Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial.
Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial.
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DOI：
10.1016/s1470-2045(20)30441-1
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发表时间：
2020-11
期刊：
影响因子：
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通讯作者：
Salles G
中科院分区：
文献类型：
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作者：
Morschhauser F;Tilly H;Chaidos A;McKay P;Phillips T;Assouline S;Batlevi CL;Campbell P;Ribrag V;Damaj GL;Dickinson M;Jurczak W;Kazmierczak M;Opat S;Radford J;Schmitt A;Yang J;Whalen J;Agarwal S;Adib D;Salles G
激活突变EZH 2，表观遗传调节，存在于约20%的滤泡性淋巴瘤患者。我们研究了tazemetostat（一种一流的口服EZH 2抑制剂）在滤泡性淋巴瘤患者中的活性和安全性。本研究是一项开放标签、单组、II期试验，在法国、英国、澳大利亚、加拿大、波兰、意大利、乌克兰、德国和美国的38家诊所或医院进行。合格患者为经组织学证实的滤泡性淋巴瘤（1、2、3a或3b级）成人（≥18岁），复发或对两种或多种全身治疗难治，东部肿瘤协作组体能状态评分为0-2，且有足够的肿瘤组织用于EZH 2突变状态的中心检测。患者按EZH 2状态分类：突变型（EZH 2 mut）或野生型（EZH 2 WT）。患者在连续28天的周期中每天两次口服800 mg tazemetostat。主要终点是根据2007年国际工作组非霍奇金淋巴瘤标准，由独立放射学委员会评估的客观缓解率。在接受一剂或多剂tazemetostat的患者中进行活性和安全性分析。本研究注册于ClinicalTrials.gov，NCT 01897571，随访正在进行中。在2015年7月9日至2019年5月24日期间，99例患者（EZH 2 mut队列中45例，EZH 2 WT队列中54例）入组了研究。在分析的数据截止日期（2019年8月9日），EZH 2 mut队列的中位随访时间为22.0个月（IQR 12.0 - 26.7），EZH 2 WT队列为35.9个月（24.9 - 40.5）。EZH 2 mut队列的客观缓解率为69%（95%CI 53-82; 45例患者中的31例），EZH 2 WT队列的客观缓解率为35%（23-49; 54例患者中的19例）。EZH 2 mut队列的中位缓解持续时间为10.9个月（95%CI 7.2-不可估计[NE]），EZH 2 WT队列为13.0个月（5.6-NE）;中位无进展生存期为13.8个月（10.7 - 22.0）和11.1个月（3.7 - 14.6）。在所有99例患者中，治疗相关的3级或更严重的不良事件包括血小板减少（3例[3%]）、中性粒细胞减少（3例[3%]）和贫血（2例[2%]）。99例患者中有4例（4%）报告了严重治疗相关不良事件。无治疗相关死亡。Tazemetostat单药治疗显示出具有临床意义的持久反应，并且在重度预治疗的复发性或难治性滤泡性淋巴瘤患者中通常耐受良好。Tazemetostat是滤泡性淋巴瘤患者的一种新型治疗方法。表酶
Activating mutations of EZH2, an epigenetic regulator, are present in approximately 20% of patients with follicular lymphoma. We investigated the activity and safety of tazemetostat, a first-in-class, oral EZH2 inhibitor, in patients with follicular lymphoma. This study was an open-label, single-arm, phase 2 trial done at 38 clinics or hospitals in France, the UK, Australia, Canada, Poland, Italy, Ukraine, Germany, and the USA. Eligible patients were adults (≥18 years) with histologically confirmed follicular lymphoma (grade 1, 2, 3a, or 3b) that had relapsed or was refractory to two or more systemic therapies, had an Eastern Cooperative Oncology Group performance status of 0–2, and had sufficient tumour tissue for central testing of EZH2 mutation status. Patients were categorised by EZH2 status: mutant (EZH2mut) or wild-type (EZH2WT). Patients received 800 mg of tazemetostat orally twice per day in continuous 28-day cycles. The primary endpoint was objective response rate based on the 2007 International Working Group criteria for non-Hodgkin lymphoma, assessed by an independent radiology committee. Activity and safety analyses were done in patients who received one dose or more of tazemetostat. This study is registered with ClinicalTrials.gov, NCT01897571, and follow-up is ongoing. Between July 9, 2015, and May 24, 2019, 99 patients (45 in the EZH2mut cohort and 54 in the EZH2WT cohort) were enrolled in the study. At data cutoff for the analysis (Aug 9, 2019), the median follow-up was 22·0 months (IQR 12·0–26·7) for the EZH2mut cohort and 35·9 months (24·9–40·5) for the EZH2WT cohort. The objective response rate was 69% (95% CI 53–82; 31 of 45 patients) in the EZH2mut cohort and 35% (23–49; 19 of 54 patients) in the EZH2WT cohort. Median duration of response was 10·9 months (95% CI 7·2–not estimable [NE]) in the EZH2mut cohort and 13·0 months (5·6–NE) in the EZH2WT cohort; median progression-free survival was 13·8 months (10·7–22·0) and 11·1 months (3·7–14·6). Among all 99 patients, treatment-related grade 3 or worse adverse events included thrombocytopenia (three [3%]), neutropenia (three [3%]), and anaemia (two [2%]). Serious treatment-related adverse events were reported in four (4%) of 99 patients. There were no treatment-related deaths. Tazemetostat monotherapy showed clinically meaningful, durable responses and was generally well tolerated in heavily pretreated patients with relapsed or refractory follicular lymphoma. Tazemetostat is a novel treatment for patients with follicular lymphoma. Epizyme.