Background

Peripheral T-cell lymphomas are aggressive non-Hodgkin lymphomas with few treatment options for relapsed or refractory disease. Valemetostat tosylate (valemetostat) is a potent, novel, dual inhibitor of EZH2 and EZH1. We investigated the clinical activity and safety of valemetostat in patients with relapsed or refractory peripheral T-cell lymphoma, and its safety in patients with relapsed or refractory adult T-cell leukaemia/lymphoma.

Methods

VALENTINE-PTCL01 was a multicentre, open-label, single-arm, phase 2 trial performed at 47 hospitals in 12 countries across Asia, Europe, North America, and Oceania. Patients with either peripheral T-cell lymphoma or adult T-cell leukaemia/lymphoma, aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–2 received oral valemetostat at 200 mg per day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with peripheral T-cell lymphoma was the CT-based objective response rate by blinded independent central review (BICR) using 2014 Lugano response criteria. Patients who received valemetostat and had a confirmed eligible peripheral T-cell lymphoma subtype on central review were included in the efficacy analysis. The primary endpoint for patients with adult T-cell leukaemia/lymphoma was the safety and tolerability of valemetostat. Safety in both cohorts was assessed in all patients who received at least one dose of valemetostat. The trial is registered with ClinicalTrials.gov, NCT04703192, and EudraCT, 2020-004954-31, and is closed to enrolment.

Findings

Between June 16, 2021, and Aug 10, 2022, 133 patients with relapsed or refractory peripheral T-cell lymphoma (median age 69·0 years [IQR 58·0–74·0]; 91 [68%] were male, and 42 [32%] were female) and 22 patients with adult T-cell leukaemia/lymphoma (66·5 years [54·0–73·0]; 15 [68%] were male, and seven [32%] were female) were enrolled. The median follow-up time was 12·3 months (95% CI 11·8–13·8). 52 (44%; 95% CI 35–53) of 119 efficacy-evaluable patients with relapsed or refractory peripheral T-cell lymphoma had an objective response. The most common grade 3−4 adverse events were thrombocytopenia (31 [23%] of 133 patients in the peripheral T-cell lymphoma group and 11 [50%] of 22 patients in the adult T-cell leukaemia/lymphoma group), anaemia (25 [19%] and ten [46%]), and neutropenia (23 [17%] and four [18%]). Serious treatment-emergent adverse events were reported in 53 (40%) patients with peripheral T-cell lymphoma and 15 (68%) patients with adult T-cell leukaemia/lymphoma; nine (7%) patients and one (5%) patient had a serious treatment-emergent adverse event considered to be treatment related, respectively. No treatment-related deaths were reported.

Interpretation

These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile.

Funding

Daiichi Sankyo.

中文翻译：

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Valemetostat 治疗复发或难治性外周 T 细胞淋巴瘤患者 （VALENTINE-PTCL01）：一项多中心、开放标签、单臂、2 期研究

 背景

外周 T 细胞淋巴瘤是侵袭性非霍奇金淋巴瘤，复发或难治性疾病的治疗选择很少。Valemetostat tosylate （valemetostat） 是一种有效的新型 EZH2 和 EZH1 双重抑制剂。我们调查了伐美司他在复发或难治性外周 T 细胞淋巴瘤患者中的临床活性和安全性，以及其在复发或难治性成人 T 细胞白血病/淋巴瘤患者中的安全性。

 方法

VALENTINE-PTCL01 是一项多中心、开放标签、单臂、2 期试验，在亚洲、欧洲、北美和大洋洲 12 个国家的 47 家医院进行。年龄在 18 岁或以上且东部肿瘤合作组体能状态为 0-2 的外周 T 细胞淋巴瘤或成人 T 细胞白血病/淋巴瘤患者接受每天 200 毫克的口服伐美司他，连续 28 天为周期，直至疾病进展或不可接受的毒性。外周 T 细胞淋巴瘤患者的主要终点是使用 2014 年卢加诺反应标准的盲法独立中心审查 （BICR） 基于 CT 的客观缓解率。接受 valemetostat 并在中央审查中确认符合条件的外周 T 细胞淋巴瘤亚型的患者被纳入疗效分析。成人 T 细胞白血病/淋巴瘤患者的主要终点是 valemetostat 的安全性和耐受性。在所有接受至少一剂 valemetostat 的患者中评估了两个队列的安全性。该试验已在 ClinicalTrials.gov、NCT04703192 和 EudraCT 注册，编号为 2020-004954-31，现已停止注册。

 发现

2021 年 6 月 16 日至 2022 年 8 月 10 日期间，133 名复发或难治性外周 T 细胞淋巴瘤患者（中位年龄 69·0 岁 [IQR 58·0–74·0];91 名 [68%] 为男性，42 名 [32%] 为女性）和 22 名成人 T 细胞白血病/淋巴瘤患者（66·5 岁 [54·0–73·0];15 名 [68%] 为男性，7 名 [32%] 为女性）。中位随访时间为 12·3 个月 （95% CI 11·8–13·8）。119 例疗效可评估的外周 T 细胞淋巴瘤患者中有 52 例 （44%;95% CI 35-53） 有客观反应。最常见的 3-4 级不良事件是血小板减少症（外周 T 细胞淋巴瘤组 133 名患者中有 31 名 [23%] 和成人 T 细胞白血病/淋巴瘤组 22 名患者中有 11 名 [50%]）、贫血（25 名 [19%] 和 10 名 [46%]）和中性粒细胞减少症（23 名 [17%] 和 4 名 [18%]）。53 例 （40%） 外周 T 细胞淋巴瘤患者和 15 例 （68%） 成人 T 细胞白血病/淋巴瘤患者报告了严重的治疗中出现的不良事件;9 名 （7%） 患者和 1 名 （5%） 患者分别发生了被认为与治疗相关的严重治疗中出现的不良事件。未报告与治疗相关的死亡。

 解释

这些数据表明，valemetostat 治疗可为复发或难治性外周 T 细胞淋巴瘤患者带来持久的反应，安全性可控。

 资金

 第一三共。