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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

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November 15, 2019, with PAP

View full prescribing information for Brukinsa

On November 15, 2019, the U. S. Food and Drug Administration approved Zanubrutinib (Brukinsa, BeiGene, Ltd.) approved for for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

On November 15, 2019, the Food and Drug Administration granted accelerated approval to Zanubrutinib (Brukinsa, BeiGene, Ltd.) for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Efficacy was evaluated in BGB-3111-206 (NCT03206970), a phase 2 open-label, multicenter, single-arm trial of 86 patients with MCL who received at least one prior therapy. Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity. Efficacy was also assessed in BGB-3111-AU-003 (NCT 02343120), a phase 1/2, open-label, dose-escalation, global, multicenter, single-arm trial of B‑cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib administered orally at 160 mg twice daily or 320 mg once daily.

The primary efficacy outcome measure in both trials was overall response rate (ORR), as assessed by an independent review committee. In trial BGB-3111-206, FDG-PET scans were required and the ORR was 84% (95% CI: 74, 91), with a complete response rate of 59% (95% CI 48, 70) and a median response duration of 19.5 months (95% CI: 16.6, not estimable). In trial BGB-3111-AU-003, FDG-PET scans were not required and the ORR was 84% (95% CI: 67, 95), with a complete response rate of 22% (95% CI: 9, 40) and a median response duration of 18.5 months (95% CI: 12.6, not estimable).

The most common adverse reactions (≥20%) included decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin, rash, bruising, diarrhea, and cough. The most common serious adverse reactions were pneumonia in 11% and hemorrhage in 5% of patients. 

The recommended zanubrutinib dose is 160 mg orally twice daily or 320 mg orally once daily.

View full prescribing information for Brukinsa.

FDA granted this application priority review and zanubrutinib received orphan product and breakthrough therapy designations for treatment of MCL. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Zanubrutinib for Mantle Cell Lymphoma

Author: Amy Kamien, PharmD BCOP
Senior Clinical Pharmacist, Oncology
Advocate Aurora Health, Aurora Sheboygan Memorial Medical Center
Sheboygan, WI

What is the potential role for zanubrutinib in the treatment of mantle cell lymphoma (MCL)?

  • Zanubrutinib is a second-generation inhibitor of Bruton’s tyrosine kinase (BTK) and was approved recently for treating relapsed or refractory (r/r) MCL.1
    • Ibrutinib (first generation) and acalabrutinib (second generation) have the same mechanism and have received approval similar to that given to zanubrutinib.2
    • National Comprehensive Cancer Network guidelines for non-Hodgkin lymphoma3 were recently updated to include zanubrutinib as a second-line treatment option, along with ibrutinib and acalabrutinib, for r/r MCL patients.
      • Ibrutinib and zanubrutinib offer once-daily dosing, whereas acalabrutinib is given twice a day. Zanubrutinib can also be given in divided doses.
      • All three agents carry a risk of bleeding events, including hemorrhage, though the risk is lower with second-generation agents.2 Patients on concurrent anticoagulation therapy should be screened and monitored, and the risks and benefits of withholding therapy around the time of planned surgery should be considered. All three agents can cause new-onset atrial fibrillation, although the risk is higher with ibrutinib therapy. All patients with cardiac risk factors, hypertension, and acute infection may be at increased risk of developing atrial fibrillation with any of the available agents.
  • Accelerated approval was given to zanubrutinib on the basis of two clinical trials demonstrating an improved overall response rate (ORR) in r/r MCL.1
  • Phase 1/2 open-label dose-escalation global multicenter single-arm trial (BGB-3111-AU-003, NCI 02343120).4
    • The trial was completed in B-cell malignancies; 37 patients with previously treated MCL were included.
    • Dosing varied based on the study design: zanubrutinib 160 mg by mouth twice daily or 320 mg by mouth daily.
    • ORR was seen in 32 of 37 patients (86.5%), which included 11 complete responses (29.7%), 21 partial responses (56.8%), and 2 with stable disease (5.4%). Duration of response (DOR) in r/r MCL was reported as 14.7 months.
  • Phase 2 open-label multicenter single-arm trial (BGB-3111-AU-206, NCI 03206970).5
    • The trial included 86 relapsed or refractory MCL patients who had been treated with at least one prior therapy.
    • Zanubrutinib 160 mg by mouth twice daily was given until the time of unacceptable tolerability or disease progression.
    • Primary endpoint: ORR by independent review committee was not reported.
    • Secondary endpoints:
      • Investigator-assessed ORR was seen in 72 of 86 patients (84.7%), which included 65 complete responses (76.5%), 7 partial responses (8.2%), and 1 with stable disease (1.2%).
      • Median progression-free survival (PFS) was 16.7 months.
      • DOR was 14 months.
      • Time to response was not reported.

What role can the pharmacist play in the management of patients on zanubrutinib?

  • Two different dosing strategies are currently approved for the same indication: 320 mg by mouth daily or 160 mg by mouth twice daily. All doses can be taken with or without food.6
    • No preference for daily versus twice daily dosing was noted in the prescribing information. However, zanubrutinib in ongoing trials for MCL and other B-cell malignancies is being studied as 160 mg by mouth twice daily.7
    • Dose adjustment to 80 mg twice daily should be considered for patients with severe hepatic impairment.
    • Dose adjustments for toxicity will depend on the starting dose.
  • Zanubrutinib is extensively metabolized by cytochrome P450 (CYP) 3A4.6
    • Concurrent CYP inhibitors would warrant dose adjustment based on the strength of inhibition.
      • With strong inhibitors: use zanubrutinib 80 mg daily.
      • With moderate inhibitors: use zanubrutinib 80 mg twice daily.
    • Avoid concurrent use of moderate to strong CYP3A inducers.
  • Safety was reported as a secondary outcome from both trials, with data pooled from the above abstracts.6
    • Adverse events (all grades) occurring in more than 20% of patients included upper respiratory tract infection (39%), neutropenia (38%), rash (36%), thrombocytopenia (27%), leucopenia (25%), and diarrhea (23%).
    • Grade 3 or higher adverse reactions included neutropenia (15%), pneumonia (10%), and hemorrhage (3.4%). Pneumonia and hemorrhage incidence did include fatalities.

Clinical Pearls

  • My BeiGene Patient Support for financial and educational assistance is available at https://www.brukinsa.com/patient-support.8
  • Zanubrutinib is available as 80-mg capsules. They should be swallowed whole and should not be opened, broken, or chewed.
  • Prescribing information for zanubrutinib contains a warning about embryo-fetal toxicity noted in animal studies and advises avoiding pregnancy during the therapy and for 1 week after the last dose for both females and males. This concern could potentially lead to the inclusion of zanubrutinib in the NIOSH List of Antineoplastics and Other Hazardous Drugs in Healthcare Settings, List 2, in future publications.

References

  1. U.S. Food and Drug Administration. FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. November 15, 2019. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanubrutinib-mantle-cell-lymphoma
  2. Owen C, Berinstein NL, Christofides A, Sehn, LH. Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma. Curr Oncol. 2019;26(2):e233-e240.
  3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. B-Cell Lymphomas. Version 1.2020. (January 22, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed January 30, 2020.
  4. Tam CS, Wang M, Simpson D, et al. Updated safety and efficacy data in the phase 1 trial of patients with mantle cell lymphoma (MCL) treated with Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (BGB-3111) [abstract]. Hematol Oncol. 2019;37:245-247.
  5. Song Y, Zhou K, Zou D, et al. Zanubrutinib in patients with relapsed/refractory mantle cell lymphoma [abstract]. Hematol Oncol. 2019;37:45-46.
  6. Brukinsa (zanubrutinib) [package insert]. San Mateo, CA: BeiGene USA, Inc.; 2019. Available at https://www.brukinsa.com/prescribing-information.pdf. Accessed December 23, 2019.
  7. Clinicaltrials.gov. National Institutes of Health: U.S. National Library of Medicine. Zanubrutinib. Available at https://clinicaltrials.gov/ct2/results?cond=&term=zanubrutinib&cntry=&state=&city=&dist=. Accessed January 7, 2020.
  8. BeiGene. MyBeiGene Patient Support. Available at https://www.brukinsa.com/patient-support. Accessed December 30, 2019.
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