BRUKINSA- zanubrutinib_capsule

Zanubrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK). Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth. BTK Occupancy in PBMCs and Lymph Nodes The median steady-state BTK occupancy in peripheral blood mononuclear cells was maintained at 100% over 24 hours at a total daily dose of 320 mg in patients with B-cell malignancies. The median steady-state BTK occupancy in lymph nodes was 94% to 100% following the approved recommended dosage. Cardiac Electrophysiology At the approved recommended doses (160 mg twice daily or 320 mg once daily), there were no clinically relevant effects on the QTc interval. The effect of BRUKINSA on the QTc interval above the therapeutic exposure has not been evaluated. In Vitro Platelet Aggregation In blood samples from healthy donors, patients on anticoagulant or antiplatelet therapy, and those with severe renal dysfunction, zanubrutinib demonstrated inhibition of platelet aggregation mediated by collagen, CRP-XL, or rhodocytin. Zanubrutinib did not show meaningful inhibition of platelet aggregation for ADP and PAR4-AP. Zanubrutinib maximum plasma concentration (C max The geometric mean (%CV) zanubrutinib steady-state daily AUC is 2,099 (42%) ng∙h/mL following 160 mg twice daily and 1,917 (59%) ng∙h/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state C max Absorption The median t max Effect of Food No clinically significant differences in zanubrutinib AUC or C max Distribution The geometric mean (%CV) apparent volume of distribution (Vz/F) of zanubrutinib is 537 (73%) L. The plasma protein binding of zanubrutinib is approximately 94% and the blood-to-plasma ratio is 0. Elimination The mean half-life (t ½ Metabolism Zanubrutinib is primarily metabolized by cytochrome P450(CYP)3A. Excretion Following a single radiolabeled zanubrutinib dose of 320 mg to healthy subjects, approximately 87% of the dose was recovered in feces (38% unchanged) and 8% in urine (less than 1% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of zanubrutinib were observed based on age (19 to 90 years), sex, race (Asian, White, and Other), body weight (36 to 144 kg), or mild, moderate or severe renal impairment (CLcr >=15 mL/min as estimated by Cockcroft-Gault). The effect of dialysis on zanubrutinib pharmacokinetics is unknown. Hepatic Impairment The total AUC of zanubrutinib increased by 11% in subjects with mild hepatic impairment (Child-Pugh class A), by 21% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 60% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. The unbound AUC of zanubrutinib increased by 23% in subjects with mild hepatic impairment (Child-Pugh class A), by 43% in subjects with moderate hepatic impairment (Child-Pugh class B) and by 194% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. Drug Interaction Studies Clinical Studies and Model-Informed Approaches CYP3A Inhibitors : max Table 18: Observed or Predicted Increase in Zanubrutinib Exposure After Coadministration of CYP3A Inhibitors Coadministered CYP3A Inhibitor Increase in Zanubrutinib C max Increase in Zanubrutinib AUC Observed Itraconazole (200 mg once daily) The assessment was conducted in healthy subjects with a single dose of zanubrutinib 20 mg. 157% 278% Fluconazole (400 mg once daily) The assessment was conducted in patients with B-cell lymphoma administered multiple doses of zanubrutinib at the respective recommended zanubrutinib dosages in Table 1. 81% 88% Diltiazem (180 mg once daily) 62% 62% Voriconazole (200 mg twice daily) 229% 230% Clarithromycin (250 mg twice daily) 101% 92% Predicted Posaconazole suspension (100 mg once daily) The predicted values were based on simulations with patients administered multiple doses of zanubrutinib at the respective recommended dosages in Table 1. 169% 180% Posaconazole suspension (100 mg twice daily) 207% 279% Posaconazole delayed-release tablets (300 mg once daily) 232% 407% Posaconazole intravenously (300 mg once daily) 205% 333% Itraconazole (200 mg once daily) 273% 320% CYP3A Inducers : max max Coadministration of multiple doses of efavirenz (moderate CYP3A inducer) is predicted to decrease zanubrutinib C max CYP3A Substrates : max CYP2C19 Substrates : max Other CYP Substrates : Transporter Systems : max Gastric Acid Reducing Agents : In Vitro Studies CYP Enzymes : Transporter Systems :.

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with: Mantle cell lymphoma (MCL) who have received at least one prior therapy. 1 Waldenström's macroglobulinemia (WM). 2 Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one antien dashCD20-based regimen. 3 Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). 4 Relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy. 5 BRUKINSA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14. 1) BRUKINSA is indicated for the treatment of adult patients with Waldenström's macroglobulinemia (WM) [see Clinical Studies (14. 2) BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one antien dashCD20-based regimen. 3) BRUKINSA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) [see Clinical Studies (14. 4) BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14.

Recommended dosage: 160 mg orally twice daily or 320 mg orally once daily; swallow whole with water and with or without food. 1 Reduce BRUKINSA dose in patients with severe hepatic impairment. 7 Advise patients not to open, break, or chew capsules. 1 Manage toxicity using treatment interruption, dose reduction, or discontinuation. 4 The recommended dosage of BRUKINSA for monotherapy or in combination with obinutuzumab is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity. BRUKINSA can be taken with or without food. Advise patients to swallow capsules whole with water. Advise patients not to open, break, or chew the capsules. If a dose of BRUKINSA is missed, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. The recommended dosage of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily [see Use in Specific Populations (8. 7) Clinical Pharmacology (12. 3) Recommended dosage modifications of BRUKINSA for drug interactions are provided in Table 1 [see Drug Interactions (7. 1) Table 1: Dosage Modifications for Use with CYP3A Inhibitors or Inducers Coadministered Drug Recommended BRUKINSA Dosage Clarithromycin 250 mg twice daily Since clarithromycin 250 mg twice daily acts as a moderate CYP3A inhibitor, it is recommended that patients be administered clarithromycin 250 mg twice daily with 80 mg BRUKINSA twice daily [see Clinical Pharmacology (12. 3) 80 mg twice daily Modify or interrupt zanubrutinib dose as recommended for adverse reactions [see Dosage and Administration (2. 4) Clarithromycin 500 mg twice daily 80 mg once daily Posaconazole suspension 100 mg once daily 80 mg twice daily Posaconazole suspension dosage higher than 100 mg once daily Posaconazole delayed-release tablets 300 mg 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. After discontinuation of a CYP3A inhibitor or moderate CYP3A inducer, resume previous dose of BRUKINSA [see Dosage and Administration (2. 2) Drug Interactions (7. 1) Recommended dosage modifications of BRUKINSA for Grade 3 or higher adverse reactions are provided in Table 2. Table 2: Recommended Dosage Modifications for Adverse Reaction Adverse Reaction Adverse Reaction Occurrence Dosage Modification Hematological toxicities [see Warnings and Precautions (5. 3) Grade 3 or Grade 4 febrile neutropenia 3 3 3 First Interrupt BRUKINSA Second Interrupt BRUKINSA Third Interrupt BRUKINSA Fourth Discontinue BRUKINSA Non-hematological toxicities [see Warnings and Precautions (5. 5) Adverse Reactions (6. 1) Severe or life-threatening non-hematological toxicities Evaluate the benefit-risk before resuming treatment at the same dosage for Grade 4 non-hematological toxicity. First Interrupt BRUKINSA Second Interrupt BRUKINSA Third Interrupt BRUKINSA Fourth Discontinue BRUKINSA. Asymptomatic lymphocytosis in CLL and MCL should not be regarded as an adverse reaction, and these patients should continue taking BRUKINSA. Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.

The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling: Hemorrhage [see Warnings and Precautions (5. 1) Infections [see Warnings and Precautions (5. 2) Cytopenias [see Warnings and Precautions (5. 3) Second Primary Malignancies [see Warnings and Precautions (5. 4) Cardiac Arrhythmias [see Warnings and Precautions (5. 5) Hepatotoxicity, including DILI [see Warnings and Precautions (5. 6) The most common adverse reactions (>=30%), including laboratory abnormalities, are neutrophil count decreased, platelet count decreased, upper respiratory tract infection, hemorrhage, and musculoskeletal pain. 1 To report SUSPECTED ADVERSE REACTIONS, contact BeiGene at 1-877-828-5596 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the WARNINGS AND PRECAUTIONS reflect exposure to BRUKINSA in nine monotherapy and 2 combination clinical trials, administered at 160 mg twice daily in 1608 patients and at 320 mg once daily in 121 patients. Among these 1729 patients, the median duration of exposure was 27. 6 months, 78% of patients were exposed for at least 12 months, and 60% of patients were exposed for at least 24 months. In this pooled safety population, the most common adverse reactions (>=30%), including laboratory abnormalities, were neutrophil count decreased (51%), platelet count decreased (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%). Mantle Cell Lymphoma (MCL) The safety of BRUKINSA was evaluated in 118 patients with MCL who received at least one prior therapy in two single-arm clinical trials, BGB-3111-206 [NCT03206970] and BGB-3111-AU-003 [NCT02343120] [see Clinical Studies (14. 1) 9 9 9 9 Fatal adverse reactions within 30 days of the last dose of BRUKINSA occurred in 8 (7%) of 118 patients with MCL. Fatal cases included pneumonia in 2 patients and cerebral hemorrhage in one patient. Serious adverse reactions were reported in 36 patients (31%). The most frequent serious adverse reactions that occurred were pneumonia (11%) and hemorrhage (5%). Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3. 8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B). Table 3 summarizes the adverse reactions in BGB-3111-206 and BGB-3111-AU-003. Table 3: Adverse Reactions (>=10%) in Patients Receiving BRUKINSA in BGB-3111-206 and BGB-3111-AU-003 Trials Body System Adverse Reaction Percent of Patients (N=118) All Grades % Grade 3 or Higher % Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral. 39 0 Pneumonia Pneumonia includes pneumonia, pneumonia fungal, pneumonia cryptococcal, pneumonia streptococcal, atypical pneumonia, lung infection, lower respiratory tract infection, lower respiratory tract infection bacterial, lower respiratory tract infection viral. 15 10 Includes fatal adverse reaction. Urinary tract infection 11 0. 8 Skin and subcutaneous tissue disorders Rash Rash includes all related terms containing rash. 36 0 Bruising Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis. 14 0 Gastrointestinal disorders Diarrhea 23 0. 8 Constipation 13 0 Vascular disorders Hypertension 12 3. 4 Hemorrhage Hemorrhage includes all related terms containing hemorrhage, hematoma. 4 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis. 4 Respiratory, thoracic, and mediastinal disorders Cough 12 0 Other clinically significant adverse reactions that occurred in <10% of patients with mantle cell lymphoma include major hemorrhage (defined as >= Grade 3 hemorrhage or CNS hemorrhage of any grade) (5%) and headache (4. Table 4: Selected Laboratory Abnormalities Based on laboratory measurements. Laboratory Parameter Percent of Patients (N=118) All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 45 20 Lymphocytosis Asymptomatic lymphocytosis is a known effect of BTK inhibition. 41 16 Platelets decreased 40 7 Hemoglobin decreased 27 6 Chemistry abnormalities Blood uric acid increased 29 2. 6 ALT increased 28 0. 9 Bilirubin increased 24 0. 9 Waldenström's Macroglobulinemia (WM) The safety of BRUKINSA was investigated in two cohorts of Study BGB-3111-302 (ASPEN). Cohort 1 included 199 patients with MYD88 mutation ( MYD88 MUT MYD88 WT [see Clinical Studies (14. 2) Among patients who received BRUKINSA, 93% were exposed for 6 months or longer, and 89% were exposed for greater than 1 year. In Cohort 1 of the ASPEN study safety population (N=101), the median age of patients who received BRUKINSA was 70 years (45-87 years old); 67% were male, 86% were White, 4% were Asian, and 10% were not reported (unknown race). In Cohort 2 of the ASPEN study safety population (N=28), the median age of patients who received BRUKINSA was 72 (39-87 years old); 50% were male, 96% were White, and 4% were not reported (unknown race). In Cohort 1, serious adverse reactions occurred in 44% of patients who received BRUKINSA. Serious adverse reactions in >2% of patients included influenza (3%), pneumonia (4%), neutropenia and neutrophil count decreased (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%). In Cohort 2, serious adverse reactions occurred in 39% of patients. Serious adverse reactions in >2 patients included pneumonia (14%). Permanent discontinuation of BRUKINSA due to an adverse reaction occurred in 2% of patients in Cohort 1 and included hemorrhage (1 patient), neutropenia and neutrophil count decreased (1 patient); in Cohort 2, permanent discontinuation of BRUKINSA due to an adverse reaction occurred in 7% of patients and included subdural hemorrhage (1 patient) and diarrhea (1 patient). Dosage interruptions of BRUKINSA due to an adverse reaction occurred in 32% of patients in Cohort 1 and in 29% in Cohort 2. Adverse reactions which required dosage interruption in >2% of patients included neutropenia, vomiting, hemorrhage, thrombocytopenia, and pneumonia in Cohort 1. Adverse reactions leading to dosage interruption in >2 patients in Cohort 2 included pneumonia and pyrexia. Dose reductions of BRUKINSA due to an adverse reaction occurred in 11% of patients in Cohort 1 and in 7% in Cohort 2. Adverse reactions which required dose reductions in >2% of patients included neutropenia in Cohort 1. Adverse reaction leading to dose reduction occurred in 2 patients in Cohort 2 (each with one event: diarrhea and pneumonia). Table 5 summarizes the adverse reactions in Cohort 1 in ASPEN. Table 5: Adverse Reactions (>=10%) Occurring in Patients with WM Who Received BRUKINSA in Cohort 1 Body System Adverse Reaction BRUKINSA (N=101) Ibrutinib (N=98) All Grades Grade 3 or 4 All Grades Grade 3 or 4 Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, laryngitis, nasopharyngitis, sinusitis, rhinitis, viral upper respiratory tract infection, pharyngitis, rhinovirus infection, upper respiratory tract congestion. 44 0 40 2 Pneumonia Pneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral. 12 4 26 10 Urinary tract infection 11 0 13 2 Gastrointestinal disorders Diarrhea 22 3 34 2 Nausea 18 0 13 1 Constipation 16 0 7 0 Vomiting 12 0 14 1 General disorders Fatigue Fatigue includes asthenia, fatigue, lethargy. 31 1 25 1 Pyrexia 16 4 13 2 Edema peripheral 12 0 20 0 Skin and subcutaneous tissue disorders Bruising Bruising includes all related terms containing bruise, contusion, or ecchymosis. 20 0 34 0 Rash Rash includes all related terms rash, maculo-papular rash, erythema, rash erythematous, drug eruption, dermatitis allergic, dermatitis atopic, rash pruritic, dermatitis, photodermatoses, dermatitis acneiform, stasis dermatitis, vasculitic rash, eyelid rash, urticaria, skin toxicity. 29 0 32 0 Pruritus 11 1 6 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain, musculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort. 45 9 39 1 Muscle spasms 10 0 28 1 Nervous system disorders Headache 18 1 14 1 Dizziness 13 1 12 0 Respiratory, thoracic, and mediastinal disorders Cough 16 0 18 0 Dyspnea 14 0 7 0 Vascular disorders Hemorrhage Hemorrhage includes epistaxis, hematuria, conjunctival hemorrhage, hematoma, rectal hemorrhage, periorbital hemorrhage, mouth hemorrhage, post procedural hemorrhage, hemoptysis, skin hemorrhage, hemorrhoidal hemorrhage, ear hemorrhage, eye hemorrhage, hemorrhagic diathesis, periorbital hematoma, subdural hemorrhage, wound hemorrhage, gastric hemorrhage, lower gastrointestinal hemorrhage, spontaneous hematoma, traumatic hematoma, traumatic intracranial hemorrhage, tumor hemorrhage, retinal hemorrhage, hematochezia, diarrhea hemorrhagic, hemorrhage, melena, post-procedural hematoma, subdural hematoma, anal hemorrhage, hemorrhagic disorder, pericardial hemorrhage, postmenopausal hemorrhage, stoma site hemorrhage, subarachnoid hemorrhage. 42 4 43 9 Hypertension 14 9 19 14 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA included localized infection, atrial fibrillation or atrial flutter, and hematuria. Table 6 summarizes the laboratory abnormalities in ASPEN. Table 6: Select Laboratory Abnormalities Based on laboratory measurements. Laboratory Abnormality BRUKINSA The denominator used to calculate the rate varied from 86 to 101 based on the number of patients with a baseline value and at least one post-treatment value. Ibrutinib All Grades Grade 3 or 4 All Grades Grade 3 or 4 Hematologic abnormalities Neutrophils decreased 50 24 34 9 Platelets decreased 35 8 39 5 Hemoglobin decreased 20 7 20 7 Chemistry abnormalities Glucose increased 45 2. 3 Creatinine increased 31 1 21 1 Calcium decreased 27 2 26 0 Potassium increased 24 2 12 0 Phosphate decreased 20 3. 1 18 0 Urate increased 16 3. 2 34 6 Bilirubin increased 12 1 33 1 Marginal Zone Lymphoma The safety of BRUKINSA was evaluated in 88 patients with previously treated MZL in two single-arm clinical studies, BGB-3111-214 and BGB-3111-AU-003 [see Clinical Studies (14. 3) 9 9 Two fatal adverse reactions (2. 3%) occurred within 30 days of the last dose of BRUKINSA, including myocardial infarction and a Covid-19en dashrelated death. Serious adverse reactions occurred in 40% of patients. The most frequent serious adverse reactions were pyrexia (8%) and pneumonia (7%). Adverse reactions lead to treatment discontinuation in 6% of patients, dose reduction in 2. 3%, and dose interruption in 34%. The leading cause of dose modification was respiratory tract infections (13%). Table 7 summarizes selected adverse reactions in BGB-3111-214 and BGB-3111-AU-003. Table 7: Adverse Reactions Occurring in >=10% Patients with MZL Who Received BRUKINSA Body System Adverse Reaction BRUKINSA (N=88) All Grades Grade 3 or 4 Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper respiratory tract infection. 4 Urinary tract infection Urinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis. 3 Pneumonia Pneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection, organizing pneumonia. , Includes 2 fatalities from COVID-19 pneumonia. 10 6 Gastrointestinal disorders Diarrhea Diarrhea includes diarrhea and diarrhea hemorrhagic. 4 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort. 3 Nausea 13 0 Skin and subcutaneous tissue disorders Bruising Bruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion. 24 0 Rash Rash includes rash, rash maculo-papular, rash pruritic, dermatitis, dermatitis allergic, dermatitis atopic, dermatitis contact, drug reaction with eosinophilia and systemic symptoms, erythema, photosensitivity reaction, rash erythematous, rash papular, seborrheic dermatitis. 21 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, neck pain. 1 Vascular disorders Hemorrhage Hemorrhage includes epistaxis, hematuria, hemorrhoidal hemorrhage, hematoma, hemoptysis, conjunctival hemorrhage, diarrhea hemorrhagic, hemorrhage urinary tract, mouth hemorrhage, pulmonary hematoma, subcutaneous hematoma, gingival bleeding, melena, upper gastrointestinal hemorrhage. 1 General disorders Fatigue Fatigue includes fatigue, lethargy, asthenia. 3 Respiratory, thoracic, and mediastinal disorders Cough Cough includes cough and productive cough. 10 0 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA included peripheral neuropathy, second primary malignancies, dizziness, edema, headache, petechiae, purpura, and atrial fibrillation or flutter. Table 8 summarizes select laboratory abnormalities. Table 8: Select Laboratory Abnormalities (>=20%) that Worsened from Baseline in Patients with MZL Laboratory Abnormality The denominator used to calculate the rate varied from 87 to 88 based on the number of patients with a baseline value and at least one post-treatment value. BRUKINSA All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 43 15 Platelets decreased 33 10 Lymphocytes decreased 32 8 Hemoglobin decreased 26 6 Chemistry abnormalities Glucose increased 54 4. 6 Creatinine increased 34 1. 1 Phosphate decreased 27 2. 3 Calcium decreased 23 0 ALT increased 22 1. 1 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma The safety data described below reflect exposure to BRUKINSA (160 mg twice daily) in 675 patients with CLL from two randomized controlled clinical trials [see Clinical Studies (14. 4) SEQUOIA The safety of BRUKINSA monotherapy in patients with previously untreated CLL/SLL was evaluated in a randomized, multicenter, open-label, actively controlled trial [see Clinical Studies (14. 4) 2 2 2 Additionally, the same BRUKINSA regimen was evaluated in 111 patients with previously untreated CLL/SLL with 17p deletion in a non-randomized single arm (Cohort 2). Randomized Cohort: Previously Untreated CLL/SLL without 17p Deletion In patients with previously untreated CLL/SLL without 17p deletion, the median age was 70, 62% were male, 89% were White, 2% were Asian, and 2% were Black. Most patients (93%) had an ECOG performance status of 0 to 1. The median duration of exposure to BRUKINSA was 26 months, with 71% exposed for more than 2 years. Serious adverse reactions occurred in 36% of patients who received BRUKINSA. Serious adverse reactions that occurred in >=5% of patients were COVID-19, pneumonia, and second primary malignancy (5% each). Fatal adverse reactions occurred in 11 (4. 6%) patients with the leading cause of death being COVID-19 (2. Adverse reactions led to permanent discontinuation of BRUKINSA in 8% of patients, dose reduction in 8%, and dose interruption in 46%. The most common adverse reactions leading to permanent discontinuation were second primary malignancy and COVID-19. The leading causes of dose modification (>=5% of all patients) were respiratory infections (COVID-19, pneumonia) and hemorrhage. Table 9 summarizes select adverse reactions in this randomized cohort. Table 9: Adverse Reactions in >=10% Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA CLL/SLL without 17p deletion BRUKINSA BR System Organ Class All Grades Grade 3 or 4 All Grades Grade 3 or 4 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, musculoskeletal discomfort, bone pain. 4 Infections and infestations Upper respiratory tract infection Upper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upper respiratory tract congestion, laryngitis, tonsillitis and upper respiratory tract inflammation, and related terms. 9 Pneumonia Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. 13 Includes 3 fatal outcomes. 5 8 Includes 2 fatal outcomes. 4 Vascular disorders Hemorrhage Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 4 Hypertension Includes multiple similar adverse reaction terms. 6 Skin and subcutaneous tissue disorders Rash Rash: Rash, dermatitis, drug eruption, and related terms. 3 30 5 Bruising Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. 6 0 Respiratory, thoracic, and mediastinal disorders Cough 15 0 10 0 Gastrointestinal disorders Diarrhea 14 0. 9 Constipation 10 0. 4 18 0 Nausea 10 0 33 1. 3 General disorders Fatigue Fatigue: fatigue, asthenia, and lethargy. 8 Neoplasms Second primary malignancy Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including lung, renal, genitourinary, breast, ovarian, and rectal), and chronic myeloid leukemia. 4 Nervous system disorders Headache 12 0 8 0 Dizziness Dizziness: dizziness and vertigo. 8 5 0 Other clinically significant adverse reactions occurring in <10% of BRUKINSA recipients in this cohort included COVID-19 (9%), edema (8%), abdominal pain (8%), urinary tract infection (7%), and atrial fibrillation or flutter (3. Table 10 summarizes select laboratory abnormalities in this cohort. Table 10: Select Laboratory Abnormalities (>=20%) that Worsened from Baseline in Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA Laboratory Abnormality 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 one post-treatment value. Grading is based on NCI CTCAE criteria. BRUKINSA BR All Grades Grade 3 or 4 All Grades Grade 3 or 4 Hematologic abnormalities Neutrophils decreased 37 15 80 53 Hemoglobin decreased 29 2. 5 66 8 Platelets decreased 27 1. 7 61 11 Leukocytes increased 21 Lymphocytes increased in 15%. 4 Chemistry abnormalities Glucose increased Nonfasting conditions. 55 7 67 10 Creatinine increased 22 0. 4 Magnesium increased 22 0 14 0. 4 Alanine aminotransferase increased 21 2. 2 Single-Arm Cohort: Previously Untreated CLL/SLL and 17p Deletion In 111 patients with previously untreated, 17p del CLL/SLL, the median age was 70, 71% were male, 95% were White, and 1% were Asian. Most patients (87%) had an ECOG performance status of 0 to 1. The median duration of exposure to BRUKINSA was 30 months. Fatal adverse reactions occurred in 3 (2. 7%) patients, including pneumonia, renal insufficiency, and aortic dissection (1 patient each). Serious adverse reactions occurred in 41% of patients treated with BRUKINSA. Serious adverse reactions reported in >=5% of patients were pneumonia (8%) and second primary malignancy (7%). Adverse reactions led to treatment discontinuation in 5% of patients, dose reduction in 5%, and dose interruption in 51%. The leading causes of dose modification (>=5% of all patients) were pneumonia, neutropenia, second primary malignancy, and diarrhea. Table 11 summarizes select adverse reactions in this cohort. Table 11: Adverse Reactions in >=10% of Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA CLL/SLL with 17p Deletion BRUKINSA System Organ Class All Grades Grade 3 or 4 Infections and infestations Upper respiratory tract infection Upper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upper respiratory tract congestion, upper respiratory tract inflammation, viral upper respiratory tract infection, and related terms. 38 0 Pneumonia Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, and related terms including specific types of infection. 20 Includes 1 fatal outcome. 8 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, bone pain. 7 Skin and subcutaneous tissue disorders Rash Rash: Rash, dermatitis, toxic skin eruption, and related terms. 28 0 Bruising Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. 9 Vascular disorders Hemorrhage Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 5 Hypertension 11 5. 4 Neoplasms Second primary malignancy Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including bladder, lung, renal, breast, prostate, ovarian, pelvis, and ureter), and malignant melanoma. 22 Includes non-melanoma skin cancer in 13%. 6 Gastrointestinal disorders Diarrhea 18 0. 9 Nausea 16 0 Constipation 15 0 Abdominal pain 12 1. 8 Respiratory, thoracic, and mediastinal disorders Cough Includes multiple similar adverse reaction terms. 18 0 Dyspnea 13 0 General disorders and administration site conditions Fatigue Fatigue: fatigue, asthenia, and lethargy. 9 Nervous system disorders Headache 11 1. 8 Clinically significant adverse reactions occurring in <10% of BRUKINSA recipients in this cohort included urinary tract infection (8%), edema (7%), atrial fibrillation or flutter (4. 5%), and COVID-19 (3. Table 12 summarizes select laboratory abnormalities in this cohort. Table 12: Select Laboratory Abnormalities (>=20%) that Worsened from Baseline in Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA Laboratory Abnormality 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 one post-treatment value. BRUKINSA All Grades (%) Grade 3 or 4 (%) Hematologic abnormalities Neutrophils decreased 42 19 Grade 4, 9%. Hemoglobin decreased 26 3. 6 Platelets decreased 23 0. 9 Chemistry abnormalities Glucose increased Non-fasting conditions. 52 6 Magnesium increased 31 0 Creatinine increased 27 0. 9 ALPINE The safety of BRUKINSA monotherapy was evaluated in patients with previously treated CLL/SLL in a randomized, multicenter, open-label, actively controlled trial [see Clinical Studies (14. 4) In ALPINE, the median duration of exposure was 24 months for BRUKINSA. Adverse reactions leading to death in the BRUKINSA arm occurred in 24 (7%) patients. Adverse reactions leading to death that occurred in >1% of patients were pneumonia (2. 8%) and COVID-19 infection (1. One hundred and four patients in the BRUKINSA arm (32%) reported >=1 serious adverse reaction. Serious adverse reactions occurring in >=5% of patients were pneumonia (10%), COVID-19 (7%), and second primary malignancies (5%). Adverse reactions led to treatment discontinuation in 13% of patients, dose reduction in 11%, and dose interruption in 42%. The leading cause of treatment discontinuation was pneumonia. The leading causes of dose modification (>=5% of all patients) were respiratory infections (COVID-19, pneumonia) and neutropenia. Table 13 summarizes select adverse reactions in ALPINE. Table 13: Adverse Reactions in >=10% of Patients with Relapsed or Refractory CLL/SLL Who Received BRUKINSA in ALPINE System Organ Class BRUKINSA Ibrutinib All Grades Grade 3 or 4 All Grades Grade 3 or 4 Infections and infestations Upper respiratory tract infection Upper respiratory tract infection: upper respiratory tract infection, sinusitis, pharyngitis, rhinitis, nasopharyngitis, laryngitis, tonsillitis, and related terms. 2 Pneumonia Pneumonia: Pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. 18 Includes fatal outcomes: pneumonia (9 patients), COVID-19 (8 patients), and hemorrhage (1 patient). 9 19 Includes fatal outcomes: pneumonia (10 patients), COVID-19 (9 patients), and hemorrhage (2 patients). 11 COVID-19 COVID-19: COVID-19, COVID-19 pneumonia, postacute COVID-19 syndrome, SARS-CoV-2 test positive. 6 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, bone pain, and musculoskeletal discomfort. 6 Vascular disorders Hemorrhage Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 7 Hypertension Includes multiple similar adverse reaction terms. 19 13 20 13 Skin and subcutaneous tissue disorders Rash Rash: Rash, Dermatitis, and related terms. 9 Bruising Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. 16 0 14 0 Gastrointestinal disorders Diarrhea 14 1. 9 General disorders Fatigue Fatigue: asthenia, fatigue, lethargy. 9 Respiratory, thoracic, and mediastinal disorders Cough 11 0. 3 11 0 Nervous system disorders Dizziness 10 0 7 0 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA included urinary tract infection (9%), supraventricular arrhythmias (9%) including atrial fibrillation or flutter (4. 6%), abdominal pain (8%), headache (8%), pruritus (6. 2%), constipation (5. 9%), and edema (4. Table 14 summarizes select laboratory abnormalities in ALPINE. Table 14: Select Laboratory Abnormalities (>=20%) that Worsened from Baseline in Patients Who Received BRUKINSA in ALPINE Laboratory Abnormality The denominator used to calculate the rate was 321 in the BRUKINSA arm, and varied from 320 to 321 in the ibrutinib arm, based on the number of patients with a baseline value and at least one post-treatment value. BRUKINSA Ibrutinib All Grades Grade 3 or 4 All Grades Grade 3 or 4 Hematologic abnormalities Neutrophils decreased 43 15 33 16 Hemoglobin decreased 28 4 32 3. 7 Lymphocytes increased 24 19 26 19 Platelets decreased 22 4 24 3. 4 Chemistry abnormalities Glucose increased 52 5 29 2. 8 Creatinine increased 26 0 23 0 Phosphate decreased 21 2. 2 Calcium decreased 21 0. 6 29 0 Follicular Lymphoma The safety of BRUKINSA in combination with obinutuzumab was evaluated in 143 adult patients with relapsed or refractory follicular lymphoma (FL) in study BGB-3111-212 (ROSEWOOD), a randomized, multicenter, open-label trial [see Clinical Studies (14. 5) 9 9 Patients were randomized to receive either BRUKINSA 160 mg twice daily until disease progression or unacceptable toxicity plus obinutuzumab (n=143) or obinutuzumab monotherapy (n=71). Obinutuzumab was dosed at 1,000 mg intravenously on Days 1, 8, and 15 of Cycle 1; on Day 1 of Cycles 2 to 6; and then every 8 weeks for up to 20 doses. At the discretion of the investigator, obinutuzumab was administered intravenously on Day 1 (100 mg) and on Day 2 (900 mg) of Cycle 1 instead of 1,000 mg on Day 1 of Cycle 1. In patients who received BRUKINSA in combination with obinutuzumab, the median age was 63, 49% were female, 63% were White, and 21% were Asian. Most patients (97%) had an ECOG performance status of 0 to 1. The median duration of BRUKINSA treatment was 12 months, with 24% of patients treated for at least 2 years. Serious adverse reactions occurred in 35% of patients who received BRUKINSA in combination with obinutuzumab. Serious adverse reactions in >=5% of patients included pneumonia (11%) and COVID-19 (10%). Fatal adverse reactions occurred in 4. 2% of patients, with the leading cause of death being COVID-19 (2. Adverse reactions led to permanent discontinuation of BRUKINSA in 17% of patients, dose reduction in 9%, and dose interruption in 40%. Adverse reactions leading to permanent discontinuation in >=2% of patients were pneumonia, COVID-19, and second primary malignancy. The leading causes of BRUKINSA dosage modification (42% of all patients) were pneumonia, COVID-19, thrombocytopenia, and neutropenia. Table 15 summarizes adverse reactions in BGB-3111-212. Table 15: Adverse Reactions in >=10% of Patients with Relapsed or Refractory FL Who Received BRUKINSA in Study BGB-3111-212 System Organ Class BGB-3111-212 BRUKINSA + Obinutuzumab Obinutuzumab All Grades Grade 3 or 4 All Grades Grade 3 or 4 General disorders and administration site conditions Fatigue Includes multiple related terms. , Fatigue: Fatigue, asthenia, and lethargy. 4 Pyrexia 13 0 20 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain , Musculoskeletal pain: Back pain, musculoskeletal pain, musculoskeletal discomfort, noncardiac chest pain, neck pain, pain in extremity, myalgia, spinal pain, bone pain, arthralgia, and related terms. 4 Vascular disorders Hemorrhage , Hemorrhage: All terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. 4 Gastrointestinal disorders Diarrhea 18 2. 4 Constipation 13 0 9 0 Abdominal pain 11 2. 1 11 0 Infections and infestations Upper respiratory tract infection , Upper respiratory tract infection: Upper respiratory tract infection, sinusitis, pharyngitis, laryngitis, rhinitis, nasopharyngitis, laryngopharyngitis, tonsillitis bacterial, and related terms. 8 10 0 Pneumonia , Pneumonia: Pneumonia, COVID-19 pneumonia, lung infiltration, lung consolidation, and related terms including specific types of infection. , Includes fatal outcomes: COVID-19 (3 patients), pneumonia (2 patients), dyspnea (1 patient). 15 13 11 7 COVID-19 , 13 9 11 4. 2 Herpes virus infection Herpes virus infection: Herpes viral infection, herpes zoster, herpes simplex, herpes simplex reactivation, varicella, and Epstein-Barr viremia. 4 0 Urinary tract infection Urinary tract infection: Urinary tract infection, cystitis, pyelonephritis, and related terms. 4 7 0 Respiratory, thoracic, and mediastinal disorders Cough 14 0 14 0 Dyspnea , 11 2. 1 13 0 Skin and subcutaneous tissue disorders Rash , Rash: Rash, erythema, dermatitis, drug eruption, skin reaction, and related terms. 11 0 14 0 Clinically relevant adverse reactions in <10% of patients who received BRUKINSA in combination with obinutuzumab included bruising, edema, pruritus, petechiae, vomiting, headache, arthralgia, hypertension, sepsis, cardiac arrhythmias, renal insufficiency, febrile neutropenia, transaminase elevation, and pneumonitis. Table 16: Select Laboratory Abnormalities (>=20%) that Worsened from Baseline in Patients Who Received BRUKINSA in Study BGB-3111-212 Laboratory Abnormality The denominator used to calculate the rate was 122 in the BRUKINSA + obinutuzumab arm, and varied from 56 to 58 in the obinutuzumab arm, based on the number of patients with a baseline value and at least one post-treatment value. BGB-3111-212 BRUKINSA + Obinutuzumab Obinutuzumab All Grades Grade 3 or 4 All Grades Grade 3 or 4 Hematologic abnormalities Platelets decreased 65 11 43 11 Neutrophils decreased 47 17 42 14 Hemoglobin decreased 31 0. 8 23 0 Lymphocytes decreased 30 11 51 25 Chemistry Glucose increased Nonfasting conditions. 53 8 41 9 Alanine aminotransferase increased 23 0 28 0 Phosphate decreased 21 0.

Lactation: Advise not to breastfeed. 2 Risk Summary Based on findings in animals, BRUKINSA can cause fetal harm when administered to pregnant women. There are no available data on BRUKINSA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of zanubrutinib to pregnant rats during the period of organogenesis was associated with fetal heart malformation at approximately 5-fold human exposures (see Data The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Embryo-fetal development toxicity studies were conducted in both rats and rabbits. Zanubrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 30, 75, and 150 mg/kg/day. Malformations in the heart (2 or 3-chambered hearts) were noted at all dose levels in the absence of maternal toxicity. The dose of 30 mg/kg/day is approximately 5 times the exposure (AUC) in patients receiving the recommended dose of 160 mg twice daily. Administration of zanubrutinib to pregnant rabbits during the period of organogenesis at 30, 70, and 150 mg/kg/day resulted in postimplantation loss at the highest dose. The dose of 150 mg/kg is approximately 32 times the exposure (AUC) in patients at the recommended dose and was associated with maternal toxicity. In a pre and postnatal developmental toxicity study, zanubrutinib was administered orally to rats at doses of 30, 75, and 150 mg/kg/day from implantation through weaning. The offspring from the middle and high dose groups had decreased body weights preweaning, and all dose groups had adverse ocular findings (e. , cataract, protruding eye). The dose of 30 mg/kg/day is approximately 5 times the AUC in patients receiving the recommended dose. Risk Summary There are no data on the presence of zanubrutinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions from BRUKINSA in a breastfed child, advise lactating women not to breastfeed during treatment with BRUKINSA and for two weeks following the last dose. BRUKINSA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8. 1) Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating BRUKINSA therapy. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with BRUKINSA and for 1 week following the last dose of BRUKINSA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus. Males Advise men to avoid fathering a child while receiving BRUKINSA and for 1 week following the last dose of BRUKINSA. Safety and effectiveness of BRUKINSA in pediatric patients have not been established. Of the 1729 patients with MCL, MZL, WM, CLL/SLL, and FL in clinical studies with BRUKINSA, 59% were >=65 years of age, and 21% were >=75 years of age. Patients >=65 years of age had numerically higher rates of Grade 3 or higher adverse reactions and serious adverse reactions (57% and 38%, respectively) than patients <65 years of age (51% and 29%, respectively). No overall differences in effectiveness were observed between younger and older patients. No dosage modification is recommended in patients with mild, moderate, or severe renal impairment (CLcr >=15 mL/min, estimated by Cockcroft-Gault). Monitor for BRUKINSA adverse reactions in patients on dialysis [see Clinical Pharmacology (12. 3) Dosage modification of BRUKINSA is recommended in patients with severe hepatic impairment [see Dosage and Administration (2. 2) [see Clinical Pharmacology (12.

CYP3A Inhibitors: Modify BRUKINSA dose with moderate or strong CYP3A inhibitors as described. 1 CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers. 1 Table 17: Drug Interactions that Affect Zanubrutinib Moderate and Strong CYP3A Inhibitors Clinical Impact Coadministration with a moderate or strong CYP3A inhibitor increases zanubrutinib C max [see Clinical Pharmacology (12. 3) Prevention or management Reduce BRUKINSA dosage when coadministered with moderate or strong CYP3A inhibitors [see Dosage and Administration (2. 3) Moderate and Strong CYP3A Inducers Clinical Impact Coadministration with a moderate or strong CYP3A inducer decreases zanubrutinib C max [see Clinical Pharmacology (12. 3) Prevention or management Avoid coadministration of BRUKINSA with strong CYP3A inducers [see Dosage and Administration (2. 3) Avoid coadministration of BRUKINSA with moderate CYP3A inducers [see Dosage and Administration (2. 3) [see Dosage and Administration (2.

NONCLINICAL TOXICOLOGY
Carcinogenicity studies have not been conducted with zanubrutinib. Zanubrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo A combined male and female fertility and early embryonic development study was conducted in rats at oral zanubrutinib doses of 30 to 300 mg/kg/day. Male rats were dosed 4 weeks prior to mating and through mating and female rats were dosed 2 weeks prior to mating and to gestation day 7. No effect on male or female fertility was noted at lower doses, but at the highest dose tested, morphological abnormalities in sperm and increased postimplantation loss were noted. The high dose of 300 mg/kg/day is approximately 10 times the human recommended dose, based on body surface area.
CLINICAL STUDIES
The efficacy of BRUKINSA was assessed in BGB-3111-206 [NCT03206970], a Phase 2, open-label, multicenter, single-arm trial of 86 previously treated patients with MCL who had received at least one prior therapy. BRUKINSA was given orally at a dose of 160 mg twice daily until disease progression or unacceptable toxicity. The median age of patients was 60. 5 years (range: 34 to 75) and the majority were male (78%). The median time since diagnosis to study entry was 30 months (range: 3 to 102) and the median number of prior therapies was 2 (range: 1 to 4). The most common prior regimens were CHOP-based (91%) followed by rituximab-based (74%). The majority of patients had extranodal involvement (71%) and refractory disease (52%). Blastoid variant of MCL was present in 14% of patients. The MIPI score was low in 58%, intermediate in 29%, and high risk in 13%. The efficacy of BRUKINSA was also assessed in BGB-3111-AU-003 [NCT02343120], a Phase 1/2, open-label, dose-escalation, global, multicenter, single-arm trial of B cell malignancies including 32 previously treated MCL patients treated with BRUKINSA. BRUKINSA was given orally at doses of 160 mg twice daily or 320 mg daily. The median age of patients with previously treated MCL was 70 years (range: 42 to 86) and 38% of patients were >=75 years old. Most patients were male (69%) and White (78%). The MIPI score was low in 28%, intermediate in 41%, and high risk in 31%. Tumor response was according to the 2014 Lugano Classification for both studies, and the primary efficacy endpoint was overall response rate as assessed by an Independent Review Committee (IRC). Table 19: Efficacy Results per IRC in Patients with MCL Study BGB-3111-206 Study BGB-3111-AU-003 ORR: overall response rate, CR: complete response, PR: partial response, DOR: duration of response, CI: confidence interval, NE: not estimable. ORR (95% CI) 84% (74, 91) 84% (67, 95) CR 59% 22% FDG-PET scans were not required for response assessment. PR 24% 62% Median DOR in months (95% CI) 19. 6, NE) The efficacy of BRUKINSA was evaluated in ASPEN [NCT03053440], a randomized, active control, open-label trial, comparing BRUKINSA and ibrutinib in patients with MYD88 L265P mutation ( MYD88 MUT The major efficacy outcome was the response rate defined as PR or better as assessed by IRC based on standard consensus response criteria from the International Workshop on Waldenström''s Macroglobulinemia (IWWM)-6 criteria. An additional efficacy outcome measure was duration of response (DOR). The median age was 70 years (range: 38 to 90) and 68% were male. Of those enrolled, 2% were Asian, 91% were White, and 7% were of unknown race. ECOG performance status of 0 or 1 was present in 93% patients at baseline and 7% had a baseline ECOG performance status of 2. A total of 82% had relapsed/refractory disease with 85% having received prior alkylating agents and 91% prior anti-CD20 therapy. The median number of prior therapies in those with relapsed/refractory disease was 1 (range: 1 to 8). A total of 91 (45%) patients had International Prognostic Scoring System (IPSS) high WM. The study did not meet statistical significance for the prespecified efficacy outcome of superior CR+VGPR as assessed by IRC, tested first in patients with R/R disease in ASPEN. Table 20 shows the response rates in ASPEN based on IRC assessment. Table 20: Response Rate and Duration of Response Based on IRC Assessment in ASPEN Standard IWWM-6 IWWM-6 criteria (Owen et al, 2013) require complete resolution of extramedullary disease (EMD) if present at baseline for VGPR to be assessed. Modified IWWM-6 Modified IWWM-6 criteria (Treon, 2015) require a reduction in EMD if present at baseline for VGPR to be assessed. Response Category BRUKINSA Ibrutinib BRUKINSA Ibrutinib Response rate (CR+VGPR+PR), n (%) 79 (77. 8) 95% CI (%) 2-sided Clopper-Pearson 95% confidence interval. 5) Complete Response (CR) 0 (0) 0 (0) 0 (0) 0 (0) Very Good Partial Response (VGPR) 16 (15. 2) Partial Response (PR) 63 (61. 7) 50 (49) 58 (58. 6) Duration of response (DOR), Event-free at 12 months (95% CI) Estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley. 9% ASPEN Cohort 2 Cohort 2 enrolled patients with MYD88 wildtype ( MYD88 WT In Cohort 2, response (CR+VGPR+PR) as assessed by IRC using IWWM-6 or modified IWWM-6 was seen in 50% (13 out of 26 response evaluable patients; 95% CI: 29. The efficacy of BRUKINSA was assessed in Study BGB-3111-214 [NCT03846427], an open-label, multicenter, single-arm trial that evaluated 66 patients with MZL who received at least one prior antien dashCD20-based therapy. BRUKINSA was given orally at a dosage of 160 mg twice daily until disease progression or unacceptable toxicity. The median age was 70 years (range: 37 to 85); 55% were male; 38% had extranodal MZL, 38% nodal, 18% splenic, and 6% had unknown subtype. The median number of prior systemic therapies was 2 (range: 1 to 6), with 27% having 3 or more lines of systemic therapy; 88% had prior rituximab-based chemotherapy; 32% had refractory disease at study entry. The efficacy of BRUKINSA was also assessed in BGB-3111-AU-003 [NCT02343120], an open-label, multicenter, single-arm trial that included 20 patients with previously treated MZL (45% having extranodal MZL, 25% nodal, 30% splenic). BRUKINSA was given orally at dosages of 160 mg twice daily or 320 mg once daily. The median age was 70 years (range: 52 to 85); 50% were male. The median number of prior systemic therapies was 2 (range: 1 to 5), with 20% having 3 or more lines of systemic therapy; 95% had prior rituximab-based chemotherapy. Efficacy was based on overall response rate (ORR) and duration of response as assessed by an Independent Review Committee (IRC) using 2014 Lugano criteria (Table 21). Table 21: Efficacy Results per IRC in Patients with MZL Parameter Study BGB-3111-214 Study BGB-3111-AU-003 ORR: overall response rate, CR: complete response, PR: partial response, DOR: duration of response, CI: confidence interval, NE: not estimable. Overall Response Rate (CT-based) Per 2014 CT-based Lugano criteria. FDG-PET scans were not considered for this response assessment. ORR, n 37 (56%) 16 (80%) (95% CI, %) (43, 68) (56, 94) CR, n 13 (20%) 4 (20%) PR, n 24 (36%) 12 (60%) Time to Response Median (range), months 2. 1) Duration of Response Based on Kaplan-Meier estimation. Estimated median follow-up for DOR was 8. 3 months for Study BGB-3111-214 and 31. 4 months for Study BGB-3111-AU-003. Median DOR (95% CI), months NE (NE, NE) NE (8. 4, NE) Rate at 12 months (95% CI) 85% (67, 93) 72% (40, 88) In study BGB-3111-214, ORR prioritizing PET-CT when available (55 patients, with the remainder assessed by CT scan) was 67% (95% CI: 54, 78) with a CR rate of 26%. The efficacy of BRUKINSA in patients with CLL/SLL was evaluated in two randomized controlled trials. SEQUOIA The efficacy of BRUKINSA in patients with previously untreated CLL/SLL was evaluated in a multicenter, open-label trial (SEQUOIA; NCT03336333). The trial required patients to be unsuitable for FCR therapy defined as either age >=65 years or age 18 to 6, creatinine clearance 30 to 69 mL/min, or history of serious or recurrent infection. Patients without 17p deletion (17p del) were randomized to receive either BRUKINSA 160 mg twice daily until disease progression or unacceptable toxicity (n=241) or bendamustine plus rituximab (BR) for 6 cycles (n=238). Bendamustine was dosed at 90 mg/m 2 2 2 Additionally, the same BRUKINSA regimen was evaluated in 110 patients with previously untreated 17p del CLL/SLL in a non-randomized cohort. Efficacy is summarized according to cohort. Randomized Cohort: Previously Untreated CLL/SLL without 17p Deletion In the randomized cohort of patients with previously untreated CLL/SLL without 17p deletion, the median age was 70 years; 62% were male, 89% were White, 3% were Asian, and 1% were Black. Fifty-three percent of patients had an unmutated IGHV gene and 29% had Binet Stage C disease. Baseline characteristics were generally similar between treatment arms. Efficacy in this cohort was based on progression-free survival as assessed by an IRC. Efficacy results are presented in Table 22 and Figure 1. Table 22: Efficacy Results per IRC in Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA (Randomized Cohort) Parameter Efficacy was assessed using the 2008 International Workshop for Chronic Lymphocytic Leukemia (iwCLL) guidelines and 2014 Lugano criteria for SLL. CLL/SLL without del(17p) BRUKINSA Bendamustine + Rituximab CI=Confidence interval, CR=complete response, CRi=complete response with incomplete hematopoietic recovery, HR=hazard ratio, NE=not estimable, nPR=nodular partial response, ORR=overall response rate, PFS=progression-free survival, PR=partial response. Progression-free survival Number of Events, n 36 (15%) 71 (30%) Disease Progression 27 (11%) 59 (25%) Death 9 (3. 7%) 12 (5%) Median PFS (95% CI), months Based on Kaplan-Meier estimation. Estimated median follow-up for PFS was 25 months. NE (NE, NE) 33. 1, NE) HR (95% CI) Based on a stratified Cox-regression model with bendamustine + rituximab as the reference group. 63) P-value Based on a stratified log-rank test, with a 2-sided significance level of 0. 0001 Overall response rate Defined as CR, CRi, PR, and nPR. No patients had CRi as best response. ORR, n (%) 225 (93) 203 (85) 95% CI, % (89, 96) (80, 90) CR, n (%) 16 (7) 36 (15) nPR, n (%) 3 (1. 2) 14 (6) PR, n (%) 206 (85) 153 (64) Figure 1: Kaplan-Meier Plot of IRC-Assessed Progression-Free Survival in Patients with Previously Untreated CLL/SLL without 17p Deletion in SEQUOIA At the time of analysis, overall survival data were immature. With an estimated median follow-up of 25. 7 months, median overall survival was not reached in either arm, with fewer than 7% of patients experiencing an event. Figure 1 Single-Arm Cohort: Previously Untreated CLL/SLL with 17p Deletion In this cohort, 110 patients with previously untreated CLL/SLL and centrally confirmed 17p deletion received BRUKINSA 160 mg twice daily until disease progression or unacceptable toxicity. The median age was 70, 71% were male, 95% were White, and 1% were Asian. Sixty percent of patients had an unmutated IGHV gene and 35% had Binet Stage C disease. Efficacy was based on overall response rate and duration of response as assessed by an IRC. Efficacy results are presented in Table 23. Table 23: Efficacy Results per IRC in Patients with Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA Parameter Efficacy was assessed using the 2008 iwCLL guidelines and Lugano criteria for SLL. del(17p) CLL/SLL DOR=duration of response. A + sign indicates a censored observation. Overall response rate Defined as CR, CRi, PR, and nPR. ORR, n (%) 97 (88) (95% CI, %) (81, 94) CR, n (%) 7 (6) nPR, n (%) 2 (1. 8) PR, n (%) 88 (80) Time to response Median (range), months 2. 9) Duration of response Median DOR (95% CI), Kaplan-Meier estimate. Estimated median follow-up for DOR was 25. NE (NE, NE) Range, months (5. 9+) Rate at 12 months, % (95% CI) 96 (89, 98) Rate at 18 months, % (95% CI) 95 (88, 98) ALPINE The efficacy of BRUKINSA in patients with relapsed or refractory CLL/SLL was evaluated in ALPINE, a randomized, multicenter, open-label, actively controlled trial (NCT03734016). The trial enrolled 652 patients with relapsed or refractory CLL/SLL after at least 1 systemic therapy. The patients were randomized in a 1:1 ratio to receive either BRUKINSA 160 mg orally twice daily (n=327) or ibrutinib 420 mg orally once daily (n=325), each administered until disease progression or unacceptable toxicity. Randomization was stratified by age, geographic region, refractoriness to last therapy, and 17p deletion/ TP53 Baseline characteristics were similar between treatment arms. Overall, the median age was 67 years, 68% were male, 81% were White, 14% were Asian, and 1% were Black. Forty-three percent had advanced stage disease, 73% had an unmutated IGHV gene, and 23% had 17p deletion or TP53 Efficacy was based on overall response rate and duration of response as determined by an IRC. For progression-free survival per IRC, the final analysis occurred with a median follow-up of 31 months. Efficacy results are shown in Table 24 and Figure 2. Table 24: Efficacy Results per IRC in Patients with Relapsed or Refractory CLL/SLL in ALPINE Parameter Efficacy was based on 2008 iwCLL guidelines for CLL and the Lugano criteria for SLL. BRUKINSA Ibrutinib CI=Confidence interval, CR=complete response, CRi=complete response with incomplete hematopoietic recovery, DOR=duration of response, HR=hazard ratio, NE=not estimable, nPR=nodular partial response, ORR=overall response rate, PR=partial response. Overall response rate Defined as CR + CRi + nPR + PR. ORR, n (%) 263 (80) 237 (73) (95% CI, %) (76, 85) (68, 78) CR, n (%) 13 (4) 8 (2. 5) nPR, n (%) 1 (0. 3) 0 (0) PR, n (%) 249 (76) 229 (70) Response Rate Ratio (95% CI) Estimate stratified by randomization stratification factors. 20) 2-sided p-value 2-sided significance level of 0. 0469 was allocated for ORR superiority testing. 0264 Duration of response Median DOR (95% CI) Based on Kaplan-Meier estimate. Estimated median follow-up for DOR was 14. NE (NE, NE) NE (NE, NE) Range, months (1. 8+) Rate at 12 months, % (95% CI) 92 (87, 95) 86 (80, 91) Progression-free survival Events, n (%) 88 (27) 120 (37) Median PFS (95% CI), months Based on Kaplan-Meier estimation. Estimated median follow-up for PFS was 30. 3, NE) 35 (33. 3) HR (95% CI) Based on a stratified Cox-regression model with ibrutinib as the reference group. 86) 2-sided p-value Based on a stratified log-rank test. 0024 The median time to response was 5. 5 months for BRUKINSA and 5. 6 months for ibrutinib. Figure 2: Kaplan-Meier Plot of Progression-Free Survival by IRC in ALPINE At the time of final analysis, the median overall survival was not reached in either arm. There were a total of 108 deaths: 48 (14. 7%) in the zanubrutinib arm and 60 (18. 5%) in the ibrutinib arm. Figure 2 The efficacy of BRUKINSA, in combination with obinutuzumab, was evaluated in Study BGB-3111-212 (ROSEWOOD; NCT03332017), an open-label, multicenter, randomized trial that enrolled 217 adult patients with relapsed or refractory FL after at least 2 prior systemic treatments. The study required prior receipt of an anti-CD20 antibody and an alkylator-based combination therapy, and excluded patients with FL Grade 3b, transformed lymphoma, and prior exposure to a BTK inhibitor. Patients were randomized in a 2:1 ratio to receive either BRUKINSA 160 mg orally twice daily until disease progression or unacceptable toxicity plus obinutuzumab, or obinutuzumab alone. Obinutuzumab was administered 1,000 mg intravenously on days 1, 8, and 15 of Cycle 1, 1,000 mg on Day 1 of Cycles 2 to 6; and then 1,000 mg every 8 weeks for up to 20 doses. At the discretion of the investigator, obinutuzumab could be administered as 100 mg on Day 1 and 900 mg on Day 2 of Cycle 1. Randomization was stratified by the number of prior lines of therapy (2 to 3 vs ˃3), rituximab-refractory status (yes vs no), and geographic region. Of the 217 patients randomized (145 to BRUKINSA plus obinutuzumab, 72 to obinutuzumab monotherapy), the median age was 64 years (range: 31 to 88), 50% were male, 64% were White, and 22% were Asian. In total, 83% had stage 3 or 4 disease and 57% met Groupe d''Etude des Lymphomes Folliculaires (GELF) criteria at enrollment. Patients had a median of 3 prior lines of therapy (range: 2-11), with 27% of patients having more than 3 prior lines of therapy. In the BRUKINSA in combination with obinutuzumab arm, 5% had received lenalidomide plus rituximab, 21% had received stem cell transplantation, 53% had refractory disease to rituximab, and 37% had progression of disease within 24 months of the first systemic therapy. Efficacy was based on overall response rate and duration of response, as determined by an IRC. Efficacy results are shown in Table 25. The median time to response in the BRUKINSA combination arm was 2. 8 months (range 2 to 23 months). Table 25: Efficacy Results per IRC in Patients with Relapsed or Refractory Follicular Lymphoma Parameter BRUKINSA + Obinutuzumab Obinutuzumab CI=Confidence interval, CR=complete response, DOR=duration of response, NE=not estimable, ORR=overall response rate, PR=partial response. Overall response rate ORR, n (%) 100 (69) 33 (46) (95% CI) Estimated using the Clopper-Pearson method. (61, 76) (34, 58) CR 57 (39) 14 (19) PR 43 (30) 19 (26) Risk difference, % (95% CI) Estimated by stratified Cochran-Mantel-Haenszel method. 5) 2-sided p-value , Significance level, 0. 0012 Duration of response Median DOR (95% CI), Estimated by Kaplan-Meier method. Estimated median follow-up for DOR was 19 months overall. 3, NE) 14 (9. 1) The estimated DOR rate at 18 months was 69% (95% CI: 58, 78) in the BRUKINSA combination arm and 42% (95% CI: 23, 60) in the obinutuzumab monotherapy arm.

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