ZUMA-25 preliminary analysis: A Phase 2 study of brexucabtagene autoleucel (brexu-cel) in patients (Pts) with relapsed/refractory (R/R) burkitt lymphoma (BL), substudy C
Year: 2025
Type: conference-abstract
Abstract: Introduction: Brexu-cel is an autologous anti-CD19 CAR T-cell therapy approved for adults with R/R MCL and R/R B-ALL. BL is a rare, highly aggressive B-cell malignancy characterized by translocation of the MYC oncogene. Pts with R/R BL have limited treatment options and outcomes are poor with a median overall survival (OS) of 2.8 mo after salvage therapy (Short NJ, et al. Am J Hematol. 2017). ZUMA-25 (NCT05537766) is a Phase 2, open-label, multicenter basket study designed to evaluate the safety and efficacy of brexu-cel in adults with rare B-cell malignancies. Here, we report the preliminary efficacy and safety of brexu-cel in pts with R/R BL in ZUMA-25 (Substudy C). Methods: Eligible pts were aged ≥18 y, had an ECOG performance status 0-1, histologically confirmed mature B-cell NHL Burkitt lymphoma/leukemia, and R/R disease after ≥1 prior line of chemoimmunotherapy. Pts underwent leukapheresis, optional bridging therapy, lymphodepleting chemotherapy, and infusion of brexu-cel (2×106 anti-CD19 CAR T cells/kg; dose was validated in a run-in phase with 3 pts before enrolling additional pts). Primary endpoint was objective response rate (ORR; complete response [CR] + partial response [PR]) by investigator assessment per the Lugano classification (Cheson BD, et al. J Clin Oncol. 2014). Key secondary endpoints were CR rate, duration of response (DOR), OS, progression-free survival (PFS), time to first response, time to best response, safety, and patient-reported outcomes (PROs) per EQ-5D-5L index. Exploratory analyses included CAR T-cell levels. Outcomes were analyzed descriptively without hypothesis testing for the primary endpoint due to early termination of the trial given low pt enrollment. Results: Twelve pts were enrolled and underwent leukapheresis, of whom 10 (83%) received brexu-cel (2 pts did not receive brexu-cel due to death from progressive disease [PD; n=1] and withdrawal from study [n=1]). There were no manufacturing failures; median vein-to-vein time (range) was 25.5 d (23-28; n=4) and 37.0 (28-51; n=6) for pts in the US and EU, respectively. As of Dec 17, 2024, median follow-up in treated pts (N=10) was 5.6 mo (range, 3.8-24.2). Median age was 50.5 y (range, 36-70), 50% were male, 30% were Hispanic/Latino. At baseline, 8 pts (80%) had an ECOG performance status of 1; 5 pts each (50%) had refractory and early relapse BL (<6 mo from first remission); median number of prior therapies was 1.5 (range, 1-6) and included chemotherapy and/or rituximab; 1 pt received prior autologous stem cell transplantation (SCT). Eight pts had bridging therapy, including radiotherapy (n=3) and/or chemotherapy (n=6). Among treated pts (N=10), ORR was 100% (95% CI, 69-100; CR rate, 50%; PR rate, 50%). Median time from infusion to first/best response was 29 d (range, 25-284), with 1 pt converting from stable disease to CR at Mo 9; no pt with PR converted to CR. Median (95% CI) DOR, PFS, and OS were 5.0 mo (2.2-not estimable [NE]), 5.8 mo (3.1-NE), and 12.9 mo (3.8-NE), respectively. Among pts with CR, the 6-mo (95% CI) DOR, PFS, and OS rates were 75% (13-96), 75% (13-96), and 100% (100-100), respectively. DOR for each of the 5 pts with CR was 4.83+, 4.96, 10.18+, 11.33+, and 14.88+ mo (+ indicates censoring); at data cutoff, 4 pts were still alive and in ongoing response without subsequent therapy and 1 pt died due to PD after subsequent therapy and SCT. Among the 5 pts with PR as best response, DOR ranged from 0.03-4.24 mo; at data cutoff, 2 pts were still alive with PD, and 3 pts died (2 due to PD [1 with subsequent SCT] and 1 due to an adverse event [AE; pneumonia, deemed unrelated to brexu-cel] with subsequent SCT). AEs occurred in all pts; 9 (90%) had Grade ≥3 AEs. The most common AEs were pyrexia (100%) and decreased neutrophil count (50%). All pts had any-grade cytokine release syndrome (CRS); 1 (10%) had Grade 3 CRS. Neurologic events occurred in 8 pts (80%); 6 (60%) had Grade 3. Median peak, area under the curve, and time to peak CAR T-cell levels were 41.9 cells/μL, 450.1 cells/μL × days, and 8 d (range, 8-57), respectively. Most evaluable pts (6/7) had stable or improved quality of life 3 months after screening. Conclusions: To our knowledge, this is the first prospective study of a commercial CAR T-cell therapy in pts with R/R BL. Preliminary efficacy, safety, and PROs are promising in this difficult-to-treat pt population; this analysis is limited by its small sample size and short follow-up.
Source: Blood
Authors: Suzanne Van Dorp, Georg Stussi, Anna Maria Frustaci, Ian Flinn, Zachary Crees, John Baird, Luke Mountjoy, Saurabh Dahiya, Nadine Kutsch, Pier Luigi Zinzani, Armando Lopez-Guillermo, Philipp Staber, Loic Ysebaert, Ramon Garcia-Sanz, Fatima De la Cruz Vicente, Lori Leslie, David Bond, Bhagirathbhai Dholaria, Chad Williams, Lang Zhou, Ioana Kloos, Liana Nikolaenko, Enrico Tiacci
Institutions: Radboud University Nijmegen, Radboud University Medical Center, Istituto Oncologico della Svizzera Italiana, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Tennessee Oncology, Washington University in St. Louis, City Of Hope National Medical Center, Colorado Blood Cancer Institute, Stanford University, University Hospital Cologne, University of Bologna, Hospital Clínic de Barcelona, Medical University of Vienna, Universidad de Salamanca, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Hackensack Meridian Health, The Ohio State University, Vanderbilt University Medical Center, University of Perugia, Azienda Ospedaliera di Perugia
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417008403
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