6 ADVERSE REACTIONS

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)]

6.1 Clinical Trials Experience

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)]. The median age of patients who received BRUKINSA in studies BGB-3111-206 and BGB-3111-AU-003 was 62 years (range: 34 to 86), 75% were male, 75% were Asian, 21% were White, and 94% had an ECOG performance status of 0 to 1. Patients had a median of 2 prior lines of therapy (range: 1 to 4). The BGB-3111-206 trial required a platelet count ≥75 × 109/L and an absolute neutrophil count ≥1 × 109/L independent of growth factor support, hepatic enzymes ≤2.5 × upper limit of normal, total bilirubin ≤1.5 × ULN. The BGB-3111-AU-003 trial required a platelet count ≥50 × 109/L and an absolute neutrophil count ≥1 × 109/L independent of growth factor support, hepatic enzymes ≤3 × upper limit of normal, total bilirubin ≤1.5 × ULN. Both trials required a creatinine clearance (CLcr) ≥30 mL/min. Both trials excluded patients with prior allogeneic hematopoietic stem cell transplant, exposure to a BTK inhibitor, known infection with HIV, and serologic evidence of active hepatitis B or hepatitis C infection, and patients requiring strong CYP3A inhibitors or strong CYP3A inducers. Patients received BRUKINSA 160 mg twice daily or 320 mg once daily. Among patients receiving BRUKINSA, 79% were exposed for 6 months or longer, and 68% were exposed for greater than one year.

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 (3.4%). One (0.8%) 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)
Body System	Adverse Reaction	All Grades %	Grade 3 or Higher %
* Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral. † 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. ‡ Includes fatal adverse reaction. § Rash includes all related terms containing rash. ¶ Bruising includes all related terms containing bruise, bruising, contusion, ecchymosis. # Hemorrhage includes all related terms containing hemorrhage, hematoma. Þ Musculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis.
Infections and infestations	Upper respiratory tract infection*	39	0
	Pneumonia†	15	10‡
	Urinary tract infection	11	0.8
Skin and subcutaneous tissue disorders	Rash§	36	0
Skin and subcutaneous tissue disorders	Bruising¶	14	0
Gastrointestinal disorders	Diarrhea	23	0.8
	Constipation	13	0
Vascular disorders	Hypertension	12	3.4
	Hemorrhage#	11	3.4‡
Musculoskeletal and connective tissue disorders	Musculoskeletal painÞ	14	3.4
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 (4.2%).

Table 4: Selected Laboratory Abnormalities* (>20%) in Patients with MCL in Studies BGB-3111-206 and BGB-3111-AU-003
Laboratory Parameter	Percent of Patients (N=118)
Laboratory Parameter	All Grades (%)	Grade 3 or 4 (%)
* Based on laboratory measurements. † Asymptomatic lymphocytosis is a known effect of BTK inhibition.
Hematologic abnormalities
Neutrophils decreased	45	20
Lymphocytosis†	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 (MYD88MUT) WM, randomized to and treated with either BRUKINSA (101 patients) or ibrutinib (98 patients). The trial also included a non-randomized arm, Cohort 2, with 26 wild type MYD88 (MYD88WT) WM patients and 2 patients with unknown MYD88 status [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 (%)
		* 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. † Pneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral. ‡ Fatigue includes asthenia, fatigue, lethargy. § Bruising includes all related terms containing bruise, contusion, or ecchymosis. ¶ 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. # Musculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain, musculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort. Þ 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.
Infections and infestations	Upper respiratory tract infection*	44	Grade 3 or 4 (%)	0	Grade 3 or 4 (%)	40	2
	Pneumonia†	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‡	31	1	25	1
	Pyrexia	16	4	13	2
	Edema peripheral	12	0	20	0
Skin and subcutaneous tissue disorders	Bruising§	20	0	34	0
	Rash¶	29	0	32	0
	Pruritus	11	1	6	0
Musculoskeletal and connective tissue disorders	Musculoskeletal pain#	45	9	39	1
Musculoskeletal and connective tissue disorders	Muscle spasms	10	0	28	1
Nervous system disorders	Headache	18	1	14	1
Nervous system disorders	Dizziness	13	1	12	0
Respiratory, thoracic, and mediastinal disorders	Cough	16	0	18	0
Respiratory, thoracic, and mediastinal disorders	Dyspnea	14	0	7	0
Vascular disorders	HemorrhageÞ	42	4	43	9
Vascular disorders	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* (≥20%) that Worsened from Baseline in Patients with WM Who Received BRUKINSA in Cohort 1
Laboratory Abnormality	BRUKINSA†		Ibrutinib†
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* Based on laboratory measurements. † 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.
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	33	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)]. The trials required an absolute neutrophil count ≥1 × 109/L, platelet count ≥50 or ≥75 × 109/L and adequate hepatic function and excluded patients requiring a strong CYP3A inhibitor or inducer. Patients received BRUKINSA 160 mg twice daily (97%) or 320 mg once daily (3%). The median age in both studies combined was 70 years (range: 37 to 95), 52% were male, 64% were White, and 19% were Asian. Most patients (92%) had an ECOG performance status of 0 to 1. Eighty percent received BRUKINSA for 6 months or longer, and 67% received treatment for more than one year.

Two fatal adverse reactions (2.3%) occurred within 30 days of the last dose of BRUKINSA, including myocardial infarction and a Covid-19–related 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)
Body System	Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
* Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper respiratory tract infection. † Urinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis. ‡ Pneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection, organizing pneumonia. § Includes 2 fatalities from COVID-19 pneumonia. ¶ Diarrhea includes diarrhea and diarrhea hemorrhagic. # Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort. Þ Bruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion. ß 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. à Musculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, neck pain. è 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. ð Fatigue includes fatigue, lethargy, asthenia. ø Cough includes cough and productive cough.
Infections and infestations	Upper respiratory tract infection*	26	3.4
	Urinary tract infection†	11	2.3
	Pneumonia‡,§	10	6
Gastrointestinal disorders	Diarrhea¶	25	3.4
	Abdominal pain#	14	2.3
	Nausea	13	0
Skin and subcutaneous tissue disorders	BruisingÞ	24	0
Skin and subcutaneous tissue disorders	Rashß	21	0
Musculoskeletal and connective tissue disorders	Musculoskeletal painà	27	1.1
Vascular disorders	Hemorrhageè	23	1.1
General disorders	Fatigueð	21	2.3
Respiratory, thoracic, and mediastinal disorders	Coughø	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*	BRUKINSA
Laboratory Abnormality*	All Grades (%)	Grade 3 or 4 (%)
* 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.
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)]. The trials required patients to be unsuitable for fludarabine, cyclophosphamide, and rituximab (FCR) therapy defined as age ≥65 years, or age 18 to <65 years with either a total Cumulative Illness Rating Scale (CIRS) >6, CLcr 30 to 69 mL/min, or history of serious or frequent infections. The trial excluded patients with AST or ALT ≥2 times the upper limit of normal (ULN) or bilirubin ≥3 times (ULN) and patients requiring a strong CYP3A inhibitor or inducer.

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)]. Patients without deletion of chromosome 17p13.1 (17p deletion) (Cohort 1) received either BRUKINSA 160 mg twice daily until disease progression or unacceptable toxicity (n=240) or bendamustine plus rituximab (BR) for 6 cycles (n=227). Bendamustine was dosed at 90 mg/m2/day intravenously on the first 2 days of each cycle, and rituximab was dosed at 375 mg/m2 on day 1 of Cycle 1 and 500 mg/m2 on day 1 of Cycles 2 to 6.

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 (2.1%).

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 (N=240)		BR (N=227)
System Organ Class Preferred Term	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, musculoskeletal discomfort, bone pain. † 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. ‡ Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. § Includes 3 fatal outcomes. ¶ Includes 2 fatal outcomes. # Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. Þ Includes multiple similar adverse reaction terms. ß Rash: Rash, dermatitis, drug eruption, and related terms. à Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. è Fatigue: fatigue, asthenia, and lethargy. ð Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including lung, renal, genitourinary, breast, ovarian, and rectal), and chronic myeloid leukemia. ø Dizziness: dizziness and vertigo.
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	33	1.7	17	0.4
Infections and infestations
Upper respiratory tract infection†	28	1.3	15	0.9
Pneumonia‡	13§	5	8¶	4
Vascular disorders
Hemorrhage#	27§	4	4	0.4
HypertensionÞ	14	7	5	2.6
Skin and subcutaneous tissue disorders
Rashß	24	1.3	30	5
Bruisingà	24	0	2.6	0
Respiratory, thoracic, and mediastinal disorders
CoughÞ	15	0	10	0
Gastrointestinal disorders
Diarrhea	14	0.8	12¶	0.9
Constipation	10	0.4	18	0
Nausea	10	0	33	1.3
General disorders
Fatigueè	14	1.3	21	1.8
Neoplasms
Second primary malignancyð	13§	6	1.3	0.4
Nervous system disorders
HeadacheÞ	12	0	8	0
Dizzinessø	11	0.8	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 (3.3%).

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*	BRUKINSA		BR
Laboratory Abnormality*	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* 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. † Lymphocytes increased in 15%. ‡ Nonfasting conditions.
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†	21	0.4	0.4
Chemistry abnormalities
Glucose increased‡	55	7	67	10
Creatinine increased	22	0.8	18	0.4
Magnesium increased	22	0	14	0.4
Alanine aminotransferase increased	21	2.1	23	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 (N=111)
System Organ Class Preferred Term	All Grades (%)	Grade 3 or 4 (%)
* 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. † Pneumonia: pneumonia, COVID-19 pneumonia, lower respiratory tract infection, and related terms including specific types of infection. ‡ Includes 1 fatal outcome. § Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, bone pain. ¶ Rash: Rash, dermatitis, toxic skin eruption, and related terms. # Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. Þ Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. ß Second primary malignancy: includes non-melanoma skin cancer, malignant solid tumors (including bladder, lung, renal, breast, prostate, ovarian, pelvis, and ureter), and malignant melanoma. à Includes non-melanoma skin cancer in 13%. è Includes multiple similar adverse reaction terms. ð Fatigue: fatigue, asthenia, and lethargy.
Infections and infestations
Upper respiratory tract infection*	38	0
Pneumonia†	20‡	8
Musculoskeletal and connective tissue disorders
Musculoskeletal pain§	38	2.7
Skin and subcutaneous tissue disorders
Rash¶	28	0
Bruising#	26	0.9
Vascular disorders
HemorrhageÞ	28	4.5
Hypertensionè	11	5.4
Neoplasms
Second primary malignancyß	22à	6
Gastrointestinal disorders
Diarrhea	18	0.9
Nausea	16	0
Constipation	15	0
Abdominal painè	12	1.8
Respiratory, thoracic, and mediastinal disorders
Coughè	18	0
Dyspneaè	13	0
General disorders and administration site conditions
Fatigueð	14	0.9
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 (3.6%).

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*	BRUKINSA
Laboratory Abnormality*	All Grades (%)	Grade 3 or 4 (%)
* 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. Grading is based on NCI CTCAE criteria. † Grade 4, 9%. ‡ Non-fasting conditions.
Hematologic abnormalities
Neutrophils decreased	42	19†
Hemoglobin decreased	26	3.6
Platelets decreased	23	0.9
Chemistry abnormalities
Glucose increased‡	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, 324 patients received BRUKINSA monotherapy, 160 mg orally twice daily and 324 patients received ibrutinib monotherapy, 420 mg orally daily until disease progression or unacceptable toxicity.

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 (1.9%).

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 Preferred Term	BRUKINSA (N=324)		Ibrutinib (N=324)
System Organ Class Preferred Term	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* Upper respiratory tract infection: upper respiratory tract infection, sinusitis, pharyngitis, rhinitis, nasopharyngitis, laryngitis, tonsillitis, and related terms. † Pneumonia: Pneumonia, COVID-19 pneumonia, lower respiratory tract infection, lung infiltration, and related terms including specific types of infection. ‡ Includes fatal outcomes: pneumonia (9 patients), COVID-19 (8 patients), and hemorrhage (1 patient). § Includes fatal outcomes: pneumonia (10 patients), COVID-19 (9 patients), and hemorrhage (2 patients). ¶ COVID-19: COVID-19, COVID-19 pneumonia, postacute COVID-19 syndrome, SARS-CoV-2 test positive. # Musculoskeletal pain: musculoskeletal pain, arthralgia, back pain, pain in extremity, myalgia, neck pain, spinal pain, bone pain, and musculoskeletal discomfort. Þ Hemorrhage: all terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. ß Includes multiple similar adverse reaction terms. à Rash: Rash, Dermatitis, and related terms. è Bruising: all terms containing bruise, bruising, contusion, or ecchymosis. ð Fatigue: asthenia, fatigue, lethargy.
Infections and infestations
Upper respiratory tract infection*	27	1.2	22	1.2
Pneumonia†	18‡	9	19§	11
COVID-19¶	14‡	7	10§	4.6
Musculoskeletal and connective tissue disorders
Musculoskeletal pain#	26	0.6	28	0.6
Vascular disorders
HemorrhageÞ	24‡	2.5	26§	3.7
Hypertensionß	19	13	20	13
Skin and subcutaneous tissue disorders
Rashà	20	1.2	21	0.9
Bruisingè	16	0	14	0
Gastrointestinal disorders
Diarrhea	14	1.5	22	0.9
General disorders
Fatigueð	13	0.9	14	0.9
Respiratory, thoracic, and mediastinal disorders
Coughß	11	0.3	11	0
Nervous system disorders
Dizzinessß	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 (4.6%).

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*	BRUKINSA		Ibrutinib
Laboratory Abnormality*	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* 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. Grading is based on NCI CTCAE criteria.
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	2.5	13	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)]. The trial required an absolute neutrophil count ≥1 × 109/L, platelet count ≥50 × 109/L, and CLcr ≥30 mL/min and excluded patients requiring a strong CYP3A inhibitor or inducer.

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 (2.1%).

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 Preferred Term	BGB-3111-212
	BRUKINSA + Obinutuzumab (N=143)		Obinutuzumab (N=71)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* Includes multiple related terms. † Fatigue: Fatigue, asthenia, and lethargy. ‡ 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. § Hemorrhage: All terms containing hematoma, hemorrhage, hemorrhagic, and related terms indicative of bleeding. ¶ Upper respiratory tract infection: Upper respiratory tract infection, sinusitis, pharyngitis, laryngitis, rhinitis, nasopharyngitis, laryngopharyngitis, tonsillitis bacterial, and related terms. # Pneumonia: Pneumonia, COVID-19 pneumonia, lung infiltration, lung consolidation, and related terms including specific types of infection. Þ Includes fatal outcomes: COVID-19 (3 patients), pneumonia (2 patients), dyspnea (1 patient). ß Herpes virus infection: Herpes viral infection, herpes zoster, herpes simplex, herpes simplex reactivation, varicella, and Epstein-Barr viremia. à Urinary tract infection: Urinary tract infection, cystitis, pyelonephritis, and related terms. è Rash: Rash, erythema, dermatitis, drug eruption, skin reaction, and related terms.
General disorders and administration site conditions
Fatigue*,†	27	1.4	25	1.4
Pyrexia	13	0	20	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*,‡	22	3.5	23	1.4
Vascular disorders
Hemorrhage*,§	20	1.4	10	1.4
Gastrointestinal disorders
Diarrhea	18	2.8	17	1.4
Constipation	13	0	9	0
Abdominal pain*	11	2.1	11	0
Infections and infestations
Upper respiratory tract infection*,¶	17	2.8	10	0
Pneumonia*,#,Þ	15	13	11	7
COVID-19*,Þ	13	9	11	4.2
Herpes virus infectionß	11	2.1	1.4	0
Urinary tract infectionà	10	1.4	7	0
Respiratory, thoracic, and mediastinal disorders
Cough*	14	0	14	0
Dyspnea*,Þ	11	2.1	13	0
Skin and subcutaneous tissue disorders
Rash*,è	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*	BGB-3111-212
	BRUKINSA + Obinutuzumab		Obinutuzumab
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* 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. Grading is based on NCI CTCAE criteria. † Nonfasting conditions.
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†	53	8	41	9
Alanine aminotransferase increased	23	0	28	0
Phosphate decreased	21	0.8	14	0