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739 Primary Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) As First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma (LBCL)

Program: Oral and Poster Abstracts
Type: Oral
Session: 704. Cellular Immunotherapies: Cellular Therapies for Low and High Grade Lymphomas
Hematology Disease Topics & Pathways:
Biological, Adults, Lymphomas, Non-Hodgkin Lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Immune Mechanism, B Cell Lymphoma, Diseases, Therapies, Lymphoid Malignancies, Biological Processes, Study Population
Monday, December 13, 2021: 2:45 PM

Sattva S. Neelapu, MD1, Michael Dickinson, MBBS2, Javier Munoz, MD, MS, MBA, FACP3, Matthew L. Ulrickson, MD3, Catherine Thieblemont, MD, PhD4, Olalekan O. Oluwole, MBBS, MPH5, Alex F. Herrera, MD6, Chaitra S. Ujjani, MD7, Yi Lin8, Peter A. Riedell, MD9, Natasha Kekre, MD, FRCPC10, Sven de Vos11, Christine Lui, MS12*, Francesca Milletti, PhD12*, Jinghui Dong, PhD12*, Hairong Xu, MD, PhD12* and Julio C. Chavez, MD13

1Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston, TX
2Department of Clinical Haematology, Peter MacCallum Cancer Centre, Royal Melbourne Hospital and and the University of Melbourne, Melbourne, VIC, Australia
3Banner MD Anderson Cancer Center, Gilbert, AZ
4Department of Hemato-Oncology, Saint Louis Hospital, Paris, France
5Vanderbilt-Ingram Cancer Center, Nashville, TN
6City of Hope National Medical Center, Duarte, CA
7Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA
8Mayo Clinic, Rochester, MN
9Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
10The Ottawa Hospital, Ottawa, ON, Canada
11David Geffen School of Medicine at UCLA, Santa Monica, CA
12Kite, a Gilead Company, Santa Monica, CA
13Moffitt Cancer Center, Tampa, FL

Background: High-risk LBCL is associated with poor prognosis after first-line anti-CD20 mAb-containing regimens, highlighting the need for novel treatments. Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is approved for treatment of relapsed/refractory (R/R) LBCL after ≥2 lines of systemic therapy. Here we report the primary analysis of ZUMA-12, a Phase 2, multicenter, single-arm study of axi-cel as part of first-line therapy in patients with high-risk LBCL.

Methods: Eligible adults had high-risk LBCL, defined by histology (double‑ or triple-hit status [MYC and BCL2 and/or BCL6 translocations] per investigator) or an IPI score ≥3, plus a positive interim PET per Lugano Classification (Deauville score [DS] 4/5) after 2 cycles of an anti-CD20 mAb and anthracycline-containing regimen. Patients underwent leukapheresis and received conditioning chemotherapy (cyclophosphamide and fludarabine) followed by a single axi-cel infusion at 2×106 CAR T cells/kg. Non-chemotherapy bridging could be administered before conditioning per investigator discretion. The primary endpoint was investigator-assessed complete response (CR) rate per Lugano. Secondary endpoints included objective response rate (ORR; CR + partial response), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and levels of CAR T cells in blood and cytokines in serum. The primary analysis occurred after all treated patients had ≥6 months of follow-up.

Results: As of May 17, 2021, 42 patients were enrolled and 40 were treated with axi-cel. Median age was 61 years (range, 23–86); 68% of patients were male, 63% had ECOG 1, 95% had stage III/IV disease, 48% had DS4, 53% had DS5, 25% had double‑ or triple-hit status per central assessment, and 78% had IPI score ≥3.

A total of 37 patients had centrally confirmed double‑ or triple-hit histology or an IPI score ≥3 and were evaluable for response, with 15.9 months of median follow-up (range, 6.0–26.7). The CR rate was 78% (n=29; 95% CI, 62–90); 89% of patients had an objective response, and median time to initial response was 1 month. Among all 40 treated patients, 90% had an objective response (80% CR rate). At data cutoff, 73% of response-evaluable patients had ongoing responses. Medians for DOR, EFS, and PFS were not reached; 12-month estimates were 81%, 73%, and 75%, respectively. The estimated OS at 12 months was 91%.

All 40 treated patients had AEs of any grade; 85% of patients had Grade ≥3 AEs, most commonly cytopenias (68%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 3 patients (8%) and 9 patients (23%), respectively. Median times to onset of CRS and NEs were 4 days (range, 1–10) and 9 days (range, 2–44), with median durations of 6 days and 7 days, respectively. All CRS and most NEs (28/29) of any grade resolved by data cutoff (1 ongoing Grade 1 tremor); 39/40 CRS events resolved by 14 days post-infusion and 19/29 NEs resolved by 21 days post-infusion. Tocilizumab was administered to 63% and 3% of patients for management of CRS or NEs, respectively; corticosteroids were administered to 35% and 33% of patients for CRS and NE management. One Grade 5 event of COVID-19 occurred (Day 350).

Median peak CAR T-cell level in all treated patients was 36 cells/µL (range, 7–560), and median expansion by AUC0–28 was 495 cells/µL × days (range, 74–4288). CAR T-cell levels peaked at a median of 8 days post-infusion (range, 8–37). Higher frequency of CCR7+CD45RA+ T cells in axi-cel product, previously associated with greater expansion of CAR T cells (Locke et al. Blood Adv. 2020), was observed in ZUMA-12, compared with the ZUMA-1 study in R/R LBCL (Neelapu et al. New Engl J Med. 2017).

Conclusion: In the primary analysis of ZUMA-12, axi-cel demonstrated a high rate of rapid and complete responses in patients with high-risk LBCL, a population with high unmet need. With 15.9 months of median follow-up, responses were durable as medians for DOR, EFS, and PFS were not yet reached and over 70% of patients remained in response at data cutoff. No new safety signals were reported with axi-cel in an earlier line. Overall, axi-cel may benefit patients exposed to fewer prior therapies, and further trials in first-line high-risk LBCL are warranted to assess axi-cel in this setting.

Disclosures: Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria. Dickinson: Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; Celgene: Research Funding; Amgen: Honoraria. Munoz: Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seagen, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium: Research Funding; Pharmacyclics/Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Innovent, Seagen, BeiGene, Debiopharm, Epizyme, Karyopharm, ADC Therapeutics, Servier, and Genmab: Consultancy, Other: advisory role; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Targeted Oncology, OncView, Kyowa Kirin, Physicians' Education Resource, and Seagen: Honoraria. Thieblemont: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bayer: Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hospira: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Herrera: Karyopharm: Consultancy; Tubulis: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Gilead Sciences: Research Funding; Merck: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ujjani: Atara, AstraZeneca, AbbVIe, ACDT, Epizyme, TG Therapeutics, Pharmacyclics, Beigene: Consultancy. Lin: Sorrento: Consultancy; Legend: Consultancy; Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Juno: Consultancy; Vineti: Consultancy; Takeda: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Riedell: Bayer: Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Morphosys: Research Funding; Celgene/Bristol-Myers Squibb Company: Consultancy, Honoraria, Research Funding; Verastem Oncology: Honoraria; Kite, a Gilead Company: Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; BeiGene: Consultancy; Calibr: Research Funding; Xencor: Research Funding; Tessa Therapeutics: Research Funding. Kekre: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Lui: Gilead Sciences: Other: stock or other ownership; Kite, a Gilead Company: Current Employment, Other: travel support. Milletti: Kite, a Gilead company: Current Employment; Gilead Sciences: Other: stock or other ownership . Dong: Kite, a Gilead Company: Current Employment; Gilead Sciences: Other: stock or other ownership ; GliaCure/Tufts: Consultancy, Other: advisory role, Patents & Royalties. Xu: Kite, A Gilead Company: Current Employment; Gilead Sciences: Other: stock or other ownership . Chavez: MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merk: Research Funding; AstraZeneca: Research Funding; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; BMS: Speakers Bureau.

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