Zanubrutinib, a potent, selective, and irreversible small-molecule inhibitor of Bruton's tyrosine kinase (BTK), is an antineoplastic agent.1, 2, 3, 4, 8, 9
Zanubrutinib is used for the treatment of mantle cell lymphoma in adults who have received at least one prior therapy.1, 2, 3 This indication is approved under accelerated approval based on overall response rate.1, 2, 3 Continued FDA approval may be contingent on verification and description of clinical benefit in additional trials.1 Zanubrutinib has been designated an orphan drug by FDA for the treatment of mantle cell lymphoma.5
This indication for zanubrutinib is based principally on the results of 2 multicenter, open-label, noncomparative studies (BGB-3111-206 and BGB-3111-AU-003) in patients with mantle cell lymphoma previously treated with at least one prior therapy.1, 2, 3 The primary measure of efficacy in both studies was overall response rate (as evaluated by an independent review committee according to the Lugano classification).1, 2
In the BGB-3111-206 study, 86 patients received zanubrutinib 160 mg orally twice daily until disease progression or unacceptable toxicity occurred.1, 2 The median age of patients enrolled in the study was 60.5 years (range: 34-75); 78% were male, 71% had extranodal involvement, 52% had refractory disease, and 14% had blastoid variant mantle cell lymphoma.1 Approximately one-half (58%) of patients had low-risk mantle cell lymphoma and 29 or 13% had intermediate- or high-risk disease, respectively.1 Patients enrolled in this study received a median of 2 prior therapies; 91 or 74% of patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy (e.g., R-CHOP) or rituximab-based chemotherapy (monotherapy or combination therapy), respectively.1, 7
In the BGB-3111-AU-003 study, patients with B-cell malignancies, including 32 patients with previously treated mantle cell lymphoma, received zanubrutinib 320 mg orally daily (administered once daily or in divided doses twice daily).1 The median age of patients with previously treated mantle cell lymphoma was 70 years (range: 42-86); 78% of these patients were Caucasian and 69% were male.1 Approximately one-half (41%) of these patients had intermediate-risk mantle cell lymphoma and 31 or 28% had high- or low-risk disease, respectively.1
In the BGB-3111-206 and BGB-3111-AU-003 studies, the overall response rate was 84% in patients with previously treated mantle cell lymphoma who received zanubrutinib; the median duration of response was 18.5-19.5 months.1, 2 Complete response was achieved in 59% or 22% of patients in the BGB-3111-206 or BGB-3111-AU-003 studies, respectively;1, 2 however, fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans were not required for response assessment in the BGB-3111-AU-003 study.1
Clinical practice guidelines from European experts provide recommendations for the treatment of mantle cell lymphoma, an uncommon type of B-cell non-Hodgkin lymphoma.25 Therapy is dependent on staging and/or age at time of diagnosis.25 In early disease, radiotherapy with conventional chemotherapy can be used in a small percentage of patients with small tumor burden.25 For more advanced disease or in the presence of high tumor burden, immunochemotherapy (e.g., rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is recommended, with a dose-intensified regimen for patients ≤65 years of age and conventional dosing for patients >65 years, followed by autologous stem cell transplantation (≤65 years only) plus rituximab maintenance therapy.25 For patients with relapsed disease, immunochemotherapy or targeted therapies with BTK inhibitors or lenalidomide are recommended.25
Waldenström's Macroglobulinemia
Zanubrutinib is used for the treatment of adults with Waldenström's macroglobulinemia.1 Zanubrutinib has been designated an orphan drug by FDA for the treatment of this cancer.5
This indication for zanubrutinib is based principally on the results of a multicenter, open-label, randomized, active control study (BGB-3111-302 or ASPEN).1, 19, 20 The study consisted of 2 separate cohorts: cohort 1 included patients with MYD88 L265P mutation (MYD88MUT) Waldenström's macroglobulinemia and cohort 2 consisted of patients with wild-type MYD88 MYD88WT Waldenström's macroglobulinemia.1, 19, 20 The primary measure of efficacy in cohort 1 was the proportion of patients achieving a complete response or very good partial response (CR/VGPR) (as evaluated by an independent review committee according to the standard consensus response criteria from the International Workshop on Waldenström's Macroglobulinemia-6 criteria).1, 19 Cohort 2 was exploratory in nature and did not have a prespecified primary efficacy endpoint.20
In cohort 1 of the ASPEN study, 102 patients with MYD88MU received zanubrutinib 160 mg orally twice daily and 99 patients received ibrutinib 420 mg once daily in 28-day cycles until disease progression or unacceptable toxicity occurred.19 The median age of patients enrolled in the study was 70 years (range: 38-90); 68% were male, 77% had extramedullary disease, 92% had bone marrow involvement, 82% had relapsed or refractory disease, and 18% were treatment-naïve and deemed unsuitable for standard immunotherapy.1, 19 Approximately 85% were in the intermediate or high prognostic category.19 The median IgM value was approximately 33 g/L (range: 2.4-108).19 Patients with relapsed or refractory disease received a median of 1 prior therapy (range: 1-8).1, 19
The rate of patients achieving CR/VGPR in cohort 1 of ASPEN was 28% with zanubrutinib compared with 19% with ibrutinib at a median follow-up of 19.4 months; the difference was not statistically significant.19 The response rate was similar when the relapsed or refractory and treatment-naïve patient groups were analyzed separately.19 Complete response was not achieved in any patients, very good partial response was achieved in 28%, partial response in 49%, and minimal response in 17% of patients treated with zanubrutinib.1, 19 Stable disease was reported in 3% of patients and progressive disease was reported in 2% of patients treated with zanubrutinib.19 The median duration of CR/VGPR was not estimable in either treatment arm.19 The proportion of patients with CR/VGPR persisting through 18 months was 93% and 64% for zanubrutinib and ibrutinib, respectively.19 Progression-free survival was 85% and 84% at 18 months for zanubrutinib and ibrutinib, respectively.19
In cohort 2 of the ASPEN study, 26 patients with MYD88WT received zanubrutinib 160 mg twice daily in 28-day cycles until disease progression or unacceptable toxicity.20 The median age of patients was 72 years (range: 39-87); 50% were male, 75% had extramedullary disease, 93% had bone marrow involvement, approximately 82% had relapsed or refractory disease, and 18% were treatment-naïve and deemed unsuitable for standard immunotherapy.20 Approximately 82% were in the intermediate or high prognostic category.20 The median IgM value was approximately 29 g/L.20 Patients with relapse or refractory disease received a median of 1 prior therapy.20
At a median follow-up of 17.9 months, no patients achieved a complete response, 27% achieved a very good partial response, 23% a partial response, and 31% a minimal response, resulting in a CR/VGPR rate of 27% and overall response rate of 81%.20 Stable disease was reported in 15% of patients and progressive disease was reported in 4% of patients.20 The proportion of patients with CR/VGPR persisting through 12 months was 75%; progression-free survival was 72% and overall survival was 96% at 12 months.20
Guidelines for the management of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma state that treatment should only be initiated in patients who are symptomatic; therefore, it is important to rule out symptoms related to comorbidities before treatment initiation.26 Additionally, due to the rare nature of Waldenström macroglobulinemia, the treatment approach has primarily been adopted from clinical data derived from phase II or retrospective studies.26
For those patients who need immediate disease control, initial plasmapheresis is recommended.26 After plasmapheresis, primary systemic therapy should begin as soon as possible with preferred regimens including bendamustine/rituximab, bortezomib/dexamethasone/rituximab, ibrutinib +/- rituximab, and zanubrutinib.26 In the setting of previously treated Waldenström macroglobulinemia, preferred regimens include all of the regimens listed prior for primary therapy plus rituximab/cyclophosphamide/dexamethasone.26 The guideline notes that many patients experience relapse after initial therapy and require further treatment.26 Administration of the same regimen used for primary treatment may be reasonable, particularly if the patient had a prolonged response and the regimen was well-tolerated.26
Zanubrutinib is used for the treatment of relapsed or refractory marginal zone lymphoma in adults who have received at least one prior anti-CD20-based regimen.1 This indication is approved under accelerated approval based on overall response rate.1, 21, 22 Continued FDA approval may be contingent on verification and description of clinical benefit in additional trials.1 Zanubrutinib has been designated an orphan drug by FDA for the treatment of marginal zone lymphoma.5
This indication for zanubrutinib is based principally on the results of 2 open-label, multicenter, single-arm trials: BGB-3111-214 and BGB-3111-AU-003.1, 21, 22 The trials included patients with histologically confirmed marginal zone lymphoma (including splenic marginal zone lymphoma, nodal marginal zone lymphoma, and extranodal subtypes) who required systemic therapy.1, 21, 22 Enrolled patients were required to have received at least one prior line of systemic therapy.21, 22 The primary measure of efficacy was overall response rate (as evaluated by an independent review committee based on the Lugano classification).21, 22
In the BGB-3111-214 study, 66 patients received zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity occurred.1 The median age of patients enrolled in the study was 70 years (range: 37-85); 55% were male, 38% had extranodal involvement, and 32% had refractory disease.1 The most common marginal zone lymphoma subtypes were extranodal and nodal, followed by splenic.21 The median number of prior therapies was 2 (range: 1-6), with 88% previously receiving a rituximab-based therapy.1, 21
In the BGB-3111-AU-003 study, 20 patients with relapsed or refractory marginal cell lymphoma received zanubrutinib 160 mg orally twice daily or 320 mg orally once daily until disease progression or unacceptable toxicity occurred.1, 22 The median age of patients was 70 years (range: 52-85); 50% were male, all patients had extranodal disease, and 20% had refractory disease.22 The most common marginal zone lymphoma subtype was extranodal (45%), followed by splenic (30%) and nodal (25%).22 The median number of prior therapies was 2 (range: 1-5), with 95% of included patients previously receiving a rituximab-based therapy.1
In the BGB-3111-214 study, the overall response rate of patients with previously treated marginal zone lymphoma was 56%.1 Complete response was achieved in approximately 20% of patients.1 At a median follow-up period of 8.3 months, the median duration of response had not been reached; the IRC-assessed duration of response rate at 12 months was 85%.1 In the BGB-3111-AU-003 study, the overall response rate of patients with previously treated marginal zone lymphoma was 80%.1 Four patients (20%) achieved complete response.1 At a median follow-up period of 31.4 months, the median duration of response had not been reached; the IRC-assessed duration of response rate was 72%.1
Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Zanubrutinib is used for the treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1 Zanubrutinib has been designated an orphan drug by FDA for the treatment of CLL.5 This indication for zanubrutinib is based principally on the results of 2 open-label, multicenter, randomized controlled trials: SEQUOIA and ALPINE.1, 23, 24
The SEQUOIA trial included patients with CLL or SLL who were unsuitable for fludarabine, cyclophosphamide, and rituximab therapy, which was defined as age ≥65 years or age 18 to <65 years with a total Cumulative Illness Rating Scale (CIRS) >6, creatinine clearance 30-69 mL/minute, or history of serious or recurrent infection.1, 23 In SEQUOIA, 479 patients with previously untreated CLL/SLL without a 17p deletion were randomly assigned to either zanubrutinib 160 mg orally twice daily until disease progression or unacceptable toxicity or bendamustine plus rituximab for 6 cycles.1, 23 In addition, the same regimen of zanubrutinib (160 mg orally twice daily) was assessed in a separate non-randomized cohort involving 110 patients with previously untreated CLL/SLL with a 17p deletion.1, 23
The median age of patients in the randomized cohort was 70 years (range: 66-75); 62% were male; 89% were white, 3% were Asian, and 1% were Black.1, 23 Thirty percent of patients in the randomized cohort had bulky disease, 53% possessed an unmutated IGHV gene, and 29% had Binet stage C disease.1, 23 The median age of patients in the non-randomized cohort was 70 years (range: 66-74); 71% were male; 95% were white and 1% were Asian.1, 23 In this cohort, 60% of patients had an unmutated IGHV gene and 35% had Binet stage C disease.1 Efficacy in the randomized cohort was based on progression-free survival assessed by an IRC, which was defined as time from randomization to progression or death without progression (whichever occurred first).1, 23 Efficacy in the nonrandomized cohort was based on overall response rate and duration of response as assessed by an IRC.1
Progression-free survival was significantly improved with zanubrutinib compared with bendamustine plus rituximab in the randomized cohort without 17p deletion; 36 (15%) patients in the zanubrutinib group experienced disease progression or death compared to 71 (30%) patients in the bendamustine plus rituximab group.1 At a median follow-up of 25 months, median progression-free survival had not been reached for the zanubrutinib group.1 The overall response rate was also improved with zanubrutinib versus bendamustine plus rituximab (93 versus 85%).1 For the non-randomized cohort with 17p deletion, the overall response rate was 88% and the median duration of response was not estimable.1 The estimated median follow-up for duration of response was 25.1 months based on Kaplan-Meier estimate.1
The ALPINE study included 652 adults with CLL or SLL who had relapsed or refractory disease after at least 1 prior systemic therapy.1, 24 The ALPINE investigators randomly assigned 327 patients to zanubrutinib 160 mg orally twice daily and 325 patients to ibrutinib 420 mg orally once daily, each given until disease progression or unacceptable toxicity.1, 24 The median age of enrolled patients was 67 years (range: 35-90); 68% were male; 81% were white, 14% were Asian, and 1% were Black.1, 24 An unmutated IGHV gene was present in 73% of patients, 43% had advanced stage disease, and 23% had a 17p deletion and/or TP53 mutation.1, 24 The median number of prior lines of therapy was 1.1, 24
Efficacy was based on overall response rate and duration of response as determined by an IRC.1 The overall response rate was 80% in the zanubrutinib group and 73% in the ibrutinib group; the median duration of response was not estimable in either group.1 The estimated median follow-up for duration of response was 14.1 months based on Kaplan-Meier estimate.1
Guidelines for CLL are available from the National Cancer Institute, with treatment individualized based on disease stage and clinical behavior.27 Observation may be an option for asymptomatic or minimally symptomatic patients.27 For symptomatic patients or patients with progressive CLL, first line agents include the BTK inhibitors acalabrutinib, zanubrutinib, and ibrutinib; venetoclax with initial use of obinutuzumab or rituximab; bendamustine and rituximab; fludarabine, cyclophosphamide, and rituximab; BTK inhibitor (ibrutinib or acalabrutinib) plus venetoclax; and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (only if Richter syndrome with histological progression is suspected clinically).27 Treatment recommendations are generally similar in guidelines on CLL from European experts.28, 29
Zanubrutinib is used for the treatment of adults with relapsed or refractory follicular lymphoma, in combination with obinutuzumab, after ≥2 lines of systemic therapy.1 This indication is approved under accelerated approval based on overall response rate and durability of response.1 Continued FDA approval for this indication may be contingent on verification and description of clinical benefit in additional trials.1 Zanubrutinib has been designated an orphan drug by FDA for the treatment of follicular lymphoma.5
Efficacy and safety of zanubrutinib, in combination with obinutuzumab, are based principally on the results from a phase 2 open-label, multicenter randomized study (ROSEWOOD).1, 30 The study enrolled 217 adult patients with relapsed or refractory follicular lymphoma who had received ≥2 prior systemic therapies (including an anti-CD20 antibody and an alkylating agent).1, 30 Enrolled patients also had to have presence of measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2, absence of transformation to aggressive B-cell lymphoma, and no prior BTK inhibitor exposure.30 The primary end point was overall response rate.30 Duration of response, progression-free survival, and overall survival were evaluated as secondary end points.30
Patients were randomly assigned (in a 2:1 ratio) to zanubrutinib 160 mg orally twice daily plus obinutuzumab 1000 mg IV on days 1, 8, and 15 of cycle 1, then on day 1 of cycles 2-6, then once every 8 weeks up to a total of 20 infusions or obinutuzumab monotherapy at the same dose.1, 30 Treatment with zanubrutinib was continued until disease progression or unacceptable toxicity occurred.1, 30 The median age of enrolled patients was 64 years (range, 31 to 88 years); 50% were male, 64% were white, and 22% were Asian.1 Stage 3 or 4 disease was present in 83% of patients and the median number of prior therapy lines was 3 (range, 2 to 11).1, 30
Results revealed a significant improvement in overall response rate with zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy (69% versus 46%; risk difference: 23%).1, 30 The complete response rate was 39% for combination therapy versus 19% for obinutuzumab monotherapy; the partial response rate was similar between the groups (30% versus 26%, respectively).1, 30 The median time to first response was 2.8 months in both groups.30 The median duration of response was not estimable in the zanubrutinib plus obinutuzumab group and 14 months in the obinutuzumab monotherapy group; the estimated median follow-up for duration of response was 19 months overall.1 Median progression-free survival was improved with combination therapy (28 versus 10.4 months).30 The estimated overall survival at 2 years was 77% with combination therapy and 71% for obinutuzumab monotherapy.30
Zanubrutinib capsules or tablets are given as monotherapy or in combination with obinutuzumab dependent upon indication for use.1 Zanubrutinib is administered orally once daily or in divided doses twice daily, without regard to meals.1
The capsules should be swallowed whole with a glass of water and should not be opened, broken, or chewed.1
The tablets should also be swallowed whole with a glass of water and should not be chewed or crushed, but may be split in half as prescribed by a clinician.1
If a dose of zanubrutinib is missed, the missed dose should be taken as soon as it is remembered on the same day; the next dose should be taken at the regularly scheduled time the following day.1
Zanubrutinib should be stored at 20-25°C (excursions permitted between 15-30°C).1
For the treatment of mantle cell lymphoma in adults who have received at least one prior therapy, the recommended dosage of zanubrutinib is 320 mg daily (administered once daily or in equally divided doses twice daily).1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Waldenström's Macroglobulinemia
For the treatment of Waldenström's macroglobulinemia in adults, the recommended dosage of zanubrutinib is 320 mg daily (administered once daily or in equally divided doses twice daily).1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of marginal zone lymphoma in adults who have received at least one anti-CD20-based therapy, the recommended dosage of zanubrutinib is 320 mg daily (administered once daily or in equally divided doses twice daily).1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults, the recommended dosage of zanubrutinib is 320 mg daily (administered once daily or in equally divided doses twice daily).1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of relapsed or refractory follicular lymphoma in adults, in combination with obinutuzumab after ≥2 lines of therapy, the recommended dosage of zanubrutinib is 320 mg daily (administered once daily or in equally divided doses twice daily).1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
Zanubrutinib therapy should be withheld for the occurrence of grade 3 or higher nonhematologic toxicity, grade 3 or grade 4 febrile neutropenia, grade 3 thrombocytopenia with significant bleeding, or prolonged (i.e., lasting longer than 10 consecutive days) grade 4 thrombocytopenia or neutropenia.1 Upon resolution or improvement of the toxicity (i.e., return to baseline or resolution to ≤grade 1), dosage modification of zanubrutinib therapy may be necessary (see Table 1).1
No dosage adjustment is necessary in patients with asymptomatic lymphocytosis with CLL and mantle cell lymphoma.1
Clinicians should refer to the obinutuzumab prescribing information for management of obinutuzumab-related adverse reactions.1
Toxicity Occurrence | Dosage Modification after Recovery from Toxicity Initial Dosage = 160 mg twice daily | Dosage Modification after Recovery from Toxicity Initial Dosage = 320 mg once daily |
|---|---|---|
First | Resume at same dosage | Resume at same dosage |
Second | Resume at 80 mg twice daily | Resume at 160 mg once daily |
Third | Resume at 80 mg once daily | Resume at 80 mg once daily |
Fourth | Discontinue zanubrutinib | Discontinue zanubrutinib |
Dosage Modification for Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes
Recommended dosage modifications of zanubrutinib with concomitant use of CYP3A inhibitors or inducers are provided in Table 2.1 The dosage of zanubrutinib should be modified or interrupted as recommended for adverse reactions.1 In addition, after discontinuation of a CYP3A inhibitor or moderate CYP3A inducer, the previous zanubrutinib dosage should be resumed.1
Concomitant Drug | Recommended Zanubrutinib Dosage Initial Dosage = 160 mg twice daily or 320 mg once daily |
|---|---|
Clarithromycin 250 mg twice daily | 80 mg twice daily |
Clarithromycin 500 mg twice daily | 80 mg once daily |
Posaconazole suspension 100 mg once daily | 80 mg twice daily |
Posaconazole suspension dosage >100 mg once daily Posaconazole delayed-release tablets 300 mg once daily Posaconazole 300 mg IV once daily | 80 mg once daily |
Other strong CYP3A inhibitor | 80 mg once daily |
Moderate CYP3A inhibitor | 80 mg twice daily |
Strong CYP3A inducer | Avoid concomitant use |
Moderate CYP3A inducer | Avoid concomitant use; if inducers can not be avoided, increase zanubrutinib dosage to 320 mg twice daily |
For patients with severe hepatic impairment (Child-Pugh class C), the manufacturer recommends a zanubrutinib dosage of 80 mg twice daily.1 Dosage adjustment is not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Patients with hepatic impairment should be monitored for signs of toxicity.1
Dosage adjustment is not recommended in patients with mild to severe renal impairment (creatinine clearance of ≥15 mL/minute).1 Patients undergoing dialysis should be monitored for signs of zanubrutinib toxicity.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Serious hemorrhagic events, sometimes fatal, have occurred in patients with hematologic malignancies receiving zanubrutinib.1 In clinical trials, hemorrhagic events (all grades), excluding purpura and petechiae, were reported in 32% of patients receiving zanubrutinib.1 Grade 3 or higher hemorrhagic events (i.e., intracranial or GI hemorrhage, hematuria, hemothorax) were reported in 3.8% of patients receiving zanubrutinib, with fatalities reported in 0.2% of patients.1 The mechanism of bleeding with zanubrutinib therapy has not been elucidated; however, in vitro studies have demonstrated inhibition of thrombin generation with zanubrutinib.7
Although hemorrhagic events have been reported in patients receiving zanubrutinib regardless of concomitant antiplatelet or anticoagulant therapy, the risk of hemorrhage may be increased in patients receiving concomitant antiplatelet or anticoagulant therapy.1
Because of the risk of bleeding, the potential benefits and risks of withholding zanubrutinib therapy for 3-7 days prior to and following surgery (based on the type of surgery and bleeding risk) should be considered.1
Patients should be monitored for signs and symptoms of bleeding.1 If intracranial hemorrhage occurs, zanubrutinib therapy should be discontinued.1
Serious and sometimes fatal infections, including bacterial, fungal, viral, or other opportunistic infections, have been reported in patients with hematologic malignancies receiving zanubrutinib.1 Grade 3 or higher infections occurred in 26% of patients receiving zanubrutinib.1 The most commonly reported grade 3 or higher infection was pneumonia, with fatal infections occurring in 3.2% of patients.1 Infections caused by hepatitis B virus (HBV) reactivation also have been reported.1
Patients should be monitored for signs and symptoms of infection (e.g., fever) and appropriate anti-infective treatment should be initiated as clinically indicated.1 Prophylaxis for herpes simplex virus (HSV) infection, Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia (PCP), and other infections according to current standards of care should be considered in patients who are at increased risk for infections.1
Cytopenias, including neutropenia, thrombocytopenia, and anemia, have been reported in patients receiving zanubrutinib.1 Grade 3 or 4 neutropenia, thrombocytopenia, or anemia was reported in 21, 8, or 8%, respectively, of patients receiving zanubrutinib.1 Grade 4 neutropenia or thrombocytopenia was reported in 10 or 2.5%, respectively, of patients receiving zanubrutinib.1
Complete blood counts (CBCs) should be monitored regularly during zanubrutinib therapy.1 In patients who develop hematologic toxicity, temporary interruption of therapy followed by dosage reduction or permanent discontinuation of therapy may be required ; appropriate therapeutic measures (e.g., hematopoietic growth factor or transfusion) should be instituted as necessary.1
Development of Second Primary Malignancy
Second primary malignancies, including non-skin carcinomas, have occurred in 14% of patients with hematologic malignancies receiving zanubrutinib.1 Non-melanoma skin cancer was the most frequent second primary malignancy, occurring in 8% of zanubrutinib-treated patients.1 Other second primary malignancies reported include malignant solid tumors, melanoma, or hematologic malignancies reported in 7, 1, or 0.7% of patients, respectively.1 Patients receiving the drug should be monitored for the development of second primary malignancies and should be advised to protect themselves from sun exposure.1
Serious cardiac arrhythmias have been reported with zanubrutinib therapy.1 Atrial fibrillation and flutter have been reported in 4.4% of patients receiving zanubrutinib.1 Grade 3 or higher atrial fibrillation and flutter occurred in 1.9% of patients.1 The risk for atrial fibrillation and flutter is increased in those with cardiac risk factors, hypertension, or acute infection.1 Grade 3 or higher ventricular arrhythmias were seen in 0.3% of patients.1
Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort) and institute appropriate management.1 Consider the risks and benefits of continued zanubrutinib therapy.1
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury, has been reported with zanubrutinib therapy.1
Bilirubin and transaminases should be evaluated at baseline and during therapy.1 In patients who develop abnormal liver tests, monitor more frequently for liver test abnormalities and clinical manifestations of hepatotoxicity.1 Zanubrutinib should be withheld if drug-induced livery injury is suspected and discontinued upon confirmation.1
Fetal/Neonatal Morbidity and Mortality
Based on animal findings, zanubrutinib may cause fetal harm if administered to pregnant women.1 Embryofetal toxicity (e.g., postimplantation loss) and teratogenicity (e.g., cardiac malformations) have been demonstrated in animals receiving zanubrutinib at exposure levels of approximately 32 and 5 times, respectively, the human exposure at the recommended twice-daily dosage.1, 7 In a pre- and postnatal development study in pregnant rats, administration of zanubrutinib at exposure levels approximately 5 times the human exposure at the recommended twice-daily dosage from implantation through weaning resulted in adverse ocular findings (e.g., cataract, protruding eye).1
Pregnancy should be avoided during zanubrutinib therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of zanubrutinib therapy in women of reproductive potential and that such women should be advised to use effective contraceptive methods while receiving the drug and for one week after the last dose.1 In addition, men should avoid fathering a child during and for one week after the last dose.1 If zanubrutinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Zanubrutinib may cause fetal harm if administered to pregnant women based on animal findings.1 There are no available data on zanubrutinib use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1
It is not known whether zanubrutinib or its metabolites are distributed into human milk or if the drug has any effect on milk production or the nursing infant.1 Because of the potential for adverse reactions to zanubrutinib in nursing infants, women should be advised to discontinue nursing during zanubrutinib therapy and for 2 weeks after the last dose.1
Females and Males of Reproductive Potential
A pregnancy test should be performed prior to initiation of zanubrutinib therapy in women of reproductive potential and such women should be advised to use effective contraceptive methods while receiving the drug and for 1 week after the last dose.1 In addition, men should avoid fathering a child during and for 1 week after the last dose.1
Safety and efficacy of zanubrutinib have not been established in pediatric patients.1
In clinical trials, 59% of zanubrutinib-treated patients were ≥65 years of age, while 21% were ≥75 years of age.1 Increased rates of grade 3 or higher adverse reactions (57% versus 51%) and serious adverse reactions (38% versus 29%) were seen in patients ≥65 years of age as compared to patients <65 years of age.1 No clinically important differences in efficacy were observed between geriatric patients and younger adults.1
Following administration of a single 80-mg dose of zanubrutinib in individuals with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment, total exposure to zanubrutinib was increased by 11, 21, or 60%, respectively, and exposure to unbound zanubrutinib was increased by 23, 43, or 194%, respectively, compared with individuals with normal hepatic function.1, 7
Dosage adjustment is required in patients with severe hepatic impairment.1 Dosage adjustment is not necessary in patients with mild or moderate hepatic impairment; however, the manufacturer recommends monitoring for signs of toxicity in such patients.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of zanubrutinib are not substantially altered in patients with mild, moderate, or severe renal impairment (creatinine clearance of ≥15 mL/minute).1 Because limited data are available in patients undergoing dialysis, the manufacturer recommends monitoring for signs of toxicity in such patients.1, 7
Adverse effects reported in ≥30% of patients receiving zanubrutinib, including laboratory abnormalities, are decreased neutrophil count, decreased platelet count, upper respiratory tract infection, hemorrhage, and musculoskeletal pain.1
Zanubrutinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A.1
In vitro studies suggest that zanubrutinib is an inducer of CYP2B6 and CYP2C8.1 In vivo, zanubrutinib is a weak inducer of CYP isoenzymes 3A4 and 2C19.7
In vitro studies also suggest that zanubrutinib is a substrate and inhibitor of P-glycoprotein (P-gp), but is not a substrate or inhibitor of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, organic anion transporting polypeptide (OATP) 1B1, or OATP1B3.1, 7
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of zanubrutinib with strong or moderate inhibitors of CYP3A may result in increased systemic exposure to zanubrutinib and possible toxicity.1 When the strong CYP3A4 inhibitor itraconazole (200 mg once daily) was administered concomitantly with zanubrutinib (20-mg dose) in healthy individuals, peak plasma concentration and AUC of zanubrutinib increased by 157 and 278%, respectively.1, 7 Simulations using physiologically based pharmacokinetic models suggest concomitant use of zanubrutinib and other strong or moderate CYP3A4 inhibitors (i.e., clarithromycin, diltiazem, erythromycin, fluconazole) may increase peak plasma concentration and AUC of zanubrutinib by 151-284 and 157-317%, respectively.1, 7
If concomitant use of zanubrutinib with a strong or moderate inhibitor of CYP3A is necessary, reduce the zanubrutinib dosage (see Table 2).1
Concomitant use of zanubrutinib with strong or moderate inducers of CYP3A may result in decreased systemic exposure to zanubrutinib and reduce zanubrutinib efficacy.1 When the strong CYP3A inducer rifampin (600 mg daily) was administered concomitantly with zanubrutinib (320-mg dose), peak plasma concentration and AUC of zanubrutinib decreased by 92 and 93%, respectively.1, 7 Simulations using physiologically based pharmacokinetic models suggest concomitant use of zanubrutinib and the moderate CYP3A4 inducer efavirenz (600 mg daily) may decrease peak plasma concentration and AUC of zanubrutinib by 58 and 60%, respectively.1, 7
Concomitant use of zanubrutinib with strong or moderate CYP3A inducers should be avoided.1 If concomitant use of a moderate CYP3A inducer is necessary, increase the zanubrutinib dosage to 320 mg twice daily (see Table 2).1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant use of zanubrutinib (160 mg twice daily) and the CYP3A substrate midazolam (single 2-mg dose) decreased peak plasma concentration and AUC of midazolam by 30 and 47%, respectively.1, 7
Concomitant use of zanubrutinib (160 mg twice daily) and the CYP2C19 substrate omeprazole (single 20-mg dose) decreased peak plasma concentration and AUC of omeprazole by 20 and 36%, respectively.1, 7
Substrates of Other CYP Isoenzymes
Concomitant use of zanubrutinib (160 mg twice daily) and the CYP2C9 substrate warfarin sodium (single 10-mg dose) had no clinically important effect on the pharmacokinetics of warfarin.1, 7
Substrates of Efflux Transport Systems
Concomitant use of zanubrutinib (160 mg twice daily) and the P-gp substrate digoxin (single 0.25-mg dose) increased peak plasma concentration and AUC of digoxin by 34 and 11%, respectively.1, 7
Concomitant use of zanubrutinib (160 mg twice daily) and the BCRP, OATP1B1, and OATP1B3 substrate rosuvastatin (single 10-mg dose) had no clinically important effect on the pharmacokinetics of rosuvastatin.1, 7
Drugs Affecting Gastric Acidity
Concomitant use of zanubrutinib and drugs that increase the pH of the upper GI tract (e.g., histamine H2-receptor antagonists, proton-pump inhibitors) had no clinically important effect on the pharmacokinetics of zanubrutinib.1
Anticoagulants and Antiplatelet Agents
Concomitant use of zanubrutinib with antiplatelet or anticoagulant therapy may increase the risk of hemorrhage.1
Zanubrutinib is a potent, selective, and irreversible, small-molecule inhibitor of Bruton's tyrosine kinase (BTK); the drug is an antineoplastic agent.1, 2, 3, 4, 8, 9, 10 BTK, a member of the tyrosine protein kinase (Tec) family of kinases, is positioned early within the B-cell antigen receptor (BCR) signaling pathway.14, 15, 16 BCR is involved in the initiation of various cascades of intracellular signaling events, including activation of BTK, which leads to cell proliferation, differentiation, apoptosis, and cell migration essential for the development and survival of normal and malignant B cells.1, 3, 4, 9, 15, 17, 18 Zanubrutinib binds covalently with a cysteine residue in the BTK active site, resulting in inhibition of BTK enzymatic activity.1, 3, 8, 10
In nonclinical studies, zanubrutinib inhibited the proliferation of malignant B cells and reduced tumor growth.1, 8 Inhibition of BTK also reduces plasma concentrations of cytokines and chemokines, which may lead to decreased cell adhesion and mobilization of cells from tissues;12 this redistribution of cells from tissues to peripheral blood may contribute to the transient increase in absolute lymphocyte count (lymphocytosis) that has been observed in patients receiving BTK inhibitors.1, 3, 9, 12 Unlike ibrutinib (another BTK inhibitor used to treat mantle cell lymphoma), zanubrutinib does not appear to target kinases other than BTK, including epidermal growth factor receptor (EGFR), tyrosine kinase expressed in hepatocellular carcinoma (TEC), and interleukin 2-inducible T-cell kinase (ITK).3, 4, 10
Systemic exposure to zanubrutinib increases in a dose proportional manner over a dosage range of 40-320 mg.1, 3 Minimal accumulation of the drug occurs with repeated dosing.1, 3 Median peak plasma concentrations of the drug are attained in 2 hours following oral administration.1, 3 Zanubrutinib is approximately 94% bound to plasma proteins and the blood to plasma ratio is 0.7-0.8.1 Zanubrutinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A.1 Following administration of a single 320-mg radiolabeled dose of zanubrutinib, approximately 87% of the dose was recovered in feces (38% as unchanged drug) and 8% was recovered in urine (less than 1% as unchanged drug).1 The mean half-life of zanubrutinib is approximately 2-4 hours.1 In patients with B-cell malignancies receiving zanubrutinib at a total daily dosage of 320 mg, median steady-state binding of the drug to BTK (BTK occupancy) in peripheral blood mononuclear cells was maintained at 100% over 24 hours, and median steady-state binding of the drug to BTK in lymph nodes was 94-100%.1, 7, 10 The recently approved tablet formulation of zanubrutinib is clinically interchangeable with the capsule formulation; administration results in a reduced pill burden.31
The pharmacokinetics of zanubrutinib do not appear to be affected substantially by age (19-90 years), sex, race, body weight (36-144 kg), or mild to severe renal impairment.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Zanubrutinib is available only from designated specialty pharmacies and distributors.6 The manufacturer should be contacted for additional information.6
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 80 mg | BeOne Medicines USA, Inc. | |
Tablets | 160 mg | Brukinsa® | BeOne Medicines USA, Inc. |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions March 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. BeOne Medicines USA, Inc. Brukinsa® (zanubrutinib) prescribing information. Pennington, NJ; 2025 Jun.
2. Song Y, Zhou K, Zou D et al. Safety and Activity of the Investigational Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Mantle Cell Lymphoma from a Phase 2 Trial . Blood . 2018; 132:148.
3. Tam CS, Trotman J, Opat S et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood . 2019; 134:851-9.
4. Wu, J, Liu, C, Tsui ST. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol . 2016; 9(1):1-7. [PubMed 27590878]
5. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
6. BeOne Medicines USA, Inc. Brukinsa® (zanubrutinib) Access To Brukinsa. From the BeiGene website. [Web]
7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 213217Orig1s000: Multi-discipline review(s). From FDA website. [Web]
8. Li CJ, Jiang C, Liu Y et al. Pleiotropic Action of Novel Bruton's Tyrosine Kinase Inhibitor BGB-3111 in Mantle Cell Lymphoma. Mol Cancer Ther . 2019; 18:267-77. [PubMed 30413649]
9. Bond, DA, Alinari, L, Maddocks, K. Bruton tyrosine kinase inhibitors for the treatment of mantle cell lymphoma: review of current evidence and future directions. Clin Adv Hematol Oncol . 2019; 17:223-33. [PubMed 31188814]
10. Tam CS, LeBlond V, Novotny W et al. A head-to-head Phase III study comparing zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia. Future Oncol . 2018; 14:2229-37. [PubMed 31188814]
12. Chang, BY, Francesco M, De Rooij MF et al. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood . 2013; 122:2414-24. [PubMed 23940282]
14. Advani RH, Buggy JJ, Sharman JP et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol . 2013; 31:88-94. [PubMed 23045577]
15. Dasmahapatra G, Patel H, Dent P et al. The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. Br J Haematol . 2013; 161:43-56. [PubMed 23360303]
16. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood . 2012; 120:1175-84. [PubMed 22715122]
17. Chavez JC, Sahakian E, Pinilla-Ibarz J. Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia. Core Evid . 2013; 8:37-45. [PubMed 23717217]
18. Dias AL, Jain D. Ibrutinib: A New Frontier in the Treatment of Chronic Lymphocytic Leukemia by Bruton's Tyrosine Kinase Inhibition. Cardiovasc Hematol Agents Med Chem . 2013; 11:265-71. [PubMed 24433470]
19. Tam CS, Opat S, D'Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenstrom macroglobulinemia: the ASPEN study. Blood . 2020;136(18):2038-2050.
20. Dimopoulos M, Sanz RG, Lee HP, et al. Zanubrutinib for the treatment of MYD88 wild-type Waldenstrom macroglobulinemia: a substudy of the phase 3 ASPEN trial. Blood Adv . 2020;4(23):6009-6018.
21. Opat S, Tedeschi A, Linton K, et al. The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma. Clin Cancer Res . 2021;27(23):6323-6332.
22. Phillips T, Chan H, Tam CS, et al. Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. Blood Adv . 2022;6(11):3472-3479.
23. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukemia and small lymphocytic lymphoma (SEQUIOA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23:1031-1043.
24. Brown JP, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lympocytic leukemia. N Engl J Med. 2023;388:319-332.
25. Dreyling M, Campo E, Jerkeman M, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv62-iv71.
26. Kumar SK, Callander NS, Adekola K, et al. Waldenström macroglobulinemia/lymphoplasmacytic lymphoma, Version 2.2024. J Natl Compr Canc Netw. 2024;(1D):e24001.
27. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ)-Health Professional Version. [Web]
28. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(1):23-33.
29. Eichhorst B, Ghia P, Niemann CU, et al on behalf of the ESMO Guidelines Committee. ESMO clinical practice guideline interim update on new targeted therapies in the first line and at relapse of chronic lymphocytic leukemia. Ann Oncol. 2024;35(9):762-767.
30. Zinzani PL, Mayer J, Flowers CR, et al. ROSEWOOD: a phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol. 2023;41(33):5107-5117.
31. Tariq B, Lin C, Mundra V, et al. Relative bioavailability, food effect, and bioequivalence studies to assess a new zanubrutinib 160-mg tablet: results from 2 phase 1 studies in healthy volunteers. Clin Pharmacol Drug Dev. 2025;1-12.