Regulatory Decision Summary for Brukinsa

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.

Product type:


Medicinal Ingredient(s):


Control Number:


Brand/Product Name:


Therapeutic Area:

Antineoplastic agents

Type of Submission:

Supplement to a New Drug Submission

Decision Issued:

Authorized; issued a Notice of Compliance in accordance with the Food and Drug Regulations

What was the purpose of this submission?

This Supplement to a New Drug Submission (SNDS) was filed to obtain market authorization for Brukinsa (zanubrutinib) for the treatment of adult patients with Marginal Zone Lymphoma (MZL) who have received 1 or more prior anti-CD20-based therapy.

Why was the decision issued?

The clinical efficacy and safety of zanubrutinib has been appropriately characterized; the claims of efficacy are supported by two single-arm pivotal trials (Study 214 and Study 003, respectively) conducted in subjects with relapsed and/or refractory (R/R) Marginal Zone Lymphoma (MZL; n = 86).

The primary endpoint represented by Individual Review Committee (IRC)-assessed overall response rate (ORR), was met in both studies. In Study 214, after a median study follow-up of 15.70 months, ORR was 68.2% (95% confidence interval [CI]: 55.56%, 79.11%), ruling out the pre-specified null hypothesis of 30% with exact 1-sided p-value <0.0001. In Study 003, after a median study follow-up of 35.24 months, the ORR was 80.0% (95% CI: 56.3% to 94.3%). A reduction in disease burden was observed, evidenced in the change from baseline in IRC-assessed target lesion sum of perpendicular diameters (SPD) (noted in a total of 87% of subjects in Study 214 and 94.4% in Study 003, with a majority of patients registering a greater than 50% reduction in tumor size, in both trials) and the rapid time in response to treatment (median time in therapeutic range [TTR] of 2.79 months in Study 214 and 2.8 months in Study 003). After a median follow-up of 8.31 months in Study 214 and 31.4 months in Study 003, the duration of response (DOR) has not been reached in either study (median 95% CI: NE [NE, NE] in Study 214 and NE [8.4, NE] in Study 003). The median progression-free survival (PFS) has not been reached in either study (median 95% CI: NE [NE, NE] in Study 214 and NE [20.3, NE] in Study 003). As of data cutoff date, the median overall survival (OS) has not been not reached in Study 214 (median 95% CI: NE [NE, NE]).

The safety profile of zanubrutinib is derived from six safety and efficacy studies and a long-term extension study conducted in subjects with B-cell malignancies (n = 847). Generally, zanubrutinib was well tolerated; most of the deaths in patients with R/R MZL and in patients with B-cell malignancies were due to progressive disease and a limited number of patients discontinued study drug due to adverse events. Overall, the safety profile of zanubrutinib in subjects with R/R MZL mirrored the safety summary of zanubrutinib in subjects with B-cell malignancies. The exposure-adjusted incidence rates (EAIR) for the all-grades treatment-emergent-adverse-events (TEAE), serious adverse events (SAE), adverse events of special interest (AESI) and ≥ grade 3 TEAE, reported in the MZL population (214 + 003 MZL group) and in the All Zanubrutinib population can be extended to, and represent safety concerns in the target population. The reported AESI of infections, cytopenias, second primary malignancies, haemorrhage, hypertension, atrial fibrillation and flutter and teratogenicity are documented class effects of previously approved bruton tyrosine kinase (BTK) inhibitors. The significant risks have been appropriately addressed in the labelling documents via detailed wording added to the Warnings And Precautions and Adverse Reactions sections of the Product Monograph and are manageable via dose adjustments and/or interruption, routine monitoring and standard medical practice.

The clinical pharmacology information supports the 160 mg (two times a day) dosing schedule in patients with R/R MZL. The review of the population pharmacokinetics analysis corroborated with the review of the Exposure-Response analyses revealed no new concerns.

Overall, no new safety concerns have been identified in subjects with B-cell malignancies as a result of this review. Routine pharmacovigilance recommendations have been flagged by the Marketed Health Products Directorate (MHPD) upon review of the Risk Management Plan (RMP). An updated Canadian RMP is expected by 15 March 2022 as per the sponsor’s undertaking in the Letter dated December 1, 2021.

The revisions to the labeling documents are consistent with the information provided in this SNDS and conform with the Product Monograph (PM) guidance document, effective November 2021.

Overall, zanubrutinib demonstrated a positive benefit/risk profile in patients with R/R MZL who have received at least one prior anti-CD20-based therapy. The claims of efficacy, coupled with the safety profile of zanubrutinib, have been sufficiently characterized to support the approval of the current SNDS when considered within the context of a life-threatening disease with limited treatment options and suboptimal response to existent therapies. From a clinical efficacy and safety perspective, there are no significant outstanding issues requiring risk management beyond the labeling or warranting consideration in addition to the RMP that would prevent the approval of zanubrutinib for the indication sought.

For further details about Brukinsa, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.

Date of Decision:



Beigene Switzerland GmbH

Drug Identification Number(s) Issued:


Prescription Status:

Available by prescription only

Date Filed: