Afinitor Phase III study on angiomyolipomas associated with TSC meets primary endpoint

A Phase III study of Afinitor® (everolimus) tablets in patients with non-cancerous kidney tumors, or angiomyolipomas, associated with tuberous sclerosis complex (TSC) met its primary endpoint of best overall angiomyolipoma response rate, which includes reduction in kidney tumor size and absence of new tumors. Findings from the trial, known as EXIST-2, were presented today at the International TSC Research Conference in Belfast, Northern Ireland.

Tuberous sclerosis complex is a genetic disorder that may cause non-cancerous tumors to form in vital organs, including the brain (SEGAs) and kidney (angiomyolipomas). These kidney tumors occur in up to 80% of patients, usually occurring between the ages of 15 and 30 and increasing in prevalence with age. Angiomyolipomas are the greatest cause of morbidity and mortality in adult TSC patients, as larger tumors may cause severe bleeding, require surgical intervention or result in kidney failure. Tumor symptoms may include nausea, vomiting, pain and bleeding.

Results of the 118-patient, randomized, placebo-controlled Phase III EXIST-2 (EXamining everolimus In a Study of TSC) trial showed 42% of patients (33 of 79) experienced a response in the everolimus arm versus 0% of patients (0 of 39) on placebo (p<0.0001) based on best overall response rate. These results add to the recent positive Phase III data from a separate trial in patients with TSC, which demonstrated reduction in the size of non-cancerous brain tumors (SEGAs) with everolimus.

"For the first time, a large placebo-controlled study has focused specifically on angiomyolipomas in TSC patients, an area with clear unmet need," said Dr. John Bissler, lead study author and Clark D. West Endowed Chair of Nephrology at Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. "In addition to the tumor reduction seen with everolimus in this trial, significant improvement in skin lesions including facial angiofibromas was observed, which can be a key concern for people living with TSC."  

Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism. Tuberous sclerosis complex is caused by defects in the TSC1 and/or TSC2 genes. When these genes are defective, mTOR activity is increased, which can cause uncontrolled tumor cell growth and proliferation, blood vessel growth and altered cellular metabolism. By inhibiting mTOR activity in this signaling pathway, everolimus may reduce cell proliferation and blood vessel growth related to angiomyolipoma associated with TSC.

"The positive findings seen in this trial coupled with the known efficacy of everolimus in patients with SEGA point to the important role of mTOR inhibition with everolimus in treating these manifestations of TSC," said Herve Hoppenot, President, Novartis Oncology. "The outcomes support our further research efforts evaluating everolimus as a treatment option across the various conditions associated with TSC."