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)

ABSTRACT

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 2×10 6 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 AUC 0-28 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, nd 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. [Formula presented] 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 Janssen Consultancy, Honoraria;Takeda Research Funding;Novartis Consultancy, Honoraria, Research Funding, Speakers Bureau;Amgen Honoraria;Celgene Research Funding;Bristol-Myers Squibb Consultancy, Honoraria;MSD Consultancy, Honoraria, Research Funding, Speakers Bureau;Roche Consultancy, Honoraria, Other travel, accommodation, expenses, Research Funding, Speakers Bureau;Gilead Sciences Consultancy, Honoraria, Speakers Bureau. 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 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;Janssen Honoraria, Membership on an entity's Board of Directors or advisory committees;Kyte Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other Travel, Accommodations, Expenses;Bristol Myers Squibb/Celgene Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other Travel, Accommodations, Expenses;Takeda 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;Incyte Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie 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;Hospira Research Funding;Bayer Honoraria;Amgen 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 Takeda Consultancy;Genentech Consultancy, Research Funding;Merck Consultancy, Research Funding;Seagen Consultancy, Research Fundi g;AstraZeneca Consultancy, Research Funding;Kite, a Gilead Company Research Funding;Gilead Sciences Research Funding;Tubulis Consultancy;ADC Therapeutics Consultancy, Research Funding;Bristol Myers Squibb Consultancy, Research Funding;Karyopharm Consultancy. Ujjani Loxo Research Funding;AstraZeneca Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Epizyme Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen Consultancy;TG Therapeutics Honoraria;Gilead Honoraria;ACDT Honoraria;Kite, a Gilead Company Honoraria;Adaptive Biotechnologies Research Funding;Atara Bio Consultancy;AbbVie Consultancy, Research Funding;Pharmacyclics Consultancy, Research Funding. 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, aGilead 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.