Abstract LB270: Absorption, distribution, metabolism and excretion (ADME) properties and absolute bioavailability of zongertinib, a selective oral HER2-specific tyrosine kinase inhibitor, in healthy male subjects

Abstract Background and Objectives: Zongertinib is a potent irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing EGFR, thereby limiting associated toxicities. Zongertinib is being evaluated as monotherapy for patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 mutations. The objectives of this non-randomized, open-label, two-part, Phase I study were to assess the absorption, distribution, metabolism and excretion (ADME) of zongertinib (Part A) and the absolute bioavailability (F) of oral zongertinib compared with intravenous (IV) microtracer infusion (Part B), in healthy male volunteers. Methods: In the first part (ADME assessment), eight subjects received a single oral dose of 60 mg (C-14)-zongertinib solution (containing radiolabeled [14C]-zongertinib [3.7 MBq] and unlabeled zongertinib). In the second part (F assessment), seven subjects received an oral dose of unlabeled zongertinib (60 mg film-coated tablet) after an overnight fast, followed by a 15-minute IV microtracer infusion of (C-14)-zongertinib solution 100 μg, containing 10 μg of [14C]-zongertinib [∼0.03 MBq] and 90 μg of unlabeled zongertinib. Results: The maximum plasma concentration of oral zongertinib solution was reached at a median of 1-h post-dose (range 0.5‒2.0 h). Mean recovery of the radioactive dose was 93.8% (92.5% in feces and 1.30% in urine). Unchanged zongertinib represented most of the circulating radioactivity in plasma (74.6%) and was the predominant excreted component in feces (31.4% of the administered dose). In contrast, only trace levels of zongertinib were detected in urine (0.18% of the dose). A significant portion of unchanged zongertinib detected in feces may result from the de-conjugation of conjugated metabolites in the gut. The major metabolic pathways involved oxidation and to a lesser extent glucuronidation and glutathione conjugation. The two most abundant circulating metabolites were M551(1) (mono-oxidation) and M656(1) (cysteine conjugate), representing 5.7% and 2.5% of total radioactivity over the 168-hour collection period (AUC0-168h), respectively. The mean F of the tablet-form zongertinib was 76.2% with low intra-individual variability. Following the IV dose, zongertinib had a low plasma clearance of 106 mL/min and the apparent volume of distribution was 138 L. Zongertinib has a manageable safety profile in both parts of the study. Conclusions: Zongertinib was rapidly absorbed with high absolute bioavailability. Unchanged zongertinib was the predominant component without any major metabolite circulating in plasma. Zongertinib was metabolized via oxidation, glucuronidation, and glutathione conjugation. Zongertinib was primarily excreted via feces, with minimal renal excretion. Citation Format: David Joseph, Rolf Grempler, Guanfa Gan, Adam Auclair, Hlaing Maw, Ralf Laux, Ralf Kiesling, Sven Wind, David Minch. Absorption, distribution, metabolism and excretion (ADME) properties and absolute bioavailability of zongertinib, a selective oral HER2-specific tyrosine kinase inhibitor, in healthy male subjects [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 LB270.