Abstract P1-18-09: Tucatinib, a HER2-selective tyrosine kinase inhibitor, increases the anti-tumor activity of trastuzumab antibody-drug conjugates in preclinical models of HER2+ breast cancer
Authors: Anita Kulukian, Janelle Taylor, Devra Olson, Margo Zaval, Robert Thurman, Shawna Hengel, Lauren Farr, Tim S Lewis, Scott R Peterson
Journal: Cancer Research (2020)

Abstract Background: Tucatinib is an orally administered, reversible HER2-targeted small molecule tyrosine kinase inhibitor that potently and selectively inhibits HER2 relative to the closely related kinase EGFR. In a phase Ib clinical trial in HER2+ metastatic breast cancer, tucatinib in combination with the HER2-targeted antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) was well tolerated and demonstrated activity in pretreated patients with HER2-positive metastatic breast cancer (Borges VF et al., 2018). Here, we present preclinical data demonstrating tucatinib potentiates the activity of T-DM1 in HER2+ breast cancer models in vitro, and in vivo. In addition, tucatinib also enhanced the activity of a camptothecin-based HER2 ADC comprising trastuzumab conjugated with 8 exatecan moieties (T-Ex). Methods: In vitro assays were conducted to evaluate the potency of tucatinib, T-DM1 and T-Ex as single agents, and in combination, using a panel of breast cancer cell lines expressing various levels of HER2. The combinatorial effects of tucatinib with T-DM1 or T-Ex was assessed by isobologram analysis to determine additivity, synergy or antagonistic properties of the drug combinations. The activity of tucatinib either alone (50 mg/kg BID) or in combination with T-DM1 (10 mg/kg single dose IV) was evaluated in vivo using the HER2+ breast cancer cell line BT-474, and in 3 patient-derived xenograft (PDX) models of HER2+ breast cancer. Results: Tucatinib demonstrated potent anti-tumor activity in HER2 overexpressing cell lines in vitro with a similar selectivity profile as T-DM1 or T-Ex. When co-administered in vitro and subjected to isobologram analysis, tucatinib and T-DM1 or T-Ex combinations produced additive or synergistic effects. Moreover, tucatinib potently inhibited a subset of cell lines that showed reduced sensitivity to either T-DM1 or T-Ex. In BT-474 cells, the co-administration of tucatinib with T-DM1 in vitro was synergistic and resulted in an increased intracellular concentration of the TDM-1 catabolite Lys-MCC-DM1. The combination of tucatinib with T-DM1 was also more effective than either single agent alone in BT-474 xenografts in vivo and increased the number of complete tumor regressions. In 2 of 3 PDX models tested, the combination of tucatinib with T-DM1 was significantly more active than T-DM1 or tucatinib alone and produced a higher proportion of partial or complete tumor regressions compared with the single agent treatments. Conclusions: These data demonstrate tucatinib results in selective and potent anti-tumor activity in HER2+ tumor derived cell lines, including cell lines that show reduced sensitivity to T-DM1 or T-Ex in vitro. The results also demonstrate that tucatinib is either additive or synergistic when combined with T-DM1 or T-Ex in vitro. In addition, tucatinib in combination with T-DM1 showed enhanced anti-tumor activity in vivo in models of HER2+ breast cancer when compared to T-DM1 as a single agent. These results, taken together with the early clinical data demonstrating preliminary safety and activity of tucatinib with T-DM1, support continued assessment of tucatinib in combination with T-DM1, as well as other HER2 targeted ADCs, in HER2+ metastatic breast cancer patients. Borges VF, Ferrario C, Aucoin N, Falkson C, Khan Q, Krop I, Welch S, Conlin A, Chaves J, Bedard PL, Chamberlain M, Gray T, Vo A, Hamilton E. JAMA Oncol. 2018;4(9):1214-1220. Citation Format: Anita Kulukian, Janelle Taylor, Devra Olson, Margo Zaval, Robert Thurman, Shawna Hengel, Lauren Farr, Tim S Lewis, Scott R Peterson. Tucatinib, a HER2-selective tyrosine kinase inhibitor, increases the anti-tumor activity of trastuzumab antibody-drug conjugates in preclinical models of HER2+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-09.