Evaluation of zongertinib for the treatment of metastatic non-squamous non-small cell lung cancer with <i>HER2</i> TKD activating mutation

INTRODUCTION: Activating ERBB2 (HER2) tyrosine kinase domain (TKD) mutations define a clinically relevant molecular subset of non-squamous non-small cell lung cancer (NSCLC). Therapeutic progress in this population has accelerated over the past several years, first with trastuzumab deruxtecan and more recently with selective HER2 tyrosine kinase inhibitors (TKIs). Earlier pan-ERBB TKIs established proof of concept but were limited by wild-type EGFR-mediated toxic effects and inconsistent durability. Zongertinib is an oral, irreversible, HER2-selective TKI that suppresses oncogenic HER2 signaling while largely sparing wild-type EGFR. In Beamion LUNG-1, the confirmed ORR was 71%, and the median PFS was 12.4 months in previously treated HER2 TKD-mutant NSCLC. AREAS COVERED: This review summarizes the molecular biology of HER2 in NSCLC, the evolution of HER2-targeted therapies, and the development of zongertinib. It also highlights clinical efficacy, safety, and key challenges, including resistance mechanisms and optimal treatment strategies. EXPERT OPINION: Zongertinib demonstrates that selective HER2 inhibition can achieve durable responses in HER2 -mutant NSCLC with a favorable safety profile. However, optimal treatment sequencing, resistance mechanisms, and biomarker-guided patient selection remain to be defined.