On March 7, 2024, the Bruton’s tyrosine kinase inhibitor zanubrutinib (Brukinsa) was granted accelerated approval in combination with the monoclonal antibody obinutuzumab for patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.1
Supporting Efficacy Data
Approval was based on findings in the open-label study BGB-3111-212 (ROSEWOOD trial; ClinicalTrials.gov identifier NCT03332017), in which 217 patients were randomly assigned 2:1 to receive zanubrutinib at 160 mg twice daily until disease progression or unacceptable toxicity plus obinutuzumab (n = 143) or obinutuzu-mab alone (n = 71). Obinutuzumab was given at 1,000 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6, and then every 8 weeks for up to 20 doses The median number of prior lines of therapy was three (range = 2–11). The trial excluded patients requiring a strong CYP3A inhibitor (eg, clarithromycin, erythromycin, diltiazem) or CYP3A inducer (eg, phenytoin, rifampin, carbamazepine).
OF NOTE
Zanubrutinib has warnings/precautions for hemorrhage, infections, cytopenia, second primary malignancies, cardiac arrhythmias, and embryofetal toxicity.
Objective response rates on independent review committee assessment were 69% (95% confidence interval [CI] = 61%–76%) in the zanubrutinib group vs 46% (95% CI = 34%–88%) in the control group (P = .0012). After a median follow-up of 19 months, the median duration of response was not reached (95% CI = 25.3 months to not evaluable) in the zanubrutinib group vs 14 months (95% CI = 9.2–25.1 months) in the control group. The estimated duration of response rate at 18 months was 69% (95% CI = 58%–78%) in the zanubrutinib group.
How It Is Used
The recommended zanubrutinib dosage is 160 mg twice daily or 320 mg once daily until disease progression or unacceptable toxicity. Product labeling provides instructions on dosage modification, including dose reduction, for grade 3 or 4 hematologic and nonhematologic adverse reactions. Product labeling provides instructions on zanubrutinib dose modification in concomitant use with moderate or strong CYP3A inhibitors. Concomitant administration with strong or moderate CYP3A inducers should be avoided. The recommended dosage in patients with severe hepatic impairment is 80 mg twice daily.
Safety Profile
In the ROSEWOOD trial, the most common adverse events of any grade with zanubrutinib plus obinutuzumab were fatigue (27% vs 25% with obinutuzumab), musculoskeletal pain (22% vs 23%), and hemorrhage (20% vs 10%). The most common grade 3 or 4 events with zanubrutinib plus obinutuzumab included pneumonia (13% vs 7%), COVID-19 infection (9% vs 4.2%), and musculoskeletal pain (3.5% vs 1.4%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (17%), platelets (11%), and lymphocytes (11%), and increased glucose (8%).
KEY POINTS
- Zanubrutinib was granted accelerated approval in combination with obinutuzumab for patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.
- The recommended zanubrutinib dosage is 160 mg twice daily or 320 mg once daily until disease progression or unacceptable toxicity.
Serious adverse events occurred in 35% of patients in the zanubrutinib group, most commonly pneumonia (11%) and COVID-19 infection (10%). Adverse events led to discontinuation of zanubrutinib in 17%, most commonly (≥ 2%) pneumonia, COVID-19 infection, and second primary malignancy. Fatal adverse events occurred in 4.2% of patients, most commonly COVID-19 infection (2.1%).
Zanubrutinib has warnings/precautions for hemorrhage, infections, cytopenia, second primary malignancies, cardiac arrhythmia, and embryofetal toxicity. Patients should be advised not to breastfeed while receiving zanubrutinib.
REFERENCE
1. Brukinsa (zanubrutinib) capsules, for oral use, prescribing information, BeiGene, Ltd, March 2024. Available at https://www.brukinsa.com/hcp. Accessed March 21, 2024.
