Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'.
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Date
2017-12ICR Author
Author
Schöffski, P
Wozniak, A
Stacchiotti, S
Rutkowski, P
Blay, J-Y
Lindner, LH
Strauss, SJ
Anthoney, A
Duffaud, F
Richter, S
Grünwald, V
Leahy, MG
Reichardt, P
Sufliarsky, J
van der Graaf, WT
Sciot, R
Debiec-Rychter, M
van Cann, T
Marréaud, S
Lia, M
Raveloarivahy, T
Collette, L
Bauer, S
Type
Journal Article
Metadata
Show full item recordAbstract
Background Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA.Patients and methods Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization.Results Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)].Conclusions The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients.Clinical trial number EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.
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Subject
Humans
Sarcoma, Clear Cell
Pyrazoles
Pyridines
RNA-Binding Protein EWS
Protein Kinase Inhibitors
In Situ Hybridization, Fluorescence
Cohort Studies
Gene Rearrangement
Adolescent
Adult
Middle Aged
Female
Male
Proto-Oncogene Proteins c-met
Young Adult
Crizotinib
Research team
Clinical and Translational Sarcoma
Language
eng
Date accepted
2017-09-05
License start date
2017-12
Citation
Annals of oncology : official journal of the European Society for Medical Oncology, 2017, 28 (12), pp. 3000 - 3008