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Updated: May 29, 2026
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Published on: June 15, 2020
Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and
Sandra L Dabora1, David Neal Franz, Stephen Ashwal
1Biogen Idec Hemophilia, Weston, Massachusetts, United States of America. sandy.dabora@gmail.com
Background:
Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.
Methods:
We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.
Results:
36 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).
Conclusions:
Sirolimus 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 Registration:
Clinicaltrials.gov NCT00126672.
Insights
Sirolimus effectively reduced tumor size in patients with tuberous sclerosis complex (TSC). Continued treatment maintained responses, and serum VEGF-D may help monitor kidney angiomyolipomas.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Tuberous sclerosis (TSC) is characterized by uncontrolled mTOR signaling due to TSC1 or TSC2 mutations.
- This signaling pathway drives the growth of various tumors associated with TSC.
Purpose of the Study:
- To evaluate the efficacy and tolerability of sirolimus, an mTOR inhibitor, in treating kidney angiomyolipomas in adults with TSC.
- To explore the impact of sirolimus on other TSC-related tumors and identify potential biomarkers.
Main Methods:
- A phase 2 multicenter trial enrolled 36 adults with TSC or TSC/LAM, administering daily sirolimus.
- Tumor size, treatment response, and adverse events were monitored over 52 weeks.
- Serum VEGF-D levels were analyzed as a potential biomarker.
Main Results:
- Sirolimus demonstrated a 44.4% overall response rate, with partial responses in 16/36 patients and stable disease in 17/36.
- A mean decrease of 29.9% in kidney tumor size was observed at 52 weeks.
- Tumors regrew upon discontinuation but responses persisted with continued treatment. Regression was also noted in SEGAs, liver angiomyolipomas, and facial angiofibromas, with stable lung function in TSC/LAM patients. Elevated serum VEGF-D levels decreased with treatment and correlated with kidney angiomyolipoma size.
Conclusions:
- Fifty-two weeks of sirolimus treatment effectively induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas in patients with TSC.
- Serum VEGF-D may serve as a valuable biomarker for monitoring kidney angiomyolipoma size.
- Further research is warranted to establish the long-term benefits and risks of sirolimus in both adult and pediatric TSC populations.
