ARTICLE IN BRIEF
Everolimus, which was approved for the treatment of subependymal giant-cell astrocytoma in patients with tuberous sclerosis complex, appears to be safe and effective, according to a three-year follow-up study.
One year after everolimus (Afinitor) was approved for the treatment of subependymal giant-cell astrocytoma (SEGA) in patients with tuberous sclerosis complex (TSC), scientists continuing to follow patients up to three years into their treatment report that the drug continues to be safe and effective.
David Neal Franz, MD, and his colleagues at Cincinnati Children's Hospital Medical Center have been tracking 28 patients in the clinical trial, the results of which were used by Novartis Pharmaceuticals Corporation to gain approval of the medication.
The FDA mandates post-marketing surveillance to ensure the drug remains safe and effective. Dr. Franz's team reported the long-term safety data at the annual American Epilepsy Society meeting. The patients have been on the treatment to keep tumors in check and reduce the frequency of seizures. The median dose was 5.3 mg/m2/day (range, 2.1 12.3) and the median duration of the treatment 1041 days.
The reduction in the primary SEGA volume was maintained, according to Dr. Franz. In 25 patients with ≥30 percent reduction in primary SEGA volume, median duration of SEGA response (up to progression or cut off date) was 23.8 ± 9.8 months. Six of nine patients with ≥30 percent but ≤50 percent reduction in SEGA volume at six months achieved ≥50 percent reduction in volume during the extension study, the scientists reported at the meeting.
Seizure frequency also decreased by 1.0 (range, 17.0 to 10.8) at six months from baseline. They did not have access to seizure data beyond the six months.
All patients reported at least one side effect, including low-grade stomatitis (78.6 percent), pyrexia (25 percent), dermatitis acneiform (25 percent), and diarrhea (21.4 percent). These adverse events (AEs) were also documented in the phase 3 study. There were no new drug related AEs, and no patient discontinued treatment due to the safety profile, said Dr. Franz.
“There were no relapses and no one required surgery,” said Dr. Franz. “As time goes by, we see patients have had fewer seizures. It also appears to be better tolerated. We've been able to lower the dosage.” The scientists will continue to study these patients up to five years.
Novartis is also sponsoring a phase 3 trial for SEGA and kidney tumors in patients with TSC. Dr. Franz's team is also conducting a study on TSC patients with intractable seizures.
“Families feel the drug is beneficial. They have shown improvements in learning, behavior and cognition. As neurologists, we see this as a multisystem disorder. Many of the children would have had to undergo repeated brain surgeries and would have had disfiguring facial tumors. The drug is keeping kidney tumors at bay, which means that we have reduced kidney failure and the possibility of transplant. The children have a better quality of life.”
The drug targets the mTOR pathway, which is critical in regulating protein synthesis and cell growth. Inhibiting mTOR promotes removal of abnormal proteins that build up in patients with TSC. The mTOR pathway is a target for chemotherapy, which is how Dr. Franz and his colleagues got the idea to try it in their TSC patients with SEGA.
That a small molecule can correct a genetic defect has led to animal studies using the mTOR inhibitor earlier to see if it can prevent the mental retardation and autism that can occur in patients with SEGA. It seems to work in animal models, said Dr. Franz. “The earlier you treat the more manifestations of the disease you can prevent,” he said.
The investigators want to understand how early they can safely treat with this drug. So far, half a dozen babies (under a year old) have been treated.
Joyce Wu, MD, associate professor of pediatrics at the University of California-Los Angeles, said that her clinic is following six patients with SEGAs. The most common side effect is mouth sores, which come and go, she said. Before FDA fast tracked the approval of everolimus, surgery was standard therapy.
Her clinic is involved in the international double-blind placebo controlled phase 3 EXIST-1 (EXamining everolimus) trial including 117 patients. Earlier this year, investigators of the study, also sponsored by Novartis, said that the trial met its primary endpoint, a reduction in SEGA volume. So far, 35 percent of patients (27 of 78) receiving everolimus experiencing a 50 percent or greater reduction in SEGA volume (sum of volumes of all target SEGAs) relative to baseline versus none of 39 patients taking a placebo (p<0.0001). The preliminary results of this ongoing study were reported last summer at the International TSC Research Conference in Washington, DC.
“There has been a lot of discussion about mTOR inhibitors,” said Dr. Wu. At least in patients with SEGA, so far, “there is a lot of benefit all around.” Dr. Wu added: “This may be just the beginning of what everolimus may be capable of achieving, There may be potential for other tumor reduction and epilepsy control in TSC, as well as for tumor reduction and epilepsy control in non-TSC patients.”
Steven Roach, MD, professor of pediatrics and neurology at Ohio State University College of Medicine and Neurologist-in-Chief at Nationwide Children's Hospital in Columbus, said that “long-term follow-up is necessary for newly developed medicines in order to detect any adverse effects from chronic use and to determine if the short-term benefits are sustainable.”
He added that the FDA approval is limited to tumors. “This is a very good option for individuals with TSC-related tumors that are not amenable to curative surgery or other procedures. Additional studies may confirm what has been suspected in earlier clinical trials: that everolimus can reduce the severity of epilepsy, cognitive dysfunction, or other TSC-related problems, at least in some individuals. If this is the case, then far more patients are likely to receive it.”