A phase 3 study of ADC Therapeutics’ blood cancer drug Zynlonta has raised concerns after the treatment arm recorded three times as many deaths as the control arm, despite the antibody-drug conjugate (ADC) already being on the market following accelerated approval from the FDA in 2021.
The late-stage LOTIS-5 trial enrolled 440 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In the study, 27 patients (13.2%) in the treatment arm died compared with nine patients (4.6%) in the control group. Patients receiving the experimental regimen were treated with Zynlonta alongside Roche’s monoclonal antibody Rituxan, while the control arm received Rituxan combined with chemotherapy agents gemcitabine and oxaliplatin.
During a conference call on Wednesday, ADC executives indicated that most deaths in the treatment group occurred among patients aged 75 years and older and were linked to infections. Company representatives also suggested that the higher death rate may partly reflect longer patient follow-up in the treatment arm compared with the control group.
ADC Therapeutics further stated in its release that the imbalance was largely attributable to a higher frequency of patients in the control arm switching earlier to subsequent therapies.
Beyond mortality concerns, the study also reported a greater proportion of serious adverse events (SAEs) in the treatment arm, reaching nearly 50%, compared with just over 34% in the control group. Treatment discontinuations were also substantially higher among patients receiving Zynlonta, occurring in 25.5% of participants versus just over 9% among controls.
The deaths, classified as Grade 5 treatment-emergent adverse events (TEAEs), undermined the otherwise favorable topline findings from the trial. LOTIS-5 successfully met its primary goal, with progression-free survival reaching 6.1 months in the Zynlonta-Rituxan arm versus 4.7 months in the control group.
The Zynlonta-Rituxan combination also delivered a higher complete response rate of almost 40%, compared with 26.7% in the control arm, while the duration of complete response lasted longer at 16.8 months versus 12.3 months. ADC additionally reported that the treatment showed no harmful impact on the secondary endpoint of overall survival.
The confirmatory trial was intended to support full FDA approval for Zynlonta and expand its use from third-line to second-line treatment. Following disclosure of the findings on Wednesday after markets closed, ADC Therapeutics’ share price dropped by 52%.
Zynlonta remains ADC Therapeutics’ only commercial product, generating $74 million in revenue last year and $20 million during the first quarter of this year. The company reported last month that it held over $230 million in cash, which management expects to sustain operations through 2028.
ADC Therapeutics CEO Ameet Mallik stated during the conference call that the company plans to meet with the FDA in August to review the data and discuss a regulatory submission strategy, with the aim of filing for approval in the fourth quarter of this year.
The company is also continuing to evaluate Zynlonta in the LOTIS-7 study, where it is being tested in combination with Roche’s bispecific antibody Columvi for B-cell non-Hodgkin lymphoma.
Zynlonta has become the focus of industry attention following the release of clinical trial data that included reports of multiple patient deaths. The findings have prompted increased scrutiny from investors, researchers, and healthcare professionals as they assess the safety profile of Zynlonta and its future development prospects.
While adverse events are carefully monitored throughout the clinical trial process, reports involving serious outcomes can significantly influence regulatory reviews, development strategies, and stakeholder confidence. The latest data surrounding Zynlonta highlight the importance of comprehensive safety evaluations in oncology drug development.
Zynlonta Faces Increased Safety Review
The reported trial outcomes have led to heightened examination of Zynlonta and its overall benefit-risk profile. Clinical investigators are reviewing available data to determine the factors that may have contributed to the observed patient deaths and whether they were directly related to treatment, disease progression, underlying health conditions, or other contributing variables.
For Zynlonta, understanding these factors will be critical in shaping future development decisions and regulatory discussions.
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