Everolimus: New Indication in Renal Angiomyolipoma Associated with Tuberous Sclerosis Complex

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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.


In April 2012, the kinase inhibitor everolimus (Afinitor) was granted accelerated approval for the treatment of adults with renal angiomyolipoma associated with tuberous sclerosis complex who do not require immediate surgery.1,2 Everolimus is already indicated for treatment of adults and children at least 3 years of age with subependymal giant cell astrocytoma associated with tuberous sclerosis complex who require therapeutic intervention but are not candidates for curative surgical resection. It is also indicated for treatment of adults with unresectable, locally advanced, or metastatic progressive neuroendocrine tumors of pancreatic origin and adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

Approval was based on durable reductions in tumor volume observed in everolimus-treated patients in a trial in which 118 patients with renal angiomyolipoma as a feature of tuberous sclerosis complex (n = 113) or sporadic lymphangioleiomyomatosis (n = 5) were randomized (2:1) to double-blind oral everolimus 10 mg once daily (n = 79) or placebo (n = 39).2 Treatment was continued until disease progression or unacceptable toxicity. Patients had to be at least 18 years of age, have at least one angiomyolipoma of ≥ 3 cm in longest diameter, and have no immediate indication for surgery.

Patients had a median age of 31 years (range, 18–61 years), 66% were female, and 89% were Caucasian. At baseline, 92% of patients had at least one angiomyolipoma ≥ 3 cm in longest diameter, 29% had angiomyolipomas ≥ 8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions; 39% had prior renal embolization or nephrectomy, and 17% were receiving enzyme-inducing antiepileptic drugs.

The major efficacy outcome measure was angiomyolipoma response rate, with response defined as a ≥ 50% reduction in angiomyolipoma volume, absence of a new angiomyolipoma lesion ≥ 1 cm, absence of kidney volume increase ≥ 20%, and no angiomyolipoma-related bleeding of at least grade 2. Disease was assessed by CT or MRI. Analyses of efficacy outcome measures were limited to the blinded treatment period that concluded 6 months after the last patient was randomized.

The median duration of follow-up was 8.3 months (range, 0.7–24.8 months). Response rates were 41.8% in the everolimus group vs 0% in the placebo group (P < .0001). Median response duration was 5.3+ months (range, 2.3+ to 19.6+ months). Three everolimus patients and eight placebo patients had angiomyolipoma progression. The time to angiomyolipoma progression was significantly longer in the everolimus group, with everolimus treatment being associated with a 92% reduction in risk for progression (HR = 0.08, 95% CI = 0.02–0.37, P < .0001).

As a condition of the accelerated approval, the manufacturer (Novartis) will continue to follow study patients to more fully characterize 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.

How It Works

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) kinase, downstream of the PI3K/AKT pathway.2,3 mTOR kinase plays a central role in cell growth, proliferation, and survival and in protein synthesis and transcription. The mTOR pathway is dysregulated in a number of cancers. Everolimus binds to an intracellular protein (FKBP-12), resulting in formation of an inhibitory complex with mTOR complex 1 (mTORC1) and inhibition of mTOR kinase activity.

Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, vascular-endothelial growth factor-dependent and -independent angiogenesis, and glucose uptake. The oncogene suppressors tuberin sclerosis complexes 1 and 2 (TSC1, TSC2) are regulators of mTORC1 signaling. Loss or inactivation of TSC1 or TSC2 leads to activation of downstream signaling. The majority of patients with tuberous sclerosis complex have mutations in TSC1 or TSC2, resulting in constitutive activation of mTOR.

How It Is Given

Everolimus is given at 10 mg once daily with or without food. Hepatic impairment results in increased everolimus exposure. In patients with mild and moderate hepatic impairment, recommended doses are 7.5 mg and 5 mg once daily, respectively, with dose reductions to 5 mg and 2.5 mg, respectively, in case of intolerance. In patients with severe hepatic impairment, a dose of 2.5 mg one daily may be used, but not exceeded, if desired benefits outweigh risks of treatment.

If treatment with moderate CYP3A4 or P-glycoprotein inhibitors is required, the everolimus dose should be reduced to 2.5 mg once daily and, if tolerated, can be increased to 5 mg. Use with strong CYP3A4 inhibitors should be avoided. If treatment with a strong inducer of CYP3A4 is required, the everolimus dose can be increased in 5 mg increments to a maximum of 20 mg once daily.

Safety Profile

The most frequent adverse event in the study was stomatitis, which occurred in 78% of everolimus patients and 23% of placebo patients.2 Grade 3 stomatitis occurred in 6% of everolimus patients. Other adverse events occurring in at least 10% of everolimus patients, all of which were grade 1 or 2, were arthralgia (22%), acne (22%), headache (20%), nausea (16%), vomiting (15%), diarrhea (14%), peripheral edema (13%), arthralgia (13%), abdominal pain (11%), upper respiratory tract infection (11%), and eczema (10%).

Amenorrhea occurred in 15% of women in the everolimus group (4% of women in the placebo group). Other adverse events involving the female reproductive system in everolimus patients were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%). The most common grade 3 or 4 adverse events (≥ 2%) in everolimus patients after stomatitis were amenorrhea and convulsion.

The most common laboratory abnormalities (> 40%, any grade) in the everolimus group were hypercholesterolemia (85% vs 46% in placebo group), anemia (61% vs 49%), hypertriglyceridemia (52% vs 10%), and hypophosphatemia (49% vs 15%). The most common grade 3 abnormality in everolimus patients was hypophosphatemia (5%).

Adverse events led to discontinuation of everolimus treatment in three patients (3.8%), with discontinuations being due to hypersensitivity, angioedema, and bronchospasm in one patient and convulsion and hypophosphatemia in one patient each. Dose interruption or reduction occurred in 52% of everolimus patients, most commonly due to stomatitis.

Everolimus carries warnings/precautions for noninfectious pneumonitis, infections, oral ulcerations, renal failure, laboratory test alterations (elevations of serum creatinine, blood glucose, and lipids and decreases in hemoglobin, neutrophils, and platelets), vaccination with live vaccines, and use in pregnancy. ■


1. U.S. Food and Drug Administration: Everolimus (2012). Available at Accessed June 8, 2012.

2. AFINITOR (everolimus) tablets prescribing information. Novartis, April 2012. Available at Accessed June 8, 2012.

3. Franz DN: Everolimus: An mTOR inhibitor for the treatment of tuberous sclerosis. Expert Rev Anticancer Ther 11:1181-1192, 2011.