A clinical trial of ADC Therapeutics’ Zynlonta had three times as many deaths in the study group compared to the control group, raising questions about antibody-drug conjugates (ADCs) on the market since the FDA granted accelerated approval in 2021.
In the phase 3 LOTIS-5 trial, which enrolled 440 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), 27 people (13.2%) died in the study group, compared with 9 (4.6%) in the control group. Zynlonta was combined with Roche’s monoclonal antibody Rituxan, while patients in the control group received Rituxan plus the chemotherapy drugs gemcitabine and oxaliplatin.
Most of the deaths in the treatment arm were in patients 75 and older and were caused by infectious diseases, ADC executives said in a conference call Wednesday. The company added that this higher rate may also be due to extended monitoring of patients in the treatment group rather than those in the control group.
“This difference is primarily driven by higher and faster switch rates to subsequent treatments in the control arm,” the ADC explained in a release.
In addition to death, the incidence of serious adverse events (SAEs) was higher in the study group (49%) versus the control group (34.5%), and treatment discontinuation occurred in the Jinronta group (25.5%) versus the control group (9.1%).
The death, called a grade 5 treatment-emergent adverse event (TEAE) in the company’s release, overshadowed the trial’s positive topline results, which met its primary endpoint of progression-free survival (6.1 months vs. 4.7 months).
The Zynlonta/Rituxan combination also resulted in a higher complete response rate (39.5% vs. 26.7%) and longer complete response duration (16.8 months vs. 12.3 months). There were also no “adverse effects” on the secondary endpoint of overall survival, the ADC said.
This confirmatory study was designed to pave the way for full approval of Jinlonta and advance it from third-line to second-line status.
The results, released after market close on Wednesday afternoon, sent ADC’s stock price plummeting 52%.
Ginronta is the Swiss company’s only commercial product, with 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 and that its runway would extend through 2028.
CEO Ameet Malik said on a conference call that the company plans to meet with the FDA in August to discuss the results and plans to apply for approval in the fourth quarter of this year.
ADC is also investigating Zynlonta in combination with Roche’s bispecific antibody Columvi as a treatment for B-cell non-Hodgkin’s lymphoma in the LOTIS-7 trial. In a phase 1b trial of the combination therapy, only 2 of 49 patients (4.1%) died.
