Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer
Ya-Kun Jiang1, Wei Li2, Ying-Yang Qiu3
1Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China.
Abstract:
Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance. Human epidermal growth factor receptor 2 (HER2) is one of the most important targets in targeted therapy for gastric cancer. Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer. The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified. However, monoclonal antibodies, due to their large molecular weight, inability to penetrate the blood-brain barrier, and drug resistance, lead to decreased therapeutic efficacy, so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer. Small-molecule tyrosine kinase inhibitors, such as lapatinib and pyrrotinib, have the advantages of small molecular weight, penetrating the blood-brain barrier and high oral bioavailability, and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future. Antibo-drug conjugate, such as T-DM1 and T-DXd, can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing, and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab. Therefore, after more detailed stratification of gastric cancer patients, various gastric cancer drugs targeting HER2 are expected to play a more significant role.
Insights
Targeted therapies, including monoclonal antibodies and small-molecule inhibitors, offer new options for HER2-positive gastric cancer. These advanced treatments aim to overcome resistance and improve outcomes, especially for patients who have not responded to traditional therapies.
Area of Science:
- Oncology
- Pharmacology
- Gastroenterology
Background:
- Targeted therapy, particularly for HER2-positive gastric cancer, complements traditional chemoradiotherapy.
- Human epidermal growth factor receptor 2 (HER2) is a key target in gastric cancer treatment.
- Trastuzumab plus chemotherapy is a standard first-line treatment for advanced gastric cancer.
Purpose of the Study:
- To review the efficacy of various HER2-targeting therapies beyond traditional monoclonal antibodies in gastric cancer.
- To explore alternative HER2-targeting strategies to overcome limitations of current treatments.
- To discuss the potential of small-molecule inhibitors and antibody-drug conjugates in gastric cancer therapy.
Main Methods:
- Review of existing literature on HER2-targeted therapies for gastric cancer.
- Analysis of the mechanisms, advantages, and limitations of different therapeutic classes.
- Discussion of clinical evidence for monoclonal antibodies, small-molecule tyrosine kinase inhibitors, and antibody-drug conjugates.
Main Results:
- Monoclonal antibodies like pertuzumab and margetuximab show verified safety and efficacy.
- Small-molecule tyrosine kinase inhibitors (e.g., lapatinib, pyrrotinib) offer advantages like blood-brain barrier penetration and oral bioavailability.
- Antibody-drug conjugates (e.g., T-DM1, T-DXd) can overcome resistance to monoclonal antibodies.
Conclusions:
- HER2-targeted therapies are crucial for gastric cancer treatment, with ongoing development of novel agents.
- Small-molecule inhibitors and antibody-drug conjugates represent promising alternatives and supplements to monoclonal antibodies.
- Personalized treatment strategies based on detailed patient stratification will enhance the role of various HER2-targeting drugs in gastric cancer.
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