Elsevier

European Journal of Cancer

Volume 50, Issue 17, November 2014, Pages 3021-3028
European Journal of Cancer

Original Research
Preclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour

https://doi.org/10.1016/j.ejca.2014.09.004Get rights and content

Abstract

Background

To explore the activity of pazopanib in solitary fibrous tumour (SFT).

Patients and methods

In a preclinical study, we compared the activity of pazopanib, sorafenib, sunitinib, regorafenib, axitinib and bevacizumab in a dedifferentiated-SFT (DSFT) xenotransplanted into Severe Combined Immunodeficiency (SCID) mice. Antiangiogenics were administered at their reported optimal doses when mean tumour volume (TV) was 80 mm3. Drug activity was assessed as TV inhibition percentage (TVI%). From May 2012, six consecutive patients with advanced SFT received pazopanib, on a national name-based programme. In one case sunitinib was administered after pazopanib failure.

Results

In the xenograft model, pazopanib showed the lowest antitumour activity (21%TVI), while regorafenib was the most active (95%TVI). Sorafenib, bevacizumab, sunitinib were markedly active (78/70/65%TVI). Axitinib was marginally active (51%TVI).

In the retrospective case-series, three patients carried malignant-SFT (MSFT), three DSFT. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: three stable disease (SD), all MSFT, three progressive disease (PD), all DSFT, corresponding to one partial response (PR), two SD, three PD by Choi criteria. Median-progression-free survival was 3 months (range 1–15). In one patient, sunitinib was started after pazopanib failure, with a response.

Conclusions

In dedifferentiated-SFT xenograft pazopanib induced a marginal antitumour activity, while regorafenib appeared the most active and promising agent. When administered in patients, pazopanib showed a modest activity in terms of tumour growth stabilisation, observed only in non-dedifferentiated cases.

Introduction

Pazopanib is an inhibitor of vascular endothelial growth factor receptor (VEGFR) 1–3 recently approved for treatment of non-adipocytic advanced soft tissue sarcoma (STS) after failure to front-line chemotherapy [1]. In a Phase 3 study on pazopanib in non-adipocytic STS the median progression-free survival (PFS) was 4.6 months for pazopanib compared with 1.6 months for placebo, with an overall survival (OS) of 12.5 months versus 10.7 months [2].

Very few data are available on the activity of pazopanib in solitary fibrous tumour (SFT), a rare STS subtype [3], the sensitivity of which to antiangiogenics like sorafenib, sunitinib and bevacizumab is reported [4], [5], [6], [7], [8], [9]. Antiangiogenics were shown to produce durable disease stabilisation in a proportion of patients by means of tumour responses that were mostly non-dimensional [5], [6]. We already reported on the activity of pazopanib in a human high-grade dedifferentiated-SFT xenotransplanted into severe combined immunodeficiency (SCID) mice [10]. When compared to dacarbazine and temozolomide, pazopanib was less active and characterised by a short lasting cytostatic effect. Thus, we decided to expand that experiment to a broader number of antiangiogenic agents (i.e. sorafenib, regorafenib, axitinib in addition to sunitinib and bevacizumab) already applied in the clinical practice. Our findings are reported herein.

Within a name-based protocol following the results of the Phase 3 trial, we treated with pazopanib six patients affected by SFT. We report herein their outcome as well.

Section snippets

Experimental model and pharmacological studies

A patient-derived human high-grade dedifferentiated-SFT xenograft model [10] was used in the study. The presence of the typical NAB2-STAT6 rearrangement – recently described in human SFT [12] – was confirmed in xenograft by RT-PCR [10].

The xenograft model was maintained by serial sub-cutis (s.c.) passages in 6 week-old female SCID mice (Charles River, Calco, IT). Briefly, when tumours reached approximately 500 mm3, they were removed, aseptically dissected, cut into small fragments (3 × 3 × 3 mm) and

Antitumour activity studies

A significant tumour growth inhibition was observed following treatment with the different anti-angiogenic agents, even if at a different extent. The only exception was pazopanib that showed a negligible antitumour effect throughout the experiment (Fig. 1, Table 1). After the first 4 weeks of treatment, the antitumour effect was maximum for regorafenib and less pronounced for sorafenib, sunitinib, bevacizumab and axitinib. In all the treated animal groups, tumour growth was resumed following

Discussion

In a mouse model of dedifferentiated-SFT, pazopanib showed the lowest antitumour activity (21%TVI), when compared to axitinib, bevacizumab, regorafenib, sorafenib and sunitinib, while regorafenib was the most active compound (95%TVI). Sorafenib, bevacizumab and sunitinib were also markedly active (78%, 70% and 65%TVI, respectively), whereas axitinib was marginally active (51%TVI). In a series of six patients with progressing metastatic SFT treated with pazopanib, the best responses according to

Funding

Associazione Italiana per la Ricerca sul Cancro (AIRC) grants 14102 to S. Pilotti and 11817 to T. Negri.

Disclosures

S. Stacchiotti, S. Provenzano, E. Fumagalli received research funds from Glaxo Smith Kline, Pfizer, Bayer.

A.P. Dei Tos and PG Casali received honoraria, compensation for advisory boards, research funds and travel coverage from Glaxo Smith Kline, Pfizer, Bayer.

G. Grignani received travel coverage by Glaxo.

A. Gronchi received honoraria from Pfizer.

Conflict of interest statement

None declared.

References (19)

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These authors equally contributed to the paper.

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