Trastuzumab deruxtecan and other HER2-targeting agents for the treatment of HER2-positive gastric cancer

ABSTRACT

Introduction

Although various new drugs have been developed, the prognosis of therapeutic advances for metastatic gastric cancer is insufficient. Trastuzumab deruxtecan (T-DXd), a new human epidermal growth factor receptor 2 (HER2)-targeting antibody–drug conjugate (ADC), has demonstrated promising results in clinical trials.

Areas covered

In this article, we review the history of anti-HER2 ADCs and focus on the efficacy and safety of T-DXd and describe the development of new anti-HER2 drugs.

Expert opinion

So far, no other anti-HER2 ADCs have demonstrated efficacy in patients with HER2-positive advanced gastric cancer with two or more previous lines of chemotherapy, including trastuzumab. However, a new drug, T-DXd, has shown a significantly higher objective response rate and a longer overall survival and, thus, was approved in Japan. In the future, new anti-HER2 drugs and/or treatment strategies including T-DXd along with cytotoxic chemotherapy or immune checkpoint inhibitors will be developed.

KEYWORDS:

• Antibody–drug conjugate
• gastric cancer
• HER2
• trastuzumab deruxtecan
• T-DXD

Article highlights

• Until trastuzumab deruxtecan (T-DXd) was approved, human epidermal growth factor receptor 2 (HER2)-targeting therapies, other than trastuzumab, had not been used in patients with HER2-positive advanced gastric cancer in Japan.

• T-DXd is a new HER2-targeting antibody–drug conjugate composed of a humanized anti-HER2 monoclonal antibody, a cleavable tetrapeptide-based linker, and a novel topoisomerase-I inhibitor payload.

• T-DXd has demonstrated significant improvements in objective response rate and overall survival compared with chemotherapy in the phase II DESTINY-Gastric01 trial and was approved in Japan ahead of the world.

• Clinical trials of new anti-HER2 drugs and/or T-DXd along with cytotoxic chemotherapy or immune checkpoint inhibitors are ongoing.

Acknowledgments

The authors would like to thank Enago (www.enago.jp) for the English language review.

Declaration of interest

K Shitara has received consultancy fees or served in advisory roles for Astellas, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono, MSD, Taiho, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, and Boehringer Ingelheim; honoraria from Novartis, AbbVie, and Yakult; and research funding from Astellas, Lilly, Ono, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD, Medi Science, and Eisai. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper received no funding.