Fyarro (nab-sirolimus) is the first and only drug indicated for the treatment of locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa) in adults.
Fyarro, developed by Aadi Bioscience, is approved by the U.S. Food and Drug Administration (FDA) in November 2021.
So far, no authorized treatment for malignant PEComas has been proposed.
What Is Perivascular Epithelioid Cell Tumor
Perivascular epithelioid cell tumors (PEComa) are a family of mesenchymal neoplasms consisting of perivascular epithelioid cells. They are very rare tumors (less than 1 case per million) that can occur in any part of the human body, including the stomach, intestines, lungs, female reproductive organs, and genitourinary organs.
PEComas are an aggressive subtype of soft tissue sarcoma.
The type of cells from which PEComas originate is unknown. Normally, there are no perivascular epithelioid cells: this name refers to the histological and immunohistochemical characteristics of the tumor when viewed under the microscope.
In the majority of cases, PEComas are benign. However, establishing the malignant potential of PEComas remains a challenge: some show malignant features, while others can be typed with “undetermined malignant potential”. The most common tumors in the perivascular epithelioid cell tumors family are renal angiomyolipoma and pulmonary lymphangioleiomyomatosis — they occur more frequently in patients with tuberous sclerosis complex.
Malignant PEComas do not have an approved treatment. Yes, cytotoxic chemotherapy regimens are often used, but their therapeutic benefit is modest. According to individual cases and retrospective analyses, mTORC1 inhibitors such as sirolimus, everolimus, and temsirolimus help some PEComa patients.      
Pathogenetically, PEComas usually carry loss-of-function mutations or deletions in the TSC1 or TSC2 genes. PEComas often show evidence of aberrant mTORC1 signaling, suggesting the therapeutic feasibility of its inhibition.
Fyarro: Efficacy and Safety of Nab-Sirolimus
The AMPECT (NCT02494570) phase 2 ( nonrandomized, open-label, multicenter) clinical trial invited adult patients (n=31) with locally advanced inoperable or metastatic perivascular epithelioid cell tumors.
Patients with lymphangioleiomyomatosis and prior treatment with mTOR inhibitors were excluded.
The main characteristics of the subjects were: median age 60 years (27–78); 81% female; 85% had metastatic disease; the most common primary sites of disease were uterus (in 24%), pelvis and retroperitoneum (18% each), lung and kidney (12% each); 13% had received chemotherapy (gemcitabine + docetaxel, doxorubicin + ifosfamide, doxorubicin+olaratumab) of advanced disease.
Fyarro was administered to patients until disease progression or unacceptable toxicity.
After 6 months of treatment, the overall response rate (ORR) was 39% (95% CI: 22–58). All responses to treatment were initially partial (PR), then improved to complete (CR) in two patients during the follow-up period.
Remarkably, the presence of the TSC2 tumor mutation contributed to the improved response to treatment: a confirmed response was recorded in 89% of patients with it and only 13% without it.
After another 1.5 years of follow-up, the median duration of response (DoR) was not reached: NR (5.6–47.2+). The DoR of 6 months or more was fair for 92% of patients, 12 months or more for 75%, 18 months or more for 75%, and 24 months or more for 66%.
The median progression-free survival (PFS) came out to 10.6 months (95% CI: 5.5–NR). The rates of PFS at 3, 6, 12, and 24 months were 79%, 69%, 47%, and 47%, respectively.
Median overall survival (OS) was documented at 40.8 months (95% CI: 22.2–NR). The probabilities of remaining alive at 6, 12, and 24 months were 93%, 89%, and 70%, respectively.
Most adverse reactions to Fyarro administration were mild-to-moderate in severity. Among the most common adverse events were mucositis (in 79% of patients), fatigue (59%), rash (56%), nausea (47%), and diarrhea (38%).
Fyarro: Mechanism of Action of Nab-Sirolimus
Sirolimus is an inhibitor of the mechanistic target of rapamycin kinase (mTOR; formerly called the mammalian target of rapamycin), a serine-threonine kinase downstream of the PI3K/AKT signaling pathway that controls key cellular processes such as survival, growth, and proliferation.
In cells, sirolimus binds to the cytosolic immunophilin protein, FK506-binding protein 12 (FKPB-12), and forms an immunosuppressive complex. The sirolimus-FKBP-12 complex binds to the mechanical target of rapamycin complex 1 (mTORC1) and inhibits its activation. In vitro and in vivo, sirolimus inhibition of mTOR has been shown to inhibit cell proliferation, angiogenesis, and glucose uptake.
Sirolimus in Fyarro is implemented in the form of nanoparticles bound to albumin and is therefore named nab-sirolimus (ABI-009). The intravenous drug compound compared to conventional oral sirolimus or everolimus is characterized by enhanced tumor growth inhibition, intratumor accumulation of the drug, and suppression of the mTOR target.
Fyarro: What’s Next
Fyarro has the potential to become a drug for the treatment of all tumors (regardless of their origin or anatomical localization) carrying TSC1 or TSC2 mutations. At least this was confirmed in the clinical trial NCT03817515 (expanded drug access program), which tested nab sirolimus in patients with neoplasms other than PEComas.
Preliminary results indicated an exit to partial response (PR) in 71% of patients (n=5/7), although they had previously undergone multiple lines of therapy.
Fyarro has helped in endometrial stromal sarcoma, ovarian cancer, leiomyosarcoma, lymphangioleiomyoma, and high-grade sarcoma.
TSC1 and TSC2 tumor mutations are very rare (incidence does not exceed 1–2%), but this does not mean that the possibility of targeted therapy should be discarded.
Aadi will soon begin a PRECISION 1 (NCT05103358) phase 2 clinical trial that will test Fyarro in patients with solid tumors carrying pathogenic inactivating alterations in TSC1 or TSC2 genes. Participants’ inoperable disease must be metastatic or locally advanced, having undergone all standard treatments.
Fyarro (nab-sirolimus). Prescribing information. US. [PDF]
Aadi Bioscience. Corporate overview. August 2021. [PDF]
Nab-sirolimus for patients with malignant perivascular epithelioid cell tumors. J Clin Oncol. 2021 Nov 20;39(33):3660-3670. [source]