On January 19, 2023, the kinase inhibitor zanubrutinib was approved for treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1
Supporting Efficacy Data
Approval was based on findings in the SEQUOIA trial (ClinicalTrials.gov identifier NCT03336333) in patients with treatment-naive CLL or SLL and in the ALPINE trial (NCT03734016) in patients with relapsed or refractory disease.
In a randomized cohort in SEQUOIA including patients without 17p deletion, participants were randomly assigned to receive zanubrutinib at 160 mg twice daily until disease progression or unacceptable toxicity (n = 241) or bendamustine plus rituximab (BR) for six cycles (n = 238). Median progression-free survival on independent review committee assessment was not reached (95% confidence interval [CI] = not estimable to not estimable) in the zanubrutinib group vs 33.7 months (95% CI = 28.1 months to not estimable) in the BR group (hazard ratio = 0.42, 95% CI = 0.28–0.63, P < .0001). In a nonrandomized cohort in the trial, 110 patients with 17p deletion received the same zanubrutinib regimen. The objective response rate on independent review committee assessment was 88% (95% CI = 81%–94%). Median duration of response was not reached after a median follow-up of 25.1 months.
In ALPINE, patients were randomly assigned to receive zanubrutinib in the same regimen (n = 327) or ibrutinib (n = 325) until disease progression or unacceptable toxicity. Objective response rate on independent review committee assessment was 80% (95% CI = 76%–85%) vs 73% (95% CI = 68%–78%; response rate ratio = 1.10, 95% CI = 1.01–1.20, P = .0264). Median duration of response was not reached in either group after a median follow-up of 14.1 months.
How It Is Used
The recommended zanubrutinib dosage is 160 mg twice daily or 320 mg once daily until disease progression or unacceptable toxicity. Product labeling provides instructions on dosage modification for grade 3 or 4 hematologic and nonhematologic adverse reactions.
Across clinical trials of zanubrutinib, the most common adverse events of any grade were decreased neutrophils (42%), upper respiratory tract infection (39%), decreased platelets (34%), hemorrhage (30%), and musculoskeletal pain (30%). Second primary malignancies, including nonskin carcinomas, occurred in 13% of patients. Atrial fibrillation or flutter occurred in 3.7%, and grade ≥ 3 ventricular arrhythmia occurred in 0.2%.
Among patients receiving zanubrutinib, serious adverse events occurred in 36% of those in the SEQUOIA randomized cohort (COVID-19, pneumonia, and second primary malignancy in 5% each), 41% of the SEQUOIA nonrandomized cohort (pneumonia in 8% and second primary malignancy in 7%), and 32% of the ALPINE cohort (pneumonia in 10%, COVID-19 in 7%, and second primary malignancy in 5%). Fatal adverse events occurred in 4.6%.
Zanubrutinib has warnings/precautions for hemorrhage, infections, second primary malignancies, cardiac arrhythmia, and embryofetal toxicity.
1. Brukinsa (zanubrutinib) capsules, for oral use, prescribing information, BeiGene, Ltd, January 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213217s007lbl.pdf. Accessed January 30, 2023.