Relative Bioavailability of Zongertinib, an Orally Administered HER2-Selective Tyrosine Kinase Inhibitor, under Fed and Fasted Conditions in Healthy Male Participants: Results from Two Randomized, Open-Label, Crossover Studies

Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is mutated in various solid tumors. Zongertinib (BI 1810631) is a novel, orally administered, HER2-specific tyrosine kinase inhibitor that spares the epidermal growth factor receptor (EGFR), limiting EGFR-related adverse events. Zongertinib has recently received accelerated approval in the United States and China for patients with advanced, previously treated, <i>HER2</i> mutant NSCLC. Two Phase I open-label crossover studies evaluated the effect of a high-fat, high-calorie meal on zongertinib bioavailability at two doses: 30 mg (NCT05380947) and 240 mg (NCT06075277). Healthy male participants were randomized to treatment sequences in which they received single doses of zongertinib (spray-dried dispersion formulations) under fed and fasted conditions. The washout interval was ≥14 days. The primary end points were the area under the concentration-time curve of zongertinib in plasma over the time from 0 to the last quantifiable data point (AUC_0-tz), and the maximum measured concentration of zongertinib in plasma (<i>C</i>_max). In NCT05380947, 13 participants received 30 mg of zongertinib. The ratios of adjusted geometric means demonstrated lower AUC_0-tz and <i>C</i>_max, under fed (<i>n</i> = 9) versus fasted (<i>n</i> = 12) conditions (fed/fasted, % [90% CI]: AUC_0-tz, 74.2% [67.6-81.6]; <i>C</i>_max, 53.5% [40.5-70.8]). In NCT06075277, the ratios of adjusted geometric means for AUC_0-tz and <i>C</i>_max were ∼26% higher under fed versus fasted conditions (fed/fasted, % [90% CI]: AUC_0-tz, 126.6% [112.1-143.1]; <i>C</i>_max, 126.1% [106.3-149.6]). In both studies, median <i>t</i>_max was delayed (NCT05380947/NCT06075277) under fed (3/4 h) versus fasted (1.5/2 h) conditions. Zongertinib demonstrated good bioavailability in healthy participants. A small dose-dependent food effect was observed.