ADC Therapeutics slumps on cancer drug safety scare
Shares in ADC Therapeutics were trading down more than 50% today after a non-Hodgkin lymphoma (NHL) trial showed more deaths with its Zynlonta drug compared to standard therapy.
The LOTIS-5 trial is designed as a confirmatory study to upgrade Zynlonta's accelerated approval by the FDA in 2021 for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more earlier lines of prior therapy, based on response rates in the LOTIS-2 study.
It is also intended to move Zynlonta (loncastuximab tesirine) up the treatment pathway into the second-line setting, unlocking a market that ADC Therapeutics has said is worth around $3 billion in the US alone. Sales of the ADC were just under $74 million last year.
The new results reveal that Zynlonta – a CD19-targeted antibody-drug conjugate – given with rituximab improved progression-free survival (PFS) by 27%, with a median PFS of 6.1 months compared to 4.7 months with rituximab and chemotherapy.
What has spooked investors seems to be the overall survival data, and the lack of a benefit on this measure with ADC Therapeutics' drug, even though the company insisted that statistically there was "no detrimental effect" with Zynlonta. Deaths were recorded in 13.2% of the treatment arm, however, compared with 4.6%, deaths in the control arm, with most occurring in older, frailer patients. There was also an overall higher rate of more severe adverse events with Zynlonta (49.0% versus 34.5%).
It's worth noting that the Swiss biotech discontinued a trial of Zynlonta in previously-untreated DLBCL (LOTIS-9) in 2023 after several deaths, which may have sensitised followers of the company to the potential for adverse safety signals. Meanwhile, the company has pointed out that the treatment arm had a longer observation time than the controls, which could explain the disparity in fatalities.
ADC Therapeutics' chief executive, Ameet Mallick, said that "based on the totality of the data, we plan to discuss the benefit-risk profile of this combination with the US FDA as we prepare for the planned supplemental Biologics License Application (sBLA) filing."
The company is hoping to have a pre-filing meeting with the FDA in August and follow up with an sBLA before the end of the year.
Analysts suggested the deaths could overshadow the PFS results, and the safety trade-off may make it harder for ADC Therapeutics to build a position for the drug earlier in treatment, if approved, and may not be strong enough to convert later-line use to full approval.
