nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors

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.

Clinicopathological features and treatment of perivascular epithelioid cell tumor.

e23538 Background: Perivascular epithelioid cell tumor (PEComa) is a rare form of mesenchymal neoplasms. No clinical trial of large sample size regarding medical treatment of PEComa has been reported so far. Previous retrospective studies with small sample size have showed efficacy of mTOR inhibitors as treatment of PEComa. This study aimed to analyze the clinicopathological features of PEComa, and the efficacy of mTOR inhibitor in advanced PEComa. Methods: Medical information of patients diagnosed with PEComa and treated in Fudan University Shanghai Cancer Center were collected. Survival analysis was performed by Kaplan-Meier method. Radiological response was assessed according to RECIST version1.1. Results: A total of 17 patients were treated in our center during June 2007 to June 2020. PEComa mostly occurs in middle-aged women. The most common primary sites are pelvis, lung and abdomen. Relapse usually occurs within 2 years after radical surgery. Radical surgery is the main treatment for PEComa of limited stage, and remains the main option for those with limited recurrent lesions. Of the 13 patients with advanced malignant PEComa in our cohorts, the objective response rate of mTOR inhibitors in advanced malignant PEComa was 45.5%, and median progression-free survival was 27.7 months (95% CI 4.7-50.5 months). 2 patients discontinued mTOR inhibitor treatment due to pneumonitis combined with dyspnea and fever respectively. Conclusions: For advanced malignant PEComa, mTOR inhibitors are effective. Lung toxicity of mTOR inhibitor should be monitored.

Perivascular epithelioid cell tumor (PEComa) of the kidney: an overview of its management and outcomes

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor with unique histological and immunohistochemical characteristics. Malignant renal cell carcinoma is even rarer and its biological behavior is still not clear. We report here a case of malignant PEComa in a male patient. The first symptom of the patient was intermittent hematuria. Ultrasound and computed tomography scan showed a solid mass in the left kidney. Fibrosarcoma was initially diagnosed after radical resection of the tumor. Six years later, the patient had a tumor recurrence and underwent a second operation, through which the diagnosis of renal malignant PEComa was made. Since then, the patient received chemotherapy, a third operation, and interventional treatment because of recurrence and metastasis of the tumor, which prolonged the life of the patient for another 6 years. Malignant PEComa involving the kidney is very rare; it seems to develop slowly but will recur and metastasize. At present, surgical resection remains the best treatment.

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.

11516 Background: Malignant PEComa is a rare, aggressive sarcoma, with no approved medical treatment. Cytotoxic chemotherapies have limited benefit for patients with advanced disease. The AMPECT trial measured the effects of nab-sirolimus (ABI-009) and is the first prospective study in advanced malignant PEComa. nab-Sirolimus is a nanoparticle albumin-bound mTOR inhibitor with significantly higher intratumoral drug levels, mTOR target suppression, and anti-tumor activity in animal models versus other mTOR inhibitors. This report presents long-term follow-up of DoR after the primary analysis. Methods: Patients (N=34) received nab-sirolimus (100mg/m2 IV, weekly, 2/3 weeks) until progression or unacceptable toxicity. Primary endpoint: ORR by IRR. Key secondary endpoints included DoR, PFS6, OS, and safety. Exploratory endpoints included correlation of tumor genotype and outcome. The sample size of 30 efficacy-evaluable patients was based on an estimated ORR of 30% and the lower bound of the 95%CI of ORR to exclude values less than 14.7%. The primary analysis was conducted when all patients were treated ≥6 months (May 22, 2019). This report updates the primary response analysis and DoR with an additional 8.5-month of follow-up. Results: As of Feb 06, 2020, of the 31 efficacy-evaluable patients, the confirmed ORR by IRR was 39% (12/31, 95%CI: 21.8, 57.8), with 1 complete response (CR) and 11 partial responses (PR), 52% stable disease (SD, 16/31, with 10/16 SD ≥12 weeks), and 10% progressive disease (3/31); the disease control rate (CR+PR+SD ≥12 weeks) was 71%. PFS6 was 71% (95%CI: 47.7, 85.1). The majority of responses (67%) were reached at the first post-baseline scan at week 6, with a median time to response of 1.4 months (95%CI: 1.3 to 2.8). The median DoR by IRR was not yet reached (range 5.6-38.7+ months; calculated median 22.2+ months) with 8/12 (67%) responders still on treatment for >1 year and 5/12 (42%) >2 years. Mutational analysis available for 25 patients identified that TSC2 loss-of-function mutations significantly correlated with response; 8/9 (89%) patients with TSC2 had a confirmed response. Conclusions: Responses of advanced malignant PEComa to nab-sirolimus were highly durable and occurred in 39% of patients based on independent review. The high disease control rate with manageable toxicities suggest that nab-sirolimus is effective and represents an important new treatment option for these patients. NCT02494570. Clinical trial information: NCT02494570 .