The FDA ( Food and Drug Administration ) has approved Everolimus ( Afinitor tablets ) 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 treated with placebo could cross over to be treated with Everolimus. Among the 203 patients who initially received placebo, 73% crossed over to receive Everolimus. Secondary endpoints included overall survival, response rate, and response duration.

The median PFS for patients treated with Everolimus was 11.0 months compared with 4.6 months for patients treated with placebo [ hazard ratio, HR=0.35; 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 ]. Investigator-determined response rate was 4.8% in patients treated with Everolimus. 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 ( more than 30% ) grade 1-4 adverse reactions were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common ( more than 5% ) grade 3-4 adverse reactions were stomatitis and diarrhea. The most common ( more than 3% ) grade 3-4 laboratory abnormalities were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase, decreased potasssium, and thrombocytopenia.

Deaths occurred in 7 patients treated with Everolimus and 1 patient treated with placebo. Causes of death in patients treated with Everolimus 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 myocardial infarction with congestive heart failure, and the other due to sudden death. Adverse events resulted in permanent discontinuation in 20% of patients treated with Everolimus and 6% of patients treated with placebo. Dose delays and/or reductions were necessary in 61% of patients treated with Everolimus and 29% of patients treated with placebo. 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% with 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 per day or dose interruption.

Source: National Cancer Institute, 2011

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