THE SAFETY OF BRUKINSA

DEMONSTRATED SAFETY PROFILE IN R/R MCL

Combined Adverse Reactions (ARs) in ≥10% of Patients With MCL (N=118)¹			Pooled Safety Population (N=1550)*²
Adverse Reaction	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
Upper respiratory tract infection	39	0	39	2
Rash	36	0	28	0.9
Diarrhea	23	0.8	19	2
Pneumonia	15	10	20	11
Musculoskeletal pain	14	3.4	30	2
Bruising	14	0	23	0.1
Constipation	13	0	13	0.3
Hypertension	12	3.4	14	7
Cough	12	0	19	0.1
Hemorrhage	11	3.4	30	4
Urinary tract infection	11	0.8	13	2

Select Laboratory Abnormalities^† (≥20%) in Patients With MCL in Studies BGB-3111-206 and BGB-3111-AU-003¹
Laboratory Parameter	Percent Of Patients (N=118)
Laboratory Parameter	All Grades (%)	Grade 3 or 4 (%)
Hematologic abnormalities
Neutrophils decreased	45	20
Platelets decreased	40	7
Hemoglobin decreased	27	6
Lymphocytosis^‡	41	16
Chemistry abnormalities
Blood uric acid increased	29	2.6
ALT increased	28	0.9
Bilirubin increased	24	0.9

No patients discontinued due to neutropenia and 2 patients had febrile neutropenia. Patients on study received growth factor support as needed.²

ARs of Special Interest in the Pooled Safety Population (N=1550)*²
Adverse Reaction	Percent of Patients (N=1550)
Adverse Reaction	All Grades (%)	Grade ≥3 (%)
Fatigue	17	1
Headache	11	0.4
Arthralgia	14	0.7
Myalgia	4	0.4
Atrial fibrillation and flutter	4	2

In the (N=1550) pooled safety population, the most common adverse reactions, including laboratory abnormalities, in ≥30% of patients included neutrophil count decreased (42%), upper respiratory tract infection (39%), platelet count decreased (34%), hemorrhage (30%), and musculoskeletal pain (30%).¹

*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

^†Based on laboratory measurements.

^‡Asymptomatic lymphocytosis is a known effect of BTK inhibition.

LONG-TERM SAFETY ANALYSIS IN MCL

The overall safety profile was unchanged at 35 months.^1,3

Most ARs occurred during the early stage of BRUKINSA treatment. There were no additional cases of:

Atrial fibrillation
Atrial flutter
Grade ≥3 cardiac ARs

With 35.3 months of follow-up, the most common (≥20%) TEAEs observed were decreased neutrophil count (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), decreased white blood cell count (33.7%), and decreased platelet count (32.6%); most were Grade 1/2 events.

The prevalence of neutropenia with any grade or Grade ≥3 decreased after the first year; no Grade ≥3 neutropenia occurred after 18 months.

No new TEAEs led to treatment discontinuation or dose reduction during the longer follow-up time.

DOSE REDUCTION AND TREATMENT
DISCONTINUATION RATES IN MCL¹

Dose reductions
due to ARs¹

0.8

(1/118)

of patients

Discontinuation
rate due to ARs¹

7

(8/118)

of patients

Median duration of treatment:
17.5 months (range: 0.2-33.9 months)²

ALT=alanine aminotransferase; ARs=adverse reactions; BTK=Bruton’s tyrosine kinase; MCL=mantle cell lymphoma; R/R=relapsed/refractory; TEAEs=treatment-emergent adverse events.

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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. BeiGene USA, Inc.; 2025. 2. Data on file. BeiGene, Ltd. 3. Song Y, Zhou K, Zou D, et al. Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. Blood. 2022;139(21):3148-3158.