Zamtocabtagene autoleucel, a tandem CD20-CD19 directed CAR-T cell therapy as second-line treatment for Relapsed/Refractory large B-cell lymphoma: primary analysis of the randomized, pivotal DALY 2-EU study. Free

Background: Zamtocabtagene autoleucel (zamto-cel) is an autologous, non-cryopreserved tandem CD20-CD19 directed CAR-T cell therapy produced on the fully automated CliniMACS® Prodigy System in 12 days. Interim results from a phase II study (NCT04792489) in adults with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after at least 2 lines of treatment had shown a promising risk-benefit profile. Here, we report the results of the primary analysis of the pivotal DALY 2-EU trial (NCT04844866), which compares zamto-cel with standard of care (SoC) as second-line (2L) therapy for r/r LBCL in non-transplant eligible (NTE) patients (pts).

Methods: DALY 2-EU is a randomized, multicenter, pivotal study. Adult NTE pts with primary refractory or relapsed (≤24 months after start of first-line [1L] therapy) LBCL were randomly assigned to receive zamto-cel or SoC (R-GemOx, n=78 or Pola-BR, n=8). The primary analysis was the comparison of zamto-cel vs R-GemOx. Key inclusion criteria were LBCL, ECOG PS ≤ 2, age ≥ 18 years (y) and one NTE criterion, age ≥ 65 y and impaired organ function or age ≥70 y. Pts in the zamto-cel arm started lymphodepletion (fludarabine and cyclophosphamide) during manufacturing, followed by infusion of a non-cryopreserved zamto-cel product, target dose 2.5 × 10⁶ CAR-T cells/kg body weight. No chemoimmunotherapy bridging except steroids was allowed. One-sided crossover to zamto-cel was implemented during the trial. The primary endpoint was event free survival (EFS), defined as the time between the date of randomization and the date of objective disease progression, failure to achieve at least partial response at or beyond week 8 leading to a new anti-lymphoma therapy, or death of any cause, whichever occurred first.The significance level of the 1-sided stratified log rank test assessing for superiority is ≤ 0.025. The disease was assessed by a blinded, independent review committee using the Lugano criteria 2014. Key secondary endpoints included remission rates, progression-free survival (PFS), and overall survival. The efficacy analyses were conducted on the intention-to-treat (ITT) set.

Results: Between 10/2021 and 07/2024, 168 pts were randomized in 12 countries (N=82 zamto-cel, N=86 SoC). Key baseline characteristics were balanced: 63% of pts were male, median age was 74 y (range 19-87), 85% had DLBCL, 57% were refractory to 1L therapy, 24% relapsed within 12 months and 18% between 1-2years after start of 1L therapy. 57% of patients had IPI 3-5, and 66% were stage III-IV. Of the 82 randomized patients, 76 (93%) received zamto-cel. Six pts did not receive zamto-cel (2× withdrawal, coronary artery stenosis, pneumonia, worsening condition, progressive disease). The median vein-to-vein time was 15 days (range 14-16).

At the data cut-off date (15 January 2025) and a median follow-up of 17 months, median EFS was 6.2 months (95% CI 3.8-13.8) for zamto-cel and 2.5 months (95% CI 2.0-3.3) for R-GemOx (HR 0.39; 95% CI 0.27-0.58; p<0.0001). The median PFS was significantly longer with zamto-cel vs R-GemOx (8.5 months [95% CI 3.8-16.8] vs 3.3 months [95% CI 2.0-3.8]; HR 0.43 [95% CI 0.28-0.65]; p<0.0001). In the ITT population, the ORR was 72% (61-81%) with a CR rate of 54% for zamto-cel vs 45% (34-57%) ORR and 14% CR rate for R-GemOx. Among all patients treated with zamto-cel in the experimental arm, the ORR was 78%, with 58% achieving CR. Among patients randomized to SoC, 29 received zamto-cel after crossover.

In the zamto-cel arm, CRS Grade (G) ≥ 3 was reported in 4 pts (5.3%; 2 pts G3, 1 pt G4, 1 pt G5). The median time to onset of CRS was 2 days (1-14), median duration was 3 days (1-24). One pt (1.3%) had ICANS G3, no G4/5. For CRS 29 (38%) pts received tocilizumab and 14 (18%) corticosteroids. Persisting neutropenia (≥ 28 days) of G4 was reported in 7 pts (9%). Within 90 days after start of treatment, 8 pts treated with zamto-cel and 8 patients treated with R-GemOx died; the main reason was progression of disease in 4 (50%) and 5 (63%) pts.

Conclusions: Zamto-cel demonstrated highly significant and clinically meaningful superiority over R-GemOx in NTE patients at high risk for treatment failure. Moreover, zamto-cel was well tolerated in this vulnerable elderly patient population with low rates of severe CRS and ICANS. This favorable risk/benefit profile suggests the use of zamto-cel as preferred treatment option in 2L for NTE patients with r/r LBCL.