LAUSR

Simple Summary By coupling the potency of cytotoxic chemotherapy with the selectivity of targeted therapy, antibody–drug conjugates represent a unique and rapidly growing class of antitumor agents. In this review, we aim to outline the unanswered questions that have emerged after the approval of trastuzumab deruxtecan in HER2-mutant non-small cell lung cancer. We also summarize data on novel therapies that are currently being investigated in the same patient population. Abstract Successful targeting of HER2-activating mutations in DESTINY-Lung02 phase II study has led to the approval of the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) as second-line treatment in patients with non-small cell lung cancer (NSCLC). Despite the impressive results, several matters need to be addressed, including the clinical activity of T-DXd in patients with disease in the central nervous system as well as the role of T-DXd in the context of HER2 overexpression. Additionally, data regarding novel agents used to target HER2 continue to accumulate. This review highlights the challenges and unanswered questions that have emerged after the approval of T-DXd in patients with HER2-mutant NSCLC.