In the first head-to-head comparison of Bruton tyrosine kinase (BTK) inhibitors, zanubrutinib demonstrated statistically significant and clinically meaningful advantages in safety and tolerability in patients with Waldenström macroglobulinemia (WM) compared with ibrutinib. Although zanubrutinib yielded a numerically higher response rate than ibrutinib, the difference was not statically significant at data cutoff.
These findings were presented as part of the ASPEN study (ClinicalTrials.gov Identifier: NCT03053440), the largest phase 3 trial of BTK inhibitors in WM to date, which was presented by Constantine Si Lun Tam, MD, during the ASCO20 Virtual Scientific Program.
Cohort 1 of the study focused on patients with WM and MYD88 mutation. Patients were randomly assigned (1:1) to receive zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily). The primary endpoint was the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) by independent review committee (IRC).
In total, 201 patients participated in cohort 1 (102 received zanubrutinib and 99 received ibrutinib). Patients were well balanced among the treatment groups, except the zanubrutinib arm included more patients older than 75 years (33.3% vs 22.2%, respectively) and more patients with anemia (65.7% vs 53.5%, respectively) compared with the ibrutinib arm.
For the primary endpoint, Dr Tam noted that because CR is rare in WM, the data effectively compared VGPR rate. At data cutoff (August 31, 2019) and a median follow-up of 19.4 months, the rate of CR+VGPR by IRC was not significantly different between the zanubrutinib vs ibrutinib treatment groups (28.4% vs 19.2%, respectively; 2-sided P =.09). However, the Dr Tam noted that the investigator-assessed response in the zanubrutinib vs ibrutinib treatment groups was statistically significant (at data cutoff: 28.4% vs 17.2%, respectively; P =.04; and as of January 2020: 30.4% vs 18.2%, respectively; P =.03).
For safety and tolerability, adverse events (AEs) leading to dose reduction (13.9% vs 23.5%), discontinuation (4.0% vs 9.2%), or death (1 vs 4) were lower with zanubrutinib than with ibrutinib, respectively. Among the most common AEs (>10%), atrial fibrillation (14% vs 2%), edema peripheral (19% vs 9%), muscle spasms (23% vs 10%), and pneumonia (12% vs 2%) were more frequent with ibrutinib than zanubrutinib, respectively, (2-sided P< .05 for all); whereas, the rate of neutropenia was higher with zanubrutinib (25%) than ibrutinib (12%; 2-sided P <.05). However, the comparison of infection rates across the ibrutinib and zanubrutinib arms were similar for all grades, (66% vs 67%, respectively) and grade 3 or higher (19.4% vs 17.8%, respectively).
“The primary objective of the study was not met. However, there are secondary indicators of improved outcomes, including the response rates as assessed by investigators, as well as an examination of the IgM reduction kinetics over time,” said, Dr Tam. “In general, zanubrutinib was better tolerated with fewer adverse events leading to death, treatment discontinuation, of treatment interruption.”
Full Article as published in Hematology Advisor June 2/20