BRUKINSA 80mg capsules medication leaflet

BRUKINSA 80 mg hard capsules

Each hard capsule contains 80 mg of zanubrutinib.

For the full list of excipients, see section 6.1

Hard capsule (capsule).

White to off-white opaque hard capsule of 22 mm in length, marked with “ZANU 80” in black ink.

BRUKINSA as monotherapy is indicated for the treatment of adult patients with Waldenström’smacroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment forpatients unsuitable for chemo-immunotherapy.

BRUKINSA as monotherapy is indicated for the treatment of adult patients with marginal zonelymphoma (MZL) who have received at least one prior anti-CD20-based therapy.

BRUKINSA as monotherapy is indicated for the treatment of adult patients with chronic lymphocyticleukemia (CLL).

BRUKINSA in combination with obinutuzumab is indicated for the treatment of adult patients withrefractory or relapsed follicular lymphoma (FL) who have received at least two prior systemictherapies.

Treatment with this medicinal product should be initiated and supervised by a physician experiencedin the use of anticancer medicinal products.

The recommended total daily dose of zanubrutinib is 320 mg. The daily dose may be taken eitheronce daily (four 80 mg capsules) or divided into two doses of 160 mg twice daily (two 80 mgcapsules). Treatment should be continued until disease progression or unacceptable toxicity.

BRUKINSA in combination with obinutuzumab

Zanubrutinib must be administered before obinutuzumab infusion. The recommended dose isobinutuzumab 1 000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and on Day 1 of every 28-daycycle from Cycles 2 to 6. At the discretion of the physician, obinutuzumab may be administered100 mg on Day 1 and 900 mg on Day 2 of Cycle 1 instead of 1 000 mg on Day 1 of Cycle 1.

Obinutuzumab maintenance (one infusion every two months for up to two years) may be prescribed.

Refer to the obinutuzumab SmPC for additional dosing information, including premedication beforeeach infusion.

Dose modifications for adverse reactions

Recommended dose modifications of zanubrutinib for Grade 3 or greater adverse reactions areprovided in Table 1.

Table 1: Recommended dose modifications for adverse reactions

Adverse reaction Adverse Dose modificationreaction (starting dose: 320 mg once daily oroccurrence 160 mg twice daily)≥ Grade 3 non-haematological First Interrupt BRUKINSAtoxicities Once toxicity has resolved to ≤Grade 1 orbaseline: Resume at 320 mg once daily or≥ Grade 3 febrile neutropenia 160 mg twice daily

Second Interrupt BRUKINSA

Grade 3 thrombocytopenia with Once toxicity has resolved to ≤Grade 1 orsignificant bleeding baseline: Resume at 160 mg once daily or80 mg twice daily

Grade 4 neutropenia (lasting > 10 Third Interrupt BRUKINSAconsecutive days) Once toxicity has resolved to ≤Grade 1 orbaseline: Resume at 80 mg once daily

Grade 4 thrombocytopenia (lasting Fourth Discontinue BRUKINSA> 10 consecutive days)

Asymptomatic lymphocytosis should not be regarded as an adverse reaction, and these patients shouldcontinue taking BRUKINSA.

For dose modification of obinutuzumab for adverse reactions, refer to the SmPC of obinutuzumab.

Dose modifications for concomitant therapy

Dose modifications for use with CYP3A inhibitors or inducers are shown in Table 2 (see also sections4.4, 4.5 and 5.2):

Table 2: Recommended dose modifications when co-administered with other medicinalproducts

CYP3A Co-administered medicinal product Recommended dose

Inhibition Strong CYP3A inhibitor (e.g., posaconazole, 80 mg once dailyvoriconazole, ketoconazole, itraconazole,clarithromycin, indinavir, lopinavir, ritonavir,telaprevir)

Moderate CYP3A inhibitor (e.g., erythromycin, 160 mg once daily or 80 mgciprofloxacin, diltiazem, dronedarone, twice dailyfluconazole, verapamil, aprepitant, imatinib,grapefruit juice, Seville oranges)

Induction Strong CYP3A inducer (e.g., carbamazepine, Avoid concomitant use; Considerphenytoin, rifampicin, St. John’s wort) alternative agents with less

CYP3A induction.

Moderate CYP3A inducer (e.g., bosentan,efavirenz, etravirine, modafinil, nafcillin)

A double dose should not be taken to make up for a forgotten dose. If a dose is not taken at thescheduled time, the next dose should be taken according to the normal schedule.

No specific dose adjustment is required for elderly patients (aged ≥65 years).

No dose modification is recommended in patients with mild to moderate renal impairment (creatinineclearance (CrCl) ≥30 mL/min, estimated by Cockcroft-Gault). There is limited data on patients withsevere renal impairment and end-stage renal disease (n=12). Patients with severe renal impairment(CrCl <30 mL/min) or on dialysis should be monitored for adverse reactions (see section 5.2).

Dose modifications are not needed in patients with mild (Child-Pugh class A) or moderate hepaticimpairment (Child-Pugh class B). Patients with mild or moderate hepatic impairment were treated in

BRUKINSA clinical studies. The recommended dose of BRUKINSA for patients with severe hepaticimpairment (Child-Pugh class C) is 80 mg orally twice daily. The safety of BRUKINSA has not beenevaluated in patients with severe hepatic impairment. These patients should be closely monitored foradverse reactions (see section 5.2).

The safety and efficacy of BRUKINSA in children and adolescents below 18 years of age have notbeen established. No data are available.

BRUKINSA is for oral use. The hard capsules can be taken with or without food. Patients should beinstructed to swallow the capsules whole with water, and not to open, break or chew the capsules.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Serious and fatal haemorrhagic events have occurred in patients treated with BRUKINSA. Grade 3 orhigher bleeding events including intracranial and gastrointestinal haemorrhage, haematuria andhaemothorax have been reported in patients (see section 4.8). Bleeding events of any grade includingpurpura and petechiae occurred in patients with haematological malignancies. The mechanism for thebleeding events is not well understood.

BRUKINSA may increase the risk of haemorrhage in patients receiving antiplatelet or anticoagulanttherapies and patients should be monitored for signs of bleeding. Dose modification may be necessaryfor Grade 3 or greater adverse reactions as recommended (see section 4.2). Warfarin or othervitamin K antagonists should not be administered concomitantly with BRUKINSA. Patients should bemonitored for signs and symptoms of bleeding and complete blood counts should be monitored. Therisks and benefits of anticoagulant or antiplatelet therapy when co-administered with BRUKINSAshould be considered. The benefit-risk of withholding zanubrutinib for 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding should be considered.

Fatal and non-fatal infections (including bacterial, viral, fungal infections, or sepsis) and opportunisticinfections (e.g., herpes viral, cryptococcal, aspergillus and pneumocystis jiroveci infections) haveoccurred in patients treated with BRUKINSA. Grade 3 or higher infections occurred in patients (seesection 4.8). The most common Grade 3 or higher infection was pneumonia. Infections due tohepatitis B virus (HBV) reactivation have also occurred. Before initiating treatment with

BRUKINSA, patients’ HBV status should be established. Consultation with a liver disease expertphysician is recommended for patients who test positive for HBV or have positive hepatitis Bserology, before initiating treatment. Patients should be monitored and managed according to themedical standards to prevent hepatitis B reactivation. Consider prophylaxis according to standard ofcare in patients who are at increased risk for infections. Patients should be monitored for signs andsymptoms of infection and treat appropriately.

Cytopenia

Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia, and anaemia based on laboratorymeasurements were reported in patients treated with BRUKINSA (see section 4.8). Complete bloodcounts should be monitored monthly during treatment (see section 4.2).

Second primary malignancies

Second primary malignancies, including non-skin carcinoma have occurred in patients treated with

BRUKINSA. The most frequent second primary malignancy was skin cancer (basal cell carcinomaand squamous cell carcinoma of skin). Patients should be advised to use sun protection.

Atrial fibrillation and flutter

Atrial fibrillation and atrial flutter have occurred in patients treated with BRUKINSA, particularly inpatients with cardiac risk factors, hypertension, acute infections and elderly (≥ 65 years). Signs andsymptoms for atrial fibrillation and atrial flutter should be monitored and managed as appropriate.

Tumour lysis syndrome has been uncommonly reported with zanubrutinib monotherapy therapy,particularly in patients who were treated for chronic lymphocytic leukaemia (CLL) (see section 4.8).

Relevant risks (e.g., high tumour burden or blood uric acid level) should be assessed and appropriateprecautions should be taken. Patients should be closely monitored and treated as appropriate.

Women of childbearing potential must use a highly effective method of contraception while taking

BRUKINSA (see section 4.6).

BRUKINSA contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

Zanubrutinib is primarily metabolized by cytochrome P450 enzyme 3A (CYP3A).

Agents that may increase zanubrutinib plasma concentrations

Concomitant use of BRUKINSA and medicinal products that strongly or moderately inhibit CYP3Acan increase zanubrutinib exposure.

Strong CYP3A inhibitors

The coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) in healthyvolunteers increased the Cmax of zanubrutinib by 2.6-fold and AUC by 3.8-fold. The coadministrationof multiple doses of strong CYP3A inhibitors voriconazole and clarithromycin in patients with B-cellmalignancies resulted in increased zanubrutinib exposures by 3.30-fold and 1.92-fold for dose-normalized AUC0-24h and 3.29-fold and 2.01-fold for dose-normalized Cmax, respectively.

If a strong CYP3A inhibitor must be used (e.g., voriconazole, ketoconazole, itraconazole,clarithromycin, indinavir, lopinavir, ritonavir, telaprevir), reduce the BRUKINSA dose to 80 mg (onecapsule) for the duration of the inhibitor use. Patients should be closely monitored for toxicity anddose modification guidance should be followed as needed (see section 4.2).

Moderate CYP3A inhibitors

The coadministration of multiple doses of moderate CYP3A inhibitors fluconazole and diltiazem inpatients with B-cell malignancies resulted in increased zanubrutinib exposures by 1.88-fold and 1.62-fold for dose-normalized AUC0-24h and 1.81-fold and 1.62-fold for dose-normalized Cmax, respectively.

If a moderate CYP3A inhibitor must be used (e.g., erythromycin, ciprofloxacin, diltiazem,dronedarone, fluconazole, verapamil, aprepitant, imatinib, grapefruit juice, Seville oranges), the

BRUKINSA dose should be reduced to 160 mg (two capsules) for the duration of the inhibitor use.

Patients should be closely monitored for toxicity and dose modification guidance should be followedas needed (see section 4.2).

Mild CYP3A inhibitors

Simulations using fasted conditions suggested that the mild CYP3A inhibitors (e.g., cyclosporine andfluvoxamine) may increase the AUC of zanubrutinib by <1.5-fold. No dose adjustment is required incombination with mild inhibitors. Patients should be closely monitored for toxicity and dosemodification guidance should be followed as needed.

Agents that may decrease zanubrutinib plasma concentrations

Concomitant use of zanubrutinib and strong or moderate inducers of CYP3A can decreasezanubrutinib plasma concentrations.

Co-administration of multiple doses of rifampicin (strong CYP3A inducer) decreased zanubrutinib

Cmax by 92% and AUC by 93% in healthy subjects. Co-administration of multiple doses of rifabutin(moderate CYP3A inducer) decreased zanubrutinib Cmax by 48% and AUC by 44% in healthysubjects. Concomitant use of zanubrutinib and strong or moderate CYP3A inducers should be avoided(see section 4.2). Mild CYP3A inducers may be used with caution during BRUKINSA treatment.

Gastric acid reducing agents

No clinically significant differences in zanubrutinib pharmacokinetics were observed whenco-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists).

Agents that may have their plasma concentrations altered by zanubrutinib

Zanubrutinib is a mild inducer of CYP3A and CYP2C19. Concomitant use of zanubrutinib candecrease the plasma concentrations of these substrate medicinal products.

Co-administration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) Cmax by30% and AUC by 47%. Narrow therapeutic index medicinal products that are metabolised by CYP3A(e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine,sirolimus, and tacrolimus) should be used with caution, as zanubrutinib may decrease the plasmaexposures of these medicinal products.

CYP2C19 substrates

Co-administration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) Cmaxby 20% and AUC by 36%. Narrow therapeutic index medicinal products that are metabolized by

CYP2C19 (e.g., S-mephenytoin) should be used with caution, as zanubrutinib may decrease theplasma exposures of these medicinal products.

Co-administration with transport substrates/inhibitors

Co-administration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) Cmax by 34%and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin(BCRP substrate) were observed when co-administered with zanubrutinib.

The coadministration of oral P-gp substrates with a narrow therapeutic index (e.g., digoxin) should bedone with caution as zanubrutinib may increase their concentrations.

Based on findings in animals, BRUKINSA may cause foetal harm when administered to pregnantwomen (see section 5.3). Women should avoid becoming pregnant while taking BRUKINSA and forup to 1 month after ending treatment. Therefore, women of childbearing potential must use highlyeffective contraceptive measures while taking BRUKINSA and for up to 1 month after stoppingtreatment. It is currently unknown whether zanubrutinib may reduce the effectiveness of hormonalcontraceptives, and therefore women using hormonal contraceptives should add a barrier method.

Pregnancy testing is recommended for women of reproductive potential prior to initiating therapy.

BRUKINSA should not be used during pregnancy. There are no data from the use of zanubrutinib inpregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

It is not known whether zanubrutinib or its metabolites are excreted in human milk and no non-clinical studies were conducted. A risk to breast-fed children cannot be excluded. Breast-feedingshould be discontinued during treatment with BRUKINSA.

No effect on male or female fertility was noted in rats but morphological abnormalities in sperm andincreased post-implantation loss were noted at 300 mg/kg/day (see section 5.3).

BRUKINSA has no or negligible influence on the ability to drive and use machines. Fatigue,dizziness, and asthenia have been reported in some patients taking BRUKINSA and should beconsidered when assessing a patient’s ability to drive or operate machines.

Zanubrutinib monotherapy

The most commonly occurring adverse reactions (≥20%) of zanubrutinib monotherapy were upperrespiratory tract infection§ (36%), bruising§ (32%), haemorrhage/haematoma§ (30%), neutropenia§(30%), musculoskeletal pain§ (27%), rash§ (25%), pneumonia§ (24%), diarrhoea (21%) and cough§(21%) (Table 3).

The most common Grade 3 or higher adverse reactions (>3%) of zanubrutinib monotherapy wereneutropenia§ (21%), pneumonia§ (14%), hypertension§ (8%), thrombocytopenia§ (6%), anaemia (6%)and haemorrhage /haematoma§ (4%).

Of the 1550 patients treated with zanubrutinib, pct. 4.8% of patients discontinued treatment due to adversereactions. The most frequent adverse reaction leading to treatment discontinuation was pneumonia§(2.6%). Adverse reactions leading to dose reduction occurred in 5.0% of patients.

Zanubrutinib in combination with obinutuzumab

The most commonly occurring adverse reactions (≥20%) of zanubrutinib in combination withobinutuzumab were thrombocytopenia§ (37%), neutropenia§ (31%) and fatigue§ (27%) (Table 4).

The most common Grade 3 or higher adverse reactions (>3%) of zanubrutinib in combination withobinutuzumab were neutropenia§ (25%), thrombocytopenia§ (16%), pneumonia§ (15%) and anaemia(5%).

Of the 143 patients treated with zanubrutinib in combination with obinutuzumab, 4.9% of patientsdiscontinued treatment due to adverse reactions. The most frequent adverse reaction leading totreatment discontinuation was pneumonia§ (4.2%). Adverse reactions leading to dose reductionoccurred in 7.0% of patients.

Platelet count decreased† (based on laboratory values) was observed in 65% (all grade) and 12%(grade 3 or 4) patients receiving zanubrutinib in combination with obinutuzumab compared to 43%(all grade) and 11% (grade 3 or 4) in patients receiving obinutuzumab. All grade and grade 3 or 4platelet counts decreased were reported for 39% and 7.8% patients who received zanubrutinibmonotherapy.

The safety profile of zanubrutinib monotherapy is based on pooled data from 1 550 patients with B-cell malignancies, including patients with chronic lymphocytic leukaemia (N = 938), Waldenströmmacroglobulinemia (N = 249), mantle cell lymphoma (N = 140), marginal zone lymphoma (N = 93),follicular lymphoma (N = 59) and other types of B-cell malignancies (N = 71), treated with

BRUKINSA in clinical studies with a median duration of exposure of 34.41 months.

The safety profile of zanubrutinib in combination with obinutuzumab is based on ROSEWOOD studydata from 143 patients with FL treated with BRUKINSA in combination with obinutuzumab in twoclinical studies with a median duration of exposure of 12.35 months.

Adverse reactions in patients treated with BRUKINSA as monotherapy or in combination withobinutuzumab for B-cell malignancies are listed in Table 3 and Table 4, respectively, by system organclass and frequency grouping. Frequencies are defined as follows: very common (≥1/10), common(≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare(<1/10 000), not known (cannot be estimated from the available data). Within each frequencygrouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Adverse reactions of zanubrutinib monotherapy reported in clinical studies in patientswith B-cell malignancies(n=1 550)

MedDRA SOC MedDRA Terms All Grades* (%) Grade 3 or higher(%)

Upper respiratory tract infection§ Very Common (36) 2

Pneumonia§# Very Common (24) 14

Pneumonia Very Common (15) 8

Lower respiratory tractinfection Common (5) <1

Urinary tract infection§ Very Common (14) 2

Bronchitis Common (4) <1

Hepatitis B reactivation Uncommon (<1) <1

Neutropenia§ Very Common (30) 21

Blood and lymphatic Febrile neutropenia Common ( 2) 2system disorders

Thrombocytopenia§ Very Common (18) 6

Anaemia§ Very Common (16) 6

Metabolism and nutritiondisorders Tumour lysis syndrome§# Uncommon (<1) <1

Nervous system disorder Dizziness§ Very Common (12) <1

Atrial fibrillation and flutter Common (5) 2

Bruising§ Very Common (32) <1

Contusion Very Common (20) 0

Petechiae Common (7) <1

Purpura Common (5) <1

Ecchymosis Common (3) <1

Vascular disorders Haemorrhage/Haematoma§ # Very Common (30) 4

Haematuria Very common (11) <1

Epistaxis Common (8) <1

Gastrointestinalhaemorrhage Uncommon (<1) <1

Hypertension§ Very Common (17) 8

Respiratory, thoracic andmediastinal disorders Cough§ Very Common (21) <1

Gastrointestinal disorders Diarrhoea Very Common (21) 2

Constipation Very Common (14) <1

Skin and subcutaneous Rash§ Very Common (25) <1tissue disorders Pruritus Common (8) <1

Dermatitis exfoliative generalized Unknown Unknown

Musculoskeletal pain§ Very Common (27) 2

Musculoskeletal andconnective tissue disorders Arthralgia Very Common (15) <1

Back pain Very common (12) <1

Fatigue§ Very common (18) 1

General disorders and Fatigue Very common (14) 1administration site Asthenia Common (4) <1conditions Oedema peripheral Common (9) <1

Neutrophil count decreased†± Very common (52) 22

Investigations† Platelets decreased†± Very common (39) 8

Haemoglobin decreased†± Very common (26) 4

* Grades were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-

CTCAE) version 4.03.† Based on laboratory measurements.± Percentages are based on number of patients with both baseline and at least one postbaseline assessment available.§ Includes multiple adverse reaction terms# Includes events with fatal outcome.

Table 4: Adverse reactions of zanubrutinib in combination with obinutuzumab reported inclinical study BGB-3111-212 in patients with follicular lymphoma (n=143)

MedDRA SOC MedDRA Terms

All grades* (%) Grade ≥3(%)

Infections and Upper respiratory tract infection§ Very common (14) <1infestations Pneumonia§# Very common (20) 15

Pneumonia Very common (13) 11

Lower respiratory tract infection Common (4) <1

Urinary tract infection§ Common (10) 2

Bronchitis Common (2) 0

Blood and lymphatic Thrombocytopenia§ Very common (37) 16system Neutropenia§ Very common (31) 25disorders

Anaemia§ Very common (12) 5

Nervous system Dizziness§ Common (4) 0disorder

Cardiac disorders Atrial fibrillation and flutter§ Common (3) 1

Vascular disorders Haemorrhage/hematoma§ Very common (16) <1

Epistaxis Common (5) 0

Hematuria Common (<1) 0

Bruising§ Very common (15) 0

Contusion Very common (8) 0

Petechiae Common (6) 0

Purpura Common (2) 0

Ecchymosis Common (1) 0

Hypertension§ Common (4) <1

Respiratory, thoracic Cough§ Very common (13) 0and mediastinaldisorders

Gastrointestinal Diarrhoea Very common (19) 3disorders Constipation Very common (13) 0

Skin and Rash§ Very common (10) 0subcutaneous Pruritus Common (7) 0tissue disorders

Dermatitis exfoliative generalized Unknown Unknown

Musculoskeletal and Musculoskeletal Pain§ Very common (18) 2connective tissue Back pain Very common (11) <1disorders

Arthralgia Common (4) 0

General disorders and Fatigue§ Very common (27) 1administration site Fatigue Very common (15) 0conditions

Asthenia Common (12) <1

Oedema peripheral Common (2) 0

Investigations†± Platelets decreased†± Very common (65) 12

Neutrophil count decreased†± Very common (48) 18

Haemoglobin decreased†± Very common (31) <1

* Adverse events were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAEversion 5.0.)† Based on laboratory measurements.§ Includes multiple adverse reaction terms.# Includes events with fatal outcome.± Percentages are based on number of patients with both baseline and at least one postbaseline assessment available.

Other special population

Of the 1 550 patients treated with BRUKINSA monotherapy, 61.3% were 65 years of age or older.

The incidence of Grade 3 or higher adverse events was slightly higher among elderly patients treatedwith zanubrutinib (69.6% of patients age ≥65 versus 62.7% of patients <65 years of age). Noclinically relevant differences in safety were observed between patients ≥65 years and younger.

Of the 143 patients treated with BRUKINSA in combination with obinutuzumab, 42.0% were65 years of age or older. The incidence of Grade 3 or higher adverse events was slightly higher amongelderly patients treated with zanubrutinib in combination with obinutuzumab (70.0% of patients age≥65 versus 62.7% of patients <65 years of age). No clinically relevant differences in safety wereobserved between patients ≥65 years and younger.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote for BRUKINSA. Patients who experience overdose should be closelymonitored and provided with appropriate supportive treatment.

Pharmacotherapeutic group: Antineoplastic agents, Bruton’s tyrosine kinase inhibitors, ATC code:

L01EL03.

Zanubrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). Zanubrutinib forms a covalent bondwith a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is asignalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells,

BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking,chemotaxis, and adhesion.

BTK occupancy in PBMCs and lymph node biopsies

The median steady-state BTK occupancy in peripheral blood mononuclear cells was maintained at100% over 24 hours at a total daily dose of 320 mg in patients with B-cell malignancies. The mediansteady-state BTK occupancy in lymph nodes was 94% to 100% following the recommended dose.

Effect on QT/QTc interval and cardiac electrophysiology

At the recommended doses (320 mg once daily or 160 mg twice daily), there were no clinicallyrelevant effects on the QTc interval. At a single dose 1.5 times the maximum recommended dose(480 mg), zanubrutinib did not prolong the QT interval to any clinically relevant extent (i.e.,≥10 msec).

Patients with Waldenström Macroglobulinemia (WM)

The safety and efficacy of BRUKINSA in WM were evaluated in a randomized, open-label,multicentre study comparing zanubrutinib and ibrutinib (ASPEN study, BGB-3111-302) in patientswho were BTK inhibitor naive. Eligible patients were at least 18 years of age with a clinical anddefinite histological diagnosis of relapsed/refractory WM or treatment-naïve when consideredunsuitable for standard chemo-immunotherapy regimens by their treating physician. Patients had tomeet at least one criterion for treatment according to consensus panel criteria from the Seventh

International Workshop on Waldenström’s Macroglobulinemia (IWWM) and have measurabledisease, as defined by a serum IgM level >0.5 g/dl. Patients with MYD88 mutation (MYD88MUT)were assigned to Cohort 1 (N=201) and were randomized 1:1 to receive either zanubrutinib 160 mgtwice daily (Arm A) or ibrutinib 420 mg once daily (Arm B) until disease progression or unacceptabletoxicity. Subjects found to have MYD88 wildtype (MYD88WT) by gene sequencing (estimated to bepresent in approximately 10% of enrolled subjects), were enrolled to Cohort 2 (N = 28) and receivedzanubrutinib 160 mg twice daily on a third, non-randomized, study arm (Arm C).

In Cohort 1 (MYD88MUT), the median age was 70 years (range, 38 to 90 years), with 71% and 60% ofpatients treated with ibrutinib and zanubrutinib respectively being >65 years old. 33% of patients inthe zanubrutinib arm and 22% in the ibrutinib were >75 years. 67% were male, and 91% were

Caucasian. At study entry, 44% of patients in the ibrutinib arm and 46% of patients in thezanubrutinib arm had an International Prognostic Scoring System (IPSS) high. One hundred andsixty-four patients had relapsed or refractory disease; the median number of prior therapies was 1(range, 1 to 8).

The primary outcome measure was rate of Complete Response (CR) or Very Good Partial Response(VGPR), as assessed by an independent review committee (IRC) with adaptation of the responsecriteria updated at the Sixth IWWM. The secondary endpoints for Cohort 1 include major responserate (MRR), duration of response, rate of CR or VGPR determined by investigator, and progression-free survival (PFS).

The testing for the superiority of the primary endpoint of VGPR or CR rate required testing in the

Relapsed/Refractory Analysis Set prior to testing in the ITT Analysis Set. Median follow-up was19.4 months. In the relapsed/refractory patients, 19.8% and 28.9% achieved VGPR or CR on theibrutinib and zanubrutinib arms, respectively. The primary efficacy endpoint was not significant in the

Relapsed/Refractory Analysis Set (2-sided p=0.1160). Table 5 summarizes the responses as assessedby IRC for the Relapsed/Refractory and intent-to-treat (ITT) Analysis Set. Responses were observedwith zanubrutinib across subgroups, including MYD88WT patients (Cohort 2) who had a VGPR or CRrate of 26.9% and an MRR of 50%.

Table 5: Primary analysis of disease response by independent review committee (ASPEN Study)

Relapsed/Refractory ITT

Ibrutinib Zanubrutinib Ibrutinib Zanubrutinib

Response Category N = 81 N = 83 N = 99 N = 102

Median follow-up time, months 18.79 18.73 19.38 19.47(range) (0.5, 30.0) (0.4, 28.7) (0.5, 31.1) (0.4, 31.2)

CR 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

VGPR 16 (19.8) 24 (28.9) 19 (19.2) 29 (28.4)

PR 49 (60.5) 41 (49.4) 58 (58.6) 50 (49.0)

VGPR or CR rate, n (%) 16 (19.8) 24 (28.9) 19 (19.2) 29 (28.4)95% CI a (11.7, 30.1) (19.5, 39.9) (12.0, 28.3) (19.9, 38.2)

Risk difference (%) b 10.7 10.295% CI a (-2.5, 23.9) (-1.5, 22.0)p-value c 0.1160

MRR (PR or better), n (%) 65 (80.2) 65 (78.3) 77 (77.8) 79 (77.5)95% CI a (69.9, 88.3) (67.9, 86.6) (68.3, 85.5) (68.1, 85.1)

Risk difference (%) b -3.5 -0.595% CI (-16.0, 9.0) (-12.2, 11.1)

Duration of major response

Event-free rate at, % (95% CI)d 85.6 87.0 87.9 85.218 months (73.1, 92.6) (72.5, 94.1) (77.0, 93.8) (71.7, 92.6)

Percentages are based on N.a 2-sided Clopper-Pearson 95% confidence interval.b Mantel-Haenszel common risk difference with the 95% confidence interval calculated using a normal approximation and

Sato's standard error stratified by the stratification factors per IRT (strata CXCR4 WT and UNK are combined) and agegroup (≤65 and >65). Ibrutinib is the reference group.c Based on CMH test stratified by the stratification factors per IRT (strata CXCR4 WT and UNK are combined) and age group(≤65 and >65)d Event-free rates are estimated by Kaplan-Meier method with 95% CIs estimated using the Greenwood’s formula.

Based on an updated data cut-off the progression free-survival event-free rate by investigatorassessment was 77.6% vs 84.9% at 30 months (ibrutinib vs zanubrutinib), with an estimated overallhazard ratio of 0.734 (95% CI: 0.380, 1.415).

Patients with Marginal Zone Lymphoma (MZL)

The efficacy of zanubrutinib was assessed in a Phase 2 open-label, multicentre, single-arm trial of 68patients with MZL who had received at least one prior anti-CD20-based therapy (MAGNOLIA study,

BGB-3111-214). Twenty-six (38.2%) patients had extranodal MZL, 26 (38.2%) had nodal MZL, 12(17.6%) had splenic MZL, and in 4 (6%) patients, the subtype was unknown. Zanubrutinib was givenorally at a dose of 160 mg twice daily until disease progression or unacceptable toxicity. The medianage of patients was 70 years (range: 37 to 95), and 53% were male. The median time since initialdiagnosis was 61.5 months (range: 2.0 to 353.6). The median number of prior treatments was 2(range: 1 to 6), with 27.9 % patients having 3 or more lines of systemic therapy; 98.5% (n=67)patients had received prior rituximab-based chemotherapy and 85.3% (n=58) patients had receivedprior treatment with alkylating agents; 5.9% patients (n=4) had prior stem cell transplantation. Sixty-three (92.6%) patients had a baseline ECOG performance status of 0 or 1. Twenty-two (32.4%)patients had refractory disease at study entry.

Tumor response was according to the 2014 Lugano Classification, and the primary efficacy endpointwas overall response rate as assessed by an Independent Review Committee (IRC) (Table 6).

Table 6: Efficacy results in Patients with MZL by Independent Review Committee (MAGNOLIAstudy)

Study BGB-3111-214(N=66) a

ORR (95% CI) 68% (55.6,79.1)

CR 26%

PR 42%

Median DoR in months (95% CI) NE (25.0, NE)

DOR Event Free Rate b at 24 months, % (95% CI) 72.9 (54.4, 84.9)

Median study follow-up in months (Min, Max) 28.04 (1.64, 32.89)a Two patients in BGB-3111-214 were not evaluable for efficacy due to central confirmation of MZL transformation todiffuse large B-cell lymphoma.b Event free rates were estimated by Kaplan-Meier method with 95% CIs estimated using the Greenwood’s formula.

ORR: overall response rate, CR: complete response, PR: partial response, DoR: duration of response, CI: confidenceinterval, NE: not estimable

In BGB-3111-214, the median time to response was 2.79 months (range: 1.7 to 11.1 months). After amedian study follow-up time of 28.04 months (range: 1.64 to 32.89 months), the median duration ofresponse (DOR) as assessed by the IRC has not been reached (95% CI 25.0 months to NE), and a totalof 72.9 % (95% CI 54.4 to 84.9) of responders were estimated to be event-free at 24 months afterinitial response.

The overall response rates observed were similar across three different MZL subtypes (extranodal,nodal and splenic).

Patients with Chronic Lymphocytic Leukaemia (CLL)

The efficacy of BRUKINSA in patients with CLL was evaluated in two randomized controlled trials.

SEQUOIA study (BGB-3111-304): An International, Phase 3, Open-label, Randomized Study of

Zanubrutinib Compared with Bendamustine plus Rituximab (BR) in Patients with Previously Untreated

CLL.

The SEQUOIA study (BGB-3111-304) is a randomized multicenter, open-label, active controlled Phase3 trial of zanubrutinib monotherapy and bendamustine in combination with rituximab in 479 patientswith previously untreated CLL without 17p deletion (del(17p)) (arms A and B; Cohort 1). Arm C(Cohort 2) is a multicenter single-arm trial of zanubrutinib monotherapy in 110 patients with previouslyuntreated CLL with centrally confirmed del(17p).

Both Cohorts enrolled patients 65 years of age or older as well as patients between 18 and 65 years ofage that were unsuitable for chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab(FCR).

Demographic and baseline characteristics were generally balanced between arm A (zanubrutinib) andarm B (BR) of Cohort 1. In both arms, the median age was 70.0 years, with a slightly higher proportionof patients of ≥ 75 years (26.1%) in arm A compared with arm B (22.3%) and a slightly lower proportionof patients 65-75 years old (55.2%) in arm A compared with arm B (58.4%). In Cohort 1, 92.7% patientshad a baseline ECOG performance status of 0 or 1 (93.7% in arm A and 91.6% in arm B). In Cohort 2(arm C zanubrutinib), 87.3% patients had a baseline ECOG performance status of 0 or 1.

Demographic and baseline characteristics were also generally similar between arm A (zanubrutinib) in

Cohort 1 and arm C (zanubrutinib) in Cohort 2.

In Cohort 1, randomisation was stratified by age (< 65 years vs ≥ 65 years), Binet stage (C versus A or

B), immunoglobulin variable region heavy chain (IGHV) mutational status (mutated vs unmutated),and geographic region (North America versus Europe versus Asia Pacific). A total of 479 patients wererandomized (intent-to-treat [ITT] analysis set), 241 to zanubrutinib continuous monotherapy and 238to 6 cycles of therapy with bendamustine and rituximab (BR).

In Cohort 1, patients in the zanubrutinib arm A received 160 mg twice daily until disease progressionor unacceptable toxicity. In arm B, patients received bendamustine at a dose of 90 mg/m2/day on thefirst 2 days of each cycle for 6 cycles and rituximab at a dose of 375 mg/m2 for Cycle 1, and at a doseof 500 mg/m2 for Cycles 2 to 6. Each treatment cycle consisted of approximately 28 days. In Cohort 2(arm C), patients received zanubrutinib 160 mg twice daily until disease progression or unacceptabletoxicity.

For Cohort 1, the primary endpoint was progression-free survival (PFS), assessed by an independentcentral review committee (IRC). Secondary endpoints included the overall response rate based on IRCassessment.

In Cohort 1, the median duration of follow-up for PFS was 25.0 months (range: 0.0 to 41.4). The PFSrate at 24 months was 85.5% (95% CI: 80.1, 89.6) for zanubrutinib and 69.5% (95% CI: 62.4, 75.5) for

BR. In Cohort 2, the median duration of follow up for PFS was 27.9 months (range: 1.0 to 38.8) andthe PFS rate at 24 months 88.9% (95% CI: 81.3, 93.6). The ORR assessed by IRC in Cohort 2 was90.0% (95% CI: 82.8, 94.9). The median time to partial response or higher as assessed by IRC was2.89 months (range: 1.8, 14.2) and 2.86 months (range: 1.9, 13.9) in the zanubrutinib arm of Cohort 1and Cohort 2, respectively.

Efficacy results for cohort 1 is presented in Table 7. The Kaplan-Meier curves for PFS for both arms in

Cohort 1 are shown in in Figure 1.

Table 7: Efficacy Results in the SEQUOIA study

Cohort 1*

Patientswithout Del(17p)

Endpoint Zanubrutinib Bendamustine + Rituximab(N=241) (N=238)

Progression-Free Survival†

Number of Events, n (%) 36 (14.9) 71 (29.8)

Disease Progression, n (%) 27 (11.2) 59 (24.8)

Death, n (%) 9 (3.7) 12 (5.0)

Median (95% CI), months a NE (NE, NE) 33.7 (28.1, NE)

Hazard Ratio (95% CI) b 0.42 (0.28, 0.63)

P value c <0.0001

Overall Response Rate† % 94.6% 85.3%(95% CI) (91.0, 97.1) (80.1, 89.5)

Overall Response Rate: CR+CRi+nPR+PR+PR-L, CR: complete response, CRi: complete response with incompletehaematopoietic recovery, nPR: nodular partial response, PR: partial response, PR-L: partial response with lymphocytoma,

CI: confidence interval, NE: not estimable, median follow-up time for PFS was 25.0 months (95% CI: 24.6, 25.2).

* ITT analysis set† Assessed by independent central review committee.a Based on Kaplan-Meier estimation.b Based on a stratified Cox-regression model with bendamustine + rituximab as the reference group.c Based on a stratified log-rank test.

At an updated ad hoc analysis with a median follow-up of 33.5 months for PFS, the investigator-assessed PFS remained consistent with the primary analysis with a HR of 0.33 (95% CI: 0.22 to 0.48,descriptive P<0.0001) in the zanubrutinib arm over the BR arm. Median PFS was not reached withzanubrutinib arm and was 39.2 months for BR arm. At 36 months after randomization, 83.6% ofpatients treated with zanubrutinib and 55.1% with BR were estimated to be progression-free and alive.

With a median follow-up of 35.8 months, the median OS was not reached for both arms; the 36-month

OS rate estimate was 90.9% (95% CI: 86.3 to 94.0) in the zanubrutinib arm and 89.5% (95% CI: 84.2to 93,1) in the BR arm, respectively.

Figure 1: Kaplan-Meier Curve of IRC-assessed PFS in the SEQUOIA study Cohort 1 (ITTpopulation)

ALPINE study (BGB-3111-305): A Phase 3, Randomized Study of Zanubrutinib Compared with

Ibrutinib in Patients with Relapsed/Refractory (R/R) CLL

The ALPINE study (BGB-3111-305) is a randomized, multicenter, open-label, Phase 3, activecontrolled trial. It enrolled 652 patients with relapsed or refractory CLL after at least one prior systemictherapy. The patients were randomized to either zanubrutinib 160 mg orally twice daily or ibrutinib 420mg orally once daily, continued until disease progression or unacceptable toxicity.

Randomization was stratified by age (< 65 years versus ≥ 65 years), geographic region (China versusnon-China), refractory status (yes or no), and del(17p)/TP53 mutation status (present or absent).

Baseline demographics and disease characteristics were generally balanced between treatment arms in

ITT analysis set and in the first 415 randomized patients.

In the ITT analysis set, the median age was 67.0 years in the zanubrutinib arm and 68.0 years in theibrutinib arm. The majority of patients in both arms had an ECOG PS of 0 or 1 (97.9% in thezanubrutinib arm; 96.0% in the ibrutinib arm). Similar demographics and baseline characteristics wereobserved in the first 415 randomized patients. The median number of prior lines of systemic therapy is1.0 the zanubrutinib arm (range, 1 to 6) and 1.0 in the ibrutinib arm (range, 1 to 8) in both the ITTanalysis set and the first 415 randomized patients.

Patients previously treated with a BTK inhibitor were excluded from study 305 and limited data forzanubrutinib after prior BCL 2 inhibitor treatment is available.

Of 652 patients total, 327 were assigned to zanubrutinib monotherapy, 325 to ibrutinib monotherapy.

The efficacy evaluation is based on the pre-specified interim analysis of the first 415 randomizedpatients of the ITT population. Of these, 207 were randomized to zanubrutinib monotherapy, 208 toibrutinib monotherapy. Efficacy results are presented in Table 8.

The primary endpoint was overall response rate (ORR, defined as partial response or better).

At the pre-specified ORR interim analysis in the first 415 randomised patients, zanubrutinibdemonstrated non-inferiority (1-sided p <0.0001) and superiority (2-sided p = 0.0006) to ibrutinib inthe protocol-specified primary endpoint ORR assessed by investigator. Response as determined by IRCalso demonstrated non-inferiority of zanubrutinib to ibrutinib (1-sided p < 0.0001). At the ORR finalanalysis, ORR assessed by the investigator continues to be higher (79.5% versus 71.1%) in thezanubrutinib arm compared with the ibrutinib arm (descriptive p = 0.0133); ORR determined by IRCwas also significantly higher in the zanubrutinib arm compared with the ibrutinib arm, demonstratingsuperiority (80.4% versus 72.9%, respectively; 2-sided p = 0.0264).

Table 8: Efficacy results in the ALPINE study (Pre-specified Interim Analysis of the First 415randomized Patients) by Investigator (protocol defined primary endpoint) and IRC Assessment

Investigator Assessed IRC Assessed(protocol-define primaryendpoint)

Endpoint Zanubrutinib Ibrutinib Zanubrutinib Ibrutinib(N=207) (N=208) (N=207) (N=208)

Overall Response Rate§n (%) 162 (78.3) 130 (62.5) 158 (76.3) 134 (64.4)(95% CI) (72.0, 83.7) (55.5, 69.1) (69.9, 81.9) (57.5, 70.9)

Response ratio a (95% CI) 1.25 (1.10, 1.41) 1.17 (1.04, 1.33)

Non-inferiority b 1-sided p-value <0.0001 1-sided p-value <0.0001

Superiority c 2-sided p-value 0.0006 2-sided p-value 0.0121

Duration of Response d: 89.8 77.9 90.3 78.012-months event-free rate (78.1, 95.4) (64.7, 86.7) (82.3, 94.8) (66.1, 86.2)% (95% CI)

Overall Response Rate : CR + CRi + nPR + PR, CR: complete response, CRi: complete response with incompletehaematopoietic recovery, nPR: nodular partial response, PR: partial response, CI: confidence interval

Median duration of response as assessed by investigator was not reached in the zanubrutinib arm at interim analysis, medianstudy follow-up time was 15.31 months (range: 0.1, 23.1) in zanubrutinib arm and 15.43 months (range: 0.1, 26.0) inibrutinib arm.§ Hypothesis testing for the noninferiority of ORR at the interim analysis is based on the first 415 randomized patients onlywith a 1-sided significance level of 0.005.a Response ratio: estimated ratio of the overall response rate in the zanubrutinib arm divided by that in the ibrutinib arm.b Stratified test against a null response ratio of 0.8558.c Stratified Cochran-Mantel-Haenszel test.d Kaplan-Meier estimate.

The median time to response as assessed by the investigator at the ORR interim analysis in first 415randomised patients was 5.59 months (range: 2.7, 14.1) in zanubrutinib arm and 5.65 months (range:2.8, 16.7) in ibrutinib arm. The results assessed by IRC were consistent (5.55 months vs. 5.63 monthsin zanubrutinib and ibrutinib arms respectively). At the ORR final analysis in all 652 randomisedpatients, the median time to response remained unchanged (5.59 months vs. 5.65 months as assessedby investigator and 5.52 months vs. 5.62 months as assessed by IRC in zanubrutinib and ibrutinibarms respectively).

In patients with del(17p) mutation in the first 415 randomized patients, the ORR assessed byinvestigator were 83.3% (95% CI 62.5, 95.3; 20 of 24 patients) in the zanubrutinib arm and 53.8%(95% CI 33.4, 73.4; 14 of 26 patients) in the ibrutinib arm. Based on IRC assessment, the ORR were79.2% (95% CI 57.8, 92.9; 19 of 24 patients) in the zanubrutinib arm and 61.5% (95% CI 40.6, 79.8;16 of 26 patients) in the ibrutinib arm. At the ORR final analysis in all 652 randomized patients, the

ORR assessed by investigator were 86.7% (95% CI 73.2, 94.9; 39 of 45 patients with del(17p)mutation) in the zanubrutinib arm and 56.0% (95% CI 41.3, 70.0; 28 of 50 patients with del(17p)mutation) in the ibrutinib arm. Based on IRC assessment, the ORR were 86.7% (95% CI 73.2, 94.9;39 of 45 patients with del(17p) mutation) in the zanubrutinib arm and 64.0% (95% CI 49.2, 77.1; 32of 50 patients with del(17p) mutation) in the ibrutinib arm.

A total of 652 patients were enrolled at the prespecified time of final PFS analysis (cut-off date 8

August 2022). The median PFS follow-up time was 28.1 months as assessed by investigator and30.7 months as assessed by IRC Zanubrutinib showed superiority in PFS over ibrutinib as assessed byboth investigator and IRC. The efficacy results for PFS are presented in Table 9, and a Kaplan Meier

Plot as assessed by IRC is provided in Figure 2.

Table 9: Efficacy results in the ALPINE study (prespecified final PFS analysis of all 652randomized patients) by Investigator and IRC assessment (cut-off date 8 August 2022)

Investigator Assessed Independently Assessed*

Endpoint Zanubrutinib Ibrutinib Zanubrutinib Ibrutinib(N=327) (N=325) (N=327) (N=325)

Progression-Free

Survival

Events, n (%) 87 (26.6) 118 (36.3) 88 (26.9) 120 (36.9)

Hazard Ratioa 0.65 (0.49, 0.86) 0.65 (0.49, 0.86)(95% CI)2-sided p-valueb 0.0024 0.0024

* By independent central review committee.a Based on a stratified Cox-regression model with ibrutinib as the reference group.b Based on a stratified log-rank test.

Figure 2: Kaplan-Meier Plot of Progression-Free Survival by Independent Central Review(ITT)(cut-off date 8 August 2022)

In patients with del(17p)/TP53 mutation, the hazard ratio for progression-free survival by investigatorassessment was 0.53 (95% CI 0.31, 0.88). Based on independent review, the hazard ratio was 0.52(95% CI 0.30, 0.88) (Figure 3).

Figure 3: Kaplan-Meier Plot of Progression-Free Survival by Independent Central Review for

Patients with Del 17P or TP53 (ITT)(cut-off date 8 August 2022)

With an estimated median follow-up of 32.8 months, the median overall survival was not reached ineither arm with 17% of patients experiencing an event.

Patients with Follicular Lymphoma (FL)

The efficacy of zanubrutinib in combination with obinutuzumab versus obinutuzumab was assessed inthe ROSEWOOD study (BGB-3111-212), a phase 2 randomized, open-label, multicentre study.

Overall, 217 patients with relapsed (defined by disease progression after completion of the mostrecent therapy) or refractory (defined as failure to achieve CR or PR to most recent therapy), grade 1-3a follicular lymphoma (FL) who had previously received at least two prior systemic therapiesincluding an anti-CD20 antibody and an appropriate alkylator-based combination therapy, wereenrolled. Patients were randomized 2:1 to either zanubrutinib 160 mg orally twice daily untilprogressive disease or unacceptable toxicity, in combination with obinutuzumab 1 000 mgintravenously (arm A) or obinutuzumab alone (arm B). Obinutuzumab was given on Day 1, 8, and 15of the first cycle, then at Day 1 of cycles 2-6. Each cycle was 28 days long. Patients received optionalobinutuzumab maintenance, one infusion every other cycle, for a maximum of 20 doses.

Patients randomized in obinutuzumab arm were allowed to crossover and to receive the combinationof zanubrutinib plus obinutuzumab in case of progressive disease or absence of response (defined bystable disease as best response) after 12 cycles. Randomization was stratified by the number of priorlines of therapy (2 to 3 versus ˃3), rituximab-refractory status (yes versus no), and geographic region(China versus other countries/regions).

Baseline demographics and disease characteristics were generally balanced between the zanubrutinibcombination arm and the obinutuzumab monotherapy arm in the 217 randomized patients. Themedian age was 64 years (range: 31 to 88), 49.8% were male, and 64.1% White. Most (97.2%) of thepatients had a baseline ECOG performance status of 0 or 1.

At screening, most patients were Ann Arbor Stage III or IV (179 patients [82.5%]). Eighty-eightpatients (40.6%) had bulky disease (defined as >1 baseline target lesion measuring >5 cm diameter).

One hundred and twenty-three patients (56.7%) met the GELF criteria.

The median number of prior anticancer therapy was 3 lines (range: 2 to 11 lines). All 217 patientsreceived >2 prior lines of therapy that included rituximab therapy (as a monotherapy or incombination with chemotherapy), and 59 of the 217 patients (27.2%) received >3 prior lines oftherapy. Of the 217 patients, 114 (52.5%) were refractory to rituximab (defined as failure to respondto, or progression during, any previous rituximab-containing regimen [monotherapy or combined withchemotherapy], or progression within 6 months of the last rituximab dose, in the induction ormaintenance treatment settings). Twelve (5.5%) patients received prior obinutuzumab.

Of 217 patients total, 145 were randomized to the zanubrutinib combination arm and 72 wererandomized to the obinutuzumab monotherapy arm. The median follow-up time is shown in Table 10.

Median duration of zanubrutinib exposure was 12.4 months at data cutoff date 31 December 2024.

Of 72 patients randomized in the obinutuzumab monotherapy arm, 36 did crossover to combinationtherapy.

The primary efficacy endpoint was overall response rate (defined partial response or completeresponse) as determined by independent central review using the Lugano Classification for NHL.

Main secondary endpoints included duration of response (DOR), progression-free survival (PFS) andoverall survival (OS). Efficacy results are summarized in Table 10 and Figure 4.

Table 10: Efficacy results Per Independent Central Review (ITT) (ROSEWOOD study)

Zanubrutinib + Zanubrutinib +

Obinutuzumab Obinutuzumab Obinutuzumab Obinutuzumab(N=145) (N=72) (N=145) (N=72)n (%) n (%) n (%) n (%)

Data cut-off date 31DEC2024 25JUN2022median follow-up time 36.83 31.52 20.21 20.40(Months)

Overall Response Rate,n (%) 102 (70.3) 32 (44.4) 100 (69.0) 33 (45.8)(95% CIa) (62.2, 77.6) (32.7, 56.6) (60.8, 76.4) (34.0, 58.0)

P valueb 0.0003 0.0012

CR 61 (42.1) 14 (19.4) 57 (39.3) 14 (19.4)

PR 41 (28.3) 18 (25.0) 43 (29.7) 19 (26.4)

Duration of Response(Months)

Median (95% CI)c 32.9 (19.6, 43.1) 14.0 (9.2, 26.5) NE (25.3, NE) 14.0 (9.2, 25.1)

Progression-free Survival(Months)

Median (95% CI)c 22.1 (16.1, 34.0) 10.3 (6.5, 13.8) 28.0 (16.1, NE) 10.4 (6.5, 13.8)

Overall Response Rate: CR + PR, CR: complete response, PR: partial responsea Estimated using the Clopper-Pearson method.b Cochran-Mantel-Haenszel method stratified by rituximab-refractory status, number of prior lines of therapy, andgeographic region per IRT.c Medians estimated by Kaplan-Meier method; 95% CIs estimated by Brookmeyer and Crowley method.d DOR rates estimated by Kaplan-Meier method; 95% CIs estimated using the Greenwood's formula. DOR was not type Ierror controlled and the CIs are nominal in nature.

Figure 4: Kaplan-Meier Plot of Progression-Free Survival by Independent Central Review(ITT)

Arm A, Zanubrutinib + Obinutuzumab; Arm B, Obinutuzumab

Overall Survival

As of 31 December 2024, 51 patients (35.2%) in the combination arm and 33 patients (45.8%) in theobinutuzumab monotherapy arm died. At 18 months, overall survival rates were 84.1% (95% CI:76.6, 89.3) in the combination arm and 71.5% (95% CI: 59.0, 80.8) in the obinutuzumab monotherapyarm. OS analysis may be confounded by 36 patients (50.0%) who crossed over from obinutuzumabmonotherapy arm to combination arm.

The European Medicines Agency has waived the obligation to submit the results of studies with

BRUKINSA in all subsets of the paediatric population for the treatment of lymphoplasmacyticlymphoma and for the treatment of mature B-cell neoplasms (see section 4.2 for information onpaediatric use).

Zanubrutinib maximum plasma concentration (Cmax) and area under the plasma drug concentrationover time curve (AUC) increase proportionally over a dose range from 40 mg to 320 mg (0.13 to1 time the recommended total daily dose). Limited systemic accumulation of zanubrutinib wasobserved following repeated administration for one week.

The geometric mean (%CV) zanubrutinib steady-state daily AUC is 2 099 (42%) ng h/mL following160 mg twice daily and 1 917 (59%) ng h/mL following 320 mg once daily. The geometric mean(%CV) zanubrutinib steady-state Cmax is 299 (56%) ng/mL following 160 mg twice daily and 533(55%) ng/mL following 320 mg once daily.

The median tmax of zanubrutinib is 2 hours. No clinically significant differences in zanubrutinib AUCor Cmax were observed following administration of a high-fat meal (approximately 1 000 calories with50% of total caloric content from fat) in healthy subjects.

The geometric mean (%CV) apparent steady-state volume of distribution of zanubrutinib during theterminal phase (Vz/F) was 522 L (71%). The plasma protein binding of zanubrutinib is approximately94% and the blood-to-plasma ratio was 0.7-0.8.

Zanubrutinib is primarily metabolized by cytochrome P450(CYP)3A.

The mean half-life (t½) of zanubrutinib is approximately 2 to 4 hours following a single oralzanubrutinib dose of 160 mg or 320 mg. The geometric mean (%CV) apparent oral clearance (CL/F)of zanubrutinib during the terminal phase was 128 (61%) L/h. Following a single radiolabelledzanubrutinib dose of 320 mg to healthy subjects, approximately 87% of the dose was recovered infaeces (38% unchanged) and 8% in urine (less than 1% unchanged).

Age (19 to 90 years; mean age 65±12.5) had no clinically meaningful effect on zanubrutinibpharmacokinetics based on population PK analysis (N=1291).

Gender (872 males and 419 females) had no clinically meaningful effect on zanubrutinibpharmacokinetics based on population PK analysis.

Race (964 White, 237 Asian, 30 Black, and 25 categorized as Other) had no clinically meaningfuleffect on zanubrutinib pharmacokinetics based on population PK analysis.

Body weight (36 to 149 kg, mean weight 76.5±16.9 kg) had no clinically meaningful effect onzanubrutinib pharmacokinetics based on population PK analysis (N=1 291).

Zanubrutinib undergoes minimal renal elimination. Based on population PK analysis, mild andmoderate renal impairment (CrCl ≥30 mL/min as estimated by Cockcroft-Gault equation) had noinfluence on the exposure of zanubrutinib. The analysis was based on 362 patients with normal renalfunction, 523 with mild renal impairment, 303 with moderate renal impairment, 11 with severe renalimpairment, and one with ESRD. The effects of severe renal impairment (CrCl <30 mL/min) anddialysis on zanubrutinib pharmacokinetics is unknown.

The total AUC of zanubrutinib increased by 11% in subjects with mild hepatic impairment (Child-

Pugh class A), by 21% in subjects with moderate hepatic impairment (Child-Pugh class B), and by60% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normalliver function. The unbound AUC of zanubrutinib increased by 23% in subjects with mild hepaticimpairment (Child-Pugh class A), by 43% in subjects with moderate hepatic impairment (Child-Pughclass B), and by 194% in subjects with severe hepatic impairment (Child-Pugh class C) relative tosubjects with normal liver function. A significant correlation was observed between the Child-Pughscore, baseline serum albumin, baseline serum bilirubin and baseline prothrombin time with unboundzanubrutinib AUC.

CYP enzymes

Zanubrutinib is a weak inducer of CYP2B6 and CYP2C8. Zanubrutinib is not an inducer of CYP1A2.

Co-administration with transport substrates/inhibitors

Zanubrutinib is likely to be a substrate of P-gp. Zanubrutinib is not a substrate or inhibitor of OAT1,

OAT3, OCT2, OATP1B1, or OATP1B3.

An in vitro study showed that the potential pharmacodynamic interaction between zanubrutinib andrituximab is low and zanubrutinib is unlikely to interfere with the anti-CD20 antibody-inducedantibody-dependent cellular cytotoxicity (ADCC) effect.

In vitro, ex vivo, and animal studies showed that zanubrutinib had no or minimal effects on plateletactivation, glycoprotein expression, and thrombus formation.

The general toxicologic profiles of zanubrutinib were characterized orally in Sprague-Dawley rats forup to 6-month treatment and in beagle dogs for up to 9-month treatment.

In rat repeat dose studies up to 6-month treatment, test article related mortality was noted at the doseof 1 000 mg/kg/day (81x clinical AUC) with histopathologic findings in the gastrointestinal tract.

Other findings were mainly noted in the pancreas (atrophy, fibroplasia, haemorrhage, and/orinflammatory cell infiltration) at the doses ≥ 30 mg/kg/day (3x clinical AUC), in the skin around thenose/mouth/eyes (inflammatory cell infiltration, erosion/ulcer) from the dose of 300 mg/kg/day (16xclinical AUC), and in the lung (presence of macrophages in the alveolar) at the dose of300 mg/kg/day. All these findings were fully or partially reversed after a 6-week recovery except forthe pancreatic findings which were not considered clinically relevant.

In dog repeat dose studies up to 9-month treatment, test article related findings were mainly noted inthe gastrointestinal tract (soft/watery/mucoid stool), skin (rash, red discoloration, and thickened/scaling), and in the mesenteric, mandibular, and gut associated lymph nodes and spleen (lymphoiddepletion or erythrophagocytosis) at the doses from 10 mg/kg/day (3x clinical AUC) to100 mg/kg/day (18x clinical AUC). All these findings were fully or partially reversed after a 6-weekrecovery.

Carcinogenicity/genotoxicity

Carcinogenicity studies have not been conducted with zanubrutinib.

Zanubrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in achromosome aberration assay in mammalian (Chinese hamster ovary) cells, nor was it clastogenic inan in vivo bone marrow micronucleus assay in rats.

Developmental and reproductive toxicity

A combined male and female fertility and early embryonic development study was conducted in ratsat oral zanubrutinib doses of 30, 100 and 300 mg/kg/day. No effect on male or female fertility wasnoted but at the highest dose tested, morphological abnormalities in sperm and increased post-implantation loss were noted. The dose of 100 mg/kg/day is approximately 13-fold higher than thehuman therapeutic exposure.

Embryo-foetal development toxicity studies were conducted in both rats and rabbits. Zanubrutinibwas administered orally to pregnant rats during the period of organogenesis at doses of 30, 75, and150 mg/kg/day. Malformations in the heart (2- or 3-chambered hearts with the incidence of0.3%-1.5%) were noted at all dose levels in the absence of maternal toxicity. The dose of30 mg/kg/day is approximately 5-fold higher than the human therapeutic exposure.

Administration of zanubrutinib to pregnant rabbits during the period of organogenesis at 30, 70, and150 mg/kg/day resulted in post-implantation loss at the highest dose. The dose of 70 mg/kg isapproximately 25-fold higher than the human therapeutic exposure and was associated with maternaltoxicity.

In a pre- and post-natal developmental toxicity study, zanubrutinib was administered orally to rats atdoses of 30, 75, and 150 mg/kg/day from implantation through weaning. The offspring from themiddle and high dose groups had decreased body weights preweaning, and all dose groups hadadverse ocular findings (e.g., cataract, protruding eye). The dose of 30 mg/kg/day is approximately 5-fold higher than the human therapeutic exposure.

Microcrystalline cellulose

Croscarmellose sodium

Sodium lauryl sulfate (E487)

Silica, colloidal anhydrous

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Shellac glaze (E904)

Iron oxide black (E172)

Propylene glycol (E1520)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

HDPE bottles with a child-resistant polypropylene closure. Each carton contains one bottle of120 hard capsules.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

BeOne Medicines Ireland Limited.10 Earlsfort Terrace

Dublin 2

D02 T380

Ireland

Tel. +353 1 566 7660

E-mail beone.ireland@beonemed.com

EU/1/21/1576/001

Date of first authorisation: 22 November 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.