FDA Approves Zanubrutinib for CLL/SLL

The FDA has approved zanubrutinib (Brukinsa) for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹

The recommended dose for the oral BTK inhibitor is 160 mg twice daily or 320 mg once daily; the prescribing label comes with warnings for hemorrhage, infections, cytopenias, second primary malignancies, and cardiac arrythmias.²

The regulatory decision is supported by efficacy data from the phase 3 SEQUOIA (NCT03336333), and ALPINE (NCT03734016) trials. Across clinical trials, the most common adverse events (AEs) were decreased neutrophil counts (42%), upper respiratory tract infections (39%), decreased platelet counts (34%) hemorrhage (30%), and musculoskeletal pain (30%). Second primary malignancies were observed in 13% of patients. Atrial fibrillation or flutter were reported in 3.7% and 0.2% of patients experienced grade 3 or higher ventricular arrhythmias.

Zanubrutinib should be swallowed whole with water. It can be taken with or without food. Coadministration with strong or moderate CYP3A inducers should be avoided and the dosage for zanubrutinib should be modified if it is being taken with a CYP3A inhibitor.

SEQUOIA

In SEQUOIA, 479 treatment-naïve patients with CLL/SLL who did not have a 17p deletion were randomly assigned 1:1 to receive either zanubrutinib (n = 241) or bendamustine (Treanda) plus rituximab (Rituxan; BR) for 6 cycles (n = 238). The median progression-free survival (PFS) was not estimable (NE) with zanubrutinib (95% CI, NE-NE) vs 33.7 months with BR (95% CI, 28.1-NE). The estimated median follow-up time was 25.0 months, and the HR was 0.42 (95% CI, 0.28-0.63; P < .001). The overall response rate (ORR) for patients receiving zanubrutinib was 93% (95% CI, 89%-96%) vs 85% (95% CI, 80%-90%) for those receiving BR. The complete response (CR) rates were 7% vs 15%, respectively.²

Moreover, in a separate nonrandomized cohort in which zanubrutinib was assessed in patients with a 17p deletion (n = 110), the ORR was 88% (95% CI, 81%-94%) and the median duration of response was not reached after a median 25.1 months of follow-up. The CR rate was 6%.

ALPINE

Data from the ALPINE trial also supported this approval, in which zanubrutinib demonstrated superior efficacy and safety when compared with ibrutinib (Imbruvica) in a population of patients with relapsed or refractory CLL/SLL. The ORR in the zanubrutinib arm (n = 327) was 80% (95% CI, 76%-85%) with 13 patients having a CR. In the ibrutinib arm (n = 325) the ORR was 73% (95% CI, 68%-78%) with 8 patients experiencing a CR. The response rate ratio was 1.10 (95% CI, 1.01-1.20; P = .0264). Median duration of response was not estimable in either arm and the median follow-up time was 14.1 months.^1,2

Safety

For patients without a 17p deletion in SEQUOIA, 36% of patients had a serious AE, the most common of which (≥ 5%) were COVID-19, pneumonia, and secondary primary malignancy. Permanent discontinuation and doe reduction were observed in 8% of patients, respectively, and dose interruptions were observed in 46%. The most common any-grade AEs with zanubrutinib were musculoskeletal pain (33%), upper respiratory tract infection (28%), and hemorrhage (27%).²

In the cohort of patients with a 17p deletion the rate of serious AEs was 41% with pneumonia (8%) and second primary malignancy (7%) having the highest incidence. Permanent discontinuation and doe reduction were observed in 5% of patients, respectively, and dose interruptions were observed in 51%. Musculoskeletal pain (38%), upper respiratory tract infection 328%), and rash (28%) were the most common any-grade AEs.²

In ALPINE, serious AEs occurred in 42.0% of patients receiving zanubrutinib compared with 50.0% of patients receiving ibrutinib. Treatment discontinuation due to AEs was 15.4% and 22.2%, respectively, and events leading to death was 10.2% compared with 11.1%. The most common AEs were neutropenia (16.0% vs 13.9%), hypertension (14.8% vs 11.1%), pneumonia (5.9% vs 8.0%), and COVID-19–related pneumonia (7.1% vs 4.0%), respectively.

Patients taking zanubrutinib should be taught to report and signs or symptoms of sever bleeding or infection. They should be informed that they will need periodic blood tests to monitor for cytopenia. They should be made aware that other malignancies have been reported with zanubrutinib, and advised to wear sun protection and monitor for other malignancies. They should also report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort.²

Zanubrutinib can cause embryo-toxicity. Patients should use effective contraception during treatment and for 1 week after the last treatment dose.²

References

1. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed January 19, 2023. https://bit.ly/3D1iUjq
2. Brukinsa. Prescribing information. BeiGene USA, Inc; 2023. Accessed January 19, 2023. https://bit.ly/3QOPmv7