The European Medicines Agency earlier today approved sunitinib malate (Sutent?, Pfizer) for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET) with disease progression in adults. Experience with sunitinib malate as initial treatment is limited in this disease. Pancreatic NET is a rare cancer reported in two to four people per million annually worldwide. [1,2] Sutent is the first treatment to be approved for patients with pancreatic NET in twenty-five years.[3]

Tumors of the neuroendocrine system are typically classified into two distinct categories: carcinoids or pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors, also known as pancreatic islet cell tumors, form in the endocrine (hormone-producing) tissues of the pancreas.[7] Subtypes include insulinomas, glucagonomas and gastrinomas. Pancreatic neuroendocrine tumors are different from pancreatic adenocarcinoma, which account for about 95% of all pancreatic cancers.[7]

Sunitinib malate is an oral multi-kinase inhibitor approved for the treatment of advanced/metastatic renal cell carcinoma (RCC) and unresectable and/or metastatic malignant gastrointestinal stromal tumor (GIST) after failure of imatinib mesilate treatment due to resistance or intolerance. In Europe, sunitinib is also indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults. Experience with sunitinib as first-line treatment is limited.

Sunitinib works by blocking multiple molecular targets implicated in the growth, proliferation and spread of cancer. Two important sunitinib targets, vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), are expressed by many types of solid tumors and are thought to play a crucial role in angiogenesis, the process by which tumors acquire blood vessels, oxygen and nutrients needed for growth. Sunitinib also inhibits other targets important to tumor growth, including KIT, FLT3 and RET.

The European approval of Sunitinib for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET) is based on results from a randomized, Phase III trial that demonstrated Sunitinib more than doubled the time period that patients were free from disease progression or death. The progression-free survival (PFS) for sunitinib was 11.4 months vs. 5.5 months for placebo (p=0.0001) in 171 patients. Additionally, while the overall survival data were not mature at the time of analysis, the overall survival favored the sunitinib arm compared with placebo (9 vs. 21 deaths) (HR 0.409, p=0.0204).[4]

Advertisement #3

“This approval represents a significant milestone in the management of pancreatic NET,” said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs, Pfizer Oncology Business Unit. “SUTENT has been a standard of care for patients with advanced/metastatic renal cell carcinoma (RCC) and imatinib-refractory gastrointestinal stromal tumor (GIST) for several years, and we are proud that it is now a treatment option for patients in Europe with progressive pancreatic NET.”

Although rare, the reported incidence of pancreatic NET appears to be rising, [2,5] accounting for approximately nine percent of neuroendocrine tumors. [5] Current treatment options have limited therapeutic benefit and the prognosis is poor for patients with advanced pancreatic NET.[6]

“As the first anti-VEGF therapy to show a substantial clinical benefit in treating progressive pancreatic NET, SUTENT represents a novel therapeutic approach for this difficult-to?treat disease.” said Dr. Eric Raymond, principal investigator of the pivotal Phase 3 study that led to the approval of Sutent for pancreatic NET in Europe. “Physicians in Europe will now be able to use a therapy with proven efficacy to treat this disease.” Dr. Raymond is professor of medical oncology and head of University Department of Medical Oncology (Service Inter Hospitalier de Cancerologie) Bichat-Beaujon, Clichy, France.

Sunitinib is also approved for the treatment of unresectable well-differentiated advanced and/or metastatic pancreatic neuroendocrine carcinoma in the Philippines, Switzerland, Colombia and Korea. In addition, it is under regulatory review for this indication in several other countries.

For more information:
[1] Ramage JK, Davies AHG, Ardill et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumors. Gut. 2005;54:iv1?16.
[2] Halfdanarson TR, Rabe KG, Rubin J et al. Pancreatic neuroendocrine tumors (pNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19:1727?33
[3] U.S. Food and Drug Administration. Drugs@FDA: Zanosar . Accessed November 17, 2010.
[4] Niccoli, P., Raoul, J., Bang, Y., et al. Updated safety and efficacy results of the phase III trial of sunitinib (SU) vs placebo (PBO) for treatment of pancreatic neuroendocrine tumors (NET). ASCO 2010.
[5] Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. Jun 20 2008;26(18):3063-3072.
[6] Yao JC, Eisner MP, Leary C, et al. Population-based study of islet cell carcinoma. Ann Surg Oncol. 2007;14(12):3492-3500.
[7] National Cancer Institute. Islet Cell Tumors (Endocrine Pancreas) Treatment ? Patient Version. Accessed January 5, 2010.

Advertisement #5