Follow-up Data Show Continuous Advantage of Zanubrutinib Over Ibrutinib for MYD88+ Waldenström Macroglobulinemia


Follow-up results of the phase 3 ASPEN trial comparing zanubrutinib with ibrutinib in patients with Waldenström macroglobulinemia were presented at 2022 ASCO.

Long-term follow-up data from the phase 3 ASPEN trial (NCT03053440) demonstrated the superiority of zanubrutinib (Brukinsa) vs ibrutinib (Imbruvica) in patients with MYD88-mutated Waldenström macroglobulinemia, according to a presentation during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.1

At a median follow-up of 44.4 months, patients with MYD88-mutated Waldenström macroglobulinemia who were enrolled to cohort 1 achieved a complete response or very good partial response (CR+VGPR) rate of 36.3% with zanubrutinib (n = 98) compared with 25.3% with ibrutinib (n =101). Notably, the response rate of CR+VGPR was noted to be numerically higher at all time points with zanubrutinib vs ibrutinib in this population.

Moreover, the median time to CR+VGPR was shorter in the zanubrutinib arm vs the ibrutinib arm, at 6.7 months (range, 1.9-42.0) and 16.6 months (range, 2.0-49.9), respectively. The event-free rate for the duration of CR+VGPR at 24 months was also found to be higher in the investigative arm vs the control arm, at 90.6% (range, 73.6%-96.9%) and 79.3% (range, 53.5%-91.8%).

“Although not statistically significant at [the previously reported] primary analysis, a consistent trend of deeper, earlier, and more durable responses [CR+VGPR] was observed [with zanubrutinib compared with ibrutinib],” lead study author Constantine S. Tam, MBBS, MD, FRACP, FRCPA, the program lead for Chronic Lymphocytic Leukemia and Low-Grade Lymphoma at Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues, wrote in a poster on the findings.

Zanubrutinib, a potent, selective, and irreversible, next-generation BTK inhibitor, has shown equipotency against BTK compared with ibrutinib. Prior ASPEN data showed that at a median follow-up of 19.4 monthszanubrutinib elicited a CR+VGPR rate of 28.4% compared with 19.2% with ibrutinib in patients with MYD88-mutated Waldenström macroglobulinemia (P = .0921).2 In September 2021, the FDA approved zanubrutinib for the treatment of adult patients with Waldenström macroglobulinemia, based on those findings.3

To enroll on ASPEN, patients were required to be at least 18 years of age and have a histologic diagnosis of Waldenström macroglobulinemia. They also needed to have measurable disease requiring treatment; an ECOG performance status of 0 to 2; adequate bone marrow, renal, and hepatic function; and a life expectancy of more than 4 months.4 Patients who had not received prior treatment for their disease were required to be considered inappropriate candidates for a standard chemoimmunotherapy regimen.

Key exclusion criteria included prior exposure to a BTK inhibitor, evidence of disease transformation at the time of study entry, major surgery within 4 weeks of study treatment, toxicity from prior anticancer treatment that was at least grade 2 in severity, and a history of other malignancies within 2 years of study entry.

A total of 201 patients with MYD88-mutated Waldenström macroglobulinemia were enrolled to cohort 1, and 28 patients with MYD88 wild-type disease comprised cohort 2.

Patients in cohort 1 were randomized 1:1 to receive oral zanubrutinib at a twice-daily dose of 160 mg (n = 102), or oral ibrutinib at a once-daily dose of 420 mg (n = 99). Treatment continued in both arms until disease progression. All patients in cohort 2 were administered 160 mg of zanubrutinib twice daily until disease progression. Stratification factors included CXCR4 status (CXCR4 mutation vs CXCR4 wild-type or missing) and number of prior lines of therapy (0 vs 1-3 vs or more than 3).

The primary end point of the trial was CR+VGPR in cohort 1. Secondary end points included further comparison of efficacy, clinical benefit, anti-lymphoma effects, and safety of zanubrutinib vs ibrutinib in cohort 1. The efficacy and safety of zanubrutinib in cohort 2 served as exploratory end points.

In cohort 1, the median age of all patients was 70 years (range, 38-90). Moreover, 33.3% of patients who received zanubrutinib were over 75 years vs 22.2% of those in the ibrutinib arm. Most patients in both arms were male, received between 1 and 3 prior lines of therapy, and were anemic. Regarding genotype, 72.7% of those in the ibrutinib arm had CXCR4 wild-type disease vs 63.7%, and 20.2% and 32.4% of patients, respectively, had CXCR4-mutated disease; 7.1% and 3.9% of patients, respectively, had unknown status.

In cohort 2, the median age was 72 years (39-87), and patients over the age of 75 years was noted to be more frequent (42.9%). Additionally, 50% of patients were male, 71.4% received between 1 and 3 prior lines of therapy, and 53.6% were anemic. Here, 96.4% of patients had CXCR4 wild-type disease and 3.6% had CXCR4-mutated disease.

Additional data from cohort 1 showed that both the median overall survival (OS) and progression-free survival (PFS) were not reached. However, investigators noted that hazard ratio (HR) estimates favored zanubrutinib for OS (HR, 0.75; 95% CI, 0.36-1.59) and PFS (HR, 0.63; 95% CI, 0.36-1.12). The 42-month OS rates were 87.5% and 85.2% for zanubrutinib and ibrutinib, respectively; the 42-month PFS rates were 78.3% and 69.7%, respectively.

Notably, patients with CXCR4-mutated disease were noted to achieve deeper and faster responses with zanubrutinib (n = 20), as well as favorable PFS (HR, 0.50; 95% CI, 0.20-1.29), vs ibrutinib (n = 33). The 42-month PFS rates in the investigative and control arms were 73.2% and 49.0%, respectively. Among this subset, 21.2% of patients achieved a VGPR or better with zanubrutinib vs 10.0% of those who received ibrutinib. Major responses occurred in 78.8% and 65.0% of patients, respectively, and overall responses occurred in 90.9% and 95.0% of patients, respectively.

In the subset of patients with CXCR4 wild-type disease, zanubrutinib (n = 65) elicited a VGPR or better rate of 44.6% vs 30.6% with ibrutinib (n = 72). Major responses were experienced by 83.1% and 84.7% of patients, respectively. Lastly, the overall response rate achieved with zanubrutinib in this subset was 96.9% vs 94.4% with ibrutinib.

In cohort 2, zanubrutinib elicited 1 CR, a CR+VGPR rate of 31%, and a major response rate of 65%. Event-free rates of OS and PFS at 42 months were 83.9% (95% CI, 62.6%-93.7%) and 53.8% (95% CI, 33.3%-70.6%), respectively.

Regarding safety in cohort 1, 99% and 100% of patients, respectively, experienced at least 1 adverse effect (AE) of any grade in the zanubrutinib and ibrutinib arms. The rates of grade 3 or higher AEs were 74.3% and 72.4%, respectively. Moreover, 3.0% and 5.1% of patients who received zanubrutinib and ibrutinib, respectively, experienced AEs that resulted in death; 8.9% and 20.4% of patients experienced AEs leading to treatment discontinuation; and 15.8% and 26.5% of patients had AEs that led to a dose reduction.

In cohort 1, grade 3 or higher AEs reported in the ibrutinib and zanubrutinib arms, respectively, included diarrhea (2.0% vs 3.0%), upper respiratory tract infection (1.0% vs 0%), muscle spasms (1.0% vs 0%), arthralgia (0% vs 3.0%), hypertension (19.4% vs 9.9%), epistaxis (0% vs 1.0%), atrial fibrillation (6.1% vs 2.0%), fatigue (1.0% vs 1.0%), pneumonia (10.2% vs 1.0%), and syncope (6.1% vs 5.0%).

Grade 3 or higher AEs of interest reported in the control and investigative arms, respectively, comprised infection (27.6% vs 21.8%), bleeding (10.2% vs 8.9%), diarrhea (2.0% vs 3.0%), hypertension (20.4% vs 9.9%), atrial fibrillation/flutter (8.2% vs 2.0%), anemia (6.1% vs 11.9%), neutropenia (10.2% vs 23.8%), thrombocytopenia (6.1% vs 10.9%), second primary malignancy (3.1% vs 5.9%) and non–skin cancers (3.1% vs 4.0%).

“Fewer AEs leading to treatment discontinuation, dose reductions, and deaths occurred in the zanubrutinib arm,” the study authors concluded. “Cumulative incidences of atrial fibrillation, diarrhea, hypertension, muscle spasm, and pneumonia were lower in patients receiving zanubrutinib. Despite a higher rate of neutropenia in the zanubrutinib arm, infection rates were similar and more patients in the ibrutinib arm had grade [3 or higher] infections.”


  1. Tam CS, Garcia-Sanz R, Opat S, et al. ASPEN: Long-term follow-up results of a phase 3 randomized trial of zanubrutinib (ZANU) versus ibrutinib (IBR) in patients with Waldenström macroglobulinemia (WM). J Clin Oncol. 2022;40(suppl 16):7521. doi:10.1200/JCO.2022.40.16_suppl.7521
  2. Tam CSL, Opat S, D’Sa S, et al. ASPEN: results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). J Clin Oncol. 2020;38(suppl 15):8007. doi:10.1200/JCO.2020.38.15_suppl.8007
  3. US FDA grants BRUKINSA (zanubrutinib) approval in Waldenström’s macroglobulinemia. News release. BeiGene. September 1, 2021. Accessed June 8, 2022.
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