Tucatinib (Irbinitinib) hemiethanolate is a potent, orally active and selective HER2 inhibitor with an IC50 of 8 nM.
Tucatinib hemiethanolate has nanomolar activity against purified HER2 enzyme and is approximately 500-fold selective for HER2 versus EGFR in cell-based assays. Tucatinib selectively inhibits the receptor tyrosine kinase HER2 relative to EGFR[1].Tucatinib blocks proliferation and the phosphorylation of HER2 and its downstream effector, Akt in HER2 overexpressing cell lines. In the EGFR overexpressing cell lines, it weakly inhibits phosphorylation and proliferation, demonstrating that Tucatinib may have potential to block HER2 signaling without causing the toxicities of EGFR inhibition[1].
Tucatinib hemiethanolate (ONT-380 hemiethanolate, 200 mg/kg/d) shows a survival benefit when each drug is dosed at the maximum-tolerated dose[1]. Tucatinib and its active metabolite causes a significant reduction in brain pErbB2 (80%)[2].Tucatinib (ARRY-380) hemiethanolate demonstrates significant dose-related tumor growth inhibition (TGI; 50% at 50 mg/kg/d and 96% at 100 mg/kg/d) with numerous partial regressions (>50% reduction from baseline size) at the higher dose level in 9/12 animals. Tucatinib (50 mg/kg/d) in combination with trastuzumab shows a 98% TGI with complete regressions in 9/12 animals and two partial regressions[3].
[1]. Moulder-Thompson S, et al. Phase 1 Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+ Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC). Clin Cancer Res. 2017 Jan 4. pii: clincanres.1496.2016.
[2]. Abstract: In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 852. doi:1538-7445.AM2012-852.
[3]. P. Lee, et al. In Vivo Activity of ARRY-380, a Potent, Small Molecule Inhibitor of ErbB2 in Combination with RP-56976. Cancer Research.