Ultra-Rare Sarcoma Subgroup Sees First Treatment Option

Oncology Live®Vol. 23/No. 5
Volume 23
Issue 05

Nab-sirolimus became a treatment option for a rare, aggressive soft-tissue sarcoma—malignant perivascular epithelioid cell tumor—following encouraging data in the first prospective clinical trial for this patient population.



A treatment option for a rare, aggressive soft-tissue sarcoma—malignant perivascular epithelioid cell tumor (PEComa)—arrived following encouraging data in the first prospective clinical trial for this patient population. Sirolimus albumin-bound particles for injectable suspension (nab-sirolimus; Fyarro) was approved by the FDA for the treatment of adult patients with locally advanced unresectable or metastatic malignant PEComa in November 2021.1

Ultra-rare sarcomas are defined by the Connective Tissue Oncology Society as those that have an approximate incidence of 1 or fewer per 1 million, a much narrower pool than the threshold that defines rare cancers (incidence < 6 per 100,000).2 Coupled with low incidence are the unique clinical challenges in drug development including a lack of understanding of the biology of the tumors, initiation and recruitment to clinical trials, and ultimately achievement of drug approvals.

Cytotoxic chemotherapy has demonstrated some response among patients with PEComa; however, investigators opted to pursue the path of developing an mTOR inhibitor following evidence of activity with sirolimus (Rapamune), everolimus (Afinitor), and temsirolimus (Torisel) in case reports.3 One distinction investigators sought to overcome with the development of nab-sirolimus was the variable absorption rates of orally available mTOR inhibitors. In preclinical models the intravenous formulation of nab-sirolimus had a higher intratumoral drug accumulation and tumor growth inhibition.

The phase 2 registrational, single-arm AMPECT trial (NCT02494570) recruited 34 patients with histologically confirmed malignant PEComa for which surgery is not a recommended option and who have not received prior treatment with an mTOR inhibitor.4 Of these patients, 2 patients were not evaluable for efficacy because of a misdiagnosis of PEComa and 1 patient did not have tissue available for confirmation of PEComa.

The primary sites of disease in the intention-to-treat population were uterus (24%), pelvis (18%), retroperitoneum (18%), lung (12%), kidney (12%), liver (3%), brain (3%), muscle (3%), ovary (3%), aorta (3%), and small bowel (3%).5 Investigators evaluated nab-sirolimus at 100 mg/m2 on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was overall response rate (ORR) by RECIST 1.1 as assessed by blinded independent central review with secondary end points of duration of response, progression-free survival (PFS) rate at 6 months, PFS, overall survival (OS), and safety.4

At the time of final analysis with a data cutoff of June 30, 2021, the confirmed overall response rate was 39% (95% CI, 22%-58%) with 2 patients achieving a complete response (CR; 7%) and 10 patients achieving a partial response (PR; 32%). Fifty-two percent of patients had stable disease. The disease control rate— comprising CR and PR plus stable disease of at least 12 weeks—was 71%. The median duration of response was not reached (range, 5.6-55.5).5

Investigators noted that 2 patients converted from a PR to a CR after 11 months and 34 months of treatment, respectively. The DOR rates at 6, 12, 24, and 36 months were 92%, 75%, 66%, and 66%, respectively. At data cutoff, approximately 50% of patients had an ongoing duration of response at 36.1 months.

In terms of secondary end point survival data, the median PFS was 10.6 months and the median OS was 40.8 months. The 6-, 12-, 24-, 36-, and 48-month PFS rates were 69%, 47%, 47%, 41%, and 34%, respectively. OS rates at the same interval were 93%, 89%, 70%, 65%, and 52%, respectively.

Authors of the findings wrote that the data exceeded “the prespecified lowerbound objective response rate of 15% below which the regimen would be considered no more active than standard doxorubicin-based chemotherapy. Responses were of rapid onset and durable. Given the aggressive natural history of the disease not known to spontaneously regress, the responses are most likely due to antitumor activity of nab-sirolimus.”3

Activation of the mTOR signaling pathway in patients with PEComa has been observed in conjunction with loss-of-function mutations or deletions in the tuberous sclerosis complex (TSC).6 In an exploratory mutational status analysis, most patients who had target lesion changes also presented with a TSC2 mutation (n = 9/12). Among these 9 responders, 89% had a confirmed overall response.5

In a safety analysis among all treated patients (n = 34) no grade 4 or 5 treatment-related adverse effects (AEs) were reported. Most AEs were grade 1 and 2; mucositis, an AE of special interest, had the highest grade 3 incidence at 18%. Investigators noted that pneumonitis had an incidence of 21% and was grade 1 or 2. Two patients discontinued treatment because of AEs—one grade 2 anemia, one grade 1 cystitis. All patients who experienced serious AEs including dehydration (6%), acute kidney injury (3%), acute coronary syndrome (3%), abdominal pain (3%), diarrhea (3%), edema (3%), enteritis (3%), and pancytopenia (3%) recovered.

As these data fuel the approval for the first-line treatment of patients with PEComa, a multi-institutional expanded access study has been initiated to evaluate the efficacy of nab-sirolimus in patients who have been previously treated with an mTOR inhibitor such as sirolimus or everolimus. At the Connective Tissue Society Virtual 2021 Annual Meeting, investigators presented data for 16 patients with malignant PEComa who progressed on prior mTOR inhibitor therapy enrolled between July 2019 and July 2021.7

Twelve patients received treatment with 1 prior mTOR inhibitor and 4 patients received 2 or more prior mTOR inhibitors including sirolimus, everolimus, temsirolimus, or sapanisertib. Best overall response among the 16 patients was a 25% PR rate. Fifty percent of patients had stable disease with 38% of those responses lasting at least 12 weeks. In terms of mutational status, among confirmed responders 1 patient had a TSC1 mutation and 3 had TCS2 mutations.7


  1. FDA approves sirolimus protein-bound particles for malignant perivascular epithelioid cell tumor. FDA. Updated November 23, 2021. Accessed February 14, 2022. bit.ly/3JtAoG4
  2. Stacchiotti S, Frezza AM, Blay JY, et al. Ultra-rare sarcomas: a consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities. Cancer. 2021;127(16):2934-2942. doi:10.1002/cncr.33618
  3. Wagner AJ, Ravi V, Riedel RF, et al. nab-sirolimus for patients with malignant perivascular epithelioid cell tumors. J Clin Oncol. 2021;39(33):3660-3670. doi:10.1200/JCO.21.01728
  4. A phase 2 study of ABI-009 in patients with advanced malignant PEComa (AMPECT). ClinicalTrials.gov. Updated January 11, 2022. Accessed February 14, 2022. https://www.clinicaltrials.gov/ct2/show/ NCT02494570
  5. Wagner AJ, Ravi V, Riedel RF, et al. Final analysis from AMPECT, an open-label phase 2 registration trial of nab-sirolimus for patients with advanced malignant perivascular epithelioid cell tumors (PEComa). Presented at: Connective Tissue Society Virtual 2021 Annual Meeting; November 10-13, 2021. Accessed February 14, 2022. bit.ly/3gKIOwe
  6. Dickson MA, Schwartz GK, Antonescu CR, Kwiatkowski DJ, Malinowska IA. Extrarenal perivascular epithelioid cell tumors (PEComas) respond to mTOR inhibition: clinical and molecular correlates. Int J Cancer. 2013;132(7):1711-1717. doi:10.1002/ijc.27800
  7. Dickson MA, Ravi V, Chen J, et al. nab-sirolimus in patients with malignant PECOMA previously treated with mTOR inhibitors: emerging experience from an expanded access program. Presented at: Connective Tissue Society Virtual 2021 Annual Meeting; November 10-13, 2021. Accessed February 14, 2022. bit.ly/3uWAGky
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