Abstract P6-17-11: The small molecule inhibitor of HER2, tucatinib, has potent and highly selective activity in preclinical modes of HER2-driven cancer
Authors: O'Brien NA , Conklin D , McDermott M , Luo T , Ayala R , Issakhanian S , Salgar S , Hurvitz S , Slamon DJ 
Published: May 2019

Abstract
Background: Pharmacologically targeting the HER2 oncoprotein provides clinical benefit for patients with HER2-amplified cancers. However, a significant number of patients do not respond to the currently approved HER2-targeted therapies, despite carrying the HER2-alteration. Small molecule inhibitors of HER2, that target other receptor tyrosine kinases such as EGFR (i.e. lapatinib), are approved and provide some clinical benefit but are often associated with increased toxicity. Tucatinib (ARRY-380) is an orally available, potent, highly selective small molecule inhibitor of the HER2 kinase. In this study, we assessed the in vitroand in vivoactivity of tucatinib, relative to approved HER2-targeting molecules, in a panel of molecularly characterized breast cancer cell lines.
Materials and Methods:The growth inhibitory activity of tucatinib, trastuzumab and lapatinib were evaluated in a panel of 48 breast cancer cell lines molecularly characterized at baselineby genomic (array-CGH) and proteomic (Reverse Phase Protein Array; RPPA) profiling. IC50values for tucatinib and lapatinibwere determined from direct cell counts using a Cellavista Cell Imaging System. Trastuzumab activity was measured as % inhibition of cell growth at fixed concentrations. In vivoefficacy of tucatinib was assessed in cell line xenograft models of HER2+/ER- and HER2+/ER+ breast cancers as a single agent or in combination with targeted therapies for breast cancer.
Results: A broad range of IC50values (3.2nM to &gt;10μM), was seen for tucatinib with a high degree of selectivity for the HER2-amplfied sub-type. High levels of total and phosphorylated HER2 (pHER2) accompanied by high levels of pEGFR and pHER3 enriched for sensitivity to tucatinib, confirming that HER2-driven cancers may be uniquely sensitive to tucatinib. The response profile for lapatinib was less clean, with responses also observed in HER2-low/EGFR-high cell lines. Sensitivity to tucatinib was also observed in HER2-amplified cell lines that were either de novoor acquired resistant to trastuzumab. Single agent tucatinib induced tumor regressions in a xenograft model of HER2+/ER+ breast cancer. Tumor regressions were further enhanced by combination with trastuzumab. The combination of tucatinib plus trastuzumab was as efficacious and better tolerated than trastuzumab plus docetaxel or trastuzumab plus pertuzumab plus docetaxel. The triple combination of tucatinib plus hormonal blockade (fulvestrant) and CDK4/6 inhibition (abemaciclib) also induced robust tumor regressions, without significant body weight loss.
Discussion: These preclinical data highlight the potential of the HER2-selective small molecule inhibitor, tucatinib, to provide benefit to patients with HER2-amplifed cancers. Furthermore, our biomarker analysis of response to tucatinib has identified a HER2-driven signature within the HER2-amplfied sub-type that selects for sensitivity to tucatinib. Selecting patients based on this profile may further enrich for individuals most likely to benefit from tucatinib-based therapies.
Citation Format: O'Brien NA, Conklin D, McDermott M, Luo T, Ayala R, Issakhanian S, Salgar S, Hurvitz S, Slamon DJ. The small molecule inhibitor of HER2, tucatinib, has potent and highly selective activity in preclinical modes of HER2-driven cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-11.