BRUKINSA® Approved in the U.S. for Chronic Lymphocytic Leukemia
Jan 19, 2023 5:03 PM
Two global Phase 3 trials in adult CLL patients demonstrated superior efficacy for BRUKINSA (zanubrutinib) in first-line and relapsed/refractory treatment settings
BRUKINSA is the only BTKi to demonstrate superior PFS vs IMBRUVICA® (ibrutinib)
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“With four US approvals in just over three years and demonstrated superiority versus ibrutinib in the final progression-free survival (PFS) analysis of the ALPINE trial, we believe BRUKINSA is well-positioned to become the BTKi of choice across multiple indications,” said
- With a median follow-up of 26.2 months in the SEQUOIA trial, BRUKINSA demonstrated a significant PFS benefit versus bendamustine plus rituximab, (HR 0.42, [95% CI: 0.28, 0.63], P<0.0001), as assessed by an Independent Review Committee (IRC) in the first-line treatment setting.1
- BRUKINSA achieved a superior overall response rate versus ibrutinib in the relapsed/refractory (R/R) treatment setting (ORR 80.4% vs 72.9%, P=0.0264), as assessed by an IRC in the ALPINE trial.2
- The overall safety profile of BRUKINSA in the ALPINE and SEQUOIA trials was consistent with prior studies.
In the pooled safety population of CLL patients who received BRUKINSA across the clinical development program (N=1,550), the most common adverse reactions (≥30%), were decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%).3
The pre-defined final PFS analysis of the ALPINE study demonstrating superior efficacy and a favorable cardiac safety profile for BRUKINSA versus IMBRUVICA in patients with R/R CLL, was presented in a late-breaking session at the 64th Annual
“Thanks to research that has delivered innovative and effective medicines, people with CLL can remain on therapy for years so tolerability is an important consideration. I’m pleased that the approval of zanubrutinib provides a new BTKi option for people with CLL/SLL, with demonstrated efficacy as well as being very well tolerated long-term,” said
ALPINE is a randomized, global Phase 3 trial (NCT03734016) 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 across
The primary endpoint of ORR, defined by pre-specified non-inferiority of BRUKINSA versus ibrutinib, was assessed by investigator and IRC using the modified 2008 iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL, and per Lugano Classification for non-Hodgkin’s lymphoma for patients with SLL. There was pre-specified hierarchical testing of non-inferiority followed by superiority in ORR as assessed by investigator and IRC. Key secondary endpoints include PFS and event rate of atrial fibrillation or flutter; other secondary endpoints include duration of response, overall survival, and incidence of adverse events.
Interim study results from ALPINE were published online in the
SEQUOIA is a randomized, multicenter, global Phase 3 trial (NCT03336333) 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. The primary endpoint of the trial is IRC-assessed PFS. Secondary endpoints include investigator-assessed PFS, IRC- and investigator-assessed ORR, overall survival, PFS and ORR in patients with del(17p), and safety.
Results for Cohort 2 (Arm C), representing high-risk patients treated with BRUKINSA monotherapy, were presented at the 62nd ASH Annual Meeting in
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IMPORTANT SAFETY INFORMATION
Warnings and Precautions
Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage, including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.6% of patients treated with BRUKINSA monotherapy in clinical trials, with fatalities occurring in 0.3% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 30% 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 pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% 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.
Grade 3 or 4 cytopenias, including neutropenia (22%), thrombocytopenia (8%) and anemia (7%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% 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 13% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer reported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanoma (1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.
Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher cases in 1.7% 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 0.2% 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.
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.
In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in ≥30% of patients who received BRUKINSA (N=1550) included decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%).
CYP3A Inhibitors: When BRUKINSA is co-administered 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.
Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.
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
The MCL and MZL indications are approved under accelerated approval based on overall response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding the potential for BRUKINSA to provide clinical benefit to patients with CLL/SLL, the future development, regulatory filing and approval, commercialization, and market access of BRUKINSA in the
IMBRUVICA® is a registered trademark of
1 Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncology. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5
2 Hillmen P, Eichorst B, Brown JR, et al. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial.
3 US Prescribing Information www.beigene.com/PDF/BRUKINSAUSPI.pdf
4 Brown JR, Eichhorst, B, Hillmen, P., et al.. (2022). Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia.
5 Brown JR, Eichhorst B, Hillmen P, et al.; Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study. Blood. 2022;140 (Supplement 2): LBA–6. doi:10.1182/blood-2022-171538
6 Tam CS, Giannopoulos K, Jurczak W, et al. SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib versus Bendamustine + Rituximab (BR) in Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Blood. 2021;138(Supplement 1, p396) doi:10.1182/blood-2021-148457
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