Pivotal Trial Underway for Zanubrutinib in Waldenström Macroglobulinemia

A head-to-head, open-label, multicenter, phase 3 clinical trial comparing the efficacy and safety of zanubrutinib (BGB-3111) with ibrutinib in patients with Waldenström macroglobulinemia (WM) is underway (ClinicalTrials.org Identifier: NCT03053440).¹ The study also seeks to evaluate the effects of CXCR4 and MYD88 mutations on patient response rates and survival outcomes.

Zanubrutinib is an investigational oral Bruton tyrosine kinase inhibitor that was granted fast track designation by the US Food and Drug Administration in July 2018 for the treatment of patients with WM.² Information about the progress of the trial, which is being sponsored by BeiGene, was published in Future Oncology.

Study investigators began enrolling WM patients in 2017 from approximately 80 sites across the European Union, Asia-Pacific and North America. Enrollment has since been completed, according to a BeiGene statement.² Enrolled patients will be assigned to 1 of 2 cohorts depending on MYD88 mutation status.

Cohort 1 will have at least 150 relapsed/refractory patients and approximately 38 treatment-naive patients, all of which are positive for MYD88^MUT. Patients in cohort 1 will be randomized in a 1:1 fashion to arm A or arm B. Patients in arm A will receive zanubrutinib 160 mg twice daily until disease progression. Patients in arm B will receive ibrutinib 420 mg once daily until disease progression.

Cohort 2 will have approximately 22 patients within the genomic subtype MYD88^WT group who are relapsed/refractory or treatment-naive. Patients in cohort 2 will effectively serve as a third arm, arm C, and will receive zanubrutinib 160 mg twice daily until disease progression. Patients will be stratified by number of prior lines of therapy and CXCR4 mutation status (CXCR4^WHIM vs CXCR4^WT).

The primary end point for the trial is complete response or very good partial response rates in cohort 1. Secondary end points include adverse events, major response rate, duration of response, and progression-free survival in cohort 1. An exploratory analysis will be done in patients with MYD88^WT across cohort 2 to assess the safety, efficacy, and pharmacokinetic profile of zanubrutinib — and investigators also plan to track quality-of-life measures from patient reports.

References

1. Tam CS, LeBlond V, Novotny, et al. A head-to-head phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia. Future Oncol. 2018;14(22):2229-2237.
2. BeiGene announces plan to pursue Accelerated Approval in the U.S. of BTK inhibitor zanubrutinib in Waldenström macroglobulinemia (WM) [news release]. Cambridge, MA and Beijing, China: BeiGene, Ltd.; July 22, 2018. http://ir.beigene.com/phoenix.zhtml?c=254246&p=irol-newsArticle&ID=2359338. Accessed September 20, 2018.