Introduction: Mantle cell lymphoma (MCL) is a form of B-cell lymphoma that makes up around 5% of non-Hodgkin lymphomas (NHLs), whereas other B-cell lymphomas make up around 85% of all NHLs.1 MCL is more common in patients older than 60 who are male. MCL can be aggressive or indolent. A protein called cyclin D1 present in lymphoma cells is overproduced in 90% of MCL cases. Cyclin D1 is a proto-oncogene. Typical treatment of MCL includes rituximab with cytarabine, which can be followed by autologous stem cell transplantation. Another common treatment regimen is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).1 Although patients usually respond to initial treatment, the disease for most eventually relapses, and the subsequent treatment options are suboptimal. Zanubrutinib (Brukinsa) was FDA approved under accelerated approval in November 2019 for relapsed or refractory MCL.
Mechanism of Action: Zanubrutinib is a selective inhibitor of Bruton tyrosine kinase (BTK). The small molecule forms a covalent bond with a cysteine residue in the active site of BTK, resulting in inhibition of its activity. BTK is a signaling molecule of B-cell antigen and cytokine receptor pathways that is needed for proliferation, trafficking, chemotaxis, and adhesion. Stopping the activity of BTK leads to inhibition of malignant B-cell proliferation and reduced tumor growth.2
Pharmacokinetics: Zanubrutinib is metabolized hepatically primarily through CYP3A4, and 87% of the drug is excreted in the feces, with 38% as unchanged drug. Zanubrutinib is highly protein bound (94%) with a time to peak of 2 hours and a half-life of 2–4 hours.2 There is no clinically significant difference in AUC or Cmax when taken with food.
Clinical Trials: BGB-3111-AU-003 [NCTO2343120] is a phase I, open-label, dose-escalation, global multicenter, single-arm trial of 32 patients who were previously treated for MCL. Patients were treated with zanubrutinib 160 mg orally twice daily or 320 mg orally daily. The median age of patients was 70 years; 69% of the study population were males and 78% were white. The primary outcome was the number of participants with adverse events. Secondary outcomes were AUC, Cmax, Tmax, half-life, inhibition activity, and tumor response. The overall response rate of the 32 patients enrolled was 84%, with a complete response rate of 22% and a partial response rate of 62%. The median duration of response was 18.5 months. The final dose regimen used in the phase II trial was zanubrutinib 160 mg orally twice daily. BGB-3111-206 [NCT03206970] is an ongoing phase II, open-label, multicenter, single-arm trial of patients previously treated for MCL. Eligible patients were 18 years and older with a diagnosis of MCL and documented treatment failures of prior regimens indicated for MCL; life expectancy was greater than 4 months, and total bilirubin was less than twice the upper limit of normal. All patients were given 160 mg orally of zanubrutinib twice daily. The median age of the cohort was 60.5, with 78% being men. The primary outcome was the rate of objective response up to 3 years. Secondary outcomes were progression-free survival, 6-month progression-free survival, duration of response, and overall survival, as well as safety and tolerability. From the interim analysis, the overall response rate of the 86 patients enrolled in the study was 84%, with a complete response rate of 59% and a partial response rate of 24%. The median duration of response was 19.5 months. Tumor response was determined according to the 2014 Lugano classification, and the overall response rate was assessed by an independent review committee.
Adverse Events/Precautions: The most common adverse reactions (greater than 20%) were decreases in neutrophil count, platelets, white blood cells, and hemoglobin. Rash, bruising, diarrhea, upper respiratory tract infection, and cough were also common. Hemorrhage has occurred in patients treated with zanubrutinib, and signs of bleeding should be monitored for. Zanubrutinib can cause embryo-fetal toxicity.2
Common Drug Interactions: Zanubrutinib is metabolized by CYP3A4, and coadministration with strong CYP3A4 inhibitors can increase the risk of toxicities. When coadministered with strong CYP3A4 inhibitors, the recommended dose is 80 mg orally once daily, and dose interruption is recommended for adverse events. When coadministered with moderate CYP3A4 inhibitors, the recommended dose is 80 mg orally twice daily. Zanubrutinib coadministration with moderate to strong CYP3A4 inducers should be avoided because of decreased serum concentrations.2
Usual Dosage: The recommended dosing for zanubrutinib is 160 mg orally (two 80-mg capsules) twice daily or 320 mg orally once daily (four 80-mg capsules). Capsules should be swallowed whole with water and can be administered with or without food. Dose adjustments should be made in the settings of hepatic impairment and management of toxicity. Zanubrutinib should be continued until disease progression or unacceptable toxicity. The out-of-pocket cost for zanubrutinib in the United States is around $12,935 for a 30-day supply.3
Available Products: Capsule (80 mg) white to off-white opaque capsules engraved with “ZANU 80” in black ink. Capsule size 0. Store at 20°C–25°C (68°F–77°F).2
Conclusion: Zanubrutinib is for the treatment of relapsed or refractory MCL. Patients must have received at least one prior therapy for MCL. Zanubrutinib’s high selectivity for BTK may result in a lower adverse event profile compared with other BTK inhibitors. Although zanubrutinib has been FDA approved under accelerated approval, clinical trials are ongoing, and additional efficacy and toxicity information is forthcoming.
References:
1. LLS.org. Leukemia & Lymphoma Society. Donate Today! Available at https://www.lls.org/. Accessed December 22, 2020.
2. Brukinsa [package insert]. San Mateo, CA: BeiGene, 2019.
3. Liu A; FiercePharma. BeiGene Nabs Landmark FDA Nod for Brukinsa, Kicking Off Challenge Against Blockbuster Imbruvica. Available at https://www.fiercepharma.com/marketing/beigene-nabs-landmark-fda-nod-for-brukinsa-kicking-off-challenge-against-blockbuster. Published November 15, 2019. Accessed December 22, 2020.