Innovative Therapies for HER2-altered Non-Small Cell Lung Cancer: a Narrative Review

HER2-directed therapies have transformed the treatment landscape of breast and gastric cancers, but targeting HER2 alterations in non-small cell lung cancer (NSCLC) has proven more challenging. HER2 mutations, found in 2-4% of NSCLC cases, define a unique molecular subset characterized by poor responses to conventional chemotherapy and the frequent development of brain metastases. Recent advances in novel therapies, particularly antibody-drug conjugates and selective tyrosine kinase inhibitors, have renewed interest in HER2 as a therapeutic target. These therapies have different efficacy and safety profiles, highlighting the need for biomarker-driven selection and optimal treatment sequencing. Combination strategies with immune checkpoint inhibitors, such as platinum-based chemotherapy plus PD-L1 inhibitors, are also being actively investigated, although overlapping toxicities, particularly pulmonary adverse events, remain a key concern. This narrative review summarizes the clinicopathological features of HER2-altered NSCLC, critically evaluates emerging HER2-targeted therapies, and discusses future treatment directions.