Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial.
Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial.
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在先前治疗的慢性淋巴细胞性白血病中，阿卡劳替尼与伊布鲁替尼：第一次随机III期试验的结果。
DOI：
10.1200/jco.21.01210
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发表时间：
2021-11-01
期刊：
影响因子：
--
通讯作者：
Jurczak W
中科院分区：
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作者：
Byrd JC;Hillmen P;Ghia P;Kater AP;Chanan-Khan A;Furman RR;O'Brien S;Yenerel MN;Illés A;Kay N;Garcia-Marco JA;Mato A;Pinilla-Ibarz J;Seymour JF;Lepretre S;Stilgenbauer S;Robak T;Rothbaum W;Izumi R;Hamdy A;Patel P;Higgins K;Sohoni S;Jurczak W
在布鲁顿的酪氨酸激酶抑制剂中，acalabrutinib的选择性高于伊曲替尼，我们假设这将改善持续治疗的耐受性。我们进行了一项开放标签、随机、非劣效性、III期临床试验，比较acalabrutinib和iacrutinib治疗慢性淋巴细胞白血病（CLL）患者的疗效。既往接受过治疗的CLL患者（中心确认的del（17）（p13.1）或del（11）（q22.3））被随机分配至口服acalabrutinib 100 mg每日2次或伊鲁替尼420 mg每日1次，直至疾病进展或出现不可接受的毒性。主要终点是独立审查委员会评估的无进展生存期（PFS）的非劣效性。总体而言，随机分配了533例患者（acalabrutinib，n = 268;伊鲁替尼，n = 265）。在数据截止日期，124例（46.3%）acalabrutinib患者和109例（41.1%）ibrutinib患者仍在接受治疗。在中位随访40.9个月后，确定acalabrutinib非劣效于伊鲁替尼，两组的中位PFS均为38.4个月（95% CI acalabrutinib，33.0 - 38.6;伊鲁替尼，33.0 - 41.6;风险比：1.00; 95% CI，0.79 - 1.27）。acalabrutinib组的所有级别房颤/房扑发生率均显著低于伊曲替尼组（9.4%对16.0%; P = .02）;在其它选定的次要终点中，3级或以上感染（30.8% v 30.0%）和Richter变换（3.8% v4.9%）组间相当，两组均未达到中位总生存期（风险比，0.82; 95% CI，0.59 - 1.15），其中acalabrutinib组63例（23.5%）死亡，伊鲁替尼组73例（27.5%）死亡。14.7%的acalabrutinib治疗患者和21.3%的伊匹替尼治疗患者因不良事件而停药。在CLL患者中首次直接比较选择性较低与选择性较高的布鲁顿酪氨酸激酶抑制剂，显示acalabrutinib具有非劣效性PFS，且心血管不良事件较少。
Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL). Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee–assessed noninferiority of progression-free survival (PFS). Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients. In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.