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Review
. 2021 Oct 7:12:103-114.
doi: 10.2147/LCTT.S307324. eCollection 2021.

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

Ibrahim Azar  1 , Samer Alkassis  2 , Jami Fukui  3 , Fares Alsawah  1 , Kalub Fedak  1 , Mohammed Najeeb Al Hallak  1 , Ammar Sukari  1 , Misako Nagasaka  1   4
Affiliations
Review

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

Ibrahim Azar et al. Lung Cancer (Auckl). .

Abstract

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: DS8201; HER2; T-DXd; antibody drug conjugate.

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Conflict of interest statement

Dr. Al Hallak is on the speaker’s bureau for Ipsen and is a consultant for HalioDx. Dr. Sukari serves on the advisory board for Merck and Eisai. He has received study funding from Eisai. Funding. Dr. Nagasaka serves on the advisory board for AstraZeneca, Caris Life Sciences, Daiichi-Sankyo, Takeda, Novartis, EMD Serono and has received study funding from Tempus. Dr. Nagasaka has been awarded the 2020 Karmanos Cancer Institute Cancer Immunology and Immunotherapy Pilot Award (P30 CA022453). All other authors have no potential conflict of interest to declare.

Figures

Figure 1
Figure 1
HER2 signaling pathway (Adapted from “HER2 Signaling Pathway”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates).
Figure 2
Figure 2
Structure of Trastuzumab Deruxtecan.
Figure 3
Figure 3
Trastuzumab Deruxtecan mechanism of action (Adapted from “Antibody–Drug Conjugate Drug Release”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates).
Figure 4
Figure 4
Schema for DESTINY-Lung02. Additional details can be found at: https://clinicaltrials.gov/ct2/show/NCT04644237.
See this image and copyright information in PMC

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