An overview of the preclinical discovery and development of trastuzumab deruxtecan: a novel gastric cancer therapeutic

ABSTRACT

Introduction

Gastric cancer is common worldwide, and while multiple therapeutic options exist, the prognosis remains poor. Tumors may overexpress HER2. While targeting HER2 with trastuzumab provides a survival benefit, options following progression are limited. Subsequent trials of HER2-targeted agents failed to improve outcomes. Recently, DESTINY-Gastric01 demonstrated a survival benefit utilizing the antibody-drug conjugate (ADC) trastuzumab deruxtecan in gastric cancer patients that progressed on trastuzumab.

Areas Covered

/The authors give background to gastric cancer/HER2 and discuss prognostic implications of HER2 overexpression. They also describe initial trials of anti-HER2 therapy, resistance mechanisms, and ADC development/optimization. Finally, the authors review DESTINY-Gastric01 and provide future perspectives.

Expert opinion

While the 2010 ToGA trial demonstrated efficacy of trastuzumab in HER2 positive gastric cancer, subsequent trials of HER2-directed therapy have disappointed. Downregulation of HER2 after trastuzumab may play a role; however, trastuzumab deruxtecan maintains some efficacy in low-level HER2 expressing tumors. The DESTINY-Gastric01 cohort was from South Korea/Japan; authors have reported differences in gastric cancer risk factors/physiology between Eastern and Western populations. DESTINY-Gastric02 will evaluate trastuzumab deruxtecan in Western patients to confirm generalizability. Pulmonary side effects are notable;physicians must be cognizant of overlapping toxicities with combination therapy.

KEYWORDS:

• Antibody-drug conjugates
• gastric cancer
• HER2
• trastuzumab
• trastuzumab deruxtecan

Article highlights

1. Gastric cancer remains highly prevalent worldwide, is one of the most common causes of cancer death, and even with discovery of targeted agents the prognosis remains poor.

2. Unlike HER2 overexpression in breast cancer, there is a large degree of heterogeneity with HER2 expression in gastric cancer that has implications for response to anti-HER2 therapies.

3. While trastuzumab did demonstrate a significant survival benefit in HER2-positive gastric cancer, subsequent studies of anti-HER2 therapy have been disappointing and effective agents for patients who progress on trastuzumab are limited.

4. While antibody-drug conjugates are a relatively new and exciting class of agent, even initial trials with the HER2-targeting antibody-drug conjugate trastuzumab emtansine in gastric cancer were also disappointing.

5. The DESTINY-Gastric01 study is a breakthrough for patients with HER2-positive gastric cancer who progressed on trastuzumab and has evidence of efficacy in tumors with a wide degree of HER2 expression, though it is also associated with clinically relevant toxicities such as pneumonitis/interstitial lung disease.

Declaration of Interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer declares that they have received honoraria from Daiichi Sankyo. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.