AbstractWe previously reported results of a first‐in‐human trial of bispecific LV20.19 chimeric antigen receptor T‐cell (CAR‐T) therapy, demonstrating high response rates in patients with relapsed, refractory (R/R) B‐cell malignancies. We now report two‐year survival outcomes and predictors of early response, late relapse, and survival. Patients from the previously reported phase 1 dose escalation and expansion trial of LV20.19 CAR‐T therapy (NCT03019055) treated at target dose of 2.5 × 10⁶ cells/kg (n = 16) were included in this updated analysis. Two‐year progression‐free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier method. The relationship of in‐vivo CAR‐T expansion, tumor burden, and effector: target ratio on early response (day 28) and late relapse (>180 days post‐CAR‐T) were assessed. Exact log‐rank testing was performed to evaluate the impacts of clinical variables on survival outcomes. With a median of 31 months (range 27–40) of follow‐up, two‐year PFS and OS were 44% and 69%. Median PFS and OS were 15.6 months and not reached, respectively. For CAR‐naïve large B‐cell lymphoma patients (n = 8), two‐year PFS and OS were 50% and 75%. No patient with progression experienced dual target antigen (CD19 or CD20) loss on post‐relapse biopsy. Lower in vivo expansion was strongly associated with late relapse. Early treatment response was impeded by high metabolic tumor volume and low effector: target ratio. Bridging therapy and higher absolute lymphocyte count on day of CAR‐T infusion were associated with inferior survival outcomes. In conclusion, this initial trial of LV20.19 CAR‐T demonstrates a signal for favorable long‐term outcomes for patients with R/R B‐cell malignancies.