Zamto-Cel Improves EFS vs R-GemOx in Transplant-Ineligible R/R LBCL

Zamtocabtagene autoleucel (zamto-cel), a tandem CD20/CD19-directed CAR T-cell therapy, significantly improved event-free survival (EFS) vs rituximab (Rituxan), gemcitabine, and oxaliplatin (R-GemOx) as second-line treatment for patients with relapsed/refractory large B-cell lymphoma (LBCL) who were ineligible for transplantation, according to results from the primary analysis of the phase 2 DALY 2-EU trial (NCT04844866) published in The Lancet Oncology.

At a median follow-up of 17.0 months, the median EFS by independent review committee (IRC) assessment was 6.21 months (95% CI, 3.84-13.77) with zamto-cel vs 2.53 months (95% CI, 1.97-3.35) with R-GemOx (HR, 0.39; 95% CI, 0.27-0.58; P <.0001). The 6-month EFS rates were 54% (95% CI, 42%-64%) and 21% (95% CI, 12%-31%), respectively, and the 12-month EFS rates were 41% (95% CI, 29%-52%) and 12% (95% CI, 5%-21%). The benefit was observed across most prespecified subgroups.

The median progression-free survival (PFS) was 8.51 months (95% CI, 3.84-16.82) with zamto-cel vs 3.35 months (95% CI, 2.04-3.81) with R-GemOx (HR, 0.43; 95% CI, 0.28-0.65; P <.0001), with 12-month PFS rates of 41% (95% CI, 30%-52%) vs 16% (95% CI, 7%-28%). The best complete response (CR) rate through week 24 or 26 was 49% (95% CI, 37.58%-60.08%) vs 14% (95% CI, 7.26%-23.83%; relative risk, 3.45; 95% CI, 1.91-6.21). The best overall response rate (ORR) was 72% vs 45%, including CRs in 54% vs 14% of patients.

No significant difference in overall survival (OS) was observed between zamto-cel and R-GemOx. Adjusted for crossover, the median OS was 17.81 months (95% CI, 9.07-not calculable) vs 15.28 months (95% CI, 8.67-not calculable; HR, 0.77; 95% CI, 0.48-1.23; P = 0.17), with 12-month OS rates of 56% (95% CI, 44%-66%) and 54% (95% CI, 40%-66%). The median duration of CR was 16.59 months (95% CI, 7.82-not calculable) with zamto-cel and not calculable with R-GemOx (HR, 0.84; 95% CI, 0.23-2.99; P = 0.49).

Regarding safety, grade 3 or higher treatment-emergent adverse events (AEs) occurred in 83% of patients treated with zamto-cel and 86% of those treated with R-GemOx. The most common grade 3/4 AEs were neutropenia (37% vs 22%), anemia (14% vs 16%), and decreased neutrophil count (26% vs 9%). Serious AEs occurred in 41% vs 66% of patients, most commonly disease progression (14% vs 50%).

With zamto-cel, any-grade cytokine release syndrome (CRS) occurred in 78% of patients and was grade 3 or higher in 5%; any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 11%, with 1 grade 3 event (1%). Prolonged grade 3 or higher cytopenias occurred in 13% of patients who received zamto-cel. Treatment-related deaths occurred in 2 patients (3%) in the zamto-cel arm, due to CRS and hemophagocytic lymphohistiocytosis, and in 1 patient (1%) in the R-GemOx arm.

“Zamto-cel treatment was associated with low rates of severe CRS or ICANS, despite a population of patients at high risk. In addition, automated manufacturing allowed rapid production of zamto-cel and treatment of almost all patients,” lead author Peter Borchmann, MD, assistant medical director in the Department of Hematology and Oncology and head of the lymphoma program at the University Hospital of Cologne in Germany, wrote in the publication with study coinvestigators.

DALY 2-EU is an open-label, multicenter, randomized phase 2 trial conducted at 45 centers across 12 European countries. Between October 2021 and July 2024, investigators randomly assigned 160 patients 1:1 to zamto-cel (n = 82) or R-GemOx (n = 78). Eligible patients were adults with relapsed/refractory LBCL within 24 months of starting first-line anthracycline- and anti-CD20–based chemoimmunotherapy, had an ECOG performance status of 2 or less, and met prespecified transplant-ineligibility criteria. The median age was 74.0 years, 58% of patients had an International Prognostic Index score of 3 to 5, and 26% had an ECOG performance status of 2.

Zamto-cel was manufactured in a fixed 12-day automated process and given as a single infusion of 2.5 × 10⁶ fresh, non-cryopreserved CAR T cells/kg; holding and bridging therapy were not permitted apart from corticosteroids. The median vein-to-vein time was 15 days, and 93% of patients assigned to zamto-cel received the infusion. R-GemOx was given for up to eight 14-day cycles. A protocol amendment allowed crossover to zamto-cel, and 29 patients from the comparator group received it, with an investigator-assessed ORR of 79% (95% CI, 60.3%-92.0%) and a CR rate of 66%.

The primary end point was IRC-assessed EFS. Key secondary end points included IRC-assessed PFS, best CR rate, duration of CR, and OS.

Among 12 patients who had disease progression after zamto-cel and underwent biopsy, CD19 loss and CD20 loss were each observed in 1 patient (8%), with no cases of loss of both antigens.

The investigators noted several limitations, including a small sample size that may be insufficient to detect rare safety events, crossover that complicates interpretation of OS, and follow-up too short to draw conclusions on durability. In addition, R-GemOx is no longer considered standard of care, so the findings can be compared with current options only indirectly.

The PFS benefit was in line with those reported for glofitamab plus GemOx in the phase 3 STARGLO trial (NCT04408638)(HR, 0.37) and mosunetuzumab plus polatuzumab vedotin in the phase 3 SUNMO trial (NCT05171647) (HR, 0.41) vs R-GemOx, though DALY 2-EU enrolled an older, frailer population.

Reference

Borchmann P, van Meerten T, Iacoboni G, et al. Zamtocabtagene autoleucel, a tandem CD20–CD19-directed CAR T-cell therapy, for second line treatment of large B-cell lymphoma in patients ineligible for transplantation (DALY 2-EU): primary analysis of an open-label, multicentre, randomised phase 2 study. Lancet Oncol. 2026;27(11):1403-1419. doi:10.1016/S1470-2045(26)00290-1