New Therapeutic Directions for Advanced Pancreatic Cancer: Targeting the Epidermal Growth Factor and Vascular Endothelial Growth Factor Pathways

Abstract

Abstract Learning Objectives After completing this course, the reader will be able to: Evaluate the existing chemotherapeutic options for advanced pancreatic cancer.Interpret data from trials of HER-1/EGFR- and VEGFR-targeted agents in advanced pancreatic cancer.Take advantage of the potential of biomarkers in selecting optimal molecular-targeted therapies for advanced pancreatic cancer. CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com In advanced pancreatic cancer, single-agent gemcitabine became the standard therapy approximately 10 years ago. Subsequently, combinations of gemcitabine with fluorouracil, cisplatin, irinotecan, oxaliplatin, or pemetrexed produced no clear survival benefit. Among the newer approaches, targeting human epidermal growth factor receptor (HER-1/EGFR) shows promise. The U.S. Food and Drug Administration recently approved erlotinib (a HER-1/EGFR tyrosine kinase inhibitor) combined with gemcitabine for the first-line treatment of advanced pancreatic cancer. This combination showed a statistically significant survival benefit over gemcitabine alone in locally advanced or metastatic disease (the median overall survival time was 6.24 months versus 5.91 months; hazard ratio, 0.82; p = .038); however, the clinical significance of this survival difference has been questioned. Additionally, a large phase III trial where the addition of cetuximab (an anti–HER-1/EGFR monoclonal antibody [mAb]) to gemcitabine failed to result in a longer overall survival time than with gemcitabine alone has been reported. Targeting vascular endothelial growth factor (VEGF) with bevacizumab (a recombinant, humanized IgG1 mAb that binds to VEGF) in combination with gemcitabine was investigated in a phase II trial, with promising outcomes that were unfortunately not supported by a subsequent phase III study. While the future treatment of pancreatic cancer may be influenced by the potential of certain biomarkers to predict better response to molecular-targeted therapies, allowing individualization of patient therapy, there are currently no clear candidates, and this remains an interesting area for further investigation.