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/m ² 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.
Competing Interests: Andrew J. WagnerHonoraria: DecipheraConsulting or Advisory Role: Lilly, Five Prime Therapeutics, Daiichi Sankyo, Deciphera, Nanocarrier, MundipharmaResearch Funding: Lilly, Plexxikon, Daiichi Sankyo, Karyopharm Therapeutics, Aadi Bioscience, Deciphera Vinod RaviStock and Other Ownership Interests: TRACON Pharma, Merck, AstraZeneca, Pfizer, Moderna TherapeuticsConsulting or Advisory Role: Daiichi SankyoResearch Funding: Novartis, TRACON Pharma, Aadi Bioscience, AthenexTravel, Accommodations, Expenses: Daiichi Sankyo Richard F. RiedelEmployment: LimbguardLeadership: LimbguardStock and Other Ownership Interests: LimbguardConsulting or Advisory Role: Daiichi Sankyo, Loxo, Ignyta, Bayer, Nanocarrier, Deciphera, SpringWorks Therapeutics, Blueprint MedicinesResearch Funding: TRACON Pharma, Bayer, Karyopharm Therapeutics, Immune Design, Aadi Bioscience, Plexxikon, Arog, Lilly, Daiichi Sankyo, Ignyta, Roche/Genetech, NanoCarrier, GlaxoSmithKline, SpringWorks Therapeutics, Blueprint Medicines, Epizyme, PhilogenPatents, Royalties, Other Intellectual Property: PandoNet - LimbguardTravel, Accommodations, Expenses: Daiichi Sankyo, Ignyta, NanoCarrier Kristen GanjooConsulting or Advisory Role: Daiichi Sankyo, Foundation Medicine, Deciphera Brian A. Van TineLeadership: PolarisHonoraria: Bionest Partners (Healthcare Consulting Firm), Horizon CME, Research to Practice, Daiichi Sankyo, Pfizer, Adaptimmune, Bayer, GlaxoSmithKline, Lilly, Cytokinetics, Apexigen, Deciphera Pharmaceuticals, Immune Design, ADRx, Ayala Pharmaceuticals, Intellisphere LLCSpeaker’s Bureau: Novartis, Lilly, Adaptimmune, GlaxoSmithKlineConsulting or Advisory Role: EMD Serono, Novartis, Epizyme,Research Funding: Pfizer, Merck, TRACON Pharma, GlaxoSmithKlinePatents, Royalties, Other Intellectual Property: Patent on the use of ME1 as a biomarker, Patent on ALEXT3102, Accuronix Therapeutics-Licensing agreement, Sigma-Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutics Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and uses thereof (014229)Expert Testimony: Health AdvancesTravel, Accommodations, Expenses: Advenchen Laboratories, GlaxoSmithKline, Lilly Rashmi ChughConsulting or Advisory Role: Ipsen, Deciphera, EpizymeResearch Funding: Novartis, Morphotek, MabVax, Epizyme, Aadi Bioscience, Advenchen Laboratories, Plexxikon, Mundipharma, SpringWorks Therapeutics, GlaxoSmithKline, Medivation, Qilu Puget Sound Biotherapeutics, AstraZeneca, JanssenPatents, Royalties, Other Intellectual Property: Wolters KluwerExpert Testimony: DOPF, LLC, Meyers Law, LLCTravel, Accommodations, Expenses: SpringWorks Therapeutics Lee CranmerConsulting or Advisory Role: Daiichi SankyoResearch Funding: Aadi Bioscience, Advenchen Laboratories, Lilly, Exelixis, Iterion Therapeutics, Philogen, CBA Research, Astellas Pharma Erlinda M. GordonStock and Other Ownership Interests: Counterpoint Biomedica, Delta NextGene, LLCResearch Funding: Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Coinventor of patents on targeting pharmaceutical agents to injured tissues Jason L. HornickConsulting or Advisory Role: Aadi Bioscience, TRACON Pharma Berta GrigorianEmployment: Aadi BioscienceStock and Other Ownership Interests: Aadi Bioscience Anita N. SchmidEmployment: Aadi BioscienceStock and Other Ownership Interests: Aadi Bioscience Shihe HouEmployment: Aadi BioscienceStock and Other Ownership Interests: Aadi Bioscience, Bristol Myers Squibb/Celgene Katherine HarrisConsulting or Advisory Role: Aadi Bioscience David J. KwiatkowskiConsulting or Advisory Role: Genetech/Roche, Novartis, Aadi BioscienceResearch Funding: Aadi Bioscience, Revolution Medicines, Genetech/Roche Neil P. DesaiEmployment: Aadi BioscienceLeadership: Aadi BioscienceStock and Other Ownership Interests: Aadi BioscienceResearch Funding: Aadi BiosciencePatents, Royalties, Other Intellectual Property: I hold patents as an employee of Aadi BioscienceTravel, Accommodations, Expenses: Aadi Bioscience Mark A. DicksonConsulting or Advisory Role: CelgeneResearch Funding: Lilly, Aadi BioscienceNo other potential conflicts of interest were reported.