Revised Everolimus Dosing and New Safety/Efficacy Data for Approval in Subependymal Giant Cell Astrocytoma

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On August 29, 2012, everolimus in a tablet for oral suspension form (Afinitor Disperz) was given accelerated approval for the treatment of pediatric and adult patients with tuberous sclerosis complex who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.1,2 Everolimus in a tablet for oral administration form (Afinitor) was granted accelerated approval for treatment of tuberous sclerosis complex with SEGA in October 2010 on the basis of a single-arm trial in 28 patients. The new approval, based on a randomized, double-blind trial, expands the indication to treatment of children aged less than 3 years and includes an increased starting dose, revised dose modification guidelines, and new safety and efficacy data from the randomized trial.

Everolimus also has indications in advanced hormone receptor–positive breast cancer, progressive neuroendocrine tumors of pancreatic origin, advanced renal cell carcinoma, and renal angiomyolipoma with tuberous sclerosis complex.

Single-arm Trial

In the randomized trial, 117 patients with subependymal giant cell astrocytoma received Afinitor Disperz at 4.5 mg/m2 per day (n = 78) or placebo (n = 39). Patients had a median age of 9.5 years (range, 0.8–26 years), 93% were Caucasian, and 57% were male.

The primary outcome measure was SEGA response rate as determined by an independent central radiology review panel, with response defined as a ≥ 50% reduction in the sum of the volumes of SEGA target lesions relative to baseline in the absence of worsening of nontarget SEGA lesions, a new SEGA lesion ≥ 1 cm, or new or worsening hydrocephalus. SEGA responses were observed in 27 (35%) of 78 patients in the everolimus group and none of the placebo patients (P < .0001). With a median follow-up of 8.4 months for the total study population, all responses were ongoing and the median response duration was 5.3 months (range, 2.1–8.4 months) in everolimus-treated patients.

How It Works

Everolimus inhibits mTOR kinase downstream of the PI3K/AKT pathway by forming an inhibitory complex with mTOR complex 1 (mTORC1). The mTOR pathway is dysregulated in several human cancers. The oncogene suppressors tuberous sclerosis complex 1 and 2 (TSC1, TSC2) are regulators of mTORC1 signaling, and loss or inactivation of either suppressor leads to activation of downstream signaling. In tuberous sclerosis complex, inactivating mutations in either the TSC1 or TSC2 gene lead to hamartoma formation throughout the body.

Everolimus in a tablet for oral suspension is the first pediatric formulation to be approved for the treatment of a tumor occurring primarily during childhood. The new dosage form (tablets for oral suspension) is more rapidly dissolved using smaller volumes of water than the tablet dosage form used in prior clinical trials and provides for smaller dose increments, allowing greater dosing flexibility. This formulation also provides another option for adult patients with SEGA.

How It Is Given

The recommended starting dose of both Afinitor Tablets and Afinitor Disperz for adult and pediatric patients with SEGA is now 4.5 mg/m2 per day, with subsequent dosing based on therapeutic drug monitoring to achieve and maintain everolimus trough levels of 5 to 15 ng/mL. Trough concentrations should be assessed approximately 2 weeks after initiation of treatment, a change in dose, a change in coadministration of CYP3A4 or Pglycoprotein inducers or inhibitors, a change in hepatic function, or a change in dosage form between Afinitor Tablets and Afinitor Disperz.

The starting dose of both forms should be reduced by approximately 50% in patients with severe hepatic impairment and in patients taking moderate inhibitors of CYP3A4 or Pglycoprotein and should be doubled when coadministered with strong inducers of CYP3A4.

Safety Profile

In the randomized trial, the most common adverse events of any grade in everolimus-treated patients (≥ 20%) were stomatitis (62% vs 26% with placebo), respiratory tract infection (31% vs 23%), pyrexia (23% vs 18%), vomiting (22% vs 13%), rash (21% vs 8%), and anxiety, aggression, or other behavioral disturbance (21% vs 3%). The most common (≥ 5%) grade 3 or 4 adverse events were stomatitis (9% vs 3%), pyrexia (6% vs 3%), pneumonia, gastroenteritis (5% vs 0%), anxiety, aggression, or other behavioral disturbance (5% vs 0%), and amenorrhea. Grade 4 adverse events were very uncommon.

Amenorrhea occurred in 17% of everolimus-treated patients aged 10 to 55 years (3/18) and in none of the females in the placebo group. Abnormalities included dysmenorrhea (6%), menorrhagia (6%), and metrorrhagia (6%).

The most common laboratory abnormalities (≥ 40%) were hypercholesterolemia (81% vs 39%), elevated partial thromboplastin time (72% vs 44%), neutropenia (46% vs 41%), and anemia (41% vs 21%). The most common grade 3 lab abnormalities (no grade 4 abnormalities) were neutropenia (9% vs 3%) and elevated partial thromboplastin time (3% vs 5%).

Serious adverse events were reported in 24% of everolimus-treated patients and 13% of placebo recipients, with pyrexia being the most common event occurring more frequently in the everolimus group. Serious adverse events due to infection were more common in patients aged less than 3 years, occurring in 46% (6/13) of everolimus-treated patients and 28.5% (2/7) of placebo patients. No adverse events resulted in permanent discontinuation of study treatment. Dose interruptions or reductions due to adverse events occurred in 55% of patients given everolimus, with stomatitis being the most common cause. No deaths occurred in either treatment group.

Additional Risk Considerations

Everolimus carries warnings/precautions for noninfectious pneumonitis, infections, oral ulcers, renal failure, laboratory test abnormalities, use of live vaccine and contact with others who have received live vaccine, and embryo-fetal toxicity. Renal function, blood glucose, lipids, and hematologic parameters should be measured prior to treatment and periodically during treatment.

The long-term effects of everolimus 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. ■


1. U.S. Food and Drug Administration: Approved drugs. Everolimus for tuberous sclerosis complex. Available at Accessed September 12, 2012.

2. AFINITOR® (everolimus) tablets for oral administration, AFINITOR DISPERZ®(everolimus tablets for oral suspension) prescribing information. Novartis Pharmaceuticals Corporation, August 2012. Available at Accessed September 12, 2012.