Zanubrutinib Bests Ibrutinib in Waldenström Macroglobulinemia

Meletios A. Dimopoulos, MD

Patients with symptomatic Waldenström macroglobulinemia (WM) achieved superior responses with Zanubrutinib (Brukinsa) compared with ibrutinib (Imbruvica), according to a final analysis of the phase 3 ASPEN study (NCT03053440), which was published in the Journal of Clinical Oncology.

At a median follow-up of 44.4 months (range, 0.4-57.3), patients in cohort 1 with MYD88-mutated WM who received ibrutinib (n = 99) or zanubrutinib (n = 102) achieved a very good partial response (VGPR) plus complete response (CR) rate of 25.3% (95% CI, 17.1%-35.0%) vs 36.3% (95% CI, 27.0%-46.4%), respectively, with no CRs (P = .07). The median times to VGPR plus CR response were 16.59 months vs 6.67 months. Patients also experienced a major response rate of 79.8% (95% CI, 70.5%-87.2%) with ibrutinib vs 81.4% (95% CI, 72.4%-88.4%) with zanubrutinib. The overall response rate (ORR) was 93.9% (95% CI, 87.3%-97.7%) for ibrutinib compared with 95.1% (95% CI, 88.9%-98.4%) for zanubrutinib.

Patients with CXCR4 mutations in cohort 1 receiving ibrutinib (n = 20) and zanubrutinib (n = 23) experienced a VGPR plus CR rate of 10.0% (95% CI, 1.2%-31.7%) vs 21.2% (95% CI, 9.0%-38.9%), respectively, with no CRs in either group (P = .35). The median time to VGPR plus CR was 31.31 months vs 11.10 months. The major response rate was 65.0% (95% CI, 40.8%-84.6%) in the ibrutinib arm vs 78.8% (95% CI, 61.1%-91.0%) in the zanubrutinib arm. The ORRs were 95.0% (95% CI, 75.1%-99.9%) compared with 90.9% (95% CI, 75.7%-98.1%) for ibrutinib and zanubrutinib.

Patients with CXCR4 wild-type disease treated with ibrutinib (n = 72) and zanubrutinib (n = 65) experienced a VGPR plus CR rate of 30.6% (95% CI, 20.2%-42.5%) vs 44.6% (95% CI, 32.3%-57.5%), respectively (P = .10), with a median time to response of 11.33 months vs 6.51 months. There were no CRs, and the ORRs were 94.4% (95% CI, 86.4%-98.5%) vs 96.9% (95% CI, 89.3%-99.6%). Patients also experienced a major response rate of 84.7% (95% CI, 74.3%-92.1%) with ibrutinib vs 83.1% (95% CI, 71.7%-91.2%) with zanubrutinib.

In open-label, phase 3 study, patients with MYD88-mutated WM were enrolled into cohort 1 and randomly assigned 1:1 to receive 160 mg of zanubrutinib twice per day or 420 mg of ibrutinib once per day. Patients with MYD88 wild-type WM were assigned to cohort 2 and received 160 mg of zanubrutinib twice per day.

Baseline characteristics were generally well balanced among arms with a median age of 70 years (range, 38-90) vs 70 years (range, 45-87) among those receiving ibrutinib and zanubrutinib in cohort 1, respectively, and 72 years (range, 39-87) in cohort 2. The rates of patients in each arm who received 1 to 3 prior lines of therapy were 74.7%, 74.5%, and 71.4%.

Results from Cohort 2

Patients in cohort 2 with MYD88 wild-type disease (n = 26) were treated only with zanubrutinib and received the agent for a median duration of 30.03 months (range, 1.4-49.0) with a relative dose intensity of 96.89%. One patient experienced a CR, and the VGPR plus CR rate was 30.8% (95% CI, 14.3%-51.8%). The median DOR of VGPR plus CR was not evaluable (NE; range, 13.8 to 44.1+), and the 24- and 42-month event-free rates were both 60.0% (95% CI, 19.5%-85.2%). The ORR was 80.8% (95% CI, 60.6%-93.4%), and patients experienced a major response rate of 65.4% (95% CI, 44.3%-82.8%) with a median duration of major response of 23.7 months (range, 0.0+ to 44.1+) and a 42-month event-free rate of 42.2% (95% CI, 18.1%-64.6%).

The median PFS was 45.8 months (range, 1.6 to 47.0+) with a 42-month PFS rate of 53.8% (95% CI, 33.3%-70.6%). The median OS was NE (range, 2.3 to 53.7+) with a 42-month OS rate of 83.9% (95% CI, 62.6%-93.7%).

Additional Results from Cohort 1

Although the median DOR of VGPR plus CR was NE for the overall populations in both arms of cohort 1, the 24- and 42-month event-free rates were 79.3% (95% CI, 53.5%-91.8%) and 72.7% (95% CI, 45.7%-87.9%) in the ibrutinib arm compared with 90.6% (95% CI, 73.6%-96.9%) and 81.7% (95% CI, 60.9%-92.1%) in the zanubrutinib arm, respectively. The median duration of major responses was NE in both groups; however, the 42-month event-free rate was 74.9% (95% CI, 62.4%-83.7%) in the ibrutinib arm vs 80.7% (95% CI, 69.5%-88.1%) in the zanubrutinib arm.

Furthermore, the PFS event rate in the ibrutinib arm was 30.3% vs 19.6% in the zanubrutinib arm (HR, 0.63; 95% CI, 0.36-1.12; P = .12), The median PFS was NE (range, 0.0+ to 55.4+) and the 42-month PFS rates were 69.7% (95% CI, 58.9%-78.2%) for ibrutinib vs 78.3% (95% CI, 68.4%-85.5%) for zanubrutinib. The OS event rate in the ibrutinib arm was 17.2% vs 11.8% in the zanubrutinib arm (HR, 0.75; 95% CI, 0.36-1.59; P = .45). The median OS was NE (range, 0.5 to 57.1+) vs NE (range, 0.4+ to 57.3+), respectively, and the 42-month OS rates were 85.2% (95% CI, 76.3%-91.0%) vs 87.5% (95% CI, 79.0%-92.7%).

Further, the median duration of treatment was 42.23 months (range, 0.3-57.0) for ibrutinib vs 43.37 months (range, 0.8-57.2) for zanubrutinib, and the relative dose intensity was 96.98% vs 98.20%, respectively.

In patients with CXCR4 mutations in cohort 1, the median DOR of VGPR plus CR was 23.2 months (range, 1.0+ to 23.2) in the ibrutinib arm vs NE (range, 14.1 to 43.3+) in the zanubrutinib group, with 24- and 42-month event-free rates of 0.0% (95% CI, NE-NE) and 0.0% (95% CI, NE-NE) in the ibrutinib arm vs 85.7% (95% CI, 33.4%-97.9%) and 64.3% (95% CI, 15.1%-90.2%) in the zanubrutinib arm, respectively. Additionally, the median duration of major responses was 38.6 months (range, 1.91-47.01) in the ibrutinib group vs NE (range, 0.01-50.81) in the zanubrutinib group with 42-month event-free rates of 38.9% (95% CI, 7.2%-71.2%) vs 70.4% (95% CI, 45.2%-85.7%).

Moreover, the PFS event rate was 55% in the ibrutinib arm compared with 24.2% in the zanubrutinib arm (HR, 0.5; 95% CI, 0.20-1.29; P = .12). The median PFS was 39.8 months (range, 0.4 to 49.8+) vs NE (range, 2.0+ to 55.1+), respectively. The 42-month PFS rates were 49.0% (95% CI, 24.5%-69.7%) for ibrutinib compared with 73.2% (95% CI, 53.3%-85.6%) for zanubrutinib. The OS event rate was 30.0% in the ibrutinib arm compared with 15.2% in the zanubrutinib arm (HR, 0.54; 95% CI, 0.16-1.81; P = .32); the median OS was 48.2 months (range, 0.5 to 50.4+) vs NE (range, 4.0+ to 57.3+) with 42-month OS rates of 78.8% (95% CI, 52.7%-91.5%) vs 84.2% (95% CI, 66.0%-93.1%).

Further, the median duration of treatment was 39.64 months (range, 0.3-50.3) vs 44.75 months (range, 1.7-57.2) and relative dose intensity was 94.47% compared with 97.44%, in the ibrutinib and zanubrutinib arms, respectively.

In patients with CXCR4 wild-type disease treated in cohort 1, the median duration of treatment was 43.40 months (range, 0.5-57.0) compared with 42.43 months (range, 0.8-54.4) in the ibrutinib and zanubrutinib arms, respectively, and relative dose intensity was 97.58% vs 98.35%,.

The median duration of VGPR plus CR was NE in both arms, with 24- and 42-month event-free rates of 83.9% (95% CI, 57.9%-94.5) and 76.9% (95% CI, 49.0%-90.8%) in the ibrutinib arm compared with 91.8 (95% CI, 71.1%-97.9%) and 86.1% (95% CI, 62.1%-95.4%) in the zanubrutinib arm, respectively. The duration of major response was NE in both arms; however, the 42-month event-free rate was 78.6% (95% CI, 65.4%-87.3%) in the ibrutinib arm vs 85.8% (95% CI, 72.4%-93.0%) in the zanubrutinib arm.

The PFS event rate for those in the ibrutinib arm was 25.0% vs 16.9% in the zanubrutinib arm (HR, 0.70; 95% CI, 0.33%-1.50%; P = .36). The median PFS was NE in both arms, and the 42-month PFS rates were 74.6% (95% CI, 62.3%-83.4%) vs 81.3% (95% CI, 68.7%-89.2%), respectively.

Safety

Treatment-emergent adverse effects (AEs) led to discontinuation in 20.4% patients in the ibrutinib arm vs 8.9% in the zanubrutinib arm in cohort 1. There was a higher risk of treatment discontinuation because of AEs (P < .05) and initiation of next treatment (P = .0977) observed for ibrutinib compared with zanubrutinib.

Aside from neutropenia, the prevalence of AEs of interest was lower with zanubrutinib vs ibrutinib, and more patients receiving ibrutinib experienced cardiovascular AEs vs zanubrutinib.

Reference

Dimopoulos MA, Opat S, D'Sa S, et al. Zanubrutinib versus ibrutinib in symptomatic Waldenström macroglobulinemia: final analysis from the randomized phase III ASPEN study. J Clin Oncol. Published online July 21, 2023. doi:10.1200/JCO.22.02830