For the first time, a product is available specifically for use in patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumors.
The product is an intravenous formulation of nanoparticle albumin-bound nab-sirolimus (Fyarro) from Aadi Biosciences. The company announced on November 23 that the drug was approved by the US Food and Drug Administration (FDA).
Although sirolimus and other oral mTOR inhibitors are used off label for the condition, Fyarro is the first medication to be approved specifically for the rare tumor, a form of soft tissue sarcoma that the company estimates strikes about 100–300 people in the US annually, predominantly women.
The company anticipates its new formulation "will become a standard of care" for the condition.
Aadi is planning a first quarter 2022 launch. The wholesale acquisition cost for a month of treatment will be approximately $39,000, a company executive said on an investors call.
In the new formulation, the goal of binding sirolimus to albumin is to deliver higher concentrations of the drug to the tumor with less toxicity. Aadi founder and CEO Neil Desai, PhD, helped invent nab technology and was a driver behind its first clinical application, nab-paclitaxel (Abraxane).
The product was approved on the basis of results from an open-label, single-arm, phase 2 trial in 34 patients, 31 of whom were evaluable for efficacy. These patients had not been previously treated with an mTOR inhibitor.
The trial, dubbed AMPECT, was the first prospective study in malignant perivascular epithelioid cell tumors (mPEComas).
The overall response rate was 39%; all 12 responses were partial at first, but two converted to complete responses, one after 11 months of treatment and the other after 34 months.
Median progression-free survival was 10.6 months and median overall survival 40.8 months. Median duration of response was not reached after a median follow-up of 36 months.
By way of comparison, a recent series of 40 malignant PEComa patients treated with oral mTOR inhibitors ― most often sirolimus ― reported a response rate of 40% and median progression-free survival of 9 months.
AMPECT investigators said their study "provides evidence that nab-sirolimus may offer an important benefit" over oral alternatives.
There's been no direct clinical comparison but nab-sirolimus "has a distinct pharmacologic profile and pharmacokinetics" with "significantly higher tumor growth inhibition, higher intratumoral drug accumulation, and greater mTOR target suppression," said the study team, led by Andrew Wagner, MD, PhD, an oncologist at Dana-Farber Cancer Institute, Boston.
There were no drug-related grade 4 adverse events or deaths in AMPECT, and no new mTOR inhibitor safety signals.
More than half of patients developed stomatitis, infections, fatigue, and rash. Grade 3 laboratory abnormalities that occurred in more than 10% included lymphocytopenia, increased glucose, and decreased potassium. There was one instance each of grade 3 acute kidney injury, acute coronary syndrome, edema, and pancytopenia.
About a third of patients required dose reductions. Three patients stopped treatment entirely because of anemia, noninfectious cystitis, and pneumonitis.
TSC2 mutations related to mTOR pathway overactivation ― a driver of malignant PEComa ― were a strong predictor of response in AMPECT, while the absence of pS6 mutations, which reflects a lack of activation, strongly predicted negative response.
The median age of the study participants was 60 years, and over 80% of the patients were women. Primary tumors were most often in the uterus, pelvis, or retroperitoneum. The lungs were the most common site of metastases.
Dosing in the trial was 100 mg/m2 IV on days 1 and 8 of a 21-day cycle, which is the approved dosing. Median time to nab-sirolimus response was 1.4 months.
AMPECT was funded by Aadi Bioscience. Wagner reported research funding from the company. Several authors are employees with stock in Aadi, including Desai, who also holds patents on the technology. Other authors reported research funding and/or being a consultant for the company.
M. Alexander Otto is a physician assistant with a master's degree in medical science, and an award-winning medical journalist who has worked for several major news outlets before joining Medscape. He is an MIT Knight Science Journalism fellow. Email: firstname.lastname@example.org.
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Cite this: Novel Sirolimus Formulation Approved for Rare Soft Tissue Sarcoma - Medscape - Nov 24, 2021.