The U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) earlier today recommended approval of everolimus tablets (Afinitor?, Novartis Pharmaceuticals) for the treatment of patients with advanced neuroendocrine tumors (NET) of pancreatic origin.

Neuroendocrine tumors arise from cells that can produce and secrete a variety of hormones that regulate bodily functions [9]. These tumors can occur anywhere in the body; however, most are found in the pancreas, gastrointestinal tract or lungs(7,10). Pancreatic NET, also known as islet cell tumors, is a rare type of cancer that is different from pancreatic exocrine cancer, generally referred to as pancreatic cancer. [6,11] There are currently limited treatment options for pancreatic NET patients. [3]

The recommendation was provided after presentation of data from the everolimus RADIANT (RAD001 In Advanced Neuroendocrine Tumors) trial program, the largest conducted in patients with advanced NET. The Phase III RADIANT-3 trial studied patients with advanced NET of pancreatic origin and showed a statistically significant improvement in progression-free survival with everolimus versus placebo. [1]

Trial Results
The RADIANT-3 trial examined the efficacy and safety of everolimus plus best supportive care (BSC) versus placebo plus BSC in 410 patients with advanced, low- or intermediate-grade pancreatic NET. Patients who met the study entry criteria were randomized 1:1 to receive either everolimus 10 mg once-daily (n=207) or daily placebo (n=203) orally, both in conjunction with BSC. [1]

The primary endpoint of RADIANT-3 is progression-free survival (PFS). Secondary endpoints include safety, objective response rate (confirmed according to RECIST), duration of response and overall survival.[1] Results from the trial showed that everolimus more than doubled median PFS from 4.6 to 11.0 months when compared with placebo and reduced the risk of cancer progression by 65% (hazard ratio=0.35 [95% CI, 0.27 to 0.45]; p<0.001) in patients with advanced pancreatic NET. [1]

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In the study, everolimus maintained a safety profile consistent with the prescribing information and previous studies of the drug. The most frequent all grade, drug-related adverse events (greater than or equal to 20%) were stomatitis/oral mucositis/ulcers (64% everolimus vs. 17% placebo; includes stomatitis, aphthous stomatitis, mouth ulceration and tongue ulceration), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), infections (23% vs. 6%), nausea (20% vs. 18%), peripheral edema (20% vs. 3%) and decreased appetite (20% vs. 7%); most were grade one or two. Grade three and four adverse events (greater than or equal to 5%) include stomatitis/oral mucositis/ulcers (7% vs. 0%; includes stomatitis, aphthous stomatitis, mouth ulceration and tongue ulceration), anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). Median exposure to everolimus was 2.3-fold longer than exposure to placebo (38 vs. 16 weeks). [1]

Next steps
The FDA can seek the advice of its advisory committees as it reviews and decides whether to approve treatments, although it is not obliged to follow the recommendation. [4,5]

“We look forward to working with the FDA as it completes its review and we are encouraged by the advisory committee’s recommendation to approve everolimus for patients with advanced pancreatic NET,” said Herve Hoppenot, President, Novartis Oncology. “The study of everolimus in this patient population is an example of our commitment to identify targeted options for patients with critical unmet medical needs.”

When pancreatic NET becomes advanced, meaning the cancer has spread to other parts of the body, it is considered aggressive and difficult to treat. [6] Approximately 60% of pancreatic NET patients are diagnosed with advanced disease, and the five-year survival rate for these patients is 27%. [3,7].

Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism. [2 Preclinical and clinical data have established the role of mTOR in the development and progression of several types of tumors, including advanced pancreatic NET, for which there are limited treatment options [1,2,3].

Earlier this year, the FDA granted everolimus priority review designation for the application and proposed indication for the treatment of advanced NET of gastrointestinal (GI), lung or pancreatic origin. Based on feedback from the FDA, Novartis amended the proposed indication to focus on patients with one specific type of NET, advanced NET of pancreatic origin.

Priority review status is granted to therapies that offer major advances in treatment or provide a treatment where no adequate therapy exists. This status accelerates the standard review time from 10 to six months. [8]. There is the potential that the outcome of an ODAC meeting could result in the FDA extending the review period.

Worldwide regulatory filings for everolimus as a treatment for advanced NET of GI, lung or pancreatic origin are being reviewed by health authorities.

[1] Yao, et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. New Eng J Med 2011;364:514-23.
[2] Motzer, et. al. Phase 3 Trial of Everolimus for Metastatic Renal Cell Carcinoma. Cancer 2010 Sep; 116(18):4256-4265.
[3] Halfdanarson, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Annals of Onc 19: 1727-1733, 2008.
[4] US Food and Drug Administration. Advisory Committees. Oncologic Drugs Advisory Committee. Accessed April 2011.
[5] US Food and Drug Administration. The Federal Advisory Committee Act. Accessed April 2011.
[6] National Library of Medicine and the National Institutes of Health. Pancreatic islet cell tumor. Accessed April 2011.
[7] Yao, et al. One Hundred Years After “Carcinoid:” Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United States. Journal of Clinical Oncology. June 20 2009; vol. 26, number 18.
[8] US Food and Drug Administration. Fast Track, Accelerated Approval and Priority Review. Accessed April 2011.
[9] National Library of Medicine and the National Institutes of Health. Neuroendocrine Tumor. Accessed April 2011.
[10] American Cancer Society Detailed Guides. Gastrointestinal Carcinoid Tumors. Accessed April 2011.
[11] American Cancer Society Detailed Guides. Pancreatic Cancer. Accessed April 2011.

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