8-K: ADC Therapeutics Reports Strong ZYNLONTA Trial Data

ADC Therapeutics announced updated positive data from its LOTIS-7 Phase 1b clinical trial for ZYNLONTA in combination with glofitamab for relapsed or refractory DLBCL.

Summary

• Updated data from the ongoing LOTIS-7 Phase 1b open-label clinical trial evaluating ZYNLONTA in combination with glofitamab (COLUMVI) in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) was announced.
• As of the November 17, 2025 cutoff date, 49 patients were efficacy evaluable with a minimum of 6 months of follow-up.
• The best overall response rate (ORR) was 89.8% (44/49 patients) as assessed by Lugano criteria.
• The ORR was 95.2% at the 120 g/kg dose and 85.7% at the selected 150 g/kg dose.
• The complete response (CR) rate was 77.6% (38/49 patients), with 33 of these 38 patients remaining in CR as of the data cutoff.
• The CR rate was 81.0% at the 120 g/kg dose and 75.0% at the selected 150 g/kg dose.
• In 24 relapsed patients, ORR was 100% and CR rate was 91.7%.
• In 25 primary refractory patients, ORR was 80% and CR rate was 64%.
• 14 patients converted from stable disease (SD) or partial response (PR) to CR over time (1 and 13 patients, respectively).
• Among 8 patients previously treated with CAR-T, 6 achieved a CR.
• The combination was generally well tolerated with a manageable safety profile.
• Grade 3 or higher treatment emergent adverse events (TEAEs) observed in > 5% of patients included neutropenia (32.7%), GGT increased (16.3%), anemia (10.2%), WBC decreased (8.2%), generalized oedema (8.2%), ALT increased (8.2%), AST increased (6.1%), and thrombocytopenia (6.1%).
• Grade 5 AEs occurred in 2 (4.1%) patients, with one at the 120 g/kg dose being treatment-related per the investigator.
• Cytokine release syndrome (CRS) of all grades across dose levels was 36.7%, with most being low grade.
• Immune effector cell-associated neurotoxicity syndrome (ICANS) was 4.1% across dose levels, with only Grade 1/2 events.

Sentiment

Score: 8

Explanation: The clinical trial data shows very strong efficacy with high overall and complete response rates in a difficult-to-treat patient population, including those previously treated with CAR-T therapy. The safety profile appears manageable. This positive clinical update significantly de-risks the development program and enhances the commercial potential of the combination therapy.

Positives

• Achieved a high best overall response rate (ORR) of 89.8% in a difficult-to-treat patient population.
• Demonstrated a strong complete response (CR) rate of 77.6%, with a majority of patients maintaining CR at data cutoff.
• Showed robust efficacy in both relapsed (100% ORR, 91.7% CR) and primary refractory (80% ORR, 64% CR) patient populations.
• 14 patients converted from stable disease or partial response to complete response over time, indicating durable responses.
• Achieved complete responses in 6 out of 8 (75%) patients previously treated with CAR-T therapy, highlighting efficacy in a highly resistant group.
• The combination therapy was generally well tolerated with a manageable safety profile, with most CRS events being low grade.

Negatives

• Grade 3 or higher treatment emergent adverse events (TEAEs) were observed in a significant portion of patients, including neutropenia (32.7%), GGT increased (16.3%), and anemia (10.2%).
• Two (4.1%) patients experienced Grade 5 adverse events, with one at the 120 g/kg dose being treatment-related.
• Cytokine release syndrome (CRS) occurred in 36.7% of patients across all grades, with a higher incidence at the 120 g/kg dose (52.4%).
• Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4.1% of patients.

Risks

• Potential for significant adverse events, including Grade 3 or higher neutropenia (32.7%), GGT increased (16.3%), anemia (10.2%), WBC decreased (8.2%), generalized oedema (8.2%), ALT increased (8.2%), AST increased (6.1%), and thrombocytopenia (6.1%).
• Risk of severe outcomes, as evidenced by two (4.1%) Grade 5 adverse events, one of which was treatment-related.
• Incidence of cytokine release syndrome (CRS) at 36.7% and immune effector cell-associated neurotoxicity syndrome (ICANS) at 4.1%, which are known toxicities associated with T-cell engaging therapies.

Future Outlook

The filing provides updated clinical trial data, indicating continued development of the ZYNLONTA and glofitamab combination therapy for relapsed or refractory DLBCL. No explicit forward-looking statements regarding commercialization timelines or further trial phases are provided.

Industry Context

Relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) remains a significant unmet medical need, particularly for patients who have failed multiple lines of therapy, including CAR-T. Combination therapies are increasingly explored to improve outcomes. Glofitamab (COLUMVI) is a CD20xCD3 T-cell engaging bispecific antibody developed by Roche, and its combination with ZYNLONTA (loncastuximab tesirine), an antibody-drug conjugate, represents a novel approach to target this aggressive lymphoma. The high response rates observed in this trial are particularly noteworthy given the challenging patient population and could position this combination as a significant therapeutic option.

Comparison to Industry Standards

• Relapsed/refractory DLBCL is a highly challenging indication where standard therapies often yield limited durable responses. The overall response rate (ORR) of 89.8% and complete response (CR) rate of 77.6% for the ZYNLONTA/glofitamab combination are exceptionally high compared to historical benchmarks for this patient population.
• For patients previously treated with CAR-T therapy, the 75% CR rate (6 out of 8 patients) is particularly strong, as this group represents a population with very limited treatment options and poor prognosis.
• Glofitamab monotherapy has demonstrated CR rates around 40% in r/r DLBCL, suggesting a significant synergistic effect when combined with ZYNLONTA, which itself has shown CR rates of approximately 48% as a monotherapy in similar settings.
• Other approved therapies for r/r DLBCL, such as polatuzumab vedotin (Polivy) in combination with bendamustine and rituximab, have reported CR rates around 40% in clinical trials.
• The safety profile, particularly the rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), appears manageable, especially when compared to the higher rates of severe neurotoxicity often associated with CAR-T cell therapies.

Stakeholder Impact

• Shareholders: Likely positive impact due to strong clinical data, potentially increasing company valuation and future revenue prospects for ZYNLONTA.
• Patients: Significant positive impact by offering a highly effective new treatment option for a severe and often fatal cancer, especially for those who have failed prior therapies.
• Healthcare Providers: Provides a promising new therapeutic option for managing relapsed or refractory DLBCL, potentially improving patient outcomes.

Key Dates

Recommendation

The reported Phase 1b data for ZYNLONTA in combination with glofitamab demonstrates exceptionally high overall and complete response rates in a very challenging patient population (relapsed or refractory DLBCL), including those who failed CAR-T therapy. These efficacy numbers are highly competitive, if not superior, to existing and emerging therapies in this space, while maintaining a manageable safety profile. This significantly de-risks the asset and points to substantial commercial potential, warranting a strong buy recommendation for long-term investors.

Keywords

ADC Therapeutics, ZYNLONTA, glofitamab, LOTIS-7, Phase 1b, DLBCL, relapsed refractory, oncology, clinical trial, antibody-drug conjugate, bispecific antibody, cancer treatment, hematology