Background:

Zamto-cel is an investigational autologous tandem CD20-CD19-directed non-cryopreserved CAR-T cell product administered as a fresh formulation to patients (pts) with relapsed/refractory Diffuse Large B Cell Lymphoma (r/r DLBCL) in the DALY II USA clinical trial (NCT04792489), a multicenter, open label, single-arm Phase 2 study. Here, we report efficacy and safety outcomes as part of a pre-planned interim analysis of 59 evaluable patients and 69 patients in the safety population.

Methods:

Eligible adults had r/r DLBCL after at least 2 prior lines of treatment including anti-CD20 monoclonal antibody and anthracycline-containing regimen and measurable disease per Lugano 2014 classification. Zamto-cel was manufactured utilizing CliniMACS Prodigy® (Miltenyi Biotec), a closed, automated system with a 14-day vein-to-vein time and administered as a fresh formulation. Lymphodepletion chemotherapy was initiated during the manufacturing process (either cyclophosphamide/ fludarabine or bendamustine) prior to receiving a single dose of zamto-cel at a dose of 2.5x106 CAR T cells/kg on Day 0. The primary endpoint was overall response rate (ORR) defined as best overall response (BOR) of either complete response (CR) or partial response (PR). Secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and CD19 and CD20 antigen expression at relapse.

Results:

As of March 29th, 2024, 69 pts received zamto-cel of which 59 were evaluable having received a fresh, conforming product and completed a minimum of 3 months follow-up. Median age was 63 years (range 25-85), 39 (66%) were male. Sixteen pts (27%) received 3 or more lines of prior treatment. The majority of pts (53%) had elevated LDH at study entry, and 49% had ≥ 2 extranodal lesions, indicative of a study population with advanced disease.

No pts received any bridging therapy, in the week after apheresis and before lymphodepletion. Only 7 pts (12%) received bendamustine as lymphodepleting regimen.

Successful manufacturing of a fresh, in specification product occurred in 91.3% out of 69 treated pts. Four patients received a cryopreserved formulation to permit time for comorbid condition management. The mean viability of the final product was 96.0% with 29.4 % transduction efficacy. No patient died or withdrew during the manufacturing process.

The ORR in the evaluable patient population (n=59) as assessed by an Independent Radiology Committee (IRC) was 72.9% (95% CI, 59.7-83.6), with a CRR of 49.2% (95% CI,35.9-62.5). The 6 month and 12 month-PFS was 55% (95%CI, 41-67) and 42% (95%CI, 28-56), respectively; 12 month-OS was 72% (95%CI, 57-83). The median DOR was 11.4 months.

All 69 treated pts were assessed for safety outcomes. Treatment-emergent adverse events (TEAEs) were mostly of grade 1-2, the majority of grade ≥ 3 were hematological. Thirty-two pts (46.4%) experienced cytokine release syndrome (CRS), all grade 1-2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 12 pts (17.4%), grade 1-2 (9 pts; 13.1%); grade 3 (3 pts; 4.3%). One patient experienced immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which resolved after 2 days.

Biopsies at progression were available in 24 pts. CD19-negative relapse (defined as H Score <100) was seen in 2 pts, CD20-negative relapse was observed in 3 pts. Only one patient experienced loss of both antigens compared to pre-treatment status, demonstrating that most lymphomas maintain target antigen expression at relapse after treatment with zamto-cel.

Conclusion:

This pre-planned interim analysis represents the first pivotal trial of a tandem CD20-CD19 directed non-cryopreserved CAR-T cell product for patients with third-line r/r DLBCL. The trial plans to enroll 100 evaluable patients and the final data will be presented upon study completion. Among the 59 evaluable patients at the interim analysis, there is encouraging activity and a favorable safety profile in DLBCL patients treated with zamto-cel. Unlike currently registered CAR-T cell products, zamto-cel is administered as a fresh product with a short vein-to-vein time of 14 days with lymphodepletion initiated during the manufacturing process. With a manufacturing success rate of 91% we have demonstrated the feasibility of this process among high-risk patients with r/r DLBCL.

Disclosures

Shah:Tundra Therapeutics: Current holder of stock options in a privately-held company; Miltenyi Biomedicine, Lilly Oncology: Research Funding; Gilead-Kite, BMS-Juno, Miltenyi, Lilly Onclogy, Novartis, Seattle Genetics, Janssen, Abbvie, Cargo, Beigene, Galapagos, AstraZeneca: Honoraria. Maziarz:Kite, a Gilead Company: Consultancy, Research Funding; Orca: Research Funding; Athersys: Other: participated in data and safety monitoring boards, Patents & Royalties; Bristol Myers Squibb: Consultancy, Research Funding; Vor BioPharma: Other: participated in data and safety monitoring boards; Autolus: Consultancy; CRISPR Therapeutics: Consultancy; Century Therapeutics: Other: participated in data and safety monitoring boards; Incyte: Consultancy, Research Funding; Novartis: Consultancy, Other: participated in data and safety monitoring boards , Research Funding; Ori-cell Therapeutic: Honoraria; Gilead Sciences: Other: stock or other ownership; Artiva Bio: Other: Leadership Role; stock or other ownership. Jacobson:Bristol Myers Squibb/Celgene: Consultancy; Instil Bio: Consultancy; Ipsen: Consultancy; ADC Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Abintus Bio: Consultancy; Pfizer: Research Funding; Caribou Biosciences: Consultancy; Daiichi Sankyo: Consultancy; Synthekine: Consultancy; Novartis: Consultancy; MorphoSys: Consultancy; Miltenyi: Consultancy; ImmPACT Bio: Consultancy; AbbVie: Consultancy. Abhyankar:Incyte: Consultancy; CSL Behring, Miltenyi Biotec.: Research Funding. Perales:Adicet: Consultancy; Allogene: Consultancy, Research Funding; Allovir: Consultancy; Caribou Biosciences: Consultancy; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Nektar Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Syncopation: Consultancy; VectivBio AG: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Omeros: Consultancy, Current equity holder in publicly-traded company; OrcaBio: Consultancy, Current holder of stock options in a privately-held company; Cidara Therapeutics: Other: DSMB member; Sellas: Other: DSMB member; Vor Biopharma: Consultancy; AbbVie: Honoraria; Astellas: Honoraria; Karyopharm: Honoraria; MorphoSys: Honoraria; Takeda: Honoraria; Medigene: Other: DSMB member; Servier: Other: DSMB member. Ghosh:Cargo: Consultancy; BMS: Consultancy; Kite/Gilead: Research Funding; Novartis: Research Funding; Cabaletta Bio: Consultancy, Research Funding. Ulrickson:ADC Therapeutics.: Consultancy; Miltenyi Biomedicine: Honoraria; Bristol Myers Squibb: Consultancy; Stemline: Consultancy; Autolus: Consultancy. Rosenthal:RMEI, Curio Science, Targeted Oncology, OncLiveU: Other: Educational Workshop Speaker Role. Munoz:Targeted Oncology, OncView, Curio, Genzyme, and Physicians' Education Resource: Honoraria; Bayer, Gilead/Kite, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium, Novartis, BeiGene: Research Funding; Pharmacyclics/Abbvie, Bayer, Gilead/Kite, Beigene, Pfizer, Janssen, Celgene/BMS, Kyowa, Alexion, Fosunkite, Seattle Genetics, Karyopharm, Aurobindo, Verastem, Genmab, Genzyme, Genentech/Roche, ADC Therapeutics, Epizyme, Beigene, Novartis, Morphosys/Incyte: Consultancy. Hardy:Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Techonology: Other: Safety Monitoring Committee. Karmali:Incyte: Speakers Bureau; BMS: Honoraria; BeiGene: Speakers Bureau; Abbvie: Honoraria; Ipsen: Speakers Bureau; Genmab: Honoraria; Genentech/Roche: Honoraria; AstraZeneca: Speakers Bureau. Awan:Loxo Oncology: Consultancy; BeiGene: Consultancy; AbbVie/Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Incyte: Consultancy; Dava Oncology: Consultancy; AstraZeneca: Consultancy; Genmab: Consultancy; Adaptive Biotechnologies: Consultancy; BMS: Consultancy. Lunning:Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy; Genmab: Consultancy. Denlinger:Bristol Myers Squibb: Research Funding; Miltenyi Biotec: Other: Advisory Board. Ancukiewicz:Miltenyi Biomedicine: Current Employment. Nallewar:Miltenyi Biomedicine: Current Employment. Coleman:Miltenyi Biomedicine: Current Employment. Eromosele:Miltenyi Biomedicine: Current Employment. Kaleta:Miltenyi Biomedicine: Current Employment. Theruvath:Miltenyi Biomedicine: Current Employment. Wijatyk:Miltenyi Biomedicine: Current Employment. Miklos:2SeventyBio: Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel Support, Research Funding; Allogene: Research Funding; Adicet: Research Funding; Janssen: Consultancy, Patents & Royalties; Juno Therapeutics: Consultancy; Miltenyi: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Adaptive Biotechnologies: Research Funding; Galapagos: Consultancy; Fosun Kite Biotechnology: Honoraria; Novartis: Consultancy.

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2024
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