Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma

Abstract

Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.

Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia

“…At a median follow-up of 29 months, the ORR was 100% for patients with TN CLL with 6 CRs. 44 The ORR was 92% in patients with relapsed/refractory CLL with 7 CRs. At 24 months, the estimated event-free survival rate was 90.4% (95% CI, 76.5% to 96.3%).…”

“…31,[41][42][43] To determine the safety and efficacy of zanubrutinib in combination with obinutuzumab, patients with B cell malignancies were treated on a phase 1 trial (NCT02569476) in two parts: in Part 1 patients received zanubrutinib (320 mg daily or 160 mg twice daily) and obinutuzumab to determine the maximum tolerated dose. 44 In Part 2, patients were continued on zanubrutinib monotherapy. Twelve patients with CLL were treated on Part 1.…”

Targeting Bruton’s Tyrosine Kinase in CLL

“…Depth of response marginally improves with prolonged therapy (33% reduction of circulating CLL cells with each additional year on ibrutinib) ( 59 ). To improve the efficacy of BTKis, multiple trials have tested the combination of BTKis with the following chemoimmunotherapy regimens: anti-CD20 monoclonal antibodies (mAbs) ( 37 – 39 , 46 , 49 , 53 , 62 ), fludarabine ( 63 ), bendamustine ( 64 ), FCR ( 65 ), fludarabine, cyclophosphamide plus obinutuzumab ( 66 , 67 ), and bendamustine plus rituximab (BR) ( 44 , 68 ). A few exceptional studies used conventional agents for an abbreviated period as part of sequential therapy ( 64 , 66 ), debulking ( 63 ), or MRD clearance ( 67 ).…”

Current Treatment Options in CLL

“…Atrial fibrillation and major bleedings occurred in three and six patients, respectively [ 108 ]. When combined with the CD20-antibody obinutuzumab, adverse events seem to occur more often but do not change in their nature; upper respiratory tract infections (51%) and neutropenia (44%) were still the most common [ 109 ]. Combination therapy of zanubrutinib and obinutuzumab resulted in an ORR of 100% for tn CLL patients and 92% for r/r CLL patients at a median follow-up of 29 months.…”