Spotlight on Trastuzumab Deruxtecan (DS-8201,T-DXd) for HER2 Mutation Positive Non-Small Cell Lung Cancer

• Published in: Lung Cancer: Targets and Therapy Vol. 12; pp. 103 - 114
• Main Authors: Azar, Ibrahim, Alkassis, Samer, Fukui, Jami, Alsawah, Fares, Fedak, Kalub, Al Hallak, Mohammed Najeeb, Sukari, Ammar, Nagasaka, Misako
• Format: Journal Article
• Language: English
• Published: Macclesfield Informa UK Limited 01.10.2021; Dove Medical Press Limited; Taylor & Francis Ltd; Dove; Dove Medical Press
• Subjects: antibody drug conjugate; Antitumor agents; Biological products; Breast cancer; Cancer; Care and treatment; Cell growth; Clinical trials; DNA topoisomerase; Drug approval; ds8201; Epidermal growth factor; ErbB-2 protein; FDA approval; Gastric cancer; Genetic aspects; Health aspects; her2; Immunotherapy; Kinases; Lung cancer; Lung cancer, Non-small cell; Lung cancer, Small cell; Monoclonal antibodies; Mutation; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Non-small cell lung carcinoma; Pertuzumab; Pharmaceutical industry; Pharmacodynamics; Pharmacokinetics; Protein-tyrosine kinase; RC254-282; Review; Small cell lung carcinoma; Stomach cancer; t-dxd; Targeted cancer therapy; Targets and Therapy [Lung Cancer]; Trastuzumab; Tumorigenesis; Tyrosine; United States
• ISSN: 1179-2728; 1179-2728
• DOI: 10.2147/lctt.s307324

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 significant bystander effect, resulted in significant anti-tumor activity. The DESTINY-LungOl trial evaluated T-DXd in HER2-positive non-squamous non-small cell lung cancer (NSCLC) and reported a progression-free survival of 14 months in HER2-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 HER2 positive lung cancer. Keywords: T-DXd, DS8201, antibody drug conjugate, HER2