Zanubrutinib Shows Lasting Responses in Waldenström Macroglobulinemia

At 2 years of additional follow up for patients on the ASPEN study (NCT03053440), researchers saw that patients with Waldenström Macroglobulinemia had long term responses with zanubrutinib (Brukinsa) compared with ibrutinib (Imbruvica), according to data published in the Journal of Clinical Oncology.¹

The randomized open-label, phase 3 study showed that higher rates of very good partial responses (VGPR) continued with the next-generation covalent Bruton’s tyrosine kinase (BTK) inhibitor compared with ibrutinib. After 60 months of treatment, 36.3% (95% CI, 27.0%-46.4%) of patients on zanubrutinib had a VGPR compared with 25.3% (95% CI, 17.1%-35.0%) of patients on ibrutinib (P = .07). The median time to the VGPRs were also faster on zanubrutinib vs ibrutinib at 16.6 months vs 6.67 months, respectively. Further, a median time to a major response was slightly quicker in the zanubrutinib arm at 2.83 months compared with 2.92 months in the ibrutinib arm.

The study initially enrolled 201 patients harboring MYD88mutation (MYD88MUT) in cohort 1 with 102 patients in the zanubrutinib arm and 99 patients were given ibrutinib. In cohort 2, 28 patients were enrolled in the study with 26 patients harboring a MYD88wild type (MYD88WT) mutation. Patients harboring a MYD88WTmutation in their disease given zanubrutinib had a VGPR of 26.9%. Of the patients in the overall cohort 1 population, 53 patients’ disease harbored a CXCR4 mutation (CXCR4MUT) and 137 patients harbored a CXCR4 wild type (CXCR4WT) mutation.

In these subgroups, 21.2% (95% CI, 9.0%-38.9%) of patients with CXCR4MUThad a VGPR to zanubrutinib and 10% (95% CI, 1.2%-31.7%) on ibrutinib had a VGPR (P = .35). The median time to their VGPR was also faster on zanubrutinib than on ibrutinib at 11.10 months compared with 31.31 months, respectively. This favoring of zanubrutinib continued in the CXCR4WT group with a VGPR of 44.6% compared with 30.6% on ibrutinib and a median time to response of 6.51 months vs 11.33 months with ibrutinib.

At baseline, 66.7% of patients on ibrutinib had extramedullary disease compared with 61.8% on zanubrutinib and 57.1% of patients in cohort 2 had extramedullary disease at the time of enrollment. The VGPR rate difference between those on zanubrutinib compared with ibrutinib was 18.8% (95% CI, 2.4%-35.1%) favoring those on zanubrutinib. This was consistent with the VGPR rates favoring those on zanubrutinib vs ibrutinib who also had lymphadenopathy, at 65.9% vs 52.5%, and splenomegaly at 20.0% vs 15.0%, respectively.

Patients at baseline with no prior therapy (n = 42) had a VGPR rate of 36.8% on zanubrutinib compared with 22.2% on ibrutinib. Patients with 1-3 prior lines of therapy (n =170) on zanubrutinib had a 36.8% VGPR rate compared with 25.7% on ibrutinib, while patients with more than 3 lines of prior therapy (n = 17) had the same VGPR rate of 28.6%. More patients on zanubrutinib than ibrutinib were older than 75 years at 33.3% vs 22.2%, respectively (P = .084).

Secondary endpoints of the follow up analysis included duration of response (DOR), progression-free survival (PFS), and overall survival (OS), as well as looking at long term safety outcomes. A median DOR was not reached in cohort 1 but in cohort 2 the median DOR was 23.7 months (range, 0.0-44.1). Median PFS was also not reached in cohort 1 for patients on zanubrutinib, but was 45.8 months (range, 1.6-47.0) in cohort 2.

The event-free rate at 42 months favored patients on zanubrutinib vs those on ibrutinib across both cohorts and subgroups at 78.3% (95% CI, 68.4%-85.5%) vs 69.7% (95% CI, 58.9%-78.2%) in cohort 1, respectively, and 53.8% (95% CI, 33.3%-70.6%) in cohort 2. A median OS was not reached on zanubrutinib in either cohort, and fewer OS events were seen for patients on the study drug (HR, 0.75; 95% CI, 0.36-1.59).

The most common reason for discontinuing treatment were adverse events (AEs) and any-grade AEs on zanubrutinib included diarrhea (22.8%), muscle spasms (11.9%), hypertension (14.9%), atrial fibrillation (6.9%), and pneumonia (5.0%). However, any grade neutropenia was higher on zanubrutinib at 28.7% of patients compared with 16.3% of patients in ibrutinib. This was also the case for grade 3 neutropenia on zanubrutinib with 19 patients experiencing it compared with 9 patients on ibrutinib, and grade 3 or greater anemia was seen in 12 patients on zanubrutinib compared with 6 patients on ibrutinib.

AEs that led to discontinuation were higher in ibrutinib with 20 patients discontinuing treatment compared with 9 on zanubrutinib. Of those who discontinued treatment, 1 patient on zanubrutinib discontinued due to cardiac related AEs and 4 patients on ibrutinib discontinued due to these as well. AEs that lead to a dose reduction was seen in 26 patients on ibrutinib compared with 16 on zanubrutinib and 2 patients in cohort 2 had to dose reduce due to AEs. Serious AEs were overall higher in the zanubrutinib arm with 57 patients experiencing these compared with 49 patients in the ibrutinib.

With these extended follow up results confirming the tolerable long-term safety and efficacy of zanubrutinib in patients with Waldenström macroglobulinemia, regardless of their mutation type, the researchers concluded that the next generation of BTK inhibitors provide earlier and more durable responses.

^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 July 21, 2023. doi:10.1200/JCO.22.02830}