FDA Approval for Everolimus
Brand name(s): Afinitor®
- Approved for Pediatric and Adult Patients with Subependymal Giant Cell Astrocytoma (SEGA)
- Approved for Advanced Hormone Receptor-positive, HER2-negative Breast Cancer in Combination with Exemestane.
- Approved for Progressive Neuroendocrine Tumors of Pancreatic Origin (PNET).
- Approved for Subependymal Giant Cell Astrocytoma (SEGA) associated with Tuberous Sclerosis (TS).
- 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.
On August 29, 2012, the Food and Drug Administration (FDA) granted accelerated approval for everolimus tablets for oral suspension (Afinitor Disperz®, made by Novartis Pharmaceuticals Corp.) for the treatment of pediatric and adult patients with tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. With this new dosage form, the currently approved indication for treatment of SEGA has been expanded to allow treatment of children younger than 3 years of age. The application also provides a higher starting dose, revisions to dose modifications, and additional safety and efficacy data in the SEGA population.
Afinitor Disperz® is the first pediatric formulation to be approved by FDA for the treatment of a tumor that occurs primarily during childhood. This new dosage form (tablets for oral suspension) is more rapidly dissolved using smaller volumes of water than the tablet dosage form used in clinical trials and provides for smaller dose increments, allowing greater dosing flexibility. This formulation also provides another option for adult patients with SEGA.
On October 29, 2010, everolimus (Afinitor® Tablets) received its initial accelerated approval for the treatment of patients with SEGA associated with TSC who require therapeutic intervention and are not candidates for curative surgical resection. The approval was based on a single-arm trial that demonstrated a 50 percent or greater reduction in SEGA tumor volume in 9 of 28 patients aged 3 to 34 years (median age: 11 years). The starting dose used in this clinical trial was 3 mg/m2/day, with therapeutic drug monitoring to achieve and maintain therapeutic trough everolimus concentrations.
Today’s approval also provides the results of a randomized double-blind placebo-controlled trial in pediatric and adult patients with SEGA, which examined a higher starting dose (4.5 mg/m2/day) and included patients less than 3 years of age. In the randomized trial, 78 patients were randomly assigned to receive everolimus and 39 to receive placebo. The median age of enrolled patients was 9.5 years (range: 0.8 to 26 years). The primary outcome measure was “SEGA Response Rate,” as determined by an independent central radiology review panel 6 months after the last patient was randomly assigned. SEGA response was defined as a 50 percent or greater reduction in the sum of the volumes of SEGA target lesions relative to baseline[RC1] in the absence of worsening of non-target SEGA lesions, a new SEGA lesion 1 cm or larger, or new or worsening hydrocephalus.
SEGA responses were observed in 27 of the 78 patients (35 percent, 95 percent CI: 24, 46) treated with everolimus. None of the 39 patients (0 percent, 95 percent CI: 0, 9) treated with placebo (p < 0.0001) demonstrated SEGA responses. With a median follow-up duration of 8.4 months for the overall study population, all responses were ongoing and the median response duration was 5.3 months (range: 2.1 to 8.4 months) in patients treated with everolimus.
In the randomized trial, the most common adverse reactions in patients receiving everolimus (incidence at least 20 percent) were stomatitis, respiratory tract infection, pyrexia, vomiting, rash, and behaviorial disturbances, including anxiety and aggression. The most common (at least 2 percent) grade 3-4 adverse reactions were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea.
Serious adverse events were reported for 19 (24 percent) of the patients treated with everolimus and 5 (13 percent) of the patients who received the placebo during the double-blind period of the randomized study[RC2] . The most common serious adverse event (reported in at least 3 patients and occurring more frequently in patients treated with everolimus) was pyrexia. Serious adverse events due to infections were more common in patients younger than 3 years of age; a total of 6 of 13 patients younger than 3 years who received everolimus had at least one serious adverse event due to infection, compared with 2 of 7 patients younger than 3 years who received placebo. No deaths occurred in either treatment group.
The recommended starting dose of Afinitor® Tablets and Afinitor Disperz® for adult and pediatric patients with SEGA is now 4.5 mg/m2/day, with subsequent dosing based on therapeutic drug monitoring to achieve and maintain everolimus trough levels of 5 to 15 ng/mL. Product labeling has also been revised to include more specific dosing guidance in patients requiring concomitant medications and frequency of therapeutic drug monitoring.
The long term effects of Afinitor® Tablets and Afinitor Disperz® on growth and pubertal development are unknown. Confirmatory studies are underway to further evaluate the long-term safety and effectiveness of everolimus in adult and pediatric patients with SEGA.
On July 20, 2012, the FDA approved everolimus tablets (Afinitor®, made by Novartis Pharmaceuticals Corporation) for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. The approval was based on a randomized double-blind multicenter trial involving 724 postmenopausal women with estrogen receptor-positive, HER2-negative, advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Patients were randomly assigned (2:1) to receive everolimus 10 mg/day plus exemestane 25 mg/day (n=485) or placebo plus exemestane 25 mg/day (n=239). Patients were not permitted to cross over to everolimus at the time of disease progression.
The median progression-free survival (PFS) by investigator assessment at the time of the final PFS analysis was 7.8 months for patients receiving everolimus and 3.2 months for patients receiving placebo [HR 0.45 (95 percent CI: 0.38, 0.54), p < 0.0001]. The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment. PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy. The objective response rates were 12.6 percent in patients receiving everolimus and 1.7 percent in patients receiving placebo. An interim analysis of overall survival (OS) conducted at 46 percent of expected events was not statistically significant [HR=0.77 (95 percent CI: 0.57, 1.04)]. The final analysis of OS is expected to occur in June 2014.
Safety was evaluated in 720 patients enrolled in the randomized trial. The most common grade 1-4 adverse reactions (incidence at least 30 percent) in patients receiving everolimus plus exemestane were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3-4 adverse reactions (at least 2 percent) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common grade 3-4 laboratory abnormalities (at least 3 percent) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.
Fatal adverse reactions occurred in 2 percent of patients receiving everolimus compared with 0.4 percent of patients receiving placebo. Adverse reactions resulting in permanent treatment discontinuation occurred in 24 percent of patients receiving everolimus and 5 percent of patients receiving placebo. Dose interruptions or reductions were necessary in 63 percent of patients receiving everolimus compared with 14 percent of patients receiving placebo.
Forty percent of patients receiving everolimus were 65 years or older and 15 percent were 75 years or older. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last everolimus dose was 6 percent in patients who were at least 65 years of age compared with 2 percent in patients younger than 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33 percent of patients 65 years or older compared with 17 percent of patients younger than 65 years of age.
The recommended dose and schedule for everolimus for this indication is 10 mg orally each day. Patients with severe or intolerable adverse reactions may require dose reduction or interruption.
On May 5, 2011, the 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.
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
|Body Surface Area (BSA)||Starting Dose|
|0.5 m2 to 1.2 m2||2.5 mg once daily|
|1.3 m2 to 2.1 m2||5 mg once daily|
|Greater than or equal to 2.2 m2||7.5 mg once daily|
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.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.