In addition to a high rate of deaths, ADC Therapeutics’ Zynlonta plus rituximab showed no overall survival benefit in patients with diffuse large B cell lymphoma, casting doubt on its value as a second-line treatment in this indication.
There were thrice as many deaths in patients treated with ADC Therapeutics’ lymphoma drug Zynlonta as in controls given standard immunotherapy, causing the biotech’s share price to crash more than 50% to $1.44 per share and potentially complicating the drug’s future.
The anti-CD19 antibody-drug conjugate (ADC) won the FDA’s accelerated approval in April 2021 for relapsed or refractory diffuse large B cell lymphoma (DLBCL) in third-line or later settings. The new data come from the confirmatory Phase 3 LOTIS-5 study intended to gather data that could support the drug’s full approval, potentially in earlier lines of treatment.
The trial enrolled a total of 440 patients with DLBCL who had undergone at least one prior line of systemic therapy. They were treated either with Zynlonta and rituximab or a standard course of rituximab plus gemcitabine and oxaliplatin.
In the Zynlonta arm, 27 patients died, compared with nine deaths in the control group, according to a news release on Thursday morning. The biotech described these deaths as treatment-emergent adverse events (TEAE), which captures side effects that arise within 105 days after the last dose of the study treatment or before the start of a new anti-cancer treatment, whichever happens earlier.
ADC did not say whether these deaths were definitively linked to or caused by the Zynlonta regimen. The biotech did, however, note that the overall rates of TEAE—including the deaths and other toxicities—“were impacted by the longer overall TEAE observation time” in experimental versus control arms.
The company also said that a “majority” of the deaths in the Zynlonta arm were in patients 75 years and older.
The rate of deaths in the Zynlonta arm was “strongly elevated,” analysts at Stephens told investors in a note on Thursday morning, adding that this in turn could “obscure thoughts on meaningful potential 2L [second-line] utilization.”
Aside from these safety concerns, ADC’s data on Thursday also demonstrated no overall survival benefit in patients treated with the Zynlonta-based schedule. The biotech presented this outcome by saying that the Zynlonta therapy “showed no detrimental effect” on overall survival, but Stephens nevertheless said the efficacy readout “underwhelms expectations.”
LOTIS-5 did meet its primary endpoint, however, of demonstrating a significant progression-free survival effect. Patients on the Zynlonta combo saw a 27% reduction in the risk of death or disease progression versus controls. Overall and complete response rates were likewise higher with the Zynlonta regimen, though ADC did not say whether these effects were statistically significant.
ADC will take LOTIS-5 data to the FDA to discuss a path forward for Zynlonta plus rituximab, Chief Medical Officer Mohamed Zaki said in a prepared statement on Thursday. The biotech plans to submit a supplemental application for the drug’s full approval in the fourth quarter.
