Zongertinib is an orally bioavailable, highly selective, and irreversible tyrosine kinase inhibitor (TKI) designed to target activating mutations in human epidermal growth factor receptor 2 (HER2/ERBB2). HER2 is a receptor tyrosine kinase involved in regulating cellular growth, proliferation, and survival. Certain activating mutations in the HER2 gene can lead to uncontrolled signaling and contribute to the development and progression of several types of cancer, particularly non-small cell lung cancer (NSCLC).
 
Zongertinib acts by covalently binding to the HER2 kinase domain, resulting in sustained inhibition of HER2-mediated signaling. Its activity encompasses a range of activating HER2 mutations, including exon 20 insertion mutations, which are associated with oncogenic signaling in a subset of NSCLC tumors. By inhibiting HER2 kinase activity, zongertinib disrupts downstream signaling pathways responsible for tumor cell proliferation and survival. An important characteristic of zongertinib is its selectivity for mutant HER2 over wild-type epidermal growth factor receptor (EGFR). This selective inhibition is designed to minimize interference with normal EGFR signaling and may help reduce certain toxicities associated with less selective HER-family inhibitors. Zongertinib has been clinically investigated as a targeted therapeutic approach for patients with advanced or metastatic NSCLC harboring HER2 tyrosine kinase domain activating mutations, particularly in patients who have previously received systemic anticancer treatment.