Targeting HER2 in lung cancers: Evolving treatment landscape and drug development strategies

ERBB2 (HER2) alterations, including mutations, amplifications, and overexpression are emerging therapeutic targets in non–small cell lung cancer (NSCLC). Despite recent advancements, standard first-line therapy remains chemotherapy with or without immunotherapy. Several therapies targeting HER2 are under development and have been evaluated in clinical trials with inconsistent efficacy, including monoclonal antibodies, tyrosine kinase inhibitors, and antibody–drug conjugates. A major landmark was recently reached when trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate, became the first Food and Drug Administration (FDA)-approved therapy for pretreated HER2-mutant NSCLC, following the promising efficacy demonstrated in the DESTINY-Lung trials. Furthermore, T-DXd has shown efficacy across various tumor types harboring HER2 alterations in the DESTINY-PanTumor trials, leading to its recent pan-tumor FDA approval for HER2-positive solid tumors, highlighting the potential of tumor-agnostic drug development strategies. In this review, the authors describe the different HER2 alterations and their clinical consequences, including their impact on prognosis and response to standard therapies. They provide an up-to-date overview of the current treatment landscape and add a comprehensive review of pivotal and ongoing clinical trials of HER2-targeted therapies, including tumor-agnostic drug development strategies.