The FDA ( Food and Drug Administration ) has granted accelerated approval to Everolimus ( Afinitor ), 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% were male, and 86% 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% ) had a 50% 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% 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% ) included stomatitis, upper respiratory tract infections, sinusitis, otitis media, and pyrexia. Grade 3 adverse reactions were reported in 36% 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% of patients ) included transaminase elevations, hypercholesterolemia and hypertriglyceridemia, leukopenia, anemia, and hyperglycemia.

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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 is the following: body surface area ( BSA ) 0.5 m2-to-1.2 m2, starting dose: 2.5 mg once daily; BSA: 1.3 m2-to-2.1 m2, starting dose: 5 mg once daily; BSA greater than or equal to 2.2 m2, starting dose: 7.5 mg once daily.

Source: National Cancer Institute, 2010

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