BRUKINSA (Page 2 of 8)
3 DOSAGE FORMS AND STRENGTHS
Capsules: Each 80 mg capsule is a size 0, white to off-white opaque capsule marked with “ZANU 80” in black ink.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Hemorrhage
Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.8% of patients treated with BRUKINSA in clinical trials, with fatalities occurring in 0.2% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 32% of patients.
Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.
Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days before and after surgery depending upon the type of surgery and the risk of bleeding.
5.2 Infections
Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher infections occurred in 26% of patients, most commonly pneumonia (7.9%), with fatal infections occurring in 3.2% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.
Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.
5.3 Cytopenias
Grade 3 or 4 cytopenias, including neutropenia (21%), thrombocytopenia (8%), and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA [see Adverse Reactions (6.1)]. Grade 4 neutropenia occurred in 10% of patients, and Grade 4 thrombocytopenia occurred in 2.5% of patients.
Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.4)]. Treat using growth factor or transfusions, as needed.
5.4 Second Primary Malignancies
Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA. The most frequent second primary malignancy was non-melanoma skin cancers (8%), followed by other solid tumors in 7% of the patients (including melanoma in 1% of patients) and hematologic malignancies (0.7%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.
5.5 Cardiac Arrhythmias
Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 4.4% of patients treated with BRUKINSA, including Grade 3 or higher cases in 1.9% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.3% of patients.
Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately [see Dosage and Administration (2.4)] , and consider the risks and benefits of continued BRUKINSA treatment.
5.6 Embryo-Fetal Toxicity
Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
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)]
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.
Body System | Adverse Reaction | Percent of Patients (N=118) | |
---|---|---|---|
All Grades % | Grade 3 or Higher % | ||
| |||
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 |
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 pain Þ | 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%).
Laboratory Parameter | Percent of Patients (N=118) | |
---|---|---|
All Grades (%) | Grade 3 or 4 (%) | |
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.
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 * | 44 | 0 | 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 |
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 Þ | 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.
Laboratory Abnormality | BRUKINSA † | 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 | 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.
Body System | Adverse Reaction | BRUKINSA (N=88) | |
---|---|---|---|
All Grades (%) | Grade 3 or 4 (%) | ||
| |||
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 | Bruising Þ | 24 | 0 |
Rash ß | 21 | 0 | |
Musculoskeletal and connective tissue disorders | Musculoskeletal pain à | 27 | 1.1 |
Vascular disorders | Hemorrhage è | 23 | 1.1 |
General disorders | Fatigue ð | 21 | 2.3 |
Respiratory, thoracic, and mediastinal disorders | Cough ø | 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.
Laboratory Abnormality * | 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)]. 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.
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 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 |
Hypertension Þ | 14 | 7 | 5 | 2.6 |
Skin and subcutaneous tissue disorders | ||||
Rash ß | 24 | 1.3 | 30 | 5 |
Bruising à | 24 | 0 | 2.6 | 0 |
Respiratory, thoracic, and mediastinal disorders | ||||
Cough Þ | 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 | ||||
Fatigue è | 14 | 1.3 | 21 | 1.8 |
Neoplasms | ||||
Second primary malignancy ð | 13§ | 6 | 1.3 | 0.4 |
Nervous system disorders | ||||
Headache Þ | 12 | 0 | 8 | 0 |
Dizziness ø | 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.
Laboratory Abnormality * | 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† | 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.
CLL/SLL with 17p Deletion | ||
---|---|---|
BRUKINSA (N=111) | ||
System Organ Class Preferred Term | All Grades (%) | Grade 3 or 4 (%) |
| ||
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 | ||
Hemorrhage Þ | 28 | 4.5 |
Hypertension è | 11 | 5.4 |
Neoplasms | ||
Second primary malignancy ß | 22à | 6 |
Gastrointestinal disorders | ||
Diarrhea | 18 | 0.9 |
Nausea | 16 | 0 |
Constipation | 15 | 0 |
Abdominal pain è | 12 | 1.8 |
Respiratory, thoracic, and mediastinal disorders | ||
Cough è | 18 | 0 |
Dyspnea è | 13 | 0 |
General disorders and administration site conditions | ||
Fatigue ð | 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.
Laboratory Abnormality * | BRUKINSA | |
---|---|---|
All Grades (%) | Grade 3 or 4 (%) | |
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.
System Organ Class Preferred Term | BRUKINSA (N=324) | Ibrutinib (N=324) | ||
---|---|---|---|---|
All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| ||||
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 | ||||
Hemorrhage Þ | 24‡ | 2.5 | 26§ | 3.7 |
Hypertension ß | 19 | 13 | 20 | 13 |
Skin and subcutaneous tissue disorders | ||||
Rash à | 20 | 1.2 | 21 | 0.9 |
Bruising è | 16 | 0 | 14 | 0 |
Gastrointestinal disorders | ||||
Diarrhea | 14 | 1.5 | 22 | 0.9 |
General disorders | ||||
Fatigue ð | 13 | 0.9 | 14 | 0.9 |
Respiratory, thoracic, and mediastinal disorders | ||||
Cough ß | 11 | 0.3 | 11 | 0 |
Nervous system disorders | ||||
Dizziness ß | 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.
Laboratory Abnormality * | 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 | 2.5 | 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.
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(%) | |
| ||||
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 infection ß | 11 | 2.1 | 1.4 | 0 |
Urinary tract infection à | 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.
Laboratory Abnormality * | 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 † | 53 | 8 | 41 | 9 |
Alanine aminotransferase increased | 23 | 0 | 28 | 0 |
Phosphate decreased | 21 | 0.8 | 14 | 0 |
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