Background

Few treatment options exist for patients with non-Hodgkin lymphoma, and outcomes remain poor for relapsed or refractory disease. We evaluated the safety and preliminary clinical activity of valemetostat, a novel inhibitor of EZH2 and EZH1, in patients with relapsed or refractory non-Hodgkin lymphomas.

Methods

This first-in-human, multicentre, open-label, single-arm, phase 1, dose-escalation and dose-expansion trial was done in 19 hospitals across Japan and the USA. Patients were included if they were aged 18 years or older in the USA or 20 years or older in Japan with a primary diagnosis of relapsed or refractory non-Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. In the dose-escalation part, patients received oral valemetostat at doses of 150 mg per day, 200 mg per day, 250 mg per day, and 300 mg per day continuously in 28-day cycles until progressive disease or unacceptable toxicities. All patients received 200 mg per day in the dose-expansion part. The primary endpoints were safety, pharmacokinetics, and the recommended phase 2 dose; the secondary endpoints were the maximum tolerated dose and the antitumour activity of valemetostat. Responses were assessed in patients who received at least one dose, with measurable lesions at baseline according to the International Working Group 2007 revised criteria for malignant lymphoma (peripheral T-cell lymphoma and B-cell non-Hodgkin lymphoma) and the modified 2009 criteria for adult T-cell leukaemia/lymphoma. The trial is registered with ClinicalTrials.gov, NCT02732275, and is currently active, but not recruiting.

Findings

Between April 7, 2016, and June 10, 2021, 90 patients (53 [59%] males and 37 [41%] females; 49 [54%] Asian, 33 [37%] White, and eight [9%] Black) were enrolled and treated with valemetostat and included in the safety analysis set. 57 (63%) patients had peripheral T-cell lymphoma, 14 (16%) had adult T-cell leukaemia/lymphoma, and 19 (21%) had B-cell non-Hodgkin lymphoma. Seven (8%) patients received valemetostat 150 mg per day, 74 (82%) received 200 mg per day, seven received 250 mg per day, and two received 300 mg per day. Median follow-up was 7·4 months (IQR 3·4–17·6). All patients had at least one treatment-emergent adverse event; the most common treatment-emergent adverse events of any grade were decreased platelet count (52 [58%] of 90 patients), dysgeusia (45 [50%]), and anaemia (38 [42%]). The most common grade 3–4 adverse events were decreased neutrophil count (21 [23%]), decreased platelet count (18 [20%]), and decreased lymphocyte count (17 [19%]). The most common serious adverse event of any grade was Pneumocystis jirovecii pneumonia (four [4%]). No treatment-related deaths occurred. The overall response rate was 54·5% (48 of 88; 95% CI 43·6–65·2) for patients in the efficacy analysis set. The maximum tolerated dose was not reached; the recommended phase 2 dose of 200 mg per day was determined. Valemetostat exposure was variable between patients and was overlapped over the dose range of 150–250 mg per day.

Interpretation

The safety profile of valemetostat monotherapy was acceptable in these patients with relapsed or refractory non-Hodgkin lymphoma. Favourable clinical activity was observed. These findings support a new indication for valemetostat in this setting.

Funding

Daiichi Sankyo.

中文翻译：

---

Valemetostat 单药治疗复发或难治性非霍奇金淋巴瘤患者：一项首次人体、多中心、开放标签、单臂、1 期研究

 背景

非霍奇金淋巴瘤患者的治疗选择很少，复发或难治性疾病的结局仍然很差。我们评估了 valemetostat（一种 EZH2 和 EZH1 的新型抑制剂）在复发或难治性非霍奇金淋巴瘤患者中的安全性和初步临床活性。

 方法

这项首次人体、多中心、开放标签、单臂、1 期、剂量递增和剂量扩展试验在日本和美国的 19 家医院进行。如果患者在美国年满 18 岁，在日本年满 20 岁，初步诊断为复发或难治性非霍奇金淋巴瘤，且东部肿瘤合作组体能状态为 0 或 1，则纳入患者。在剂量递增部分，患者以 150 毫克/天、200 毫克/天、250 毫克/天和 300 毫克/天的剂量连续接受口服伐美司他，周期为 28 天，直至疾病进展或不可接受的毒性。所有患者在剂量扩展部分每天接受 200 mg。主要终点是安全性、药代动力学和推荐的 2 期剂量;次要终点是 valemetostat 的最大耐受剂量和抗肿瘤活性。根据国际工作组 2007 年修订的恶性淋巴瘤标准（外周 T 细胞淋巴瘤和 B 细胞非霍奇金淋巴瘤）和 2009 年修订的成人 T 细胞白血病/淋巴瘤标准，评估接受至少一剂药物的患者的反应，基线时有可测量的病变。该试用版已在 ClinicalTrials.gov 和 NCT02732275 注册，目前处于活跃状态，但尚未招募。

 发现

在 2016 年 4 月 7 日至 2021 年 6 月 10 日期间，90 名患者（53 名 [59%] 男性和 37 名 [41%] 女性;49 名 [54%] 亚洲人，33 名 [37%] 白人和 8 名 [9%] 黑人）入组并接受伐美司他治疗，并纳入安全性分析集。57 例 （63%） 患者患有外周 T 细胞淋巴瘤，14 例 （16%） 患有成人 T 细胞白血病/淋巴瘤，19 例 （21%） 患有 B 细胞非霍奇金淋巴瘤。7 例 （8%） 患者接受 valemetostat 每天 150 毫克，74 例 （82%） 每天服用 200 毫克，7 名患者每天服用 250 毫克，2 名患者每天服用 300 毫克。中位随访时间为 7·4 个月 （IQR 3·4–17·6）。所有患者都至少有 1 例治疗中出现的不良事件;任何级别最常见的治疗中出现的不良事件是血小板计数减少 （90 例患者中有 52 例 [58%]） 、味觉障碍 （45 例 [50%]）和贫血 （38 例 [42%]）。最常见的 3-4 级不良事件是中性粒细胞计数降低 （21 [23%]）、血小板计数降低 （18 [20%]）和淋巴细胞计数降低 （17 [19%]）。任何级别最常见的严重不良事件是耶氏肺孢子菌肺炎 （4 [4%]）。未发生与治疗相关的死亡。疗效分析集中患者的总体缓解率为 54·5%（88 例中的 48 例;95% CI 43·6-65·2）。未达到最大耐受剂量;确定了推荐的 2 期剂量为每天 200 毫克。Valemetostat 暴露因患者而异，并且在每天 150-250 mg 的剂量范围内重叠。

 解释

valemetostat 单药治疗在这些复发或难治性非霍奇金淋巴瘤患者中的安全性是可接受的。观察到良好的临床活动。这些发现支持在这种情况下 valemetostat 的新适应证。

 资金

 第一三共。