Although not statistically significant, zanubrutinib appeared to be associated with a higher complete response (CR) and very good partial response (VGPR) rate and demonstrated clinically meaningful advantages in safety and tolerability compared to ibrutinib for patients with Waldenström macroglobulinemia (WM), according to results from the ASPEN trial presented at the virtual 2020 ASCO Annual Meeting.

“BTK plays a critical role in B-cell receptor signaling and BTK inhibition is an emerging standard of care for patients with [WM},” explained Constantine Si Lun Tam, MBBS, MD, Peter MacCallum Cancer Center, Victoria, Australia, during his presentation.

The randomized, phase 3 ASPEN trial compared zanubrutinib, a potent and selective BTK inhibitor, with ibrutinib, a first generation BTK inhibitor, for patients with MYD88-mutated WM. Researchers noted that this is the first trial to compare BTK inhibitors head-to-head in any disease.

Patients with WM and a MYD88 mutation were randomized in a 1:1 ratio to receive either zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily. Patients were stratified based on CXCR4 mutation status and number of prior lines of therapy (0 vs 1-3 vs >3). An additional cohort including 28 patients without MYD88 mutations received zanubrutinib 160 mg daily.

The primary end point was the proportion of patients achieving a CR or VGPR.

A total of 201 patients were enrolled and randomized to zanubrutinib (n = 102) or ibrutinib (n = 99) between January 2017 and July 2018. Treatment arms were well balanced, although the zanubrutinib arm contained a higher proportion of patients aged >75 years, as well as more anemia.

At a median follow-up of 19.4 months, the rate of CR and VGPR was 28.4% in the zanubrutinib group compared with 19.2% in the ibrutinib group (P = .0921).

Additionally, zanubrutinib demonstrated lower rates of atrial fibrillation, contusion, diarrhea, edema peripheral, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to discontinuation or death compared with ibrutinib.

Neutropenia was higher with zanubrutinib (29.7%) compared with ibrutinib (13.3%), but rates of grade ≥3 infections were similar (17.8% vs 19.4%, respectively).

“In conclusion, the phase 3 ASPEN study saw that zanubrutinib was associated with a CR+VGPR rate of 28.4% compared with 19.2% for ibrutinib. This was a statistically nonsignificant finding… and therefore 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 over time,” explained Dr Tam.

“In general, zanubrutinib was better tolerated with fewer adverse events leading to death, treatment discontinuation, or treatment interruption,” he concluded.—Janelle Bradley

Constantine T, Opat S, D’Sa Shirley, et al. ASPEN: Results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). Presented at: the 2020 ASCO Annual Meeting; May 29-31, 2020. Abstract 8007.