TY - JOUR
T1 - Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
T2 - Interim Analysis of a Randomized Phase III Trial
AU - Hillmen, Peter
AU - Eichhorst, Barbara
AU - Brown, Jennifer R.
AU - Lamanna, Nicole
AU - O'Brien, Susan M.
AU - Tam, Constantine S.
AU - Qiu, Lugui
AU - Kazmierczak, MacIej
AU - Zhou, Keshu
AU - Šimkovič, Martin
AU - Mayer, Jiří
AU - Gillespie-Twardy, Amanda
AU - Shadman, Mazyar
AU - Ferrajoli, Alessandra
AU - Ganly, Peter S.
AU - Weinkove, Robert
AU - Grosicki, Sebastian
AU - Mital, Andrzej
AU - Robak, Tadeusz
AU - Österborg, Anders
AU - Yimer, Habte A.
AU - Salmi, Tommi
AU - Ji, Meng
AU - Yecies, Jessica
AU - Idoine, Adam
AU - Wu, Kenneth
AU - Huang, Jane
AU - Jurczak, Wojciech
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2023/2/10
Y1 - 2023/2/10
N2 - PURPOSEZanubrutinib 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 METHODSALPINE (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.RESULTSBetween 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.CONCLUSIONZanubrutinib 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.
AB - PURPOSEZanubrutinib 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 METHODSALPINE (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.RESULTSBetween 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.CONCLUSIONZanubrutinib 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.
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U2 - 10.1200/JCO.22.00510
DO - 10.1200/JCO.22.00510
M3 - Article
C2 - 36395435
AN - SCOPUS:85147720922
SN - 0732-183X
VL - 41
SP - 1035
EP - 1045
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 5
ER -