BeiGene Announces Clinical Data on BRUKINSA™ (Zanubrutinib) at the 61st American Society of Hematology (ASH) Annual Meeting
Oral presentations on data from two clinical trials in chronic lymphocytic leukemia or small lymphocytic lymphoma
Poster presentation on data from clinical trial of BRUKINSA combined with tislelizumab in B-cell malignancies
“The data presented today showing clinical activity and tolerability of BRUKINSA in patients with CLL or SLL are promising for its potential use in patients living with these cancers,” said
“The results presented today on BRUKINSA, a BTK inhibitor designed to maximize target occupancy and minimize off-target binding, demonstrated robust clinical activity and a safety profile consistent with what we’ve observed to date in our clinical trials, including safety data that supported the recent U.S.
Initial Results from SEQUOIA Trial Arm C in Treatment-Naïve (TN) CLL or SLL Patients with Del(17p)
Initial results from Arm C in the open-label, Phase 3 SEQUOIA trial (NCT03336333) of BRUKINSA as a monotherapy demonstrated a high ORR in patients with TN CLL or SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)]. The safety profile was consistent with that observed in previous clinical trials of BRUKINSA in B-cell malignancies. At the data cutoff of
- The ORR was 92.7% (101/109); the partial response (PR) rate was 78.9% (86/109); the PR rate with lymphocytosis was 11.9% (13/109); and the complete response (CR) rate was 1.9% (2/109); only four cases of disease progression occurred;
- 36.7% of patients (40/109) experienced at least one grade ≥3 adverse event (AE) and only one patient discontinued treatment due to AEs;
- The most common grade ≥3 AEs, occurring in more than two patients, were neutropenia (10.1%), pneumonia (3.7%) and hypertension (2.8%);
- 23.9% of patients (26/109) experienced at least one serious AE; and
- One patient experienced a fatal AE, pneumonia leading to sepsis and death, which was considered related to treatment drug by the study investigator.
Updated Results from a Phase 1/2 Trial in Patients with CLL or SLL
Updated results from the open-label, dose-escalation, single-arm, global Phase 1/2 trial (NCT02343120) showed that BRUKINSA was generally well-tolerated and active in patients with relapsed/refractory (R/R) or TN CLL/SLL, irrespective of del(17p) status (n=123; 101 R/R, 22 TN). At the data cutoff of
- The ORR was 95.9% (118/123); the PR rate was 73.2% (90/123); the PR rate with lymphocytosis was 6.5% (8/123); the CR rate was 16.3% (20/123), including one patient who achieved a CR with incomplete bone marrow recovery;
- The median duration of treatment was 25.8 months and 80% of patients (98/123) remained on study treatment; two-year progression-free survival (PFS) was 91% in R/R patients and 95% in TN patients;
- 61.8% of patients (76/123) experienced at least one grade ≥3 AE and only five patients discontinued treatment due to AEs;
- The most common AEs (≥ 20%) were contusion (47.2%), upper respiratory tract infection (42.3%), diarrhea (31.7%), cough (29.3%), headache (23.6%), and fatigue (20.3%);
- 47.2% of patients (58/123) experienced at least one serious AE; and
- One patient experienced a fatal AE, neoplasm-malignant recurrent squamous cell carcinoma, considered unrelated to treatment drug by the study investigator.
BRUKINSA in Combination with PD-1 Inhibitor Tislelizumab in Patients with Previously Treated B-Cell Lymphoid Malignancies
Preliminary findings from the open-label, multicenter, Phase 1b trial (NCT02795182) showed that BRUKINSA in combination with the investigational anti-PD-1 antibody tislelizumab demonstrated a generally manageable toxicity profile in patients with R/R B-cell malignancies. A total of 70 patients enrolled in the trial, including 54 patients with aggressive non-Hodgkin’s lymphomas (NHLs) which consist of diffuse large B-cell lymphoma, transformed follicular lymphoma, Richter’s transformation, and central nervous system (CNS) lymphoma. At the data cutoff of
- Of the 54 patients with aggressive NHLs, the ORR was 37.0% (20/54); the PR rate was 20.4% (11/54); the CR rate was 16.7% (9/54); stable disease (SD) rate was 9.3% (5/54);
- 71.4% of patients (50/70) experienced at least one grade ≥3 AE and 14.3% of patients (10/70) discontinued BRUKINSA and/or tislelizumab treatment due to AEs;
- The most common grade ≥3 AEs were neutropenia (12.9%), anemia (10.0%), thrombocytopenia (7.1%), pneumonia (5.7%), neutrophil count decreased (5.7%), tumor lysis syndrome (4.3%), sepsis (4.3%), immune-mediated enterocolitis (4.3%), hypertension (4.3%), lymphocyte count decreased (2.9%), hemolytic transfusion reaction (2.9%), febrile neutropenia (2.9%), back pain (2.9%), acute kidney injury (2.9%), abscess limb (2.9%), and abdominal pain (2.9%);
- Grade ≥3 immune-related AEs (irAEs) were reported in 15.7% of patients (11/70) with immune-mediated enterocolitis (4.3%), and pneumonitis (2.9%) occurring in more than one patient; and
- Five patients experienced fatal AEs, four of which in the setting of progressive disease were considered unrelated to treatment including multi-organ dysfunction, septic shock and pneumonia, respiratory failure, and aspiration pneumonia, and one of toxic epidermal necrolysis which was considered related to treatment by the study investigator.
About BRUKINSA™ (zanubrutinib)
BRUKINSA (zanubrutinib) is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by
New Drug Applications (NDAs) in
BRUKINSA is not approved for use outside
IMPORTANT SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)
Warnings and Precautions
Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% 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 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was 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 (27%), thrombocytopenia (10%) and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.
Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.
Second Primary Malignancies
Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.
Atrial fibrillation and atrial flutter have occurred in 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 0.6% 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 at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 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 in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).
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.
BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
This indication is 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.
Please see full Prescribing Information at beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at beigene.com/PDF/BRUKINSAUSPPI.pdf
About the Zanubrutinib Clinical Trial Program
Clinical trials of zanubrutinib include:
- Fully-enrolled Phase 3 ASPEN clinical trial in patients with Waldenström macroglobulinemia (WM) comparing zanubrutinib to ibrutinib (NCT03053440), currently the only approved BTK inhibitor for WM;
- Phase 3 SEQUOIA trial comparing zanubrutinib with bendamustine plus rituximab in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (NCT03336333);
- Phase 3 ALPINE trial comparing zanubrutinib to ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL (NCT03734016);
- Phase 2 trial in combination with GAZYVA® (obinutuzumab) in patients with R/R follicular lymphoma (FL) (NCT03332017);
- Phase 3 trial comparing zanubrutinib and rituximab to bendamustine and rituximab in patients with untreated MCL (NCT04002297);
- Phase 2 MAGNOLIA trial in patients with R/R marginal zone lymphoma (MZL) (NCT03846427);
- Phase 2 ROSEWOOD trial (NCT03332017) in
Chinacomparing obinutuzumab and zanubrutinib vs obinutuzumab alone in treating patients with R/R FL;
- Completed Phase 2 trials in patients with R/R MCL (NCT03206970) and R/R CLL/SLL (NCT03206918); and
- Completed enrollment in Phase 2 clinical trial in patients with WM (NCT03332173).
Tislelizumab (BGB-A317) is an investigational humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug candidate produced from BeiGene’s immuno-oncology biologics program and is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.
Select ongoing clinical trials of tislelizumab include a Phase 3 clinical trial in patients with second-line or third-line non-small cell lung cancer (NSCLC); a Phase 3 clinical trial in first-line patients with hepatocellular carcinoma (HCC); a Phase 3 clinical trial in second-line patients with esophageal squamous carcinoma (ESCC); a Phase 3 clinical trial in first-line patients with gastric cancer (GC); a Phase 3 clinical trial in first-line patients with ESCC; and a Phase 2 clinical trial in second- or third-line patients with HCC. The aforementioned trials are enrolling patients in multiple countries, including the United States, Europe, and China.
In addition to a pivotal Phase 2 clinical trial in patients with relapsed or refractory (R/R) classical Hodgkin’s lymphoma (cHL) and a pivotal Phase 2 clinical trial in patients with locally advanced or metastatic urothelial cancer, BeiGene is conducting a Phase 3 clinical trial in first-line patients with non-squamous NSCLC; a Phase 3 clinical trial in first-line patients with squamous NSCLC; a Phase 3 clinical trial in patients with first-line nasopharyngeal cancer (NPC); a Phase 3 clinical trial in first-line patients with urothelial carcinoma (UC); a Phase 3 clinical trial in patients with localized ESCC; and a Phase 2 trial in patients with MSI-H or dMMR solid tumors. These studies have been enrolling patients primarily in China.
New drug applications (NDA) for tislelizumab in patients with R/R cHL and in patients with previously treated locally advanced or metastatic UC have been accepted and granted priority review by the China National Medical Products Administration (NMPA, formerly known as CFDA). BeiGene has full development and commercial rights to tislelizumab worldwide.
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 promising clinical results from trials of BRUKINSA (zanubrutinib) and tislelizumab and BeiGene’s further advancement of, and anticipated clinical development, regulatory milestones and commercialization of BRUKINSA (zanubrutinib) and tislelizumab. Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including
1 ABRAXANE®, REVLIMID® and VIDAZA® are registered trademarks of
Source: BeiGene, LTD.