Zanubrutinib Misses Response Endpoint in Waldenstrom Macroglobulinemia, But Trends Toward Clinical Benefit

Zanubrutinib did not show a statistically significant improvement in complete response and very good partial response rates compared with ibrutinib in patients with Waldenström macroglobulinemia, missing the primary endpoint of the phase III ASPEN trial.

Constantine S. Tam, MD

Zanubrutinib (Brukinsa) did not show a statistically significant improvement in complete response (CR) and very good partial response (VGPR) rates compared with ibrutinib (Imbruvica) in patients with Waldenström macroglobulinemia, missing the primary endpoint of the phase III ASPEN trial (NCT03053440).1

In the entire population of a randomized cohort of the trial, the VGPR rate, as assessed by an independent review committee (IRC), was 28.4% with zanubrutinib and 19.2% with ibrutinib in this patient population, which was not found to be a statistically significant difference (2-sided descriptive P = .0921). No patients in either arm achieved a CR.

Specifically, in relapsed/refractory patients, the IRC-assessed VGPR rate with zanubrutinib was 28.9% compared with 19.8% with ibrutinib, which also was not statistically significant (2-sided P = .1160); no patients achieved a CR.

BeiGene, the manufacturer of the next-generation BTK inhibitor, stated in a press release that it plans to discuss these data with US and European regulatory authorities and will plan to present the findings at an upcoming medical meeting.

“Waldenström macroglobulinemia is a devastating and incurable disease with significant morbidity. These meaningful results help us advance the understanding of the role of BTK specificity and off-target effects during treatment,” study investigator Constantine S. Tam, MD, disease group lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at the Peter MacCallum Cancer Center, and director of Hematology at St. Vincent’s Hospital, Australia, stated in a press release.

“Despite not reaching the primary endpoint, 28.4% of zanubrutinib patients achieved VGPR as compared to 19.2% in the ibrutinib arm, and zanubrutinib had a more favorable safety profile, suggesting improved clinical benefit for zanubrutinib over standard BTK [inhibitor] therapy in the treatment of patients with Waldenström macroglobulinemia,” added Tam.

The multicohort, open-label, randomized ASPEN trial was conducted in 229 patients with either treatment-naïve or relapsed/refractory Waldenström macroglobulinemia from the United States, Europe, and Australia. The study included a randomized cohort of patients with MYD88 mutations (n = 201) and a nonrandomized cohort of MYD88 wild-type status because they historically responded poorly to treatment with ibrutinib (n = 28).

In the randomized cohort, patients with relapsed/refractory (n = 83) or treatment-naïve disease (n = 19) were randomized to receive zanubrutinib; on the ibrutinib arm, 81 patients had relapsed/refractory disease and 18 patients were previously untreated. Zanubrutinib was given at 160 mg twice daily and ibrutinib was administered at 420 mg once daily.

The primary endpoint was CR or VGPR; secondary endpoints included major response rate (MRR), duration of response, progression-free survival (PFS), and safety.

The data cutoff date was August 31, 2019. At a median follow-up of 19.4 months, results also showed that the MRR in the relapsed/refractory group, as assessed by IRC, was 78.3% in the zanubrutinib arm and was 80.2% in the ibrutinib arm. Overall, the MRR was 77.5% and 77.8%, respectively.

The study was not powered to detect a statistically significant improvement in PFS. However, follow-up data for PFS are still short, early PFS and overall survival (OS) data for zanubrutinib were directionally consistent with the higher VGPR rates in the zanubrutinib arm, BeiGene stated in the press release.

Additionally, in cohort 1, the 12-month PFS rate was 89.7% (81.7-94.3) compared with 87.2% (78.6-92.5) in all patients on zanubrutinib and ibrutinib, respectively. In relapsed/refractory patients, the 12-month PFS rates were 92.4% (83.8-96.5) with zanubrutinib compared with 85.9% (75.9-91.9) of patients on ibrutinib.

Twelve-month OS rates were 97.0% (90.9-99.0) for all patients on zanubrutinib and 93.9% (86.8-97.2) in all patients in the ibrutinib arm; for relapsed/refractory patients, these rates were 98.8% (91.6-99.8) and 92.5% (84.1-96.6) on zanubrutinib and ibrutinib, respectively.

Regarding safety, grade >3 adverse events (AEs) were 58.4% with zanubrutinib arm and 63.3% with ibrutinib. Four (4.0%) patients discontinued zanubrutinib due to AEs and there was one (1.0%) fatal AE; 9 patients (9.2%) discontinued ibrutinib due to AEs and there were 4 (4.1%) fatal AEs.

Any-grade atrial fibrillation or flutter was 2.0% with zanubrutinib and 15.3% with ibrutinib. Additional AEs of special interest including minor bleeding (48.5% for zanubrutinib vs 59.2% for ibrutinib), major hemorrhage (5.9% vs 9.2%, respectively), and diarrhea (20.8% vs 31.6%). The rate of neutropenia was higher with zanubrutinib at 29.7% compared with ibrutinib at 13.3%.

“Our researchers sought to design a BTK inhibitor that would improve efficacy and decrease side effects in patients by maximizing BTK inhibition and minimizing off-target binding. We took a bold approach to our clinical development plan by evaluating zanubrutinib directly against ibrutinib in patients with WM and are encouraged by the improvements in VGPR rates and safety,” Jane Huang, MD, chief medical officer, Hematology at BeiGene, stated in the press release.

“The ASPEN trial, which was the largest prospective trial for patients with WM ever run, showed consistent safety advantages for patients treated with zanubrutinib compared to ibrutinib. While falling short of a statistically significant improvement in CR and VGPR, we believe the trial demonstrated that zanubrutinib is a highly potent BTK inhibitor that has clinical benefit and trends toward increased response quality,” added Huang.

Data from the nonrandomized cohort of ASPEN previously demonstrated an overall response rate (ORR) of 80.8% with zanubrutinib, as well as an MRR of 53.8% and a VGPR rate of 23.1%.2

In November 2019, the FDA granted an accelerated approval to zanubrutinib capsules for the treatment of adult patients with mantle cell lymphoma who have received ≥1 prior therapy.


  1. BeiGene announces results of phase 3 ASPEN trial of zanubrutinib compared to ibrutinib for the treatment of patients with Waldenström’s macroglobulinemia [news release]: BeiGene. Published December 16, 2019. Accessed December 16, 2019.
  2. Dimopoulos MA, Opat S, Lee H-P, et al. Major responses in MYD88 wildtype (Myd88wt) Waldenström macroglobulinemia (WM) patients treated with Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (BGB-3111). Presented at: 2019 European Hematology Association Congress; June 14-17, 2019; Amsterdam, The Netherlands.