FDA Approves Zanubrutinib in Adult Patients with CLL/SLL

Zanubrutinib has been granted FDA approval for the treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

The FDA has approved the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), according to a press release.1 

The approval was based on data from 2 phase 3 randomized studies that looked at zanubrutinib vs ibrutinib (Imbruvica) in patients with relapsed/refractory CLL in the ALPINE study (NCT03734016), and zanubrutinib vsbendamustine and rituximab (Rituxan) for the treatment of treatment-naïve patients with CLL in the SEQUOIA study (NCT03336333). Both studies showed that zanubrutinib was significantly non-inferior to these therapies and had a durable response in both treatment groups.

In the SEQUOIA trial, the median progression-free survival (PFS) was not reached in the zanubrutinib arm vs 33.7 months (95% CI, 28.1-NE) in the bendamustine and rituximab arm (HR, 0.42; 95% CI, 0.28-0.63; P =< .0001). The estimated median follow-up was 25.0 months.

In a separate non-randomized cohort of the study, 110 were given zanubrutinib, all who had previously untreated CLL/SLL with 17p deletion. The overall response rate (ORR) in this cohort was 88% (95% CI, 81-94). The median duration of response (DOR) was not reached after a median follow-up of 25.1 months.

In the ALPINE study, of the 415 evaluated patients the ORR among patients on the zanubrutinib was 80% (95% CI, 76-85) and 73% (95% CI, 68-78) in the ibrutinib arm (HR, 1.10; 95% CI, 1.01-1.20; P = .0264). The median DOR was not reached in either arm, after a median follow-up of 14.1 months.

“While previously approved BTK inhibitors have been transformational for some patients with CLL, there continues to be an unmet need as not all patients achieve a favorable clinical response while others are unable to tolerate currently approved BTK [inhibitor] therapies,” Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute, and a principal investigator in the 2 studies, stated in a press release.4 “As demonstrated in both the ALPINE AND SEQUOIA studies, zanubrutinib was generally well-tolerated in CLL patients with low rates of atrial fibrillation and showed strong efficacy compared [with] ibrutinib and chemoimmunotherapy, respectively.”

In terms of safety, the most frequent adverse events which occurred in at least 30% of patients who received zanubrutinibwereneutrophil count decrease (42%), upper respiratory tract infection (39%), platelet count decrease (34%), hemorrhage (30%), and musculoskeletal pain (30%).

According to the FDA label, the recommended dose of zanubrutinib is 160 mg twice daily and orally or 320 mg once daily and orally until disease progression or unacceptable toxicity.

Zanubrutinib is approved for 3 indications in the United States for mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom macroglobulinemia. The BTK inhibitor has been investigated in 3,900 patients across 35 clinical trials worldwide and is approved for 20 indications in 40 different countries. 

FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed January 19, 2023. https://bit.ly/3D1iUjq
Hillmen P, Eichhorst B, Brown JR, et al. first interim analysis of alpine study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: European Society of Hematology Congress; June 9-17, 2021. Virtual. Accessed May 10, 2022. Abstract LB1900.
BeiGene announces U.S. FDA acceptance of supplemental new drug application for Brukinsa (zanubrutinib) in chronic lymphocytic leukemia. News release. BeiGene. February 22, 2022. Accessed May 11, 2022.