Abstract PS4-06-02: Combinatory treatments of VRN101099 with antibody therapies for HER2-driven breast cancer

Abstract Many systemic therapeutic options for advanced metastatic HER2-positive breast cancer have been approved, including antibody-based therapies, chemotherapies, and tyrosine kinase inhibitors (TKIs). However, brain metastasis and acquired resistance are still major unmet medical needs for HER2-driven metastatic breast cancer and advanced solid cancers. VRN101099 is an orally bioavailable, highly selective HER2 kinase inhibitor, demonstrating excellent specificity over other kinases, including EGFR. This compound potently inhibits HER2 by covalently binding to Cys805 within the ATP-binding pocket, leading to robust catalytic inhibition of HER2 kinase. In vitro studies show that VRN101099 exhibits potent anti-proliferative effects against HER2-driven breast cancer cell lines, such as BT-474 and SK-BR-3. Furthermore, VRN101099's irreversible binding properties enable effective inhibition of various HER2 activating mutants, including L755S, V777L, D769H/Y and L869R. Notably, VRN101099 demonstrates brain penetrability. Given its distinct mechanism of action—kinase catalytic inhibition—which differs from that of antibody-based HER2 therapies (e.g., Trastuzumab, Pertuzumab, T-DM1, T-DXd, Zanidatamab), VRN101099 holds promise for synergistic therapeutic effects when combined with these agents, particularly in the treatment of metastatic HER2-positive breast cancer. Moreover, VRN101099 induces internalization of the HER2 receptor, promoting internalization of the antibody-drug conjugate. In BT474 or SKBR3, HER2 amplified breast cancer cells, xenograft models with subcutaneous or intracranial implantation, VRN101099 showed combinatory and synergistic anti-tumor effects with Trastuzumab, Pertuzumab, T-DM1, T-DXd, and Zanidatamab. The first-in-human dose escalation study of VRN101099 monotherapy will determine the maximal tolerable dose, and an optimal dose finding study for the combination will be followed. Citation Format: H. Jung, S. Kim, S. Kim, Y. Lee, J. Yoo, J. Kwon, S. Han, D. Park, D. Shin, H. Kim, J. Kim, Y. Ko, S. Kim. Combinatory treatments of VRN101099 with antibody therapies for HER2-driven breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-06-02.