ADC Therapeutics stock halves after Zynlonta Phase III records three times more deaths than control arm

The Lausanne-based company said its Phase III LOTIS-5 trial met its primary endpoint, showing that Zynlonta (loncastuximab tesirine) plus rituximab, the anti-CD20 antibody that remains a backbone of B-cell lymphoma treatment across multiple lines of therapy, significantly improved progression-free survival compared with rituximab plus a chemotherapy regimen consisting of gemcitabine and oxaliplatin, commonly known as R-GemOx, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The study enrolled 440 patients after at least one prior line of systemic therapy.

A clinical success…

According to ADC Therapeutics, the combination reduced the risk of disease progression or death by 27% compared with the control treatment, a difference the company said was statistically significant. Median progression-free survival reached 6.1 months in the Zynlonta-rituximab arm, compared with 4.7 months in the R-GemOx control arm.

The response data also favoured the Zynlonta combination. Overall response rate was 58.1% versus 45.2%, complete response rate was 39.5% versus 26.7%, and median duration of complete response was 16.8 months versus 12.3 months. Among patients who achieved a complete response, 48.5% in the Zynlonta arm remained in complete response at 24 months, compared with 16.7% in the control arm.

However, the trial did not show that patients lived longer overall. ADC Therapeutics reported an overall survival hazard ratio of 0.96, meaning survival was nearly the same in both treatment groups. The company said the results may have been influenced because patients in the control arm switched to other anti-lymphoma treatments earlier and more often than those receiving Zynlonta plus rituximab.

… overshadowed by death

The more difficult issue is safety. While overall treatment-emergent adverse event rates were similar between arms, serious adverse events were higher with Zynlonta plus rituximab, at 49.0% compared with 34.5% in the control group. Treatment-emergent adverse events leading to drug withdrawal were also more frequent, at 25.5% versus 9.1%.

Most strikingly, Grade 5 treatment-emergent adverse events, meaning adverse events that resulted in death, occurred in 27 patients, or 13.2%, in the Zynlonta-rituximab arm, compared with 9 patients, or 4.6%, in the R-GemOx arm. That represents roughly a threefold imbalance in fatal adverse events. ADC Therapeutics said the majority of these events in the experimental arm occurred in patients aged 75 years or older, and that comparisons were affected by a longer overall adverse-event observation period in the Zynlonta arm, driven partly by earlier switching to subsequent therapies in the control group.

For regulators, LOTIS-5 is important because Zynlonta’s current approvals are conditional on further evidence. The CD19-directed antibody-drug conjugate received accelerated approval in the US in 2021 and conditional approval in the European Union for adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Its existing position is therefore essentially in third-line treatment and beyond.

LOTIS-5 was designed not only to support the confirmatory evidence package behind Zynlonta’s current approval, but also to test whether the drug could move earlier in the treatment sequence. The trial evaluated the antibody-drug conjugate after one or more prior lines of therapy, potentially positioning Zynlonta plus rituximab as a second-line option for patients with relapsed or refractory DLBCL who are not suitable for, cannot access, or relapse after CAR-T and other complex therapies.

ADC Therapeutics said it plans to meet the US Food and Drug Administration in August before a planned supplemental biologics licence application submission in the fourth quarter of 2026. Chief Executive Officer Ameet Mallik said the company would discuss the “benefit-risk profile” of the combination with the agency.

The stock falls

Investors appear unconvinced that the result is straightforwardly positive. ADC Therapeutics’ shares fell about 57% on the day following the announcement, dropping from roughly $3.08 pre-announcement to $1.32 on June 4th. The market reaction underlines the central tension in the readout: Zynlonta plus rituximab achieved the trial’s primary efficacy endpoint, but the benefit appears modest and may be difficult to separate from the safety burden in an older, heavily pre-treated lymphoma population.

The outcome leaves ADC Therapeutics with a regulatory argument, but not an easy one. The company can point to a positive Phase III trial, improved complete response rates and longer response durability. Regulators, however, will have to weigh those gains against the absence of an overall survival advantage and the higher rate of serious and fatal adverse events.