ASPEN: Comparing Zanubrutinib With Ibrutinib in Waldenström Macroglobulinemia

Treatment with the selective Bruton tyrosine kinase (BTK) inhibitor zanubrutinib resulted in a higher combined complete response (CR) and very good partial response (VGPR) rate than therapy with the first-generation BTK inhibitor ibrutinib in patients with Waldenström macroglobulinemia (WM), according to findings from the phase III ASPEN trial. Trial results were first reported at the 2019 American Society of Hematology (ASH) Annual Meeting; the updated data included an additional 5 months of follow-up.

Study author Constantine Tam, MD, of the Peter MacCallum Cancer Center in Melbourne, Australia, who presented the findings of this trial as part of the ASCO20 Virtual Scientific Program, said, “Compared with other therapies, zanubrutinib’s ability to be selective against a panel of target enzymes provides the opportunity to inhibit BTK with reduced side effects.”

ASPEN enrolled 201 patients with WM and a MYD88 mutation (MYD88MUT WM) and 28 patients with wild-type MYD88 WM (MYD88WT WM). Patients with MYD88MUT were randomized to either twice-daily zanubrutinib 160 mg (n=102) or once-daily ibrutinib 420 mg (n=99). Randomization was stratified by CXCR4 status (CXCR4WHIM vs. CXCR4WT vs. missing) and number of prior lines of therapy (0 vs. 1-3 vs. >3). The 28 patients with MYD88WT WM were not randomized, but were treated with twice-daily zanubrutinib 160 mg, since ibrutinib has little efficacy in MYD88WT WM. Treatments were administered until disease progressed or adverse effects (AEs) became intolerable.

Efficacy was determined by the proportion of patients who achieved either a CR or VGPR during treatment, which was the primary endpoint. The trial also assessed the incidence, duration, and severity of treatment-emergent AEs.

In both the zanubrutinib and ibrutinib groups, the median age was 70 years (range = 38-90). A higher proportion of patients in the zanubrutinib group were >75 years of age (33% vs. 22%). Most patients within both the zanubrutinib and ibrutinib treatment arms entered the trial having received 1 to 3 prior lines of therapy (74.5% vs. 74.7%, respectively). A higher proportion of patients in the zanubrutinib arm (65.7%) had a hemoglobin level of ≤11 g/dL, compared to 53.5% of patients in the ibrutinib group.

Treatment with zanubrutinib was associated with fewer discontinuations than treatment with ibrutinib (n=4 vs. n=9, respectively) and fewer deaths were attributed to AEs (n=1 vs. n=4). A lower proportion of zanubrutinib-treated patients experienced an AE that led to dose reductions (13.9% vs. 23.5%) or doses being held (46.5% vs. 56.1%). In contrast, neutropenia was more common with zanubrutinib compared to ibrutinib (all-grade events, 25% vs. 12%, respectively).

Atrial fibrillation/flutter was significantly higher for ibrutinib than zanubrutinib (15.3% vs. 2%, respectively; p<0.05). Dr. Tam noted that with prolonged therapy, ibrutinib may be associated with higher cardiovascular toxicity than zanubrutinib.

With a median follow-up of 19.4 months, the CR+VGPR rate in the intention-to-treat (ITT) population, as assessed by an independent review committee (IRC), was higher with zanubrutinib than ibrutinib (28.4% vs. 19.2%, respectively; p=0.09). The investigator-assessed CR+VGPR rate for zanubrutinib was the same as the IRC assessed rate (28.4%) but was slightly lower for ibrutinib (17.4%), so for this comparison a 2-sided descriptive p value did achieve statistical significance (p=0.04). The major response rate, which also includes partial responses in addition to CR and VGPR, was roughly equal between groups (zanubrutinib: 77.5% vs. ibrutinib: 77.8%).

Dr. Tam added that the rates of progression-free survival (PFS) at 12 months were excellent for both zanubrutinib and ibrutinib (89.7% and 87.2%, respectively). So far, he added, there have been no differences between the treatment groups in terms of overall survival (OS). The 12-month OS rates were 97% for zanubrutinib and 93.9% for ibrutinib. The quality of life (QoL) responses were improved in both treatment arms, but QoL appeared better in the zanubrutinib group.

In the MYD88WT group, the major response rate with zanubrutinib was 50% and the VGPR rate was 26.9%; CRs were not observed. PFS at 12 months was 72%.

“True to our study hypothesis,” said Dr. Tam, “zanubrutinib, being a more targeted drug, may be associated with fewer side effects and better tolerability.”

The authors disclosed interests with BeiGene, which funded the study.


Tam C, Opat S, D’Sa S, et al. ASPEN: Results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). J Clin Oncol 38: 2020 (suppl; abstr 8007) Presented as part of the ASCO20 Virtual Scientific Program. May 29-31, 2020.