Background

Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine–rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL.

Methods

We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0–2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine–rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m² of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m² of body surface area the day before or on day 1 of cycle 1, and 500 mg/m² of body surface area on day 1 of cycles 2–6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment.

Findings

Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine–rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7–29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B).

Interpretation

Zanubrutinib significantly improved progression-free survival versus bendamustine–rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL.

Funding

BeiGene.

中文翻译：

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Zanubrutinib 对比苯达莫司汀和利妥昔单抗治疗未经治疗的慢性淋巴细胞白血病和小淋巴细胞淋巴瘤 (SEQUOIA)：一项随机、对照、3 期试验

背景

Zanubrutinib 是新一代选择性布鲁顿酪氨酸激酶抑制剂，对复发性慢性淋巴细胞白血病 (CLL) 和小淋巴细胞淋巴瘤 (SLL) 具有疗效。我们将 zanubrutinib 与苯达莫司汀-利妥昔单抗进行了比较，以确定其作为 CLL 或 SLL 患者一线治疗的有效性。

方法

我们在 14 个国家和地区的 153 家学术或社区医院进行了一项开放标签、多中心、3 期研究。符合条件的患者患有未经治疗的 CLL 或 SLL，需要根据 CLL 标准国际研讨会进行治疗；年龄在 65 岁或以上，或 18 岁或以上并有合并症；Eastern Cooperative Oncology Group 体能状态评分为 0–2。一个中央交互式网络响应系统通过顺序块方法（随机块大小为四的排列块）将没有 del(17)(p13·1) 的患者随机分配到 zanubrutinib（A 组）或苯达莫司汀-利妥昔单抗（B 组）。del(17)(p13·1) 患者被纳入 C 组并接受 zanubrutinib。Zanubrutinib 以 160 mg 每天两次口服给药（28 天一个周期）；苯达莫司汀 90 mg/m ²六个周期第 1 天和第 2 天的体表面积加利妥昔单抗，第 1 周期前一天或第 1 天体表面积375 mg/m ² ，以及周期第 1 天体表面积500 mg/m ² 2-6，静脉内给药。主要终点是独立审查委员会在 A 组和 B 组的意向治疗人群中的无进展生存期，优势的最小双侧 α 为 0·05。在接受至少一剂研究治疗的所有患者中分析安全性。该研究已在 ClinicalTrials.gov 注册，NCT03336333，并停止招募。

发现

2017年10月31日至2019年7月22日期间，共招募了590名患者；没有 del(17)(p13·1) 的患者被随机分配到 zanubrutinib（A 组；n=241）或苯达莫司汀-利妥昔单抗（B 组；n=238）。中位随访 26·2 个月 (IQR 23·7–29·6)，两组均未达到独立审查委员会的中位无进展生存期（A 组 95% CI 不可估计 [NE] 至 NE； B 组 28·1 个月到 NE）。A 组与 B 组相比，无进展生存期显着改善（HR 0·42 [95% CI 0·28 至 0·63]；双侧 p<0·0001）。最常见的 3 级或更严重的不良事件是中性粒细胞减少症（A 组 240 名患者中的 27 名 [11%]，B 组 227 名患者中的 116 名 [51%]，C 组 111 名患者中的 17 名 [15%]）。A 组 240 名患者中有 88 名（37%）发生严重不良事件，B 组 227 名患者中有 113 名（50%）发生严重不良事件，

解释

与苯达莫司汀-利妥昔单抗相比，Zanubrutinib 显着改善了无进展生存期，其安全性可接受，与之前的研究一致。这些数据支持 zanubrutinib 作为未治疗的 CLL 和 SLL 的潜在新治疗选择。

资金

北基因。