Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial
- Author(s)
- Hillmen, P; Eichhorst, B; Brown, JR; Lamanna, N; O'Brien, SM; Tam, CS; Qiu, L; Kazmierczak, M; Zhou, K; Simkovic, M; Mayer, J; Gillespie-Twardy, A; Shadman, M; Ferrajoli, A; Ganly, PS; Weinkove, R; Grosicki, S; Mital, A; Robak, T; Osterborg, A; Yimer, HA; Salmi, T; Ji, M; Yecies, J; Idoine, A; Wu, K; Huang, J; Jurczak, W;
- Journal Title
- Journal of Clinical Oncology
- Publication Type
- Research article
- Abstract
- PURPOSE: Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities. PATIENTS AND METHODS: ALPINE (ClinicalTrials.gov identifier: NCT03734016) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled. RESULTS: Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib. CONCLUSION: Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.
- Publisher
- American Society of Clinical Oncology
- Keywords
- Humans; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy; *Atrial Fibrillation; Adenine/therapeutic use; *Lymphoma, B-Cell/drug therapy; Protein Kinase Inhibitors/therapeutic use
- Department(s)
- Clinical Haematology
- PubMed ID
- 36395435
- Publisher's Version
- https://doi.org/10.1200/JCO.22.00510
- Open Access at Publisher's Site
https://doi.org/10.1200/JCO.22.00510- Terms of Use/Rights Notice
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Creation Date: 2023-05-30 07:27:46
Last Modified: 2023-05-30 07:28:52