Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

Abstract

BackgroundTuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.MethodsWe completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.Results36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).ConclusionsSirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.Trial RegistrationClinicaltrials.gov NCT00126672

Tuberous sclerosis complex: the past and the future

“…Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria, and are not sufficient to make a definite diagnosis of TSC. Note that 10-25 % of TSC patients have no mutation identified by conventional genetic testing, and a normal result does not exclude TSC [83][84][85][86][87]. In a randomized, double-blind, placebo-controlled phase III trial (EXIST-2), Bissler et al offered definitive evidence of the efficacy of everolimus for the treatment of angiomyolipomas in adults with TSC, with an acceptable safety profile [88].…”

“…For asy mptomatic, g rowing angiomyolipomas measuring >3 cm in diameter, treatment with an mTORi is recommended as the most effective firstline therapy in the short term [83][84][85]88]. However, more studies are needed to confirm the long-term benefits and safety of this treatment strategy.…”

“…Topical treatment of facial angiofibromas with sirolimus has extensively been reported to yield positive results [6]. In selected LAM patients with moderate-to-severe lung disease or rapid progression, treatment with an mTORi may be used to stabilize or improve lung function, quality of life, and functional performance [83][84][85]98]. Recently, it has been demonstrated that everolimus has a partial effect on epilepsy, decreasing the frequency and severity of seizures [96,99].…”

“…However, some of the surveillance recommendations can be challenging to follow, e.g., the need for frequent general anesthesia for serial brain and abdominal MRI in mentally retarded patients. Since angiomyolipomas have the potential to produce vascular collagen (i.e., collagen IV) and vascular endothelial growth factor-D (VEGF-D), these surrogate biomarkers were used in a few studies to assess disease burden and to monitor clinical response to treatment of angiomyolipoma [83,88,98]. A clear correlation has been noted between these biomarkers and angiomyolipoma volume.…”

A Case Report on the Effect of Everolimus in Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex

“…It was noted that serum VEGF-D levels were elevated at baseline in patients with renal AML lesions, and when a decrease in AML size was noted a corresponding decrease in VEGF levels was also noted [7].…”