HER2 Therapies in Non-Small Cell Lung Cancer (NSCLC)

This review discusses the role of human epidermal growth factor receptor 2 (HER2/ERBB2) as a key oncogenic driver in non-small cell lung cancer (NSCLC), including exon 20 activating mutations, gene amplification, and protein overexpression. These forms differ in their biological effects and predictive value, but HER2 mutations, especially exon 20 insertions, are the primary oncogenic mechanism. Regarding diagnosis, Next-Generation Sequencing (NGS) is used to identify mutations, whereas Immunohistochemistry (IHC) and in situ hybridization are used to assess HER2 expression. Concerning treatment, in advanced HER2-positive, Non-Squamous NSCLC tumors, the first-line treatment is Platinum-based + Pemetrexed chemotherapy, with or without immunotherapy, because no HER2-targeted antibody therapy has yet been approved for initial treatment. After progression, HER2-targeted antibody-drug conjugates like Trastuzumab-Deruxtecan and Ado Trastuzumab-Emtansine may offer patients clinical benefits. New HER2-selective tyrosine kinase inhibitors, such as zongertinib and sevabertinib, have shown promising results, including patients previously treated with antibody–drug conjugates (ADCs). Recent advances, including next-generation ADCs such as SHR-A1811 and A166, and bispecific antibodies, such as zenocutuzumab for NRG1 fusion–positive disease, which are also expanding treatment options. Overall, advances in diagnostics and new targeted therapies are changing how HER2-altered NSCLC is treated and are helping to make care more personalized.