April 13, 2011 (Honolulu, Hawaii) — Everolimus, the drug fast-tracked through approval for tuberous sclerosis in the United States, appears to reduce brain lesions and seizure frequency but still has an ill-defined target patient population.
Presenting here at the American Academy of Neurology 63rd Annual Meeting, lead investigator David Franz, MD, from the Cincinnati Children's Hospital in Ohio, made a case for the new indication.
"Everolimus offers patients with tuberous sclerosis–associated subependymal giant cell astrocytoma a viable alternative to surgical resection," he said.
Surgery is the current standard treatment. Dr. Franz' team first described everolimus as an alternative to resection in November 2010 in the New England Journal of Medicine (2010;363:1801-1811).
That same month, the Novartis product, already marketed as Afinitor for the treatment of advanced renal cell carcinoma, was also approved by the US Food and Drug Administration for children and adults with subependymal giant cell astrocytoma who require therapeutic intervention but are not candidates for curative surgical resection.
During a platform session here at the meeting, Dr. Franz reviewed positive results of the phase 2 study supporting the new approach.
The prospective work included 28 patients with subependymal giant cell astrocytoma and evidence of serial growth.
Investigators administered oral everolimus at 3 mg/m2 per day titrated to achieve target trough concentrations of 5 to 15 ng/mL. The median duration of treatment was 21.5 months.
Most patients, 75%, experienced reductions in subependymal giant cell astrocytoma volume of 30% or more. At month 6, there were reductions in left and right ventricular volumes and tuber size. None of the patients developed a new lesion, and no one required surgical resection or other therapy.
Table. Mean Volume Reduction
Among the patients with 24-hour video electroencephalography available at baseline and at 6 months, 9 showed reductions, 6 showed no change, and 1 had an increase.
Everolimus is a kinase inhibitor and, like other mammalian target of rapamycin inhibitors, its effect is reportedly only on the C1 and not on the C2 protein. According to the prescribing information for the drug, the effectiveness of everolimus is based on analysis of volume change and improvement in disease-related symptoms or increase in overall survival has not been demonstrated.
During the question period at the meeting, session coordinator Howard Goodkin, MD, from the University of Virginia Health System in Charlottesville, wanted to know whether there are any new data on cognitive changes with everolimus. Dr. Franz said his group is currently investigating this in another study.
Unclear Patient Population
Asked by Medscape Medical News to comment, Cecil Hahn, MD, from the Hospital for Sick Children in Toronto, Ontario, Canada, said it's encouraging to see volume shrinkage and fewer seizures. "However, it remains unclear which tuberous sclerosis patients should receive treatment. The patient population has yet to be clearly defined," he noted.
Elizabeth Donner, MD, also at the Hospital for Sick Children in Toronto, agreed this is an important question that will require further study. "I suspect this drug will be marketed to everyone, but there is considerable risk with a product like this, and for many patients, this could be inappropriate."
The slow-growing benign brain tumors are estimated to occur in up to 20% of patients with tuberous sclerosis, a genetic disorder that affects about 25,000 to 40,000 Americans.
Tuberous sclerosis is caused by mutations in C1 or C2 that result in constitutive mammalian target of rapamycin activation. It is characterized by hamartoma formation in multiple organs and disabling neurologic disorders, including epilepsy.
This study was funded by Novartis Pharmaceuticals. Dr. Franz has received compensation from Novartis and UCB Pharma.
American Academy of Neurology (AAN) 63rd Annual Meeting: Abstract IN3-2.004. Presented April 11, 2010.
Presenting here at the American Academy of Neurology 63rd Annual Meeting, lead investigator David Franz, MD, from the Cincinnati Children's Hospital in Ohio, made a case for the new indication.
"Everolimus offers patients with tuberous sclerosis–associated subependymal giant cell astrocytoma a viable alternative to surgical resection," he said.
Surgery is the current standard treatment. Dr. Franz' team first described everolimus as an alternative to resection in November 2010 in the New England Journal of Medicine (2010;363:1801-1811).
That same month, the Novartis product, already marketed as Afinitor for the treatment of advanced renal cell carcinoma, was also approved by the US Food and Drug Administration for children and adults with subependymal giant cell astrocytoma who require therapeutic intervention but are not candidates for curative surgical resection.
During a platform session here at the meeting, Dr. Franz reviewed positive results of the phase 2 study supporting the new approach.
The prospective work included 28 patients with subependymal giant cell astrocytoma and evidence of serial growth.
Investigators administered oral everolimus at 3 mg/m2 per day titrated to achieve target trough concentrations of 5 to 15 ng/mL. The median duration of treatment was 21.5 months.
Most patients, 75%, experienced reductions in subependymal giant cell astrocytoma volume of 30% or more. At month 6, there were reductions in left and right ventricular volumes and tuber size. None of the patients developed a new lesion, and no one required surgical resection or other therapy.
Table. Mean Volume Reduction
| Region Measured | Volume, cm3 |
| Left ventricular | 3.22 |
| Right ventricular | 3.15 |
| Tuber size | 3.39 |
| Subependymal nodule | No change |
Among the patients with 24-hour video electroencephalography available at baseline and at 6 months, 9 showed reductions, 6 showed no change, and 1 had an increase.
Everolimus is a kinase inhibitor and, like other mammalian target of rapamycin inhibitors, its effect is reportedly only on the C1 and not on the C2 protein. According to the prescribing information for the drug, the effectiveness of everolimus is based on analysis of volume change and improvement in disease-related symptoms or increase in overall survival has not been demonstrated.
During the question period at the meeting, session coordinator Howard Goodkin, MD, from the University of Virginia Health System in Charlottesville, wanted to know whether there are any new data on cognitive changes with everolimus. Dr. Franz said his group is currently investigating this in another study.
Unclear Patient Population
Asked by Medscape Medical News to comment, Cecil Hahn, MD, from the Hospital for Sick Children in Toronto, Ontario, Canada, said it's encouraging to see volume shrinkage and fewer seizures. "However, it remains unclear which tuberous sclerosis patients should receive treatment. The patient population has yet to be clearly defined," he noted.
Elizabeth Donner, MD, also at the Hospital for Sick Children in Toronto, agreed this is an important question that will require further study. "I suspect this drug will be marketed to everyone, but there is considerable risk with a product like this, and for many patients, this could be inappropriate."
The slow-growing benign brain tumors are estimated to occur in up to 20% of patients with tuberous sclerosis, a genetic disorder that affects about 25,000 to 40,000 Americans.
Tuberous sclerosis is caused by mutations in C1 or C2 that result in constitutive mammalian target of rapamycin activation. It is characterized by hamartoma formation in multiple organs and disabling neurologic disorders, including epilepsy.
This study was funded by Novartis Pharmaceuticals. Dr. Franz has received compensation from Novartis and UCB Pharma.
American Academy of Neurology (AAN) 63rd Annual Meeting: Abstract IN3-2.004. Presented April 11, 2010.
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