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Role of Chemotherapy, VEGFR Inhibitors and Mtor Inhibitors in Advanced Perivascular Epithelioid Cell Tumours (Pecomas)

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Role of Chemotherapy, VEGFR Inhibitors and Mtor Inhibitors in Advanced Perivascular Epithelioid Cell Tumours (Pecomas) Author Manuscript Published OnlineFirst on June 19, 2019; DOI: 10.1158/1078-0432.CCR-19-0288 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Research article Role of chemotherapy, VEGFR inhibitors and mTOR Inhibitors in advanced Perivascular Epithelioid Cell Tumours (PEComas). Running title: Systemic treatment in advanced PEComas. Author list: 1Roberta Sanfilippo, 2Robin L. Jones, 3Jean-Yves Blay, 4Axel LeCesne, 1Salvatore Provenzano, 2Georgios Antoniou, 4Olivier Mir, 1Giovanni Fucà, 1Elena Fumagalli, 1Rossella Bertulli, 1Silvia Stacchiotti, 3Mehdi Brahmi, 5Federica Grosso, 3Armelle Dufresne, 6,7Nadia Hindi, 8Marta Sbaraglia, 9Alessandro Gronchi, 10Paola Collini, 8,11Angelo P. Dei Tos, 1,12Paolo G. Casali. Authors’ affiliation: 1. Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; 2. Sarcoma Unit, Royal Marsden Hospital, London, United Kingdom; 3. Department of Medical Oncology, Centre Léon Bérard, Lyon, France; 4. Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France; 5. Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy; 6. Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 7. Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; 8. Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy; 9. Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy; 10. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; 11. Department of Medicine, University of Padova School of Medicine, Padova, Italy; 1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2019; DOI: 10.1158/1078-0432.CCR-19-0288 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 12. Oncology and Haemato-Oncology Department, University of Milan, Milan, Italy. Keywords: advanced PEComa; systemic treatment; chemotherapy; mTOR inhibitors; TKIs ADDITIONAL INFORMATION Financial support: none. Corresponding author: Dr Roberta Sanfilippo, Medical Oncology Unit 2, Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori Via G. Venezian, 1 - 20133 Milan, Italy Telephone: +39 02 2390 2638 Fax: +39 02 2390 2804 Email: [email protected] Conflict of interest disclosure statement: Dr. Sanfilippo reported research support from Eli Lilly and PharmaMar outside the present work. Dr. Jones reported consulting for Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, Pharmamar. Dr. Blay reported research support from Novartis and GSK outside the present work. Dr. Mir reported consulting for Amgen, Astra-Zeneca, Bayer, Blueprint Medicines, Bristol Myers-Squibb, Eli-Lilly, Incyte, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor Pharma; board membership for Amgen, Astra-Zeneca, Bayer, Blueprint Medicines, Bristol Myers-Squibb, Eli-Lilly, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor Pharma; receiving speaking fees from Eli- Lilly, Roche, Servier as well as stock ownership for Amplitude surgical and Transgene. Dr. Dei Tos reported research support from Eli Lilly and PharmaMar outside the present work. Dr. Casali 2 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2019; DOI: 10.1158/1078-0432.CCR-19-0288 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. reported consulting for Eisai, Eli Lilly, Deciphera Pharmaceuticals and Nektar Therapeutics; receiving honoraria from Eisai, Eli Lilly, Pfizer and PharmaMar as well as research support outside the present work from Amgen Dompé, Arog Pharmaceuticals, Bayer, Blueprint Medicines, Eli Lilly, Daiichi Sankyo Pharma, Deciphera Pharmaceuticals, Epizyme Inc., Novartis, Pfizer, PharmaMar. The other authors declare no potential conflicts of interest. Word count: 2166 Total number of figures and tables: 4 3 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2019; DOI: 10.1158/1078-0432.CCR-19-0288 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. STATEMENT OF TRANSLATIONAL RELEVANCE Perivascular epitheliod cell tumours (PEComas) are rare mesenchymal neoplasms for which a standard strategy for systemic treatment in the advanced setting is not established as there are no published prospective clinical trials or sufficiently large retrospective case series. The activity of mTOR inhibitors in PEComas was reported, but data regarding response rate and progression-free survival (PFS) are still unclear. This is the first multicenter, international effort that aims to clarify the role of chemotherapy, VEGFR inhibitors and mTOR Inhibitors in advanced PEComas. The present study provides the rationale for the selection of systemic therapy in patients with advanced/metastatic PEComas and represents a benchmark in terms of tumor response, PFS and overall survival (OS) for future prospective trials. 4 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2019; DOI: 10.1158/1078-0432.CCR-19-0288 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Purpose. Perivascular epitheliod cell tumours (PEComas) are rare mesenchymal neoplasms for which the role systemic treatments is not established as there are no published prospective clinical trials or sufficiently large retrospective case series. The aim of the present study is to clarify the activity of conventional chemotherapy and biological agents in advanced/metastatic PEComas. Methods. This was an observational, retrospective, international study including patients with advanced/metastatic PEComa treated with systemic therapy at 5 European sarcoma reference centres and within the Italian Rare Cancer Network. Survival analyses were performed using the Kaplan-Meier method and the Cox hazards regression models. Results. A total of 53 patients were included. Cytotoxic chemotherapy regimens were active only in a small proportion of PEComas. Gemcitabine-based regimens (objective response rate [ORR]: 20%, median PFS: 3.4 months) seemed to have the same activity of anthracycline-based regimens (ORR: 13%, median PFS: 3.2 months). Anti-angiogenic agents resulted in disease stabilization in some patients, with a number having density changes/ tissue response on imaging, with an ORR of 8.3% and a median PFS of 5.4 months. mTOR inhibitors were the most active agents, with an ORR of 41% and a median PFS of 9 months. Conclusions. Our study provides data for the selection of systemic therapy in patients with advanced/ metastatic PEComa: mTOR inhibitors are the most active agents. Anti-angiogenics and chemotherapy with gemcitabine-based regimens or anthracycline- based regimens, are options in further line, but with a lower response rate and progression free survival. 5 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2019; DOI: 10.1158/1078-0432.CCR-19-0288 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Perivascular epitheliod cell tumours (PEComas) are rare mesenchymal neoplasms characterized by epitheliod, sometimes pleomorphic cells with a perivascular distribution (1). Within the group of soft tissue sarcomas, the family of PEComas has only relatively recently been recognized as a distinct subtype with specific morphological and immunohistochemical characteristics (2). PEComas include angiomyolipoma (AML), clear cell sugar tumour of the lung and lymphangioleiomyomatosis (LAM), which are often characterized by a benign clinical course. In contrast, other entities such as epithelioid angiomyolipoma and malignant PEComa can have an aggressive clinical course and develop distant metastases. The latter are typically large in size, with mitosis, necrosis and nuclear pleomorphism (1), although standard pathological criteria to discriminate a benign or malignant variant are not established (3). The activity of mTOR inhibitors both in LAM and in malignant PEComas was reported (4-7). Indeed, these tumours harbour mutations and loss of heterozygosity of TSC2 gene or more rarely of TSC1 gene and can be associated with tuberous–sclerosis complex or be sporadic. TSC1 and TSC2 gene products contribute to a molecular complex which negatively regulates the mammalian target of rapamycin complex 1 (mTORC1). As a consequence of TSC1 or TSC2 alterations, the mTOR pathway is constitutively activated. This gave the rationale to use mTOR inhibitors (e.g. sirolimus) in the clinical setting. However, given the rarity of these tumours and the few available data, a precise estimation of response rate and median progression-free survival (PFS)
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