Health Canada Approves Everolimus for Pediatric Brain Tumors

Yael Waknine

September 14, 2011

September 14, 2011 — Health Canada has conditionally approved everolimus tablets (Afinitor; Novartis) for the treatment of brain tumors caused by tuberous sclerosis complex (TSC) in children 3 years and older. It is the first medication approved in Canada for these tumors. Everolimus has already been approved in Europe and the United States for this indication.

"This medication gives us the opportunity to share the good news with parents that there is now an effective, approved therapy for their child's tumor in a case where surgery is not an option. This represents an important new advancement for patients suffering from [TSC], and allows us to look forward with new optimism," observed Philippe Major, MD, a pediatric neurologist with CHU Sainte-Justine in Montreal, Quebec, in a company news release.

TSC is an unpredictable genetic disorder that affects 1 in 6000 births and is associated with the formation of benign tumors in the brain and other organs, such as the kidneys, heart, eyes, lungs, and skin. Slow-growing brain tumors, known as subependymal giant cell astrocytomas (SEGAs), occur in up to 10% of TSC patients, who are primarily children and adolescents. The tumors can lead to epilepsy, swelling in the brain, developmental delays, autism, kidney failure, and skin lesions.

Everolimus is directed at the molecular target of rapamycin (mTOR), a critical downstream effector of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway that is normally inhibited by the TSC1 and TSC2 genes that are defective in patients with TSC. By inhibiting mTOR activity, everolimus reduces cell growth, angiogenesis, and glucose uptake related to the brain tumors.

Health Canada's approval was based on data from a prospective, open-label, single-group phase 2 clinical study (n = 28) showing that 32% (n = 9) of treated patients achieved more than 50% shrinkage of their largest SEGA tumor at 6 months, relative to baseline; 75% (n = 21) experienced a decrease in size of 30% or more (< .001 for both). Although the SEGAs did not resolve completely, new tumors did not occur during treatment.

These findings were recently confirmed in a randomized phase 3 trial of 117 patients, from infancy to adulthood, known as EXIST-1. In that study, 35% of patients receiving everolimus tablets experienced a 50% or greater reduction in total SEGA volume from baseline, relative to placebo (P < .0001).

In the phase 2 study, treatment with everolimus also resulted in a clinically relevant reduction in the overall frequency of seizures in 9 of 16 patients (56%) affected at the start of the trial (P = .022).

Adverse events reported in 30% or more of patients included mouth sores, upper respiratory tract infections, sinusitis, middle-ear infections, and fever. Common laboratory test abnormalities included elevated liver enzymes, creatinine, and glucose, as well as hyperlipidemia, leukopenia, anemia, and thrombocytopenia.

Because everolimus is immunosuppressive, potentially serious adverse reactions include noninfectious pneumonitis and infections for which patients should be monitored carefully and treated as needed. Temporary dose reductions and/or interruption or discontinuation of therapy might be warranted. Live vaccinations and close contact with those who have received live vaccines should be avoided during treatment with everolimus.

Everolimus therapy is not recommended for patients with severe hepatic impairment, and women of childbearing potential should use contraception because of the risk for fetal harm.

Concomitant use of strong or moderate CYP3A4 or P-glycoprotein inhibitors should be avoided in patients receiving everolimus therapy; dose increases are recommended for coadministered strong CYP3A4 inducers.

Other indications for everolimus that are approved by the US Food and Drug Administration include the treatment of unresectable, locally advanced, or metastatic progressive neuroendocrine tumors of pancreatic origin, and advanced renal cell carcinoma refractory to sunitinib or sorafenib therapy.

Everolimus, marketed as Zortress (Novartis), is indicated for use with low-dose cyclosporine, basiliximab, and corticosteroids to prevent organ rejection in adult kidney transplant patients who are at low to moderate immunologic risk.

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