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.

Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status.

Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is an albumin-bound 130-nm particle form of paclitaxel that demonstrated higher efficacy and was well tolerated compared with solvent-based paclitaxel (Taxol) and docetaxel (Taxotere) in clinical trials for metastatic breast cancer. Nab-paclitaxel enhances tumor targeting through gp60 and caveolae-mediated endothelial transcytosis and the association with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine) in the tumor microenvironment. The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to correlate with resistance to paclitaxel. To evaluate the importance of HER2 and SPARC status in determining the relative efficacy of nab-paclitaxel compared with polysorbate-based docetaxel, nude mice bearing six different human tumor xenografts were treated with nab-paclitaxel (MX-1: 15 mg/kg, once a week for 3 weeks; LX-1, MDA-MB-231/HER2+, PC3, and HT29: 50 and 120 mg/kg, every 4 days three times ; MDA-MB-231: 120 and 180 mg/kg, every 4 days three times) and polysorbate-based docetaxel (15 mg/kg). HER2 and SPARC status were analyzed by RT-PCR and immunohistochemical staining. MDA-MB-231 and MX-1 breast and LX-1 lung cancers were HER2 negative and low in SPARC expression. Nab-paclitaxel at submaximum-tolerated dosage was significantly more effective than polysorbate-based docetaxel at its maximum-tolerated dosage in these three HER2-negative tumors. The HER2-positive tumors had variable SPARC expression, with MDA-MB-231/HER2+