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Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton's tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the Part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being <=grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment due to adverse events. Response was assessed by an independent review committee (IRC) for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit-risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This study is registered on www.clinicaltrials.gov (NCT02343120).Copyright © 2022 American Society of Hematology.

The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.

Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton's tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit-risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell malignancy studies. We constructed a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAEs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N = 779). Assessments included type, incidence, severity, and outcome of TEAEs. Median age was 65 years; 20% were ≥75 years old. Most patients had Waldenström macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Median treatment duration was 26 months (range, 0.1-65); 16% of patients were treated for ≥3 years. Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (UTI), and fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (5%), URI, UTI, sepsis, diarrhea, and musculoskeletal pain (2% each). Atrial fibrillation and major hemorrhage occurred in 3% and 4% of patients, respectively. Atrial fibrillation, hypertension, and diarrhea occurred at lower rates than those reported historically for ibrutinib. Grade ≥3 adverse events included neutropenia (23%), thrombocytopenia (8%), and anemia (8%). Serious TEAEs included pneumonia (11%), sepsis (2%), and pyrexia (2%).Treatment discontinuations and dose reductions for adverse events occurred in 10% and 8% of patients, respectively. Thirty-nine patients (4%) had fatal TEAEs, including pneumonia (n = 9), sepsis (n = 4), unspecified cause (n = 4), and multiple organ dysfunction syndrome (n = 5). This analysis demonstrates that zanubrutinib is generally well tolerated with a safety profile consistent with known BTK inhibitor toxicities; these were manageable and mostly reversible.

The phase I/II AU-003 study in patients with treatment-naive (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47.2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95.9% (TN, 100%; R/R, 95%) with 18.7% achieving complete response (CR). Ongoing response at 3 years was reported in 85.7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87.5% (CR 16.7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade >=3 adverse events were neutropenia (15.4%), pneumonia (9.8%), hypertension (8.9%) and anaemia (6.5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade >=3 neutropenia and Grade >=3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.Copyright © 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Zanubrutinib, a highly selective Bruton tyrosine kinase inhibitor, was evaluated in a phase 1/2 study in patients with various B-cell malignancies. In the subgroup of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), zanubrutinib was administered as 160 mg twice daily (n 5 14), 320 mg once daily (n 5 18), or #160 mg total dose (n 5 5). Herein, we report results for patients receiving a total daily dose of 320 mg (N 5 32). Median study follow-up was 18.8 months. Eighteen patients discontinued treatment, 10 because of progressive disease and 8 because of adverse events (AEs); 1 AE (peripheral edema) was considered to be related to zanubrutinib treatment. The most common AEs were diarrhea (43.8%), contusion (37.5%), constipation (31.3%), and upper respiratory tract infection (31.3%). Infection was the most commonly reported AE of interest (18.8% of patients experienced grade $3 infection). At least 1 AE of grade $3 was reported in 59.4% of patients; grade $3 AEs that were reported in .2 patients were anemia (12.5%), pneumonia (9.4%), and myalgia (9.4%). Overall response rate was 84%, with 25% achieving a complete response. Median duration of response was 18.5 months. Median progression-free survival (PFS) was 21.1 months. Zanubrutinib was well tolerated and demonstrated activity in patients with R/R MCL. The trial is registered at www.clinicaltrials.gov as #NCT02343120.Copyright © 2021 American Society of Hematology. All rights reserved.

Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment-naive (TN) and relapsed/refractory (R/R) patients with WM. Method(s): Patients had TN or R/R WM and required treatment as per International Workshop on WM (IWWM) criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the 73 patients evaluable (24 TN, 49 R/R). Result(s): Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (55% aged > 65 years; 21% aged > 75 years). At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AE) in 13% (only one related), disease progression (10.4%), and other (3.9%). Results are presented for TN and R/R combined. The overall response rate was 96% and VGPR/CR rate was 45%. The rates of VGPR/CR increased over time; 22% at 6 mos, 33% at 12 months and 45% at 24 months. Three-year progression-free survival (PFS) was 81%, and overall survival (OS) was 85%. The most commonly reported AEs were upper respiratory tract infection (52%), contusion (33%, all grade 1) and cough (22%). AEs of interest include neutropenia (18.2%), major hemorrhage (4%), atrial fibrillation/flutter (5%), and grade 3 diarrhea (3%). Conclusion(s): Long-term follow up with continued zanubrutinib treatment demonstrated deep and durable responses in the majority of WM patients. The rates of VGPR/CR increased with prolonged therapy. Disease progression was uncommon. The safety profile of long-term zanubrutinib therapy in these patients w

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenstrom macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients withWM who were either treatmentna ive (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per InternationalWorkshop onWaldenstromMacroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n 5 50) or 320 mg once daily (n 5 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0months for patientswith R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with singleagent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.Copyright © 2020 by The American Society of Hematology.

Zanubrutinib, a highly selective Bruton tyrosine kinase inhibitor, was evaluated in a phase 1/2 study in patients with various B-cell malignancies. In the subgroup of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), zanubrutinib was administered as 160 mg twice daily (n = 14), 320 mg once daily (n = 18), or ≤160 mg total dose (n = 5). Herein, we report results for patients receiving a total daily dose of 320 mg (N = 32). Median study follow-up was 18.8 months. Eighteen patients discontinued treatment, 10 because of progressive disease and 8 because of adverse events (AEs); 1 AE (peripheral edema) was considered to be related to zanubrutinib treatment. The most common AEs were diarrhea (43.8%), contusion (37.5%), constipation (31.3%), and upper respiratory tract infection (31.3%). Infection was the most commonly reported AE of interest (18.8% of patients experienced grade ≥3 infection). At least 1 AE of grade ≥3 was reported in 59.4% of patients; grade ≥3 AEs that were reported in >2 patients were anemia (12.5%), pneumonia (9.4%), and myalgia (9.4%). Overall response rate was 84%, with 25% achieving a complete response. Median duration of response was 18.5 months. Median progression-free survival (PFS) was 21.1 months. Zanubrutinib was well tolerated and demonstrated activity in patients with R/R MCL. The trial is registered at www.clinicaltrials.gov as #NCT02343120.

Mantle cell lymphoma is an aggressive B-cell malignancy. Current frontline chemoimmunotherapies produce high response rates but relapse is inevitable. Furthermore, the elderly and those with comorbidities are precluded from standard regimens and stem cell transplant, leaving them with limited options. Targeted therapies, including Bruton tyrosine kinase inhibitors, are an effective treatment strategy in mantle cell lymphoma. Zanubrutinib is a potent next-generation Bruton tyrosine kinase inhibitor that has demonstrated complete and sustained Bruton tyrosine kinase occupancy, minimal off-target effects and favorable pharmacokinetic/pharmacodynamic properties. Described herein is an ongoing Phase III study comparing the efficacy and safety of zanubrutinib plus rituximab followed by zanubrutinib monotherapy versus bendamustine plus rituximab followed by observation in transplant-ineligible patients with previously untreated mantle cell lymphoma.

Background: Marginal zone lymphoma (MZL) is the third most common lymphoma and represents approximately 5% to 15% of all non-Hodgkin lymphomas. Improved understanding of the disease biology, including genetic and molecular characteristics, has changed the therapeutic landscape of MZL, and there is increasing evidence that targeted therapies, including Bruton tyrosine kinase inhibitors, have improved efficacy and have shown tolerable toxicity profiles over chemotherapy- based approaches. Zanubrutinib, a potent and selective Bruton tyrosine kinase inhibitor, has established therapeutic activity in B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom macroglobulinemia. Aim(s): To examine the safety and preliminary efficacy of single-agent zanubrutinib in a phase 1/2 study of patients with relapsed/refractory MZL. Method(s): Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 17) or 320 mg once daily (n = 3) until disease progression or unacceptable toxicity. Efficacy end points included the proportion of patients achieving a complete or partial response in accordance with Lugano classification (J Clin Oncol. 2014;32:3059). Result(s): Between September 2014 and August 2018, 20 patients with relapsed/refractory MZL started treatment with zanubrutinib; 65% of patients were aged > 65, and 15% were aged > 75 years. Patient distribution across MZL subtypes was as follows: extranodal (mucosa-associated lymphoid tissue), 45%; splenic, 30%; and nodal, 25%. The median number of prior therapies was 2, with RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) being the most common type of therapy. At a median follow-up of 22.16 months, 60% of patients remained on treatment. Reasons for treatment discontinuation included disease progression (25%), adverse events (AEs) in 5% of patients (with 1 patient having treatment-related diarrhea), patient's withdrawal of consent (5%), and other (5%). Therapy was well-tole

Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment- naive (TN) and relapsed/refractory (R/R) patients with WM. Aim(s): To examine the safety and preliminary efficacy of single-agent zanubrutinib in patients with TN or R/R WM. Method(s): Patients had TN or R/R WM and required treatment as per IWWM criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the efficacy evaluable patients. Result(s): Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (54% were aged > 65 and 21% > 75 years). A total of 73 out of 77 patients were considered efficacy evaluable. At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AEs) in 13% of patients (only one treatment-related), disease progression (10.4%) and other (3.9%). Five grade 5 AEs occurred: abdominal sepsis, septic arthritis, scedosporium infection, (patient with prior history of scedosporium abscess) bronchiectasis, and gastric adenocarcinoma (none related). Results are presented for TN and R/R patients combined. The overall response rate was 96% and the VGPR/CR rate was 45% (Table). The rates of VGPR/CR increased over time; 22% at 6 months, 33% at 12 months and 45% at 24 months. The VGPR/CR rate was the highest among patients with the MYD88L265P/CXCR4WT genotype (59%). Of the patients with known MYD88WT, 62.5% had a major response. The rate of progression-free and overall survival at 3 years were 81% and 85%, respectively. The most c

Background: Investigational Bruton tyrosine kinase (BTK) inhibitor zanubrutinib has demonstrated greater selectivity vs other TEC and EGFR family kinases in biochemical assays and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients treated at 160 mg twice daily (bid; Tam et al. Blood 2016;128:642). A recent update of clinical data suggested that complete and sustained 24-hour BTK occupancy is associated with durable responses in patients with non-Hodgkin lymphomas (Tam et al. Blood 2017;130:152). Here, we present updated safety and efficacy data from patients with mantle cell lymphoma (MCL). Method(s): Study AU-003 is a global, open-label, multicenter, phase 1b trial investigating zanubrutinib in patients with B-cell malignancies. After dose escalation, the expansion phase enrolled disease specific cohorts at the recommended phase 2 dose of zanubrutinib (320 mg/day once daily or 160 mg bid). Treatment emergent adverse events (TEAEs) were summarized according to NCI CTCAE v4.03 and response was assessed per International Conference on Malignant Lymphoma criteria (Cheson et al. J Clin Oncol 2014;32:3059). Positron-emission tomographic (PET) scan was not required for response assessment. Result(s): As of 28 Feb 2018, 43 patients were enrolled: 38 relapsed/refractory and 5 treatment-naive (Table). Median follow-up was 10.3 months (range, 0.1-39.2). Twenty patients have discontinued treatment (12 due to progressive disease; 8 due to TEAEs). Most common TEAEs of any cause (>=15% of patients) included diarrhea (30.2%), petechiae/purpura/contusion (30.2%), upper respiratory tract infection (27.9%), constipation (18.6%), fatigue (18.6%), and rash (16.3%). Two cases of atrial fibrillation/flutter (4.7%) and 3 cases of major hemorrhage (7.0%; renal hematoma, gastrointestinal hemorrhage, and tumor

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 1 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P 5 .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities.Copyright © 2019 by The American Society of Hematology

Background: Zanubrutinib, an investigational BTK inhibitor, achieves high plasma concentrations and sustained complete BTK occupancy in blood and lymph nodes, with greater selectivity for BTK vs other TEC and EGFR family kinases in biochemical assays, and favorable pharmacokinetic/ pharmacodynamic properties in preclinical studies. Aim(s): To present updated zanubrutinib safety and efficacy data in patients (pts) with WM. Method(s): This is a global, open-label, multicenter, phase 1/2 study in pts with B-cell malignancies with indication-specific expansion cohorts. Pts received doses of zanubrutinib ranging from 40 mg once daily to the final recommended phase 2 dose of 160 mg twice daily or 320 mg once daily until disease progression (PD) or unacceptable toxicity. We report here on the 77 WM pts from the cohorts who had no prior BTK therapy. The primary endpoint is safety/tolerability. Secondary endpoints include response rate and PFS assessed by IRC. Result(s): As of September 16th, 2018, 77 pts with WM received zanubrutinib (Table). The most common (>15%) adverse events (AEs) of any grade were upper respiratory tract infection (46%), contusion (30%), cough (20%), headache (18%), back pain (17%), diarrhea (17%), urinary tract infection (16%), and constipation (16%). Grade >=3 AEs in >=5% of pts were neutropenia (10%) anemia (8%), hypertension (5%), and basal cell carcinoma (5%). The most common serious AEs were cellulitis (5%), pneumonia (4%), pyrexia (3%), febrile neutropenia (3%), and atrial fibrillation (3%). Sixteen pts discontinued treatment, 8 due to AE, 4 due to PD, 1 due to investigator decision, and 3 others (radiation therapy [n = 1], not compliant with taking drug [n = 2]). Five fatal AEs occurred: abdominal sepsis, septic arthritis, scedosporium infection, bronchiectasis, and gastric adenocarcinoma, of which one was considered related to treatment (septic arthritis) Regarding AEs of special interest with BTK inhibitor therapy, 2 pts (3%) had major haemo