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.

中文翻译：

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克唑替尼在伴有 MET 改变的晚期透明细胞肉瘤患者中的活性和安全性：欧洲癌症研究和治疗组织 II 期试验 90101“CREATE”。

背景透明细胞肉瘤 (CCSA) 是一种孤儿恶性肿瘤，其特征是特异性 t(12;22) 易位，导致 EWSR1 基因重排和 MET 过表达。我们前瞻性地研究了酪氨酸激酶抑制剂克唑替尼在晚期或转移性 CCSA 患者中的疗效和安全性。患者和方法 CCSA 患者每天两次口服克唑替尼 250 mg。主要终点为客观缓解率（ORR），次要终点包括缓解持续时间、疾病控制率（DCR）、无进展生存期（PFS）、无进展生存期（PFR）、总生存期（OS）、OS率和安全。该研究设计侧重于 MET+ 疾病，通过荧光原位杂交记录了 EWSR1 基因的重排。结果 在 43 名同意接受当地诊断为 CCSA 的患者中，36 人已集中确认 CCSA，其中 28 人符合条件、接受治疗和可评估。28 名患者中有 26 名患有 MET+ 疾病，其中 1 人获得确认的部分缓解，17 人疾病稳定 (SD) (ORR 3.8%，95% 置信区间：0.1-19.6)。MET+ CCSA 的其他疗效终点是 DCR：69.2%（48.2% 至 85.7%），中位 PFS：131 天（49-235），中位 OS：277 天（232-442）。3、6、12 和 24 个月的 PFR 分别为 53.8% (34.6-73.0)、26.9% (9.8-43.9)、7.7% (1.3-21.7) 和 7.7% (1.3-21.7)。在两名可评估的 MET 患者中，一名病情稳定，一名病情进展。最常见的治疗相关不良事件是恶心 [18/34 (52.9%)]、疲劳 [17/34 (50.0%)]、呕吐 [12/34 (35.3%)]、腹泻 [11/34 (32.4%) )]、便秘 [9/34 (26.5%)] 和视力模糊 [7/34 (20.6%)]。结论 MET + CCSA 中使用克唑替尼的 PFS 与单药多柔比星在非选择性转移性软组织肉瘤中一线取得的结果相似。PFS 与帕唑帕尼在先前治疗的肉瘤患者中取得的结果相似。临床试验编号 EORTC 90101，EudraCT 编号 2011-001988-52，NCT01524926。