TY - JOUR T1 - Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial. JF - Lancet Oncol Y1 - 2019 A1 - Martin-Broto, Javier A1 - Stacchiotti, Silvia A1 - Lopez-Pousa, Antonio A1 - Redondo, Andres A1 - Bernabeu, Daniel A1 - de Alava, Enrique A1 - Casali, Paolo G A1 - Italiano, Antoine A1 - Gutierrez, Antonio A1 - Moura, David S A1 - Peña-Chilet, Maria A1 - Diaz-Martin, Juan A1 - Biscuola, Michele A1 - Taron, Miguel A1 - Collini, Paola A1 - Ranchere-Vince, Dominique A1 - Garcia Del Muro, Xavier A1 - Grignani, Giovanni A1 - Dumont, Sarah A1 - Martinez-Trufero, Javier A1 - Palmerini, Emanuela A1 - Hindi, Nadia A1 - Sebio, Ana A1 - Dopazo, Joaquin A1 - Dei Tos, Angelo Paolo A1 - LeCesne, Axel A1 - Blay, Jean-Yves A1 - Cruz, Josefina KW - Adult KW - Aged KW - Angiogenesis Inhibitors KW - Antineoplastic Agents KW - Female KW - Humans KW - Indazoles KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Pyrimidines KW - Response Evaluation Criteria in Solid Tumors KW - Soft Tissue Neoplasms KW - Solitary Fibrous Tumors KW - Sulfonamides KW - Survival Analysis AB -

BACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.

FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).

INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

VL - 20 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/30578023?dopt=Abstract ER -