Zanubrutinib Shows Clinical Activity, Tolerability in Waldenstrom Macroglobulinemia

Constantine Si Lun Tam, MBBS, MD

Zanubrutinib (Brukinsa) was associated with a higher complete response or very good partial response (CR+VGPR) rate, as well as clinically meaningful advantages in safety and tolerability, compared with ibrutinib (Imbruvica) in patients with Waldenström macroglobulinemia (WM), according to results of the phase 3 ASPEN trial (NCT03053440). However, the trial did not meet its primary study hypothesis, which was superiority with CR+VGPR by an independent review committee (IRC), in the zanubrutinib arm.¹

While not statistically significant, the data could spark change for patients with this rare type of blood cancer, according to Constantine Si Lun Tam, MD, MBBS, associate professor, department of Hematology, Peter MacCallum Cancer Centre, St. Vincent's Hospital, The University of Melbourne in Victoria, Australia. Tam recently discussed the trial at the 2020 ASCO Virtual Scientific Program.

"The totality of data from the two trials presented at ASCO suggests that zanubrutinib may be a preferred treatment option for patients with WM, regardless of whether they have received prior treatment," said Tam, principal investigator for the ASPEN trial, in a press release about the findings.²

Participants with WM and a MYD88 mutation (N = 201) were randomized 1:1 to receive either 160 mg twice daily of zanubrutinib (n = 102) or 420 mg once daily of ibrutinib (n = 99). Patients were stratified based on CXC4 mutational status, as well as how many prior therapies they received (0; 1 to 3; and 3 or more). Another cohort of 28 patients without MYD88 mutations was also given 160 mg daily.

Notably, a third (33.3%) of the patients randomized to zanubrutinib were elderly (over 75 years), compared to 22.2% in the ibrutinib arm. Additionally, the zanubrutinib arm had higher rates of anemia than the ibrutinib group (hemoglobin ≤ 110 g/L; 65.7% versus 53.5%, respectively).

At median follow-up of 19.4 months, the rates of CR+VGPR for patients with MYD88 mutations — the primary endpoints – were 28.4% for the zanubrutinib arm and 19.2% for the ibrutinib arm (P=0.0921).

"WM can be a devastating disease for patients and their families. We must offer therapies that are both effective in managing WM and well-tolerated to offer the best quality of life. In the ASPEN trial, zanubrutinib demonstrated a more favorable safety profile and was shown to be a more tolerable option for patients than ibrutinib, especially when considering adverse events of particular interest such as atrial fibrillation, hypertension and diarrhea," Tam said.

The zanubrutinib arm also had lower rates of atrial fibrillation (2.0% versus 15.3%, respectively), hypertension (10.9% versus 17.3%), major bleeding (5.9% versus 9.2%), grade 3 or higher adverse events (AEs; 58.4% versus 63.3%), AEs leading to discontinuation (4.0% versus 9.2%), and AE-related deaths (1.0% versus 4.1%) compared to ibrutinib.

While the rate of grade 3 or higher infections was similar between the zanubrutinib and ibrutinib arm (17.8% versus 19.4%, respectively), zanubrutinib did have a higher rate of neutropenia (29.7% versus 13.3%).

"These results reinforce that zanubrutinib is a highly effective BTK inhibitor with clinically meaningful improvements in safety and tolerability compared to ibrutinib. Importantly, since WM is typically a disease of older individuals, zanubrutinib appears to have advantages related to cardiovascular safety risks over ibrutinib," said Jane Huang, MD, Chief Medical Officer, Hematology at BeiGene. "The choice to evaluate zanubrutinib directly against ibrutinib underscores our bold approach to R&D and our commitment to develop better treatments for patients across the globe."

References

1. Tam C, 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). Presented at: 2020 ASCO Virtual Scientific Program; May 29, 2020. Abstract number 8007.
2. BeiGene Presents Updated Head to Head Results from Phase 3 Trial of Zanubrutinib vs. Ibrutinib in Patients with Waldenstrom’s Macroglobulinemia at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. Published May 29, 2020. https://www.globenewswire.com/news-release/2020/05/29/2040883/0/en/BeiGene-Presents-Updated-Head-to-Head-Results-from-Phase-3-Trial-of-Zanubrutinib-vs-Ibrutinib-in-Patients-with-Waldenstr%C3%B6m-s-Macroglobulinemia-at-the-2020-American-Society-of-Clini.html. Accessed May 29, 2020.

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