FDA Approval for Everolimus

Brand name(s): AFINITOR®

• Approved for Progressive Neuroendocrine Tumors of Pancreatic Origin (PNET) in unresectable, locally advanced or metastatic disease.
• Approved for Subependymal Giant Cell Astrocytoma (SEGA) associated with Tuberous Sclerosis (TS) that cannot be surgically removed.
• Approved for Advanced Renal Cell Carcinoma after Failure of Treatment with Sunitinib or Sorafenib.

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

Progressive Neuroendocrine Tumors of Pancreatic Origin (PNET)

On May 5, 2011, the Food and Drug Administration (FDA) approved everolimus (Afinitor^® Tablets, made by 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 treated with placebo could cross over to be treated with everolimus. Among the 203 patients who initially received placebo, 73 percent 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 [HR 0.35 (95 percent 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 percent CI: 0.71, 1.55)]. Investigator-determined response rate was 4.8 percent 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 percent) grade 1-4 adverse reactions were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common (more than 5 percent) grade 3-4 adverse reactions were stomatitis and diarrhea. The most common (more than 3 percent) 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 percent of patients treated with everolimus and 6 percent of patients treated with placebo. Dose delays and/or reductions were necessary in 61 percent of patients treated with everolimus and 29 percent 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 percent of patients (1.7 percent 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.

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Subependymal Giant Cell Astrocytoma (SEGA) associated with Tuberous Sclerosis (TS)

On October 29, 2010, the FDA granted accelerated approval to everolimus (Afinitor^® made by Novartis), an mTOR inhibitor, for patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require therapy but are not candidates for surgical resection. Afinitor was originally approved in March 2009 for the treatment of adult patients with advanced renal cell carcinoma (RCC) whose disease was resistant to sunitinib or sorafenib.

The efficacy and safety of everolimus in patients with SEGA was demonstrated in a single-arm open-label clinical trial.  Twenty-eight patients whose SEGA lesions had demonstrated evidence of growth on serial imaging received everolimus orally once daily at a starting dose of 3 mg/m²/day with subsequent titration to a whole blood concentration of 5-15 ng/mL.  The median age was 11 years (range 3-34), 61 percent were male, and 86 percent were Caucasian.  The primary efficacy endpoint was reduction in the volume of the primary SEGA lesion at 6 months.  The median duration of treatment on this trial was 24.4 months (range 4.7-37.3 months).

Nine of 28 patients (32 percent, 95 percent CI: 16 percent - 52 percent) had a 50 percent reduction or greater in the volume of their largest SEGA lesion at 6 months.  Three of the four patients with a history of prior surgery had more than a 50 percent reduction in tumor volume.  Median response duration for the nine patients who responded was 266 days (range 97 to 946 days).  No complete responses were observed.

All patients experienced at least one adverse event.  The most common adverse events (incidence of at least 30 percent) included stomatitis, upper respiratory tract infections, sinusitis, otitis media, and pyrexia.  Grade 3 adverse reactions were reported in 36 percent of patients and included convulsion, infections (sinusitis, pneumonia, tooth infection, and viral bronchitis), stomatitis, aspiration, cyclic neutropenia, sleep apnea syndrome, vomiting, dizziness, white blood cell count decreased, and neutrophil count decreased.  Convulsions (grade 4) were noted in a single patient.  No deaths were observed during the study.

Laboratory abnormalities (seen in than 30 percent of patients) included transaminase elevations, hypercholesterolemia and hypertriglyceridemia, leukopenia, anemia, and hyperglycemia.

Live vaccines and close contact with those who have received live vaccines should be avoided.

The recommended starting dose of everolimus for this indication is based on body surface area as shown in the following table with subsequent titration to attain a blood trough concentration of 5-10 ng/mL.

Recommended Starting Dose of Everolimus for Treatment of Patients with SEGA

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Advanced Renal Cell Carcinoma after Failure of Treatment with Sunitinib or Sorafenib

On March 30, 2009, the FDA approved everolimus tablets (AFINITOR ®, made by Novartis Pharmaceuticals Corporation) for the treatment of patients with advanced renal cell carcinoma after failure of treatment with Sunitinib or Sorafenib.

The efficacy and safety of everolimus were evaluated in an international, multicenter, randomized, double-blind trial comparing everolimus to placebo. All patients received best supportive care. The trial was conducted in patients with metastatic renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Prior therapy with bevacizumab, interleukin-2, or interferon-α was also permitted. Randomization was stratified according to prognostic score and prior anticancer therapy.

A total of 416 patients were randomly selected (2:1 ratio) to receive everolimus (n=277) or placebo (n=139). Demographics were well balanced between the two arms. Progression-free survival (PFS) was the trial's primary endpoint. The median PFS was 4.9 and 1.9 months in the everolimus and placebo arms, respectively (HR = 0.33, p value < 0.0001). The treatment effect was similar across prognostic scores and prior treatment status. The overall survival results were not mature; 32 percent of patients had died by the time of data cut-off. The objective response rates were 2 percent and 0 percent for everolimus and placebo, respectively. After documented radiological progression, patients receiving placebo could receive everolimus.

The most common adverse reactions (incidence ≥30 percent) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥ 3 percent) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine (incidence ≥50 percent). The most common grade 3/4 laboratory abnormalities (incidence ≥3 percent) were phopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7 percent), infection (0.7 percent) and acute renal failure (0.4 percent) occurred on the everolimus arm but not on the placebo arm.