Data Suggest Next-Gen BTK Inhibitor Is More Favorable in Rare Form of NHBCL

Zanubrutinib is the latest of 3 Bruton tyrosine kinase (BTK) inhibitors approved for rare B-cell malignancies, such as Waldenström macroglobulinemia, a non-Hodgkin B-cell lymphoma (NHBCL); as a next-generation BTK inhibitor, zanubrutinib is designed to have less off-target effects.

Compared with earlier generations of Bruton tyrosine kinase (BTK) inhibitors, zanubrutinib (Brukinsa) may offer a more favorable clinical profile while lowering the economic impact of treatment for Waldenström macroglobulinemia (WM), said researchers of a recent analysis.

Zanubrutinib is the latest of 3 BTK inhibitors approved for B-cell malignancies, such as WM, along with ibrutinib and acalabrutinib. As a next-generation BTK inhibitor that is more targeted, zanubrutinib is designed to have less off-target effects. Data from the ASPEN trial, which led to zanubrutinib’s approval for WM—a rare form of non-Hodgkin B-cell lymphoma— in 2021, suggested that the treatment is more tolerable than first-generation BTK inhibitor ibrutinib.

“Great progress has been made in the treatment of patients with WM, and novel agents are still being produced to help curb the devastating effects of this disease,” commented the researchers. “With demonstrated improvements in the safety profile over ibrutinib, zanubrutinib may provide patients with flexible dosing, a better tolerated treatment option, and beneficial effects of BTK inhibition.”

Recent data coming from long-term follow-up of patients in the ASPEN trial showed that at a median of 43 months, the combined complete response (CR) rate and very good response rate (VGPR) was 36% among the 102 patients receiving zanubrutinib compared with 22% among the 99 patients receiving ibrutinib. All of these patients had the MYD88 mutation. Among the 28 patients without the mutation who received zanubrutinib, there was a combined CR and VGPR rate of 31%.

Compared with ibrutinib, zanubrutinib was associated with a higher combined CR and VGPR rate among patients who had both MYD88 and CXCR4 mutations and among patients who had the MYD88 mutation and wild-type CXCR4. There were similar safety findings among patients with and without the MYD88 mutation who received zanubrutinib.

Pulling data from the ASPEN trial, research has pointed to zanubrutinib being more cost effective than ibrutinib. The researchers of the current review explained: “A partitioned survival model was used to estimate life years, quality-adjusted life years, and costs for patients with WM treated with ibrutinib or zanubrutinib over a 30-year lifetime horizon. Patients who received zanubrutinib experienced a gain of 0.94 life years and 0.84 quality-adjusted life years, with an additional cost of $11,132. The additional cost was driven by patients experiencing a longer time to treatment failure and thus remaining on zanubrutinib longer.”

Findings from an Excel-based model showed that total direct medical costs per patient were lower for zanubrutinib compared with ibrutinib ($152,348 vs. $167,924, respectively), and zanubrutinib was also associated with a lower cost per response, which the researchers attribute to cost of the drug.

A more recent phase 2 study of 44 Chinese patients with relapsed or refractory WM showed similar efficacy findings to the initial analysis of the ASPEN trial, which showed a major response rate (MRR) of 77% among patients receiving zanubrutinib. Data from the recent phase 2 trial showed a MRR of 73% among patients with the MYD88L265P mutation a MRR of 50% among patients with MYD88WT at a median 33 months of follow-up.

Looking toward the future of BTK inhibition, the researchers emphasized the importance of combination approaches to mitigate resistance to treatment.


Muñoz J, Paludo J, Sarosiek S, Castillo J. Coming of age for BTK inhibitor therapy: A review of zanubrutinib in Waldenströmmacroglobulinemia. Cells. 2022;11(20):3287. doi:10.3390/cells11203287

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