Original ResearchPreclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour
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.
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Regorafenib in advanced solitary fibrous tumour: Results from an exploratory phase II clinical study
2023, European Journal of CancerToward Better Understanding and Management of Solitary Fibrous Tumor
2022, Surgical Oncology Clinics of North AmericaCitation Excerpt :Although some chemotherapy agents have efficacy in this disease, objective responses with these agents are uncommon, as noted earlier, and duration of benefit is short.116,120 Targeted therapies using antiangiogenic agents show efficacy in advanced SFTs and are recommended in patients with progression on prior therapies121–123,127,138 (see earlier discussion “systemic therapy”). Given the rarity and complex nature of sarcoma diagnosis and management, the authors would recommend management of all sarcomas, including SFTs, at an expert referral center to ensure that provision of care meets internationally agreed standards.
What's new in the management of meningeal solitary fibrous tumor/hemangiopericytoma?
2020, Bulletin du CancerAbnormal vascularization of soft-tissue sarcomas on conventional MRI: Diagnostic and prognostic values
2019, European Journal of RadiologyCitation Excerpt :Besides vascularization patterns on MRIs, a common point between ASPS and SFT in general, and the atypical undifferentiated clear cell sarcomas from our series is the high expression rate of pro-angiogenesis-related genes. Previous studies showed recurrent overexpressed angiogenesis-promoting genes [12,30] explaining the efficacy of tyrosine-kinase inhibitors for ASPS and SFT [12,30–32]. Though progression-free survival improved, the OS in the sole phase 3 of placebo-controlled clinical trials (which evaluated an anti-angiogenic molecule (i.e. pazopanib) in metastatic STS patients) did not.
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These authors equally contributed to the paper.