Zanubrutinib Shows Promise for Patients With B-Cell Malignancies Intolerant of Other BTK Inhibitors

Results from a Phase 2, Single-Arm, Multicenter Trial 

Study findings published in The Lancet Haematology show zanubrutinib is a safe and effective treatment option for patients with B-cell malignancies who are intolerant of other Bruton’s tyrosine kinase (BTK) inhibitors.

The ongoing, multicenter, open-label, single-arm phase 2 study aimed to assess the effect of zanubrutinib on treatment duration among patients with previously treated B-cell malignancies, including chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, or marginal zone lymphoma. The primary end point [MOU1] was recurrence and change in the severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary end points included overall response rate (ORR), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS).

The study enrolled 67[MOU2]  patients previously treated for B-cell malignancies who were either intolerant to ibrutinib (n = 57)[MOU3]  or intolerant to acalabrutinib or acalabrutinib and ibrutinib (n = 10). Patients were given zanubrutinib at 160 mg twice daily or 320 mg once daily. Analyses included all patients who received any dose of zanubrutinib.

There were a total of 115 intolerance events reported for ibrutinib and 18 reported for acalabrutnib. The majority of intolerance events (81 [70%] for ibrutinib; 15 [83%] for acalabrutinib) did not recur with utilization of zanubrutinib. Of the intolerance events that did recur, 7 (21%) of 34 for ibrutinib and 2 (67%) of 3 for acalabrutinib were of the same severity with zanubrutinib and 27 (79%) for ibrutinib and 1 (33%) for acalabrutinib were of lower severity with zanubrutinib. There were no intolerance events that occurred at a higher severity with zanubrutinib.

Safety analysis with zanubrutinib showed 64 (96%) of 67 patients experienced adverse events. The most common adverse events were contusion (22% of patients), fatigue (21%), myalgia (15%), arthralgia (13%), and diarrhea (13%). Serious adverse events were reported in 8 (12%) patients. A total of 3 patients reported grade 2 atrial fibrillation. No treatment-related deaths were reported.

A total of 64 patients were eligible for efficacy analysis. Median follow-up was 12 months. The DCR was 93.8% (95% confidence interval [CI], 84.8 to 98.3) and the ORR was 64.1% (95% CI, 51.1 to 75.7). The median duration of response was not reached. The 12-month event-free DOR rate was 95% (95% CI, 69.5 to 99.3). In addition, median PFS was not reached. The 18-month PFS was 83.8% (95% CI, 62.6 to 93.6). 

“These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib,” the authors concluded.

Source:

Shadman M, Flinn IW, Levy MY, et al. 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. The Lancet Haematol. 2023;10(1):e35-e45. doi:https://doi.org/10.1016/S2352-3026(22)00320-9