FDA Approves Zanubrutinib for Treatment of CLL or SLL


Bruton’s tyrosine kinase inhibitor zanubrutinib (Brukinsa; BeiGene USA, Inc) approved for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma.

The FDA has approved zanubrutinib (Brukinsa; BeiGene USA, Inc) for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in both newly diagnosed or previously treated patients, including those previously administered ibrutinib (Imbruvica). The approval of the Bruton’s tyrosine kinase inhibitor (BTKi) was based on efficacy findings from a pair of phase 3 clinical trials—ALPINE (NCT03734016) and SEQUOIA (NCT03336333).1

“With 4 US approvals in just over 3 years and demonstrated superiority versus ibrutinib in the final progression-free survival (PFS) analysis of the ALPINE trial, we believe Brukinsa is well-positioned to become the BTKi of choice across multiple indications,” said Mehrdad Mobasher, MD, MPH, chief medical officer, Hematology at BeiGene, in a press release. “We’re grateful to the patients who participated in the ALPINE and SEQUOIA studies; and with this new approval, we’re excited to expand our impact to even more patients.”2

The efficacy of zanubrutinib in patients with treatment-naïve CLL/SLL was evaluated in the SEQUOIA trial. Investigators randomized 479 patients 1:1 without 17p deletion to receive either zanubrutinib until disease progression or unacceptable toxicity, or bendamustine plus rituximab (BR) for 6 cycles. The main efficacy outcome measure was PFS as determined by independent review committee (IRC).

Median PFS was not reached (95% CI: NE, NE) in the zanubrutinib cohort compared with 33.7 months (95% CI: 28.1, NE) in the BR cohort (HR= 0.42, 95% CI: 0.28, 0.63; p=<0.0001). The estimated median follow-up for PFS was 25.0 months.

In a separate non-randomized cohort in the SEQUOIA trial, zanubrutinib was analyzed among 110 patients with previously untreated CLL/SLL with 17p deletion. The overall response rate (ORR) per IRC was 88% (95% CI: 81, 94), while the median duration of response (DOR) was not reached after a median follow-up of 25.1 months.

The efficacy of zanubrutinib in patients with relapsed or refractory CLL/SLL was evaluated in the ALPINE trial, which randomized 652 patients 1:1 to receive zanubrutinib or ibrutinib. The median number of prior lines of therapy was 1 (range 1-8). The trial’s main efficacy outcome measures at the time of response analysis were ORR and DOR as determined by an IRC.

ORR was 80% (95% CI: 76, 85) in the zanubrutinib cohort compared with 73% (95% CI: 68, 78) in the ibrutinib cohort (response rate ratio 1.10, 95% CI: 1.01, 1.20; p=0.0264). Median DOR was not reached in either trial cohort after a median follow-up of 14.1 months.

A pre-defined final PFS analysis of the ALPINE study showing superior efficacy and a favorable cardiac safety profile for zanubrutinib compared with ibrutinib in patients with relapsed or refractory (R/R) CLL was presented at the 64th Annual American Society for Hematology Meeting and published in The New England Journal of Medicine.2

After a median follow-up of 29.6 months, zanubrutinib showed superior PFS compared with ibrutinib in patients with R/R CLL (HR: 0.65 [95% CI, 0.49-0.86] P=.0024, for both investigator and IRC). Further, zanubrutinib showed a favorable cardiac safety profile, with significantly lower rates of atrial fibrillation (5.2% vs 13.3%). There were no deaths attributed to cardiac disorders in patients administered zanubrutinib compared to 6 with ibrutinib (0% vs 1.9%).

The most common adverse events associated with zanubrutinib (≥30%) across clinical trials were reduced neutrophil count (42%), upper respiratory tract infection (39%), reduced platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%). Second primary malignancies, such as non-skin carcinomas, were observed in 13% of patients. Atrial fibrillation was reported in 3.7% of patients, with grade 3 or higher ventricular arrhythmias reported in 0.2% of patients.

The recommended dose of zanubrutinib is 160 mg, taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.

“We have seen striking data from the Brukinsa development program demonstrating significant and consistent efficacy across CLL patient sub-types, including the high-risk del17p/TP53 mutated population, and regardless of treatment setting,” said Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute. “With extensive follow-up across the CLL development program and the combined results from the SEQUOIA and ALPINE trials, Brukinsa is established as a new standard of care for CLL.”2


1. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic leukemia. News release. FDA newsroom. January 19, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma.

2. BRUKINSA® Approved in the U.S. for Chronic Lymphocytic Leukemia. News release. Beigene. January 19, 2023. https://ir.beigene.com/news/brukinsa-approved-in-the-u-s-for-chronic-lymphocytic-leukemia/4022a38f-ea68-4b11-ba1f-45478e2c0697/

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