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, associated with tuberous sclerosis complex (TSC), who do not require immediate surgery.
This approval was based on durable reductions in tumor volume in everolimus-treated patients in a randomized (2:1), double-blind, placebo-controlled trial conducted in 118 patients with renal angiomyolipoma as a feature of TSC (n=113) or sporadic lymphangioleiomyomatosis (n=5).
Key eligibility requirements included at least one angiomyolipoma of ≥ 3 cm in longest diameter on CT or MRI based on local radiology assessment, no immediate indication for surgery, and age ≥ 18 years. 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 6 months after the last patient was randomized.
Of the 118 patients enrolled, 79 were randomly allocated to everolimus and 39 to placebo. The median age of patients was 31 years (range, 18-61 years), 92% of patients had at least one angiomyolipoma of ≥ 3 cm in longest diameter, 29% had angiomyolipomas ≥ 8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions. Forty-six (39%) patients had prior renal embolization or nephrectomy.
Renal angiomyolipoma responses were noted in 33 patients [41.8% (95% CI: 30.8, 53.4)] and no patient in the placebo arm achieved a response (p<0.0001). The median response duration was 5.3+ months (range 2.3+ to 19.6+ months). There were 3 patients in the everolimus arm and 8 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 [HR 0.08 (95% CI: 0.02, 0.37); p <0.0001].
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 reaction leading to everolimus dose adjustment was stomatitis.
The most common adverse reactions (≥ 10%) 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.
The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, amenorrhea, and convulsion. The most common laboratory abnormalities occurring more frequently in everolimus-treated patients were hypercholesterolemia, hypertriglyceridemia, anemia, hypophosphatemia, leucopenia, and elevated alkaline phosphatase. The most common Grade 3-4 laboratory abnormality was hypophosphatemia.
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.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022334s017lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).