Novartis drug Afinitor® recommended by CHMP for EU approval

Novartis announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for 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. If approved, everolimus will be the first mTOR inhibitor available for these patients.

“This positive recommendation is an important milestone for patients in the European Union with advanced pancreatic NET who have a difficult to treat cancer and limited treatment options,” said Hervé Hoppenot, President, Novartis Oncology. “We are encouraged that this positive opinion may lead to an approval that will allow us to provide these patients a new targeted treatment approach.”

The recommendation was based on Phase III data from the RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors) trial showing treatment with everolimus 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 everolimus in all patient subgroups, including those who had not received prior chemotherapy [1].

Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism [4]. Preclinical and clinical data have established the role of mTOR in the development and progression of advanced pancreatic NET [1],[4].

The European Commission generally follows the recommendations of the CHMP and delivers its final decision within three months of the CHMP recommendation. The decision will be applicable to all 27 EU member states plus Iceland and Norway.

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 [5]. These tumors can occur anywhere in the body; however, most are found in the pancreas (pancreatic NET), gastrointestinal tract or lungs (carcinoid tumors) [6],[7]. 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 [3],[8].

Approximately 60% of pancreatic NET patients are diagnosed with advanced disease [2]. This means that the cancer has already spread to other parts of the body, and is considered aggressive and difficult to treat [3]. The five-year survival rate for these patients is 27%[6].

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 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. The primary endpoint is progression-free survival [1].

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 (>=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 (>=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 weeks vs. 16 weeks)[1].

About Afinitor (everolimus)

Afinitor® (everolimus) tablets is approved in the US for the treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease. The US Food and Drug Administration determined that the safety and effectiveness of Afinitor in the treatment of patients with carcinoid tumors have not been established.

In the European Union (EU), Afinitor is approved for the treatment of patients with advanced renal cell carcinoma whose disease has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy.

In the EU, everolimus is available 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. Halfdanarson, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Annals of Onc 19: 1727-1733, 2008.
3. 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 April 2011.
4. Motzer, et. al. Phase 3 Trial of Everolimus for Metastatic Renal Cell Carcinoma. Cancer 2010 Sep; 116(18):4256-4265.
5. National Library of Medicine and the National Institutes of Health. Neuroendocrine Tumor. Available at http://www.cancer.gov/dictionary/?CdrID=44904. Accessed April 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. American Cancer Society Detailed Guides. Gastrointestinal Carcinoid Tumors. Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003102-pdf.pdf. Accessed April 2011.
8. American Cancer Society Detailed Guides. Pancreatic Cancer. Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003131-pdf.pdf. Accessed April 2011.