Safety and Activity of the Investigational Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Mantle Cell Lymphoma from a Phase 2 Trial
Authors: Song Yuqin , Zhou Keshu , Zou Dehui , Zhou Jianfeng , Hu Jianda , Yang Haiyan , Zhang Huilai , Ji Jie , Xu Wei , Jin Jie , Lv Fangfang , Feng Ru , Gao Sujun , Zhou Daobin , Guo Haiyi , Wang Aihua , Hilger James , Huang Jane , Novotny William , Osman Muhtar , Zhu Jun 
Published: October 2019

Abstract
Background: The Bruton tyrosine kinase (BTK) inhibitor zanubrutinib,has demonstrated greater selectivity for BTK versus other TEC- and EGFR-family kinases in biochemical assays and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. In a phase 1 clinical trial, zanubrutinib showed complete and sustained 24-hour BTK occupancy in both blood and lymph node biopsies from patients treated at 160 mg twice daily (bid; Tam et al. Blood 2016;128:642), and was associated with durable responses in patients with non-Hodgkin lymphoma (Tam et al. Blood 2017;130:152). Here, we present initial safety and efficacy data from a phase 2 trial of zanubrutinib in patients with relapsed or refractory mantle cell lymphoma (R/R MCL).
Methods: Conducted in China, BGB-3111-206 (clinicaltrials.gov NCT03206970) is a pivotal, single-arm, open-label, multicenter phase 2 study. Patients with R/R MCL aged 18-75 years and with 1-4 prior treatment regimens received zanubrutinib 160 mg bid until disease progression (PD) or unacceptable toxicity. The primary objective is to evaluate the efficacy of zanubrutinib as measured by overall response rate (ORR) assessed by an Independent Review Committee (IRC). Response was assessed with PET-CT scans (in subjects with FDG-avid disease) and CT or MRI scans (in subjects with FDG non-avid disease) at each response assessment and for confirmation of complete response (CR) per the International Conference on Malignant Lymphoma (Lugano) criteria (Cheson, 2014). Key secondary endpoints included progression free survival (PFS), time to response (TTR), duration of response (DOR) and safety. Treatment-emergent adverse events (TEAEs) were assessed according to NCI CTCAE v4.03.
Results: As of 27 March 2018, 86 patients with R/R MCL were enrolled and treated. Patient characteristics are summarized in the Table. Over one-half (52.3%) of patients were refractory to their last prior therapy. Median follow-up was 36 weeks (range,1-56) at the data cut. Twenty-one patients discontinued zanubrutinib (13 for PD; 6 for TEAEs; 1 withdrew consent; and 1 per investigator's discretion). One patient was not evaluable for response due to a lack of central pathologic confirmation of MCL. Of the 85 evaluable patients, ORR per the IRC was 84% (n=71; Table), with CR reported in 59% of patients (n=50). The estimated event-free rate for responders was 90% at 24 weeks after response. In total, 12 patients have progressed; the estimated PFS rate was 82% at 24 weeks. The most frequent (≥15%) TEAEs due to any cause included decreased neutrophil count (31.4%), upper respiratory tract infection (29.1%), rash (29.1%), decreased platelet count (22.1%), and decreased white blood cell (WBC) count (17.4%). Grade ≥3 TEAEs due to any cause reported in >2 patients included decreased neutrophil count (11.6%), lung infection (5.8%), anemia (4.7%), and decreased WBC count (3.5%). Petechia/purpura/contusion and hematuria were each reported in 4 patients (4.7%, all grade 1/2); major hemorrhage (serious or grade ≥3 bleeding or central nervous system bleeding of any grade)was reported in 1 patient (1.2%); no cases of atrial fibrillation/flutter or tumor lysis syndrome were reported. Six patients died within 30 days of last study treatment, 1 from PD, 4 due to Grade 5 TEAEs and 1 due to a Grade 5 event that was not treatment emergent. TEAEs leading to discontinuation of zanubrutinib included (n=1 each): infection, pneumonia, lung infection, interstitial lung disease, and twoGrade 5 TEAEs (cerebral hemorrhage and road traffic accident).
Conclusions: Zanubrutinib was shown to be highly active in patients with R/R MCL, as demonstrated by a high rate of CR documented by PET-based imaging. Zanubrutinib was generally well-tolerated, consistent with previous reports of zanubrutinib treatment in patients with various B-cell malignancies.

Disclosures
Song: Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhou:Affiliated Cancer Hospital of Zhengzhou University: Employment; Health and Family Planning Commission of Henan Province: Patents & Royalties: Scientific and technological innovative talents "51282" Project leaders; Henan Cancer Hospital: Consultancy, Employment; Natural Science Foundation of China: Research Funding. Jin:College of Medicine, Zhejiang University: Employment; The National Natural Science Foundation of China: Research Funding. Guo:BeiGene (Shanghai) Co., LTD: Employment. Wang:BeiGene (Shanghai) Co., LTD: Employment. Hilger:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Huang:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Novotny:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Osman:BeiGene USA: Employment, Equity Ownership. Zhu:Beijing Cancer Hospital: Employment.