Rare Daily Staff

The U.S. Food and Drug Administration approved Aadi Bioscience’s Fyarro for intravenous use for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor, an ultra-rare and aggressive form of sarcoma with a strong female predominance.

Advanced malignant perivascular epithelioid cell tumor (PEComa) are a rare subset of soft-tissue sarcomas with an undefined cell of origin. While there is no formal epidemiology for malignant PEComa, it is estimated that there are about 100-300 new patients per year in the United States.

Malignant PEComas may arise in almost any body site (typically the uterus, retroperitoneum, lung, kidney, liver, genitourinary, and gastrointestinal tract with a female predominance) and can have an aggressive clinical course including distant metastases and ultimately death. The estimated prognosis based on retrospective reports is 12-16 months. Cytotoxic chemotherapies typically used for sarcoma show minimal benefit and there are currently no drugs approved for this disease.

Malignant PEComas have been shown to frequently harbor mutations in the TSC1 and/or TSC2 genes that result in the activation of mTOR pathway making it a rational therapeutic target for this disease. An mTOR inhibitor, Fyarro (sirolimus protein-bound particles for injectable suspension) (albumin-bound) is the first and only FDA-approved treatment for advanced malignant PEComa in adults.

The approval of Fyarro was based on the phase 2 registrational AMPECT trial in which the overall response rate as assessed by independent review was 39 percent with 2 patients achieving a complete response after prolonged follow up. The median duration of response has not been reached with a median follow-up of 36 months, and a range of 5.6 to 55.5+ months and ongoing. Among responders, 92 percent had a response lasting greater than or equal to 6 months; 67 percent had a response lasting greater than or equal to 12 months; and 58 percent had a response lasting greater than or equal to 2 years.

As is the case with other therapeutics of the mTOR class, the Fyarro prescribing information includes warnings and precautions related to stomatitis, myelosuppression, infections, hypokalemia, hyperglycemia, interstitial lung disease, hemorrhage, and hypersensitivity reactions. Grade 3 non-hematologic events occurring in more than 10 percent of patients included stomatitis, rash, fatigue and infections. Grade 3 laboratory abnormalities occurring in more than 10 percent of patients that worsened from baseline included lymphocytopenia, increased glucose, and decreased potassium.

“The approval of Fyarro, the first approved drug for advanced malignant PEComa, an aggressive sarcoma with a poor prognosis and few treatment options, will provide physicians with a new weapon for treating patients with this rare disease,” added Andrew Wagner, a senior oncologist at Dana-Farber Cancer Institute and the principal investigator in the pivotal AMPECT registrational trial. “In our AMPECT trial, FYARRO demonstrated durable responses in mTOR inhibitor-naïve patients with locally advanced unresectable or metastatic PEComa, with an acceptable and manageable safety profile. This is a drug that will be welcomed by the physician community as the only approved therapeutic option for patients with advanced malignant PEComa.”

Based on data from the AMPECT trial with Fyarro and following discussions with the FDA about other emerging data with Fyarro, Aadi plans to initiate a tumor-agnostic registrational trial in mTOR inhibitor-naïve solid tumors harboring TSC1 or TSC2 inactivating alterations by the end of 2021 or early 2022. Aadi also has ongoing studies to evaluate dosing of Fyarro in combination regimens.

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