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

Abstract

Ibrahim Azar,1 Samer Alkassis,2 Jami Fukui,3 Fares Alsawah,1 Kalub Fedak,1 Mohammed Najeeb Al Hallak,1 Ammar Sukari,1 Misako Nagasaka1,4 1Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI, USA; 2Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, USA; 3University of Hawaii Manoa Cancer Center, John A. Burns School of Medicine, Honolulu, HI, USA; 4Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, JapanCorrespondence: Misako NagasakaDepartment of Oncology, Karmanos Cancer Center/Wayne State University, Detroit, MI, USATel [phone]Fax [phone]Email [email protected]: 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-Lung01 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

Keywords

• t-dxd
• ds8201
• antibody drug conjugate
• her2