Zanubrutinib Displays PFS Benefit Over Bendamustine/Rituximab in CLL and SLL

In the first comparison of zanubrutinib vs chemoimmunotherapy, zanbrutinib was shown to improve progression-free survival in patients with treatment-naïve chronic lymphocytic leukemia and small lymphocytic lymphoma, and may be less toxic.

Zanubrutinib (Brukinsa) significantly improved progression-free survival (PFS) compared with the combination of bendamustine plus rituximab (Rituxan) in patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to data from cohort 1 of the phase 3 SEQUOIA trial (BGB-3111-304; NCT03336333).1

Findings from cohort 1 revealed that at a median of 26.2 months, zanubrutinib, administered to 241 patients, reduced the risk of disease progression or death by 58% vs bendamustine plus rituximab, administered to 238 patients (HR, 0.42; 95% CI, 0.28-0.63). Moreover, zanubrutinib showed an acceptable safety profile which was consistent with findings derived from previous studies.

The highly selective, second-generation Bruton’s tyrosine kinase inhibitor (BTK), zanubrutinib, works to amplify BTK occupancy and reduce off-target effects. Previously in February 2022, the FDA accepted a supplemental new drug application for zanubrutinib as a potential treatment option for adult patients with CLL or SLL.

Within the international, open-label, randomized, phase 3 SEQUOIA study, patients with untreated CLL or SLL who met International Workshop on Chronic Lymphocytic Leukemia criteria were enrolled. Eligibility for the trial was open to patients aged 65 years or older who were ineligible to receive treatment with fludarabine, cyclophosphamide, and rituximab.2

Other enrollment criteria included having measurable disease by imaging, an ECOG performance status of 0, 1, or 2, a life expectancy of 6 months or more, adequate bone marrow function, and adequate renal and hepatic function.

In order to enroll into cohort 1 of the trial, patients were not allowed to have del(17p) per central fluorescence in-situ hybridization. Patients were randomized in a 1:1 ratio to receive zanubrutinib at a dose of 160 mg twice a day until disease progression, unacceptable toxicity, or end of study (arm A; n = 241), or bendamustine given intravenously at a dose of 90 mg/m2 on days 1 and 2 in addition to rituximab at 375 mg/m2 in cycle 1 and at 500 mg/m2 in cycles 2 through 6 (arm B; n = 238).

For cohorts 2 and 3 of the trial, patients consisted of those with del(17p). Investigators are currently examining the use of zanubrutinib as a monotherapy in arm C and zanubrutinib in combination with venetoclax (Venclexta) in arm D.

The primary end point for cohort 1 of the trial is PFS per independent review committee (IRC) assessment, with key secondary end points consisting of investigator-assessed PFS, objective response rate per IRC and investigator assessment, overall survival, and safety.

The median age across arms A and B was 70 years (range, 66-75) with most patients in arms A and B aged 65 years or older (81.3% vs 80.7%), male (63.9% vs 60.5%), and were based in Europe (72% vs 72%). In arm A, 6% of patients had an ECOG performance status of 2 vs 8% of those in arm B. Then, 29.0% vs 29.4% of patients had Binet stage C disease, and 28.6% vs 30.7% of patients had bulky disease, respectively.

Among the patients enrolled in zanubrutinib arm, 42% had cytopenias at baseline vs 46% of those in the doublet arm. A total of 56% of patients had del(13q), 53% had unmutated IGHV gene, 18% had del(11q), and 6.5% had a TP53 mutation in arm A vs 54%, 52%, 19%, and 6%, in arm B.

A total of 479 patients without del(17p) underwent randomization with 241 assigned to the zanubrutinib arm and 238 assigned to receive bendamustine plus rituximab. With a median follow-up of 26.2 months, (interquartile range [IQR], 23.7-29.6), 36 (15%) of the 241 patients in group A had progressed or died per independent review committee compared with 71 (30%) of 238 patients in group B.

There were 34 patients in the zanubrutinib arm who discontinued treatment with 20 due to toxicity, 11 from disease progression, 2 as a result of patient withdrawal, and 1 because of investigator discretion. For patients given bendamustine plus rituximab, 39 patients discontinued treatment. The most common reason for discontinuation in the trial was toxicity (n = 31), investigator discretion (n = 3), another unspecified reason (n = 3), progressive disease (n = 1), and patient withdrawal (n = 1). Further, 206 patients in the zanubrutinib arm continued to receive treatment at the time of data cutoff, and 188 patients in the bendamustine plus rituximab arm completed treatment.

In regard to safety, the most common grade 3 or worse adverse event (AE) was reported to be neutropenia in 27 patients (11%) in group A, 116 (51%) in group B, and 17 (15%) in group C). Serious AEs were observed in 88 (37%) in group A, 113 (50%) in group B, and 45 (41%) in group C.

Further, AEs which led to death occurred in 11 (5%) of those enrolled in group A, 12 (5%) in group B, and 3 (3%) in group C. These AEs were most commonly a result of COVID-19 (4 [2%] in group A), diarrhea, and aspiration pneumonia (2 each [1%] in group B).

  1. 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;S1470-2045(22)00293-5. doi:10.1016/S1470-2045(22)00293-5
  2. A study comparing zanubrutinib with bendamustine plus rituximab in participants With previously untreated CLL or SLL (SEQUOIA). Updated June 27, 2022, Accessed July 27, 2022.
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