On January 19, 2023, the FDA approved zanubrutinib (Brukinsa; BeiGene USA), a BTK inhibitor, for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The FDA granted zanubrutinib an orphan drug designation for this indication.
Zanubrutinib was previously approved for mantle-cell lymphoma, Waldenström’s macroglobulinemia, and relapsed or refractory marginal-zone lymphoma.
This new approval for CLL or SLL was based on results of several studies and cohorts. In the SEQUOIA study, a cohort of 479 patients with treatment-naïve CLL or SLL and no 17p deletion were randomized (1:1) to zanubrutinib monotherapy until disease progression or unacceptable adverse events or to bendamustine plus rituximab for 6 cycles. The main efficacy measure was progression-free survival (PFS). At an estimated median follow-up of 25 months, the median PFS was not reached (95% confidence interval [CI], not estimable) in the zanubrutinib arm versus 33.7 months (95% CI, 28.1-not estimable) in the bendamustine plus rituximab arm (hazard ratio, 0.42; 95% CI, 0.28-0.63; P ≤.001).
In a separate, nonrandomized, cohort of the SEQUOIA study, 110 patients with treatment-naïve CLL or SLL and 17p deletion received zanubrutinib monotherapy. The overall response rate (ORR) was 88% (95% CI, 81-94). At a median follow-up of 25.1 months, the median duration of response (DOR) was not reached.
A second study called ALPINE included 652 patients with relapsed or refractory CLL or SLL who were randomized (1:1) to zanubrutinib or to another BTK inhibitor—ibrutinib. The median number of previous lines of therapy in this study was 1 (range, 1-8). The ORR was 80% (95% CI, 76-85) in the zanubrutinib arm versus 73% (95% CI, 68-78) in the ibrutinib arm (response rate, 1.10; 95% CI, 1.01-1.20; P = .0264). At a median follow-up of 14.1 months, the median DOR was not reached in either arm.
Across the different cohorts and studies, the most common (≥30%) adverse events with zanubrutinib were decreased neutrophil count (42%), upper respiratory tract infection (39%), platelet count decreased (34%), hemorrhage (30%), and musculoskeletal pain (30%). In addition, 3.7% of patients had atrial fibrillation or flutter, and 0.2% of the patients had grade ≥3 ventricular arrhythmias. In all, 13% of patients had second primary malignancies.