Zanubrutinib may produce superior outcomes to ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), results of the phase 3 ALPINE trial suggest.

According to investigator assessment, zanubrutinib was associated with improved responses and progression-free survival (PFS) but reduced cardiotoxicity compared with ibrutinib. These findings were published in the Journal of Clinical Oncology.

Investigators reported results for the first 415 patients enrolled in the ALPINE trial ( Identifier: NCT03734016). The patients were randomly assigned to receive zanubrutinib (n=207) or ibrutinib (n=208). 

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In the overall cohort, the median age at baseline was 67 (range, 35-90) years. Patients had received a median of 1 prior lines of therapy (range, 1-8). Bulky disease was present in 51% of patients, and 19% had a 17p deletion or TP53 mutation.

The median follow-up was 15.3 months, and the primary endpoint was investigator-assessed objective response rate (ORR). The ORR was significantly higher with zanubrutinib than with ibrutinib — 78.3% and 62.5%, respectively (P <.001). 

Among patients with del(17P) or a TP53 mutation, the ORR was 80.5% with zanubrutinib and 50.0% with ibrutinib. Among patients with an 11q deletion, the ORR was 83.6% and 69.1%, respectively.

The 12-month PFS rate was higher in the zanubrutinib arm than in the ibrutinib arm — 94.9% and 84.0%, respectively (hazard ratio [HR], 0.40; 95% CI, 0.23-0.69). Among patients with del(17P) or a TP53 mutation, the 12-month PFS was 91.5% and 74.4%, respectively.

The 12-month overall survival rate was 97.0% with zanubrutinib and 92.7% with ibrutinib (HR, 0.54; 95% CI, 0.25-1.16).

The investigators found that cardiotoxicity was less frequent with zanubrutinib. Overall cardiac disorders occurred in 13.7% of patients in the zanubrutinib arm and 25.1% of those in the ibrutinib arm. Atrial fibrillation occurred in 2.5% and 10.1%, respectively (P =.001).  

The rate of grade 3 or higher adverse events was 55.9% in the zanubrutinib arm and 51.2% in the ibrutinib arm. Treatment discontinuation due to adverse events occurred in 7.8% and 13.0%, respectively. 

“Owing to the favorable benefit-risk profile for zanubrutinib shown in the ALPINE trial, zanubrutinib is preferred over ibrutinib for the treatment of most patients with relapsed/refractory CLL/small lymphocytic lymphoma,” Suzanne Lentzsch, MD, PhD, associate editor of the Journal of Clinical Oncology, wrote in a comment. 

Disclosures: This research was supported by BeiGene. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Hillmen P, Eichhorst B, Brown JR, et al. Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: Interim analysis of a randomized phase III trial. J Clin Oncol. Published online November 17, 2022. doi:10.1200/JCO.22.00510