Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial

被引：193

作者：

Tam, Constantine S. ^{[1
,2
,3
,4
]}

Brown, Jennifer R. ^{[5
]}

Kahl, Brad S. ^{[6
]}

Ghia, Paolo ^{[7
,8
]}

Giannopoulos, Krzysztof ^{[9
,10
]}

Jurczak, Wojciech ^{[11
]}

Simkovic, Martin ^{[12
,13
]}

Shadman, Mazyar ^{[14
,15
]}

Osterborg, Anders ^{[16
,17
]}

Laurenti, Luca ^{[18
]}

Walker, Patricia ^{[19
]}

Opat, Stephen ^{[20
,21
]}

Chan, Henry ^{[22
]}

Ciepluch, Hanna ^{[23
]}

Greil, Richard ^{[24
,25
]}

Tani, Monica ^{[26
]}

Trneny, Marek ^{[27
]}

Brander, Danielle M. ^{[28
]}

Flinn, Ian W. ^{[29
]}

Grosicki, Sebastian ^{[30
]}

Verner, Emma ^{[31
,32
]}

Tedeschi, Alessandra ^{[33
]}

Li, Jianyong ^{[34
]}

Tian, Tian ^{[35
]}

Zhou, Lei ^{[36
]}

Marimpietri, Carol ^{[35
]}

Paik, Jason C. ^{[35
]}

Cohen, Aileen ^{[35
]}

Huang, Jane ^{[35
]}

Robak, Tadeusz ^{[37
]}

Hillmen, Peter ^{[38
]}

机构：

[1] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[2] Univ Melbourne, Parkville, Vic, Australia

[3] St Vincents Hosp Melbourne, Fitzroy, Vic, Australia

[4] Royal Melbourne Hosp, Parkville, Vic, Australia

[5] Dana Farber Canc Inst, Boston, MA 02115 USA

[6] Washington Univ, Sch Med, St Louis, MO USA

[7] Univ Vita Salute San Raffaele, Milan, Italy

[8] IRCCS Osped San Raffaele, Milan, Italy

[9] Med Univ Lublin, Expt Hematooncol Dept, Lublin, Poland

[10] St Johns Canc Ctr, Hematol Dept, Lublin, Poland

[11] Maria Sklodowska Curie Natl Res Inst Oncol, Krakow, Poland

[12] Univ Hosp, Dept Internal Med Haematol, Hradec Kralove, Czech Republic

[13] Charles Univ Prague, Fac Med, Prague, Czech Republic

[14] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA

[15] Univ Washington, Dept Med, Seattle, WA USA

[16] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden

[17] Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden

[18] Fdn Policlin Univ A Gemelli UCSC, Rome, Italy

[19] Peninsula Private Hosp, Frankston, Vic, Australia

[20] Monash Hlth, Clayton, Vic, Australia

[21] Monash Univ, Clayton, Vic, Australia

[22] North Shore Hosp, Auckland, New Zealand

[23] Copernicus Reg Oncol Ctr, Gdansk, Poland

[24] Paracelsus Med Univ, Med Dept Hematol Med Oncol Rheumatol & Infectiol, Salzburg, Austria

[25] Salzburg Canc Res Inst Ctr Clin Canc & Immunol Tr, Salzburg, Austria

[26] Santa Maria delle Croci Hosp, Hematol Unit, Ravenna, Italy

[27] Charles Univ Prague, Gen Hosp, Fac Med 1, Dept Med 1, Prague, Czech Republic

[28] Duke Univ, Sch Med, Hematol Malignancies & Cellular Therapy, Durham, NC USA

[29] Sarah Cannon Res Inst, Tennessee Oncol, Nashville, TN USA

[30] Med Univ Silesia, Dept Hematol & Canc Prevent, Hlth Sci Fac, Katowice, Poland

[31] Concord Repatriat Gen Hosp, Concord, NSW, Australia

[32] Univ Sydney, Sydney, NSW, Australia

[33] ASST Grande Osped Metropolitano Niguarda, Milan, Italy

[34] Nanjing Med Univ, Affiliated Hosp 1, Jiangsu Prov Hosp, Dept Hematol, Nanjing, Peoples R China

[35] BeiGene USA, San Mateo, CA USA

[36] BeiGene, Beijing, Peoples R China

[37] Med Univ Lodz, Lodz, Poland

[38] St James Univ Hosp, Leeds, W Yorkshire, England

来源：

LANCET ONCOLOGY | 2022年 / 23卷 / 08期

关键词：

IBRUTINIB; ACALABRUTINIB; OBINUTUZUMAB; GUIDELINES;

D O I：

10.1016/S1470-2045(22)00293-5

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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/m(2) 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/m(2) 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 alpha 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. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved.

引用

页码：1031 / 1043

页数：13