Everolimus in tuberous sclerosis complex - Phase 3 trial shows promising results

In The Lancet, David Neal Franz and colleagues from Cincinnati Children’s Hospital Medical Center report on an international, double-blind, placebo-controlled phase 3 trial of the efficacy of the mTORC1 inhibitor everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. Everolimus is a rapamycin analogue with improved bioavailability compared with sirolimus. 

This study is the latest to to show the effectiveness of everolimus in slowing the cell growth that is overactive in patients with TSC.

The phase III study was conducted among 117 patients with TSC who were randomly assigned to either everolimus or a placebo. Patients were 9 ½ years old on average but ranged from infants to adults. No patient on placebo showed improvement in their tumors. Tumor volume was measured by MRI assessment of the brain.Thirty-five percent of patients in this study on everolimus had at least a 50 percent reduction in tumor volume after an average of 42 weeks on medication.

Every patient in this study experienced a decrease in size of their tumors, and no patient required surgery for their tumors after treatment with everolimus. The earlier phase II study of everolimus by the same group was published in The New England Journal of Medicine in 2010. Based on that data, the U.S. Food and Drug Administration granted accelerated approval of everolimus for patients with subependymal giant cell astrocytomas, or SEGAs. The new, placebo-controlled study was conducted to confirm these earlier results.

In the current trial the patient reported quality of life, as measured by a validated quality of life and neuropsychological assessments, also improved at three months and six months after treatment with everolimus. The investigators also found that more patients had mutations in the TSC2 gene than in the TSC1 gene, and that TSC2 mutations correlated with lower response of the subependymal giant cell astrocytomas, which is in keeping with the results of earlier studies showing an increased severity of symptoms in patients with mutations in TSC2

Advances in the knowledge about tuberous sclerosis complex have shown that inactivating mutations in the Tsc1 and Tsc2 tumour suppressor genes leading to constitutive activation of the mammalian target of rapamycin (mTOR) as one of the main causes of astrocytomas.mTOR functions as an integrator of signalling within two multiprotein complexes (mTORC1 and mTORC2) leading to increased protein synthesis, and thus cell proliferation and survival. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms eg, hydrocephalus, requiring surgery. The same mTOR pathway associated with overactive cell growth in TSC also is implicated in other cancers and neurological conditions, such as Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, Huntington’s disease and autism. This makes everolimus, an mTOR inhibitor, a potential candidate to treat these mTOR-associated disorders

Based on studies by John Bissler, MD, a nephrologist at Cincinnati Children’s, the US Food and Drug Administration (FDA) earlier this year approved everolimus as the first medication to shrink non-cancerous kidney tumors that strike up to 80 percent of people with TSC. This allows many patients to maintain kidney function for years to come without the need for repeated surgical intervention.Prior to FDA approval, surgery was considered standard therapy for SEGAs, but everolimus has now become a potential alternative to surgery and the first targeted medical therapy for TSC.

Citation: Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2012; published online Nov 14. (12)61134-9.[abstract]