Spotlight on Trastuzumab Deruxtecan (DS-8201,T-DXd) for Mutation Positive Non-Small Cell Lung Cancer.

Human epidermal growth factor receptor 2 () is a proto-oncogene that, when mutated or overexpressed, plays an important role in oncogenesis. The landscape of -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 receptor. inhibition has also been approved for -positive gastric cancer. is amplified in 9% and mutated in 3% of lung cancer. Historically, -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 significant bystander effect, resulted in significant anti-tumor activity. The DESTINY-Lung01 trial evaluated T-DXd in -positive non-squamous non-small cell lung cancer (NSCLC) and reported a progression-free survival of 14 months in -mutated NSCLC, earning its breakthrough designation by the FDA. In this review, we will discuss the structural characteristics, pharmacodynamics, and pharmacokinetics of T-DXd. We will also shed light on the preclinical and ongoing clinical trials of T-DXd along with future directions in the management of positive lung cancer.