Three times as many deaths in the study arm versus the control arm in a trial of ADC Therapeutics' Zynlonta have raised questions about the antibody-drug conjugate (ADC), which has been on the market since the FDA granted it accelerated approval in 2021.
In the phase 3 LOTIS-5 trial, which included 440 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), there were 27 deaths (13.2%) in the study arm compared to nine (4.6%) in the control group. Zynlonta was paired with Roche’s monoclonal antibody Rituxan, while those in the control arm received Rituxan plus the chemotherapies gemcitabine and oxaliplatin.
Most of the deaths in the treatment arm were among patients age 75 and older and were due to infections, ADC execs said on a conference call on Wednesday. The company added that the higher rate could also be chalked up to extended monitoring of patients in the treatment arm as opposed to those in the control arm.
“This difference is primarily driven by a higher rate of and earlier switching to subsequent therapies in the control arm,” ADC explained in its release.
In addition to the deaths, there was a higher rate of serious adverse events (SAEs) in the study arm (49%) versus the control arm (34.5%) and withdrawals from treatment in the Zynlonta arm (25.5%) versus the control arm (9.1%).
The deaths, which are referred to as Grade 5 treatment emergent adverse events (TEAEs) in the company’s release, overshadowed the positive topline results from the trial, which achieved its primary endpoint of progression-free survival (6.1 months vs. 4.7 months).
The Zynlonta/Rituxan combo also provided a higher complete response rate (39.5% vs. 26.7%) and a longer duration of complete response (16.8 months vs. 12.3 months). There also was no “detrimental effect” on the secondary endpoint of overall survival, ADC said.
The confirmatory trial was designed to pave the way for full approval of Zynlonta and to advance it from third-line to second-line use.
With the results, which were disclosed Wednesday afternoon after the market closed, ADC’s share price plummeted by 52%.
Zynlonta is the Swiss company’s lone commercial product, generating sales of $74 million last year and $20 million in the first quarter of this year. ADC reported a month ago that it had $231 million in cash, with its runway extending into 2028.
CEO Ameet Mallik said during the conference call that the company will meet with the FDA in August to discuss the results and its plan to submit for approval in the fourth quarter of this year.
ADC also is investigating Zynlonta in the LOTIS-7 trial in combination with Roche’s bispecific antibody Columvi as a treatment for B-cell non-Hodgkin lymphoma. In a phase 1b study of the combo, there were just two deaths among 49 patients (4.1%).