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Zanubrutinib induces high rates of high-quality responses in patients with Waldenström macroglobulinemia and MYD88 mutations

The ASPEN study is an open-label, randomised head-to-head study that compares the efficacy and safety of the Bruton's Tyrosine Kinase (BTK) inhibitors zanubrutinib and ibrutinib in patients with Waldenström's macroglobulinemia who require therapy. Results of this trial, presented at EHA 2020, indicate that, although not significant, zanubrutinib was associated with a higher rate of complete and very good partial responses in this setting. In addition, zanubrutinib also demonstrated clinically meaningful advantages in safety and tolerability over ibrutinib.


In recent years, BTK inhibition emerged as the new standard of care for patients with Waldenström macroglobulinemia (WM). Currently, the first-generation BTK inhibitor ibrutinib is approved for all lines of therapy for these patients. However, treatment-associated toxicity and resistance to ibrutinib have exposed the need for second-generation inhibitors. Zanubrutinib is an investigational, next-generation BTK inhibitor that is specifically designed to maximize BTK occupancy and minimize off-target inhibition of TEC-and EGFR-family kinases.

In the randomised, phase III ASPEN trial, WM patients harbouring a MYD88 mutation were randomly assigned (1:1) to receive either zanubrutinib (N=102, 160 mg twice daily) or ibrutinib (N=99, 420 mg once daily). Patients without MYD88 mutation (N=28) were assigned to a separate cohort, where they received zanubrutinib. Results of this cohort will be reported separately. Randomisation was stratified by CXCR4 mutational status and the number of prior treatment lines (0 versus 1-3 versus >3). The primary endpoint of the ASPEN trial was the proportion of patients achieving a complete response or very good partial response (CR+VGPR) as assessed by an independent review committee.


In total, 201 patients were randomised from January 2017 to July 2018. Of the 98 patients in the ibrutinib arm and 101 patients in the zanubrutinib arm who were treated, 77.8% and 79.4% respectively remained on study treatment after a median follow-up of 19.4 months. While the treatment groups were generally well balanced for important baseline factors, patients in the zanubrutinib arm were more likely to be older (aged >75 years: 33.3% versus 22.2%) and more frequently suffered from anaemia (haemoglobin ≤ 11g/dL) (65.7% versus. 53.5%). At a median follow-up of 19.4 months, the rate of CR+VGPR as assessed by an independent review committee was 28.4% with zanubrutinib as compared to 19.2% with ibrutinib. However, this 10.2% difference did not meet the criteria for statistical significance (2-sided p=0.0921). When responses were assessed according to the investigator, the difference in VGPR rate did cross the boundary for significance (30.4% versus 18.2%, p=0.0302). In addition, also the area under the curve (AUC) for a reduction in IgM over time was significantly greater for zanubrutinib versus ibrutinib (p=0.037). Landmark analysis at 12 months also showed a trend towards a better progression-free (89.7% versus 87.2%) and overall survival (97.0% versus 93.9%) with zanubrutinib.

Finally, zanubrutinib demonstrated clinically meaningful advantages in safety and tolerability. In fact, there was a reduction in the risk of atrial fibrillation/flutter (2.0% vs. 15.3%, p= 0.0008) with zanubrutinib and this drug was also associated with lower rates of major bleeding (5.9% vs. 9.2%), diarrhoea (20.8% vs. 31.6%) and hypertension (10.9% vs. 17.3%). There was no difference in the rate of infection (17.8% vs. 19.4%), despite higher rates of neutropenia with zanubrutinib. Fewer adverse events in the zanubrutinib arm lead to death (4.1% vs. 1.0%), treatment discontinuation (9.2% vs. 4.0%), dose reduction (23.5% vs. 13.9%) or dose interruption (56.1% vs. 46.5%). Both drugs were associated with a substantial improvement in quality of life. However, this was mainly the case for patients experiencing a deep response to therapy and this proportion was larger with zanubrutinib than with ibrutinib.


Although the ASPEN trial did not meet its primary endpoint of a statistically superior rate of CR+VGPR with zanubrutinib compared to ibrutinib, zanubrutinib was associated with a 10% higher rate of CR+VGPR (28.4% versus 19.2%) compared to ibrutinib. In addition, a deeper and sustained IgM reduction over time was reported with this second-generation BTK inhibitor and zanubrutinib also showed signals for a better PFS, OS and quality of life compared to ibrutinib.

Last but not least, zanubrutinib demonstrated clinically meaningful advantages in safety and tolerability over ibrutinib. These findings warrant further studies with this agent in patients with WM to potentially challenge ibrutinib as a standard of care in this setting.


Dimopoulos M, Opat S, D’Sa S, et al. ASPEN: Results of a phase 3 randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström Macroglobulinemia (WM). Presented at EHA 2020; Abstract S225.

Speaker M. Dimopoulos


M. Dimopoulos, MD, PhD, National and Kapodistrian University of Athens, Athens, Greece


See: Keyslides


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