nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors

Abstract

PURPOSE Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor nab-sirolimus (AMPECT, NCT02494570 ). PATIENTS AND METHODS Patients with malignant PEComa were treated with nab-sirolimus 100 mg/m2 intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis. RESULTS Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a TSC2 mutation achieved a confirmed response versus 2 of 16 (13%) without TSC2 mutation ( P < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade ≥ 4 treatment-related events occurred. CONCLUSION nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab-sirolimus represents an important new treatment option for this disease.

Spectrum of Presentations and Management Strategies in Renal Angiomyolipoma

“…Nab-sirolimus was studied in a phase-2 clinical trial (AMPECT) that included four patients with kidney PEComa. In the 34 evaluable patients, an ORR of 39% was reported, including response seen in three of the renal PEComa patients ( 36 ). Based on this trial, the FDA approved nab-sirolimus as the first drug specifically indicated for the treatment of patients with malignant PEComas.…”

“…While oral treatments are tempting options, oral mTOR inhibitors treatment usually needs monitoring and might not achieve reliable absorption and sufficient intra-tumoral concentration. This has led to the evaluation of the novel agent nab-sirolimus which is an intravenous (IV) preparation in patients with malignant PEComas ( 36 ). Nab-sirolimus was studied in a phase-2 clinical trial (AMPECT) that included four patients with kidney PEComa.…”

Small molecule inhibitors targeting the cancers

“… 328 While in 2021, the sirolimus protein‐bound particle was approved for malignant perivascular epithelioid cell tumor based on the phase II AMPECT trial showing an ORR of 39%. 631 But both the on‐target immunosuppressive roles and resistance caused by subsequent phosphorylation of AKT ser473 by mTORC2 restrict the use of rapamycin and its analogs. mTOR kinase inhibitors are under development, which can simultaneously suppress the activity of both mTORC1 and mTORC2 and have been discussed above.…”

Novel Therapeutics in the Treatment of Uterine Sarcoma

“…The objective response rate for these patients was 39%, and the median PFS was 10.6 months. 78 The most common toxicities were stomatitis, rash, and fatigue.…”