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Advances in the treatment of human epidermal growth factor receptor 2-positive gastric cancer
1Department of Medical Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan. toshihiro.kudo@oici.jp.
Abstract:
Human epidermal growth factor receptor 2 has been a pivotal biomarker for gastric cancer treatment strategies for many years. However, more than a decade after the ToGA trial demonstrated the efficacy of trastuzumab in improving survival, the development of treatments targeting human epidermal growth factor receptor 2 remains challenging. Several large-scale clinical trials of tyrosine kinase inhibitors, non-trastuzumab anti-human epidermal growth factor receptor 2 antibodies, and antibody-drug conjugates have failed to meet the primary endpoints. The concept of trastuzumab beyond progression and the complexity of resistance mechanisms to anti-human epidermal growth factor receptor 2 therapy after trastuzumab treatment presented significant obstacles, leading to trastuzumab being the sole therapy for human epidermal growth factor receptor 2-positive gastric cancer for some time. Nevertheless, the landscape has shifted in recent years, especially since the introduction of the antibody-drug conjugate trastuzumab deruxtecan in 2020. This has rekindled the interest in developing treatments targeting human epidermal growth factor receptor 2 in gastric cancer.
Insights
Human epidermal growth factor receptor 2 (HER2) targeted therapies for gastric cancer faced challenges, but new antibody-drug conjugates like trastuzumab deruxtecan have renewed interest in HER2-positive treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Gastroenterology
Background:
- Human epidermal growth factor receptor 2 (HER2) is a key biomarker in gastric cancer treatment.
- Trastuzumab, approved over a decade ago, remains the sole HER2-targeted therapy despite numerous clinical trial failures.
Purpose of the Study:
- To review the challenges and recent advancements in HER2-targeted therapies for gastric cancer.
- To highlight the impact of new antibody-drug conjugates in overcoming resistance mechanisms.
Main Methods:
- Review of clinical trials and literature on HER2-targeted therapies in gastric cancer.
- Analysis of resistance mechanisms to anti-HER2 treatments.
- Evaluation of the efficacy of novel antibody-drug conjugates.
Main Results:
- Multiple clinical trials of tyrosine kinase inhibitors, antibodies, and antibody-drug conjugates failed to meet primary endpoints.
- Trastuzumab resistance and progression present significant hurdles in HER2-positive gastric cancer management.
- The introduction of trastuzumab deruxtecan in 2020 has shown promise, shifting the therapeutic landscape.
Conclusions:
- Despite past setbacks, recent developments, particularly trastuzumab deruxtecan, offer renewed hope for effective HER2-targeted gastric cancer treatment.
- Further research into overcoming resistance mechanisms is crucial for advancing HER2-positive gastric cancer therapy.
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