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.

Conflict of interest statement

Conflict-of-interest disclosure: C.S.T. received research funding from Janssen, AbbVie, BeiGene, Pharmacyclics, and TG Therapeutics and served as a consultant for BeiGene, Janssen, Roche, AbbVie, and LOXO. H.Q. served as a consultant for Celgene, Janssen Cilag, Takeda, Karyopharm, and Amgen and received research funding from Celgene and Amgen. A.N. received research funding from Parexel and travel funding from Amgen, Janssen, and Novartis. X.B. received honoraria from Roche and served as a consultant for AbbVie. H.M.P. received honoraria from Takeda, Janssen, Amgen, Celgene, and Allergan; served as a consultant for Takeda, Janssen, Amgen, and Allergan; and received research funding from Allergan. M.F.L. received honoraria from Vifor Pharma and travel funding from Amgen. N.W. has equity ownership in Icon Consolidated Holdings and received travel funding from Celgene. J.H. is an employee of, has a leadership role in, and has equity ownership in BeiGene USA. A.C. is an employee of, has equity ownership in, and received travel funding from BeiGene USA. R.E. is an employee of BeiGene and has equity ownership in BeiGene USA and Roche. R.P. is an employee of BeiGene USA and has equity ownership in BeiGene USA and Amgen. W.R. is an employee of, has equity ownership in, and received travel funding from BeiGene USA. J.S. is an employee of and has equity ownership in BeiGene USA. I.W.F. served as a consultant for AbbVie, Seattle Genetics, TG Therapeutics, and Verastem and received research funding from Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, Roche, TG Therapeutics, Trilliam Therapeutics, AbbVie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, AstraZeneca, Juno Therapeutics, Unum Therapeutics, and MorphoSys. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Patient disposition. PD, progressive disease; Pt, patient; TN, treatment naïve.

Figure 2.

PFS probability. (A) CLL/SLL. (B) FL.