Brukinsa (zanubrutinib) - 5 indications

Scroll down for more information on each indication:

• for the treatment of mantle cell lymphoma; approved November of 2019
• for Waldenström’s macroglobulinemia; approved September of 2021
• for relapsed or refractory (R/R) marginal zone lymphoma; approved September of 2021
• for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); approved January of 2023
• for relapsed or refractory follicular lymphoma; approved March of 2024

General Information

Brukinsa (zanubrutinib) is a kinase inhibitor. 

Brukinsa is specifically indicated for the following indications:

• for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy 
• for the treatment of adult patients with Waldenström’s macroglobulinemia
• for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen
• for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
• for the treatment of relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy

Brukinsa is supplied as a capsule for oral administration. The recommended dose is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity. Brukinsa can be taken with or without food. Capsules should be swallowed whole with water. Capsules should not be opened, broken or chewed. If a dose of Brukinsa is missed, it should be taken as soon as possible on the same day with a return to the normal schedule the following day.

Mechanism of Action

Brukinsa (zanubrutinib) is a small-molecule inhibitor of BTK. Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

Side Effects

Adverse effects associated with the use of Brukinsa may include, but are not limited to, the following:

• neutrophil count decreased
• platelet count decreased
• upper respiratory tract infection
• white blood cell count decreased
• hemoglobin decreased
• rash
• bruising
• diarrhea
• cough

Indication 1 - for the treatment of mantle cell lymphoma

approved November of 2019

Clinical Trial Results

Brukinsa was approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

A single-arm clinical trial of Brukinsa included 86 patients with mantle cell lymphoma who had received at least one prior treatment. The trial measured how many patients experienced complete or partial shrinkage of their tumors after treatment (overall response rate). In the trial, 84% of patients had tumor shrinkage with a median duration of response (time between the initial response to therapy and subsequent disease progression or relapse) of 19.5 months. This trial was supported by an additional single-arm trial that included 32 patients, in which 84% of patients had tumor shrinkage with a median duration of response of 18.5 months.

Indication 2 - for Waldenström’s macroglobulinemia

approved September of 2021

Clinical Trial Results

The FDA approval was primarily based on efficacy results from the multicenter, open-label Phase 3 ASPEN trial comparing Brukinsa to ibrutinib in patients with WM. A total of 201 patients with a MYD88 mutation (MYD88MUT) were enrolled in the randomized Cohort 1. The primary efficacy endpoint of the ASPEN trial was very good partial response (VGPR) rate in the overall intention-to-treat (ITT) population as assessed by independent review committee (IRC). Based on the modified Sixth International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) response criteria (Treon 2015), the VGPR rate was 28% with Brukinsa, compared to 19% with ibrutinib; based on the IWWM-6 response criteria, the VGPR rate was 16% with Brukinsa, compared to 7% with ibrutinib. The major efficacy outcome is defined as response rate of partial response (PR) or better as assessed by IRC. Based on either IWWM-6 response criteria, the response rate was 78% with Brukinsa, compared to 78% with ibrutinib, and the event-free duration of response (DoR) at 12 months was 94% with Brukinsa, compared to 88% with ibrutinib.

Indication 3 - for relapsed or refractory (R/R) marginal zone lymphoma

approved September of 2021

Clinical Trial Results

Accelerated approval was based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA approval was based on efficacy results from two single-arm clinical trials, with ORR as assessed by independent review committee (IRC) per 2014 Lugano Classification as the primary endpoint.

In the multicenter, pivotal Phase 2 MAGNOLIA trial in patients with R/R MZL who received at least one anti-CD20-based regimen, a total of 66 patients were evaluated, including 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and four with unknown subtype. Based on assessment using CT scan, the ORR was 56% with a complete response (CR) rate of 20%; based on assessment prioritizing PET-CT scan, the ORR was 67% with a CR rate of 26%. The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months. Responses were observed in all MZL subtypes.

In the global Phase 1/2 trial of BGB-3111-AU-003, a total of 20 patients were evaluated, including nine with extranodal subtype, five with nodal subtype, and six with splenic subtype. Based on assessment using CT scan, the ORR was 80% with a CR rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months.

Indication 4 -  chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

approved January of 2023

Clinical Trial Results

FDA approval was based on two global Phase 3 clinical trials: ALPINE and SEQUOIA

ALPINE is a randomized, global trial comparing Brukinsa against ibrutinib in previously treated patients with relapsed or refractory chronic lymphocytic leukemia CLL or SLL. In the trial, a total of 652 patients were randomized into two arms, with the first arm receiving Brukinsa (160 mg orally twice daily) and the second arm receiving ibrutinib (420 mg orally once daily) until disease progression or unacceptable toxicity.

Brukinsa achieved a superior overall response rate versus ibrutinib in the relapsed/refractory (R/R) treatment setting (ORR 80.4% vs 72.9%).

With a median follow-up of 29.6 months, Brukinsa demonstrated superior PFS compared with ibrutinib in patients with R/R CLL. Additionally, Brukinsa demonstrated a favorable cardiac safety profile, with significantly lower rates of atrial fibrillation/flutter (5.2% vs 13.3%) and zero deaths due to cardiac disorders with Brukinsa vs. six with ibrutinib (0% vs 1.9%).

SEQUOIA was a randomized, multicenter, global trial designed to evaluate the efficacy and safety of Brukinsa compared to bendamustine + rituximab (B+R) in patients with treatment-naïve CLL or SLL. The trial consists of three cohorts:

• Cohort 1 (n=479): randomized 1:1 to receive Brukinsa (n=241) or B+R (n=238) until disease progression or unacceptable toxicity, in patients not harboring del(17p); data from this group comprise the primary endpoint;
• Cohort 2 (n=110): patients with del(17p) receiving Brukinsa as a monotherapy; and
• Cohort 3 (enrollment ongoing): patients with del(17p) or pathogenic TP53 variant receiving Brukinsa in combination with venetoclax.

Patients with del(17p) were not randomized to Cohort 1, as they experience poor clinical outcomes and poor response to chemoimmunotherapy.

Results for Cohort 2 (Arm C), representing high-risk patients treated with Brukinsa monotherapy with del(17p) achieved significant efficacy, with an 18-month PFS of 90.6%, as assessed by investigator. 

With a median follow-up of 26.2 months in the SEQUOIA trial, Brukinsa demonstrated a significant PFS benefit versus bendamustine plus rituximab in the first-line treatment setting.

Indication 5 - Relapsed or refractory follicular lymphoma (FL)

approved March of 2024

This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Clinical Trial Results

The FDA approval of Brukinsa for the treatment of relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy was based on the overall response rate (ORR) from the ROSEWOOD trial as assessed by an independent review committee (IRC). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory MAHOGANY trial. 

ROSEWOOD was a global, randomized, open-label Phase 2 study of Brukinsa plus obinutuzumab compared with obinutuzumab alone in 217 patients with R/R FL who received at least two prior lines of systemic therapy. In the study, the ORR by IRC was 69% in the Brukinsa plus obinutuzumab arm versus 46% in the obinutuzumab arm, with a median follow-up of approximately 20 months. Responses were durable, with an 18-month landmark duration of response (DOR) of 69% in the Brukinsa combination arm.