Zanubrutinib Prolongs PFS vs Bendamustine-Rituximab in Untreated CLL and SLL: SEQUOIA Trial

Zanubrutinib significantly improved progression-free survival (PFS) vs bendamustine–rituximab as a frontline therapy for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to a phase 3 study published in The Lancet Oncology.

“Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed [CLL] and [SLL],” wrote Constantine Tam, MD, Alfred Hospital, Melbourne, Australia, and colleagues. “We compared zanubrutinib with bendamustine–rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL.”

This open-label, multicenter, phase 3 study was conducted across 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 to 2.

Researchers used a central interactive web response system to randomize 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 6 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 to 6, were administered intravenously.

The primary end point was PFS 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. 

Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to the  zanubrutinib (group A; n = 241) or the bendamustine–rituximab (group B; n = 238). At median follow-up of 26.2 months (IQR 23.7 to 29.6), median PFS was not reached in either. PFS was significantly improved in group A vs group B (hazard ratio [HR], 0.42; 95% CI, 0.28 to 0.63]; two-sided P <.0001).

The most common grade 3 or worse adverse event (AE) 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 AEs 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. AEs leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and 3 (3%) of 111 patients in group C, most commonly due to COVID-19 (4 [2%] of 240 patients in group A), diarrhea, and aspiration pneumonia (2 each [1%] of 227 patients in group B).

“Zanubrutinib significantly improved [PFS] versus bendamustine–rituximab, with an acceptable safety profile consistent with previous studies,” the study authors concluded. “These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL.”

Source:

Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5