Optimized Glofitamab Schedule Halves Mortality Risk After CAR T Failure in Diffuse Large B-Cell Lymphoma: A Phase 2 Trial with External Control Arm Conducted by The LYSA Group

Background Failure after anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in diffuse large B-cell lymphoma (DLBCL) is associated with poor survival and no established standard of care. We previously reported the phase 2 LYSA BiCAR trial of short-ramp-up glofitamab after CAR T-cell failure. Here, we present the final survival results and a pre-specified external comparative effectiveness analysis against a contemporary control arm constructed from academic data. Methods BiCAR is a multicenter, single-arm trial in adults with CD20-positive DLBCL refractory to, or in first relapse/progression after anti-CD19 CAR T-cell therapy. Participants received obinutuzumab pretreatment followed by intravenous glofitamab with an accelerated step-up to 30 mg within 8 days, then 30 mg every 21 days for up to 11 cycles. For comparative analyses, we constructed an external control arm from patients included in the French DESCAR-T registry and the ALYCANTE phase 2 trial who experienced CAR T-cell failure, who subsequently started non-bispecific systemic therapy, met key BiCAR eligibility criteria, and initiated treatment within a ±1-month window around the BiCAR treatment period. To minimise datasource bias, both arms, glofitamab (BICAR) and control, were constructed from individual patient data from the DESCAR-T registry and the ALYCANTE trial. A propensity score including major prognostic variables was estimated and applied using stabilized inverse probability of treatment weighting with multiple imputation. Additional weighting schemes and restrictions were applied in sensitivity analyses, and restricted mean survival time (RMST) was evaluated by treatment arm. Results Among 47 enrolled BiCAR patients, 46 received glofitamab. At a median follow-up of 30.4 months, median overall survival (OS) was 17.3 months, and the 2-year OS rate was 38.3%. For comparative effectiveness, 45 glofitamab-treated patients and 133 controls formed the analysis cohort. In the primary weighted analysis, median OS was 19.6 months for glofitamab and 7.6 months for controls, with a hazard ratio for death of 0.49 (95% CI, 0.31–0.79; P =0.007). Multiple sensitivity analyses yielded consistent estimates. Glofitamab significantly improved the RMST of 5 months ( P =0.007) over a 2-year follow-up. Conclusions In this robust comparative effectiveness study, short-ramp-up glofitamab immediately after CAR T-cell failure significantly increases the chance of survival compared to contemporaneous non–bispecific salvage therapies, supporting its use as a preferred option for eligible patients with DLBCL who fail anti-CD19 CAR T-cell therapy. Trial registration.ClinicalTrials.gov identifier NCT04703686.