AUTHORS
Tom Van Meerten, MD, PhD, Peter Borchmann, MD2, Pierre Bories, MD3, Peter Dreger, Prof. Dr. med.4, Laszlo Gopsca, MD5, Pim G.N.J. Mutsaers, MD6, Matthias Edinger, MD7, Lajos Gergely, MD8, Bastian von Tresckow, MD9, Peter Neumeister, MD10, Normann Steiner, MD11, Ulrich Jaeger, MD12, Ana Triguero13, Laimonas Griškevicius, MD14, Gloria Iacoboni, MD15, François Lemonnier Sr, MD, PhD16, Jaap A. Van Doesum17, Marie Jose Kersten, MD18, Nirav N. Shah, MD, MS19, Stefan Miltenyi, PhD20, Toon Overstijns, MD21, Corinne Brillant, MD22, Wael Nasri, MD23, Pearl Van Heteren, MD24, Silke Holtkamp, PhD25, Peter Vandenberghe, MD, PhD26
AFFILIATIONS
1 University Medical Center Groningen, University of Groningen, Groningen, Netherlands
2 University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne Lymphoma Working Group, Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany
3 University Cancer Institute Toulouse Oncopole, Toulouse, France
4 University Hospital Heidelberg, Heidelberg, Germany
5 South-Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
6 Erasmus University Rotterdam, Rotterdam, Netherlands
7 University Hospital Regensburg, Regensburg, Germany
8 University of Debrecen, Debrecen, Hungary
9 Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer consortium (DKTK partner site Essen), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
10 Medical University Graz, Graz, Austria
11 Medical University Innsbruck, Innsbruck, Austria
12 Medical University of Vienna, Vienna, Austria
13 Hospital Clínic De Barcelona, Barcelona, Spain
14 Vilnius University Hospital Santaros Klinikos and Vilnius University, Vilnius, Lithuania
15 Vall d'Hebron University Hospital, Barcelona, Spain
16 CHU Mondor, Créteil, France
17 University Medical Center Groningen, Groningen, Netherlands
18 Amsterdam University Medical Center, Amsterdam, Netherlands
19 Medical College of Wisconsin, Milwaukee, Wisconsin, United States
20 Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
21 Miltenyi Biomedicine, Bergisch Gladbach, Germany
22 Miltenyi Biomedicine, Bergisch Gladbach, Germany
23 Miltenyi Biomedicine, Bergisch Gladbach, Germany
24 Miltenyi Biomedicine, Bergisch Gladbach, Germany
25 Miltenyi Biomedicine, Bergisch Gladbach, Germany
26 University Hospital Leuven, Leuven, Belgium
ABSTRACT
Background
DALY 2-EU is a randomized study comparing zamtocabtagene autoleucel (zamto-cel), a tandem CD20-CD19 CAR-T cell therapy, with standard-of-care (SoC) chemoimmunotherapy in transplant-ineligible patients with R/R LBCL. Between Oct 2021 and Jul 2024, 168 patients were randomized to zamto-cel or SoC (R-GemOx or Pola-BR). Following a protocol amendment (Feb 2023), patients randomized to SoC who relapsed or progressed within one year of randomization or failed to achieve a partial (PR) or complete (CR) response at or beyond week 8 after randomization became eligible to crossover and receive zamto-cel in third line. We report updated efficacy and safety outcomes from this crossover cohort after approximately one year of follow-up.
Methods
Thirty-one patients in the SoC arm met protocol-defined crossover criteria and were approved for crossover; 29 (94%) received zamto-cel (2.5 × 10^6 CAR-positive viable T cells/kg). The leukapheresis product was collected after randomization and cryopreserved. Zamto-cel was manufactured after crossover approval, in alignment with the trial site. Chemoimmunotherapy, radiation, and steroids were permitted as bridging therapy. Exploratory efficacy endpoints included investigator-assessed ORR, CR rate, PFS, and EFS in the Crossover Efficacy Analysis Set (n=29). Safety was assessed according to ASTCT criteria for CRS and ICANS. Other safety endpoints included TEAEs occurring from infusion to 90 days post-infusion and before new anti-lymphoma therapy in the Crossover Safety Analysis Set (n=29).
Results
In this crossover cohort (n=30), baseline characteristics reflected a heavily pretreated, high-risk population. Fifty-three percent were refractory to first-line therapy, and among those with relapsed disease, 71.4% had an early relapse (<12 months from the start of first-line therapy). The median age was 74 years (41% were ≥75 years), 50% had IPI 3–5 and 20% had ECOG ≥2.
Zamto-cel was manufactured for all patients on the first attempt. Four patients received a cryopreserved product due to infection in 2 patients, compression of the bile ducts in 1 patient and paralytic ileus in 1 patient. At the one-year data cutoff of DALY 2-EU (July 15, 2025), ORR was 79.3%, including a CR rate of 65.5%. Median duration of response (DOR) was not reached and the estimated 12-month DOR rate was 73% (95% CI, 0.49–0.87).
With a median follow-up of 11.0 months, median PFS and EFS were both 16.6 months (95% CI, 6.54–NC), with estimated 12-month PFS and EFS rates of 65% (95% CI, 0.39–0.81). Three additional events of progression were observed since the primary analysis (cut-off January 15, 2025). Median OS was not reached, with an estimated 12-month OS rate of 77%. Between zamto-cel infusion and the end of follow-up, nine deaths were reported, including 5 that occurred since the primary analysis, all attributable to malignant neoplasm progression.
Any-grade CRS and ICANS occurred in 48.3% of patients (Grade ≥3: 6.9%) and 17.2% (Grade ≥3: 3.4%), respectively. Any-grade neutropenia occurred in all patients, with Grade ≥3 in 79.3%. Grade ≥3 events peaked at day 5 following zamto-cel infusion (62.1%) and resolved rapidly thereafter, declining to 6.9% at week 6. Grade ≥3 anemia was reported in 6 (20.7%) patients and thrombocytopenia in 9 (31%) patients. Eleven (37.9%) patients received transfusions within 12 months after crossover approval. B-cell aplasia (<5 B cells per μl) was observed in all 29 (100%) patients at crossover and persisted in most participants throughout the follow-up (8/13 [61.5%] of evaluable patients at week 36). The highest incidence of hypogammaglobulinemia (IgG <4 g/L) was observed at week 14 (7/24 [29.2%] of evaluable patients); one patient received immunoglobulin replacement therapy. Treatment-emergent infections occurred in 14 (48.3%) patients (Grade ≥3 in 7 [24.1%] patients). The most frequently reported infection was pneumonia (3 patients).
Conclusion
In this crossover cohort of transplant-ineligible patients with R/R LBCL who experienced inadequate response or progression after second-line SoC therapy, third-line treatment with zamto-cel demonstrated high complete response rates and durable disease control, with an estimated 12-month PFS rate of 65% and median OS not reached. The safety profile was manageable and consistent with previous studies of zamto-cel. These findings support zamto-cel as an effective treatment option in the third-line setting for this high-risk patient population.
DISCLOSURES
Tom Van Meerten, MD, PhD: Kite/Gilead - Honoraria; Genentech - Research Funding; Siemens Healthineers - Research Funding; Kite/Gilead - Consultancy (Includes expert testimony)