Preliminary Safety and Efficacy from a Multicenter, Investigator-Initiated Phase II Study in Untreated TP53 Mutant Mantle Cell Lymphoma with Zanubrutinib, Obinutuzumab, and Venetoclax (BOVen)
Authors: Kumar Anita , Soumerai Jacob D. , Abramson Jeremy S. , Batlevi Connie Lee , Chadha Puja , Dogan Ahmet , Falchi Lorenzo , Flaherty Kelsey , Friedman Chaya , Grieve Clare , Ho Caleb , Johnson P. Connor , Joseph Ashlee , Khan Niloufer , Mi Joanna , Martignetti Rosalba , Matasar Matthew J. , Owens Colette , Ruiters Jade , Sechio Sidney , Seshan Venkatraman , Simkins Elizabeth , Abdel-Wahab Omar , Zelenetz Andrew D. 
Published: November 2021

Abstract
Background: TP53 mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with chemoimmunotherapy (Eskelund Blood 2017) and there is no standard frontline treatment for this high-risk patient population. The combination of Bruton's Tyrosine Kinase (BTK) inhibition and the BCL2 inhibition have been shown to be synergistic and active in relapsed, refractory MCL, including in patients with TP53 mutation (Tam NEJM 2018). Obinutuzumab, ibrutinib, and venetoclax has been shown to be well tolerated and associated with high response rates in relapsed and untreated MCL patients (Le Gouill Blood 2021). We hypothesize that treatment with zanubrutinib (B; BGB-3111; BTK inhibitor), obinutuzumab (O; CD20 antibody), and venetoclax (Ven; BCL2 inhibitor) (BOVen) will be well tolerated and efficacious in untreated TP53 mutant MCL.
Methods: In this multicenter, investigator-initiated phase 2 trial (NCT03824483), eligible pts had previously untreated MCL with TP53 mutation (any variant allele frequency allowed) and ECOG PS&lt;=2, ANC &gt;1, PLT &gt;75, HGB &gt;=9 (unless if due to MCL). BOVen is administered in 28D cycles: B 160 mg PO BID starting D1; O 1000 mg IV D1 or split D1-2, 8, 15 of C1, D1 of C2-8; Ven ramp up initiated C3D1 (target 400 mg QD). Tx duration is 2 years at minimum and primary endpoint is 2-year progression-free survival. Adverse events (AE) were assessed per CTCAE v5.
Results: 12 patients have been enrolled of the 25 total planned accrual. The median age on study was 67.5 years (range 29 - 79); 83% were male (10/12); various histologic subtypes were included (9 conventional MCL, 2 non-nodal leukemic, and 1 blastoid variant); 100% stage IV (12/12); by MIPI: 75% high risk (9/12), 17% intermediate (2/12), and 8% low risk MIPI score (1/12); 90% Ki67 &gt;=30% (n=9/10); 50% Ki67&gt;=50% (n=5/10); and 50% 17p deletion (n=6/12).
All 12 patients were evaluable for toxicity. The grade 3 treatment-related AEs were limited to infusion-related reaction (17%, n=2 pts), neutropenia (8%, n=1 pt) that resolved with GCSF support, and elevation of transaminases (8%, n=1 pt). The most common treatment-related AEs (occurred in more than 1 patient) were low-grade and included: infusion-related reaction (17%, grade 1-2, n=3), neutropenia (17%, grade 1-2, n=2), thrombocytopenia (25%, grade 1, n=3), nausea (33%, grade 1, n=4), elevation of transaminases, (17%, grade 1, n=2), and rash (17%, grade 1, n=2). There was one treatment-related serious adverse event of fever without neutropenia that occurred on C3D2 after BOVen treatment. Pt was discharged after brief hospitalization in stable condition with resolution of fever and negative infectious work up. No dose reductions or modifications were required. No pts had laboratory/clinical TLS (Howard).
Median follow up was 4 months (0 - 11 months). One pt has progressed and eleven pts remain on study in continued response. Of the 10 patients who have undergone disease restaging by Lugano criteria at C3 post BO, 80% (n=8/10) achieved PET-CR which has been maintained in 2 patients at C7. One patient, who has TP53, CARD11, and SMARCA4 mutations, achieved stable disease at C3, converted to a partial response at C7, and is now progressing during C12. The other patient had progressive disease by Lugano criteria at C3 with a mixed response on PET/CT with some sites of tumor regression, but after the addition of venetoclax pt had resolution of bulky palpable adenopathy and systemic symptoms. All patients had baseline positive peripheral blood flow cytometry (PBFC) and at C3 90% (n=9/10) had negative PBFC.
Conclusions: BOVen was well tolerated in untreated TP53 mutant MCL. The preliminary efficacy is promising in this high-risk subset of MCL, however, follow-up is limited. Updated response data, including minimal residual disease assessment using a next-generation immunosequencing (IS) assay, will be presented at the meeting.

Disclosures
Kumar: Kite Pharmaceuticals: Other: advisory board , Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Abbvie Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding. Soumerai: AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Consultancy; BostonGene: Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy, Research Funding. Abramson: Morphosys: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Kymera: Consultancy; Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; BeiGene: Consultancy; Kite Pharma: Consultancy; C4 Therapeutics: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Bluebird Bio: Consultancy; Genmab: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Batlevi: Kite Pharma: Consultancy; TG Therapeutics: Consultancy; Viatris: Current holder of individual stocks in a privately-held company; Juno/Celgene: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Karyopharm: Consultancy; Medscape: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; TouchIME: Honoraria; Dava Oncology: Honoraria; Life Sciences: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Dogan: Takeda: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; Peer View: Honoraria; Roche: Consultancy, Research Funding; EUSA Pharma: Consultancy; Seattle Genetics: Consultancy. Falchi: Roche: Research Funding; Genmab: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genetech: Research Funding. Ho: Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees. Khan: Seattle Genetics: Research Funding. Matasar: IGM Biosciences: Research Funding; Merck: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Juno Therapeutics: Consultancy; Pharmacyclics: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Teva: Consultancy; Takeda: Consultancy, Honoraria; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Bayer: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Abdel-Wahab: Foundation Medicine Inc: Consultancy; Prelude Therapeutics: Consultancy; Merck: Consultancy; LOXO Oncology: Consultancy, Research Funding; H3B Biomedicine: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Gilead: Honoraria, Research Funding; MEI Pharma: Honoraria, Research Funding; AstraZeneca: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Pharmacyclics: Honoraria; Amgen: Honoraria; Novartis: Honoraria; MorphoSys: Honoraria; Genentech/Roche: Honoraria, Research Funding; Verastem: Honoraria; Abbvie: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; Beigene: Honoraria, Other, Research Funding; SecuraBio: Honoraria; LFR: Other; MethylGene: Research Funding; NCCN: Other.