The approval was based on Phase III data from the RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors) trial showing 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. The FDA determined that the safety and effectiveness of Afinitor in the treatment of patients with carcinoid tumors have not been established.
"The FDA approval of Afinitor represents an important step forward for patients with advanced pancreatic NET," said James Yao, MD, Associate Professor of Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. "Patients will now have access to a treatment that has been shown to significantly delay tumor growth and reduce the risk of disease progression."
Approximately 60% of pancreatic NET patients are diagnosed with advanced disease. This means that the cancer has already spread to other parts of the body, and is considered aggressive and difficult to treat. The five-year survival rate for these patients is 27%.
"With this approval, US physicians can now offer their patients with progressive pancreatic NET a new treatment helping to fulfill a critical unmet need," said Hervé Hoppenot, President, Novartis Oncology. "This is the third indication for Afinitor in the US in just over two years, providing further evidence that inhibiting mTOR plays an important role in treating multiple tumor types."
Afinitor targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism. Preclinical and clinical data have established the role of mTOR in the development and progression of several types of tumors, including advanced pancreatic NET,
Novartis has submitted marketing applications for everolimus for the treatment of patients with advanced NET of gastrointestinal, lung or pancreatic origin to the European Medicines Agency (EMA) and the Swiss Agency for Therapeutic Products (Swissmedic), and additional regulatory submissions are being reviewed by health authorities 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. These tumors can occur anywhere in the body; however, most are found in the pancreas (pancreatic NET), gastrointestinal tract or lungs (carcinoid tumors),. 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,. There have been limited treatment options for patients with pancreatic NET.
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 Afinitor 10 mg once-daily (n=207) or daily placebo (n=203) orally, both in conjunction with BSC.
The primary endpoint of RADIANT-3 is progression-free survival. Secondary endpoints include safety, objective response rate (confirmed according to RECIST), duration of response and overall survival.
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 FDA determined that the safety and effectiveness of Afinitor in the treatment of patients with carcinoid tumors have not been established.
Afinitor is approved in the European Union (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 and also in the US for the treatment of patients with advanced RCC after failure of treatment with sunitinib or sorafenib.
Afinitor is also approved in the US to treat patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgical resection. The effectiveness of Afinitor is based on an analysis of change in SEGA volume. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been shown. Novartis has submitted marketing applications for everolimus for this use to the European Medicines Agency (EMA) and the Swiss Agency for Therapeutic Products (Swissmedic), and additional regulatory submissions are under way worldwide.
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. In the US, everolimus is available in different dosage strengths under the trade name Zortress® for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant.
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. As an investigational compound the safety and efficacy profile of everolimus has not yet been established in all countries in pancreatic or any other type of NET. 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. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for pancreatic or any other type of NET, or additional indications anywhere else in the world.
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, 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, rash, diarrhea, fatigue, acneiform dermatitis, infections, weakness, nausea, peripheral swelling, decreased appetite, headache, pneumonitis, abnormal taste, nose bleeds, mucosal inflammation, weight decreased and vomiting. The most common grade 3-4 adverse drug reactions (incidence >=2%) are mouth ulcers, fatigue, decreased white blood cell count, diarrhea, infections, pneumonitis and diabetes mellitus. Cases of hepatitis B reactivation and pulmonary embolism have been reported.