Twenty-seven patients died in the Zynlonta arm of ADC Therapeutics’ LOTIS-5 Phase 3 confirmatory trial. Nine died in the control. That 3-to-1 gap in treatment-emergent Grade 5 events triggered a 66% stock collapse over a month, dropping shares to $1.14 and prompting a 17% workforce cut: roughly 32 of 193 roles.
The anti-CD19 ADC won accelerated approval in 2021 for third-line-or-later DLBCL; LOTIS-5 was its shot at full approval and, crucially, a second-line label. The combination with rituximab met the primary PFS endpoint: 6.1 months versus 4.7 months. But it showed no overall survival benefit and left a death-rate gap FDA can’t ignore.
ADC Therapeutics called the fatalities treatment-emergent adverse events and said a majority occurred in patients 75 and older. The company doesn’t say the deaths were definitively linked to Zynlonta. But a 13.2% Grade 5 rate against 4.6% in the control arm makes the second-line commercial case harder to argue.
The strategic reorganization will cost about $3 million in severance and extend the company’s cash runway into 2028. ADC is still going for it: CEO Ameet Mallik said the company continues to “believe in the favorable overall benefit-risk profile.”
Whether FDA signs off on a drug with a 13.2% Grade 5 rate (against 4.6% in controls) in a setting where effective alternatives exist will set a floor for what “verified clinical benefit” in confirmatory data actually requires. Zynlonta met PFS. That may not be enough.
ADC’s pre-sBLA meeting with FDA is scheduled for August. A supplemental BLA submission targets Q4 2026.
Sarah Chen