Treatment of Angiosarcoma with Pazopanib and Paclitaxel: Results of the EVA (Evaluation of Votrient® in Angiosarcoma) Phase II Trial of the German Interdisciplinary Sarcoma Group (GISG-06).

Daniel Pink,Thomas Brodowicz,Stephan Richter,Maxim Kebenko,Peter Reichardt,Lars H Lindner,Marietta Kirchner,Sebastian Bauer,Dimosthenis Andreou,Bernd Kasper,Viktor Grünwald,Joanna Szkandera,Peter Hohenberger

doi:10.3390/cancers13061223

Abstract

Simple SummaryThere are very few systemic treatment options for patients with advanced angiosarcomas. We therefore examined whether combined treatment with paclitaxel and pazopanib was active and well tolerated. However, we did not meet a preplanned interim target of 6/14 patients without progression of the disease at 6 months, after which finding we stopped recruitment, having enrolled a total of 26 patients. Of the patients enrolled, 46% were progression-free at 6 months. Two patients showed a complete and seven patients a partial tumor response to treatment. The progression-free survival of patients with superficial tumors was significantly longer compared to the patients with visceral tumors. A total of 10 drug-related serious adverse effects were reported in 5 patients, including a fatal hepatic failure. The results in patients with superficial tumors appear promising. Future studies should evaluate the safety and efficacy of vascular endothelial growth factor receptor (VEGFR) and immune checkpoint inhibitors with or without paclitaxel in a randomized, multiarm setting.We aimed to evaluate the efficacy and toxicity of paclitaxel combined with pazopanib in advanced angiosarcoma (AS). The primary end point was progression-free survival (PFS) rate at six months (PFSR6). Planned accrual was 44 patients in order to detect a PFSR6 of >55%, with an interim futility analysis of the first 14 patients. The study did not meet its predetermined interim target of 6/14 patients progression-free at 6 months. At the time of this finding, 26 patients had been enrolled between July 2014 and April 2016, resulting in an overrunning of 12 patients. After a median follow-up of 9.5 (IQR 7.7–15.4) months, PFSR6 amounted to 46%. Two patients had a complete and seven patients a partial response. Patients with superficial AS had a significantly higher PFSR6 (61% vs. 13%, p = 0.0247) and PFS (11.3 vs. 2.7 months, p < 0.0001) compared to patients with visceral AS. The median overall survival in the entire cohort was 21.6 months. A total of 10 drug-related serious adverse effects were reported in 5 patients, including a fatal hepatic failure. Although our study did not meet its primary endpoint, the median PFS of 11.6 months in patients with superficial AS appears to be promising. Taking recent reports into consideration, future studies should evaluate the safety and efficacy of VEGFR and immune checkpoint inhibitors with or without paclitaxel in a randomized, multiarm setting.

Highlights

Angiosarcomas (AS) are very rare malignant mesenchymal tumors with morphological and functional features resembling endothelial cells [1]
Taking the results of these studies into consideration, the median progression-free survival (PFS) of 8 months observed in our trial suggests that the combination of paclitaxel with pazopanib is an active treatment of advanced AS, but it remains unclear whether the combined treatment offers advantages compared to single-agent treatment with paclitaxel
In terms of toxicity of the combined paclitaxel and pazopanib regimen, only 19% of the patients in our trial developed serious adverse effects, compared to 32% of the patients treated with BWP in the ANGIOTAX-PLUS study developing drug-related serious adverse effects and no patients treated with weekly paclitaxel (WP) [12]

Summary

Introduction

Angiosarcomas (AS) are very rare malignant mesenchymal tumors with morphological and functional features resembling endothelial cells [1]. While most tumors arise spontaneously, some AS are associated with endogenous and exogenous risk factors, mainly previous radiotherapy and chronic lymphedema [4]. Their prognosis is worse compared to most soft tissue sarcomas, with reported 5-year overall survival (OS) probabilities of 35–40% for patients with localized tumors treated with curative intent and a median survival of 8–12 months for patients with metastases [4]. The course of the disease appears to be influenced by the site of origin, with visceral AS in particular showing a poorer outcome, it remains unclear whether this is a result of differences in tumor biology or clinical presentation [4,5]

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