Treatment with the Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) Demonstrates High Overall Response Rate and Durable Responses in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Updated Results from a Phase 1/2 Trial
Authors: Cull Gavin , Simpson David , Opat Stephen , Burger Jan A. , Trotman Judith , Marlton Paula , Gottlieb David , Munoz Javier , Seymour John F. , Roberts Andrew W. , Wu Ken , Atwal Siminder , Novotny William , Huang Jane , Tam Constantine S. 
Published: February 2020

Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor, designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. In non-clinical studies it has been shown to be highly potent, selective, bioavailable, and irreversible with potentially advantageous pharmacokinetic and pharmacodynamic properties. Zanubrutinib trials have allowed use of anticoagulant and antiplatelet agents, and co-administration with strong or moderate CYP3A inhibitors at a reduced dose; proton pump inhibitors or other gastric acid-reducing agents have not been shown to affect zanubrutinib exposure. Zanubrutinib has been shown to achieve complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes (Tam et al. Blood 2019), and preliminary data at median follow-up of 13.7 months indicated durable clinical responses in patients with CLL/SLL. Here, we present updated zanubrutinib safety and efficacy data in a larger cohort of these patients, with an additional 12 months of follow-up.
Methods: This is a global, open-label, multicenter, phase 1/2 study in patients with various B-cell malignancies with indication-specific expansion cohorts. Patients 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 122 patients with CLL/SLL with no prior BTK therapy. The primary endpoint was safety/tolerability. Secondary endpoints included response rate and progression-free survival (PFS).
Results: As of December 13, 2018, 117 patients with CLL and 5 patients with SLL had received zanubrutinib (Table 1). Twenty-two (18%) had received no prior therapy for CLL/SLL (median follow-up of 27.2 months [range, 11.1-42.8] in treatment-naïve patients). The most common (≥15%) adverse events (AEs) of any grade were contusion (46%; 41% grade 1), upper respiratory tract infection (39%), diarrhea (30%), cough (28%), headache (23%), fatigue (20%), urinary tract infection (UTI; 17%), back pain (17%), rash (17%), nausea (16%), and neutropenia (16%). Grade ≥3 AEs in ≥5% of patients were neutropenia (14%), pneumonia (6%), and anemia (6%). The most common serious AEs were pneumonia (6%) and UTI (2%). Treatment has been discontinued in 21/122 patients (17%): 13 due to PD (11%; 1 patient developed Richter transformation), 4 due to AE, 2 due to withdrawal of consent, and 1 each due to investigator decision and stem cell transplant. One fatal AE occurred (recurrent squamous cell carcinoma while on study drug; unrelated). AEs of interest included major hemorrhage (hemarthrosis and grade 3 purpura; 2%), bleeding (including contusion, hematuria, petechia, purpura; 57%), neutropenia (including decreased neutrophil count and febrile neutropenia; 19%), thrombocytopenia (6%), fatigue (20%), headache (23%), atrial fibrillation (3%; 2 grade 3), hypertension (8%), diarrhea (30%; no grade ≥3), secondary malignancies (20%), and arthralgia/myalgia (19%). Of the 120 efficacy-evaluable patients (enrolled at least 3 months prior to data cutoff), 22 were treatment-naïve (TN) and 98 were relapsed/refractory (R/R; Table 2). Based on iwCLL criteria (2008, with 2012 modification for partial response with lymphocytosis [PR-L]), with a median follow-up of 25.1 months, the overall response rate (ORR; PR-L or better) was 97% (116 of 120), complete response rate (CRR; complete response [CR] or CR with incomplete bone marrow recovery [CRi]) was 14%. The ORR was comparable between TN and R/R patients. Median PFS was not reached; PFS rate at 1 year was 97% and at 2 years was 89%. For patients with del(17p), ORR was 94% and CRR was 6%; PFS rate at 2 years was 75%.
Conclusions: These data suggest that zanubrutinib monotherapy was generally well tolerated and active in the treatment of patients with CLL/SLL irrespective of 17p deletion status. The ORR, CRR, and 2-year PFS rates suggest this next generation BTK inhibitor can achieve deep and durable responses in patients with CLL/SLL.

Disclosures
Cull: Amgen: Other: Travel, accommodation ; AbbVie: Other: Travel, accommodation; Glycomimetics: Other: Travel, accommodation. Simpson:Amgen: Research Funding; BeiGene: Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Research Funding; MSD: Research Funding; Acerta: Research Funding; Pharmacyclics: Research Funding; Sanofi: Research Funding; GSK: Research Funding; Jannsen: Honoraria. Opat:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Burger:Gilead Sciences: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; BeiGene: Research Funding; AstraZeneca: Honoraria; Aptose Biosciences, Inc: Research Funding. Trotman:Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Janssen: Research Funding; BeiGene: Research Funding. Marlton:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Gottlieb:AbbVie: Consultancy; Gilead: Consultancy; Merck: Consultancy; Haemalogix P/L: Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Sydney: Employment; Novartis: Consultancy. Munoz:Incyte: Research Funding; Portola: Research Funding; Celgene: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau. Seymour:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria. Roberts:AbbVie: Other: Unremunerated speaker for AbbVie, Research Funding; Janssen: Research Funding; Australasian Leukaemia and Lymphoma Group: Membership on an entity's Board of Directors or advisory committees; Walter and Eliza Hall Institute: Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.; BeiGene: Research Funding. Wu:BeiGene: Employment, Equity Ownership. Atwal:BeiGene: Employment, Equity Ownership. Novotny:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Tam:BeiGene: Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Honoraria; Roche: Honoraria; Janssen: Honoraria, Research Funding.

OffLabel Disclosure:
Zanubrutinib is an investigational agent and has not yet been approved in the US