Novartis drug Afinitor® gains EU approval to treat patients with advanced pancreatic neuroendocrine tumors

Novartis announced today that the European Commission has approved Afinitor® (everolimus) tablets for the treatment of unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumors (NET) of pancreatic origin in adults with progressive disease[3].

The approval was based on Phase III data from the largest clinical trial to date in advanced pancreatic NET. The RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors) trial showed treatment with Afinitor more than doubled the time without tumor growth (median 4.6 to 11.0 months) and reduced the risk of cancer progression by 65% when compared with placebo in patients with advanced pancreatic NET (hazard ratio=0.35 [95% confidence interval (CI), 0.27 to 0.45]; p<0.001). A consistent improvement in progression-free survival was seen with Afinitor in all patient subgroups, including patients who had not received prior chemotherapy[1].

Approximately 60% of pancreatic NET patients are diagnosed with advanced disease[4]. This means that the cancer has already spread to other parts of the body, and is considered aggressive and difficult to treat[5]. The five-year survival rate for these patients is 27%[6].

“Today’s approval of Afinitor means that thousands of advanced pancreatic NET patients across Europe will have a new targeted approach for the treatment of this aggressive cancer type for which few therapeutic options are available,” said Hervé Hoppenot, President, Novartis Oncology. “We remain committed to the development of everolimus and to further researching the role of mTOR inhibition in multiple tumor types to address significant unmet medical needs for patients.”

Afinitor 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[1],[2]. Afinitor is the first mTOR inhibitor approved in the EU for the treatment of NET of pancreatic origin.

The decision applies in all 27 European Union member states, plus Iceland and Norway. Additional regulatory submissions for everolimus in advanced NET are under way worldwide.

About neuroendocrine tumors of pancreatic origin (pancreatic NET)

Neuroendocrine tumors arise from cells that can produce and secrete a variety of hormones that regulate bodily functions[7]. These tumors can occur anywhere in the body; however, most are found in the pancreas (pancreatic NET), gastrointestinal tract or lungs (carcinoid tumors)[6],[8]. Pancreatic NET, also known as islet cell tumors, is a rare type of cancer different from pancreatic exocrine cancer, which is generally referred to as pancreatic cancer[5],[9].

About RADIANT-3

RADIANT-3 is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial examined the efficacy and safety of Afinitor 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. The primary endpoint is progression-free survival[1].

About Afinitor (everolimus)

Afinitor® (everolimus) tablets is approved in the European Union (EU) for the treatment of unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumors (NET) of pancreatic origin in adults with progressive disease. Afinitor is also approved in the EU for the treatment of patients with advanced renal cell carcinoma (RCC) whose disease has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy.

Everolimus is also available in the EU in different dosage strengths for the non-oncology patient population under the trade name Certican® for the prevention of organ rejection in heart and kidney transplant recipients.

Everolimus is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Not all indications are available in every country. Access to everolimus outside of the approved indications has been carefully controlled and monitored in clinical trials designed to better understand the potential benefits and risks of the compound. As an investigational compound the safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications.

Important Safety Information about Afinitor (everolimus) tablets

Afinitor can cause serious side effects including lung or breathing problems, infections, and renal failure which can lead to death. Mouth ulcers and mouth sores are common side effects. Afinitor can affect blood cell counts, kidney and liver function, and blood sugar and cholesterol levels. Afinitor may cause fetal harm in pregnant women. Women taking Afinitor should not breast feed.

The most common adverse drug reactions (incidence >=15%) are mouth ulcers, diarrhea, feeling weak or tired, skin problems (such as rash or acne), infections, nausea, swelling of extremities or other parts of the body, loss of appetite, headache, inflammation of lung tissue, abnormal taste, nose bleeds, inflammation of the lining of the digestive system, weight decreased and vomiting. The most common Grade 3-4 adverse drug reactions (incidence >=2%) are mouth ulcers, feeling tired, low white blood cells (a type of blood cell that fights infection), diarrhea, infections, inflammation of lung tissue, and diabetes. Cases of hepatitis B reactivation and blood clot in the lung and leg have been reported.

References

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. Afinitor® (everolimus) tablets Summary of Product Characteristics. Basel, Switzerland: Novartis; September 2011.
4. Halfdanarson, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Annals of Onc 19: 1727-1733, 2008.
5. National Library of Medicine and the National Institutes of Health. Pancreatic islet cell tumor. Available at http://www.nlm.nih.gov/medlineplus/ency/article/000393.htm. Accessed August 2011.
6. 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.
7. National Library of Medicine and the National Institutes of Health. Neuroendocrine Tumor. Available at http://www.cancer.gov/dictionary/?CdrID=44904. Accessed August 2011.
8. American Cancer Society Detailed Guides. Gastrointestinal Carcinoid Tumors. Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003102-pdf.pdf. Accessed August 2011.
9. American Cancer Society Detailed Guides. Pancreatic Cancer. Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003131-pdf.pdf. Accessed August 2011.