On November 14, 2019, the oral Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib was granted accelerated approval in the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.1,2
Supporting Efficacy Data
The approval was based on findings from the phase II BGB-3111-206 study, in which 86 patients who had received at least one prior therapy received oral zanubrutinib at 160 mg twice daily, and the phase I/II BGB-3111-AU-003 study, in which 32 previously treated patients received oral zanubrutinib at 160 mg twice daily or 320 mg once daily.2 Response was assessed by independent review committee.
Zanubrutinib has warnings/precautions for hemorrhage, infections, second primary malignancies (including skin cancers), cardiac arrhythmia, and embryofetal toxicity.
Among all patients in the two study populations, 75% were Asian and 21% were white, 94% had Eastern Cooperative Oncology Group performance status of 0 to 1, and the median number of prior lines of therapy was two. The BGB-3111-206 trial required a platelet count ≥ 75 x 109/L and an absolute neutrophil count ≥ 1 x 109/L. Among the 86 patients in the 206 trial, the median age was 60.5 years, the median time since diagnosis was 30 months, 71% had extranodal involvement (71%), 52% had refractory disease, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score was low risk in 58%, intermediate risk in 29%, and high risk in 13%. Among the 32 patients from BGB-3111-AU-003, the median age was 70 years; 78% were white; and the MIPI score was low risk in 28%, intermediate risk in 41%, and high risk in 31%.
In BGB-3111-206, fluorodeoxyglucose positron-emission tomography [FDG-PET] scans were required for response assessment. The overall response rate was 84%, with a complete response rate of 59%, and the median duration of response was 19.5 months. In BGB-3111-AU-003 (FDG-PET scans not required), the overall response rate was 84%, with a complete response rate of 22%, and the median duration of response was 18.5 months.
How It Works
Zanubrutinib is a small-molecule inhibitor of BTK, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. In nonclinical studies, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth.
How It Is Used
The recommended dose of zanubrutinib in adult patients with previously treated MCL is 160 mg twice daily or 320 mg once daily, with treatment continuing until disease progression or unacceptable toxicity. The recommended dose for patients with severe hepatic impairment is 80 mg twice daily.
Full prescribing information provides instructions for dose modification including interruption and dose reduction for the first to third occurrences of grade ≥ 3 nonhematologic adverse reactions, grade 3 febrile neutropenia, grade 3 thrombocytopenia with significant bleeding, grade 4 neutropenia (lasting > 10 consecutive days), and grade 4 thrombocytopenia (> 10 consecutive days). Treatment should be discontinued for a fourth occurrence of adverse reactions. Asymptomatic lymphocytosis should not be regarded as an adverse reaction, and treatment should not be discontinued on the basis of its occurrence.
Zanubrutinib should be given at 80 mg once daily for concomitant use with a strong CYP3A inhibitor, with dosing interrupted as recommended for adverse reactions, and at 80 mg twice daily for concomitant use with a moderate inhibitor, with dosing modified as recommended for adverse reactions. The previous dose of zanubrutinib can be resumed after discontinuation of a CYP3A inhibitor. Concomitant use with moderate or strong CYP3A inducers should be avoided.
Safety data reflect the use of single-agent zanubrutinib in clinical trials at 160 mg twice daily in 524 patients and at 320 mg once daily in 105 patients. In these trials, 79% of patients received the agent for at least 6 months and 61% for more than 1 year. Among the 629 patients, the most common adverse events of any grade were decreased neutrophil count (53%), decreased platelet count (39%), upper respiratory tract infection (38%), decreased white blood cell count (30%), decreased hemoglobin (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%).
Both the BGB-3111-206 and BGB-3111-AU-003 trials required a creatinine clearance ≥ 30 mL/min, and both excluded patients requiring strong CYP3A inhibitors or strong CYP3A inducers. The most common adverse events of any grade (≥ 20%) in the combined population of the two trials were upper respiratory tract infection, neutropenia, rash, thrombocytopenia, leukopenia, and diarrhea. The most common adverse events of grade ≥ 3 (≥ 5%) were neutropenia, pneumonia, thrombocytopenia, and leukopenia. Major hemorrhage, defined as ≥ grade 3 hemorrhage or central nervous system hemorrhage of any grade, occurred in 5% of patients. The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils and lymphocytosis.
Serious adverse reactions were reported in 31% of patients, with the most common being pneumonia and hemorrhage. Adverse events led to treatment discontinuation in 7%, with the most common cause being pneumonia. Fatal events within 30 days of the last dose of zanubrutinib occurred in eight patients (7%).
Zanubrutinib has warnings/precautions for hemorrhage, infections, second primary malignancies (including skin cancers), cardiac arrhythmia, and embryofetal toxicity. Patients should be monitored for signs and symptoms of infection, including opportunistic infections. Complete blood cell counts must be monitored during treatment. Patients should be advised to use sun protection. Patients should be monitored for atrial fibrillation and atrial flutter. Patients should not breastfeed while receiving zanubrutinib. ■
1. U.S. Food and Drug Administration: FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanubrutinib-mantle-cell-lymphoma. Accessed November 26, 2019.
2. Brukinsa (zanubrutinib) capsules prescribing information, November 2019, BeiGene, Ltd. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213217s000lbl.pdf. Accessed November 26, 2019.