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Emerging tyrosine kinase inhibitors for esophageal cancer
1Memorial Sloan-Kettering Cancer Center, Department of Medicine, Gastrointestinal Oncology Service, 300 East 66th Street, New York, NY 10065, USA.
Introduction:
Because of the poor prognosis for patients with esophagogastric cancers (EGCs), increasing attention has focused on targeted agents.
Areas Covered:
Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), and MET. We briefly discuss preclinical data and the rationale for targeting these pathways and summarize the results of clinical trials of tyrosine kinase inhibitors (TKIs) against these targets.
Expert Opinion:
While anti-EGFR therapy has been extensively investigated, completed Phase III trials suggest that this is not a promising target. A Phase III trial of an anti-VEGF antibody failed to show improvement in the primary endpoint of overall survival but response rates and progression-free survival were improved; a Phase III trial of an anti-VEGF receptor 2 antibody in second-line therapy did show improved survival. As such, Phase II and III evaluations of anti-VEGF TKIs are ongoing. The only Food and Drug Administration-approved targeted therapy in EGC is trastuzumab, an anti-Her2 antibody, and the results of a Phase III evaluation of lapatinib, an anti-Her2 TKI, are awaited. Phase III evaluation of an mTOR inhibitor has been negative. Finally, MET inhibition appears to have significant clinical potential and early testing of MET TKIs is underway.
Insights
Targeted therapies for esophagogastric cancers (EGCs) show varied success. While anti-EGFR and mTOR inhibitors are not promising, anti-VEGF and anti-Her2 agents offer potential, with MET inhibition showing significant clinical promise.
Area of Science:
- Oncology
- Gastroenterology
- Pharmacology
Background:
- Esophagogastric cancers (EGCs) have a poor prognosis, driving research into targeted therapies.
- Key molecular targets include EGFR, VEGF, Her2, mTOR, and MET.
Purpose of the Study:
- To review preclinical data and clinical trial outcomes for targeted agents in EGC.
- To assess the efficacy and potential of various targeted therapies in EGC treatment.
Main Methods:
- Review of preclinical studies and clinical trials (Phase II and III) of targeted agents in EGC.
- Focus on tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting specific pathways.
Main Results:
- Anti-EGFR therapy has not shown promise in Phase III trials.
- Anti-VEGF therapies demonstrate mixed results, with some improving survival and progression-free survival.
- Trastuzumab (anti-Her2) is FDA-approved; further anti-Her2 TKIs are under investigation.
- mTOR inhibitors have yielded negative Phase III results.
- MET inhibition shows significant potential, with ongoing early-phase trials.
Conclusions:
- Targeted therapy in EGC is an evolving field with varied outcomes.
- Anti-VEGF and anti-Her2 therapies, along with MET inhibition, represent promising avenues for future EGC treatment.
- Continued investigation of targeted agents is crucial for improving patient prognosis in EGC.
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