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

Abstract

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.

• Authors: Constantine S Tam, Jennifer R Brown, Brad S Kahl, Paolo Ghia, Krzysztof Giannopoulos, Wojciech Jurczak, Martin Šimkovič, Mazyar Shadman, Anders Österborg, Luca Laurenti, Patricia Walker, Stephen Opat, Henry Chan, Hanna Ciepluch, Richard Greil, Monica Tani, Marek Trněný, Danielle M Brander, Ian W Flinn, Sebastian Grosicki, Emma Verner, Alessandra Tedeschi, Jianyong Li, Tian Tian, Lei Zhou, Carol Marimpietri, Jason C Paik, Aileen Cohen, Jane Huang, Tadeusz Robak, Peter Hillmen
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 23 Issue 8 Pg. 1031-1043 (08 2022) ISSN: 1474-5488 [Electronic] England
• PMID: 35810754 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Piperidines
• Pyrazoles
• Pyrimidines
• Rituximab
• Bendamustine Hydrochloride
• zanubrutinib

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Bendamustine Hydrochloride
• COVID-19
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, pathology)
• Piperidines
• Pyrazoles
• Pyrimidines
• Rituximab
• Sequoia