ADC Therapeutics SA  announced topline data from its Phase 3 LOTIS-5 confirmatory trial evaluating ZYNLONTA^® (loncastuximab tesirine-lpyl) in combination with rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). ZYNLONTA plus rituximab achieved statistical significance on the trial's primary endpoint of progression-free survival (PFS) and demonstrated no detrimental effect on the key secondary efficacy endpoint of overall survival (OS). In addition, a higher complete response (CR) rate and duration of CRs (DoCR) were observed with ZYNLONTA plus rituximab. Overall, treatment emergent adverse event (TEAE) rates were similar between arms. Similar rates of overall Grade ≥3 TEAEs greater than 5% were observed across both arms, with hematologic TEAEs higher in the control arm and infection, hepatotoxicity, and edema/effusion higher in the test arm. Serious adverse events (SAEs), TEAEs leading to study drug withdrawal, and Grade 5 events were higher in the test arm, with the majority of Grade 5 TEAEs in the test arm occurring in patients aged 75 years or older.

"In the context of a positive study, based on the totality of the data, we plan to discuss the benefit-risk profile of this combination with the U.S. FDA as we prepare for the planned supplemental Biologics License Application (sBLA) filing," said Ameet Mallik, Chief Executive Officer of ADC Therapeutics. "We would like to extend our thanks to the patients, investigators, and clinical teams who contributed to this important trial."

The LOTIS-5 trial is a randomized, open‐label, two‐arm, multicenter study evaluating ZYNLONTA plus rituximab versus the standard immunochemotherapy rituximab gemcitabine‐oxaliplatin (R‐GemOx), for the treatment of r/r DLBCL after one or more lines of systemic therapy. The study met the primary endpoint of PFS (per independent review committee) with statistical significance (HR = 0.73; p-value = 0.008 two sided), with a median PFS of 6.1 months for ZYNLONTA plus rituximab vs 4.7 months for R-GemOx. Overall survival showed no detrimental effect with ZYNLONTA plus rituximab compared to the control arm (HR = 0.96, impacted by the earlier use and a higher rate of new anti-lymphoma treatment switching in the control arm). Overall response rate (ORR) was 58.1% vs. 45.2%, CR rate was 39.5% vs. 26.7%, median duration of response (DOR) was 9.2 months vs. 7.7 months, and median DoCR was 16.8 months vs. 12.3 months for ZYNLONTA plus rituximab compared to R-GemOx, respectively. Of patients achieving CR, 48.5% vs. 16.7% remained in CR at 24 months in favor of ZYNLONTA plus rituximab. Of note, results in North America were consistent with the overall study results.

Overall, TEAE rates were similar between arms (98.5% vs. 97.5%). Higher rates of SAEs were seen in the test arm (49.0% vs. 34.5%). Grade ≥3 TEAEs observed in > 5% of patients were hematologic (40.7% vs. 59.4%), followed by infection/infestations (24.5% vs. 15.7%), then hepatotoxicity (17.2% vs. 8.1%) and oedema/effusion (7.4% vs. 0.5%) when comparing ZYNLONTA plus rituximab to R-GemOx. A higher rate of Grade 5 TEAEs was observed in the ZYNLONTA plus rituximab arm (27 pts/13.2%) vs. R-GemOx (9 pts/4.6%). Of note, the majority of Grade 5 TEAEs in the test arm occurred in patients aged 75 years or older. Higher rates of TEAEs leading to any drug withdrawal occurred in the ZYNLONTA plus rituximab arm (25.5% vs. 9.1%). In this study, the TEAE reporting window was defined as 105 days after the last dose of study treatment or the start of new anticancer therapy, whichever is earlier. The rates of TEAEs in this study were impacted by the longer overall TEAE observation time in the test vs. control arm. This difference is primarily driven by a higher rate of and earlier switching to subsequent therapies in the control arm.

"LOTIS-5 was designed to address a clear unmet need in r/r DLBCL in patients who cannot access or who progress on a CAR-T or other complex therapies," said Mehdi Hamadani, MD, Professor of Medicine, Associate Director of Clinical Research, Section Chief of Hematologic Malignancies at Medical College of Wisconsin and principal investigator for the trial. "Based on these results, I believe this combination may provide an additional option in treating relapsed or refractory DLBCL."

"Based on these topline results from LOTIS-5, we look forward to discussing next steps for this combination of ZYNLONTA plus rituximab with the U.S. FDA," said Mohamed Zaki, MD, PhD, Chief Medical Officer of ADC Therapeutics. "We intend to conduct a pre-sBLA meeting in August and are preparing for a planned sBLA submission in the fourth quarter of 2026."

In addition, the Company will continue to evaluate a broad range of value maximizing alternatives, including but not limited to near-term cost reduction initiatives.