This year has been disappointing for physicians and patients hoping for new treatment options for pancreatic cancer. Pfizer terminated its Phase III development of axitinib in pancreatic cancer in January. Sanofi-Aventis and Regeneron Pharmaceuticals also stopped their late-stage study of aflibercept for the same disease last month.
Both these trials ended as independent review boards determined that the combination of gemcitabine and either drug would not produce statistically significant survival improvements compared to gemcitabine alone. Single-agent gemcitabine thus remains the standard treatment for advanced pancreatic cancer.
“How to treat a nonresectable pancreatic cancer has been a challenging topic for all medical oncologists,” commented Yale University Cancer Center researchers Jia Li, Ph.D., and Muhammad Wasif Saif, M.D., in the Journal of the Pancreas. “Numerous combinations using gemcitabine as a backbone have been tested in clinical trials; unfortunately, none of the combinations including the ones with biological agents were significantly superior to gemcitabine alone.
“In general, all combinations significantly rely on the backbone of gemcitabine,” Drs. Li and Saif continued. “Thinking beyond the gemcitabine box and exploring novel agents are very crucial now.”
Even as clinical researchers throw more combinations of drugs at the disease as first- or second-line therapies, pancreatic cancer remains the fourth leading cause of cancer deaths in the U.S. Complete remissions are extremely rare. Due to difficulties in diagnosis, the aggressive nature of pancreatic cancer, and the limited systemic treatments available, the five-year survival rate for patients who have pancreatic adenocarcinoma remains at only about 5%.
About 95% of exocrine pancreatic cancers are adenocarcinomas. The remaining 5% include adenosquamous carcinomas, squamous cell carcinomas, and giant cell carcinomas.
Drugs That Have Failed
The failure of newer noncytotoxic drugs to significantly impact pancreatic cancer is of particular concern, as these medications have proven useful in other intractrable cancers. Neither axitinib or aflibercept were conventional cytotoxics. Axitinib is a small molecule tyrosine kinase inhibitor with multiple targets including VEGFR-1, 2, and 3, platelet-derived growth factor receptor, and cKIT. Aflibercept is a fusion protein that binds all forms of VEGF-A, VEGF-B, and placental growth factor with what is said to be a higher affinity than their natural receptors.
Additionally, trials reported at the 2007 American Society of Clinical Oncology annual meeting conducted by the Cancer and Leukemia Group B and Southwest Oncology Group showed no survival benefit for the combinations of gemcitabine and bevacizumab (Avastin, an anti-VEGF mAb) or cetixuimab (Erbitux, an anti-EGFR receptor mAb).
Tarceva (erlotinib), an epidermal growth factor receptor inhibitor, in combination with gemcitabine, was approved for the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in 2007. Added to gemcitabine, it produces a modest two-week survival benefit and causes significant toxicity.
It has prompted clinicians to question the clinical relevance of its use, but it is generally belived that until physicians can rationally select which agents should be used for any given patient with advanced pancreatic cancer, gemcitabine plus erlotinib can be considered as one of several acceptable choices.