ADC Therapeutics said its Phase III confirmatory trial for loncastuximab tesirine (Zynlonta) ran into a safety stumbling block after reporting higher fatalities in the treatment arm of LOTIS-5. The study met its primary endpoint of progression-free survival versus rituximab monotherapy in relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Despite the efficacy signal, ADC reported that overall patient deaths were higher in the Zynlonta plus rituximab arm than in the control. The company also disclosed that Grade 5 treatment-emergent adverse events (TEAEs) were three times higher in the treatment group, with infections identified as the leading cause of death. Company leadership said overall survival did not show a detrimental effect as a key secondary endpoint, and ADC pointed to possible explanation related to observation-window definitions and differential switching to subsequent therapies. Still, investors highlighted that the Grade 5 TEAE rate appeared higher than earlier LOTIS-2 results. For the ADC space, the readout underscores the sensitivity of confirmatory trials to TEAE profiles and trial design details—particularly infection risk—when comparing add-on regimens against established controls.