Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Brown, N Engl J Med. 2023 Jan 26;388(4):319-332
In this randomized phase 3 study, 652 patients with relapsed chronic lymphocytic leukemia were randomly assigned to treatment with either zanubrutinib or ibrutinib. The median age of patients who enrolled in the study was 67 years. Deletion 17p was noted in 23% patients, and IGHV genes were unmutated in 73% patients. Patients had received a median of 1 prior line of therapy for CLL. At 24 months, the investigator assessed rates of progression-free survival were 78.4% in the zanubrutinib group compared to 65.9% in the ibrutinib group. Similarly, the overall response rate was higher in the zanubrutinib group at 83.5% compared to the ibrutinib group at 74.2%. In addition the 24 month progression-free survival amongst patients with deletion 17p was 72.6% in the zanubrutinib group compared to 54.6% in the ibrutinib group. There was no difference in the overall survival between the two treatment arms. Treatment with zanubrutinib was associated with a lower cumulative incidence of cardiac toxicity, including a lower incidence of atrial fibrillation or flutter. In addition, there was a lower incidence of grade 3 infection in patients with zanubrutinib compared to ibrutinib. However, the rates of hypertension were similar between the two treatment groups. Overall, the rates of treatment discontinuation due to toxicity were much lower with zanubrutinib compared to ibrutinib. In summary, results of this trial for the first time demonstrated the superiority of zanubrutinib, a novel Bruton tyrosine kinase inhibitor (BTKi), in the management of patients with relapsed CLL compared to ibrutinib, the first-in-class BTKi.
This trial is important for many reasons: 1) it led to the approval of zanubrutinib, another BTKi in the relapsed CLL setting; 2) it convincingly demonstrated the superiority of zanubrutinib to ibrutinib in patients with relapsed CLL, suggesting that using this agent might be beneficial for patients who are to start therapy for relapsed CLL; 3) the risk of cardiac toxicity, in particular atrial fibrillation, was noted to be much lower with zanubrutinib compared to ibrutinib, suggesting that this second-generation BTKi may be better tolerated in patients who may have a higher risk of developing this cardiac arrhythmia; 4) patients with deletion 17p, that constitutes a high-risk subgroup of patients, also experienced a significant benefit with the use of zanubrutinib compared to ibrutinib. The approval of zanubrutinib and relapsed CLL now provides clinicians the opportunity to prescribe another second-generation BTKi, in addition to acalabrutinib, that was previously approved for relapsed CLL.