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Activity and safety of crizotinib in patients with advanced clear cell sarcoma with MET alterations. European Organization for Research and Treatment of Cancer phase 2 trial 90101 "CREATE"

Schöffski, P; Wozniak, A; Casali, PG; Rutkowski, P; Blay, J-Y; Lindner, LH; Strauss, SJ; ... Bauer, S; + view all (2017) Activity and safety of crizotinib in patients with advanced clear cell sarcoma with MET alterations. European Organization for Research and Treatment of Cancer phase 2 trial 90101 "CREATE". Annals of Oncology , 28 (12) pp. 3000-3008. 10.1093/annonc/mdx527. Green open access

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Abstract

BACKGROUND: Clear cell sarcoma (CCSA) is an orphan malignancy, characterised 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 (TKI) crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary endpoint was objective response rate (ORR), secondary endpoints included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), overall survival rate (OSR) and safety. The study design focused on MET + disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization (FISH). RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and evaluable. 26/28 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 endpoints in MET + CCSA were DCR:69.2% (48.2-85.7%), 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 evaluable MET - patients, one had SD 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%]), diarrhea (11/34[32.4%]), constipation (9/34[26.5%] and blurred vision (7/34[20.6%]). CONCLUSIONS: The PFR with crizotinib in MET + CCSA is similar to results achieved first-line in metastatic soft tissue sarcomas with single-agent doxorubicin. In further lines, the PFS is similar to pazopanib in previously treated sarcoma patients.

Type: Article
Title: Activity and safety of crizotinib in patients with advanced clear cell sarcoma with MET alterations. European Organization for Research and Treatment of Cancer phase 2 trial 90101 "CREATE"
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/annonc/mdx527
Publisher version: http://doi.org/10.1093/annonc/mdx527
Language: English
Additional information: VC The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Clear cell sarcoma, EWSR1 gene rearrangement, MET gene, crizotinib, tyrosine kinase inhibitor
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10024456
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