Zanubrutinib more effective and better tolerated than ibrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma

The final analysis of the phase 3 ALPINE trial shows that zanubrutinib confers superior progression-free survival (PFS) in comparison with ibrutinib for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). “Zanubrutinib improved progression-free survival compared to ibrutinib by about 12% at 2 years, and even more in the highest risk disease subgroup,” says lead author Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at the Dana-Farber Cancer Institute in Boston, Massachusetts, noting that the results confirm and extend interim results. Published in The New England Journal of Medicine,1 the final analysis of the study focused on PFS, a secondary end point. A preplanned interim analysis previously published showed a superior overall response rate (the primary end point) with zanubrutinib versus ibrutinib.2 Both the interim and final analyses showed that zanubrutinib was also better tolerated than ibrutinib, with fewer adverse cardiac events such as atrial fibrillation/flutter being reported. The ALPINE trial is the first head-to-head trial showing the superiority of zanubrutinib (a second-generation Bruton tyrosine kinase (BTK) inhibitor) over ibrutinib (a firstgeneration BTK inhibitor) for relapsed or refractory CLL/SLL. The multinational trial included 652 adults with relapsed or refractory CLL/SLL who were randomized 1:1 to zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily) until disease progression or unacceptable toxicity. All patients had received at least one previous course of therapy. At a median follow-up of 29.6 months, PFS was superior in patients treated with zanubrutinib compared to those treated with ibrutinib (hazard ratio [HR] for disease progression or death, 0.65; 95% CI, 0.49–0.86; p = .002). At 24 months, the PFS rates were 78.4% and 65.9% for zanubrutinib and ibrutinib, respectively. Zanubrutinib’s superiority was also seen in the longer PFS in the zanubrutinib group versus the ibrutinib group among the highest risk patients (those with del(17p) and/or TP53 mutations) (HR, 0.53; 95% CI, 0.31–0.88). Zanubrutinib was also associated with fewer cardiac adverse events in comparison with ibrutinib (21.3% vs. 29.6%), including atrial fibrillation/flutter (a secondary end point) of any grade, which was significantly less common in patients treated with zanubrutinib versus ibrutinib (5.2% vs. 13.3%); the same was true for grade 3 or higher atrial fibrillation/flutter (2.5% vs. 4.0%). Overall, six patients, all treated with ibrutinib, died of a cardiac event. Adverse cardiac events leading to treatment discontinuation occurred in one zanubrutinib patient (0.3%) and 14 ibrutinib patients (4.3%). Jason Romancik, MD, an assistant professor in the Department of Hematology and Medical Oncology at the Emory University School of Medicine in Atlanta, Georgia, who was not involved with the study, says that he thinks the results will affect the standard way of treating patients with relapsed or refractory CLL/ SLL. “While there will still be a role for ibrutinib when it is used in combination with venetoclax or with chemoimmunotherapy in CLL and other lymphoid malignancies, I suspect that the use of ibrutinib will decrease overall in CLL/SLL based on these results.” On January 19, 2023, the Food and Drug Administration approved zanubrutinib as a treatment for relapsed or refractory CLL/SLL on the basis of the ALPINE results and for untreated CLL/SLL on the basis of the SEQUOIA trial.3