FDA Grants Priority Review to Nab-Sirolimus for Advanced Malignant PEComa

The FDA has granted priority review to a new drug application (NDA) for the nanoparticle albumin-bound mTOR inhibitor nab-sirolimus (ABI-009) for the treatment of patients with malignant perivascular epithelioid cell neoplasm (PEComa).¹

The application is based on findings from the AMPECT registration 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.2 Specifically, the independently-assessed objective response rate (ORR) achieved with the agent was 39% (95% CI, 22%-58%), meeting the primary end point of the trial.

The regulatory agency is anticipated to make a decision on the application by November 26, 2021, per the Prescription Drug User Fee Act.

“We are pleased with FDA’s acceptance of our NDA with priority review for [nab-sirolimus] in patients with advanced malignant PEComa, an ultra-rare sarcoma,” Neil Desai, PhD, founder, chief executive officer, and president of Aadi Bioscience, Inc., stated in a press release. “We look forward to working with the FDA during its review and would like to thank the many patients, caregivers, and physicians whose contributions have been invaluable and allowed us to develop this important therapy. In parallel, we continue to work on our commercial preparations to ensure a timely launch for the PEComa patient population.”

Advanced PEComa is a rare, aggressive sarcoma for which no approved therapeutic options exist. AMPECT is the first prospective clinical trial to examine the safety and efficacy of nab-sirolimus in patients with advanced malignant PEComa.

To be eligible for enrollment, patients needed to have histologically confirmed malignant PEComa; they needed to have metastatic or inoperable locally advanced disease. Moreover, patients needed to be at least 18 years of age and an ECOG performance status of 0 or 1. They could not have previously received treatment with mTOR inhibitors.

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

Study participants were given nab-sirolimus intravenously, at a dose of 100 mg/m² on day 1 and day 8 every 28 days until disease progression or intolerable toxicity.

Of the 34 patients enrolled to the trial, the median age is 60 years (range, 27-78), with 44% of patients aged 65 years or older. Moreover, 82% of patients are female, 71% are White, 15% have locally advanced disease, and 85% have metastatic disease.

Additional results from the primary analysis of May 22, 2019, 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. The disease control rate achieved with nab-sirolimus was 71% (95% CI, 52.0%-85.8%).

Moreover, the ORR achieved 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.

Additionally, 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.

Regarding safety, no grade 4 or 5 treatment-related adverse effects (AEs) were reported with nab-sirolimus, nor were any unexpected AEs. Eighteen percent of patients who received the agent experienced pneumonitis, but all cases were grade 1 or 2 in severity.

Six percent of patients discontinued treatment with the mTOR inhibitor because of an AE; 1 patient did so because of grade 2 anemia, and the other patient did so because of grade 1 cystitis. Overall, the agent was determined to be safe and well tolerated as a long-term treatment.

Investigators concluded that a pan-tumor study focused on examining nab-sirolimus in patients whose tumors harbor TSC1 and TSC2 loss-of-function mutations is warranted.

References

1. Aadi Biosciences announces FDA acceptance and priority review for the new drug application of FYARRO for the treatment of advanced malignant PEComa. News release. Aadi Bioscience, Inc. July 26, 2021. Accessed July 26, 2021. https://bit.ly/3x5zN6N
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