Bispecific anti‐cd20/19 car‐t—zamtocabtagene autoleucel for relapsed/refractory dlbcl—interim analysis results of daly‐ii‐usa study

Background: DALY II USA is the first multicenter trial of fresh, bispecific targeted CD20/CD19, chimeric antigen receptor (CAR) T-cell therapy for patients (pts) with R/R diffuse large B-cell lymphoma (DLBCL). While CD19 CAR T-cell therapy is an established treatment for pts with R/R DLBCL, relapse remains a clinical challenge. One proposed mechanism of resistance is either loss of epitope, recognition, or downregulation of the CD19 receptor. To improve outcomes, dual targeting of B-cell receptors has been proposed. Reported here is the preplanned interim futility analysis after treatment of 22 evaluable pts. Aim: To assess safety and efficacy of dual CAR-T therapy with zamtocabtagene autoleucel (zamto-cel) administered fresh in R/R DLBCL. Methods: Eligible pts were >18 y, ECOG PS 0–1, with R/R DLBCL after ≥2 prior lines of systemic therapy. No bridging chemotherapy was allowed. Apheresis material was shipped fresh without cryopreservation to a central manufacturing site. A fixed 12-day process of CAR-T production was performed using the CliniMACS Prodigy® (Miltenyi Biotec). A single infusion of 2.5x106 cells/kg fresh zamto-cel was administered after lymphodepletion which was initiated during manufacturing to facilitate a fresh infusion. Evaluation of response rate is the primary objective of this study. Results: As of 1 September 2022, 28 pts have enrolled (All treated) with 22 evaluable per protocol. Most (69%) of treated patients presented advanced disease with IPI score of at least 3 and abnormal baseline LDH and 28% were previously treated with CD19 and or CD79 targeting agents. Six pts were not included in the primary efficacy analysis. One received a frozen product and 5 received a non-conforming fresh product. Per Independent Radiology Committee (IRC) 18 (82%) of 22 evaluable pts had either complete (CR—46%) or partial response (PR—36%) exceeding the preplanned futility threshold. The response rate in the evaluable set was similar to that in the all-treated population (Tbl. 1). Post-progression biopsies were available in 5 pts. There was no isolated CD19 loss, but 1pt had dual target loss CD19+CD20 in relation to the pre-treatment status. PFS at 6 months for evaluable pts was 64% and 61% for all treated. The treatment was well tolerated. Among all 28 treated pts., there were no grade 3–4 CRS events and only two transient and reversible Grade 3 ICANS (9%). There was no treatment-related mortality. Summary/Conclusion: The prespecified efficacy threshold of zamto-cel was exceeded in the interim analysis Treatment demonstrated a favorable safety profile, with promising ORR and PFS in advanced DLBCL population often pre-treated with agents not available in previous similar studies. We also demonstrate the feasibility of a rapid manufacturing process with 100% fresh infusion in eligible pts. Encore Abstract—previously submitted to EHA 2023 Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies, immunotherapy No conflicts of interests pertinent to the abstract.