BRUKINSA TOLERABILITY vs OTHER BTKis1-3

Study 215 is an ongoing Phase 2 exploratory study in patients (N=92) with B-cell malignancies who were intolerant to acalabrutinib or ibrutinib*

Primary endpoint: Recurrence and change in severity of acalabrutinib- and/or ibrutinib-intolerant events (investigator assessed)

  • AEs were collected retrospectively and evaluated and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. In patients with CLL, treatment-emergent cytopenias were graded per iWCLL criteria†

Select secondary endpoints: DCR, ORR, PFS, and PROs

There are no head-to-head trials between BRUKINSA and acalabrutinib.

All data are exploratory and descriptive in nature.

*This analysis included patients with CLL/SLL, MCL, MZL, or WM (N=92). Of the 35 patients who were intolerant to acalabrutinib, 21 were intolerant to acalabrutinib only, and 14 were intolerant to both ibrutinib and acalabrutinib.

†AEs were considered to have recurred if the same Medical Dictionary for Regulatory Activities preferred term, independent of grade, occurred while on BRUKINSA.

~70% OF INTOLERANCE EVENTS THAT OCCURRED WITH ACALABRUTINIB OR IBRUTINIB DID NOT OCCUR WITH BRUKINSA1,2

Incidence and severity of AEs with BRUKINSA (primary endpoint)1
BRUKINSA tolerability in acalabrutinib-intolerant patients (n=35)1
pi-chart

*Rounded rates do not total 100%.

The most common AEs (≥15%) in acalabrutinib-intolerant patients were diarrhea (34%) and fatigue (29%).1

BRUKINSA tolerability in ibrutinib-intolerant patients (n=57)2
pi-chart

The most common AEs (≥20%) in ibrutinib-intolerant patients were fatigue (32%), contusion (25%), COVID-19 (25%), and arthralgia (21%).2

There are no head-to-head trials between BRUKINSA and acalabrutinib.

No AEs that occurred with acalabrutinib or ibrutinib occurred at a higher grade with BRUKINSA1,2

  • <10% of patients treated with BRUKINSA discontinued treatment due to AEs2

Response rates maintained or improved with BRUKINSA1

94%
of patients treated with BRUKINSA maintained or improved their response after acalabrutinib or ibrutinib intolerance (secondary endpoint)1

All data are exploratory and descriptive in nature.

Assessed by investigator. Median follow-up for ibrutinib-intolerant patients was 25.2 months with a data cutoff of January 3, 2023. Median follow-up for acalabrutinib-intolerant patients was 18.9 months with a data cutoff of May 1, 2024.1,2

AEs=adverse events; BID=twice daily; BTKis=Bruton’s tyrosine kinase inhibitors; CLL=chronic lymphocytic leukemia; COVID-19=coronavirus disease 2019; DCR=disease control rate; iWCLL=International Workshop on Chronic Lymphocytic Leukemia; MCL=mantle cell lymphoma; MZL=marginal zone lymphoma; NCI=National Cancer Institute; ORR=overall response rate; PFS=progression-free survival; PROs=patient-reported outcomes; QD=once daily; SLL=small lymphocytic lymphoma; WM=Waldenström’s macroglobulinemia.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage

Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.8% of patients treated with BRUKINSA in clinical trials, with fatalities occurring in 0.2% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 32% of patients.

Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days before and after surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher infections occurred in 26% of patients, most commonly pneumonia (7.9%), with fatal infections occurring in 3.2% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (21%), thrombocytopenia (8%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA. Grade 4 neutropenia occurred in 10% of patients, and Grade 4 thrombocytopenia occurred in 2.5% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA. The most frequent second primary malignancy was non-melanoma skin cancers (8%), followed by other solid tumors in 7% of the patients (including melanoma in 1% of patients) and hematologic malignancies (0.7%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 4.4% of patients treated with BRUKINSA, including Grade 3 or higher cases in 1.9% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.3% of patients.

Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment.

Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including BRUKINSA.

Evaluate bilirubin and transaminases at baseline and throughout treatment with BRUKINSA. For patients who develop abnormal liver tests after BRUKINSA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold BRUKINSA. Upon confirmation of DILI, discontinue BRUKINSA.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥30%), including laboratory abnormalities, in patients who received BRUKINSA (N=1729) are decreased neutrophil count (51%), decreased platelet count (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%).

DRUG INTERACTIONS

CYP3A Inhibitors: When BRUKINSA is coadministered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

INDICATIONS

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with:

  • Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
  • Waldenström’s macroglobulinemia (WM)
  • Mantle cell lymphoma (MCL) who have received at least one prior therapy
  • Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen
  • Relapsed or refractory follicular lymphoma (FL), in combination with obinutuzumab, after two or more lines of systemic therapy

The MCL, MZL and FL indications are approved under accelerated approval based on overall response rate and durability of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please see full Prescribing Information.

References: 1. Shadman M, Flinn IW, Levy MY, et al. Zanubrutinib is well tolerated and effective in acalabrutinib-intolerant patients with B-cell malignancies. Presented at: 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024. Poster 4632. 2. Shadman M, Levy MY, Burke JM, et al. Updated safety and efficacy results of zanubrutinib in patients with B-cell malignancies who are intolerant of ibrutinib and/or acalabrutinib. Poster presented at: European Hematology Association (EHA) 2023 Hybrid Congress; June 8-15, 2023. Abstract P633. 3. Shadman M, Flinn IW, Levy MY, et al. Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study. Lancet Haematol. 2023;10(1):e35-e45.