HER2 Alterations in Non-Small Cell Lung Cancer: Emerging Perspectives on the Therapeutic Landscape

Over the past decade, significant achievements in elucidating the molecular pathogenesis of non–small cell lung cancer (NSCLC) have catalyzed a paradigm shift from empiric therapies to precision oncology. In this context, HER2 alterations, including protein overexpression, gene amplification, and activating mutations, constitute distinct molecular subsets within NSCLC. In the past few years, targeted therapeutic modalities such as antibody–drug conjugates (ADCs), particularly trastuzumab deruxtecan (the first agent to be granted FDA approval for HER2-mutant NSCLC), alongside selective tyrosine kinase inhibitors (TKIs), including zongertinib and sevabertinib, have demonstrated robust systemic efficacy and notable intracranial penetration. This comprehensive review delineates the molecular landscape and clinical phenotypes of HER2-altered NSCLC, synthesizes interim and mature data from ongoing clinical trials evaluating anti-HER2 therapies, and critically examines efficacy and safety results from different classes of targeted agents. Further research is crucial to uncover potential mechanisms of resistance in NSCLC with HER2 mutations and define sequencing or combinatorial strategies pertinent to optimizing individualized patient management.