P Schöffski1,2, A Wozniak2, S Stacchiotti3, P Rutkowski4,5, J-Y Blay6, L H Lindner7, S J Strauss8, A Anthoney9, F Duffaud10,11, S Richter12,13, V Grünwald14, M G Leahy15, P Reichardt16, J Sufliarsky17, W T van der Graaf18,19, R Sciot20, M Debiec-Rychter21, T van Cann1,2, S Marréaud22, M Lia22, T Raveloarivahy22, L Collette22, S Bauer23. 1. Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven. 2. Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. 3. Department of Medical Oncology, IRCCS Fondazione Istituto Nazionale Tumori, Milano, Italy. 4. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute, Warsaw. 5. Oncology Center, Warsaw, Poland. 6. Department of Medical Oncology, Centre Léon Bérard & Université Claude Bernard Lyon I, Lyon, France. 7. Medical Clinic III, University Hospital of Munich, Munich, Germany. 8. Department of Oncology, University College London Hospital NHS Trust, London. 9. Institute of Oncology, Leeds Teaching Hospitals National Health Service Trust, St. James's University Hospital, Leeds, UK. 10. Department of Medical Oncology, CHU la Timone Boulevard J Moulin Marseille, Marseille. 11. Aix Marseille University (AMU), Marseille, France. 12. University Cancer Center, Dresden. 13. Medical Department I, University Hospital Carl Gustav Carus, Dresden. 14. Department of Haematology, Haemostasis and Oncology, Hannover Medical School, Hannover, Germany. 15. The Christie NHS Foundation Trust, Manchester, UK. 16. HELIOS Klinikum Berlin-Buch, Sarcoma Center Berlin-Brandenburg, Berlin, Germany. 17. National Cancer Institute, Bratislava, Slovakia. 18. Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. 19. The Institute of Cancer Research, London, UK. 20. Department of Pathology, University Hospitals Leuven, Leuven. 21. Department of Human Genetics, KU Leuven, Leuven. 22. European Organization for Research and Treatment of Cancer, Brussels, Belgium. 23. Department of Internal Medicine, West German Cancer Center, University Hospital, University of Duisburg-Essen, Duisburg, Germany.
Abstract
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.
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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