What is zanubrutinib?
Zanubrutinib is an oral small molecule inhibitor of Bruton's tyrosine kinase (BTK), which is involved in the signaling cascade and proliferation of B-cell malignancies. Zanubrutinib is the third BTK inhibitor approved by the FDA; however, its selectivity leads to fewer off-target effects compared to other agents.
How does zanubrutinib work?
BTK is a signaling molecule of the B-cell antigen receptor (BCR). Zanubrutinib irreversibly binds to a cysteine residue on the BTK active site, inhibiting B-cell proliferation, trafficking, chemotaxis, and adhesion.
What is this approved for?
Zanubrutinib was granted accelerated approval by the FDA for use in adults with relapsed or refractory mantle cell lymphoma (MCL) who have received at least one previous therapy.
What is the basis for this approval?
Zanubrutinib was studied in two trials conducted in patients with MCL who were relapsed or refractory to at least one prior line of therapy. In the phase II BGB-3111-206 trial, 86 patients received zanubrutinib 160 mg twice daily in 28-day cycles for up to 3 years or until disease progression or unacceptable toxicity. The median age of patients was 60.5 years, and they had received a median of two prior therapies. The majority of patients had Ann Arbor stage III or IV disease, extranodal involvement, and intermediate- or high-risk disease. The primary outcome of overall response rate (ORR) was 84 percent and complete response (CR) was achieved in 68.6 percent. Median duration of response was 19.5 months. In the phase I/II BGB-3111-AU-003 trial, 32 patients received zanubrutinib 160 mg twice daily or 320 mg once daily. ORR and CR was 84 percent and 22 percent, respectively. Duration of response was 18.5 months, similar to the BGB-3111-206 trial (Clin Cancer Res 2020; doi: 10.1158/1078-0432.CCR-19-3703).
How do you administer this drug?
Zanubrutinib is available as an 80 mg capsule and administered orally at a dose of 160 mg twice daily or 320 mg once daily. Capsules should be swallowed whole and can be taken with or without food.
Are there any pre-medications needed?
Zanubrutinib has minimal to low emetic risk. No routine pre-medications are recommended.
What are the common side effects associated with zanubrutinib (> or =20%)?
The most common adverse events were neutropenia (38%), thrombocytopenia (27%), upper respiratory tract infections (38%), rash (36%), bruising (23%), diarrhea (23%), and cough (20%).
What are the uncommon side effects associated with zanubrutinib (less than 20%)?
Hypertension (12%), musculoskeletal pain (19%), headache (4%), and hyperuricemia (6%) were also seen in studies. Rare but serious adverse effects include hemorrhage, second primary malignancies including skin cancers, cardiac arrhythmias, and embryo-fetal toxicity.
Are there any important drug interactions I should be aware of?
Zanubrutinib is primarily metabolized by CYP3A. Coadministration with CYP3A inhibitors increased zanubrutinib exposure significantly. The dose of zanubrutinib should be reduced to 80 mg once daily with strong CYP3A inhibitors and 80 mg twice daily for moderate CYP3A inhibitors. CYP3A inducers can decrease zanubrutinib exposure and should be avoided. Additionally, zanubrutinib was also shown to induce CYP2B6 and to increase concomitant digoxin exposure (P-gp substrate); however, no dose adjustments are recommended in the package insert. Co-administration with other CYP3A and CYP2C19 substrates can result in lower exposure of the other agents and should be monitored.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
No dose adjustments are needed in patients with mild to moderate hepatic dysfunction. However, patients with severe hepatic function should receive 80 mg orally twice daily. No dose adjustments are necessary for those with mild or moderate renal dysfunction.
What should my patients know about zanubrutinib?
* Patients should be advised to discuss any upcoming procedures with their health care providers. Zanubrutinib may need to be interrupted for major surgeries or procedures due to the risk for hemorrhage.
* Patients should communicate starting or stopping other medications to account for drug-drug interactions.
* Patients should use sun protection while taking zanubrutinib to decrease the risk of skin cancers.
* Pregnancy should be avoided due to the risk for embryo-fetal toxicity and both men and women should use effective contraception during treatment and at least 1 week following the last dose of zanubrutinib. Breastfeeding should be avoided during treatment and at least 2 weeks after the last dose.
What else should I know about zanubrutinib?
Secondary malignancies occurred in 9 percent of patients taking zanubrutinib monotherapy, including basal cell carcinoma and squamous cell carcinoma. Additionally, cardiac arrhythmias such as atrial fibrillation and atrial flutter occurred in 2 percent of patients. Close monitoring is recommended in those with cardiac risk factors, hypertension, and infection.
What useful links are available regarding zanubrutinib?
* Info on Zanubrutinib: https://www.brukinsa.com/hcp/
* FDA Approval Announcement: https://bit.ly/2YxyX4O
Any ongoing clinical trials related to Zanubrutinib?
Zanubrutinib is being studied alone and in combination with other therapies for additional B-cell malignancies, including marginal zone lymphoma, chronic lymphocytic leukemia, and Richter's transformation. More information is available about these trials at http://clinicaltrials.gov.
ALEXANDRA LOVELL, PHARMD, is Clinical Pharmacy Specialist, Leukemia at MD Anderson Cancer Center, Houston. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/ Manager, Clinical Pharmacy Services at Washington University School of Medicine, Saint Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.