BGB-3111-111 is the first study of the efficacy and safety of zanubrutinib in Japanese patients with TN CLL/SLL, R/R CLL/SLL, TN WM, and R/R WM. In this study, zanubrutinib was shown to be effective and tolerable in Japanese patients; the ORR was high in all cohorts (92−100%). Zanubrutinib has also been shown to be highly effective and have a sustained response in these patient populations in multiple global studies, including 3 phase 3 studies (SEQUOIA, ALPINE, and ASPEN) [9,10,11]. Zanubrutinib is the only BTK inhibitor to have shown superiority over ibrutinib in patients with R/R CLL/SLL in a head-to-head phase 3 study [10].

The demographic and disease characteristics of the Japanese patients with CLL/SLL enrolled in this study had several notable differences in comparison to the global populations of the ALPINE and SEQUOIA studies. The ECOG PS in Japanese patients was notably lower than that in global studies (ECOG PS of 0: 85.7% of Japanese patients with TN CLL/SLL versus 45.6% of patients in SEQUOIA [9]; 100% of Japanese patients versus 39.4% of patients with R/R CLL/SLL in ALPINE) [10]. Del(17p) was present in 13.8% of patients with R/R CLL/SLL in ALPINE [10], and SEQUOIA had separate cohorts of patients with and without del(17p) [9]; del(17p) was not present in Japanese patients with CLL/SLL in BGB-3111-111. Among Japanese patients with R/R CLL/SLL, 40% (2/5) had unmutated IGHV versus 73% (239/327) in ALPINE [10]. In patients with TN CLL/SLL, 36% (5/14) of Japanese patients had unmutated IGHV versus 53% (125/234) in SEQUOIA [9]. The lower prevalence of risk factors in Japanese patients may contribute to better outcomes compared with patients in global studies.

In the head-to-head phase 3 ALPINE trial (NCT03734016) of zanubrutinib versus ibrutinib in patients with R/R CLL/SLL, zanubrutinib demonstrated a superior ORR and PFS compared with the first-generation BTK inhibitor ibrutinib [10, 22]. In a planned interim analysis of the study (median follow-up, 15 months), zanubrutinib demonstrated superiority over ibrutinib in the primary endpoint of investigator-assessed ORR (PR or better, 78.3% versus 62.5%, respectively) [22]. Later, in the predefined final analysis of PFS (median study follow-up, 29.6 months), zanubrutinib continued to demonstrate an improved ORR (83.5% versus 74.2% in patients treated with ibrutinib) and demonstrated superiority over ibrutinib in the key secondary endpoint of PFS (hazard ratio [HR], 0.65; 95% CI, 0.49–0.86; P = 0.002) [10]. Patients treated with zanubrutinib had a 24-month PFS rate of 78.4%, and median PFS was not reached. Consistent results were observed with longer follow-up (median study follow-up, 42.5 months), where zanubrutinib showed PFS benefit over ibrutinib across subgroups with high-risk features [23]. Similar results are shown here in Japanese patients with R/R CLL/SLL, who had an ORR of 100% and a PFS rate of 100% at 12 and 24 months. The ORR observed at the data cutoff of 10 May 2022 was high, with a median follow-up of 17.7 months (100% in R/R CLL/SLL by investigator), and has further deepened over time.

In the phase 3 SEQUOIA trial (NCT03336333), zanubrutinib was shown to be highly effective in patients with TN CLL/SLL, regardless of del(17p) mutation status, and significantly improved PFS compared with bendamustine and rituximab (BR) (HR, 0.42; 95% CI, 0.28–0.63; P < 0.0001) at a median study follow-up of 26.2 months [9]. In SEQUOIA, investigator-assessed PFS at 24 months was higher in patients without del(17p) who were treated with zanubrutinib (87.7%) versus patients treated with BR (76.5%) and was similar in patients with del(17p) who were treated with zanubrutinib (87.0%). Investigator-assessed ORR (PR-L or better) was 97.5% with zanubrutinib versus 88.7% with BR in patients without del(17p) and 96.4% in patients with del(17p) who were treated with zanubrutinib [9]. In comparison, Japanese patients with TN CLL/SLL in BGB-3111-111 had an ORR of 100%, a median PFS that was not reached, and an event-free rate of 85.7% at 12 months and 71.4% at 24 months; these values were consistent with those in SEQUOIA. In patients with TN CLL/SLL, CR rates were 21% and 9% in Japanese patients and global patients enrolled in SEQUOIA, respectively [9]. In patients with R/R CLL/SLL, CR rates were 20% and 7% in Japanese patients and global patients enrolled in ALPINE, respectively [10]. While response rates were higher in Japanese patients with R/R CLL/SLL, a lower proportion of Japanese patients had high-risk characteristics compared with those in global studies.

The global phase 3 ASPEN trial (NCT03053440) was a head-to-head comparison of zanubrutinib versus ibrutinib in patients with WM with mutated MYD88 in cohort 1. In ASPEN, zanubrutinib showed improved safety and similar efficacy (VGPR + CR rate and PFS) compared with the first-generation BTK inhibitor ibrutinib [11]. At a median study follow-up of 44.4 months, patients treated with zanubrutinib had fewer investigator-assessed PFS events than patients treated with ibrutinib (HR, 0.63; 95% CI, 0.36–1.12); the investigator-assessed PFS rate was 78.3% with zanubrutinib and 69.7% with ibrutinib at 42 months [11]. Zanubrutinib also had an investigator-assessed ORR of 95.1% versus 93.9% in patients treated with ibrutinib, with a larger difference detected in VGPR + CR (25.3% with ibrutinib and 36.3% with zanubrutinib) [11]. ORR and PFS were similar between Japanese patients with WM enrolled in BGB-3111–111 and global patients with WM enrolled in ASPEN. ORR was 92.3% in Japanese patients with TN WM, 100% in Japanese patients with R/R WM, and 94.7% in all Japanese patients with WM both at the 10 May 2022 data cutoff (median follow-up, 14.8 months) and the 10 May 2023 data cutoff (median follow-up, 26.8 months). This earlier ORR was compared against the historical control rate [19] of 52% and found to be significantly higher (P = 0.0026 for TN WM; P < 0.0001 for overall WM). Looking at the quality of response, the elevated IgM levels decreased over time and hemoglobin levels increased, suggesting an improvement of anemia. Median PFS was not reached, and the 24-month PFS rate was 83.9%, 100.0%, and 88.1% in the TN, R/R, and overall WM groups, respectively.

Zanubrutinib demonstrated consistent efficacy and tolerability and had a similar safety profile compared with those in the global studies (ALPINE [10], SEQUOIA [9], and ASPEN [11]), with no new safety signals emerging with prolonged treatment and longer follow up time. In the ALPINE study, zanubrutinib demonstrated a more favorable safety profile compared with ibrutinib in R/R CLL/SLL, with lower rates of grade ≥ 3 and serious AEs and fewer AEs leading to treatment discontinuation or dose reduction [10]. A statistically lower incidence of atrial fibrillation was demonstrated through predefined analysis (2.5% with zanubrutinib and 10.1% with ibrutinib; 2-sided P = 0.001); the rate of major hemorrhage was low in the zanubrutinib arm (2.9% versus 3.9% in those treated with ibrutinib) [22]. Zanubrutinib also demonstrated better tolerability compared with BR in the SEQUOIA study in patients with TN CLL/SLL, including lower rates of grade ≥ 3 and serious AEs in long-term follow-up [9]. In patients with symptomatic WM in the ASPEN trial, zanubrutinib demonstrated a more favorable safety profile compared with ibrutinib; rates of AEs, including cardiovascular AEs, were lower with zanubrutinib [11].

Overall, the rates of TEAEs leading to treatment discontinuation or death were comparable in global and Japanese patients with CLL/SLL and WM. 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. In Japanese patients with TN CLL/SLL: 3 of 14 patients (21.4%) discontinued treatment due to AEs, while 20 patients (8.3%) discontinued treatment due to AEs in SEQUOIA [9]. Among Japanese patients with R/R CLL/SLL, 1 of 5 patients (20%) discontinued treatment due to AEs, and 50 (15.4%) discontinued due to AEs in ALPINE [10]. Among Japanese patients with WM, 1 of 21 patients discontinued treatment due to AEs (4.8%), while 9 (8.9%) discontinued treatment due to AEs in ASPEN [11]. Atrial fibrillation/flutter in the BGB-3111–111 study occurred in 1 patient (5.3%) with CLL/SLL and 1 patient (4.8%) with WM; the incidence was similar in the global ALPINE (5.2%) [10], SEQUOIA (3.3%) [9], and ASPEN (7.9%) studies [11]. Overall, the incidences of secondary primary malignancies were similar among Japanese patients (10.9%) and the patients in the global studies (ALPINE 12.3% [10], SEQUOIA 15.7% [9], ASPEN 16.8% [11]). In the R/R CLL/SLL group, secondary primary malignancy was reported in 1 of 5 patients (gastric cancer: the patient’s gastrointestinal endoscopy identified a mucosal abnormality requiring follow-up prior to the first dose) representing 20% versus 12.3% of patients with R/R CLL/SLL in the ALPINE study, however, the difference in incidence may be due to the small sample size [10]. Nevertheless, monitoring for signs of other cancers is warranted. Major hemorrhage occurred in 4 of 19 patients (21.1%) with CLL/SLL in the BGB-3111-111 study versus 3.7% in ALPINE [10] and 5.0% in SEQUOIA [9]. Of patients with CLL/SLL who experienced major hemorrhage, 2 were receiving antithrombotic therapy (rivaroxaban and aspirin), 2 had causes of hemorrhage (trauma and endoscopic submucosal dissection), 1 had hyphemia after multiple laser photocoagulation for diabetic retinopathy, all were not considered related to study treatment, and none of the 4 events led to treatment discontinuation. In the overall population, 6 of 55 patients (10.9%) experienced major hemorrhage and 1 case led to treatment discontinuation; Given the known risk for bleeding in patients treated with BTK inhibitors, physicians should account for concomitant medications and procedures that may increase the risk of hemorrhage when treating this population. Overall, the safety profile of zanubrutinib in Japanese patients did not significantly differ from the profile seen in the global studies, and the overall results suggest that zanubrutinib is well tolerated and has a safety profile in the Japanese population consistent with that in the rest of the world.

This study had several limitations. The overall low number of enrolled patients compared with global studies may limit the applicability of the findings to the broader population of patients in Japan with TN CLL/SLL, R/R CLL/SLL, or WM. The BGB-3111-111 study was conducted during the start of the COVID-19 pandemic (the first patient received zanubrutinib on 30 January 2020, and the data cutoff was 10 May 2023), and the safety profile may have been impacted by patients being vaccinated for COVID-19 only later in the study. COVID-19 infections were reported in 8 of 55 patients (14.5%) during this period. Longer follow-up is needed to evaluate the findings for DoR, PFS, and OS.