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Targeting FGFR2 Positive Gastroesophageal Cancer: Current and Clinical Developments
Anderley Gordon1, Edwina Johnston1, David K Lau1
1Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation, London, UK.
Abstract:
Despite recent advances in the systemic treatment of gastroesophageal cancers, prognosis remains poor. Comprehensive molecular analyses have characterized the genomic landscape of gastroesophageal cancer that has established therapeutic targets such as human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR) and programmed death ligand 1 (PD-L1). The aberrant fibroblast growth factor receptor 2 (FGFR2) pathway is attractive for targetable therapy with FGFR inhibition based on preclinical data showing a pivotal role in the progression of gastric cancer (GC). FGFR2 amplification is the most common FGFR2 gene aberration in gastroesophageal cancer, and most associated with diffuse GC, which is often linked to poorer prognostic outcomes. There has been considerable progress with drug development focused on FGFR inhibition. At present, there is no approved FGFR inhibitor for FGFR2 positive gastroesophageal cancer. A selective FGFR2b monoclonal antibody bemarituzumab is currently being investigated in the first phase III randomized trial for patients with first line advanced GC, which may change the treatment paradigm for FGFR2b positive GC. The role of FGFR signalling, specifically FGFR2, is less established in oesophageal squamous cell cancer (ESCC) with a paucity of evidence for clinical benefit in these patients. Precision medicine is part of the wider approach in gastrointestinal cancers; however, it can be challenging due to heterogeneity and here circulating tumour DNA (ctDNA) for patient selection may have future clinical utility. In our review, we outline the FGFR pathway and focus on the developments and challenges of targeting FGFR2 driven gastroesophageal cancers.
Insights
Targeting fibroblast growth factor receptor 2 (FGFR2) offers a promising therapeutic strategy for gastroesophageal cancers. Research explores FGFR2 inhibition and its potential to improve outcomes in advanced gastric cancer.
Area of Science:
- Oncology
- Molecular Biology
- Gastroenterology
Background:
- Gastroesophageal cancers have a poor prognosis despite advances in systemic treatment.
- Fibroblast growth factor receptor 2 (FGFR2) pathway aberrations, particularly FGFR2 amplification, are implicated in gastric cancer progression.
- FGFR2 amplification is common in diffuse gastric cancer, associated with worse outcomes.
Purpose of the Study:
- To review the fibroblast growth factor receptor (FGFR) pathway in gastroesophageal cancers.
- To focus on the developments and challenges in targeting FGFR2-driven gastroesophageal cancers.
- To discuss the potential of FGFR inhibitors in precision medicine for these cancers.
Main Methods:
- Review of preclinical data on FGFR2's role in gastric cancer.
- Analysis of current drug development for FGFR inhibitors.
- Examination of ongoing clinical trials, including bemarituzumab for advanced gastric cancer.
- Discussion of the role of FGFR signaling in esophageal squamous cell cancer.
- Consideration of circulating tumor DNA (ctDNA) for patient selection.
Main Results:
- FGFR2 amplification is a key aberration in gastroesophageal cancer, especially diffuse gastric cancer.
- Several FGFR inhibitors are in development, with bemarituzumab in a Phase III trial for advanced gastric cancer.
- The clinical benefit of targeting FGFR2 in esophageal squamous cell cancer is less established.
- Biomarker strategies, like ctDNA, are crucial for patient selection in precision medicine.
Conclusions:
- Targeting the FGFR2 pathway represents a significant opportunity for precision medicine in gastroesophageal cancers.
- Further research and clinical trials are needed to establish the efficacy of FGFR inhibitors.
- Overcoming challenges like tumor heterogeneity is essential for successful FGFR-targeted therapies.
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