A Phase II Trial of the Bruton Tyrosine-Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Relapsed/Refractory Waldenström Macroglobulinemia

Gang An, Daobin Zhou, Shu Cheng, Keshu Zhou, Jianyong Li, Jianfeng Zhou, Liping Xie, Jie Jin, Liye Zhong, Lingzhi Yan, Haiyi Guo, Chenmu Du, Jinhua Zhong, Yiling Yu, Binghao Wu, Lugui Qiu, Gang An, Daobin Zhou, Shu Cheng, Keshu Zhou, Jianyong Li, Jianfeng Zhou, Liping Xie, Jie Jin, Liye Zhong, Lingzhi Yan, Haiyi Guo, Chenmu Du, Jinhua Zhong, Yiling Yu, Binghao Wu, Lugui Qiu

Abstract

Purpose: Although Bruton tyrosine kinase (BTK) inhibitors have demonstrated promising efficacy in patients with Waldenström macroglobulinemia (WM), data in Asian populations are scarce. This trial is the first to investigate the effect of a BTK inhibitor in Chinese patients with relapsed/refractory (R/R) WM.

Patients and methods: Patients with R/R WM with at least one prior regimen were enrolled into this single-arm, multicenter, phase II study (NCT03332173) and received zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR), as assessed by an independent review committee. Secondary endpoints included progression-free survival, overall response rate, duration of major response, and safety.

Results: Forty-four patients were enrolled. After a median follow-up of 33.0 (range, 3.2-36.5) months, MRR in all patients was 69.8%, with very good partial response or better in 32.6% of patients. All mutation groups benefited from zanubrutinib treatment (MRR in patients with MYD88 L265P mutation, 73%; MRR in patients with MYD88 wild type mutation, 50%). A higher response rate was seen in the MYD88 L265P/CXCR4 WT population, compared with the other populations. Median progression-free survival and median duration of major response were not reached. The most frequently reported grade ≥3 treatment-emergent adverse events (AEs) were neutrophil count decreased (31.8%), and platelet count decreased and pneumonia (20.5% each). No case of atrial fibrillation/flutter occurred.

Conclusions: Zanubrutinib achieved a high rate of response that was durable and deep in patients with R/R WM across all subgroups, and potentially confers a positive benefit-risk profile for WM.

©2021 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Kaplan–Meier plots of survival in Chinese patients with R/R WM receiving zanubrutinib. A, PFS as assessed by the investigator. B, PFS by genotype as assessed by the investigator. C, PFS for major responders, as assessed by the investigator. D, CI, confidence interval; CXCR4, C-X-C motif chemokine receptor 4; MYD88, myeloid differentiation primary response gene 88; OS, overall survival; PFS, progression-free survival; R/R, relapsed refractory; WM, Waldenström macroglobulinemia; WT, wild-type; WHIM, warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome.
Figure 2.
Figure 2.
Disposition of patients receiving zanubrutinib (median follow-up, 33.0 months). aOne patient discontinued study treatment and subsequently died due to ‘progression of WM’ that was reported as an AE. bThe patient achieved MR and was discontinued per the investigator's discretion. AE, adverse event; MR, minor response; WM, Waldenström macroglobulinemia; PD, progressive disease.
Figure 3.
Figure 3.
Genetic variants in three progressive disease samples in Chinese patients with R/R WM. Abbreviations: BOR, best overall response; BOR, best overall response; CXCR4, C-X-C motif chemokine receptor 4; MYD88, myeloid differentiation primary response gene 88; R/R, relapsed/refractory; WM, Waldenström macroglobulinemia; PD, progressive disease; PFS, progression-free survival.

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Source: PubMed

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