Abstract LB298: The effect of food on zongertinib plasma exposure in healthy volunteers

Abstract Background: Zongertinib (BI 1810631) is an irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing EGFR, thereby limiting associated toxicities. The study objective was to compare the relative bioavailability of a single 240-mg dose of zongertinib in spray-dried dispersion formulation delivered orally in fed and fasted conditions. Methods: In this open-label, 2-way crossover trial (NCT06075277), healthy male volunteers were randomized to receive a single dose of zongertinib under fasted (reference [R]) and fed (test [T]) conditions. In the T condition, volunteers consumed a high-fat, high-calorie breakfast 30 min before drug administration. In the R condition, participants fasted overnight for ≥10 h before scheduled dosing. The extent of food effect on drug exposure was estimated by the ratio of the geometric means of endpoints calculated for T and R conditions (T/R), with a ratio value >100% indicating higher plasma zongertinib concentrations in the T versus the R condition. Ratios were calculated for area under the concentration-time curve (AUC) from drug intake to last measurement (AUC0-tz), maximum measured concentration of zongertinib (Cmax), and AUC from time of drug intake to extrapolated infinity (AUC0-∞). Results: Sixteen volunteers (mean [SD] age, 47.9 [8.9] y; mean [SD] body mass index, 25.0 [2.85] kg/m2) enrolled and received trial medication, and all completed the study. AUC0-tz, Cmax, and AUC0-∞ values were higher during treatment under T versus R conditions (adjusted geometric mean ratio [90% CI lower-upper limit]): AUC0-tz,127% (112%-143%); Cmax, 126% (106%-150%); and AUC0-∞, 126% (112%-142%). Intersubject variability (observed geometric coefficient of variation) was also lower under T versus R conditions: AUC0-tz, 15.4% versus 37.5%; Cmax, 15.7% versus 45.5%; and AUC0-∞, 15.3% versus 37.1%. Treatment-emergent adverse events (TEAEs) were reported for 11/16 volunteers (68.8%) and were all Grade 1/mild (n=7) or Grade 2/moderate (n=4). The most frequently reported TEAE was headache (4 volunteers, 25.0%), while cough, nasal congestion, presyncope, fatigue, pain, myalgia, back pain, erythema, skin lesion, nausea, nasopharyngitis, and oropharyngeal pain were reported by 1 volunteer each (6.3% per TEAE). Conclusions: Taking zongertinib 240 mg after a high-fat, high-calorie meal resulted in an ∼26% increase in plasma zongertinib exposure, which is not considered clinically relevant, and reduced overall between-subject variability in exposure compared with taking it under fasted conditions. Zongertinib was safe and well tolerated, with no unexpected safety findings reported. Zongertinib can be administered with or without food. Citation Format: Hélène Pereira, Behbood Sadrolhefazi, Yeuk Ki Law, Sven Wind, David Minich, Rolf Grempler, Philipp M. Roessner. The effect of food on zongertinib plasma exposure in healthy volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB298.