Targeting FGFR2 Positive Gastroesophageal Cancer: Current and Clinical Developments.

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.

Neoadjuvant and Adjuvant Therapy Approaches to Gastric Cancer.

OPINION STATEMENT: Gastric cancer is an aggressive malignancy, requiring a multimodality approach to achieve optimal curative rates even when the disease is amenable to surgical resection. Neoadjuvant and adjuvant approaches differ across the globe-a preference for peri-operative chemotherapy exists in Europe, in contrast to the adoption of adjuvant chemotherapy in Asia and adjuvant chemoradiotherapy in North America. There are nuances and limitations associated with each therapeutic strategy and an understanding of these distinct approaches is integral to judicious clinical application of the available data. Although a multimodal approach provides a clear survival benefit above a surgical-only approach, data report low completion rates of adjuvant therapy components and strongly suggest a need to refine patient selection particularly for ongoing treatment in the post-operative period. This may be achieved using a risk-stratified strategy. Hence, there is a need to transition from a generalised approach to a multimodality treatment towards one guided by individual patient clinical features and biomarker profiles in order to improve tolerability and patient outcomes irrespective of geographical variation in clinical practice. While the evidences supporting molecular features such as microsatellite instability and predictive gene signatures are provocative, prospective validation is required before these can be confidently used to direct clinical decision-making.