On January 19, 2023, the Food and Drug Administration (FDA) approved zanubrutinib for chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL).

Efficacy in patients with treatment-naïve CLL/SLL was evaluated in SEQUOIA (NCT03336333). In the randomised cohort including patients without 17p deletion, a total of 479 patients were randomised 1:1 to receive either zanubrutinib until disease progression or unacceptable toxicity or bendamustine plus rituximab (BR) for 6 cycles.

The main efficacy outcome measure was progression-free survival (PFS) as determined by an independent review committee (IRC). The median PFS was not reached (95% CI: NE, NE) in the zanubrutinib arm and was 33.7 months (95% CI: 28.1, NE) in the BR arm (HR= 0.42, 95% CI: 0.28, 0.63; p=<0.0001).

The estimated median follow-up for PFS was 25.0 months. In a separate non-randomised cohort of SEQUOIA, zanubrutinib was evaluated in 110 patients with previously untreated CLL/SLL with 17p deletion. The overall response rate (ORR) per IRC was 88% (95% CI: 81, 94). The median duration of response (DOR) was not reached after a median follow-up of 25.1 months.

Efficacy in patients with relapsed or refractory CLL/SLL was evaluated in ALPINE (NCT03734016). A total of 652 patients were randomised 1:1 to receive either zanubrutinib or ibrutinib. The median number of prior lines of therapy was 1 (range 1-8). The main efficacy outcome measures at this time of response analysis were ORR and DOR as determined by an IRC. The ORR was 80% (95% CI: 76, 85) in the zanubrutinib arm and 73% (95% CI: 68, 78) in the ibrutinib arm (response rate ratio 1.10, 95% CI: 1.01, 1.20; p=0.0264). The median DOR was not reached in either arm, after a median follow-up of 14.1 months.

Across clinical trials of zanubrutinib, the most common adverse reactions (≥30%) were neutrophil count decreased (42%), upper respiratory tract infection (39%), platelet count decreased (34%), haemorrhage (30%), and musculoskeletal pain (30%). Second primary malignancies, including non-skin carcinomas, developed in 13% of patients. Atrial fibrillation or flutter were reported in 3.7% of patients, and Grade 3 or higher ventricular arrhythmias in 0.2% of patients.

The recommended zanubrutinib dosage is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

View full prescribing information for zanubrutinib.

Source: FDA