Zanubrutinib Shows Encouraging Tolerability, Activity in BTK Inhibitor–Intolerant B-Cell Malignancies

Zanubrutinib demonstrated clinical activity and tolerability in previously treated patients with B-cell malignancies who were intolerant to therapy with ibrutinib and/or acalabrutinib, according to results of the phase 2 BGB-3111-215 trial.

Zanubrutinib (Brukinsa) demonstrated clinical activity and tolerability in previously treated patients with B-cell malignancies who were intolerant to therapy with ibrutinib (Imbruvica) and/or acalabrutinib (Calquence), according to results of the phase 2 BGB-3111-215 trial that were presented during the 2021 Pan Pacific Lymphoma Conference.1

Results showed that intolerable adverse events (AEs) that were experienced on ibrutinib (75%; n = 86/115) and acalabrutinib (75%; n = 9/12) did not recur when patients received zanubrutinib treatment. Of the ibrutinib-intolerant AEs that did occur, 90% (n = 26/29) of them recurred at a lower severity; this rate was 33% (n = 1/3) with acalabrutinib-intolerant AEs. Ten percent of ibrutinib-intolerant AEs (n = 3/29) and 67% (n = 2/3) of acalabrutinib-intolerant AEs occurred at the same severity and zero AEs occurred at a higher severity.

Moreover, the investigator-assessed disease control rate (DCR) in patients who had been on study for more than 90 days (n = 48) was 89.6%; the objective response rate (ORR) was 50.0%, the complete response (CR) rate was 2.1%, the very good partial response (VGPR) rate was 4.2%, the partial response (PR) rate was 33.3%, and the PR with lymphocytes (PR-L) rate was 10.4%. The stable disease (SD), progressive disease (PD), not evaluable (NE), and not done (ND) rates were 39.6%, 4.2%, 2.1%, and 4.2%, respectively. The median time to best overall response was 12.4 weeks (range, 11-49).

“These data suggest that zanubrutinib may provide a therapeutic option in patients intolerant to other BTK inhibitors across hematologic malignancies,” said Mazyar Shadman, MD, of Fred Hutchinson Cancer Research Center, and coinvestigators, wrote in a poster presentation of the data.

While BTK inhibition is utilized and has demonstrated efficacy in patients with B-cell malignancies, its use has limitations due to discontinuations from AEs in select patients. These discontinuations also tend to occur early on in a patient’s treatment course.

Zanubrutinib, a selective BTK inhibitor, is FDA approved to treat patients with mantle cell lymphoma (MCL) and is currently being investigated in other B-cell tumors. In prior data of zanubrutinib vs ibrutinib in patients with Waldenström macroglobulinemia (WM) in the phase 3 ASPEN trial, zanubrutinib was linked with lower rates of AEs that led to death (1% vs 4.1% with ibrutinib), discontinuation (4.0% vs 9.2%, respectively), dose reductions (13.9% vs 23.5%), dose holds (46.5% vs 56.1%), and a lower rate of atrial fibrillation/flutter (2.0% vs 15.3%).2

In the multicenter, single-arm, open-label, phase 2 US BGB-3111-215 trial, investigators evaluated the efficacy and safety of zanubrutinib in ibrutinib- and/or acalabrutinib-intolerant patients with previously treated B-cell malignancies. The primary end point was recurrence and change of severity of AEs; secondary end points were investigator-assessed ORR, DCR, progression-free survival, and patient-reported outcomes.

Patients must have received prior treatment and had chronic lymphocytic leukemia (CLL)/small lymphocyte lymphoma (SLL), WM, MCL, or marginal zone lymphoma (MZL) that was intolerant to a prior BTK inhibitor. The study was broken into 2 cohorts: intolerant to ibrutinib (n = 50; cohort 1) and intolerant to acalabrutinib alone or to acalabrutinib and ibrutinib (n = 40; cohort 2). Upon enrollment, patients underwent screening within 14 days before receiving zanubrutinib at 160 mg twice daily or 320 mg daily. Treatment was administered until disease progression, unacceptable toxicity, treatment consent withdrawal, or study termination.

To be eligible for enrollment, patients had to meet ibrutinib/acalabrutinib intolerance, which consisted of grade 2 or higher nonhematologic toxicity for more than 7 days, grade 3 or higher nonhematologic toxicity for any duration, grade 3 neutropenia with infection or fever, grade 4 hematologic toxicity that persists until BTK inhibitor therapy is discontinued due to toxicity, and resolution of BTK inhibitor–toxicities to grade 1 or lower or baseline prior to initiating zanubrutinib.

Additional criteria for acalabrutinib intolerance included the following: grade 1 or higher nonhematologic toxicity for more than 7 days, grade 1 or higher nonhematologic toxicity for any duration with at least 3 recurrent episodes, and inability to use acid-reducing agents or anticoagulants due to current treatment with BTK inhibition.

Patients also needed to have resolution of grade 1 toxicities from BTK inhibition to grade 0 or baseline, prior to starting treatment with zanubrutinib. Those who had disease progression on any BTK inhibitor were excluded from enrollment.

Overall (n = 64), 65.6% of patients had CLL, 15.6% had WM, 9.4% had SLL, 4.7% had MCL, and 4.7% had MZL. The median age was 71 years (range, 49-91), 54.7% of patients were male, and 57.8% of patients had an ECOG performance status of 0. The median number of prior therapies was 2 (range, 1-12); 85.9% had received ibrutinib alone, 12.5% received ibrutinib in combination with another agent, and 10.9% received acalabrutinib alone. The median time on the most recent prior BTK inhibitor was 9.2 months (range, 0.5-73.7). More than half (62.5%) of patients received the 160-mg twice-daily dose of zanubrutinib.

At the data cutoff date of March 21, 2021, 7 (10.9%) patients had discontinued zanubrutinib and 2 had discontinued from the study (3.1%) because of death and patient withdrawal (n = 1 each). Three patients (4.7%) stopped zanubrutinib treatment due to AEs, none of which were due to a recurrence of a prior intolerance event. Two patients (3.1%) discontinued because of PD, 1 (1.6%) from physician decision, and 1 (1.6%) from patient withdrawal. A total 89.1% of patients remained on treatment.

Most patients (96.9%) remained on study and the median zanubrutinib exposure was 5.9 months (range, 0.6-16.6). The median follow-up was 6 months (range 0.7-16.6).

When broken out by cohort, the DCR and ORR in cohort 1 (ibrutinib-intolerant) was 90.2% and 51.2%; the CR, VGPR, PR, and PR-L rates were 2.4%, 4.9%, 34.1%, and 9.8%, respectively. The SD, PD, NE, and ND rates were 39.0%, 2.4%, 2.4%, and 4.9%, respectively. The median time to best overall response was 23.6 weeks (range, 11-49).

In cohort 2 (acalabrutinib-/acalabrutinib- and ibrutinib-intolerant), the DCR was 85.7% and the ORR was 42.9%. There were 0 CRs or VGPRs; the PR rate was 28.6% and the PR-L rate was 14.3%. The SD, PD, NE, and ND rates were 42.9%, 14.3%, 0%, and 0%, respectively. The median time to best overall response was 12.4 weeks (range, 12-26).

Additional data showed that all grade 4 intolerance events did not recur on zanubrutinib, which was comprised of neutropenia (n = 2), increased alanine aminotransferase (n = 1), and increased aspartate transaminase (n = 1). A total 68.3% of (n = 28/41) of grade 3 intolerance events did not recur on zanubrutinib and of those that recurred, all of them did so at a lower severity.

Twenty ibrutinib- and 7 acalabrutinib-intolerance events occurred in 1 patient and did not recur on zanubrutinib therapy. Furthermore, dizziness and insomnia, which were ibrutinib-intolerance events, occurred in 1 patient and recurred while on zanubrutinib at the same severity and lower severity, respectively.

Supplementary safety findings showed that 81.3% of all patients experienced had at least 1 AE; and 10.9% of patients had decreased neutrophil count/neutropenia, which was the most common grade 3 or higher AE. Bleeding events occurred in 28.1% (n = 18) of patients at either grade 1 (21.9%) or grade 2 (6.3%). One patient had grade 2 fibrillation, which was a recurrence of ibrutinib intolerance (grade 3). This patient was given digoxin and is currently on zanubrutinib.

Fifteen (23.4%) patients experienced infections as grade 1 (1.6%), grade (17.2%), grade 3 (3.1%; COVID-19 and gastroenteritis salmonella), and grade 5 (1.6%; COVID-19–related pneumonia).


  1. Shadman M, Sharman JP, Levy MY, et al. Preliminary results of the phase 2 study of zanubrutinib in patients with previously treated B‑cell malignancies intolerant to ibrutinib and/or acalabrutinib. Presented at: 2021 Pan Pacific Lymphoma Conference; August 9-13, 2021; Big Island, HI.
  2. Dimopoulos M, Opat S, D’Sa S, et al. ASPEN: results of a phase 3 randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; virtual. Abstract S225.