Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and...

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.