The following is a summary of “Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study” published in the January 2023 issue of Haematology by Shadman et al.

For individuals intolerant of ibrutinib, acalabrutinib, or both, we hypothesized that zanubrutinib, a highly selective next-generation BTK inhibitor, would be safe and effective. In addition, researchers wanted to determine whether zanubrutinib could reduce treatment-related toxicities and discontinuations in previously treated B-cell malignancies. Therefore, in an ongoing Phase 2, multicenter, open-label, single-arm study in 20 US centers, patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both were given zanubrutinib 160 mg twice daily or 320 mg once daily. Investigator-assessed adverse events were the primary outcome. The secondary endpoints were the investigator-assessed response rate, duration, disease control rate, and progression-free survival. All medication recipients were analyzed in this study.

About 67 intolerant individuals (36 [54%] men and 31 [46%] women) were enrolled between October 14, 2019, and September 8, 2021. Around 3  (5%), 1 (2%), and 63 (94%) patients were White. Zanubrutinib prevented most intolerance incidents (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib). 7 (21%) of 34 ibrutinib intolerance episodes and 2 (67%) of 3 acalabrutinib intolerance events recurred at the same severity with zanubrutinib, whereas 27 (79%) recurred at a lower severity. No severe occurrences occurred. No grade 4 intolerance occurred. The most prevalent adverse effects of zanubrutinib were contusion (15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (10 [15%]), arthralgia (9 [13%]), and diarrhea (9 [13%]). 3(4%). (all grade 2). 

About 8 (12%) of 67 patients reported significant adverse effects (anemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths were reported. Follow-up was 12·0 months (IQR 8·2–15·6). Disease control was 93·8% (60; 95% CI 84·8–98·3), and the overall response was 64·1% (41; 95% CI 51·1–75·7) in 64 efficacy-evaluable patients. The 12-month event-free response rate was 95·0% (95% CI 69·5–99·3). 18-month progression-free survival was 83·8% (95% CI 62·6–93·6). Previous BTK inhibitor intolerants have few treatment alternatives. These findings imply that B-cell malignancy patients with intolerance to ibrutinib or acalabrutinib may benefit from zanubrutinib, a safe and effective medication. BeiGene funds this study.