On December 22, 2023 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, reported the U.S. Food and Drug Administration (FDA) has approved a label update for BRUKINSA (zanubrutinib) to include superior progression-free survival (PFS) results from the Phase 3 ALPINE trial comparing BRUKINSA against IMBRUVICA (ibrutinib) in previously treated patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) (Press release, BeiGene, DEC 22, 2023, View Source [SID1234638776]).

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"The ALPINE trial is the first and only study to demonstrate PFS superiority in a head-to-head comparison versus ibrutinib in CLL," said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene. "BRUKINSA was approved in the U.S. for CLL at the beginning of 2023, and we submitted additional data from the ALPINE PFS analysis supporting it as the BTK inhibitor of choice in CLL, solidifying it as an important treatment option for patients. When making treatment decisions, it is critical that physicians and patients understand the totality of data supporting BRUKINSA’s robust efficacy and differentiated safety in CLL."

The updated label is based on a prespecified analysis of the ALPINE trial, which demonstrated superior efficacy and a favorable cardiac safety profile for BRUKINSA versus ibrutinib in patients with R/R CLL and was presented in a late-breaking session at the 64th Annual American Society for Hematology (ASH) (Free ASH Whitepaper) Meeting and Exposition and published simultaneously in The New England Journal of Medicine. The updated label includes data at a median follow-up of 31 months, in which BRUKINSA demonstrated superior PFS compared with ibrutinib in patients with R/R CLL (HR: 0.65 [95% CI, 0.49-0.86] P=.0024, for both investigator and independent review committee). 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 versus six with ibrutinib (0% vs. 1.9%).

Please see Important Safety Information below.

At the recent 65th Annual ASH (Free ASH Whitepaper) Meeting and Exposition, BeiGene presented extended follow-up data from the ALPINE trial at a median follow-up of 39 months. The data demonstrate that BRUKINSA continues to show sustained PFS benefit versus ibrutinib (HR: 0.68 [95% CI, 0.53-0.86] P=0.0011) among R/R CLL patients receiving more than three years of treatment, with durable PFS benefits observed across subgroups, including patients with 17p deletion or TP53 mutation (HR: 0.52 [95% CI, 0.33-0.83] P=0.0047). PFS benefit is consistent across multiple sensitivity analyses, demonstrating that PFS advantage with BRUKINSA was primarily driven by efficacy and not tolerability. The overall safety and tolerability profile was consistent with previous ALPINE analyses, including persistently lower rates of cardiovascular events reported with BRUKINSA. The most commonly reported treatment emergent adverse events (≥20%) with BRUKINSA were COVID-19-related, neutropenia, hypertension, and upper respiratory tract infection.

BRUKINSA is approved in more than 65 countries, including the U.S., China, EU, Great Britain, Canada, Australia, South Korea, and Switzerland, in selected indications and under development for additional indications globally. In the U.S., BRUKINSA is approved for the treatment of adult patients with CLL or small lymphocytic lymphoma, Waldenström’s macroglobulinemia, mantle cell lymphoma who have received at least one prior therapy, and relapsed or refractory marginal zone lymphoma who have received at least one anti-CD20-based regimen. The global BRUKINSA development program includes more than 5,000 subjects enrolled to date in 29 countries and regions.

About Chronic Lymphocytic Leukemia (CLL)
A life-threatening cancer of adults, CLL is a type of mature B-cell malignancy in which abnormal leukemic B lymphocytes (a type of white blood cells) arise from the bone marrow and flood peripheral blood, bone marrow, and lymphoid tissues.i,ii CLL is the most common type of leukemia in adults, accounting for about one-quarter of new cases of leukemia.ii,iii Approximately 18,740 new cases of CLL will be diagnosed in the United States in 2023.iii

About BRUKINSA (zanubrutinib)
BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared with other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.

U.S. Indications and Important Safety Information for BRUKINSA (zanubrutinib)

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
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.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Hemorrhage
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.

Infections
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 jiroveci 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 (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.

Cardiac Arrhythmias
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.

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
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%).

Drug Interactions
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.

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

Please see full U.S. Prescribing Information and U.S. Patient Information.