Efficacy and Safety of Zanubrutinib in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Initial Results of the MAGNOLIA (BGB-3111-214) Trial
Authors: Opat Stephen , Tedeschi Alessandra , Linton Kim , McKay Pamela , Hu Bei , Chan Henry , Jin Jie , Zinzani Pier Luigi , Browett Peter , Coleman Morton , Sobieraj-Teague Magdalena , Ke Xiaoyan , Sun Mingyuan , Marcus Robert , Portell Craig A. , Zhou Keshu , Thieblemont Catherine , Co Melannie , Wang Weige , Tankersley Chris , Zhou Wenxiao , Cappellini Massimo , Huang Jane , Trotman Judith 
Published: November 2020

Background: Marginal zone lymphoma (MZL) is rare and heterogeneous and it has been difficult to define optimal therapeutic strategies. Like other indolent non-Hodgkin lymphomas, advanced stage disease is considered incurable, with most patients experiencing a continuing pattern of relapse and remission. MZL is typically dependent on B-cell receptor (BCR) signaling suggesting a role for BCR pathway targeting via inhibition of Bruton's tyrosine kinase (BTK). The utility of this approach was confirmed by the pivotal phase 2 study demonstrating a 48% objective response rate (ORR) to ibrutinib in patients with relapsed/refractory (R/R) MZL (Noy et al. Blood. 2017;129:2224-2232).
Zanubrutinib (BGB-3111) is a potent, highly specific, and irreversible next-generation BTK inhibitor. It was specifically designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases, which are thought to be related to atrial fibrillation, thrombocytopenia, and bleeding events. In an early-phase study (BGB-3111-AU-003) of 20 patients with R/R MZL treated with zanubrutinib, at a median follow-up of 27.1 months, the ORR was 80%, with a complete response (CR) rate of 15%, and partial response (PR) rate of 65% (Tedeschi et al. EHA 2020, abstract 2804). Presented here are initial efficacy and safety data in patients with R/R MZL enrolled in the MAGNOLIA trial (BGB-3111-214).
Methods: MAGNOLIA is a phase 2, multicenter, single-arm study of adult patients requiring systemic treatment for R/R MZL who had previously received one or more lines of therapy including at least one CD20-directed regimen. All patients were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary end point was ORR as determined by an independent review committee in accordance with the Lugano classification. Secondary end points include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), and safety.
Results: In total, 68 patients were enrolled and treated. The median age was 70 years (range, 37-95), with 28% aged ≥75 years. MZL subtypes included extranodal (mucosa-associated lymphoid tissue) in 38%, nodal in 38%, splenic in 18%, and unknown in 6% of patients. The median number of prior therapies was 2 (range, 1-6), and 35% of patients had disease refractory to last therapy.
At a median follow-up of 6.8 months (range, 1.6-12.8), 67 patients were evaluable for efficacy. Investigator-assessed ORR (CR + PR) was 60% (CR 15%, PR 45%, stable disease 27%). Responses were observed in all MZL subtypes, with an ORR of 58%, 64%, 58%, and 50% in extranodal, nodal, splenic, and unknown subtypes, respectively. CR rate was 23% for extranodal MZL, 12% for nodal, and 50% for unknown subtype. CR was not observed in patients with splenic MZL. The median DOR and median PFS were not reached.
Twenty-one (30.9%) patients discontinued study treatment. Treatment discontinuation was mainly due to disease progression (16 patients; 23.5%); 1 withdrew consent, 2 required prohibited medications, and 2 due to adverse events (AEs) - 1 from pyrexia (later attributed to disease transformation) and 1 from myocardial infarction. The most common treatment-emergent AEs reported in ≥10% of patients were diarrhea (19.1%), bruising (17.6%), constipation (13.2%), pyrexia (10.3%), upper respiratory tract infection (10.3%), and nausea (10.3%). Most AEs were low grade. Neutropenia was the most common grade ≥3 AE (7.3%). Treatment-related serious AEs included atrial flutter, pyrexia, pneumonia, and thrombocytopenia (1 patient each). One patient with pre-existing coronary artery disease died from myocardial infarction, which was assessed as unrelated to zanubrutinib. All-grade AEs of interest included neutropenia (10.3%), thrombocytopenia (10.3%), and atrial flutter (1.5%). To date, no major hemorrhage, serious opportunistic infection, or tumor lysis syndrome have been reported.
Conclusion: Preliminary results of this phase 2 study suggest that zanubrutinib is active in R/R MZL, with a favorable safety profile. (NCT03846427)

Disclosures
Opat: Beigene: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: 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; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Epizyme: Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tedeschi:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: 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, Speakers Bureau; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Department of Hematology Niguarda Hospital Milano: Current Employment; Sunesis: Consultancy. Linton:The Christie NHS Foundation Trust and The University of Manchester: Current Employment; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Conference/travel support; Roche: Consultancy, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hartley-Taylor: Honoraria. McKay:Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TAKEDA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Beatson West of Scotland Cancer Centre: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Gilead, Takeda, and Janssen: Other: For lectures etc. Hu:Kite: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectar: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Beigene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Chan:Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company). Jin:The First Affiliated Hospital of Zhejiang University: Current Employment. Zinzani:Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Browett:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; University of Auckland: Current Employment; BeiGene: Research Funding. Coleman:BeiGene: Research Funding; Acerta: Research Funding; Innocare: Research Funding. Sobieraj-Teague:Flinders Medical Centre: Current Employment; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ke:Peking University Third Hospital: Current Employment. Sun:Institute of Hematology and Blood Disease Hospital,Chinese Academy of Medical Sciences and Peking Union of Medical College: Current Employment. Marcus:Gilead: Consultancy; Roche: Honoraria; Janssen: Honoraria, Speakers Bureau. Portell:Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; TG Therapeutics: Research Funding; Infinity: Research Funding. Zhou:Henan Cancer Hospital: Current Employment. Thieblemont:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Hospira: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Co:BeiGene: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Wang:BeiGene: Current Employment. Tankersley:Clovis Oncology, Inc: Ended employment in the past 24 months; BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Zhou:BeiGene: Current Employment, Current equity holder in publicly-traded company; Beth Israel Deaconess Medical Center: Ended employment in the past 24 months. Cappellini:BeiGene Ltd.: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; BeiGene Aus Pty. Ltd.: Current Employment. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Trotman:BeiGene: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Other: Travel/accommodations/expenses, Research Funding.

OffLabel Disclosure:
Zanubrutinib has not been approved for MZL in the US