Current Targeted Therapies in HER2-Positive Gastric Adenocarcinoma
Fabiana G Curea1, Mohamed Hebbar2, Silvia M Ilie1,3
11 Department of Oncology-Radiotherapy, Institute of Oncology "Prof. Dr. Alexandru Trestioreanu," Bucharest, Romania .
Abstract:
Gastric cancer is one of the most common types of cancer in the world, usually diagnosed at an advanced stage. Despite the advances in specific anticancer agents' development, the survival rates remain modest, even in early stages. In 15%-20% of cases, the human epidermal growth factor receptor 2 (HER2) overexpression was identified. We conducted a general review to summarize the progress that has been made in the targeted treatment of HER2-positive esogastric junction or gastric adenocarcinoma. According to our findings, trastuzumab is the only validated anti-HER2 agent in locally advanced or metastatic disease and its adjuvant effectiveness is assessed in a RTOG phase III study. In a previously treated advanced disease, the maytansine derivate TDM 1 failed to be approved as a second-line regimen, and the tyrosine kinase inhibitor, lapatinib, shows modest results. The antiangiogenics have not been analyzed in specific populations and targeting the mesenchymal-epithelial transition factor (MET) receptor, overexpressed in up to 46% of the advanced disease, seems encouraging. Regarding the checkpoint inhibitors, based on KEYNOTE 059 multilevel ongoing trial, stratified according to the HER2 and programmed death-ligand (PD-L) 1 status, pembrolizumab was approved for third-line treatment of gastric or gastroesophageal junction adenocarcinoma.
Insights
Targeted therapies for HER2-positive gastric cancer show promise, with trastuzumab as the primary validated agent. Research is ongoing for other targets like MET and checkpoint inhibitors, offering potential new treatment avenues.
Area of Science:
- Oncology
- Gastroenterology
- Pharmacology
Background:
- Gastric cancer is a prevalent malignancy often diagnosed at advanced stages.
- Survival rates for gastric cancer remain suboptimal despite therapeutic advancements.
- Human epidermal growth factor receptor 2 (HER2) overexpression occurs in 15-20% of gastric cancer cases.
Purpose of the Study:
- To review advancements in targeted therapies for HER2-positive esogastric junction and gastric adenocarcinoma.
- To summarize the efficacy and limitations of current and emerging anti-HER2 agents.
- To explore potential therapeutic targets beyond HER2 in advanced gastric cancer.
Main Methods:
- A comprehensive literature review was conducted.
- Focus was placed on targeted treatments for HER2-positive gastric and esophagogastric junction adenocarcinomas.
- Efficacy data for various agents, including trastuzumab, TDM 1, lapatinib, antiangiogenics, and checkpoint inhibitors, were analyzed.
Main Results:
- Trastuzumab is the sole validated anti-HER2 agent for locally advanced or metastatic disease.
- Trastuzumab's adjuvant effectiveness is under investigation in a Phase III trial.
- Other agents like TDM 1 and lapatinib have shown limited success in advanced settings.
- Targeting the MET receptor and utilizing checkpoint inhibitors like pembrolizumab show encouraging results for specific patient populations.
Conclusions:
- Trastuzumab remains the cornerstone of HER2-targeted therapy in advanced gastric cancer.
- Emerging strategies targeting MET and immune checkpoints offer new hope for treatment-resistant or HER2-negative/low disease.
- Further research is needed to optimize targeted therapy combinations and identify predictive biomarkers.
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