BOSTON—A late-breaking presentation at the 64th American Society of Hematology Annual Meeting in New Orleans on Dec. 13 demonstrated that zanubrutinib outperformed ibrutinib in terms of both objective response rate and progression-free survival for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Jennifer Brown, MD, of the Department of Medical Oncology at the Dana-Farber Cancer Institute in Boston discussed the results of the Phase 3 ALPINE study, which compared zanubrutinib directly with ibrutinib.1
Ibrutinib, the first Bruton tyrosine kinase (BTK) inhibitor, received U.S. Food and Drug Administration (FDA) approval for treatment of CLL in 2014 and dramatically changed the treatment landscape for the disease. A second-generation BTK inhibitor, zanubrutinib has approval for use in relapsed or recurrent mantle cell lymphoma and marginal zone lymphoma, and the FDA has set a target action date for a CLL/SLL indication of Jan. 20, 2023.
The ALPINE study enrolled 652 patients from 15 countries randomized to receive zanubrutinib (327) or ibrutinib (325). The two groups were balanced by age, sex, immunoglobulin heavy chain variable (IGHV) mutation status and TP53 mutated without del(17p). The median age in the zanubrutinib group was 67, and in the ibrutinib group it was 68. Both groups had a median of one prior therapy.
At a median follow-up of 29.6 months, patients in the zanubrutinib group had a 35% reduction in risk of progression (HR: 0.65 [95% CI, 0.49-0.86]; 2-sided P=0.0024). Median progression-free survival (PFS) was 35 months in the ibrutinib group, while it was not reached in the zanubrutinib group. Across all major predefined subgroups, zanubrutinib provided superior PFS. In addition, zanubrutinib had a higher objective response rate (86.2 vs. 75.7%, nominal 2-sided P=0.0007).
One of the major challenges with ibrutinib has been its toxicity. Particularly in a population such as veterans, who frequently have cardiovascular disease and other comorbidities, ibrutinib’s high rate of adverse events has led to significant discontinuation and dose reduction rates. In the ALPINE study, the rate of discontinuation was 26.3% for patients in the zanubrutinib arm compared to 41.2% in the ibrutinib arm, with the difference largely driven by a lower rate of adverse events (16.2% vs. 22.8%) and progressive disease (7.3% vs. 12.9%).
Cardiac disorders related to the medication were also lower, 0.3% for zanubrutinib compared to 4.3% for ibrutinib. The rates of Grade 3 or higher adverse events, serious adverse events, dose interruption and dose reduction were all also lower with the second-generation BTK inhibitor. Notably, the rate of atrial fibrillation was lower, 5.2% vs 13.3%, for zanubrutinib as was the number of fatalities related to cardiac disorders, zero for zanubrutinib vs. six for ibrutinib. Overall mortality in the study was 14.7% for zanubrutinib vs. 18.5% for ibrutinib.
- Brown JR, Eichhorst B, Hillmen P, Lamanna N, O’Brien SM, et al. Zanubrutinb Demonstrates Superior Progression-Free Survival Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study. LBA-6. 2022 ASH Annual Meeting. Dec. 13, 2022.
