Regulatory Decision Summary for Brukinsa

The purpose of this Supplement to a New Drug Submission (SNDS) was to seek the authorization of a new indication for Brukinsa (zanubrutinib) in combination with obinutuzumab for the treatment of adult patients with follicular lymphoma who have received at least two prior therapies. The final indication is for Brukinsa in combination with obinutuzumab for the treatment of adult patients with relapsed or refractory grade 1, 2 or 3a follicular lymphoma (FL) who have received at least two prior systemic therapies. This submission was part of Access New Active Substances Work Sharing Initiative (NASWSI) with Switzerland and the United Kingdom. Canada led the Clinical Efficacy and Safety of the one pivotal and three supportive clinical studies, and the Clinical Pharmacology. The United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) and Switzerland’s Siwssmedic (SMC) were the peer reviewers.

The Sponsor conducted a global, phase II, multi-center, active-controlled, open-label randomized (2:1) pivotal study (BGB3111-212) to compare the efficacy and safety of Brukinsa plus obinutuzumab compared to obinutuzumab monotherapy in the treatment of 217 patients with relapsed refractory follicular lymphomas (R/R FL) that have been treated with 2 or more prior systemic therapies. In addition, R/R FL patients were evaluated in a supportive single arm phase I study (BGB3111-GA101). The primary endpoint was the objective response rates (ORR) as determined by blinded independent central review (BICR) in the intent to treat (ITT) population. Secondary endpoints in the ITT population included duration of response (DoR as per BICR) progression free survival (PFS as per BICR), overall survival (OS) and quality of life (QoL).

In the primary efficacy analysis of patients with R/R FL, Brukinsa + obinutuzumab, administered at a dose of 160 mg twice daily, demonstrated a durable, clinically meaningful, and statistically significant superior ORR rate compared to obinutuzumab monotherapy (69% compared to 46%, respectively). A consistent ORR was observed across all analyzed subgroups favouring the combination arm compared to the obinutuzumab arm including age, performance status and risk levels. Notably, the number of complete responses (CR) was 2-fold higher (39%) in the combination arm as compared to obinutuzumab arm (19%). This is a clinically meaningful result as CR is typically associated with longer remissions. PFS, OS and QoL secondary endpoints also supported the combination arm versus the monotherapy arm, although the OS results were considered too immature to be conclusive at this time. Since these endpoints were not included in the statistical testing hierarchy, the results and p values could only be considered as descriptive. Finally, the ORR (72%) from the non-pivotal GA101 study was consistent with one identified in the pivotal study, further supporting the primary endpoint.

The overall safety profile of Brukinsa in combination with obinutuzumab was evaluated in 179 patients from the pivotal study 212 (n = 143) and supportive study GA101 (n = 36) with R/R FL previously treated with systemic therapy. Consistent with the previously established Brukinsa safety profile, the significant toxicities of special interest for Brukinsa continue to be carcinogenicity (skin cancer), cardiovascular (arrhythmias and hypertension), gastrointestinal (diarrhea), hematologic (cytopenias), immune related (infections and viral reactivations), respiratory (interstitial lung disease), vascular disorders (hemorrhage), tumour lysis syndrome and teratogenicity (embryofetal toxicity). These risks and toxicities overlap with those listed in the obinutuzumab product monograph (PM) except for the additional obinutuzumab associated risks of infusion related reactions, progressive multifocal leukoencephalopathy (PML), disseminated intravascular coagulation (DIC), and hypersensitivity. Notably, no new significant safety risks were identified with the combination of obinutuzumab and Brukinsa in the pivotal or supportive studies in the target population. There was a notable increased incidence of ≥ grade 3 thrombocytopenia in the pivotal study, however, despite the longer median duration of treatment, this increase did not lead to an increased risk of severe hemorrhage (grade 3 or 4). Additionally, regardless of the treatment duration, dose reductions and dose discontinuations were infrequent and comparable in both arms. To this end, all of the significant safety risks of the combination of Brukinsa and obinutuzumab are clearly highlighted in the Adverse Reactions table, the Serious Warnings and Precautions Box, and Warnings and Precautions section of the Brukinsa product monograph (PM). Moreover, the significant risks are manageable, as demonstrated in the pivotal trial, by dose modification, dose discontinuation and/or standard medical practice. These mitigation strategies are clearly outlined in the PM.

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 relapse refractory FL patient population that require additional consideration in the RMP.

The clinical pharmacological data support the intended use of Brukinsa in the target population and the key clinical pharmacology findings, relevant risks and uncertainties are properly addressed in the final Product Monograph.

The labelling documents conformed to the necessary regulatory requirements and were consistent with the labelling guidance documents.

In conclusion, the pivotal study demonstrated an acceptable efficacy and safety profile of Brukinsa when used in combination with obinutuzumab in patients with relapsed or refractory grade 1, 2 or 3a follicular lymphoma (FL) who have received at least two prior systemic therapies. As such, the proposed combination of Brukinsa and obinutuzumab was shown to have a positive benefit/harm/uncertainty profile under the proposed conditions of use.

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