Abstract LB197: Tucatinib has selective activity in HER2-positive cancers and significant combined activity with approved and novel breast cancer targeted therapies

Abstract Pharmacologically targeting the HER2 oncoprotein with therapeutics such as the monoclonal antibody (mAb), trastuzumab, provides clinical benefit for patients with HER2-positive (HER2+) cancers. However, a significant number of patients eventually progress on these therapies. Efforts to overcome therapeutic resistance through combination therapy with small molecule inhibitors of HER2 have been limited by toxicities associated with off-target activity and/or limited efficacy. In this preclinical study, we explore single-agent and combined activity of tucatinib, a novel HER2-selective small molecule inhibitor. Tucatinib demonstrated potent, selective activity in a panel of 456 human cancer cell lines, with activity restricted to cell lines (breast and non-breast) with HER2-amplification, including models of acquired resistance to trastuzumab. Within the HER2+ population, tucatinib response tracked strongly with HER2-driven signaling. Single agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab induced a complete and sustained blockade of HER2/PI3K/AKT-signaling. Efficacy of the tucatinib/trastuzumab combination matched that induced by current standard of care (SOC) trastuzumab/pertuzumab/docetaxel combination, with the exception that the chemotherapy-sparing tucatinib/trastuzumab combination did not require a dosing holiday to achieve the same efficacy. In xenograft models of HER2+ breast cancer that also express estrogen receptor (ER) (HER2+/ER+), tucatinib showed combined efficacy with inhibitors of CDK4/6 and ER, indicating potential novel therapeutic strategies for difficult-to-treat subtypes of HER2+ breast cancer. These data support expanded clinical investigations of tucatinib as a combination partner for other novel and approved targeted therapies for HER2-driven malignancies. Citation Format: Neil A. O'Brien, Holly K. Huang, Martina S. McDermott, Athena Madrid, Tong Luo, Raul Ayala, Shawnt Issakhanian, Ke Wei Gong, Ming Lu, Jun Zhang, Dennis J. Slamon. Tucatinib has selective activity in HER2-positive cancers and significant combined activity with approved and novel breast cancer targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB197.