Regulatory Decision Summary for Brukinsa

Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin lymphoma (NHL). In this NDS, BeiGene presented an open-label, multi-center, single-arm Phase 2 study (BGB-3111-206) of 86 previously treated patients who were given zanubrutinib at 160 mg twice daily, and an open-label, dose escalation and expansion, global, multi-center, single arm Phase 1/2 study (BGB-3111-AU-003) of 32 previously treated patients who were given zanubrutinib either at 160 mg twice daily or 320 mg once daily to support an indication for Brukinsa to treat in patients with relapsed/refractory (R/R) MCL. 

Overall response rate (ORR) as assessed by an Independent Review Committee (IRC) according to the 2014 Lugano Classification was the primary efficacy endpoint and was met in both studies. For study BGB-3111-206 after a median follow-up of 18.5 months, the independent review committee (IRC) assessed overall response rate (ORR) was 83.7% (95% confidence interval [CI]: 74.2,90.8) with a complete response (CR) rate of 68.6% and a partial response (PR) rate of 15.1%. The median duration of response (DoR) was 19.5 months (95% CI: 16.6, NE). The investigator assessed ORR was consistent with the ICR assessment. For study BGB-3111-AU-003 after a median follow-up of 18.8 months, the IRC assessed ORR was 84.4% (95% CI: 67.2, 94.7) with a CR rate of 25% and a PR rate of 59.4%. The median DoR was 18.5 months (95% CI: 12.6, NE). Overall response rate was similar to Study 206 but CR rate differed which was attributable to the different imaging modalities that were used to assess response in the two studies; PET/CT scans in Study 206 and mostly CT scans in Study AU-003. Those response rate results are considered to be associated with long-term clinical benefit, as shown by the long median DoR, relative to other products in that therapeutic class.

The safety of Brukinsa was evaluated in the 118 patients with MCL who received at least one prior therapy at a dose of 320 mg daily in Study 206 and Study AU-003. The median duration of treatment was 22.8 months in this pooled analysis R/R MCL group. There were no new safety signals identified in the relapsed/refractory (R/R) MCL patients. The significant safety risks in R/R MCL patients are the same as those identified for the previous approved Waldenström’s macroglobulinemia patient population treated with Brukinsa. These are skin cancer, atrial fibrillation, diarrhea, cytopenias and lymphocytosis, new infections and viral reactivations, interstitial lung disease, hemorrhage and teratogenicity. These risks were consistent with the known safety profile of Brukinsa and other Bruton’s Tyrosine Kinase (BTK) inhibitors. All significant safety risks are clearly highlighted in the product monograph (PM) and are considered manageable with dose modification, dose discontinuation and/or standard medical practice.

Key clinical pharmacology and non-clinical findings were reviewed previously in the original NDS for Waldenström’s macroglobulinemia patients. Specific population pharmacokinetic analyses supported the recommended dose of 320 mg QD or 160 mg BID of zanubrutinib for the treatment of MCL patients. The clinical pharmacological and non-clinical data support the intended use of Brukinsa in the target population. Relevant risks and uncertainties are considered properly addressed in the PM.

This submission was considered to comply with the Quality data requirements of Section C.08.002 of the Food and Drug Regulations.

The labelling documents conform to the necessary regulatory requirements and are consistent with the labelling guidance documents.

The Risk Management Plan that involved notably routine pharmacovigilance activities and risk minimization measures in the Canadian Product Monograph was considered acceptable as a result of this review.

In summary, durable responses were seen in R/R MCL patients treated with Brukinsa and the safety issues identified were manageable and generally consistent with the known safety profile Brukinsa and other BTK inhibitors. Considering that the key safety concerns are aptly labelled in the PM, Brukinsa is considered to have a positive benefit-risk profile under the proposed conditions of use for the treatment of adult patients with MCL who have received at least one prior therapy.