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Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL. Method(s): SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 x 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either >=65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age (<65 y vs >=65 y), Binet Stage (C vs A/B), IGHV mutational status, and geographic region. The primary endpoint was independent...Copyright © 2021 American Society of Hematology

Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL. Method(s): SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 x 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either >=65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age (<65 y vs >=65 y), Binet Stage (C vs A/B), IGHV mutational status, and geographic region. The primary endpoint was independent...Copyright © 2021 American Society of Hematology

Zanubrutinib (zanu) is a selective nextgeneration Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimal off-target effects. SEQUOIA (NCT03336333) is an open-label, global phase 3 study that randomised treatment naive (TN) patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m2 on day 1 and 2 and rituximab 375 mg/m2 in cycle 1, 500 mg/m2 in cycles 2-6 for 6 x 28-day cycles (BR). Adult patients who met International Workshop on CLL (iwCLL) criteria for treatment were eligible if they were >= 65 years or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridisation was required. Patients were stratified by age (<65 years vs. >=65 years), Binet Stage (C vs. A/B), immunoglobulin heavy chain gene (IGHV) mutational status and geographical region. The primary end-point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end-points included PFS by investigator assessment (INV), overall response rate (ORR; by IRC and INV), overall survival (OS) and safety. Responses for CLL and SLL were assessed per modified iwCLL criteria and Lugano criteria respectively. Adverse events (AEs) were recorded until disease progression. From 31 Oct 2017-22 Jul 2019, 479 patients without del(17p) were randomised to zanu ( n = 241) and BR ( n = 238). Treatment groups were well balanced for demographical and disease characteristics (zanu vs. BR): median age, 70.0 years vs. 70.0 years; unmutated IGHV, 53.4% (125/234) vs. 52.4% (121/231); and del(11q), 17.8% vs. 19.3%. At median followup (26.2 months), PFS was significantly prolonged with zanu versus BR as assessed by IRC (hazard ratio [HR] 0.42, 95% CI 0.28-0.63, 2-sided p < 0.0001), and INV (HR 0.42, 95% CI 0.27-0.66, 2-sided p = 0

Background: Patients with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Several new options targeting B-cell receptor signaling have emerged as potential effective therapies in this high-risk group. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor, designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. It has been shown to be highly potent, selective, and bioavailable with potentially advantageous pharmacokinetic and pharmacodynamic properties. In an early phase study, zanubrutinib demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and has been associated with durable clinical responses in patients with CLL/SLL (Tam, Blood 2019). Here, we present safety and efficacy data in treatment-naive (TN) patients with del(17p) CLL/SLL who are enrolled in the non-randomized Arm C of the SEQUOIA (BGB-3111-304) trial. Method(s): The SEQUOIA trial is an open-label, global, multicenter, phase 3 study that includes a non-randomized cohort (Arm C) of TN patients with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult patients with CLL/SLL who met iwCLL criteria for treatment (Hallek, Blood 2008) were eligible if they were either >= 65 y of age or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response assessment was evaluated by investigator for CLL per modified iwCLL criteria (Hallek, Blood 2008; Cheson, J Clin Oncol 2012) and for SLL per Lugano criteria (Cheson, J Clin Oncol 2014). Result(s): In total, 109 patients with centrally confirmed del(17p) were enrolled into Arm C

Background: Patients (pts) with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor. In the ASPEN study of pts with Waldenstrom macroglobulinemia, zanubrutinib was associated with important safety advantages compared to ibrutinib, especially regarding cardiovascular toxicity (Blood; in press). The initial results from Arm C of the SEQUOIA (BGB-3111-304) trial of zanubrutinib in a large cohort of TN CLL/SLL pts with del(17p) were recently presented with a median follow-up of 10 months (Blood 2019;134:851). Presented here is an updated analysis for safety and efficacy in this cohort. Method(s): The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm C) of TN pts with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446) were eligible if they were aged >=65 y or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response was evaluated by investigator for CLL...Copyright © 2020 American Society of Hematology

Background: Patients with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Several new options targeting B-cell receptor signaling have emerged as potential effective therapies in this high-risk group. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor, designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. It has been shown to be highly potent, selective, and bioavailable with potentially advantageous pharmacokinetic and pharmacodynamic properties. In an early phase study, zanubrutinib demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and has been associated with durable clinical responses in patients with CLL/SLL (Tam, Blood 2019). Here, we present safety and efficacy data in treatment-naive (TN) patients with del(17p) CLL/SLL who are enrolled in the non-randomized Arm C of the SEQUOIA (BGB-3111-304) trial. Method(s): The SEQUOIA trial is an open-label, global, multicenter, phase 3 study that includes a non-randomized cohort (Arm C) of TN patients with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult patients with CLL/SLL who met iwCLL criteria for treatment (Hallek, Blood 2008) were eligible if they were either >= 65 y of age or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response assessment was evaluated by investigator for CLL per modified iwCLL criteria (Hallek, Blood 2008; Cheson, J Clin Oncol 2012) and for SLL per Lugano criteria (Cheson, J Clin Oncol 2014). Result(s): In total, 109 patients with centrally confirmed del(17p) were enrolled into Arm C

Background: Patients (pts) with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor. In the ASPEN study of pts with Waldenstrom macroglobulinemia, zanubrutinib was associated with important safety advantages compared to ibrutinib, especially regarding cardiovascular toxicity (Blood; in press). The initial results from Arm C of the SEQUOIA (BGB-3111-304) trial of zanubrutinib in a large cohort of TN CLL/SLL pts with del(17p) were recently presented with a median follow-up of 10 months (Blood 2019;134:851). Presented here is an updated analysis for safety and efficacy in this cohort. Method(s): The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm C) of TN pts with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446) were eligible if they were aged >=65 y or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response was evaluated by investigator for CLL...Copyright © 2020 American Society of Hematology