nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors
Andrew J Wagner, Vinod Ravi, Richard F Riedel, Kristen Ganjoo, Brian A Van Tine, Rashmi Chugh, Lee Cranmer, Erlinda M Gordon, Jason L Hornick, Heng Du, Berta Grigorian, Anita N Schmid, Shihe Hou, Katherine Harris, David J Kwiatkowski, Neil P Desai, Mark A Dickson, Andrew J Wagner, Vinod Ravi, Richard F Riedel, Kristen Ganjoo, Brian A Van Tine, Rashmi Chugh, Lee Cranmer, Erlinda M Gordon, Jason L Hornick, Heng Du, Berta Grigorian, Anita N Schmid, Shihe Hou, Katherine Harris, David J Kwiatkowski, Neil P Desai, Mark A Dickson
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.
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References
- Doyle LA, Argani P, Hornick JL: PEComa, in WHO Classification of Tumors Editorial Board. Soft Tissue and Bone Tumours. Lyon, France, International Agency for Research on Cancer, 2020, pp 312-314
- Folpe AL, Kwiatkowski DJ: Perivascular epithelioid cell neoplasms: Pathology and pathogenesis. Hum Pathol 41:1-15, 2010
- 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 127:2934-2942, 2021
- Sanfilippo R, Jones RL, Blay JY, et al. : Role of chemotherapy, VEGFR inhibitors, and mTOR inhibitors in advanced perivascular epithelioid cell tumors (PEComas). Clin Cancer Res 25:5295-5300, 2019
- Benson C, Vitfell-Rasmussen J, Maruzzo M, et al. : A retrospective study of patients with malignant PEComa receiving treatment with sirolimus or temsirolimus: The Royal Marsden Hospital experience. Anticancer Res 34:3663-3668, 2014
- Italiano A, Delcambre C, Hostein I, et al. : Treatment with the mTOR inhibitor temsirolimus in patients with malignant PEComa. Ann Oncol 21:1135-1137, 2010
- Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. : Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: Targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol 28:835-840, 2010
- Dickson MA, Schwartz GK, Antonescu CR: Extrarenal perivascular epithelioid cell tumors (PEComas) respond to mTOR inhibition: Clinical and molecular correlates. Int J Cancer 132:1711-1717, 2013
- Weeber F, Koudijs MJ, Hoogstraat M, et al. : Effective therapeutic intervention and comprehensive genetic analysis of mTOR signaling in PEComa: A case report. Anticancer Res 35:3399-3403, 2015
- Martignoni G, Pea M, Reghellin D: PEComas: The past, the present and the future. Virchows Arch 452:119-132, 2008
- Kenerson H, Folpe AL, Takayama TK: Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms. Hum Pathol 38:1361-1371, 2007
- Huang J, Manning BD: The TSC1-TSC2 complex: A molecular switchboard controlling cell growth. Biochem J 412:179-190, 2008
- AFINITOR® (everolimus) [prescribing information. East Hanover, NJ, Novartis, 2021.
- RAPAMUNE (sirolimus) [prescribing information]. Philadelphia, PA, Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer, 2019.
- Feldman ME, Apsel B, Uotila A, et al. : Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7:e38, 2009
- Hou S, Schmid AN, Desai NP: ABI-009 (nab-Sirolimus) improves tumor accumulation and antitumor activity over oral mTOR inhibitors. Cancer Res 79, 2019. (13 suppl; abstr 348)
- Sholl LM, Do K, Shivdasani P, et al. : Institutional implementation of clinical tumor profiling on an unselected cancer population. J Clin Invest Insight 1:e87062, 2016
- Comandone A, Petrelli F, Boglione A: Salvage therapy in advanced adult soft tissue sarcoma: A systematic review and meta-analysis of randomized trials. Oncologist 22:1518-1527, 2017
- Ryan CW, Merimsky O, Agulnik M, et al. : PICASSO III: A phase III, placebo-controlled study of doxorubicin with or without palifosfamide in patients with metastatic soft tissue sarcoma. J Clin Oncol 34:3898-3905, 2016
- Seddon B, Strauss SJ, Whelan J, et al. : Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): A randomised controlled phase 3 trial. Lancet Oncol 18:1397-1410, 2017
- Tap WD, Jones RL, Van Tine BA, et al. : Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: An open-label phase 1b and randomised phase 2 trial. Lancet 388:488-497, 2016
- Penel N, Van Glabbeke M, Marreaud S, et al. : Testing new regimens in patients with advanced soft tissue sarcoma: Analysis of publications from the last 10 years. Ann Oncol 22:1266-1272, 2011
- Kratz F: Albumin as a drug carrier: Design of prodrugs, drug conjugates and nanoparticles. J Control Release 132:171-183, 2008
- Schnitzer JE, Liu J, Oh P: Endothelial caveolae have the molecular transport machinery for vesicle budding, docking, and fusion including VAMP, NSF, SNAP, annexins, and GTPases. J Biol Chem 270:14399-14404, 1995
- Kremer P, Hartung G, Bauder-Wust U, et al. : Efficacy and tolerability of an aminopterin-albumin conjugate in tumor-bearing rats. Anticancer Drugs 13:615-623, 2002
- Gradishar WJ, Tjulandin S, Davidson N, et al. : Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23:7794-7803, 2005
- Socinski MA, Bondarenko I, Karaseva NA, et al. : Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: Final results of a phase III trial. J Clin Oncol 30:2055-2062, 2012
- Gonzalez-Angulo AM, Meric-Bernstam F, Chawla S, et al. : Weekly nab-rapamycin in patients with advanced nonhematologic malignancies: Final results of a phase I trial. Clin Cancer Res 19:5474-5484, 2013
- TORISEL® (temsirolimus) [prescribing information]. Philadelphia, PA, Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer, 2018.
- Salussolia CL, Klonowska K, Kwiatkowski DJ: Genetic etiologies, diagnosis, and treatment of tuberous sclerosis complex. Annu Rev Genomics Hum Genet 20:217-240, 2019
Source: PubMed