Multinational randomized phase 2 trial of second-line zamtocabtagene autoleucel for R/R LBCL in transplantation-ineligible patients

Anti-CD19 CAR T-cell therapy is the standard second-line treatment for patients with relapsed or refractory large B-cell lymphoma. However, there is no evidence from randomized controlled trials in patients ineligible for transplantation. To addrress this gap, the randomized phase 2 DALY 2-EU trial, at 45 centers across 12 countries, compared zamtocabtagene autoleucel (zamto-cel; CAR T-cell therapy directed at CD20 and CD19) versus rituximab-gemcitabine-oxaliplatin (R-GemOx) chemoimmunotherapy in transplantation-ineligible relapsed or refractory large B-cell lymphoma (R/R LBCL) who had received first-line chemoimmunotherapy. The primary endpoint was event-free survival assessed by a masked independent review committee. A total of 160 patients were randomized to zamto-cel (n=82) or R-GemOx (n=78). Median vein-to-vein time for zamto-cel was 15 days (IQR 15-16). With a median follow-up of 17.0 months (IQR 9.0-22.8), event-free survival was longer in the zamto-cel group than in the R-GemOx group (6.21 months versus 2.53 months; HR 0.39; 95% CI 0.27-0.58; p<0.0001). Grade 3 or higher treatment-emergent adverse events occurred in 83% of patients with zamtocel and 86% of patients with R-GemOx; serious adverse events occurred in 41% and 66%, respectively. Treatment-related deaths occurred in two patients with zamto-cel and one patient with R-GemOx. The authors conclude that the risk-benefit ratio observed in DALY 2-EU supports considerationof zamto-cel as second-line standard treatment option for patients with R/R LBCL who are ineligible for transplantation.