Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia; St Vincent's Hospital Melbourne, Fitzroy, VIC, Australia; Royal Melbourne Hospital, Parkville, VIC, Australia.
Dana-Farber Cancer Institute, Boston, MA, USA.
Lancet Oncol. 2022 Aug;23(8):1031-1043. doi: 10.1016/S1470-2045(22)00293-5. Epub 2022 Jul 7.
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.
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/m of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m of body surface area the day before or on day 1 of cycle 1, and 500 mg/m 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.
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).
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.
BeiGene.
泽布替尼是一种新一代、选择性布鲁顿酪氨酸激酶抑制剂，在复发性慢性淋巴细胞白血病（CLL）和小淋巴细胞淋巴瘤（SLL）中具有疗效。我们将泽布替尼与苯达莫司汀-利妥昔单抗进行比较，以确定其在 CLL 或 SLL 患者中作为一线治疗的有效性。
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。符合条件的患者为未经治疗的 CLL 或 SLL，需要根据国际 CLL 工作组标准进行治疗；年龄在 65 岁或以上，或 18 岁或以上且有合并症；东部肿瘤协作组体能状态评分为 0-2。中央交互式网络响应系统通过顺序块方法（大小为 4 的随机块）对无 del(17)(p13·1)的患者进行分组，将患者随机分配至泽布替尼组（A 组）或苯达莫司汀-利妥昔单抗组（B 组）（分组块大小为 4）。del(17)(p13·1)患者被纳入 C 组，并接受泽布替尼治疗。泽布替尼每天口服 160mg，2 次/天（28 天为 1 个周期）；苯达莫司汀 90mg/m2体表面积在第 1 和第 2 天使用 6 个周期，利妥昔单抗在第 1 周期前一天或第 1 天使用 375mg/m2体表面积，第 2-6 周期使用 500mg/m2体表面积；静脉给药。主要终点是意向治疗人群中 A 组和 B 组的无进展生存期，A 组和 B 组的最小双侧 α 值为 0.05，以证明优越性。所有接受至少一剂研究治疗的患者均进行安全性分析。该研究在 ClinicalTrials.gov 注册，NCT03336333，目前已关闭招募。
2017 年 10 月 31 日至 2019 年 7 月 22 日期间，共纳入 590 例患者；无 del(17)(p13·1)的患者被随机分配至泽布替尼组（A 组，n=241）或苯达莫司汀-利妥昔单抗组（B 组，n=238）。中位随访时间为 26.2 个月（IQR 23.7-29.6），两组均未达到无进展生存期（A 组 95%CI 无法估计[NE]至 NE；B 组 28.1 个月至 NE）。A 组与 B 组相比，无进展生存期显著改善（HR 0.42 [95%CI 0.28 至 0.63]；双侧 p<0.0001）。最常见的 3 级或更高级别的不良事件是中性粒细胞减少症（A 组 240 例患者中有 27 例[11%]，B 组 227 例患者中有 116 例[51%]，C 组 111 例患者中有 17 例[15%]）。A 组 240 例患者中有 88 例（37%）发生严重不良事件，B 组 227 例患者中有 113 例（50%），C 组 111 例患者中有 45 例（41%）。A 组 240 例患者中有 11 例（5%）发生与治疗相关的死亡事件，B 组 227 例患者中有 12 例（5%），C 组 111 例患者中有 3 例（3%），最常见的死亡原因是 COVID-19（A 组 240 例患者中有 4 例[2%]）、腹泻和吸入性肺炎（B 组 227 例患者各有 2 例[1%]）。
泽布替尼显著改善了无进展生存期，与苯达莫司汀-利妥昔单抗相比，安全性特征可接受，与先前的研究一致。这些数据支持泽布替尼作为未治疗的 CLL 和 SLL 的潜在新治疗选择。
百济神州。
