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

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

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.

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.

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) is not available. In addition, the role of conventional chemotherapy or other biological agents (i.e. anti-angiogenic agents) is not established as there are no published prospective clinical trials or sufficiently large retrospective case series. The aim of this multicentre, international study was to report on the activity of chemotherapy, anti-angiogenic drugs and mTOR inhibitors in patients with advanced/metastatic PEComa.

MATERIALS AND METHODS Patients population This was a retrospective, international study including patients treated at 5 European sarcoma reference centres (Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, IT; Royal Marsden Hospital NHS Foundation Trust, London GB, Centre Léon Bérard, Lyon, FR; Institut Gustave Roussy, Villejuif, FR; Hospital Universitario Virgen del Rocio, Sevilla, ES) and within the Italian Rare Cancer Network. We reviewed all consecutive cases of PEComa, malignant PEComa, or

epitheliod angiomyolipoma treated between January 2000 and June 2018 with systemic therapy (including cytotoxic chemotherapy, VEGFR inhibitors and mTOR inhibitors) for locally advanced and/or metastatic disease. All diagnoses were made according to the 2013 WHO classification of Tumours of Soft Tissue and Bone by expert pathologists. In Italy, all cases were centralized and reviewed in Treviso General Hospital, Treviso, or at Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan. Institutional approval was obtained at each participating centre before study initiation. Anonymised data for patient demographics and disease diagnosis, staging, treatment, clinical course and outcomes were recorded. Response Evaluation Criteria in Solid Tumors (RECIST 1.1) were used to assess response (8) Any radiological reduction in the sum of the longest diameter of target lesions that did not reach the criteria for an objective partial response (PR) was defined as a minor response (MR). Authorization from reviewing ethics committees was obtained according to the local rules of each institutions. The study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from patients alive at the time of data collection and analysis.

Statistical analyses Survival analyses were performed using the Kaplan-Meier method and the Cox hazards regression models. Progression-free survival (PFS) and overall survival (OS) were censored at the time of the last-follow up. Events for PFS were the date of the first documented evidence of progressive disease (PD) from each treatment start. OS event was considered to be death from any cause. Statistical analyses were performed using Prisma software and R software (v3.5.0). When corresponding p values were below the 5% threshold, statistical tests were considered significant.

RESULTS Patients and disease characteristics Overall, 53 patients with a diagnosis of PEComa treated with systemic therapy for locally advanced/metastatic disease were identified. Patients and disease characteristics are summarised in Table 1. Median age was 54 years (range 26-76). Sixteen (30.2%) patients were males and 37 (69.8%) females. The diagnosis was malignant PEComa in 42 (79.2%) cases out of 53 and epithelioid angiomyolipoma in 11 (20.8%).

Overall treatment outcomes Median follow up was 32.5 months (interquartile range [IQR], 9.1-58.8). Twenty-four patients (45.3%) received only one line of treatment, 14 (26.4%) two lines, 7 (13.2%) three lines and other 8 (15.1%) received four or more lines. OS of the overall population starting from the first medical therapy was 30.1 months (IQR 15.4-nr) (Figure 1). Clinical outcomes and specifics for each treatment category are summarized in Table 2 and Supplementary Table S1.

Anthracycline-based regimens Twenty-three patients treated with anthracycline-based chemotherapy were identified, and all were evaluable for response. Fifteen patients (65.2%) received anthracycline with ifosfamide (AI), 2 (8.7%) received anthracycline combined with dacarbazine, 1 (4.4%) patient received doxorubicin and olaratumab and 5 (21.7%) received single agent anthracycline. Fourteen (60.9%) patients were treated with an anthracycline as first-line therapy, 5 (21.7%) in second-line, and 4 (17.4%) in third- or more lines. At the time of analysis, one patient continued on treatment. Three (13%) patients had a partial response (PR), 10 (43.5%) had stable disease (SD), and 10 (43.5%) had progressive disease (PD). The median PFS was 3.2 months (IQR 1.8-14) (Figure 2, panel A).

Gemcitabine-based regimens Fifteen patients were treated with gemcitabine-based regimens and all were evaluable for response. Nine (60%) patients were treated with gemcitabine as first-line therapy, 3 (20%) in second-line, 3 (20%) in third-line. At the time of analysis, all patients completed their treatment. Three (20%) had a partial response, 2 (13.3%) SD, and 10 (66.7%) PD. The median PFS was 3.4 (IQR 2.3-4.9) months (Figure 2, panel B).

VEGFR inhibitors Twelve patients received anti-angiogenic agents and were available for response. Nine patients (75%) received pazopanib, 2 (16.7%) received sorafenib, 1 (8.3%) patient received sunitinib. Three (25%) patients were treated in second-line, 4 (33.3%) in third-line, and 5 (41.7%) in fourth- or more lines. At the time of analysis, all patients had completed anti-angiogenic therapy. Treatment was discontinued for PD in all patients but one (toxicity). One patient (8.3%) had a partial response (to sorafenib), 9 (75%) had SD to anti-angiogenic therapy and 2 (16.7) had PD. Prolonged disease

stabilization was observed in 2 patients, one with pazopanib and the other with sorafenib, both lasting 12 months. The median PFS was 5.4 months (IQR 2.5 – 9.6) (Figure 2, panel C). Supplementary Figure S1 in the Supplement shows a tissue response in an abdominal mass after 1 month of pazopanib as fourth-line therapy in a woman with uterine PEComa. The patient had a complicated response so then underwent surgery. Unfortunately, the patients died 2 months later for a progressive deterioration of general conditions. This patient did not respond to anthracycline or trabectedin but had a partial response to gemcitabine lasting 3 months. Patient did not receive mTOR inhibitors as the initial diagnosis was leiomyosarcoma. mTOR inhibitors Forty patients were treated with mTOR inhibitors and all but one were evaluable for response. Thirty-two patients (80%) received sirolimus, 5 (12.5%) received everolimus, 3 (7.5%) patients received temsirolimus. Thirty (75%) patients were treated in first-line setting, 8 (20%) in second- line, 2 (5%) in third-line. At the time of the last follow-up, 13 (32.5%) patients were still on treatment. Sirolimus was given orally at a dose between 1 and 10 mg daily according to plasma drug level (optimal value between 14-20 ng/mL). Temsirolimus was given at 25 mg intravenous weekly. Everolimus was given orally at 5 mg daily. One patient (2.6%) had a complete response (CR), 15 (38.5%) PR, 14 (35.9%) SD, and 9 (23%) PD. Eleven (28.2%) had a long-lasting response, of more than 1 year. The median PFS was 9 months (IQR 4.4 – 39.4) (Figure 2, panel D). Notably, median PFS of responding patients was 15.4 months (IQR 8.5 – 47.3). One female patient with a retroperitoneal PEComa and metastases in the lung was treated with sirolimus, but treatment was stopped after 19 months because of pneumonitis. She progressed after 2 months and responded to sirolimus re-challenge, with a durable response of 12 months prior to experiencing a further disease progression. At the time of such progression, the plasma value of sirolimus was 5.5 ng/mL. The dose of sirolimus was increased from 5 mg to 8 mg. The plasma value increased to 16 ng/dl and the disease was stabilized for over 6 months. Another patient with hepatic metastases from visceral PEComa, underwent surgery of all hepatic lesions after a partial response to sirolimus (Supplementary Figure S2). The pathology report highlighted a pathological complete response defined as the absence of residual tumor cells, replaced by fibromyxoid stroma, on hematoxylin and eosin evaluation in the entire resected specimen. The patient did not receive mTOR inhibition after surgery and progressed three months

later. Sirolimus was resumed at progression and a further partial response during over 1 year was observed (still ongoing at time of last follow-up). In eight (20%) patients treated with mTOR inhibitors, the primary tumour site was the uterus, while in 32 (80%) the primary site was extra-uterine. In the group of uterine PEComas, 1 out of 8 patients had a PR (12.5%), and 3 (37.5%) had SD. In the group of extra-uterine PEComas, 16 out of 31 evaluable patients by RECIST had a PR (51.6%) and 10 (32.3%) had stable disease. Notably, we observed a non-significant trend, toward a worse PFS for patients with uterine vs extra uterine PEComa (median PFS 6.4 vs 10.4 months, respectively; hazard ratio 1.51; 95%CI 0.94-2.43; P = 0.09) (Supplementary Figure S3).

DISCUSSION Our results show that standard soft tissue sarcoma chemotherapy regimens are active only in a small proportion of PEComas, as demonstrated by the relatively short median PFS. 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 can result in disease stabilization in some patients (remarkably, a prolonged disease stabilization lasting 12 months was observed in 2 patients), with a number having density changes/ tissue response on imaging, as is often observed with this class of drugs. Indeed, the PFS with anti-angiogenic agents (5.4 months) slightly contrasts with the ORR (8.3%). mTOR inhibitors were the most active agents in this histological subtype, with an ORR of 41% and a progression- free survival of 9 months. Notably, a subset of responding patients experienced a response in excess of 1 year (28.2%). Re-challenge with mTOR inhibitors can also result in new responses in these patients. We saw hints that plasma drug monitoring could be an additional information in the management of patients when using these agents. Prior to stopping therapy, it could be advisable to document the plasma level and increase the dose when necessary. However, published data are contrasting regarding this issue. Indeed, in the paper of Wagner et al. (6) one patient of the 3 reported, had a partial response lasting 10 months despite a sirolimus level of 9.4 ng/mL. Interestingly, extra uterine PEComas show higher response rate to mTOR inhibitors then uterine PEComas, with a non-significant trend towards longer progression-free survival. To our knowledge, this academic, retrospective, international study is the largest series of systemic therapy for locally advanced/metastatic PEComas. Thus, it may provide a benchmark in terms of tumor response, PFS and OS for future prospective trials. While published data on the use

of chemotherapy and antiangiogenetic agents in PEComa (9-10) are scant, the activity of mTOR inhibitors has been reported (6). Published reports are limited to few cases (6,11-14) with the largest case series comprising 10 patients (14). A clinical study of mTOR inhibitors is currently ongoing in the USA (ClinicalTrials.gov Identifier: NCT02494570). Recently, an attempt to expand the knowledge about the molecular landscape of these tumours was made. A subset of PEComas harbouring a translocation in TFE3 gene was reported (15). As the presence of the translocation is mutually exclusive with TSC1-2 mutations, this may help to subclassify PEComas and, in the future, may help to tailor a distinct treatment strategy (16), although the differential prevalence of TFE3 translocations and TSC1-2 mutations in uterine and extra-uterine is unknown. These observations if confirmed in a future study, could explain, at least in part, the heterogeneity of responses seen to mTOR inhibitors, with the suggestion of a differential response rate between uterine and extra-uterine PEComas to mTOR inhibitors. Moreover, uterine PEComa tumors often have a distinct morphology and immunohistochemistry (17).

CONCLUSIONS In summary, despite the limitations of a retrospective design, our study provides data for the selection of systemic therapy in patients with advanced/ metastatic PEComa. Anti-angiogenics and chemotherapy with anthracycline or gemcitabine-based regimens are both options. mTOR inhibitors are the most active agents, with a subgroup of patients having durable benefit. The overall survival of this population calculated from the time of systemic treatment initiation for advanced disease is approximately 30 months, which is consistent with other metastatic soft tissue sarcomas (18).

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TABLES Table 1. Patients and disease characteristics at time of first-line systemic treatment initiation

Total (N=53) Characteristics N (%)

Center INT/RTR 32 (60.4) Royal Marsden 10 (18.8) French sarcoma group 9 (17) Spanish sarcoma group 2 ( 3.8 ) Sex Male 16 (30.2) Female 37 (69.8) Age (years) Median (range) 54 (26-76) Histopathology Malignant PEComa 42 (79.2) Epithelioid Angiomyolipoma 11 (20.8) Primary site Kidney 6 (11.3) Retroperitoneum 11 (20.8) Uterus 11 (20.8) Soft tissue 7 (13.2) Gastrointestinal 5 (9.4) Pelvis 6 (11.3) Lung 1 (1.9) Other 6 (11.3) Primary tumor resection No 8 (15.1) Yes 45 (84.9) Stage Locally advanced 3 (5.7) Metastatic 50 (94.3) Synchronous metastases No 29 (54.7) Yes 24 (45.3) Metastatic sites Lymphnodes 4 (7.5) Lung 12 (22.6) Soft Tissue 5 (9.4) Liver 10 (18.8) Peritoneum 9 (17) Other 14 (26.4) Not applicable 3 (5.7) Abbreviations. INT: Istituto Nazionale dei Tumori di Milano; RTR: Italian Rare Cancer Network

Table 2. Overall treatments outcomes.

DCR (95% CI) ORR (95% CI) Median PFS (IQR) Regimen N (%) (%) (%) (months) Anthracycline-based 56.5 (34.5-76.8) 13 (2.8-33.6) 3.2 (1.8-14) chemo (N=23) 1st line 14 (60.9) 2nd line 5 (21.7) ≥ 3rd line 4 (17.4) Gemcitabine-based 33.3 (11.8-61.6) 20 (4.3-48.1) 3.4 (2.3-4.9) chemo (N=15) 1st line 9 (60) 2nd line 3 (20) ≥ 3rd line 3 (20) VEGFR inhibitors 83.3 (51.6-97.9) 8.3 (0.2-38.5) 5.4 (2.5-9.6) (N=12) 1st line 0 (0) 2nd line 3 (25) 3rd line 9 (75) mTOR inhibitors 76.9 (60.7-88.9) 41 (25.6-57.9) 9 (4.4-39.4) (N=40) 1st line 30 (75) 2nd line 8 (20) 3rd line 2 (5) Abbreviations. DCR: disease control rate; ORR: objective response rate; PFS: progression-free survival; VEGFR: vascular endothelial growth factor receptor; mTOR: mammalian target of rapamycin

FIGURE LEGENDS

Figure 1. Kaplan-Meier curve for overall survival in the entire population.

Figure 2. Kaplan-Meier curves for progression-free survival of patients treated with anthracycline-based chemotherapy (panel A), gemcitabine-based chemotherapy (panel B), VEGFR inhibitors (Panel C) and mTOR inhibitors (Panel D).

Role of chemotherapy, VEGFR inhibitors and mTOR Inhibitors in advanced Perivascular Epithelioid Cell Tumours (PEComas).

Roberta Sanfilippo, Robin L Jones, Jean-Yves Blay, et al.

Clin Cancer Res Published OnlineFirst June 19, 2019.

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