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U.S. Department of Health and Human Services

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Everolimus 2011

On May 5, 2011, the U. S. Food and Drug Administration approved everolimus (Afinitor Tablets, Novartis Pharmaceuticals Corporation), for the treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of everolimus in the treatment of patients with carcinoid tumors have not been established. 

The approval was based on a randomized, controlled trial of everolimus 10 mg/d (n=207) versus placebo (n=203) in patients with unresectable, locally advanced or metastatic pancreatic neuroendocrine tumors. Patients were stratified by prior cytotoxic chemotherapy and by WHO performance status. Treatment with somatostatin analogs was allowed as part of best supportive care. The primary endpoint was progression-free survival (PFS) as assessed by the investigator. After documented radiological progression, patients on the placebo arm could cross over to everolimus. Among the 203 patients randomized to placebo, 73% crossed over to everolimus. Secondary endpoints included overall survival, response rate, and response duration.

The median PFS was 11.0 and 4.6 months in the everolimus and placebo arms, respectively [HR 0.35 (95% CI: 0.27, 0.45), p < 0.001]. An improvement in PFS was observed across all patient subgroups, irrespective of prior somatostatin analog use. An interim analysis showed no difference in overall survival [HR 1.05 (95% CI: 0.71, 1.55)].
Investigator-determined response rate was 4.8% in the everolimus arm. There were no complete responses.

Safety data were evaluated in 204 patients who received everolimus during the double-blind portion of the randomized trial described above and in 858 patients with advanced neuroendocrine tumors in the safety database. The most common (> 30%) grade 1-4 adverse reactions were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common (> 5%) grade 3-4 adverse reactions were stomatitis and diarrhea. The most common (> 3%) grade 3-4 laboratory abnormalities were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia.

Deaths occurred in 7 patients on everolimus and 1 patient on placebo. Causes of death on the everolimus arm included acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. After crossover to open-label everolimus, there were 3 additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to MI with CHF, and the other due to sudden death. Adverse events resulted in permanent discontinuation in 20% and 6% of patients in the everolimus and placebo arms, respectively. Dose delays and/or reductions were necessary in 61% of everolimus patients and 29% of placebo patients. Opportunistic infections in patients with advanced neuroendocrine tumors included hepatitis B reactivation (resulting in death), mycobacterial infection, and invasive aspergillus. Pneumonitis was seen in 11% of patients (1.7% were grade 3/4) in the safety database.

The recommended dose and schedule for everolimus is 10 mg orally each day. Patients with severe or intolerable adverse reactions may require temporary dose reductions to 5 mg/daily or dose interruption. 

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022344s9s10lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).