nab-Sirolimus for patients with advanced malignant PEComa with or without prior mTOR inhibitors: Biomarker results from AMPECT and an expanded access program.
Authors: Dickson Mark Andrew , Ravi Vinod , Riedel Richard F. , Ganjoo Kristen N. , Van Tine Brian Andrew , Chugh Rashmi , Cranmer Lee D. , Gordon Erlinda Maria , Chen James Lin , Murphy Martina Cathryn , Schmid Anita N. , Desai Neil , Alonzo Palma Norma , Kwiatkowski David J. , Wagner Andrew J. 
Published: June 2022

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Background: Malignant perivascular epithelioid cell tumor (PEComa) is a rare and aggressive sarcoma. nab-Sirolimus is an albumin-bound intravenous (IV) mTOR inhibitor (mTORi) approved for the treatment of adult patients with locally advanced unresectable or metastatic malignant PEComa. The AMPECT trial (NCT02494570) was the first prospective study in advanced malignant PEComa. In exploratory biomarker analyses, TSC1 or TSC2 alterations were associated with response. We report data from the final analysis of AMPECT patients, who were naïve to mTORi, and in patients with malignant PEComa with prior mTORi exposure treated with nab-sirolimus in an expanded access program (EAP) (NCT03817515). Methods: In AMPECT, patients with malignant PEComa naïve to mTORi received nab-sirolimus (100 mg/m2 IV days 1 and 8 of every 21-day cycle) until progression or unacceptable toxicity. The primary endpoint was ORR by independent radiology review. Other endpoints included duration of response (DOR) and disease control rate (DCR), defined as complete response (CR), partial response (PR), or stable disease (SD) at ≥12 weeks. In the EAP, patients with malignant PEComa and prior mTORi exposure received the same dose of nab-sirolimus as in AMPECT. Responses and DCR were evaluated post hoc via electronic medical record review. Genetic profiling, including TSC1 or TSC2 status, was assessed in both protocols, but no specific mutation criteria were required for enrollment. Results: Data include 47 total efficacy-evaluable patients, 31 in AMPECT and 16 with malignant PEComa and prior mTORi exposure treated in the EAP from July 2019–July 2021. Prior mTORi on the EAP included sirolimus, everolimus, temsirolimus, or sapanisertib; 12 patients had exposure to 1 prior mTORi and 4 to ≥2 prior mTORi, and 50% had had progressive disease as best response on mTORi. In AMPECT, ORR was 39% (12/31 patients), and DCR was 71%. Median DOR was not reached after 3 years of follow-up. On the EAP, 4/16 patients (25%) achieved PR (DOR range: 1.3+–25.2+ months, 3 ongoing), and 8/16 (50%) had SD as best response; the DCR was 63% (10/16). Of patients with known TSC1 or TSC2 inactivating alterations in the combined datasets (n = 23), 57% had a response (AMPECT, 64%; EAP, 44%). There were no Grade 4 or 5 treatment-related adverse events on either protocol Conclusions: nab-Sirolimus provided durable responses in mTORi-naïve patients with malignant PEComa and clinical benefit in an expanded access protocol for patients with malignant PEComa with prior mTORi therapy. Although AMPECT and the EAP cannot be directly compared, response rates showed similar trends regardless of prior mTORi exposure and in patients with TSC1 or TSC2 alterations. Based on the emerging biomarker results, a tissue-agnostic study in patients with TSC1 and TSC2 alterations has been initiated (NCT05103358). Clinical trial information: NCT02494570, NCT03817515.