Introduction: ZUMA-5 is a multicenter Phase 2 study of axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL; follicular lymphoma [FL] and marginal zone lymphoma [MZL]). After a median of ≥3 years of follow-up, medians of progression-free survival (PFS) in patients with FL and MZL were 40.2 months and not reached, respectively, and no new safety signals were observed (Neelapu et al. ASH 2022. Abstract 4660). Here, we report updated outcomes from ZUMA-5 after a median follow-up of ≥4 years.
Methods: Eligible patients had R/R FL or MZL after ≥2 lines of therapy including an anti-CD20 monoclonal antibody plus an alkylating agent. Patients underwent leukapheresis at enrollment, then received lymphodepletion and axi-cel infusion (2×10 6 CAR T cells/kg). The primary endpoint was overall response rate (ORR; complete response [CR] + partial response [PR]). Time-to-event endpoints were assessed by investigators in all enrolled patients. Exploratory analyses included lymphoma-specific survival, using competing risk assessment, in which deaths unrelated to progression, axi-cel, or lymphodepletion were competing risks.
Results: In 159 enrolled patients (FL: 127, MZL: 31) at data cutoff (March 31, 2023), median follow-up was 52.5 months (range, 20.3-69.4; FL: 53.7, MZL: 43.8). The ORR in enrolled patients remained consistent with prior analyses (90% ORR, 75% CR rate). Median duration of response (DOR) was 55.5 months (95% CI, 38.6-not estimable; FL: 55.5, MZL: not reached). Medians for DOR were 60.4 months in those with a best response of CR and 4.9 months in those with a PR. At data cutoff, responses were ongoing in 48% of patients, consistent by disease type. Median PFS was 57.3 months (95% CI, 34.9-not estimable; FL: 57.3, MZL: 46.9); estimated 48-month PFS rate was 52% (FL: 53%, MZL: 47%; Figure 1). After data cutoff of the prior analysis, 1 patient with FL had disease progression. PFS rates at 48 months in patients with FL were consistent regardless of high-risk characteristics, including progression <2 years from initiating first anti-CD20-containing chemoimmunotherapy (POD24). Median time to next therapy was 62.2 months (95% CI, 37.8-not estimable; FL: 62.2, MZL: 46.9). Median overall survival (OS) was not reached (95% CI, 62.2-not estimable); 48-month OS rate was 72% (FL: 72%, MZL: 68%).
Among enrolled patients with FL, the 48-month cumulative incidence of lymphoma-specific progression or death was 34%, while the cumulative incidence of competing risks was 13% (Figure 2). Additionally, the cumulative incidence of lymphoma-specific death at 48 months was 14%; the cumulative incidence of other or unknown death was 14%.
After the 3-year analysis, among 152 treated patients (124 FL; 28 MZL), 6 experienced serious adverse events, 1 of which was related to axi-cel (FL, Grade 3 myelodysplastic syndrome). No new neurologic events, hypogammaglobulinemia cases, Grade ≥3 cytopenias, or Grade ≥3 infections occurred. Seven additional patients died due to progression (n=2; both patients received subsequent therapy after progression), new malignancy (n=1; not axi-cel related), and other causes (n=4; 2 cardiac arrest, 1 infection, and 1 unknown).
Among treated patients with FL, those with ongoing response at 48 months continued to have higher median postinfusion CAR T-cell expansion by peak (52.2 cells/µL) and area under the curve (583.6 cells/µL×days) than those who relapsed (29.6 cells/µL and 337.6 cells/µL×days) or had no response (25.4 cells/µL and 269.9 cells/µL×days). Additionally, those with ongoing response had a higher proportion of naive (CCR7+CD45RA+) T cells in axi-cel product (25%) than relapsed (13%) or nonresponding patients (9%). Similar trends were observed in MZL.
Conclusions: With a median ≥4 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable response and long-term survival in patients with R/R FL and R/R MZL. Late progression or lymphoma-specific death was uncommon in FL, suggesting curative potential for those patients. The long-term safety profile of axi-cel was manageable.
Disclosures
Neelapu:Sana Biotechnology: Consultancy, Other: Advisory board member, Research Funding; Allogene: Consultancy, Other: Advisory board member, Research Funding; Adicet Bio: Consultancy, Other: Advisory board member, Research Funding; Kite, A Gilead Company: Consultancy, Other: Advisory Board Member, Research Funding; Bluebird Bio: Consultancy, Other: Advisory board member; Athenex: Consultancy, Other: Advisory board member; Astellas Pharma: Consultancy, Other: Advisory board member; Morphosys: Consultancy, Other: Advisory board member; Bristol Myers Squibb: Consultancy, Other: Advisory Board Member, Research Funding; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; Longbow Immunotherapy: Current holder of stock options in a privately-held company; Janssen: Consultancy, Other: Advisory board member; Carsgen: Consultancy; Sellas Life Sciences: Consultancy, Other: Advisory board member; Incyte: Consultancy, Other: Advisory board member; Chimagen: Consultancy, Other: Advisory board member; Caribou: Consultancy, Other: Advisory board member; Fosun Kite: Consultancy, Other: Advisory board member; N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual property); Takeda: Consultancy, Other: Advisory board member; Precision Biosciences: Research Funding; Orna Therapeutics: Consultancy, Other: Advisory board member; Synthekine: Consultancy, Other: Advisory board member; Merck: Consultancy, Other: Advisory Board Member. Chavez:Janssen: Research Funding; Eli Lilly: Speakers Bureau; BeiGene: Speakers Bureau; Novartis: Consultancy; Kite, a Gilead Company: Consultancy; GenMab: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; AstraZeneca: Consultancy, Research Funding; AdiCet: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding. Sehgal:Kite/Gilead: Research Funding; Cytoagents: Research Funding; Chimagen: Research Funding; Bristol Myers Squibb: Research Funding; PeerView Live: Speakers Bureau; OncLive: Speakers Bureau. Epperla:Beigene: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ulrickson:Gilead Sciences: Consultancy; Stemline: Consultancy. Bachy:Bristol Myers Squibb: Honoraria, Other: Personal Fees, Research Funding; Takeda: Honoraria; Hospices Civils de Lyon Claude Bernard Lyon 1 University: Current Employment; Pfizer: Honoraria, Other: Personal Fees; Novartis: Honoraria, Other: Personal Fees; Incyte: Honoraria; Amgen: Research Funding; Kite, a Gilead Company: Honoraria, Other: Personal Fees; Roche: Consultancy, Honoraria. Munshi:Kite, a Gilead company: Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Casulo:GenMab: Research Funding; SecuraBio: Research Funding; Abbvie: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Verastem: Research Funding; Gilead Sciences: Research Funding; Follicular Lymphoma Foundation: Other: Leadership role; Lymphoma Research Foundation: Other: Leadership Role; Genentech: Consultancy, Research Funding. Maloney:Bristol Myers Squibb: Consultancy, Honoraria, Other: Member of the JCAR017 EAP-001 Safety Review Committee and Member, CLL Strategic Council, Member of the JCAR017-BCM-03 Scientific Steering Committee under BMS, Research Funding; Pharmacyclics: Consultancy, Honoraria; Kite, a Gilead Sciences: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Rights to royalties from Fred Hutch for patents licensed to Juno Therapeutics/BMS, Research Funding; Janssen: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Other: Member of the Scientific Advisory Board; Incyte: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria, Other: Member, Scientific Review Committee, Research Scholars Program in Hematologic Malignancies; Fred Hutch: Other: rights to royalties for patents licensed to Juno; Bioline Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board ; MorphoSys: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Navan Technologies: Current holder of stock options in a privately-held company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board , Research Funding; Genentech: Consultancy, Honoraria, Other: Chair and Member of the Lymphoma Steering Committee; Mustang Bio: Consultancy, Honoraria; Navan Technologies: Consultancy, Honoraria, Other: Member of the Scientific Advisory Board; Novartis: Consultancy, Honoraria; Chimeric Therapeutics: Other: Member of the Scientific Advisory Board; ImmPACT Bio: Other: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program; Interius: Other: Member, Clinical Advisory Board; Lyell Immunopharma: Other: Member, CAR T Steering Committee. de Vos:BeiGene: Consultancy. Reshef:Atara Biotherapeutics: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; J&J: Research Funding; Instil Bio: Consultancy; Regeneron: Consultancy; TScan: Consultancy, Research Funding; CareDx: Research Funding; Synthekine: Consultancy, Research Funding; Quell Biotherapeutics: Consultancy; Orca: Consultancy; MidaTech: Consultancy; Allogene: Consultancy; Capstan: Consultancy; Bayer: Consultancy; Jasper: Consultancy; Precision Biosciences: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria, Other: Travel support, Research Funding; Sanofi: Research Funding; Immatics: Research Funding; TCR2: Research Funding. Leslie:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/PCYC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Astrazeneca: Consultancy, Other: Travel support, Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LLS: Other: Educational role/ Leadership role in LLS light the night events (unpaid); Celgene/ Bristol Myers Squibb: Other: Travel support, Speakers Bureau; CLL: Other: Educational role; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LRF: Other: Educational role; Janssen/ J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SeaGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau. Oluwole:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; ADC: Consultancy, Speakers Bureau; Cargo: Consultancy; Caribou: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company/ Gilead: Consultancy, Research Funding; Nektar: Consultancy; Novartis: Consultancy; TGR: Consultancy; Allogene: Research Funding; Daiichi Sankyo: Research Funding; Gilead: Consultancy, Honoraria. Yakoub-Agha:Novartis: Honoraria; Kite, a Gilead Company: Honoraria, Other: travel support; Janssen: Honoraria; Bristol Myers Squibb: Honoraria. Rosenblatt:Synergys: Other; University of Miami Miller School of Medicine: Patents & Royalties: Intellectual property; Biograph 55: Research Funding. Peng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current holder of stock options in a privately-held company. Lui:Kite, a Gilead Company: Current Employment, Current holder of stock options in a privately-held company, Other: Travel support; Gilead Sciences: Current equity holder in publicly-traded company. Wulff:Kite, a Gilead Company: Current Employment. Shen:Atara: Other: Intellectual property , Patents & Royalties; Kite, a Gilead Company: Current Employment, Current holder of stock options in a privately-held company, Other: Intellectual property , Patents & Royalties. Poddar:Kite, a Gilead Company: Current Employment, Other: Travel support; UCLA: Other: Intellectual property , Patents & Royalties. Lee:Gilead: Current holder of stock options in a privately-held company, Other; Kite, a Gilead Company: Current Employment, Other: Travel expenses . Miao:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current holder of stock options in a privately-held company. Nikolajeva:Gilead Sciences: Current equity holder in publicly-traded company; Kite, A Gilead Company: Current Employment, Other: Travel support. Jacobson:Miltenyi Biotec: Consultancy; Pfizer: Research Funding; Synthekine: Consultancy; Morphosys: Consultancy; Ipsen: Consultancy; Daiichi-Sankyo: Consultancy; ImmPACT Bio: Consultancy; Instil Bio: Consultancy; Caribou Bio: Consultancy; Abintus Bio: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Novartis: Consultancy; Kite, a Gilead company: Consultancy, Research Funding.
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