Fixed-duration pirtobrutinib plus venetoclax-rituximab versus venetoclax-rituximab for patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (BRUIN CLL-322): an open-label, multicentre, randomised, controlled, phase 3 trial.

Pirtobrutinib, a non-covalent BTK inhibitor, is approved for use after treatment with a covalent BTK inhibitor as a continuous therapy option.

Pirtobrutinib，一种非共价 Bruton 酪氨酸激酶（BTK）抑制剂，已被批准在共价 BTK 抑制剂治疗后使用，作为持续治疗的选项。

We aimed to evaluate the addition of pirtobrutinib to VR as a fixed-duration regimen in patients with relapsed or refractory chronic lymphocytic leukaemia.

我们旨在评估将pirtobrutinib添加到VR作为固定期限方案在复发或难治性慢性淋巴细胞白血病患者中的效果。

Methods

This open-label, multicentre, randomised, controlled, phase 3 trial was conducted at 152 sites (comprising community hospitals and academic centres) across 22 countries.

这项开放标签、多中心、随机、对照的III期试验在22个国家的152个地点（包括社区医院和学术中心）进行。

Eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic lymphocytic leukaemia (including small lymphocytic lymphoma), and had previously been treated with at least one line of therapy that could include a covalent BTK inhibitor.

符合条件的患者年龄在18岁或以上，确诊为慢性淋巴细胞性白血病（包括小淋巴细胞性淋巴瘤），并且之前至少接受过一种治疗方案，该方案可能包括共价BTK抑制剂。

Patients who had previously received a non-covalent BTK inhibitor, venetoclax, or another BCL2 inhibitor were not eligible.

之前接受过非共价BTK抑制剂、维奈克拉或另一种BCL2抑制剂的患者不符合资格。

Enrolled patients were randomly assigned (1:1) using an interactive web-based randomisation system, stratified by del(17p) status and previous exposure to covalent BTK inhibitors, and assigned to receive either pirtobrutinib plus VR (PVR) or VR.

入组患者通过交互式网络随机化系统按1:1比例随机分配，根据del(17p)状态和之前是否接触过共价BTK抑制剂进行分层，并被分配接受pirtobrutinib加VR（PVR）或仅VR治疗。

Both groups received oral venetoclax (25 cycles) and intravenous rituximab (six cycles); the PVR group also received oral pirtobrutinib for 28 cycles, with a three-cycle pirtobrutinib-rituximab lead-in before venetoclax initiation.

两组患者均接受口服维奈克拉（25个周期）和静脉注射利妥昔单抗（六个周期）；PVR组还额外接受口服pirtobrutinib治疗28个周期，并在维奈克拉治疗开始前进行三个周期的pirtobrutinib-利妥昔单抗先行治疗。

For this prespecified interim analysis, the primary endpoint was progression-free survivalin the intention-to-treatpopulation, assessed by a masked independent review committee (IRC) as per 2018 International Workshop on Chronic Lymphocytic Leukemia guidelines.

在这项预先指定的中期分析中，主要终点是意向治疗人群中无进展生存期，由一名蒙面独立审查委员会（IRC）根据2018年国际慢性淋巴细胞白血病研讨会指南进行评估。

Safety analyses were conducted in the safety population, defined as all randomly assigned patients who took at least one dose of any study treatment.

安全性分析是在安全性人群中进行的，该人群被定义为所有随机分配的患者，他们至少接受了任何研究治疗的一次剂量。

All analyses were based on a data cutoff date of Feb 2, 2026.

所有分析均基于2026年2月2日的数据截止日期。

The trial is registered at ClinicalTrials.gov, NCT04965493, and is ongoing but no longer recruiting.

该试验已在ClinicalTrials.gov注册，注册号为NCT04965493，目前正在进行中，但已不再招募新参与者。

Results

Between Oct 13, 2021, and Oct 28, 2024, 784 patients were screened, of whom 639 were randomly assigned: 321 to the PVR group and 318 to the VR group.

2021年10月13日至2024年10月28日期间，共筛查了784名患者，其中639名被随机分配：321名进入PVR组，318名进入VR组。

The median age of patients was 68·0 years (IQR 60·0-74·0), of whom 439 (69%) were male and 200 (31%) were female.

患者的中位年龄为68.0岁（四分位数间距60.0-74.0），其中439名（69%）为男性，200名（31%）为女性。

The median number of previous therapies was 2 (IQR 1-3); 510 (80%) of 639 patients had previous exposure to covalent BTK inhibitors, of whom 362 (71%) discontinued their most recent drug of this class owing to progressive disease.

先前治疗的中位数为2次（四分位数间距1-3）；639名患者中有510名（80%）曾接受过共价BTK抑制剂治疗，其中362名（71%）因疾病进展而停用该类药物的最新一种。

At a median follow-up of 27·3 months (IQR 19·5-38·7), PVR showed a significant improvement in IRC-assessed progression-free survivalcompared with VR (hazard ratio0·547 [95% CI 0·400-0·748]; p=0·0001).

在中位随访27.3个月（四分位数间距19.5-38.7）时，与VR相比，PVR显示出IRC评估的无进展生存期显著改善（风险比0.547 [95% CI 0.400-0.748]；p=0.0001）。

The median 24-month progression-free survivalrate was 87% (95% CI 82·3-90·4) in the PVR group versus 72% (65·7-77·0) in the VR group, and the median progression-free survivalwas not reached (IQR 31·7-not estimable) in the PVR group versus 39·7 months (21·5-50·0) in the VR group.

在PVR组中，24个月无进展生存率的中位数为87%（95%置信区间82.3-90.4），而在VR组中为72%（65.7-77.0），PVR组的无进展生存期中位数未达到（四分位数间距31.7-不可估计），而VR组为39.7个月（21.5-50.0）。

This benefit was consistent across prespecified subgroups, including patients with previous exposure to covalent BTK inhibitors.

这一益处在预先设定的亚组中是一致的，包括之前接受过共价BTK抑制剂治疗的患者。

The most frequent treatment-emergent adverse eventof any grade in both groups was diarrhoea, reported in 106 (34%) of 316 patients in the PVR group and 110 (35%) of 311 patients in the VR group.

在两组中，任何级别中最常见的治疗后不良事件是腹泻，PVR组316名患者中有106名（34%）报告了腹泻，VR组311名患者中有110名（35%）报告了腹泻。

The frequency of treatment-emergent adverse events of grade 3 or higher was similar in both groups (249 [79%] of 316 patients in the PVR group vs 227 [73%] of 311 patients in the VR group); the rate of tumour lysis syndrome of grade 3 or higher was lower in the PVR group (1%; three of 316) than in the VR group (4%; 12 of 311).

两组中3级或更高级别的治疗后不良事件发生频率相似（PVR组316名患者中有249名（79%），VR组311名患者中有227名（73%））；PVR组中3级或更高级别的肿瘤溶解综合征发生率低于VR组（PVR组为1%（3/316），VR组为4%（12/311））。

Rates of atrial fibrillation or flutter of any grade were low (11 [3%] of 316 patients in the PVR group vs eight [3%] of 311 patients in the VR group).

任何级别的房颤或房扑发生率均较低（PVR组316名患者中有11名[3%]，VR组311名患者中有8名[3%]）

Rates of treatment discontinuation owing to treatment-emergent adverse events deemed as related to any of the study drugs were similar: 5% (17 of 316 patients) in the PVR group versus 5% (16 of 311 patients) in the VR group.

因治疗相关不良事件导致的治疗中断率相似：PVR组316名患者中有17名（5%），VR组311名患者中有16名（5%）

There were five treatment-related deaths: one in the PVR group and four in the VR group.

治疗相关死亡共五例：PVR组一例，VR组四例。

interpretation

In patients with previously treated chronic lymphocytic leukaemia, PVR showed significant improvement in progression-free survivalcompared with VR, with consistent results in patients who had previously received covalent BTK inhibitors and no new safety signals.

在既往接受过治疗的慢性淋巴细胞白血病患者中，与VR相比，PVR在无进展生存期方面显示出显著改善，且在既往接受过共价BTK抑制剂治疗的患者中结果一致，未发现新的安全信号。

To our knowledge, these results represent the first randomised phase 3 evidence comparing a novel fixed-duration regimen to the current standard of VR in relapsed or refractory chronic lymphocytic leukaemia, supporting PVR as a potential new standard of care.

据我们所知，这些结果代表了首次在复发或难治性慢性淋巴细胞白血病中，将一种新的固定期限方案与当前的VR标准进行比较的随机III期证据，支持将PVR作为潜在的新护理标准。

funding

Eli Lilly and Company.

礼来公司