On April 26, 2012, the U.S. Food and Drug Administration granted accelerated approval to everolimus (Afinitor tablets, Novartis) for the treatment of adults with renal angiomyolipoma (benign kidney tumors), associated with tuberous sclerosis complex (TSC), a genetic tumor-causing disorder, who do not require immediate surgery.
This approval was based on durable reductions in tumor volume in everolimus-treated patients in a randomized, double-blind, placebo-controlled trial conducted in 118 patients with renal angiomyolipoma as a feature of TSC or sporadic lymphangioleiomyomatosis. Patients received daily everolimus, 10 mg orally, or matching placebo until disease progression or unacceptable toxicity. Angiomyolipoma response rate, the primary efficacy endpoint, and angiomyolipoma time-to-progression, a key secondary endpoint, were based on independent central radiology review. Analyses of efficacy outcome measures were limited to the blinded treatment period that concluded six months after the last patient was randomized.
Of the 118 patients enrolled, 79 were randomly allocated to everolimus and 39 to placebo. Renal angiomyolipoma responses were noted in 33 patients and no patient in the placebo arm achieved a response. The median response duration was 5.3+ months (range 2.3+ to 19.6+ months). There were three patients in the everolimus arm and eight patients receiving placebo with documented angiomyolipoma progression by central radiologic review. The time-to-angiomyolipoma progression was also statistically significantly longer in the everolimus arm.
Treatment-emergent adverse reactions resulting in permanent discontinuation occurred in 3.8% of everolimus-treated patients. Adverse reactions leading to permanent discontinuation of everolimus were hypersensitivity reaction (characterized byangioedema and bronchospasm), convulsion, and hypophosphatemia. Interruptions or reductions of everolimus due to adverse reactions occurred in 52% of patients.
The most common adverse reactions in everolimus-treated patients included stomatitis, nausea or vomiting, acne or eczema, headache, cough, diarrhea, arthralgia, peripheral edema, abdominal pain, and upper respiratory infection. Additionally, 15% of everolimus-treated female patients developed secondary amenorrhea.
At the time of this analysis, the median duration of follow-up was 8.3 months (range: 0.7- 24.8 months). As a condition of this accelerated approval, Novartis will continue to follow these patients to more fully characterize the angiomyolipoma response duration, provide additional information on the need for nephrectomy or renal embolization to control tumor hemorrhage, and provide updated information on time-to-angiomyolipoma progression.
The recommended everolimus dose and schedule is 10 mg orally daily.
See the FDA Announcement