SEQUOIA AND ALPINE: 2 GLOBAL PHASE 3 TRIALS IN CLL

1L: SEQUOIA

DESIGNED TO EVALUATE SUPERIORITY OF BRUKINSA vs BR IN FIRST-LINE CLL1,2

A global Phase 3, randomized, open-label, multicenter trial conducted in patients with previously untreated CLL/SLL.
Trial was initiated in 2017.*

Study design from the SEQUOIA study of BRUKINSA® (zanubrutinib) for CLL

Cohort 2 rationale: Because patients with CLL/SLL whose tumors exhibit del(17p) have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy, those with del(17p) mutations were assigned to receive BRUKINSA in this separate single-arm exploratory analysis.

*The primary endpoint was PFS per IRC in the ITT population in the BRUKINSA arm and the BR arm, with minimum 2-sided alpha of 0.05 for superiority.2

†Patients received bendamustine 90 mg/m2/day on the first 2 days of each cycle for 6 cycles, rituximab 375 mg/m2 for Cycle 1, and rituximab 500 mg/m2 for Cycles 2-6.1

1L=first line; BID=twice daily; BR=bendamustine+rituximab; CLL=chronic lymphocytic leukemia; IRC=independent review committee; ITT=intent to treat; iWCLL=International Workshop on Chronic Lymphocytic Leukemia; ORR=overall response rate; PD=progressive disease; PFS=progression-free survival; SLL=small lymphocytic lymphoma.

SEE SEQUOIA EFFICACY DATA

BASELINE PATIENT CHARACTERISTICS IN A RANGE OF PATIENTS, INCLUDING THOSE WITHOUT DEL(17p) AND WITH DEL(17p) MUTATIONS

Patient characteristics1-3

Baseline Patient Characteristics Cohort 1
Patients Without Del(17p)		 Cohort 2
Patients With Del(17p)
BRUKINSA
(n=241)		 BR
(n=238)		 BRUKINSA (n=111)
Median age, years 70
(IQR: 66-75)		 70
(IQR: 66-74)		 70
(IQR: 66-74)
Age ≥65 years 81% 81% 86%
Male 64% 61% 71%
Caucasian 92% 87% 95%
ECOG PS 2 6% 8% 13%
Binet stage C 29% 29% 35%
Target lesion ≥5 cm 29% 31% 40%
Unmutated IgHV, n/N (%) 125/234 (53%) 121/231 (52%) 67/103 (60%)
Del(17p) 1% 0% 99%
Del(11q) 18% 19% 33%
TP53 mutation 6% 6% 43%
Complex karyotype status
<3 abnormalities 35% 33% 49%
≥3 abnormalities 8% 5% 29%
<5 abnormalities 40% 36% 57%
≥5 abnormalities 3% 1% 21%
Samples not yet evaluated 58% 63% 23%

Comorbidities3

Baseline Patient Characteristics Cohort 1
Patients Without Del(17p)		 Cohort 2
Patients With Del(17p)
BRUKINSA
(n=241)		 BR
(n=238)		 BRUKINSA
(n=111)
History of cardiac disorders* 27% 29% 29%
History of afib/flutter 5% 11% 7%
Hypertension 56% 55% 51%

*Cardiac disorders is a grouped term of 33 conditions that includes atrial fibrillation, myocardial ischemia, coronary artery disease, myocardial infarction, cardiac arrest, cardiac failure, acute coronary syndrome, angina pectoris, tachycardia, and bradycardia.2,3

Afib=atrial fibrillation; BR=bendamustine+rituximab; ECOG PS=Eastern Cooperative Oncology Group performance status; IQR=interquartile range.

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2L: ALPINE

DESIGNED TO EVALUATE SUPERIORITY OF BRUKINSA vs IBRUTINIB IN SECOND-LINE CLL1,4

A global Phase 3, randomized, open-label, multicenter trial conducted in patients with relapsed/refractory CLL/SLL who received ≥1 prior systemic therapy.*

Study design from the ALPINE study of BRUKINSA® (zanubrutinib) for CLL

*Statistical analysis for PFS and ORR was initially conducted for noninferiority. When noninferiority was met, superiority was tested. Assessments were made by the investigators, with similar results by IRC.

2L=second line; afib=atrial fibrillation; BID=twice daily; CLL=chronic lymphocytic leukemia; IRC=independent review committee; iWCLL=International Workshop on Chronic Lymphocytic Leukemia; ORR=overall response rate; PD=progressive disease; PFS=progression-free survival; QD=once daily; SLL=small lymphocytic lymphoma.

SEE ALPINE EFFICACY DATA

BRUKINSA WAS STUDIED IN A RANGE OF PATIENTS, INCLUDING THOSE WITH AND WITHOUT MUTATIONS ASSOCIATED WITH POOR PROGNOSIS

Patient characteristics3,4

Baseline Patient Characteristics* BRUKINSA
(n=327)		 Ibrutinib
(n=325)
Median age, years 67
(range:
35–90)		 68
(range:
35–89)
Age ≥65 years 61% 62%
Male 65% 71%
Caucasian 80% 82%
ECOG PS 2 2% 4%
Binet stage C 44% 42%
Median prior lines of therapy 1
(range: 1–6)		 1
(range: 1–12)
Prior treatments
Anti-CD20 antibody 84% 83%
Alkylators (other than bendamustine) 84% 80%
Purine analogue 54% 52%
Bendamustine 26% 29%
PI3K/SYK inhibitor 3% 6%
BCL2 inhibitor 2% 3%
iMiD 2% 0.3%
Alemtuzumab 0.6% 0.3%
Chemoimmunotherapy 80% 76%
Del(17p) deleted/abnormal 14% 15%
Unmutated IgHV 73% 74%
Del(11q) deleted/abnormal 28% 27%
TP53 mutation 9% 8%
Complex karyotype status†
Yes 17% 22%
No 47% 40%
Missing 36% 39%

Comorbidities3

Baseline Patient Characteristics* BRUKINSA
(n=327)		 Ibrutinib
(n=325)
History of cardiac disorders‡ 28% 29%
History of afib/flutter 6% 6%
Hypertension 49% 48%

*Values based on patients enrolled in the ITT population.3

†Complex karyotype is defined as having 3 or more abnormalities.3

‡Cardiac disorders is a grouped term that includes atrial fibrillation, myocardial ischemia, coronary artery disease, myocardial infarction, arrhythmia, atrial flutter, cardiac failure, tachycardia, bradycardia, and cardiac aneurysm.3

Afib=atrial fibrillation; ECOG PS=Eastern Cooperative Oncology Group performance status; iMiD=immunomodulatory drug; ITT=intent to treat.

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EFFICACY ACROSS
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EFFICACY
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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. BRUKINSA. Package insert. BeiGene USA, Inc.; 2025. 2. 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 Oncol. 2022;23(8):1031-1043. 3. Data on file. BeiGene USA, Inc. 4. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332.