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'
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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DOI：
10.1093/annonc/mdx527
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发表时间：
2017-12-01
影响因子：
50.5
通讯作者：
Bauer, S.
中科院分区：
文献类型：
--
作者：
Schoffski, P.;Wozniak, A.;Bauer, S.
背景资料：透明细胞肉瘤（CCSA）是一种罕见的恶性肿瘤，其特征是特异性t（12; 22）易位，导致EWSR 1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.Patients和方法的患者的疗效和安全性：CCSA患者口服克唑替尼250毫克，每日两次。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）、无进展率（PFR）、总生存期（OS）、OS率和安全性。研究设计集中在METthorn病与记录的EWSR 1基因重排荧光原位hybridization.Results：在43个同意CCSA的本地诊断患者，36个集中确认CCSA，其中28人是合格的，治疗和评估。28例患者中有26例患有METthorn病，其中1例获得确认的部分缓解，17例疾病稳定（SD）（ORR 3.8%，95%置信区间：0.1-19.6）。METthornCCSA中的其他疗效终点为DCR：69.2%（48.2%-85.7%），中位PFS：131天（49-235），中位OS：277天（232-442）。3、6、12和24个月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2例可评估的MET -患者中，1例疾病稳定，1例疾病进展。最常见的治疗相关不良事件为恶心[18/34（52.9%）]、疲乏[17/34（50.0%）]、呕吐[12/34（35.3%）]、腹泻[11/34（32.4%）]、便秘[9/34（26.5%）]和视物模糊[7/34（20.6%）]。结论：METthornCCSA中克唑替尼的PFS与非选择性转移性软组织肉瘤一线治疗的结果相似，阿霉素。PFS与帕唑帕尼在既往接受过治疗的肉瘤患者中获得的结果相似。
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 250mg 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 METthorndisease 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 METthorndisease, 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 METthornCCSA 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 METthornCCSA 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.