Zanubrutinib versus ibrutinib in Waldenström macroglobulinaemia

Zanubrutinib demonstrated a non-significant improvement in response rate and lower rates of several adverse events compared with ibrutinib in patients with Waldenström macroglobulinaemia (WM).

In the phase 3 ASPEN trial, presented by Prof. Meletios Dimopoulos (University of Athens, Greece), treatment with the two Bruton's tyrosine kinase (BTK) inhibitors, zanubrutinib and ibrutinib, was compared head-to-head in patients with WM [1]. Zanubrutinib has greater selectivity for BTK inhibition when compared with ibrutinib, which has off-target effects on expression of EGFR, FGR, FRK, HER2, HER4, ITK, JAK 3, LCK and TEC, which, for example, are thought to exacerbate diarrhoea, thrombocytopenia, bleeding, atrial fibrillation, rash and fatigue [2].

ASPEN enrolled 201 WM patients with a confirmed MYD88 mutation, and 28 patients with wildtype MYD88. WM patients with MYD88 mutation were randomised to either twice-daily zanubrutinib 160 mg (n=102) or once-daily ibrutinib 420 mg (n=99). The 28 patients without MYD88 mutations were included as a separate cohort and treated with the zanubrutinib regimenand analysed separately, because ibrutinib is known to be ineffective in these patients. The primary endpoint of this study was the proportion of participants achieving either a complete response (CR) or very good partial response (VGPR). Safety was the key secondary endpoint.

Although the median age in both groups was 70 years (range=38-90), more patients in the zanubrutinib group were >75 years of age (33% vs 22%). In both arms, most patients enrolled had had 1-3 prior lines of prior therapy (75% in both arms). A higher proportion of patients in the zanubrutinib arm (65.7%) had a haemoglobin level of ≤11 g/dL, compared to 53.5% of patients in the ibrutinib group.

With a median follow-up of 19.4 months, the CR+VGPR rate, as assessed by an independent review committee, was insignificantly higher with zanubrutinib than ibrutinib (28.4% vs 19.2%, respectively; P=0.09). Including partial responses to the CR/VGPR rates generated comparable major response rates (zanubrutinib: 77.5% vs ibrutinib: 77.8%). Progression-free survival (PFS) at 12 months was similar for both zanubrutinib and ibrutinib (89.7% and 87.2%, respectively). Likewise, overall survival data was similar; the 12-month rates were 97% for zanubrutinib and 93.9% for ibrutinib. The quality of life responses were somewhat better in the zanubrutinib group. In the 28 patients with wild-type MYD88, the major response rate with zanubrutinib was 50% and the VGPR rate was 26.9%. There were no CRs observed. PFS at 12 months was 72%.

With regard to safety, fewer trial discontinuations were reported in the zanubrutinib arm than the ibrutinib arm (4 vs 9, respectively). Zanubrutinib also appeared to be more tolerable; 13.9% of zanubrutinib- versus 23.5% of ibrutinib-treated patients required dose reductions or doses being withheld (46.5% vs 56.1%, respectively). Of note, neutropenia was more common with zanubrutinib compared with ibrutinib (all-grade events: 25% vs 12%, respectively). Atrial fibrillation was significantly higher for ibrutinib than zanubrutinib (15.3% vs 2%, respectively; P<0.05).

In conclusion, there was a numerical but statistically insignificant improvement in the CR+VGPR rate in WM patients with MYD88 mutation receiving zanubrutinib compared with ibrutinib, but the benefit was extended by the better safety profile seen in the zanubrutinib group. For WM patients with wildtype MYD88, some benefit was also observed for zanubrutinib.

1. 
   
   1. Dimopoulos M, et al. ASPEN: results of a phase 3 randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). EHA25 Virtual, 11-21 June 2020, Abstract S225.
   2. Tam CS et al. Phase 1 study of selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood 2019;134(11):851–859.

Posted on 9 September 20206 September 2023