Biomarkers and novel agents in esophago-gastric cancer: are we making progress?

Abstract

Esophago-gastric cancer (EGC) provides a formidable healthcare challenge. Conventional chemotherapy provides modest survival benefit in patients with advanced disease especially in the second-line setting. The recent paradigm shift in the oncology community towards targeting growth factor pathways and the immune system using novel targeted agents has now demonstrated clinical utility in EGC, but recent trial results have highlighted the complexity of disease pathogenesis and significant challenges remain. Here, we describe the current role of targeted therapies in EGC, and their corresponding biomarkers. We aim to provide a comprehensive review of the current climate of novel agents and their biomarkers in advanced EGC.

Keywords:

• biomarkers
• esophageal cancer
• gastric cancer
• targeted agents
• translational medicine

Financial & competing interests disclosure

A Dahle-Smith has received travel/educational funding from Lilly and Boston Biomedical. RD Petty has received research funding from Roche, AstraZeneca, Life Technologies and Aridhia; travel/educational funding from Bayer, Lilly, GSK and Sanofi and has had an advisory role for Lilly, Bayer, Pfizer and MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Esophago-gastric cancer (EGC) has a poor prognosis.

• Palliative chemotherapy provides a 9- to 11-month survival in patients with advanced EGC.

• Single agent second line chemotherapy can provide small survival and quality of life benefits in patients with good performance status.

• Targeted treatment with trastuzumab in addition to chemotherapy increases survival to 13.8 months in patients whose tumors harbored either HER2 overexpression or HER2 amplification. This confirmed that targeted anti-cancer therapies have a role in the treatment of advanced EGC.

• Anti-EGFR mAbs have not demonstrated survival in EGC, however, EGFR tyrosine kinase inhibitor may confer survival benefit in a subgroup of patients. Translational studies are ongoing to establish biomarkers of gefitinib response.

• The VEGF2 mAb ramucirumab has demonstrated improved overall survival as a single agent and in combination with paclitaxell chemotherapy in the second-line setting in advanced EGC. There are no predictive biomarkers of ramucirumab response. The VEGF tyrosine kinase inhibitor apatinib has shown some promise in Phase II studies, which remain to be validated in a Phase III clinical trial.

• Inhibitors of the c-MET and FGFR2 pathways are currently being investigated. However Phase III trials to date have not shown effiacy, even in biomarker selected subgroups.

• The immunotherapy pembrolizumab, an mAb against programmed death-1, is currently being investigated in a Phase II study in EGC.

• A number of growth factor pathways and immune responses are being exploited as druggable targets in EGC. It is important to discover and develop reliable and reproducible assays for predictive biomarkers in tandem with novel agent development to ascertain patient subgroups most likely to benefit from targeted treatment.

• Genomic landscape studies are beginning to define a new molecular classification of EGC, which could identify new targets and direct treatment to molecularly defined subgroups.

Notes