Zanubrutinib

Risk Summary

Based on findings in animals, zanubrutinib can cause fetal harm when administered to pregnant women. There are no available data on zanubrutinib 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). Women should be advised to avoid pregnancy while taking zanubrutinib. If zanubrutinib is used during pregnancy, or if the patient becomes pregnant while taking zanubrutinib, the patient should be apprised of the potential hazard to the fetus.

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. In the U.S. 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 post-implantation 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 post-natal 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.g. 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 zanubrutinibzin a breastfed child, advise lactating women not to breastfeed during treatment with zanubrutinibzin and for at least two weeks following the last dose.

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 bone marrow micronucleus assay in rats.

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 but at the highest dose tested, morphological abnormalities in sperm and increased post-implantation loss were noted. The high dose of 300 mg/kg/day is approximately 10 times the human recommended dose, based on body surface area.

• Hemorrhage
• Infections
• Cytopenias
• Second Primary Malignancies
• Cardiac Arrhythmias

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 zanubrutinib in seven clinical trials, administered as a single agent at 160 mg twice daily in 730 patients, at 320 mg once daily in 105 patients, and at 40 mg to 160 mg once daily (0.125 to 0.5 times the recommended dosage) in 12 patients. Among 847 patients receiving zanubrutinib, 73% were exposed for at least 1 year, 57% were exposed for at least 2 years and 26% were exposed for at least 3 years.

In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in ≥30% of patients included neutrophil count decreased (54%), upper respiratory tract infection (47%), platelet count decreased (41%), hemorrhage (35%), lymphocyte count decreased (31%), rash (31%) and musculoskeletal pain (30%).

Mantle Cell Lymphoma (MCL)

The safety of zanubrutinib 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]. The median age of patients who received zanubrutinib 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 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 zanubrutinib 160 mg twice daily or 320 mg once daily. Among patients receiving zanubrutinib, 79% were exposed for 6 months or longer, and 68% were exposed for greater than one year.

Fatal events within 30 days of the last dose of zanubrutinib 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 zanubrutinib, 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 Zanubrutinib in BGB-3111-206 and BGB-3111-AU-003 Trials:

^* 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.

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%), hyperuricemia (6%) and headache (4.2%).

Table 4. Selected Laboratory Abnormalities^* (>20%) in Patients with MCL in Studies BGB-3111-206 and BGB-3111-AU-003:

^* Based on laboratory measurements.
^† Asymptomatic lymphocytosis is a known effect of BTK inhibition.

Waldenström’s Macroglobulinemia (WM)

The safety of zanubrutinib was investigated in two cohorts of Study BGB-3111-302 (ASPEN). Cohort 1 included 199 patients with MYD88 mutation (MYD88^MUT) WM, randomized to and treated with either zanubrutinib (101 patients) or ibrutinib (98 patients). The trial also included a non-randomized arm, Cohort 2, with 26 wild type MYD88 (MYD88^WT) WM patients and 2 patients with unknown MYD88 status.

Among patients who received zanubrutinib, 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 zanubrutinib 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 zanubrutinib 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 zanubrutinib. 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 zanubrutinib 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 zanubrutinib due to an adverse reaction occurred in 7% of patients and included subdural hemorrhage (1 patient) and diarrhea (1 patient).

Dosage interruptions of zanubrutinib 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 zanubrutinib 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 Zanubrutinib in Cohort 1:

^* 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, photodermatosis, 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.

Clinically relevant adverse reactions in <10% of patients who received zanubrutinib 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 Zanubrutinib in Cohort 1:

^* 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.

Marginal Zone Lymphoma

The safety of zanubrutinib was evaluated in 88 patients with previously treated MZL in two single-arm clinical studies, BGB-3111-214 and BGB-3111-AU-003. 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 zanubrutinib 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 Caucasian and 19% were Asian. Most patients (92%) had an ECOG performance status of 0 to 1. Eighty percent received zanubrutinib 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 zanubrutinib, 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 Zanubrutinib:

^* Upper respiratory tract infections 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 fatal events of 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.
^èHemorrhage 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.

Clinically relevant adverse reactions in <10% of patients who received zanubrutinib included peripheral neuropathy, second primary malignancies, dizziness, edema, headache, petechiae, purpura and atrial fibrillation or flutter.

Table 8 summarizes selected laboratory abnormalities.

Table 8. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with MZL:

^* 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.