Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naive Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with Del(17p): Initial Results from Arm C of the Sequoia (BGB-3111-304) Trial
Authors: Tam Constantine S. , Robak Tadeusz , Ghia Paolo , Kahl Brad S. , Walker Patricia , Janowski Wojciech , Simpson David , Shadman Mazyar , Ganly Peter S. , Laurenti Luca , Opat Stephen , Tani Monica , Ciepluch Hanna , Verner Emma , Simkovic Martin , Österborg Anders , Trněný Marek , Tedeschi Alessandra , Paik Jason , Marimpietri Carol , Feng Shibao , Huang Jane , Hillmen Peter , Brown Jennifer R. 
Published: February 2020

Background: Patients with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Several new options targeting B-cell receptor signaling have emerged as potential effective therapies in this high-risk group. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor, designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. It has been shown to be highly potent, selective, and bioavailable with potentially advantageous pharmacokinetic and pharmacodynamic properties. In an early phase study, zanubrutinib demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and has been associated with durable clinical responses in patients with CLL/SLL (Tam, Blood 2019). Here, we present safety and efficacy data in treatment-naive (TN) patients with del(17p) CLL/SLL who are enrolled in the non-randomized Arm C of the SEQUOIA (BGB-3111-304) trial.
Methods : The SEQUOIA trial is an open-label, global, multicenter, phase 3 study that includes a non-randomized cohort (Arm C) of TN patients with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult patients with CLL/SLL who met iwCLL criteria for treatment (Hallek, Blood 2008) were eligible if they were either ≥ 65 y of age or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response assessment was evaluated by investigator for CLL per modified iwCLL criteria (Hallek, Blood 2008; Cheson, J Clin Oncol 2012) and for SLL per Lugano criteria (Cheson, J Clin Oncol 2014).
Results : In total, 109 patients with centrally confirmed del(17p) were enrolled into Arm C (complete accrual). As of 19 April 2019 (data cutoff), all patients had received ≥1 dose of zanubrutinib and were included in the safety analysis. Median age was 70.0 y (range, 42-86) and median follow-up in the safety analysis set was 6.3 mo (Table 1). At data cutoff, 106 patients remained on study treatment. Adverse events (AEs) reported in ≥10% of treated patients included contusion (20.2%), rash (11.0%), upper respiratory tract infection (10.1%), and nausea (10.1%). Grade ≥3 AEs were reported in 33 patients (30.3%). Grade ≥3 AEs that occurred in &gt;1 patient included neutropenia/decreased neutrophil count (n = 10), anemia, pneumonia, nephrolithiasis, and hypertension (each n = 2). One patient died due to grade 5 pneumonia that occurred 8 days after the last dose of zanubrutinib. AEs of interest (pooled terms) included infections (39.4%), bruising (24.8%), minor bleeding (18.3%), neutropenia (13.8%), arthralgia/myalgia (8.3%), diarrhea (8.3%), anemia (6.4%), hypertension (6.4%), thrombocytopenia (5.5%), fatigue (5.5%), headache (4.6%), petechiae (4.6%), second primary malignancy (2.8%), and major bleeding (2.8%). To date, no AEs of atrial fibrillation have been reported. At data cutoff, 90 patients were evaluable for efficacy with median follow-up of 7.0 mo; of these, 87 patients remained on study treatment. The overall response rate was 92.2% (Table 2). Two patients had disease progression due to Richter transformation and 1 patient died due to grade 5 pneumonia. No patient had progressed with CLL/SLL.
Conclusions : In this study, we have completed enrollment of one of the largest prospective cohorts of TN patients with del(17p) CLL/SLL. Preliminary results suggested that zanubrutinib was active and generally well tolerated. Clinical trial information: NCT03336333.

Disclosures
Tam: Novartis: Honoraria; BeiGene: Honoraria; Roche: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Robak:Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Morphosys AG: Research Funding. Ghia:AbbVie: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria. Kahl:BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Walker:Alfred Health: Employment; Peninsula Health: Employment. Janowski:AstraZeneca: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Simpson:GSK: Research Funding; Sanofi: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; MSD: Research Funding; Celgene: Research Funding; Roche: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Research Funding; Amgen: Research Funding; Jannsen: Honoraria. Shadman:AbbVie: Consultancy, Research Funding; Sunesis: Research Funding; TG Therapeutic: Research Funding; Acerta Pharma: Research Funding; Atara Biotherapeutics: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy; Astra Zeneca: Consultancy; Gilead: Consultancy, Research Funding; Verastem: Consultancy; Pharmacyclics: Consultancy, Research Funding; Mustang Bio: Research Funding; Sound Biologics: Consultancy; BeiGene: Research Funding. Ganly:Canterbury District Health Board: Employment. Opat:Takeda: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Epizyme: 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; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ciepluch:Copernicus Wojewodzkie Centrum Onkologii Gdansk: Employment. Verner:Janssen-Cilag Pty Ltd: Research Funding. Simkovic:Roche: Honoraria; University Hospital Hradec Kralove: Employment; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria. Österborg:Abbvie: Research Funding; Kancera AB: Research Funding; BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding. Trněný:Gilead Sciences: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Tedeschi:Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Paik:BeiGene: Employment, Equity Ownership. Marimpietri:BeiGene: Employment, Equity Ownership. Feng:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Apellis: Research Funding; Gilead: Research Funding; Roche: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Brown:Juno/Celgene: Consultancy; Verastem: Consultancy, Research Funding; Sunesis: Consultancy; Octapharma: Consultancy; Invectys: Other: Data safety monitoring board; Morphosys: Other: Data safety monitoring board; Teva: Honoraria; TG Therapeutics: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Janssen: Honoraria; Dynamo Therapeutics: Consultancy; AbbVie: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy; Catapult Therapeutics: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Pharmacyclics: Consultancy; Sun Pharmaceuticals: Research Funding.

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