Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma

Abstract

Zanubrutinib, a highly selective Bruton tyrosine kinase inhibitor, was evaluated in a phase 1/2 study in patients with various B-cell malignancies. In the subgroup of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), zanubrutinib was administered as 160 mg twice daily (n = 14), 320 mg once daily (n = 18), or ≤160 mg total dose (n = 5). Herein, we report results for patients receiving a total daily dose of 320 mg (N = 32). Median study follow-up was 18.8 months. Eighteen patients discontinued treatment, 10 because of progressive disease and 8 because of adverse events (AEs); 1 AE (peripheral edema) was considered to be related to zanubrutinib treatment. The most common AEs were diarrhea (43.8%), contusion (37.5%), constipation (31.3%), and upper respiratory tract infection (31.3%). Infection was the most commonly reported AE of interest (18.8% of patients experienced grade ≥3 infection). At least 1 AE of grade ≥3 was reported in 59.4% of patients; grade ≥3 AEs that were reported in >2 patients were anemia (12.5%), pneumonia (9.4%), and myalgia (9.4%). Overall response rate was 84%, with 25% achieving a complete response. Median duration of response was 18.5 months. Median progression-free survival (PFS) was 21.1 months. Zanubrutinib was well tolerated and demonstrated activity in patients with R/R MCL. The trial is registered at www.clinicaltrials.gov as #NCT02343120.

Conflict of interest statement

Conflict-of-interest disclosure: C.S.T. receives research funding from Janssen and AbbVie and honoraria from Janssen, AbbVie, BeiGene, Novartis, and Roche. S.O. has acted as a consultant/advisor for AbbVie, Janssen, Gilead, Roche, Mundipharma, Merck, Bristol Myers Squibb, and Celgene; has received research funding from AbbVie, BeiGene, Janssen, Gilead, Roche, Celgene, and Epizyme; and has received honoraria from AbbVie, Janssen, Gilead, Roche, Mundipharma, Merck, Bristol Myers Squibb, and Celgene. D.S. is an employee of and has equity ownership in BeiGene; has received honoraria from AbbVie, Janssen, and Roche; has received research funding from AbbVie, Amgen, BeiGene, Celgene, Roche, MSD, Acerta, Pharmacyclics, Sanofi, and GSK; and has received travel expenses from AbbVie. G.C. has received research funding from BeiGene, Acerta, and Glycomimetics. J.M. has received honoraria from Kyowa and Seattle Genetics; has acted as a consultant/advisor for Pharmacyclics, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa, Alexion, BeiGene, Fosunkite, Innovent, and Seattle Genetics; has been a member of the speakers’ bureau for Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech, BeiGene, and Verastem; and has received research funding from Kite Pharma, Celgene, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium. T.J.P. has acted as a consultant/advisor for Bayer, Gilead, Seattle Genetics, Genentech, Incyte, and Pharmacyclics and has received research funding from Pharmacyclics and AbbVie. W.S.K. has received research funding from Roche, Takeda, Mundipharma, J&J, Celltrion, Kyowa Kirin, and Donga. S.R. has received research funding from Janssen and has acted as a consultant/advisor for Janssen, Kite, Sunesis, AstraZeneca, and Roche. S.K.A. is an employee of and has equity ownership in BeiGene. R.W. is an employee of and has equity ownership in BeiGene. W.N. is an employee of and has equity ownership in BeiGene. J.H. is an employee of, has a leadership role with, and has equity ownership in BeiGene. M.W. has equity ownership in MORE Health; has received honoraria from Pharmacyclics, Janssen, AstraZeneca, OMI, Targeted Oncology, and OncLive; has acted as a consultant/advisor for Pharmacyclics, Celgene, Janssen, AstraZeneca, MORE Health, Pulse Biosciences, Nobel Insights, Guidepoint Global, Kite Pharma, Juno, Celgene, and Loxo Oncology; has received research funding from Pharmacyclics, Janssen, AstraZeneca, Kite Pharma, Juno, Celgene, Loxo Oncology, VelosBio, and Verastem; and has received travel expenses from Janssen, Pharmacyclics, Celgene, OMI, Kite Pharma, and AstraZeneca. J.T. has received research funding from BeiGene, Roche, Pharmacyclics, Celgene, and Takeda.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Forest plot of ORR by IRC assessment (N = 32).a2-sided Clopper-Pearson 95% confidence intervals. bMIPI score was calculated with cutoffs as low (<5.7), intermediate (5.7 to <6.2), and high (≥6.2). cDerived from baseline tumor biopsy/aspiration per investigator assessment. dExtranodal disease is defined as patients with extranodal baseline target or nontarget lesions, or bone marrow involvement by biopsy per investigator assessment. eRefractory disease is defined as best overall response of stable disease or progressive disease from last prior anti-cancer treatment regimen. Hyper-CVAD, cyclophosphamide, vincristine, doxorubicin, cytarabine, methotrexate, and Ara C; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; LDi, longest transverse diameter of a lesion; MIPI, MCL International Prognostic Index.

Figure 2.

Best percentage change from baseline in target lesion sum of the products of target lesion perpendicular diameters (SPDs) by overall response assessed by IRC (N = 32).

Figure 3.

Duration of response, progression-free survival, and overall survival probability. (A) IRC-assessed DOR in patients with CR or PR (n = 27). PFS (B) and OS (C) in the safety population (N = 32). The gray shaded areas are 95% CI for the KM curve.