FDA Approves Sirolimus Protein-Bound Particles for Malignant PEComa

FDA

The FDA has approved sirolimus albumin-bound particles for injectable suspension (Fyarro) for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor.¹

The regulatory decision was supported by data from the phase 2 registrational AMPECT trial (NCT02494570), which showed that the agent elicited highly durable responses, with a long-term median duration of response (DOR) that had not yet been reached a median follow-up of 36 months. Specifically, the independently-assessed objective response rate (ORR) achieved with the agent was 39% (n = 12/31), with 2 patients achieving a complete response after prolonged follow-up.

Responses experienced with the agent have ranged from 5.6 months to 55.5+ months and on going. Among those who responded to treatment, 92% experienced a response that lasted for greater than or equal to 6 months; 67% achieved a response that lasted for greater than or equal to 12 months; and 58% had a response lasting greater than or equal to 2 years.

“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,” Andrew Wagner, MD, PhD, a senior oncologist at Dana-Farber Cancer Institute and the principal investigator in the pivotal AMPECT registrational trial, stated in a press release. “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.”

AMPECT is the first prospective clinical trial to evaluate the safety and efficacy of nab-sirolimus in patients with advanced malignant PEComa. The trial enrolled patients with histologically confirmed malignant PEComa who had metastatic or inoperable locally advanced disease.² Moreover, patients needed to be at least 18 years of age and have an ECOG performance status of 0 or 1. Patients could not have received prior treatment with mTOR inhibitors.

The primary end point of the trial was ORR per independent radiology review, and key secondary end points included DOR, median progression-free survival (PFS), median overall survival (OS), and safety. Exploratory end points include mutational analysis and biomarkers.

Participants were administered the agent intravenously, at a dose of 100 mg/m², on day 1 and day 8 every 28 days until progressive disease or intolerable toxicity.

Results from the primary analysis of the trial, which were presented during the 2020 ASCO Annual Meeting, indicated that 39% (95% CI, 21.8%-57.8%) of 31 patients achieved a confirmed complete response plus partial response as their best response, 52% (95% CI, 33.1%-69.8%) achieved stable disease, and 10% (95% CI, 2.0%-25.8%) experienced disease progression.² The disease control rate achieved with the agent was 71% (95% CI, 52.0%-85.8%).

Moreover, the ORR experienced by patients with metastatic disease (n = 29) was 46% (95% CI, 26.6%-66.6%), and the ORR in those with locally advanced disease (n = 5) was 0%.

The median PFS per independent review was 8.9 months (95% CI, 5.5–not reached [NR]) among 31 evaluable patients. The 3-month PFS rate with the agent was 78.5% (95% CI, 58.5%-89.9%); these rates at 6 months and 12 months were 69.5% (95% CI, 47.6%-83.7%) and 45.4% (95% CI, 22.6%-65.7%), respectively.

Among 34 evaluable patients, the median OS with nab-sirolimus had not yet been reached (95% CI, 22.2–NR). The 6- and 12-month OS rates were 93.2% (95% CI, 75.5%-98.3%) and 88.8% (95% CI, 68.7%-96.3%), respectively.

Moreover, patients whose tumors harbored a TSC2 mutation were found to be significantly more likely respond to treatment with nab-sirolimus (n = 8/9; 89%; P < .001). Notably, all patients with a TSC2 mutation experienced a target lesion response with the agent. All noted TSC2 mutations were observed in the subset of patients with metastatic disease.

Prescribing information for the agent includes warnings and precautions associated with stomatitis, myelosuppression, infections, hypokalemia, hyperglycemia, interstitial lung disease, hemorrhage, and hypersensitivity reactions.

Grade 3 non-hematologic effects that were reported in more than 10% of patients included stomatitis, rash, fatigue and infections. Grade 3 laboratory abnormalities that occurred in more than 10% of patients and worsened from baseline included lymphocytopenia, increased glucose, and decreased potassium.

“Patients living with locally advanced or metastatic PEComa are in urgent need of new treatment options. The approval of Fyarro is a significant advancement for treating patients with this disease," Robert G. Maki, MD, PhD, clinical director of the Sarcoma Program, and professor of medicine at the University of Pennsylvania, stated in a press release. "Treating sarcoma patients in my practice, I have seen the need for a therapy that addresses the specific molecular alterations of advanced malignant PEComa. I am encouraged that Fyarro provided a clinically meaningful benefit in overall response rate, with some patients responding for up to several years. I am pleased to have Fyarro as a new therapeutic option to offer my advanced malignant PEComa patients."

References

1. Aadi Bioscience announces FDA approval of its first product Fyarro for patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa). News release. Aadi Bioscience; November 23, 2021. Accessed November 23, 2021. https://yhoo.it/3nIYc0i
2. Wagner AJ, Ravi V, Riedel RF, et al. Long-term follow-up for duration of response (DoR) after weekly nab-sirolimus in patients with advanced malignant perivascular epithelioid cell tumors (PEComa): results from a registrational open-label phase II trial, AMPECT. J Clin Oncol. 2020;38(suppl 15):11516. doi:10.1200/JCO.2020.38.15_suppl.11516