On January 19, the U.S. Food and Drug Administration (FDA) approved the kinase inhibitor zanubrutinib (Brukinsa) for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
SEQUOIA Trial: Treatment-Naive Patients
Efficacy in treatment-naive patients with CLL/SLL was evaluated in SEQUOIA (ClinicalTrials.gov identifier: NCT03336333). In the randomized cohort including patients without 17p deletion, a total of 479 patients were randomly assigned 1:1 to receive either zanubrutinib until disease progression or unacceptable toxicity, or bendamustine plus rituximab for six cycles. The main efficacy outcome measure was progression-free survival as determined by an independent review committee. The median progression-free survival was not reached (95% confidence interval [CI] = not evaluable to not evaluable) in the zanubrutinib arm and was 33.7 months (95% CI = 28.1 months to not evaluable) in the bendamustine plus rituximab arm (hazard ratio [HR] = 0.42, 95% CI = 0.28–0.63, P ≤ .0001). Estimated median follow-up for progression-free survival was 25.0 months. In a separate nonrandomized cohort of SEQUOIA, zanubrutinib was evaluated in 110 previously untreated patients with CLL/SLL and 17p deletion. Overall response rate per independent review committee was 88% (95% CI = 81%–94%). The median duration of response was not reached after a median follow-up of 25.1 months.
ALPINE Trial: Relapsed or Refractory Disease
Efficacy in patients with relapsed or refractory CLL/SLL was evaluated in ALPINE (ClinicalTrials.gov identifier: NCT03734016). A total of 652 patients were randomly assigned 1:1 to receive either zanubrutinib or ibrutinib. The median number of prior lines of therapy was one (range = 1–8). The main efficacy outcome measures at this time of response analysis were overall response rate and duration of response as determined by an independent review committee. The overall response rate was 80% (95% CI = 76%–85%) in the zanubrutinib arm and 73% (95% CI = 68%–78%) in the ibrutinib arm (response rate ratio = 1.10, 95% CI = 1.01–1.20, P = .0264). The median duration of response was not reached in either arm after a median follow-up of 14.1 months.
Across clinical trials of zanubrutinib, the most common adverse reactions (occurring in ≥ 30% of patients) were decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%). Second primary malignancies, including nonskin carcinomas, developed in 13% of patients. Atrial fibrillation or flutter were reported in 3.7% of patients, and grade 3 or higher ventricular arrhythmias occurred in 0.2% of patients.
The recommended zanubrutinib dosage is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Orphan Drug designation.
