Zanubrutinib Approved in First-line or Relapsed/Refractory CLL/SL


The approval makes zanubrutinib available to all patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) whether they are newly diagnosed or previously treated.

The FDA has approved zanubrutinib (Brukinsa), a second-generation Bruton tyrosine kinase (BTK) inhibitor, for the treatment of all patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) regardless of whether or not they are newly diagnosed or have been previously treated, including those who received ibrutinib (Imbruvica).

The approval was based on the findings from 2 phase 3 clinical trials. SEQUOIA (NCT03336333) included 479 patients randomly assigned to receive either zanubrutinib or bendamustine plus rituximab (BR). ALPINE (NCT03734016) randomly assigned 625 patients to either zanubrutinib or ibrutinib, a first-generation BTK inhibitor.

CLL will account for nearly one-third (31.4%) of new leukemia cases in the United States in 2023 (18,740 out of 59,610 new cases), according to statistics from the American Cancer Society.

“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,” Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, said in a statement. “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.”

In SEQUOIA, the median progression-free survival (PFS) was not reached in the zanubrutinib arm and was 33.7 months in the BR arm. The results were published in The Lancet Oncology.1 Among the 110 patients with previously untreated CLL/SLL with 17p deletion, the overall response rate (ORR) was 88% and the median duration of response was not reached after a median follow-up for 25.1 months.

Recent data from ALPINE were presented December 2022 at the 64th American Society of Hematology (ASH) Annual Meeting and published simultaneously in New England Journal of Medicine.2 Those results highlighted a 35% benefit in PFS for patients receiving zanubrutinib compared with ibrutinib after 2.5 years. Zanubrutinib demonstrated an ORR of 80.4% compared with 72.9% for ibrutinib. The median duration of response was not reached in either arm after a median follow-up of 14.1 months.

Brown presented the ALPINE data at the ASH meeting. “PFS is the gold standard for measuring efficacy in CLL clinical trials,” she said in a statement when the data were released. “The ALPINE data showing superior efficacy and consistent benefit across patient subgroups including

patients with high-risk del(17p)/TP53, along with a favorable cardiovascular safety profile, provide compelling evidence for Brukinsa as a practice-changing [BTK] inhibitor for patients with CLL.”

In a pooled analysis across clinical trials, the most common adverse reactions were decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%). Only 3.7% of patients reported atrial fibrillation or flutter and only 0.2% of patients had grade 3 or higher ventricular arrythmias.

One of the benefits of zanubrutinib over ibrutinib is the favorable benefit-risk profile and the decreased off-target inhibition-related toxicities, according to a study published in Journal of Clinical Oncology.3

According to the FDA, the recommended dosage of zanubrutinib is 160 mg taken orally twice daily or 320 mg orally once daily until the patient experiences disease progression or unacceptable toxicity.

Zanubrutinib is already approved to treat adults with Waldenström’s macroglobulinemia, mantle cell lymphoma who have received at least 1 prior therapy, and relapsed or refractory marginal zone lymphoma who have received at least 1 anti-CD20–based regimen. The mantle cell and marginal zone lymphoma indications were both approved under accelerated approval and continued approval may be contingent on confirmatory trials.

“With 4 US approvals in just over 3 years and demonstrated superiority versus ibrutinib in the final progression-free survival analysis of the ALPINE trial, we believe Brukinsa is well-positioned to become the BTK [inhibitor] of choice across multiple indications,” said Mehrdad Mobasher, MD, MPH, chief medical officer, Hematology at BeiGene.


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;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5

2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. Published online December 13, 2022. doi:10.1056/NEJMoa2211582

3. Hillmen P, Eichhorst B, Brown JR, et al. Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: interim analysis of a randomized phase III trial. J Clin Oncol. 2022;JCO2200510. doi:10.1200/JCO.22.00510

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