Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial

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.

FIG 1.

ALPINE study CONSORT diagram. A total of 491 patients had been screened at the time of random assignment of the 415th patient. All 415 randomly assigned patients were included in the efficacy analyses.

FIG 2.

Subgroup analysis for ORR. Forest plot showing ORR in prespecified baseline and disease subgroups. The rate difference (unstratified estimates of the differences in response rates) and 95% CI (normal approximations) are shown as a blue dot and black bars. A rate difference of greater than zero represents response rates favoring zanubrutinib. ECOG PS, Eastern Cooperative Oncology Group performance status; IGHV, immunoglobulin heavy chain variable region; ORR, overall response rate.

FIG 3.

Investigator-assessed PFS and OS. (A) Kaplan-Meier estimates of PFS for all patients. (B) Kaplan-Meier estimates of PFS for patients with or without del(17p)/TP53 mutations. (C) Kaplan-Meier estimates of OS for all patients. Ibr, ibrutinib; OS, overall survival; PFS, progression-free survival; Zanu, zanubrutinib.

FIG 4.

Time to adverse events of interest and cardiac disorders. Kaplan-Meier plot of time to (A) cardiac disorders, on the basis of System Organ Class in Medical Dictionary for Regulatory Activities (includes atrial fibrillation and atrial flutter); (B) atrial fibrillation/flutter; (C) grade 3 or higher neutropenia; (D) grade 3 or higher infection. For these plots, patients without the events of interest were censored on the last date of safety follow-up (30 days after treatment discontinuation or initiation of a new anticancer therapy or death, whichever is earliest).