Zanubrutinib

Zanubrutinib is an oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK), a signalling enzyme of the B-cell antigen receptor and cytokine receptor pathways. Malignant B cells in many lymphomas and in chronic lymphocytic leukaemia depend on this signalling, so blocking BTK reduces their proliferation and survival and shrinks the tumour.

Mechanism of Action

• BTK signalling: in B cells, BTK activates the pathways needed for proliferation, trafficking, chemotaxis and adhesion. Once switched on by Src-family kinases, BTK phosphorylates phospholipase C gamma, which leads to calcium mobilisation and activation of the NF-κB and MAP kinase pathways that drive genes for B-cell growth and survival.
• Covalent inhibition: zanubrutinib forms a covalent bond with a cysteine residue (cysteine 481) in the ATP-binding pocket, the active site of BTK, and so switches off the enzyme. Other kinases that carry a cysteine at the same position may also be bound, with varying affinity.
• Cellular effect: blocking B-cell receptor signalling reduces proliferation, trafficking, chemotaxis and adhesion of malignant B cells.
• Target occupancy: at the recommended total daily dose of 320 mg, median steady-state BTK occupancy in blood cells stayed at 100% over 24 hours, and in lymph nodes it was 94–100%.
• Anti-CD20 antibodies: in laboratory studies the potential for a pharmacodynamic interaction with rituximab was low, and zanubrutinib was unlikely to interfere with the antibody-dependent cellular cytotoxicity of anti-CD20 antibodies.
• Platelets: in vitro, ex vivo and animal studies showed no or minimal effect on platelet activation, glycoprotein expression and thrombus formation.
• Cardiac electrophysiology: no clinically relevant effect on the QTc interval at the recommended doses, nor at a single dose 1.5 times the maximum recommended dose (480 mg).

Pharmacokinetics

• Absorption: median time to peak concentration about 2 hours. Cmax and AUC rise in proportion to the dose from 40 to 320 mg, and accumulation after repeated dosing is limited. A high-fat meal has no clinically significant effect, so the capsules can be taken with or without food.
• Distribution: about 94% bound to plasma proteins; blood-to-plasma ratio 0.7–0.8; apparent volume of distribution in the terminal phase about 522 L.
• Metabolism: mainly by cytochrome P450 3A (CYP3A).
• Elimination: mean half-life about 2 to 4 hours after a single dose of 160 or 320 mg; apparent oral clearance about 128 L/h. After a radiolabelled 320 mg dose, about 87% was recovered in faeces (38% unchanged) and about 8% in urine (less than 1% unchanged).
• Special populations: age (19–90 years), sex, race and body weight (36–149 kg) had no clinically meaningful effect. Renal elimination is minimal, and mild or moderate renal impairment (creatinine clearance of 30 mL/min or more) did not change exposure; the effect of severe impairment and dialysis is unknown. Total AUC was 11% higher in mild, 21% higher in moderate and 60% higher in severe hepatic impairment (Child-Pugh A, B and C); unbound AUC was 23%, 43% and 194% higher.

Zanubrutinib is indicated in adults:

• Waldenström’s macroglobulinaemia (WM): as monotherapy in patients who have received at least one prior therapy, or as first-line treatment in patients unsuitable for chemo-immunotherapy.
• Marginal zone lymphoma (MZL): as monotherapy in patients who have received at least one prior anti-CD20-based therapy.
• Chronic lymphocytic leukaemia (CLL): as monotherapy.
• Follicular lymphoma (FL): in combination with obinutuzumab in patients with refractory or relapsed disease who have received at least two prior systemic therapies.

• Hypersensitivity to zanubrutinib or to any of the excipients.

The most common reactions (20% or more) with monotherapy, in 1,550 patients with B-cell malignancies, were upper respiratory tract infection (36%), bruising (32%), haemorrhage or haematoma (30%), neutropenia (30%), musculoskeletal pain (27%), rash (25%), pneumonia (24%), diarrhoea (21%) and cough (21%). The most common reactions of grade 3 or higher (more than 3%) were neutropenia (21%), pneumonia (14%), hypertension (8%), thrombocytopenia (6%), anaemia (6%) and haemorrhage or haematoma (4%). Treatment was stopped because of adverse reactions in 4.8% of patients (most often pneumonia, 2.6%) and the dose was reduced in 5.0%. With obinutuzumab, the most common reactions were thrombocytopenia (37%), neutropenia (31%) and fatigue (27%).

Very common (≥1/10): upper respiratory tract infection, pneumonia, urinary tract infection, neutropenia, thrombocytopenia, anaemia, dizziness, bruising (including contusion), haemorrhage or haematoma (including haematuria), hypertension, cough, diarrhoea, constipation, nausea, rash, musculoskeletal pain (including joint pain and back pain), fatigue, decreased neutrophil count, decreased platelet count, decreased haemoglobin.

Common (≥1/100 to <1/10): lower respiratory tract infection, bronchitis, febrile neutropenia, atrial fibrillation and flutter, petechiae, purpura, ecchymosis, epistaxis, pruritus, asthenia, peripheral oedema.

Uncommon (≥1/1,000 to <1/100): hepatitis B reactivation, tumour lysis syndrome, gastrointestinal haemorrhage.

Not known: generalised exfoliative dermatitis.

Serious reactions to watch for are haemorrhage (including intracranial and gastrointestinal bleeding), serious and opportunistic infections including hepatitis B reactivation, grade 3 or 4 cytopenias, atrial fibrillation or flutter, second primary malignancies (mainly skin cancer) and, uncommonly, tumour lysis syndrome. Asymptomatic lymphocytosis is not regarded as an adverse reaction.

Zanubrutinib is metabolised mainly by CYP3A, so inhibitors and inducers of this enzyme change its exposure.

• Strong CYP3A inhibitors (posaconazole, voriconazole, ketoconazole, itraconazole, clarithromycin, indinavir, lopinavir, ritonavir, telaprevir): itraconazole raised Cmax 2.6-fold and AUC 3.8-fold in healthy volunteers; in patients voriconazole and clarithromycin raised dose-normalised AUC 3.30-fold and 1.92-fold. If one must be used, reduce the zanubrutinib dose to 80 mg once daily for as long as the inhibitor is taken.
• Moderate CYP3A inhibitors (erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil, aprepitant, imatinib, grapefruit juice, Seville oranges): fluconazole and diltiazem raised dose-normalised AUC 1.88-fold and 1.62-fold. Reduce the dose to 160 mg once daily or 80 mg twice daily while the inhibitor is taken.
• Mild CYP3A inhibitors (ciclosporin, fluvoxamine): simulations suggest an AUC increase of less than 1.5-fold; no dose adjustment, but monitor for toxicity.
• CYP3A inducers: rifampicin (strong) lowered Cmax by 92% and AUC by 93%; rifabutin (moderate) lowered Cmax by 48% and AUC by 44%. Avoid strong inducers (carbamazepine, phenytoin, rifampicin, St John’s wort) and moderate inducers (bosentan, efavirenz, etravirine, modafinil, nafcillin); consider alternatives with less CYP3A induction. Mild inducers may be used with caution.
• Acid-reducing agents: proton pump inhibitors and H2-receptor antagonists did not change zanubrutinib exposure in a clinically significant way.
• Substrates of CYP3A and CYP2C19: zanubrutinib is a mild inducer of both. It lowered midazolam exposure (CYP3A) by 47% (AUC) and omeprazole exposure (CYP2C19) by 36%. Use with caution with narrow-therapeutic-index CYP3A substrates (alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) and CYP2C19 substrates (such as S-mephenytoin).
• P-glycoprotein substrates: digoxin Cmax rose by 34% and AUC by 11%. Use oral P-gp substrates with a narrow therapeutic index, such as digoxin, with caution. Rosuvastatin (BCRP substrate) was not affected.
• Anticoagulants and antiplatelet medicines: may add to the bleeding risk. Warfarin and other vitamin K antagonists should not be given together with zanubrutinib.
• Food: avoid grapefruit and grapefruit juice (they raise exposure) and St John’s wort (lowers exposure). Food does not significantly affect absorption.

Treatment should be started and supervised by a physician experienced in anticancer medicinal products. The capsules are for oral use, taken with or without food. Patients swallow them whole with water and must not open, break or chew them. The 160 mg film-coated tablets are also taken with or without food and swallowed with water, without chewing or crushing; the scored tablet can be divided into two equal halves when a dose adjustment is needed.

Recommended Dose

• Total daily dose 320 mg: either 320 mg once daily (four 80 mg capsules, or two 160 mg tablets) or 160 mg twice daily (two 80 mg capsules, or one 160 mg tablet, each time).
• Duration: continue until disease progression or unacceptable toxicity.
• Follicular lymphoma with obinutuzumab: zanubrutinib is given before the obinutuzumab infusion. The obinutuzumab dose is 1,000 mg intravenously on days 1, 8 and 15 of cycle 1 and on day 1 of each 28-day cycle from cycles 2 to 6; at the physician’s discretion, cycle 1 can start with 100 mg on day 1 and 900 mg on day 2 instead of 1,000 mg on day 1. Obinutuzumab maintenance (one infusion every two months for up to two years) may be prescribed. See the obinutuzumab SmPC for further dosing and premedication.

Dose Adjustments for Side Effects

• Triggers (grade 3 or higher): non-haematological toxicity, febrile neutropenia, grade 3 thrombocytopenia with significant bleeding, grade 4 neutropenia lasting more than 10 consecutive days, and grade 4 thrombocytopenia lasting more than 10 consecutive days.
• First occurrence: interrupt treatment; once the toxicity is grade 1 or less (or back to baseline), resume at 320 mg once daily or 160 mg twice daily.
• Second occurrence: interrupt, then resume at 160 mg once daily or 80 mg twice daily.
• Third occurrence: interrupt, then resume at 80 mg once daily.
• Fourth occurrence: discontinue.
• For obinutuzumab dose changes, see its SmPC.

With CYP3A Inhibitors or Inducers

• Strong CYP3A inhibitor: 80 mg once daily.
• Moderate CYP3A inhibitor: 160 mg once daily or 80 mg twice daily.
• Strong or moderate CYP3A inducer: avoid the combination.
• Monitor closely for toxicity and follow the dose modification guidance above as needed.

Special Populations

• Elderly (65 years and over): no specific dose adjustment.
• Renal impairment: no change for mild to moderate impairment (creatinine clearance of 30 mL/min or more). Data in severe impairment (below 30 mL/min) or on dialysis are limited (12 patients); monitor for adverse reactions.
• Hepatic impairment: no change for mild (Child-Pugh A) or moderate (Child-Pugh B) impairment. In severe impairment (Child-Pugh C) the recommended dose is 80 mg twice daily; safety has not been evaluated in this group, so monitor closely.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed Dose

Do not take a double dose to make up for a forgotten one. Take the next dose at the normal time.

Haemorrhage

Serious and fatal bleeding has occurred, including intracranial and gastrointestinal haemorrhage, haematuria and haemothorax (grade 3 or higher), and bleeding of any grade such as purpura and petechiae. The mechanism is not well understood. Zanubrutinib can add to the bleeding risk of antiplatelet or anticoagulant therapy, so patients should be monitored for signs of bleeding and have regular blood counts; the benefit and risk of such therapy should be weighed. Warfarin or other vitamin K antagonists must not be given together. Consider withholding zanubrutinib for 3 to 7 days before and after surgery, depending on the type of surgery and the bleeding risk.

Infections

Fatal and non-fatal infections (bacterial, viral, fungal, sepsis) and opportunistic infections (for example herpes virus, cryptococcus, aspergillus and Pneumocystis jirovecii) have occurred; pneumonia is the most common grade 3 or higher infection. Hepatitis B reactivation has occurred. Hepatitis B status must be established before starting, and a liver specialist consulted if serology is positive. Monitor for reactivation as per medical standards, consider prophylaxis in patients at increased risk of infection, and treat infections promptly.

Cytopenias

Grade 3 or 4 neutropenia, thrombocytopenia and anaemia (by laboratory measurement) have been reported. Complete blood counts should be checked monthly during treatment.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinomas, have occurred; skin cancer (basal cell and squamous cell carcinoma) is the most frequent. Patients should be advised to use sun protection.

Atrial Fibrillation and Flutter

These have occurred, particularly in patients with cardiac risk factors, hypertension, acute infections and in those aged 65 or over. Signs and symptoms should be monitored and managed as appropriate.

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported uncommonly with monotherapy, particularly in chronic lymphocytic leukaemia. Risk factors such as high tumour burden or high uric acid should be assessed, precautions taken and patients closely monitored.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use highly effective contraception during treatment and for up to 1 month after the last dose. It is not known whether zanubrutinib reduces the effect of hormonal contraceptives, so users of these should add a barrier method. A pregnancy test is recommended before starting.
• Pregnancy: zanubrutinib should not be used in pregnancy. There are no human data, and animal studies showed reproductive toxicity and possible foetal harm.
• Breastfeeding: not known whether it passes into human milk; a risk to the breast-fed child cannot be excluded, so breastfeeding should be stopped during treatment.
• Fertility: no effect on male or female fertility in rats, but sperm abnormalities and increased post-implantation loss occurred at 300 mg/kg/day.

Sodium

Each dose of the capsules contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Lactose in the Tablets

Each 160 mg film-coated tablet contains 312.2 mg of lactose monohydrate, an excipient with known effect; the SmPC gives the related precautions.

Effect on Driving

Zanubrutinib has no or negligible influence on the ability to drive and use machines, but fatigue, dizziness and asthenia have been reported and should be considered.

Brukinsa capsules need no special storage conditions. The capsules are supplied in bottles with a child-resistant closure, 120 capsules per bottle. The 160 mg film-coated tablets likewise need no special storage conditions and are supplied in bottles with a child-resistant closure, 60 tablets per bottle. Keep out of the sight and reach of children.

Capsules: 3 years. Film-coated tablets: 2 years. Do not use after the expiry date on the pack.

Prescription only (Rx), under restricted medical prescription (Annex II B): treatment is started and supervised by a specialist physician experienced in anticancer medicinal products. Zanubrutinib is taken at home as capsules or tablets, so it is supplied to the patient or to the treating clinic on prescription.