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Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene that, when mutated or overexpressed, plays an important role in oncogenesis. The landscape of HER2-positive breast cancer has changed dramatically over the past 2 decades with the FDA approval of a growing number of agents (antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates) targeting the HER2 receptor. HER2 inhibition has also been approved for HER2-positive gastric cancer. HER2 is amplified in 9% and mutated in 3% of lung cancer. Historically, HER2-targeted therapy for lung cancer with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate a survival benefit. Trastuzumab deruxtecan (T-DXd) is a novel antibody–drug conjugate with a tetrapeptide linker, which delivers a topoisomerase I inhibitor with a drug-to-antibody ratio of 7~8. The potency of the active payload, as well as its …