Regulatory Decision Summary for Brukinsa

The purpose of this Supplement to a New Drug Submission (SNDS) was to seek authorization of Brukinsa (zanubrutinib) for the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

The Sponsor consented to information sharing between Health Canada and Health Technology Assessment organizations as part of an aligned review pathway.

The initial proposed indication was for the treatment of adult patients with CLL or SLL. Following review, the indication of Brukinsa was revised for alignment with the other products, and specifies its use for the treatment of adult patients with CLL.

Clinical safety and efficacy of Brukinsa (zanubrutinib) for the proposed indication were supported primarily by two randomized Phase 3 studies in patients with chronic lymphocytic leukemia (CLL), including a small number of patients with a diagnosis of small lymphocytic leukemia (SLL). Study BGB-3111-304 (SEQUOIA) was a multicentre, open-label randomized trial of patients with treatment-naïve (TN) CLL/SLL without the 17p deletion (del[17]) treated with Brukinsa or bendamustine plus rituximab (B+R) (Cohort 1). Additional efficacy was evaluated in SEQUOIA Cohort 2, a multicentre single-arm trial of Brukinsa monotherapy in patients with TN CLL/SLL with centrally confirmed del(17p) mutation. Study BGB-3111-305 (ALPINE) was a multicentre, open-label randomized trial of patients with relapsed or refractory (R/R) CLL/SLL, including patients with del(17p), treated with Brukinsa or ibrutinib.

In SEQUOIA, the primary efficacy endpoint of progression-free survival (PFS) by independent central review (IRC) demonstrated a 58% reduction in the risk of disease progression or death in patients with TN CLL/SLL treated with Brukinsa compared to those treated with B+R (HR = 0.42 [95% confidence interval (CI): 0.28, 0.63]; p<0.0001). IRC-assessed overall response rate (ORR) was also higher in the zanubrutinib arm (94.6% [95% CI: 91.0, 97.1]) compared to the B+R arm (85.3% [95% CI: 80.1, 89.5]). Patients with del(17p), enrolled in the single-arm Cohort 2, had similar efficacy outcomes as those without del(17p) in Cohort 1. After a median follow-time of 30.4 months, IRC-assessed ORR in Cohort 2 was 90.0% (95% CI: 91.0, 97.1).

In ALPINE, the protocol-specified primary endpoints of non-inferiority (1-sided p<0.0001) and superiority (2-sided p = 0.0006) for investigator-assessed ORR of zanubrutinib over ibrutinib in the first 415 patients enrolled, were met. Response as determined by IRC demonstrated non-inferiority of zanubrutinib to ibrutinib, but not superiority.

These 2 pivotal Phase 3 studies allowed a robust assessment of the safety of Brukinsa compared to B+R (for patients with TN CLL/SLL) and to ibrutinib (for patients with R/R CLL/SLL). Patients enrolled in these studies were representative of the general CLL population in terms of age, sex, race, geographic region, disease status, and overall health, and the size and treatment duration of the studies were sufficient to allow for evaluation of the safety profile of Brukinsa in the target patient population.

Overall, the safety profiles of patients treated with Brukinsa in both Cohorts of SEQUOIA and in ALPINE were consistent with the previously established toxicities associated with Brukinsa in other B-cell malignancies. In SEQUOIA, zanubrutinib had notably lower rates of cytopenias (particularly neutropenia) and gastrointestinal adverse events (particularly nausea and vomiting) compared with B+R, as well as lower rates of pyrexia, rash, and infusion-related reactions. In ALPINE, Brukinsa was compared with the first-generation Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib, and demonstrated lower incidences of diarrhea and atrial fibrillation/flutter. In a pre-specified analysis in the first 415 patients enrolled, the rate of atrial fibrillation and atrial flutter was 2.5% in the Brukinsa arm compared to 10.1% in the ibrutinib arm (p = 0.0014), with a rate difference of -7.7% (95% CI: -12.3, -3.1). Additionally, rates of adverse events, serious adverse events, Grade 3 or higher adverse events, and adverse events leading to treatment discontinuation or modification were comparable with the previously reported toxicity profile of Brukinsa as well as with other BTK inhibitors used for the treatment of patients with CLL.

The large pooled Safety Analysis Set (N = 1,550 patients with B-cell malignancies) did not identify any new safety signals for zanubrutinib, and the overall safety profile appeared consistent across CLL populations.

Overall, the safety profile of Brukinsa is considered acceptable in the target population of patients with this severe, life-threatening disease, with adverse events typically manageable through the use of Brukinsa dose modifications and/or standard medical care. Appropriate labelling in the final Brukinsa Product Monograph, including recommendations regarding adverse event monitoring and dose modifications, is required to adequately manage the risk associated with Brukinsa therapy.

The initial proposed indication was for the treatment of adult patients with CLL or SLL. However, due to the rarity of SLL, these patients comprise only a small proportion of the total number of patients in any clinical trials, and, from a regulatory perspective, an indication specific for CLL is a consistent approach with other products approved in Canada. Of particular relevance is the Canadian labelling for the other BTK inhibitors, which do not include SLL in the indication statements. Therefore, the indication of Brukinsa was revised for alignment with the other products, and specifies its use for the treatment of adult patients with CLL. However, to ensure all relevant information is available for patients and prescribers, it was considered informative and appropriate to include the number of patients with SLL enrolled in each of the pivotal trials in the final Brukinsa Product Monograph.

A Risk Management Plan (RMP) was submitted by the Sponsor and was considered acceptable by the Marketed Health Products Directorate. It was concluded that, overall, there were no new safety concerns specific to the CLL patient population that require additional consideration in the RMP.

The benefit-risk profile of Brukinsa, based primarily on the results of SEQUOIA and ALPINE, is favourable and represents a new treatment option for patients with CLL.