IRC Determines BRUKINSA® (Zanubrutinib) Demonstrates Superior Overall Response Rate Versus Ibrutinib in Final Response Analysis of ALPINE Trial in Chronic Lymphocytic Leukemia
Apr 11, 2022 6:00 AM
Final Response Analysis from Global Phase 3 ALPINE Trial Provides Additional Support for Potential Use of BRUKINSA in Relapsed or Refractory CLL/SLL
BRUKINSA Safety Results Consistent with ALPINE Interim Analysis
After achieving superiority in the primary endpoint of investigator-assessed overall response rate at the interim analysis, in this final response analysis, BRUKINSA met the primary endpoint of superiority over ibrutinib in ORR as determined by IRC, with a response rate of 80.4% versus 72.9% (2-sided p=0.0264). ORR is defined as the combined rate of complete responses (CR) and partial responses (PR). A total of 652 patients were enrolled in the ALPINE trial across
BRUKINSA was generally well tolerated with safety results consistent with previous studies. A prespecified safety analysis showed the rate of atrial fibrillation or flutter continued to be lower in the BRUKINSA arm. The rate of atrial fibrillation or flutter at 24.2 months of median follow-up was 4.6% (n=15) in the BRUKINSA arm and 12.0% (n=39) in the ibrutinib arm. Among 324 patients in each arm, 13.0% (n=42) of patients who received BRUKINSA discontinued treatment due to adverse events compared to 17.6% (n=57) of patients who received ibrutinib. The most commonly reported grade 3 or higher adverse events for BRUKINSA versus ibrutinib, respectively, were neutropenia (14.2% vs. 13.9%), hypertension (12.7% vs. 10.2%), pneumonia (4% vs. 7.4%), neutrophil count decreased (4.3% vs. 4.0%), COVID-19 pneumonia (4.3% vs. 3.1%).
“We are pleased to announce updated topline data from the Phase 3 ALPINE trial for BRUKINSA, which demonstrated a superior overall response rate versus ibrutinib in CLL patients who have seen their disease return or spread after prior therapy,” said Dr.
Interim results from the ALPINE trial representing a 12-month study follow-up were presented at the 26th
About Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia is the most common form of leukemia in adults. CLL accounts for about one quarter of new cases of leukemia, and in 2021 there were more than 21,000 new cases diagnosed in the
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 were randomized into two arms, with the first receiving BRUKINSA (160 mg orally twice daily) and the second receiving ibrutinib (420 mg orally once daily) until disease progression or unacceptable toxicity. The primary analysis 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 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. The study is ongoing with a planned formal analysis of PFS when the target number of events is reached.
BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by
BRUKINSA has previously been approved for three indications in
BRUKINSA is supported by a broad clinical program which includes more than 3,900 subjects in 35 trials across 28 markets. To date, BRUKINSA has received more than 20 approvals covering more than 40 countries and regions, including
* This indication 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.
Warnings and Precautions
Fatal and serious hemorrhagic events have 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 3.4% of patients treated with BRUKINSA monotherapy. Hemorrhage events of any grade occurred in 35% of patients treated with BRUKINSA monotherapy.
Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration 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) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 27% of patients, most commonly pneumonia. 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.
Grade 3 or 4 cytopenias, including neutropenia (26%), thrombocytopenia (11%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia occurred in 3.6% 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 monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 8% of patients. Other second primary malignancies included malignant solid tumors (4.0%), melanoma (1.7%) and hematologic malignancies (1.2%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.
Atrial fibrillation and atrial flutter were reported in 3.2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 1.1% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.
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.
The most common adverse reactions, including laboratory abnormalities, in ≥ 30% of patients who received BRUKINSA (N = 847) included decreased neutrophil count (54%), upper respiratory tract infection (47%), decreased platelet count (41%), hemorrhage (35%), decreased lymphocyte count (31%), rash (31%) 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 moderate or strong CYP3A inducers.
Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.
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 future development, regulatory filings and potential commercialization of BRUKINSA in
iii Global Burden of Disease Cancer Collaboration. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017. JAMA Oncol. 2019;5(12):1749-1768.
v Haselager MV et al. Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing? Front Oncol. 2020; 10: 592205.