Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study
Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study
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DOI：
10.1016/s1470-2045(20)30451-4
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发表时间：
2020-11-01
期刊：
影响因子：
51.1
通讯作者：
Stacchiotti, Silvia
中科院分区：
文献类型：
--
作者：
Gounder, Mrinal;Schoffski, Patrick;Stacchiotti, Silvia
上皮样肉瘤是一种罕见的侵袭性软组织肉瘤亚型。超过90%的肿瘤失去了INI 1表达，导致对转录抑制因子EZH 2的致癌依赖。在这项研究中，我们报告了tazemetostat（一种口服选择性EZH 2抑制剂）在上皮样肉瘤患者中的临床活性和安全性。方法在这项开放标签、2期篮子研究中，患者来自澳大利亚、比利时、加拿大、法国、德国、意大利、台湾、美国、和英国的7个不同的INI 1阴性实体瘤或滑膜肉瘤患者队列。符合上皮样肉瘤队列（队列5）的患者年龄为16岁或以上，患有组织学证实的局部晚期或转移性上皮样肉瘤;通过免疫组织化学分析或双等位基因SMARCB 1（编码INI 1的基因）改变或两者记录的INI 1表达缺失;东部肿瘤协作组体能状态评分为0-2。患者接受800 mg tazemetostat口服，每天两次，连续28天为一周期，直至疾病进展、不可接受的毒性或撤回知情同意。主要终点是根据实体瘤疗效评价标准（第1.1版）测量的评估者评估的客观缓解率。次要终点为缓解持续时间、32周时的疾病控制率、无进展生存期、总生存期以及药代动力学和药效学分析（主要结果在其他地方报告）。至缓解时间也作为探索性终点进行评估。在修改的意向治疗人群（即接受一剂或多剂tazemetostat的患者）中评估了活性和安全性。结果2015年12月22日至2017年7月7日期间，共有62例上皮样肉瘤患者入组本研究，并被认为符合纳入本队列的条件。ClinicalTrials.gov所有62例患者均纳入改良的意向治疗分析。在数据截止日期（2018年9月17日），62例患者中有9例（15% [95% CI 7-26]）出现客观缓解。中位随访13.8个月（IQR 7.8-19.0）时，未达到中位缓解持续时间（95% CI 9.2-无法估计）。16例（26% [95% CI 16-391）患者在32周时疾病得到控制。至缓解的中位时间为3.9个月（IQR 1.9-7.4）。中位无进展生存期为5.5个月（95% CI 3.4-5.9），中位总生存期为19.0个月（11.0-无法估计）。3级或更严重的治疗相关不良事件包括贫血（4例[6%]）和体重减轻（2例[3%]）。2例患者发生治疗相关严重不良事件（1例癫痫发作和1例咯血）。Tazemetostat耐受性良好，在以INI 1/SMARCB 1缺失为特征的晚期上皮样肉瘤患者队列中显示出临床活性。Tazemetostat有可能改善晚期上皮样肉瘤患者的预后。目前正在进行tazemetostat+多柔比星一线治疗的1b/3期试验。版权所有（C）2020爱思唯尔有限公司保留所有权利。
Background Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma.Methods In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid turnouts or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing.Findings Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13.8 months (IQR 7.8-19.0), median duration of response was not reached (95% CI 9.2-not estimable). 16 (26% [95% CI 16-391) patients had disease control at 32 weeks. Median time to response was 3.9 months (IQR 1.9-7.4). Median progression-free survival was 5.5 months (95% CI 3.4-5.9), and median overall survival was 19.0 months (11.0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths.Interpretation Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway. Copyright (C) 2020 Elsevier Ltd. All rights reserved.