Tucatinib

Tucatinib (Irbinitinib) is a potent, orally active and selective HER2 inhibitor with an IC₅₀ of 8 nM. IC50 & Target: IC50: 8 nM (HER2)^[1] In Vitro: Tucatinib 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].
In Vivo: Tucatinib (ONT-380, 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) 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].