Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study

The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88–mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7% v 22.8%), muscle spasms (28.6% v 11.9%), hypertension (25.5% v 14.9%), atrial fibrillation/flutter (23.5% v 7.9%), and pneumonia (18.4% v 5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4% v 34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib. Zanubrutinib continues to demonstrate meaningful efficacy and favorable safety in patients with WM.


INTRODUCTION
][3][4] Despite not meeting its primary end point at a median follow-up of 19.4 months in ASPEN, zanubrutinib demonstrated comparable efficacy and favorable safety compared with ibrutinib. 5With 2 years of additional follow-up in ASPEN, we present long-term efficacy and safety analyses.

METHODS
The open-label, phase III ASPEN study (ClinicalTrials.govidentifier: NCT03053440) compared ibrutinib versus zanubrutinib in patients with WM.Cohort 1 included patients with mutant myeloid differentiation primary response 88 (MYD88 MUT ) randomly assigned 1:1 to zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily; cohort 2 included patients with wild-type MYD88 (MYD88 WT ) who received zanubrutinib 160 mg twice a day. 5Study design, methods, and primary analysis results have been described. 5,6The ASPEN study was approved by the independent institutional review board or independent ethics committee at each study site and was conducted in accordance with applicable regulatory requirements, the principles of the Declaration of Helsinki, and Good Clinical Practice guidelines of the International Conference on Harmonization.All patients provided written informed consent.

Efficacy
Very good partial response (VGPR) rates increased over time and were numerically higher with zanubrutinib than ibrutinib at all time points (Fig 1A).The median time to VGPR was faster for patients on zanubrutinib (6.7 months) versus ibrutinib (16.6 months); the median time to overall (minor response or better) or major (partial response or better) responses were similar between arms.Median durations of response were not reached (Table 2).
In patients with CXCR4 MUT , higher major response rates and faster median time to response were observed with zanubrutinib versus ibrutinib (Table 2).Regardless of CXCR4 mutational status or mutation type (nonsense v frameshift), VGPR 1 complete response (CR) rates were numerically higher for zanubrutinib versus ibrutinib. 7In patients with baseline extramedullary disease, the VGPR 1 CR rate difference was 18.8% (95% CI, 2.4 to 35.1) favoring zanubrutinib, consistent with the greater median reduction observed in lymphadenopathy (65.9% v 52.5%) and splenomegaly (20.0%v 15.0%) for zanubrutinib versus ibrutinib, respectively.VGPR 1 CR rates were 36.8%versus 22.2% in patients on zanubrutinib versus ibrutinib, respectively, with zero lines of prior therapy; 36.8% versus 25.7% with one to three lines of prior therapy; 28.6% versus 28.6% with greater than three lines of prior therapy.One CR was reported (cohort 2); the VGPR 1 CR rate was 30.8% and the major response rate was 65.4% in 26 patients with confirmed MYD88 WT WM.
Any-grade AEs of diarrhea, muscle spasms, hypertension, atrial fibrillation/flutter, and pneumonia were more common with ibrutinib versus zanubrutinib; neutropenia was less common with ibrutinib versus zanubrutinib (cohort 1; Data Supplement, Tables 1 and 2).Incidences of AEs observed with zanubrutinib were similar between cohorts (Data Supplement, Table 3).More patients on ibrutinib experienced cardiovascular AEs, including one incidence of ventricular arrhythmia (Data Supplement, Table 4).
Except for neutropenia, prevalence of AEs of interest (Data Supplement, Table 5) were lower with zanubrutinib than ibrutinib at all time points (Fig 1D  7).

DISCUSSION
In ASPEN, zanubrutinib demonstrated meaningful efficacy by consistently exhibiting high-quality responses and favorable safety across 2 years of additional follow-up.High VGPR 1 CR rates observed with zanubrutinib across mutational groups also reflect a clinical benefit because achieving immunoglobulin M (IgM) reduction of >90% is associated with less IgM-related morbidity.Overall Survival Probability (%) In other studies, no patients with MYD88 WT WM achieved a major response with ibrutinib or a VGPR/CR with acalabrutinib. 8,9In the ASPEN study, 31% of patients with MYD88 WT WM achieved a VGPR/CR with zanubrutinib, including one CR, after 44-month follow-up.Furthermore, PFS and OS in patients with MYD88 WT WM in our study were compared favorably with those receiving ibrutinib 6 rituximab treatment in other studies, although all were limited by small sample size, and cross trial comparison was not possible. 10,11Our findings support zanubrutinib as the preferred treatment for patients with MYD88 WT WM.
Zanubrutinib exhibited fewer side effects associated with off-target binding, especially cardiovascular toxicities.With zanubrutinib, no cases of ventricular arrhythmia were observed; neutropenia occurred early and was neither treatment-limiting nor associated with a higher infection rate.Zanubrutinib was associated with longer treatment duration and lower risk of dose reduction or discontinuation because of AEs. 12 Patients previously intolerant to ibrutinib or acalabrutinib did not experience a recurrence of treatment-related AEs with zanubrutinib. 12udy limitations include an open-label design, unknown CXCR4 mutational status, and more patients with CXCR4 mutations randomly assigned to zanubrutinib versus ibrutinib (cohort 1), all of which may have influenced the VGPR 1 CR rates observed.VGPR 1 CR rate was chosen as the primary end point for this study because of the prolonged responses and infrequent PFS/OS events expected and because response rates and depth of response are associated with PFS and time to next treatment in patients with WM. [13][14][15] Although potential false negatives may have occurred because of assay sensitivity or lower bone marrow disease involvement in patients with MYD88 WT WM, the assay was sufficient for detection congruent with expected mutation rates. 16Potential associations between CXCR4 nonsense versus frameshift mutations and treatment outcomes were evaluated (manuscript in preparation).
Extended follow-up results confirm improved long-term safety and tolerability of zanubrutinib compared with ibrutinib and support deeper, earlier, and more durable responses in patients with WM regardless of previous treatment or CXCR4 and MYD88 mutational statuses.

TABLE 1 .
Patient Baseline Characteristics a Assessed by investigator.b Confirmatory genotyping by NGS was performed for ad hoc analyses.Nineteen patients (11 in cohort 1, two in cohort 2) had unknown CXCR4 mutation status because of withdrawal of consent (one), quality control failure (nine), or sample not collected (nine); two patients in cohort 2 had unknown MYD88 mutation status because of insufficient sample.

TABLE 2 .
Overall and Mutational Efficacy Outcomes as Assessed by Investigator With Zanubrutinib and Ibrutinib in Cohorts 1 and 2
a Discontinued before first assessment.b Median follow-up time estimated by reverse Kaplan-Meier method for VGPR 1