Zanubrutinib Significantly Improves PFS in Treatment-Naïve CLL/SLL Across Various High-Risk Subsets

Patients with treatment-naïve chronic lymphocytic leukemia and small lymphocytic lymphoma, achieved superior progression-free survival with zanubrutinib vs a combination of bendamustine plus rituximab.

Compared with a doublet regimen of bendamustine plus rituximab (Rituxan; BR), zanubrutinib (Brukinsa) improved outcomes for patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Specifically, significant improvements in progression-free survival (PFS) were observed across high-risk subgroups, according to data from cohort 1 of the phase 3 SEQUOIA trial (BGB-3111-304; NCT03336333) presented during the 2022 Pan Pacific Lymphoma Conference.1

Among 241 treated patients, zanubrutinib reduced the risk of disease progression or death by 58% vs BR (n = 238) in all patients examined in cohort 1 (HR, 0.42; 95% CI, 0.28-0.63). In the high-risk subgroup of patients with unmutated IGHV, zanubrutinib (n = 125) resulted in a 76% reduction in the risk of disease progression or death vs BR (n = 121; HR, 0.24; 95% CI, 0.13-0.43). Moreover, in the subgroup of patients with del(11q), zanubrutinib (n = 43) reduced the risk of disease progression or death by 79% compared with BR (n = 46; HR, 0.21; 95% CI, 0.09-0.50).

“These data demonstrate that a chemotherapy-free treatment using a potent and selective BTK inhibitor was well tolerated and effective for patients with treatment-naïve CLL/SLL,” Brad S. Kahl, MD, a professor of medicine in the Division of Oncology at the Washington University School of Medicine, and colleagues, wrote in a poster presentation.

A highly selective, second-generation BTK inhibitor, zanubrutinib, was designed to amplify BTK occupancy and reduce off-target effects. Preliminary data have shown that the agent produces high response rates in untreated patients who have CLL and del(17p).2

SEQUOIA enrolled patients with untreated CLL or SLL who met International Workshop on Chronic Lymphocytic Leukemia criteria. Patients were required to be at least 65 years of age or to be ineligible to receive treatment with fludarabine, cyclophosphamide, and rituximab. Anticoagulation and CYP3A inhibitors were permitted.

To enroll to cohort 1, patients could not have del(17p) per central fluorescence in-situ hybridization. These patients were randomized 1:1 to receive zanubrutinib at 160 mg twice daily until disease progression, unacceptable toxicity, or end of study (arm A; n = 241), or bendamustine at 90 mg/m2 on days 1 and 2 plus rituximab at 375 mg/m2 in cycle 1 and at 500 mg/m2 in cycles 2 through 6 (arm B; n = 238).

Cohorts 2 and 3 of the trial comprise patients with del(17p); in these cohorts, investigators are examining the use of zanubrutinib monotherapy (arm C) and zanubrutinib in combination with venetoclax (Venclexta; arm D).

The primary end point for cohort 1 is PFS per independent review committee (IRC) assessment, and key secondary end points include 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); most patients in arms A and B, respectively, were aged 65 years or older (81.3% vs 80.7%), male (63.9% vs 60.5%), and were based in Europe (72.2% vs 72.3%). Moreover, 6.2% of those in arm A had an ECOG performance status of 2 vs 8.4% of those in arm B; 29.0% vs 29.4% of patients, respectively, had Binet stage C disease, and 28.6% vs 30.7% of patients, respectively, had bulky disease.

Additionally, 42.3% of those in the zanubrutinib arm had cytopenias at baseline vs 45.8% of those in the BR arm. In arm A, 53.4% of patients had unmutated IGHV, 17.8% had del(11q), and 6.5% had a TP53 mutation; these rates were 52.4%, 19.3%, and 5.8%, respectively, in arm B.

A total of 479 patients without del(17p) underwent randomization; 241 were randomly assigned to the zanubrutinib arm and 238 were assigned to the BR arm. The median follow-up was 26.4 months (interquartile range [IQR], 24.2-29.5) in the experimental arm and 25.9 months (IQR, 23.4-29.6) in the control arm. All patients were evaluable for efficacy.

Moreover, 240 patients ended up receiving treatment zanubrutinib, and 227 patients received BR; these patients were included in the safety analysis.

A total of 34 patients in the zanubrutinib arm discontinued treatment; 20 did so because of toxicity, 11 because of disease progression, 2 due to patient withdrawal, and 1 per investigator discretion. In the BR arm, 39 patients discontinued treatment; the most common reason for discontinuation was toxicity (n = 31), followed by investigator discretion (n = 3), another unspecified reason (n = 3), progressive disease (n = 1), and patient withdrawal (n = 1).

At the time of data cutoff, 206 patients in the zanubrutinib arm continued to receive treatment; 188 patients in the BR arm completed treatment, and 15 crossed over to receive zanubrutinib upon centrally confirmed disease progression.

Additional data showed that at a median follow-up of 30.5 months, the 24-month PFS rate in cohort 2, which was comprised of patients with del(17p), was 88.9% (95% CI, 81.3%-93.6%) with zanubrutinib per IRC assessment.

Any-grade adverse effects (AEs) occurred in 93.3% of those who received zanubrutinib vs 96.0% of those who were given BR; grade 3 or higher effects were reported in 52.5% and 79.7% of patients, respectively.

In the zanubrutinib arm, the most common AEs were contusion (any grade, 19.2%), upper respiratory tract infection (any grade, 17.1%; grade ≥3, 0.8%), neutropenia (any grade, 15.4%; grade ≥3, 11.3%), diarrhea (any grade, 13.8%), arthralgia (any grade, 13.3%; grade ≥3, 0.8%), fatigue (any grade, 11.7%; grade ≥3, 1.3%), rash (any grade, 10.8%), constipation (any grade, 10.0%; grade ≥3, 0.4%), nausea (any grade, 10.0%), pyrexia (any grade, 7.1%), vomiting (any grade, 7.1%), anemia (any grade, 4.6%; grade ≥3, 0.4%), thrombocytopenia (any grade, 3.8%; grade ≥3, 1.7%), and infusion-related reaction (any grade, 0.4%).

Investigators recorded serious AEs in 36.7% of those in the zanubrutinib arm vs 49.8% of those in the BR arm; fatal AEs occurred in 11 patients in both arms. Moreover, 7.5% of those who received zanubrutinib and 37.4% of those who were given BR experienced AEs that led to dose reductions; AEs resulted in dose interruptions or delays in 46.3% and 67.8% of patients, respectively. Fewer patients in the zanubrutinib arm discontinued treatment due to AEs vs those in the BR arm, at 8.3% and 13.7%, respectively.

AEs of special interest reported in the zanubrutinib arm included anemia (any grade, 4.6%; grade ≥3, 0.4%), neutropenia (any grade, 15.8%; grade ≥3, 11.7%), thrombocytopenia (any grade, 4.6%; grade ≥3, 2.1%), arthralgia (any grade, 13.3%; grade ≥3, 0.8%), atrial fibrillation (any grade, 3.3%; grade ≥3, 0.4%), bleeding (any grade, 45.0%; grade ≥3, 3.8%), diarrhea (any grade, 13.8%; grade ≥3, 0.8%), hypertension (any grade, 14.2%; grade ≥3, 6.3%), infections (any grade, 62.1%; grade ≥3, 16.3%), myalgia (any grade, 3.8%), and other cancers (any grade, 12.9%; grade ≥3, 7.1%).

“Consistent with other zanubrutinib studies, zanubrutinib appeared well tolerated with no new safety signals identified; the rate of atrial fibrillation was low,” the study authors concluded.


Kahl BS, Giannopoulos K, Jurczak W, et al. SEQUOIA: results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 2022 Pan Pacific Lymphoma Conference; July 18-22, 2022; Koloa, Hawaii.

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