Tucatinib is an orally administered, reversible, HER2-targeted, small-molecule tyrosine kinase inhibitor that selectively inhibits HER2. In a phase 1b clinical trial in HER2+ metastatic breast cancer (MBC), tucatinib in combination with ado-trastuzumab emtansine (T-DM1) was well tolerated and demonstrated activity in pretreated patients with HER2+ MBC.1
At SABCS 2019, preclinical data were presented evaluating whether tucatinib potentiates the activity of T-DM1 in HER2+ breast cancer models in vitro and in vivo, and whether it enhances the activity of a camptothecin-based HER2 antibody-drug conjugate comprised of trastuzumab conjugated with 8 exatecan moieties (T-Ex).2
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 to determine additivity, synergy, or antagonistic properties of the drug combinations. Moreover, the activity of tucatinib either alone (50 mg/kg twice daily) or in combination with T-DM1 (10 mg/kg single-dose intravenously) 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.
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 coadministered in vitro, tucatinib and T-DM1 or T-Ex combinations produced additive or synergistic effects. Moreover, tucatinib inhibited a subset of breast cancer cell lines that showed reduced sensitivity to either T-DM1 or T-Ex. In BT-474 cells, the coadministration of tucatinib with T-DM1 in vitro was synergistic. 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.
These data demonstrate that tucatinib results in selective and potent anti-tumor activity in HER2+ breast cancer–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, and that tucatinib in combination with T-DM1 showed enhanced anti-tumor activity in vivo in models of HER2+ breast cancer compared with T-DM1 as a single agent. The authors suggest that, taken together with the early clinical data demonstrating preliminary safety and activity of tucatinib with T-DM1, these results presented at SABCS 2019 support continued assessment of tucatinib in combination with T-DM1, as well as other HER2-targeted antibody-drug conjugates, in HER2+ MBC patients.
References
- Borges VF, et al. JAMA Oncol. 2018;4:1214-1220.
- Kulukian A, et al. SABCS 2019. Abstract P1-18-09.