefan D. Gross, Li Ren, Samuel Kintz, Joseph P. Lyssikatos. ELVN-002; a potent, selective HER2 inhibitor with a differentiated binding mode conferring the potential for enhanced efficacy in combination with HER2-targeting antibody-drug conjugates [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 4712.