Pharmacokinetics and Safety of Tucatinib in Healthy Japanese and Caucasian Volunteers: Results From a Phase Ⅰ Study

Tucatinib is a highly selective human epidermal growth factor receptor 2 (HER2) -directed tyrosine kinase inhibitor approved in multiple countries for metastatic HER2-positive breast cancer and in the US for metastatic HER2-postive metastatic colorectal cancer. This phase Ⅰ study (N＝36) compared the pharmacokinetic (PK) and safety profiles of tucatinib administered at 50-, 150-, and 300-mg doses taken twice daily orally in healthy Japanese (n＝18［n＝6 per tucatinib dose cohort］) and Caucasian volunteers (n＝18［n＝6 per tucatinib dose cohort］) to assess ethnicity effects on PK and dose proportionality of tucatinib. Ethnicity effects between both populations were evaluated using an analysis of covariance (ANCOVA) model and dose proportionality of tucatinib was assessed using a log-transformed linear regression model. Tucatinib steady-state exposure (AUCss) and maximum plasma concentration (Cmax) geometric mean values were similar between Japanese and Caucasian volunteers, with ANCOVA-adjusted geometric mean ratios (90％ confidence intervals) of 2.63 (1.04, 6.62), 1.11 (0.76, 1.62), and 1.33 (0.91, 1.95) for Cmax and 1.97 (0.85, 4.56), 1.05 (0.70, 1.58), and 1.04 (0.72, 1.49) for AUCss in the tucatinib 50-, 150-, and 300-mg cohorts, respectively. Thirty-three treatment-emergent adverse events (TEAEs) in 13 Caucasian volunteers and 2 TEAEs in 2 Japanese volunteers were reported. All TEAEs were grade 1, and the majority resolved by the end of study. At the approved therapeutic dose of 300 mg twice daily, tucatinib had a manageable safety profile and exposures were similar between Japanese and Caucasian volunteers. These findings indicate there is no need for dose alteration of tucatinib based on ethnicity.