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

High Resolution Image Download MS PowerPoint Slide 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, HER2 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 ( C max ). In NCT05380947, 13 participants received 30 mg of zongertinib. The ratios of adjusted geometric means demonstrated lower AUC 0-tz and C max, under fed ( n = 9) versus fasted ( n = 12) conditions (fed/fasted, % 90% CI: AUC 0-tz, 74.2% 67.6–81.6; C max, 53.5% 40.5–70.8). In NCT06075277, the ratios of adjusted geometric means for AUC 0-tz and C max were ∼26% higher under fed versus fasted conditions (fed/fasted, % 90% CI: AUC 0-tz, 126.6% 112.1–143.1; C max, 126.1% 106.3–149.6). In both studies, median t 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.