Market reaction - ADC Therapeutics SA (NYSE:ADCT) saw its shares drop 45.9% in after-hours trading following the release of topline data from the Phase 3 LOTIS-5 trial. The swing in price came despite the trial meeting its primary efficacy endpoint.
Trial design and efficacy outcome - LOTIS-5 evaluated ZYNLONTA in combination with rituximab for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after one or more lines of systemic therapy. The study reached its primary endpoint, with median progression-free survival (PFS) of 6.1 months for the ZYNLONTA plus rituximab arm compared with 4.7 months for the control arm, R-GemOx.
Additional efficacy measures favored the investigational combination: overall response rate (ORR) was 58.1% versus 45.2%, and complete response (CR) rate was 39.5% compared with 26.7% in the control arm.
Safety profile and concerns - The efficacy signal was accompanied by a notable increase in safety events in the ZYNLONTA plus rituximab group. Serious adverse events occurred in 49.0% of patients receiving the combination versus 34.5% in the control arm. Treatment-emergent Grade 5 adverse events were reported in 13.2% of patients in the combination arm compared with 4.6% in the control arm, with the majority of fatal events occurring in patients aged 75 years or older.
Discontinuations due to adverse events were also higher in the investigational arm: 25.5% of patients discontinued treatment for this reason versus 9.1% in the control arm.
Company next steps and regulatory process - ADC Therapeutics said it will discuss the benefit-risk profile of the ZYNLONTA plus rituximab regimen with the U.S. Food and Drug Administration as it prepares a supplemental Biologics License Application (sBLA). The company intends to hold a pre-sBLA meeting in August and aims to submit the sBLA in the fourth quarter of 2026.
Clinical population - LOTIS-5 enrolled patients with relapsed or refractory DLBCL who had received one or more prior systemic therapies.
Context for investors and markets - The combination of a positive efficacy signal and clear safety liabilities resulted in an acute reassessment by investors, reflected in the substantial after-hours drop in the stock price. The outcome touches on both biotechnology clinical development risk and market sensitivity to safety data, particularly when fatal events are concentrated in an older subset of participants.
Further regulatory dialogue and the planned pre-sBLA meeting in August will be important milestones for clarifying the agency's view of the benefit-risk balance prior to the companys planned sBLA submission in Q4 2026.