Zanubrutinib Yields High Response Rates in Japanese Patients With CLL/SLL and Waldenström Macroglobulinemia

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Zanubrutinib (Brukinsa) demonstrated high response rates, which were durable, at a median follow-up of over 2 years in Japanese patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or Waldenström macroglobulinemia (WM), according to data from the phase 1/2 BGB-3111-111 trial (NCT04172246) published in the International Journal of Hematology.1

At the May 10, 2022, data cutoff, the objective response rate (ORR) assessed by independent review committee (IRC) was 100% in the treatment-naive (n = 14), relapsed/refractory (R/R; n = 5), and overall CLL/SLL (n = 19) groups. The median follow-up times were 16.0 and 17.7 months in the treatment-naive and R/R groups, respectively. Additionally, the IRC-assessed ORR among patients with WM was 92.3% in the treatment-naive group (n = 13), 100% in the R/R group (n = 6), and 94.7% in the overall WM group (n = 19) in part 2, with median follow-ups of 14.8 and 15.0 months in the treatment-naive and R/R groups, respectively.

At the most recent data cutoff of May 10, 2023, the investigator-assessed objective response rate (ORR) was 100% in patients with CLL/SLL, in the treatment-naive, relapsed/refractory (R/R) groups, and overall CLL/SLL groups, with median follow-ups of 28.0 months and 18.4 months, in the treatment-naive and R/R groups, respectively. In the WM cohort, the ORR assessed by investigator was 92.3% (95% CI, 64.0%-99.8%) in those who were treatment-naive, 100% (95% CI, 54.1%-100%) in those with R/R disease, and 94.7% (95% CI, 74.0%-99.9%) in those from the overall cohort. The median follow-ups in the WM cohort among the treatment-naive and R/R groups were 26.8 months and 26.9 months, respectively.

“BGB-3111-111 is the first study of the efficacy and safety of zanubrutinib in Japanese patients with treatment-naive CLL/SLL, R/R CLL/SLL, treatment-naive WM, and R/R WM,” the study authors wrote. “In this study, zanubrutinib was shown to be effective and tolerable in Japanese patients; the ORR was high in all cohorts (92%−100%).”

Zanubrutinib Background and BGB-3111-111 Study Design

In January 2023, the FDA approved zanubrutinib for the treatment of patients with CLL/SLL.2 The regulatory decision was supported by data from the phase 3 SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials.

BGB-3111-111 was a multicenter, open-label study that evaluated the efficacy and safety of zanubrutinib in Japanese patients with B-cell malignancies.1 The study included patients 20 years of age or older with adequate organ function, a confirmed diagnosis of CLL/SLL, mantle cell lymphoma (MCL), WM, marginal zone lymphoma, or follicular lymphoma, and an ECOG performance status of 0 to 2. Notably, part 2 of the study assessed zanubrutinib in patients with treatment-naive or R/R CLL/SLL (n = 19) and those with treatment-naive or R/R WM (n = 21).

In part 1, the safety profile and pharmacokinetics (PK) of zanubrutinib were evaluated, in which patients with B-cell malignancies were treated with oral zanubrutinib at 160 mg twice daily. The safety profile was assessed after the first 6 patients were treated in the 28-day cycle.

Furthermore, part 2 evaluated the efficacy, safety profile, and PK of zanubrutinib in patients specifically with R/R MCL, treatment-naive CLL/SLL, R/R CLL/SLL, and treatment-naive R/R WM. These respective patients received 160 mg of oral zanubrutinib twice daily.

The primary end point was IRC-assessed ORR. Secondary end points included progression-free survival (PFS), duration of response (DOR), time to response by IRC, investigator-assessed ORR, overall survival (OS), and safety.

Baseline Patient Characteristics

In the overall group, which included patients with CLL/SLL and WM, the median age was 71.0 (range, 37-84), of which 74.5% of patients were 65 years of age and older. Most patients were males (69.1%) and had an ECOG performance status of 0 (80.0%). The median number of prior lines of therapy among patients with R/R disease was 2.0 (range, 1-8). Of note, patients with MYD88L265P-mutated disease included those in the treatment-naive (84.6%), R/R (75.0%), and overall (81.0%) groups of the WM cohort. Those with CXR4WHIM-mutated disease included patients with WM in the treatment-naive (30.8%) and overall (19.0%) groups. The majority of patients with CLL/SLL had mutated IGHV (treatment-naive, 64.3%; R/R, 60.0%; all, 63.2%).

Additional Efficacy and Safety Data

At the May 10, 2023, data cutoff, the median DOR per investigator assessment was not reached (NR) in patients with treatment-naive CLL/SLL; those with R/R CLL/SLL had an investigator-assessed DOR of 23.3 months. Notably, the 12-month event-free rates were 64.3% (95% CI, 34.3%-83.3%) and 100% in the treatment-naive CLL/SLL and R/R CLL/SLL groups, respectively. Additionally, among those in the WM group, the median DOR per investigator assessment was NR in both the treatment-naive and R/R groups. The event-free rate at 12 months was 100% in both the treatment-naive and R/R groups.

Furthermore, the median investigator-assessed time to response was 2.8 months (range, 2.7-22.3) and 2.8 months (range, 2.8-16.6) in the treatment-naive and R/R CLL/SLL groups, respectively. Patients in the WM group followed a similar trend, with an investigator-assessed median time to overall response of 2.3 months (range, 1.0-5.6) and 2.7 months (range, 0.9-2.8) in the treatment-naive and R/R groups, respectively.

In the treatment-naive CLL/SLL group, the 12-month investigator-assessed PFS event-free rate was 85.7% (95% CI, 53.9%-96.2%) and was 71.4% (95% CI, 40.6%-88.2%) at 24 months. At both 12 and 24 months, the PFS event-free rates were 100% each in the R/R CLL/SLL group. In the treatment-naive WM group, the investigator-assessed PFS event-free rates at 12 and 24 months were 92.3% (95% CI, 56.6%-98.9%) and 83.9% (95% CI, 49.4%-95.7%). Moreover, the 12-month OS rates were each 100% in the treatment-naive and R/R CLL/SLL groups. The 24-month OS rate was 92.9% (95% CI, 59.1%-99.0%) in the treatment-naive group and 100% in the R/R group. In the WM group, the 12- and 24-month OS rates were 100% in the treatment-naive group and 83.3% (95% CI, 27.3%-97.5%) in the R/R group.

Regarding safety, 3 patients in the CLL/SLL group died due to adverse effects (AEs; treatment-naive, n = 2; R/R, n = 1), 2 deaths of which occurred within 30 days of the final dose. One patient with R/R WM died due to an AE more than 30 days following the final dose; no deaths occurred in the treatment-naive WM group. The most common any-grade treatment-emergent AEs (TEAEs) reported in the overall population included decreased platelet count (18.2%), pyrexia (18.2%), COVID-19 (14.5%), and decreased neutrophil count (12.7%). Of note, the most common grade 3 or greater TEAEs included decreased neutrophil count (10.9%), decreased platelet count (9.1%), neutropenia (5.5%), increased amylase, cellulitis, COVID-19, pneumonia, and decreased appetite (3.6% each).

“Overall, the rates of TEAEs leading to treatment discontinuation or death were comparable in global and Japanese patients with CLL/SLL and WM,” the study authors wrote in their conclusion. “Given the smaller sample size for the Japanese study and the shorter follow-up time, differences in AE incidence may be observed when compared with the larger randomized trials.”

References

1. Izutsu K, Ishikawa T, Shimada K, et al. Zanubrutinib in Japanese treatment-naive and relapsed/refractory patients with Waldenström macroglobulinemia and CLL/SLL. Int J Hematol. 2025;121(4):483-493. doi:10.1007/s12185-025-03925-1
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed May 22, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma