CONSISTENT SAFETY ACROSS LINES OF THERAPY,
INCLUDING LOW RATES OF CARDIAC EVENTS IN 1L AND 2L CLL

1L: SEQUOIA

SEQUOIA (STUDY 304)
COHORT 1: OVERALL INCIDENCE OF ADVERSE REACTIONS (ARs)*1,2

Adverse Reactions ARs in ≥10% of Patients Without Del(17p) Pooled Safety Population†
BRUKINSA (n=240) BR (n=227) BRUKINSA (N=1729)
All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%)
Musculoskeletal pain 33 2 17 0.4 24 2
Upper respiratory tract infection 28 1 15 0.9 38 3
Pneumonia 13‡ 5 8§ 4 17 11
Hemorrhage 27‡ 4 4 0.4 32 4
Hypertension 14 7 5 3 14 7
Rash 24 1 30 5 25 0.6
Bruising 24 0 3 0 21 0.1
Cough 15 0 10 0 20 0.1
Diarrhea 14 0.8 12§ 0.9 20 2
Constipation 10 0.4 18 0 13 0.3
Nausea 10 0 33 1 11 0.2
Fatigue 14 1 21 2 18 1
Second primary malignancy 13‡ 6 1 0.4 15 7
Headache 12 0 8 0 11 0.3
Dizziness 11 0.8 5 0 11 0.3

*Median duration of exposure was 26.1 months for BRUKINSA and 5.6 months for BR in Cohort 1.3

†Includes chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, hairy cell leukemia, diffuse large B-cell lymphoma, and Richter’s transformation.2

‡Includes 3 fatal outcomes.1

§Includes 2 fatal outcomes.1

Adverse reactions at ~5 years reported in ≥10% of patients (BRUKINSA vs BR, respectively) in the SEQUOIA trial (Cohort 1) included: COVID-19 (39% vs 12%), contusion (22% vs 4%), diarrhea (21% vs 14%), upper respiratory tract infection (20% vs 14%), hypertension (20% vs 12%), arthralgia (19% vs 11%), fatigue (18% vs 18%), cough (16% vs 11%), rash (14% vs 20%), nausea (14% vs 33%), constipation (14% vs 19%), pneumonia (14% vs 11%), neutropenia (13% vs 46%), vomiting (13% vs 15%), urinary tract infection (13% vs 10%), headache (12% vs 11%), back pain (12% vs 8%), pyrexia (11% vs 27%), edema peripheral (11% vs 9%), dizziness (11% vs 5%), pain in extremity (11% vs 7%), pruritus (10% vs 8%).4

Median duration of exposure at ~5 years was 60.5 months for BRUKINSA and 5.6 months for BR.4

SEQUOIA (STUDY 304)
COHORT 2: OVERALL INCIDENCE OF ARs*1,2

Adverse Reactions ARs in ≥10% of Patients With Del(17p) Pooled Safety Population†
BRUKINSA (n=111) BRUKINSA (N=1729)
All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%)
Upper respiratory tract infection 38 0 38 3
Pneumonia 20‡ 8 17 11
Musculoskeletal pain 38 3 24 2
Rash 28 0 25 0.6
Bruising 26 0.9 21 0.1
Hemorrhage 28 5 32 4
Hypertension 11 5 14 7
Second primary malignancy 22§ 6 15 7
Diarrhea 18 0.9 20 2
Nausea 16 0 11 0.2
Constipation 15 0 13 0.3
Abdominal pain 12 2 11 0.9
Cough 18 0 20 0.1
Dyspnea 13 0 8 0.6
Fatigue 14 0.9 18 1
Headache 11 2 11 0.3

*Median duration of exposure was 30 months in Cohort 2.3

†Includes chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, hairy cell leukemia, diffuse large B-cell lymphoma, and Richter’s transformation.2

‡Includes 1 fatal outcome.1

§Includes non-melanoma skin cancer in 13%.1

Adverse reactions at ~5 years reported in ≥15% of BRUKINSA patients in the SEQUOIA trial (Cohort 2) included: COVID-19 (33%), upper respiratory tract infection (28%), arthralgia (26%), diarrhea (22%), contusion (22%), back pain (19%), constipation (19%), nausea (18%), cough (18%), basal cell carcinoma (17%), rash (17%), fall (17%), hypertension (16%), urinary tract infection (16%), and pneumonia (15%).5

Median follow-up was 65.8 months.5

There were no new safety signals at ~5 years with BRUKINSA4

SEQUOIA (STUDY 304): INCIDENCE OF LABORATORY ABNORMALITIES*1

Select Lab Abnormalities (≥20%) That Worsened From Baseline in Cohorts 1 and 2

Laboratory Abnormality Cohort 1:
Patients Without Del(17p)		 Cohort 2:
Patients With Del(17p)
BRUKINSA (n=239)† BR (n=227)† BRUKINSA (n=111)‡
All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%)
Neutrophils decreased 37 15 80 53 42 19§
Hemoglobin decreased 29 3 66 8 26 4
Platelets decreased 27 2 61 11 23 0.9
Leukocytes increased 21 21 0.4 0.4 NR NR
Glucose increased# 55 7 67 10 52 6
Creatinine increased 22 0.8 18 0.4 27 0.9
Magnesium increased 22 0 14 0.4 31 0
Alanine aminotransferase increased 21 2 23 2 NR NR

*Median duration of exposure was 26.1 months for BRUKINSA and 5.6 months for BR in Cohort 1, and 30 months for BRUKINSA in Cohort 2.3

†In Cohort 1, the denominator used to calculate the rate was 239 in the BRUKINSA arm and 227 in the BR arm, based on the number of patients with a baseline value and at least 1 post-treatment value. Grading is based on NCI CTCAE criteria.1

‡In Cohort 2, the denominator used to calculate the rate varied from 110 to 111 based on the number of patients with a baseline value and at least 1 post-treatment value. Grading is based on NCI CTCAE criteria.1

§Grade 4, 9%.1

Lymphocytes increased in 15%.1

#Patients on study were not required to fast for lab tests.1

SEQUOIA (STUDY 304): SELECT ADVERSE EVENTS (AEs) OF SPECIAL INTEREST*1-3

Adverse Events SEQUOIA Pooled Safety Population†
BRUKINSA (n=240) BR (n=227) BRUKINSA (N=1729)
All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%)
Fatigue 12 1 15 0.9 18 1
Headache 11 0 7 0 11 0.3
Myalgia 4 0 1 0 4 0.3
Arthralgia 13 0.8 9 0.4 14 0.6
Atrial fibrillation/flutter 3 0.4 3 1 4 2
Hypertension 14 6 11 5 14 7
Major bleeding‡ 5 4 2 2 5 4

*Median duration of exposure was 26.1 months for BRUKINSA and 5.6 months for BR in Cohort 1.3

†Includes chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, hairy cell leukemia, diffuse large B-cell lymphoma, and Richter’s transformation.2 

‡In SEQUOIA, major bleeding included subdural hematoma and subdural hemorrhage.3

SEQUOIA (STUDY 304):
LOWER RATES OF DOSE REDUCTIONS AND DISCONTINUATION DUE TO AEs3

Rates of dose reduction and discontinuation from SEQUOIA

SEQUOIA (STUDY 304):
LOW RATES OF AFIB IN PATIENTS WITHOUT DEL(17p) AT THE INITIAL ANALYSIS3

Rates of afib/flutter in patients without del(17p)/TP53 for BRUKINSA® (zanubrutinib) vs BR
  • Grade ≥3 rate of afib was 0.4% with BRUKINSA vs 1.3% with BR
Rates of afib remained consistent at the ~5-year milestone4

Median duration of treatment at the initial analysis in Cohort 1 was 26.1 months for BRUKINSA and 5.6 months for BR; in Cohort 2 it was 30 months for BRUKINSA.3

1L=first line; 2L=second line; afib=atrial fibrillation; BR=bendamustine+rituximab; CLL=chronic lymphocytic leukemia; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; NR=not reported.

2L: ALPINE

ALPINE (STUDY 305): OVERALL INCIDENCE OF ADVERSE REACTIONS (ARs)*1,2

Adverse Reactions ARs in ≥10% of Patients Pooled Safety Population†
BRUKINSA (n=324) Ibrutinib (n=324) BRUKINSA (N=1729)
All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%)
Upper respiratory tract infection 27 1 22 1 38 3
Pneumonia 18‡ 9 19§ 11 17 11
COVID-19 14‡ 7 10§ 5 10 5
Musculoskeletal pain 26 0.6 28 0.6 24 2
Hemorrhage 24‡ 3 26§ 4 32 4
Hypertension 19 13 20 13 14 7
Rash 20 1 21 0.9 25 0.6
Bruising 16 0 14 0 21 0.1
Diarrhea 14 2 22 0.9 20 2
Fatigue 13 0.9 14 0.9 18 1
Cough 11 0.3 11 0 20 0.1
Dizziness 10 0 7 0 11 0.3

Rates of hypertension were comparable between BRUKINSA and ibrutinib1

  • A medical history of hypertension was reported in more than half of these patient events for both BRUKINSA and ibrutinib2

*Median duration of exposure was 28.4 months for BRUKINSA and 24.3 months for ibrutinib.6

†Includes chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, hairy cell leukemia, diffuse large B-cell lymphoma, and Richter’s transformation.2

‡Includes fatal outcomes: pneumonia (9 patients), COVID-19 (8 patients), and hemorrhage (1 patient).1

§Includes fatal outcomes: pneumonia (10 patients), COVID-19 (9 patients), and hemorrhage (2 patients).1

Adverse events at ~3.5 years reported in ≥10% of patients (BRUKINSA vs ibrutinib, respectively) in the ALPINE trial included: COVID-19 (46% vs 33%), neutropenia (32% vs 30%), upper respiratory tract infection (29% vs 20%), hypertension (27% vs 25%), diarrhea (19% vs 26%), arthralgia (17% vs 19%), anemia (17% vs 19%), pneumonia (15% vs 17%), contusion (15% vs 12%), and fatigue (11% vs 15%).7

Median duration of exposure at ~3.5 years was 41.2 months for BRUKINSA and 37.8 months for ibrutinib.7

There were no new safety signals at ~3.5 years with BRUKINSA7

ALPINE (STUDY 305): INCIDENCE OF LAB ABNORMALITIES*1

Select Lab Abnormalities (≥20%) That Worsened From Baseline

Laboratory Abnormality BRUKINSA (n=321) Ibrutinib (n=321)†
All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%)
Neutrophils decreased 43 15 33 16
Hemoglobin decreased 28 4 32 4
Lymphocytes increased 24 19 26 19
Platelets decreased 22 4 24 3
Glucose increased‡ 52 5 29 3
Creatinine increased 26 0 23 0
Phosphate decreased 21 3 13 2
Calcium decreased 21 0.6 29 0

*Median duration of exposure was 28.4 months for BRUKINSA and 24.3 months for ibrutinib.6

†The denominator used to calculate rates of lab abnormalities varied from 320 to 321 in the ibrutinib arm based on the number of patients with a baseline value and at least 1 post-treatment value. Grading is based on NCI CTCAE criteria.

‡Patients on study were not required to fast for lab tests.

LOW RATES OF CARDIAC DISORDERS, INCLUDING AFIB/FLUTTER, AND NO CARDIAC DEATHS AT THE ~3.5-YEAR MILESTONE vs IBRUTINIB*7

Afib/flutter
all grades

Cumulative event rate of afib/flutter at ~3 years from ALPINE

*Median duration of treatment: 28.4 months in the initial analysis and 41.2 months in the milestone analysis.6,7

Cardiac AEs Initial Analysis6,8 ~3.5-Year Milestone7
BRUKINSA (n=324) Ibrutinib (n=324) BRUKINSA (N=324) Ibrutinib (n=324)
Cardiac AEs 69 (21%) 96 (30%) 84 (26%) 115 (36%)
Serious cardiac AEs 6 (2%) 25 (8%) 13 (4%) 32 (10%)
Cardiac AEs leading to treatment discontinuation 1 (0.3%)* 14 (4%)† 3 (0.9%)‡ 16 (5%)§
Fatal cardiac AEs 0 (0%) 6 (2%) 0 (0%) 6 (2%)

6 cardiovascular (CV) deaths occurred with ibrutinib in patients with and without a history of CV risk
No deaths occurred with BRUKINSA6,7

  • Early onset death: 3 of the fatal cardiac events occurred within 4 months after initiation of ibrutinib in patients with coexisting cardiac conditions
  • Late onset death: 3 of the fatal cardiac events occurred 2-3 years after the initiation of ibrutinib, including in 1 patient who had no history of cardiac disorders

*BRUKINSA cardiac-related discontinuation in 1 patient was for ventricular extrasystoles.6

†Ibrutinib cardiac-related discontinuations were for atrial fibrillation (5), cardiac arrest (2), cardiac failure (2), cardiac failure acute (1), congestive cardiomyopathy (1), myocardial infarction (1), palpitations (1), and ventricular fibrillation (1).6

‡Cardiac AEs leading to treatment discontinuation included ventricular extrasystoles, atrial fibrillation/flutter, and cardiac failure for BRUKINSA.7

§Cardiac AEs leading to treatment discontinuation included atrial fibrillation/flutter, cardiac arrest, cardiac failure, cardiac failure acute, congestive cardiomyopathy, myocardial infarction, palpitations, and ventricular fibrillation for ibrutinib.7

SELECT ARs OF SPECIAL INTEREST IN ALPINE (STUDY 305)*1,2,6

Adverse Reactions ALPINE Pooled Safety Population†
BRUKINSA (n=324) Ibrutinib (n=324) BRUKINSA (N=1729)
All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%)
Fatigue 13 0.9 14 0.9 18 1
Headache 8 0 9 0 11 0.3
Myalgia 3 0 4 0 4 0.3
Arthralgia 14 0 15 0.3 14 0.6
Atrial fibrillation and flutter 5 3 13 4 4 2
Hypertension 19 13 20 13 14 7
Major hemorrhage‡ 4 3 4 4 5 4

*Median duration of exposure was 28.4 months for BRUKINSA and 24.3 months for ibrutinib.6

†Includes chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, hairy cell leukemia, diffuse large B-cell lymphoma, and Richter’s transformation.2

‡Hematuria was the most common major hemorrhage.2

ALPINE (STUDY 305): LOWER RATES OF DOSE REDUCTIONS AND DISCONTINUATION DUE TO ADVERSE EVENTS (AEs)6

Rates of dose reduction and discontinuation from ALPINE
1 patient in the BRUKINSA arm discontinued treatment due to a cardiac AE vs 14 patients in the ibrutinib arm*6

*BRUKINSA cardiac-related discontinuation in 1 patient was for ventricular extrasystoles. Ibrutinib cardiac-related discontinuations were for atrial fibrillation (5), cardiac arrest (2), cardiac failure (2), cardiac failure acute (1), congestive cardiomyopathy (1), myocardial infarction (1), palpitations (1), and ventricular fibrillation (1).6

2L=second line; afib=atrial fibrillation; COVID-19=coronavirus disease 2019; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

Dr Anthony Nguyen discusses the safety profile of BRUKINSA vs ibrutinib in CLL

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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage

Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.8% of patients treated with BRUKINSA in clinical trials, with fatalities occurring in 0.2% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 32% of patients.

Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days before and after surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher infections occurred in 26% of patients, most commonly pneumonia (7.9%), with fatal infections occurring in 3.2% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (21%), thrombocytopenia (8%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA. Grade 4 neutropenia occurred in 10% of patients, and Grade 4 thrombocytopenia occurred in 2.5% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA. The most frequent second primary malignancy was non-melanoma skin cancers (8%), followed by other solid tumors in 7% of the patients (including melanoma in 1% of patients) and hematologic malignancies (0.7%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 4.4% of patients treated with BRUKINSA, including Grade 3 or higher cases in 1.9% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.3% of patients.

Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment.

Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including BRUKINSA.

Evaluate bilirubin and transaminases at baseline and throughout treatment with BRUKINSA. For patients who develop abnormal liver tests after BRUKINSA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold BRUKINSA. Upon confirmation of DILI, discontinue BRUKINSA.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥30%), including laboratory abnormalities, in patients who received BRUKINSA (N=1729) are decreased neutrophil count (51%), decreased platelet count (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%).

DRUG INTERACTIONS

CYP3A Inhibitors: When BRUKINSA is coadministered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

INDICATIONS

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with:

  • Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
  • Waldenström’s macroglobulinemia (WM)
  • Mantle cell lymphoma (MCL) who have received at least one prior therapy
  • Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen
  • Relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy

The MCL, MZL and FL indications are approved under accelerated approval based on overall response rate and durability of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please see full Prescribing Information.

References: 1. BRUKINSA. Package insert. BeOne Medicines USA, Inc.; 2025. 2. Data on file. BeiGene USA, Inc. 3. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. 4. Shadman M, Munir T, Robak T, et al. Zanubrutinib versus bendamustine and rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma: median 5-year follow-up of SEQUOIA. J Clin Oncol. 2025;43(7):780-787. 5. Tam CS, Ghia P, Shadman M, et al. SEQUOIA 5-year follow-up in arm C: frontline zanubrutinib monotherapy in patients with del(17p) and treatment-naive CLL/SLL [oral presentation]. Presented at: American Society of Clinical Oncology (ASCO) 2025 Annual Meeting; May 30-June 3, 2025. 6. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. 7. Brown JR, Eichhorst B, Lamanna N, et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE. Blood. 2024;144(26):2706-2717. 8. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: results from final analysis of ALPINE randomized phase 3 study. Presented at: American Society of Hematology (ASH) Annual Meeting and Exposition; December 10-13, 2022.