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”

Summary

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.Clinical trial number: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926

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