b'Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included peripheral neuropathy,Table 9: Adverse Reactions in 10% Patients with Previously Untreated CLL/SLL without 17p DeletionTable 11: Adverse Reactions in 10% of Patients with Previously Untreated CLL/SLL and 17p DeletionTable 13: Adverse Reactions in 10% of Patients with Relapsed or Refractory CLL/SLL Who Received second primary malignancies, dizziness, edema, headache, petechiae, purpura, and atrial fibrillation or flutter.in SEQUOIA (Continued) in SEQUOIA (Continued) BRUKINSA in ALPINE (Continued)Table 8 summarizes select laboratory abnormalities. CLL/SLL without 17p deletion CLL/SLL with 17p Deletion BRUKINSA IbrutinibBRUKINSA (N=240) BR (N=227) BRUKINSA (N=111) System Organ Class (N=324) (N=324)Table 8: Select Laboratory Abnormalities (20%) that Worsened from Baseline in Patients with MZL System Organ ClassSystem Organ Class Preferred Term All Grades Grade 3 or 4 All Grades Grade 3 or 4a BRUKINSA Preferred Term All Grades Grade 3 or 4 All Grades Grade 3 or 4 Preferred Term All Grades Grade 3 or 4 (%) (%) (%) (%)Laboratory Abnormality (%) (%) (%) (%) (%) (%)All Grades (%) Grade 3 or 4 (%) Neoplasms Musculoskeletal and connective tissue disordersHematologic abnormalities i Neoplasms dSecond primary malignancy 13* 6 1.3 0.4 Second primary malignancyh 22 6 Musculoskeletal pain 26 0.6 28 0.6Neutrophils decreased 43 15 Nervous system disorders Vascular disordersPlatelets decreased 33 10 Headachee 12 0 8 0 Gastrointestinal disorders Hemorrhagee 24* 2.5 26 3.7Lymphocytes decreased 32 8 Dizzinessj 11 0.8 5 0 Diarrhea 18 0.9 Hypertensionf 19 13 20 13Hemoglobin decreased 26 6 * Includes 3 fatal outcomes. Nausea 16 0 Includes 2 fatal outcomes. Constipation 15 0 Skin and subcutaneous tissue disordersChemistry abnormalities aMusculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain,g Rashg 20 1.2 21 0.9Glucose increased 54 4.6 musculoskeletal discomfort, bone pain. Abdominal pain 12 1.8 hbUpper respiratory tract infection: upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, pharyngitis, upperRespiratory, thoracic, and mediastinal disorders Bruising 16 0 14 0 Creatinine increased 34 1.1 respiratory tract congestion, laryngitis, tonsillitis and upper respiratory tract inflammation, and related terms. g Gastrointestinal disordersPhosphate decreased 27 2.3 cPneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms includingCough 18 0 d specific types of infection. Dyspneag 13 0 Diarrhea 14 1.5 22 0.9Calcium decreased 23 0 e Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. General disordersALT increased 22 1.1 f I ncludes multiple similar adverse reaction terms. General disorders and administration site conditions ia g Fatigue 14 0.9Rash: Rash, dermatitis, drug eruption, and related terms. i Fatigue 13 0.9 14 0.9 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 Bruising: all terms containing bruise, bruising, contusion, or ecchymosis.one post-treatment value.h Fatigue: fatigue, asthenia, and lethargy. Nervous system disorders Respiratory, thoracic, and mediastinal disordersiSecond primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including lung, renal, genitourinary,fCough 11 0.3 11 0Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma breast, ovarian, and rectal), and chronic myeloid leukemia. Headache 11 1.8The safety data described below reflect exposure to BRUKINSA (160 mg twice daily) in 675 patients with CLLj Dizziness: dizziness and vertigo. *Includes 1 fatal outcome. Nervous system disordersfrom two randomized controlled clinical trials [see Clinical Studies (14.4)]. The trials required patients to beOther clinically significant adverse reactions occurring in 10% of BRUKINSA recipients in this cohort Includes non-melanoma skin cancer in 13%. Dizzinessf 10 0 7 0unsuitable for fludarabine, cyclophosphamide, and rituximab (FCR) therapy defined as age 65 years, or age 18included COVID-19 (9%), edema (8%), abdominal pain (8%), urinary tract infection (7%), and atrial fibrillationaUpper 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. * Includes fatal outcomes: pneumonia (9 patients), COVID-19 (8 patients), and hemorrhage (1 patient).to 65 years with either a total Cumulative Illness Rating Scale (CIRS) 6, CLcr 30 to 69 mL/min, or history ofor flutter (3.3%). b Includes fatal outcomes: pneumonia (10 patients), COVID-19 (9 patients), and hemorrhage (2 patients).serious or frequent infections. The trial excluded patients with AST or ALT 2 times the upper limit of normal (ULN)Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, and related terms including specific types of infection. aTable 10 summarizes select laboratory abnormalities in this cohort. cMusculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, bone pain. Upper respiratory tract infection: upper respiratory tract infection, sinusitis, pharyngitis, rhinitis, nasopharyngitis, laryngitis, or bilirubin 3 times (ULN) and patients requiring a strong CYP3A inhibitor or inducer. d tonsillitis, and related terms.Rash: Rash, dermatitis, toxic skin eruption, and related terms.SEQUOIA Table 10: Select Laboratory Abnormalities (20%) that Worsened from Baseline in Patients with PreviouslyeBruising: all terms containing bruise, bruising, contusion, or ecchymosis. bPneumonia: Pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific Untreated CLL/SLL without 17p Deletion in SEQUOIA f Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. types of infection.The safety of BRUKINSA monotherapy in patients with previously untreated CLL/SLL was evaluated in ag cCOVID-19: COVID-19, COVID-19 pneumonia, postacute COVID-19 syndrome, SARS-CoV-2 test positive.randomized, multicenter, open-label, actively controlled trial [see Clinical Studies (14.4)]. Patients withoutBRUKINSA BR h Includes multiple similar adverse reaction terms. dMusculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, bone pain, anddeletion of chromosome 17p13.1 (17p deletion) (Cohort 1) received either BRUKINSA 160 mg twice daily untilLaboratory Abnormalitya Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including bladder, lung, renal, breast,musculoskeletal discomfort.disease progression or unacceptable toxicity (n=240) or bendamustine plus rituximab (BR) for 6 cycles (n=227).All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) i prostate, ovarian, pelvis, and ureter), and malignant melanoma. eHemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding.Bendamustine was dosed at 90 mg/m2/day intravenously on the first 2 days of each cycle, and rituximab wasHematologic abnormalities Fatigue: fatigue, asthenia, and lethargy. f Includes multiple similar adverse reaction terms.dosed at 375 mg/m2 on day 1 of Cycle 1 and 500 mg/m2 on day 1 of Cycles 2 to 6. Neutrophils decreased 37 15 80 53 Clinically significant adverse reactions occurring in 10% of BRUKINSA recipients in this cohort includedgRash: Rash, Dermatitis, and related terms.urinary tract infection (8%), edema (7%), atrial fibrillation or flutter (4.5%), and COVID-19 (3.6%). hBruising: all terms containing bruise, bruising, contusion, or ecchymosis.Additionally, the same BRUKINSA regimen was evaluated in 111 patients with previously untreated CLL/SLLHemoglobin decreased 29 2.5 66 8 Table 12 summarizes select laboratory abnormalities in this cohort. i Fatigue: asthenia, fatigue, lethargy.with 17p deletion in a non-randomized single arm (Cohort 2). Platelets decreased 27 1.7 61 11 Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included urinary tract infection Randomized Cohort: Previously Untreated CLL/SLL without 17p Deletion Leukocytes increased 21b 21 0.4 0.4 Table 12: Select Laboratory Abnormalities (20%) that Worsened from Baseline in Patients with(9%), supraventricular arrhythmias (9%) including atrial fibrillation or flutter (4.6%), abdominal pain (8%), headache In patients with previously untreated CLL/SLL without 17p deletion, the median age was 70, 62% were male,Previously Untreated CLL/SLL and 17p Deletion in SEQUOIA(8%), pruritus (6.2%), constipation (5.9%), and edema (4.6%).89% were White, 2% were Asian, and 2% were Black. Most patients (93%) had an ECOG performance statusChemistry abnormalitiesof 0 to 1. Glucose increasedc 55 7 67 10 Laboratory Abnormalitya BRUKINSA Table 14 summarizes select laboratory abnormalities in ALPINE.The median duration of exposure to BRUKINSA was 26 months, with 71% exposed for more than 2 years. Creatinine increased 22 0.8 18 0.4 All Grades (%) Grade 3 or 4 (%) Table 14: Select Laboratory Abnormalities (20%) that Worsened from Baseline in Patients Who Received Serious adverse reactions occurred in 36% of patients who received BRUKINSA. Serious adverse reactionsMagnesium increased 22 0 14 0.4 Hematologic abnormalities BRUKINSA in ALPINE that occurred in 5% of patients were COVID-19, pneumonia, and second primary malignancy (5% each).Alanine aminotransferase increased 21 2.1 23 2.2 Neutrophils decreased 42 19b Laboratory Abnormalitya BRUKINSA IbrutinibFatal adverse reactions occurred in 11 (4.6%) patients with the leading cause of death being COVID-19 (2.1%). a Hemoglobin decreased 26 3.6 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%)Adverse reactions led to permanent discontinuation of BRUKINSA in 8% of patients, dose reduction in 8%, andThe denominator used to calculate the rate was 239 in the BRUKINSA arm and 227 in the BR arm, based on the number of dose interruption in 46%. The most common adverse reactions leading to permanent discontinuation werepatients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria. Platelets decreased 23 0.9 Hematologic abnormalitiesbLymphocytes increased in 15%. second primary malignancy and COVID-19. The leading causes of dose modification (5% of all patients) werecNeutrophils decreased 43 15 33 16respiratory infections (COVID-19, pneumonia) and hemorrhage. Nonfasting conditions. Chemistry abnormalitiesSingle-Arm Cohort: Previously Untreated CLL/SLL and 17p Deletion Glucose increasedc 52 6 Hemoglobin decreased 28 4 32 3.7Table 9 summarizes select adverse reactions in this randomized cohort. In 111 patients with previously untreated, 17p del CLL/SLL, the median age was 70, 71% were male, 95%Magnesium increased 31 0 Lymphocytes increased 24 19 26 19Table 9: Adverse Reactions in 10% Patients with Previously Untreated CLL/SLL without 17p Deletionwere White, and 1% were Asian. Most patients (87%) had an ECOG performance status of 0 to 1. The medianCreatinine increased 27 0.9 Platelets decreased 22 4 24 3.4in SEQUOIA duration of exposure to BRUKINSA was 30 months.CLL/SLL without 17p deletion Fatal adverse reactions occurred in 3 (2.7%) patients, including pneumonia, renal insufficiency, and aorticaThe denominator used to calculate the rate varied from 110 to 111 based on the number of patients with a baseline value and atChemistry abnormalitiesdissection (1 patient each). bleast one post-treatment value. Grading is based on NCI CTCAE criteria. Glucose increased 52 5 29 2.8BRUKINSA (N=240) BR (N=227) Grade 4, 9%.System Organ ClassSerious adverse reactions occurred in 41% of patients treated with BRUKINSA. Serious adverse reactionscNon-fasting conditions.Creatinine increased 26 0 23 0Preferred Term All Grades Grade 3 or 4 All Grades Grade 3 or 4 reported in 5% of patients were pneumonia (8%) and second primary malignancy (7%).(%) (%) (%) (%) ALPINE Phosphate decreased 21 2.5 13 2.2Musculoskeletal and connective tissue disorders Adverse reactions led to treatment discontinuation in 5% of patients, dose reduction in 5%, and doseThe safety of BRUKINSA monotherapy was evaluated in patients with previously treated CLL/SLL in a randomized,Calcium decreased 21 0.6 29 0a interruption in 51%. The leading causes of dose modification (5% of all patients) were pneumonia,multicenter, open-label, actively controlled trial [see Clinical Studies (14.4)]. In ALPINE, 324 patients receivedaMusculoskeletal pain 33 1.7 17 0.4 neutropenia, second primary malignancy, and diarrhea. BRUKINSA monotherapy, 160 mg orally twice daily and 324 patients received ibrutinib monotherapy, 420 mgThe denominator used to calculate the rate was 321 in the BRUKINSA arm, and varied from 320 to 321 in the ibrutinib arm, based Infections and infestations Table 11 summarizes select adverse reactions in this cohort. orally daily until disease progression or unacceptable toxicity. on the number of patients with a baseline value and at least one post-treatment value. Grading is based on NCI CTCAE criteria.Upper respiratory tract infectionb 28 1.3 15 0.9 In ALPINE, the median duration of exposure was 24 months for BRUKINSA. Adverse reactions leading to deathFollicular Lymphoma Table 11: Adverse Reactions in 10% of Patients with Previously Untreated CLL/SLL and 17p Deletion Pneumoniac 13* 5 8 4 in SEQUOIA in the BRUKINSA arm occurred in 24 (7%) patients. Adverse reactions leading to death that occurred in 1% ofThe safety of BRUKINSA in combination with obinutuzumab was evaluated in 143 adult patients with patients were pneumonia (2.8%) and COVID-19 infection (1.9%). relapsed or refractory follicular lymphoma (FL) in study BGB-3111-212 (ROSEWOOD), a randomized,Vascular disorders CLL/SLL with 17p Deletion multicenter, open-label trial [see Clinical Studies (14.5)]. The trial required an absolute neutrophil countd One hundred and four patients in the BRUKINSA arm (32%) reported 1 serious adverse reaction. Serious 1109/L, platelet count 50109/L, and CLcr 30 mL/min and excluded patients requiring a strong Hemorrhage 27* 4 4 0.4 System Organ Class BRUKINSA (N=111) adverse reactions occurring in 5% of patients were pneumonia (10%), COVID-19 (7%), and second primaryCYP3A inhibitor or inducer.Hypertensione 14 7 5 2.6 Preferred Term All Grades Grade 3 or 4 malignancies (5%).(%) (%) Patients were randomized to receive either BRUKINSA 160 mg twice daily until disease progression or Skin and subcutaneous tissue disorders Adverse reactions led to treatment discontinuation in 13% of patients, dose reduction in 11%, and doseunacceptable toxicity plus obinutuzumab (n=143) or obinutuzumab monotherapy (n=71). Obinutuzumabf Infections and infestations interruption in 42%. The leading cause of treatment discontinuation was pneumonia. The leading causes of dosewas 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 Rash 24 1.3 30 5 Upper respiratory tract infectiona 38 0 modification (5% of all patients) were respiratory infections (COVID-19, pneumonia) and neutropenia.g every 8 weeks for up to 20 doses. At the discretion of the investigator, obinutuzumab was administered Bruising 24 0 2.6 0 Pneumoniab 20* 8 Table 13 summarizes select adverse reactions in ALPINE. 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.Respiratory, thoracic, and mediastinal disorders Musculoskeletal and connective tissue disorders In patients who received BRUKINSA in combination with obinutuzumab, the median age was 63, 49%Coughe 15 0 10 0 c Table 13: Adverse Reactions in 10% of Patients with Relapsed or Refractory CLL/SLL Who Receivedwere female, 63% were White, and 21% were Asian. Most patients (97%) had an ECOG performance Musculoskeletal pain 38 2.7 BRUKINSA in ALPINEGastrointestinal disorders Skin and subcutaneous tissue disorders BRUKINSA Ibrutinib status of 0 to 1. The median duration of BRUKINSA treatment was 12 months, with 24% of patients0.9 d System Organ Class (N=324) (N=324) treated for at least 2 years. Diarrhea 14 0.8 12 Rash 28 0 Preferred Term All Grades Grade 3 or 4 All Grades Grade 3 or 4 Serious adverse reactions occurred in 35% of patients who received BRUKINSA in combination with Constipation 10 0.4 18 0 Bruisinge 26 0.9 (%) (%) (%) (%) obinutuzumab. Serious adverse reactions in 5% of patients included pneumonia (11%) and COVID-19Nausea 10 0 33 1.3 Vascular disorders Infections and infestations (10%). Fatal adverse reactions occurred in 4.2% of patients, with the leading cause of death being General disorders Hemorrhagef 28 4.5 Upper respiratory tract infectiona 27 1.2 22 1.2 COVID-19 (2.1%).Fatigueh 14 1.3 21 1.8 Hypertensiong 11 5.4 Pneumoniab 18* 9 19 11 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 COVID-19c 14* 7 10 4.6 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.'