nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors

Abstract

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.

Conflict of interest statement

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.

Figures

FIG 1.

Response to nab-sirolimus in patients with PEComa. (A) Waterfall plot of maximum reduction in sum of longest diameters of target tumors, evaluated at the 1.5-year follow-up after the primary analysis. *A patient with unconfirmed PR is considered having SD as best response per RECIST v1.1 and a patient with a complete response of target tumor reduction has a PR as best response because of unresolved nontarget lesions. (B) Spider plot showing change in the sum of target tumor measurements over time. Arrowheads indicate patients who were still on treatment at the time of the 1.5-year follow-up. (C) Swimmer plot showing the treatment duration and response to treatment of individual patients, including reasons for off therapy and survival. (D) Co-Mut plot showing correlation between mutational status and other biomarkers, and response. Each column represents a different patient. Response, clinical features, and pS6 staining by IHC are shown at the top. Then, relevant genes, mutation frequency, and type are shown. Six patients had tumors NE for mutational status because of inadequate tumor sample; PRs occurred in two patients (33%) of this group. CR, complete remission; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; NE, not evaluable; PEComa, perivascular epithelioid cell tumor; PR, partial response; SD, stable disease.

FIG 2.

(A) Kaplan-Meier curves for DOR, PFS, and OS for all patients and (B) PFS and OS by mutational status. DOR, duration of response; OS, overall survival; PFS, progression-free survival; WT, wildtype.

FIG 3.

Next-generation sequencing of 25 patient samples.