FDA cites 'significant concerns' with ADC lymphoma trial
ADC Therapeutics' chief executive, Ameet Mallik.
ADC Therapeutics' chances of upgrading its accelerated approval for diffuse large B-cell lymphoma therapy Zynlonta to a full approval have taken a knock.
In its second-quarter results update, the Swiss biotech said that a meeting with the FDA earlier this month on its confirmatory LOTIS-5 trial of Zynlonta (loncastuximab tesirine) revealed that the US regulator has "substantial concerns regarding the benefit-risk or verification of clinical benefit" in the study.
In June, alarm bells were rung after an update to the results revealed that 13.2% of patients treated with Zynlonta in LOTIS-5 died, compared to 4.6% of the control arm. The FDA is concerned by this "imbalance in Grade 5 events, when assessed in the context of a marginal treatment benefit," ADC told investors this afternoon.
Zynlonta has accelerated approval in the US as a third-line or later treatment for DLBCL, and LOTIS-5 was designed to convert that to a full approval and move the drug up the treatment pathway into the second-line setting.
While the combination of Zynlonta and rituximab improved progression-free survival (PFS) by 27% compared to rituximab plus chemotherapy, there was no benefit on overall survival (OS). Add in the imbalance in deaths between the groups, and ADC's plans for the drug seem speculative at best.
In a statement, the company said it is now "assessing the best regulatory path forward" for Zynlonta and the LOTIS-5 data, whilst also investigating the combination of the drug and Roche's CD20-targeting T-cell engager (TCE) Columvi (glofitamab) as a second-line or later regimen in DLBCL.
It has completed the phase 1 LOTIS-7 trial of Zynlonta/Columvi, and said preliminary results suggest it could be "potentially practice-changing," based on an overall response rate of 90% including 78% complete responses.
Work is now underway on a pivotal trial of the combination as a "foundational therapy in DLBCL," said chief executive Ameet Mallik.
Investors seemed less confident in that assessment, and shares in ACT on the NYSE were down more than 13% at the time of writing, likely because the LOTIS-5 result could – at least in principle – lead to Zynlonta's accelerated approval being rescinded.
Sales of the drug in the second quarter came in at just under $19 million, slightly up on the same period of 2025, and the company is sitting on cash reserves of $219 million, with another pricey phase 3 trial in the offing, and recorded a net loss of $16.6 million for the three-month period.
