Evolving treatment strategies for HER2-altered non–small-cell lung cancer: the rise of TKIs and ADCs

Human epidermal growth factor receptor 2 (HER2) is an actionable oncogenic driver in a small subset of non-small cell lung cancer (NSCLC), occurring as gene mutations and less frequently as gene amplification or protein overexpression. Until recently, HER2-driven NSCLC lacked effective targeted treatments, and patients were managed with conventional chemotherapy and immunotherapy. However, the therapeutic landscape has rapidly evolved with the advent of novel HER2-directed antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs). Following the 2022 approval of the antibody-drug conjugate fam-trastuzumab deruxtecan (T-DXd), the therapeutic landscape of HER2-mutant NSCLC further expanded in 2025 with the regulatory approval of two highly selective oral HER2 tyrosine kinase inhibitors, zongertinib and sevabertinib. This review provides a comprehensive update on these emerging HER2-targeted therapies, including their clinical trial data, mechanisms of action, and comparative benefits over older pan-HER agents. We discuss the emerging therapeutic scope in HER2-"low" NSCLC, challenges with immunotherapy in HER2-driven tumors, and known resistance mechanisms to TKIs and ADCs. An evidence-based treatment algorithm is proposed, integrating new agents into current practice and addressing special considerations such as central nervous system (CNS) metastases. We also outline ongoing trials that may further shift first-line standards. In summary, recent breakthroughs in HER2-targeted TKIs and ADCs are transforming outcomes in this rare NSCLC subset, though optimizing sequencing, managing resistance, and improving patient selection through biomarker development remain priorities for future research.