Search

BTK inhibitor exposure increases significantly when coadministered with CYP3A inhibitors, which may lead to dose-related toxicities. This study explored the pharmacokinetics, efficacy, and safety of zanubrutinib when coadministered with moderate or strong CYP3A inhibitors in 26 patients with relapsed or refractory B-cell malignancies. Coadministration of zanubrutinib (80 mg BID) with moderate CYP3A inhibitors fluconazole and diltiazem or zanubrutinib (80 mg QD) with strong CYP3A inhibitor voriconazole resulted in comparable exposures to zanubrutinib (320 mg QD) with AUC0-24h geometric least squares mean ratios approaching 1 (0.94, 0.81, and 0.83, for fluconazole, diltiazem, and voriconazole, respectively). The most common treatment-emergent adverse events were contusion (26.9%), back pain (19.2%), constipation and neutropenia (15.4% each), and rash, diarrhea, and fall (11.5% each). This study supports current United States Prescribing Information dose recommendations for the coadministration of reduced-dose zanubrutinib with moderate or strong CYP3A inhibitors and confirms the favorable efficacy and safety profile of zanubrutinib. [ABSTRACT FROM AUTHOR]

The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naive patients with CLL//SLL without del(17p) who were unsuitable for fludarabine//cyclophosphamide/rituximab. Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m²) and rituximab (cycle 1: 375 mg/m²; cycles 2-6: 500 mg/m²); stratification factors were age (<65 y vs. ≥65 y), Binet Stage, IGHV mutation, and geographic region. Primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. From 31 Oct 2017-22 Jul 2019, 479 patients were enrolled (zanubrutinib = 241; BR = 238). Baseline characteristics (zanubrutinib vs. BR): median age, 70.0 y vs. 70.0 y; unmutated IGHV, 53.4% vs. 52.4%; del(11q), 17.8% vs. 19.3%. With median follow-up of 26.2 mo, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided p <0.0001), and INV (HR 0.42; 2-sided p = = 0.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status and unmutated IGHV (HR 0.24; 2-sided p <0.0001), but not mutated IGHV (HR 0.67; 2-sided p = 0.1858). For zanubrutinib vs. BR, 24-mo PFS-IRC = 85.5% vs. 69.5%; ORR-IRC = 94.6% vs. 85.3%; complete response rate = 6.6% vs. 15.1%; ORR-INV = 97.5% vs. 88.7%; and 24-mo OS = 94.3% vs. 94.6%. Select adverse event (AE) rates (zanubrutinib vs. BR): atrial fibrillation (3.3% vs. 2.6%), bleeding (45.0% vs. 11.0%), hypertension (14.2% vs. 10.6%), infection (62.1% vs. 55.9%), and neutropenia (15.8% vs. 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs. BR) = = 20 patients (8.3%) vs. 31 patients (13.7%); AEs leading to death = 11 patients (4.6%) vs. 11 patients (4.8%). No sudden deaths occurred. In summary, zanubrutinib significantly improved PFS-IRC vs. BR and was well tolerated, supporting the potential utility of frontline zanubrutinib in treatment-naive CLL/SLL. [ABSTRACT FROM AUTHOR]

Background: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL.Methods: We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment.Findings: Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7-29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B).Interpretation: Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL.Funding: BeiGene. [ABSTRACT FROM AUTHOR]