Evaluating zongertinib in the treatment of patients with HER2-mutant non-small cell lung cancer

HER2 mutations define a distinct molecular subset of non-small cell lung cancer (NSCLC) associated with poor outcomes and limited benefit from conventional systemic therapies. Zongertinib is a next-generation, HER2-selective irreversible tyrosine kinase inhibitor (TKI) designed to spare wild-type EGFR and improve tolerability. Zongertinib has demonstrated clinically meaningful systemic and intracranial activity with a manageable safety profile across multiple cohorts in the phase Ia/Ib Beamion LUNG-1 study, including previously treated, treatment-naïve, post-HER2 antibody-drug conjugate (ADC), non-tyrosine kinase domain mutation, and brain metastases populations. This review summarizes the pharmacologic rationale, clinical efficacy, safety, biomarker analyses, and ongoing phase III development of zongertinib in HER2-mutant NSCLC.