ADC Therapeutics nosedives on 27 deaths in confirmatory trial for lymphoma drug

ADC Therapeutics' Zynlonta Trial Sees 27 Deaths, No OS Benefit

ADC Therapeutics' Zynlonta, combined with rituximab, faced significant challenges in the confirmatory Phase 3 LOTIS-5 study for diffuse large B cell lymphoma (DLBCL). The trial reported 27 deaths in the Zynlonta arm compared to nine in the control group, leading to a more than 50% crash in the biotech's share price. While the regimen showed no overall survival benefit, it did meet its primary endpoint of significant progression-free survival, reducing the risk of death or disease progression by 27%. The company plans to discuss these results with the FDA and submit a supplemental application for full approval in Q4.

• The LOTIS-5 trial revealed a concerning safety profile for Zynlonta plus rituximab, with 27 treatment-emergent adverse event (TEAE) related deaths in the experimental arm compared to nine in the control group. The company noted that these deaths were impacted by a longer observation time and a majority occurred in patients 75 years and older, raising questions about the drug's safety, particularly in older populations.
• Despite the safety issues, the Zynlonta combination met its primary endpoint, demonstrating a significant 27% reduction in the risk of death or disease progression (PFS) compared to standard immunotherapy. However, the trial failed to show an overall survival benefit, which analysts described as "underwhelming expectations" and could complicate its potential for broader second-line utilization.
• ADC Therapeutics intends to engage with the FDA to discuss the LOTIS-5 data and the path toward full approval for Zynlonta plus rituximab. The company plans to submit a supplemental application in the fourth quarter, aiming to convert its existing accelerated approval for third-line or later DLBCL into a full approval, potentially for earlier lines of treatment, despite the mixed safety and overall survival results.

Unpacking LOTIS-5: Zynlonta's Mixed Safety and Efficacy Outcomes

The PV-R-CHP versus R-CHOP retrospective analysis (2026) at Kansai Medical University Hospital evaluated polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone against standard R-CHOP in 153 patients. At one year, PV-R-CHP demonstrated superior progression-free survival (89.3% versus 70.9%, HR 0.30, p=0.013) and overall survival (92.5% versus 80.0%, HR 0.28, p=0.041), with particular benefit observed in non-GCB DLBCL patients. Safety profiles were comparable between regimens, with lymphopenia representing the most frequent grade ≥3 toxicity.

The SMART regimen study (2026) examined BTK inhibitor combinations in 84 newly diagnosed DLBCL patients, with 60.7% receiving orelabrutinib, rituximab, and lenalidomide (OR2) and 39.3% receiving zanubrutinib, rituximab, and lenalidomide (ZR2). Over a median 13.5-month follow-up, the regimen achieved a median progression-free survival of 32.4 months with one-year and two-year PFS rates of 85.3% and 63.3%, respectively. Grade ≥3 adverse events occurred in 60.7% of patients, predominantly neutropenia (54.8%), while maintaining an acceptable safety profile.

A comprehensive zanubrutinib meta-analysis (2026) encompassing 47 studies and 1,346 patients revealed distinct efficacy patterns based on treatment history. Previously untreated patients achieved pooled complete response rates of 79.7% and overall response rates of 95.0% with a median progression-free survival of 31.2 months. In contrast, relapsed/refractory patients demonstrated more modest outcomes with pooled complete response rates of 44.7% and overall response rates of 67.5%, achieving a median progression-free survival of 5.9 months and median overall survival of 21.8 months.

Addressing Unmet Needs in Relapsed/Refractory DLBCL

Despite R-CHOP chemoimmunotherapy providing a 60-70% chance of cure, approximately 30-40% of DLBCL patients experience refractory or relapsing disease. Multiple attempts to improve outcomes through R-CHOP intensification, consolidation, or maintenance therapy have largely failed since 2000. Standard salvage approaches remain suboptimal, particularly in the rituximab era.

• Treatment resistance and failure patterns - Salvage chemotherapy and autotransplantation show reduced effectiveness in rituximab-exposed patients, with those progressing through rituximab-containing regimens responding poorly to subsequent therapies

• Lack of standardized salvage therapy - No established standard therapy exists for patients who relapse after or are ineligible for salvage autologous stem cell transplantation, leaving a significant treatment gap

• Patient eligibility constraints - Not all DLBCL patients are candidates for aggressive regimens due to age, performance status, comorbidities, with relapse occurring more frequently in older patients (40% vs. 27%, P = 0.0019)

• Subset-specific therapeutic challenges - Treatment failure reduction with rituximab-chemotherapy combinations occurs predominantly in germinal center B-cell-like subsets, while non-GCB and poor-risk patients require focused therapeutic approaches

• Prognostic and dosing limitations - Current body surface area-based chemotherapy dosing is empirical, and better prognostic stratification along with smarter clinical trial designs incorporating ctDNA endpoints are needed

• Economic burden of newer therapies - CAR T-cell therapy presents substantial economic challenges with median costs of 355,165€ per patient, with drug acquisition costs accounting for 97% of overall expenses

• Ambiguous targeted therapy results - Preliminary clinical trial results exploring targeted therapies based on driver genetic alterations remain inconclusive, highlighting the need for more effective precision medicine approaches

Zynlonta's Future: Navigating the DLBCL Treatment Landscape

Recent investigational therapies for relapsed/refractory DLBCL demonstrate promising activity compared to historical outcomes. The acalabrutinib, lenalidomide and rituximab (R2A) combination achieved a 54.5% objective response rate with 31.8% complete remissions and median duration of response of 12.9 months. Similarly, polatuzumab vedotin-based combinations show encouraging results, with Pola-ZR/G achieving 70% overall response rates and 45% complete responses, while polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) demonstrated 73.6% overall response rates in Japanese patients. CD20-directed bispecific antibodies including epcoritamab and glofitamab achieved overall response rates of 51% and 53% respectively, though median progression-free survival was limited at 2.6 months.

For frontline therapy, the investigational anti-CD20 antibody zuberitamab combined with CHOP (Hi-CHOP) showed superiority over standard R-CHOP in randomized trials. Hi-CHOP achieved higher complete response rates (75.2% vs 67.9%) and demonstrated trends toward improved duration of response, progression-free survival, and overall survival. Particularly notable benefits were observed in the germinal-center B cell-like subtype, where Hi-CHOP produced statistically significant improvements in response rates and survival outcomes. The addition of atezolizumab to R-CHOP yielded a 77.5% complete response rate with 3-year progression-free survival of 77.4%, though this combination carries additional immune-related toxicity risks.

Historical standard-of-care data with R-CHOP demonstrates the benchmark against which newer therapies are measured. Published outcomes show 3-year overall survival rates ranging from 51% in high-risk patients to 87% in low-risk patients, with 4-year overall survival reaching 94% in very good prognosis patients but only 56% in poor prognosis cases. The 5-year overall survival of 76% in young poor prognosis patients highlights the continued need for therapeutic advancement. While newer investigational approaches show promise, particularly in relapsed/refractory settings where standard salvage therapies have limited efficacy, the challenge remains translating these advances into meaningful long-term survival benefits that surpass established R-CHOP outcomes in appropriate patient populations.

Zynlonta's Confirmatory Trial: A Pivotal Test of Benefit-Risk

The recent readout from the LOTIS-5 study for ADC Therapeutics' Zynlonta (loncastuximab tesirine) in combination with rituximab marks a critical juncture for the CD19-directed antibody-drug conjugate, which is already approved as a monotherapy for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). While Zynlonta monotherapy demonstrated substantial antitumour activity and an acceptable safety profile in the pivotal single-arm Phase 2 LOTIS-2 trial, the confirmatory Phase 3 LOTIS-5 trial presents a complex picture.

The trial successfully met its primary endpoint of progression-free survival (PFS), indicating a reduction in the risk of disease progression or death. However, this positive signal is overshadowed by a concerning lack of overall survival (OS) benefit and a notable imbalance in fatal outcomes, with significantly more deaths reported in the Zynlonta arm compared to the control group. This discrepancy between PFS and OS, coupled with the safety signal, poses a substantial challenge for the drug's path to full approval for the combination regimen.

For clinical teams, this raises important questions about the optimal use of Zynlonta. While it addresses an unmet need in heavily pretreated R/R DLBCL, the real-world efficacy has already been observed to be lower in higher-risk patients compared to the LOTIS-2 population. The new data suggest that careful patient selection and a thorough understanding of the benefit-risk profile, especially in combination, will be paramount. The company's strategy moving forward will likely involve:

• Intensive discussions with regulatory bodies to clarify the path to full approval, potentially requiring additional data or a more restricted label.

• A re-evaluation of Zynlonta's competitive positioning in a rapidly evolving landscape that includes CAR-T therapies, bispecific antibodies, and other ADCs like polatuzumab vedotin, where comparative efficacy and safety are key differentiators.

• A deeper dive into identifying specific patient populations who might derive a more favorable benefit-risk from Zynlonta, potentially leveraging biomarkers such as total metabolic tumor volume (MTV) identified in LOTIS-2.

Ultimately, the LOTIS-5 results underscore the high bar for confirmatory trials in oncology and the critical importance of demonstrating a clear overall survival advantage, particularly when safety signals emerge. The future trajectory of Zynlonta will depend heavily on how these complex data are interpreted and addressed by both the company and regulatory authorities.