Emerging HER2-directed therapeutic agents for gastric cancer in early phase clinical trials
Hazel Lote1,2, Ian Chau1
1Department of Medicine, Royal Marsden Hospital, London and Surrey, UK.
Introduction:
HER2 positive gastric cancer is a distinct subgroup overexpressing the HER2 receptor. For a decade, first-line Trastuzumab was the only licensed HER2-directed therapy for HER2 positive advanced gastric cancer following results from the ToGA trial in 2010 demonstrating a survival benefit when added to chemotherapy. Within the last year, significant advances have taken place in the field of HER2-directed gastric cancer therapy.
Areas Covered:
This review discusses pivotal clinical trial results and summarizes current clinical trials of HER2-directed therapy in gastric cancer. Evidence for HER2-directed antibodies, immunotherapy, immune stimulating antibody conjugates, antibody-drug conjugates (including DESTINY trial results), and tyrosine kinase inhibitors are placed into clinical context. Key challenges including resistance mechanisms and drug toxicities are outlined. Search terms 'HER2' and 'gastric cancer' were entered into ClinicalTrials.gov, PubMed, and Google. Only English-language studies were included.
Expert Opinion:
Clinical management of HER2 positive gastric cancer patients is likely to change significantly over the next 5 years. Checkpoint inhibition is likely to be used alongside HER2-directed therapy and chemotherapy first-line in advanced disease. Trastuzumab deruxtecan is likely to be offered second-line and beyond. The sheer number of clinical trials of HER2-directed therapy in gastric cancer are testament to progress and potential.
Insights
Advances in HER2-directed therapies are transforming HER2 positive gastric cancer treatment. New antibody-drug conjugates and immunotherapies show promise, offering improved options beyond traditional chemotherapy and Trastuzumab.
Area of Science:
- Oncology
- Gastroenterology
- Pharmacology
Background:
- HER2 positive gastric cancer is a specific subtype characterized by HER2 receptor overexpression.
- For ten years, Trastuzumab has been the sole approved first-line HER2-directed therapy for advanced HER2 positive gastric cancer.
- Recent advancements have introduced novel HER2-directed therapies, significantly impacting treatment paradigms.
Purpose of the Study:
- To review pivotal clinical trial outcomes and ongoing research in HER2-directed gastric cancer therapy.
- To contextualize various HER2-directed agents, including antibodies, immunotherapies, and antibody-drug conjugates.
- To address challenges such as resistance mechanisms and drug toxicities.
Main Methods:
- Comprehensive literature review of clinical trial results for HER2-directed therapies in gastric cancer.
- Inclusion of evidence from antibodies, immunotherapy, immune stimulating antibody conjugates, antibody-drug conjugates, and tyrosine kinase inhibitors.
- Systematic search of ClinicalTrials.gov, PubMed, and Google using terms 'HER2' and 'gastric cancer', limited to English-language studies.
Main Results:
- Trastuzumab deruxtecan demonstrates significant efficacy in DESTINY trials, positioning it for second-line and beyond treatment.
- Emerging evidence supports the use of checkpoint inhibition in combination with HER2-directed therapy and chemotherapy for first-line treatment.
- Multiple ongoing clinical trials highlight the rapid progress and therapeutic potential in this field.
Conclusions:
- The clinical management of HER2 positive gastric cancer is poised for substantial evolution in the next five years.
- Combination therapies involving checkpoint inhibitors and HER2-directed agents are expected in first-line settings.
- Novel agents like Trastuzumab deruxtecan are anticipated as key components of later-line treatment strategies.
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