Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up

Abstract

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n = 50) or 320 mg once daily (n = 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Conflict of interest statement

Conflict-of-interest disclosure: J.T. receives research funding from BeiGene, Janssen, Celgene, Pharmacyclics, and Roche. S.O. consults for AbbVie, Janssen, Gilead, Roche, Mundipharma, Merck, BMS, and Celgene; receives research funding from AbbVie, BeiGene, Janssen, Gilead, Roche, Celgene, and Epizyme; and receives honoraria from AbbVie, Janssen, Gilead, Roche, Mundipharma, Merck, BMS, and Celgene. D.G. is an employee of the University of Sydney; consults for Novartis, Gilead, AbbVie, and Merck; receives research funding from Haemalogix P/L; and serves on advisory committees for Haemalogix P/L. D.S. receives research funding from Amgen, BeiGene, AbbVie, Roche, Celgene, MSD, Acerta, Pharmacyclics, Sanofi, and Glaxo-Smith-Kline and receives honoraria from Janssen, Roche, and AbbVie. P.M. receives honoraria from Celgene, Roche, and AbbVie and serves on advisory committees for AbbVie, Roche, Novartis, Janssen, Astellas, and Celgene. G.C. receives travel, accommodations, and expenses from Amgen, Glycomimetics, and AbbVie. J.M. consults for Pharmacyclics, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, BeiGene, and Seattle Genetics; receives research funding from Kite Pharma, Celgene, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, and Janssen; receives honoraria from Kyowa and Seattle Genetics; and participates in a speakers bureau for BeiGene, Kite Pharma, Gilead, Fosunkite, Kyowa, Bayer, Pharmacyclics, and AstraZeneca. A.T. receives honoraria from BeiGene, participates in a speakers bureau for Janssen Cilag SpA, and serves on advisory committees for Janssen Cilag SpA, Sunesis, and Astra Zeneca. A.W.R. receives research funding from AbbVie and Janssen and receives royalties from Walter and Eliza Hall Institute. J.F.S. consults for Roche; receives research funding from AbbVie, Celgene, Janssen, and Roche; receives honoraria from AbbVie, Acerta, Celgene, Gilead, Janssen, Roche, and Takeda; participates in a speakers bureau for AbbVie and Roche; and serves on advisory committees for AbbVie, Acerta, Celgene, Gilead, Janssen, Roche, and Takeda. S.K.A., E.H., Z.T., Y.Y., W.N., J.D.H., and J.H. are employees of and have equity ownership in BeiGene. C.S.T. receives research funding from Janssen and AbbVie and receives honoraria from Janssen, AbbVie, BeiGene, Novartis, and Roche.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Best overall response by MYD88/CXCR4 genotype. For efficacy-evaluable patients with tumors harboring the MYD88L265P mutation, best response is reported separately for those with CXCR4WT disease and those with an accompanying CXCR4WHIM mutation. No genotype data were available for 8 patients. The CXCR4 genotype is unknown (CXCR4UNK) for an additional 7 patients with MYD88L265P disease.

Figure 2.

Waterfall plot of maximal percentage of IgM reductions and corresponding best overall response. Patients included are those who received ≥1 dose of zanubrutinib, had no prior BTK inhibitor exposure, and had baseline IgM or M-paraprotein ≥5 g/L. Only patients with data at both baseline and any postbaseline visits are included. If the nephelometric IgM test result was missing at baseline, the M-paraprotein result by SPEP was used throughout and summarized together with nephelometric IgM test results for this endpoint.

Figure 3.

Kaplan-Meier plots of PFS. PFS for TN (A) and R/R (B) patients is shown. Gray areas indicate 95% CIs.