Miltenyi's Dual-Target CAR-T Therapy Shows Superior Efficacy in Pivotal Trial for Relapsed Large B-Cell Lymphoma
核心洞察
Zamtocabtagene autoleucel (zamto-cel (搜索)) demonstrated statistically significant superiority over standard chemoimmunotherapy in the pivotal DALY 2-EU trial for second-line relapsed/refractory large B-cell lymphoma (搜索).
The dual CD20 (搜索)-CD19 (搜索) targeting CAR-T therapy achieved a median event-free survival of 6.2 months versus 2.5 months for R-GemOx (搜索) (HR 0.39; p<0.0001) in transplant-ineligible patients.
Zamto-cel (搜索)'s 12-day manufacturing process enables a 14-16 day vein-to-vein time, potentially reducing the need for bridging therapy in high-risk patients.
Miltenyi Biomedicine (搜索) announced positive results from its pivotal DALY 2-EU trial, demonstrating that zamtocabtagene autoleucel (zamto-cel (搜索)) significantly outperformed standard chemoimmunotherapy in patients with second-line relapsed or refractory large B-cell lymphoma (r/r LBCL) who were ineligible for stem cell transplantation. The randomized Phase II study represents the first CAR-T randomized trial in this patient population.
Trial Design and Patient Population
The DALY 2-EU trial (NCT04844866) enrolled 168 patients across 12 European countries, randomizing them 1:1 to receive either zamto-cel (搜索) (n=82) or standard chemoimmunotherapy with R-GemOx (搜索) or Pola-BR (搜索) (n=86). The study population was characterized by high-risk features, with a median age of 74 years, 57% of patients having a high International Prognostic Index (IPI≥3), and 67% presenting with stage III/IV disease.
Eligible patients had r/r LBCL that was refractory or relapsed within 24 months from first-line treatment, had received at least an anthracycline and rituximab-containing regimen, and were ineligible for stem cell transplant due to age, comorbidities, or other medical reasons.
Efficacy Outcomes
The primary analysis, assessed by a blinded independent review committee, showed zamto-cel (搜索) achieved superior efficacy across multiple endpoints. The median event-free survival (EFS) for zamto-cel was 6.2 months (95% CI 3.8-13.8) compared to 2.5 months (95% CI 2.0-3.3) for R-GemOx (搜索), representing a 61% reduction in risk of events (HR 0.39; 95% CI 0.27-0.58; p<0.0001).
Progression-free survival also favored zamto-cel (搜索), with a median of 8.5 months (95% CI 3.8-16.8) versus 3.3 months (95% CI 2.0-3.8) for R-GemOx (搜索) (HR 0.43; 95% CI 0.28-0.65; p<0.0001). In the intent-to-treat population, the overall response rate was 72% with a 54% complete response rate for zamto-cel, compared to 45% overall response rate and 14% complete response rate for R-GemOx.
Safety Profile
Zamto-cel (搜索) demonstrated a favorable safety profile in this elderly, high-risk population. Grade ≥3 cytokine release syndrome (CRS) was reported in 4 patients (5.3%), while Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in only 1 patient (1.3%).
Novel Dual-Target Approach
Zamto-cel (搜索) represents the first tandem CD20 (搜索)-CD19 (搜索) directed, non-cryopreserved CAR-T cell therapy. The dual targeting approach addresses a key limitation of CD19-directed CAR-T therapies, where relapse can occur due to CD19 antigen escape, limited CAR-T cell persistence, or inhibition of CAR-T cell function.
The therapy is manufactured using Miltenyi's proprietary closed, automated system with a 12-day manufacturing time, resulting in a vein-to-vein time of 14-16 days. This rapid turnaround reduces the likelihood of requiring bridging therapy and increases treatment accessibility for high-risk patients with urgent therapeutic needs.
Clinical Context and Expert Perspectives
Dr. Peter Borchmann, lead investigator of the DALY 2-EU trial and Assistant Medical Director in the Department of Hematology and Oncology at the University Hospital of Cologne (搜索), Germany, stated: "Zamto-cel (搜索) demonstrated clinically meaningful and statistically significant superiority over R-GemOx (搜索) in transplant-ineligible patients with high-risk disease, improving event-free survival while maintaining a favorable tolerability profile. These findings highlight the potential of zamto-cel as an important new treatment option for a clinically vulnerable patient population with limited therapeutic choices."
Dr. Toon Overstijns, Chief Executive Officer of Miltenyi Biomedicine (搜索), commented: "The DALY 2-EU results mark an important milestone in our commitment to advancing cell and gene therapies. Zamto-cel (搜索) - the first tandem CD20 (搜索)-CD19 (搜索) (directed), non-cryopreserved CAR-T cell therapy - demonstrated meaningful clinical benefit with promising efficacy and safety, bringing us closer to providing much needed treatment options for patients with high-risk lymphomas."
Broader Development Program
The DALY 2-EU results complement previous zamto-cel (搜索) data from other studies. In the DALY II USA trial (NCT04792489), a single-arm Phase II study in patients with r/r DLBCL after at least two prior lines of treatment, the overall response rate was 72.9% (95% CI, 59.7-83.6) with a complete response rate of 49.2% (95% CI, 35.9-62.5) in the evaluable patient population (n=59).
A dedicated cohort for relapsed/refractory central nervous system lymphoma (搜索) within the DALY II USA trial showed promising results, with overall response rates of 80% and 100% and complete response rates of 50% and 100% in primary CNS lymphoma and secondary CNS lymphoma patients, respectively. Zamto-cel (搜索) is also being explored in relapsed/refractory mantle cell lymphoma (搜索) and Richter's transformation (搜索).
The trial allowed for crossover, with 29 patients receiving zamto-cel (搜索) following failure to achieve a response with either R-GemOx (搜索) (n=28) or Pola-BR (搜索) (n=1). Additional analyses with longer follow-up periods are planned and will be presented at future meetings.