Zanubrutinib Improved Long-Term Response Rates for Patients With Waldenström Macroglobulinemia

At long-term follow-up of 43 months, zanubrutinib had higher complete response and very good partial response rates and clinically meaningful advantages in long-term safety and tolerability compared to ibrutinib in Waldenström macroglobulinemia (WM), according to a phase 3 study.

The randomized, open-label, phase 3 ASPEN study compared zanubrutinib, a potent and selective Bruton tyrosine kinase inhibitor (BTKi), with the first-generation BTKi, ibrutinib, in patients with Waldenström macroglobulinemia (WM). Cohort 1 included patients with MYD88 mutations who were randomized on a 1:1 basis to receive either 160 mg zanubrutinib twice daily (n = 102), or 420 mg ibrutinib once daily (n = 99). Patients were stratified based on CXCR4 mutations and prior lines of therapy. Cohort 2 included patients without MYD88 mutations, who received 160 mg zanubrutinib twice daily (n = 28).The primary endpoint was the proportion of patients with complete response/very good partial response (CR+VGPR). 

This data had a median follow-up duration of 43 months, with median treatment durations of 42 (zanubrutinib) and 41 (ibrutinib) months, and 67% and 58% of patients remaining on treatment, respectively. In cohort 1, the investigator-assessed CR+VGPR rate was 36% in the zanubrutinib arm and 22% in the ibrutinib arm (P = .02). In cohort 2, the CR+VGPR rate was 31% (1 CR). CR+VGPR rates for wild-type CXCR4 were 45% vs 28% in the zanubrutinib and ibrutinib arms respectively (P = .04). For mutated CXCR4, the CR+VGPR rates were 21% vs 5% (P = .15) in the zanubrutinib and ibrutinib arms respectively. Median progression-free survival and overall survival were not yet reached.

Rates of atrial fibrillation, diarrhea, hypertension, localized infection, hemorrhage, muscle spasms, pneumonia, grade ≥3 infection, and adverse events leading to discontinuation/death were lower in the zanubrutinib arm versus the ibrutinib arm, as were exposure-adjusted incidence rates of atrial fibrillation/flutter and hypertension (0.2 vs 0.8 and 0.5 vs 1.0 persons/100 person-months; P < .05); though the rate of neutropenia was higher. Zanubrutinib safety outcomes were similar between cohorts. 

Jorge J. Castillo, MD, Dana-Farber Cancer Institute, Boston, MA, and colleagues concluded, “At a median follow-up of 43 months, zanubrutinib had higher CR+VGPR rates and clinically meaningful advantages in long-term safety/tolerability versus ibrutinib.”

Source:

Castillo JJ, Tam CS, Garcia-Sanz R, et al. IBCL-117 ASPEN: Long-Term Follow-Up Results of a Phase 3 Randomized Trial of Zanubrutinib vs Ibrutinib in Patients With Waldenström Macroglobulinemia. Clin Lymph, Myel, and Leuk. 2022;22:S385. doi:10.1016/S2152-2650(22)01551-8