ADC Therapeutics’ Phase 3 LOTIS‑5 trial of ZYNLONTA® plus rituximab in relapsed/refractory DLBCL met its primary endpoint, reducing disease progression risk by 27% versus R‑GemOx. The regimen improved response durability but showed higher rates of serious adverse events and Grade 5 events, particularly in older patients, supporting a planned U.S. sBLA filing in late 2026.
Written By: Samiksha Jadhav, BPharm
Fact-Checked By: Chikkula Pavan Kumar, PharmD
Reviewed By: Pharmacally Editorial Team
ADC Therapeutics reported positive topline results from the Phase 3 LOTIS-5 trial (NCT04384484) evaluating ZYNLONTA® (loncastuximab tesirine-lpyl) plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
The regimen met the study’s primary endpoint, delivering a statistically significant progression-free survival (PFS) benefit over rituximab, gemcitabine, and oxaliplatin (R-GemOx). Median PFS reached 6.1 months versus 4.7 months, corresponding to a 27% reduction in the risk of disease progression or death (HR=0.73; p=0.008).
LOTIS-5 serves as the confirmatory trial supporting ZYNLONTA’s existing accelerated approval in relapsed or refractory large B-cell lymphoma and could help expand its role in later-line treatment settings.
Secondary Efficacy Gains
The investigational arm demonstrated superior outcomes across several secondary efficacy measures. Overall response rates reached 58.1% compared with 45.2% for R-GemOx, while complete response rates were 39.5% versus 26.7%. Median duration of response was 9.2 months compared with 7.7 months, and complete responses lasted a median of 16.8 months versus 12.3 months.
48.5% of patients who achieved complete remission with ZYNLONTA plus rituximab remained in remission at 24 months, compared with 16.7% in the control arm, highlighting the durability of responses observed with the antibody-drug conjugate combination.
Safety Profile and Tolerability
Treatment-emergent adverse event rates were generally similar across treatment arms. While hematologic toxicities occurred more frequently with R-GemOx, infections, hepatotoxicity, and edema or effusion were reported more often with ZYNLONTA plus rituximab.
A higher rate of serious adverse events was observed with ZYNLONTA plus rituximab compared with R-GemOx (49.0% vs. 34.5%), as were adverse events leading to treatment discontinuation (25.5% vs. 9.1%). Grade 5 treatment-emergent adverse events were also more frequent in the investigational arm, occurring in 27 patients (13.2%) compared with 9 patients (4.6%) in the control group. The majority of Grade 5 events in the ZYNLONTA arm occurred in patients aged 75 years or older.
Despite these findings, overall survival analysis showed no detrimental effect for ZYNLONTA plus rituximab (HR=0.96). ADC Therapeutics noted that the result was influenced by earlier treatment switching and greater use of subsequent anti-lymphoma therapies in the control arm. The company plans to discuss the overall benefit-risk profile with the U.S. FDA as part of its planned supplemental Biologics License Application submission.
Mechanism of Action
ZYNLONTA is a CD19-directed antibody-drug conjugate that delivers a pyrrolobenzodiazepine (PBD) payload into malignant B cells, triggering DNA damage and tumor cell death. DLBCL remains the most common subtype of non-Hodgkin lymphoma, and many patients experience relapse despite advances such as CAR-T cell therapy.
Regulatory Pathway and Outlook
Based on the positive findings, ADC Therapeutics plans to discuss the combination’s benefit-risk profile with the U.S. Food and Drug Administration. The company expects to hold a pre-supplemental Biologics License Application (sBLA) meeting in August 2026 and plans to submit an sBLA during the fourth quarter of 2026.
Principal investigator Mehdi Hamadani, MD, said the combination could provide an important additional treatment option for patients who cannot access or who progress after CAR-T and other complex therapies. ADC Therapeutics plans to present full LOTIS-5 results at a future medical meeting.
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About the Writer
Samiksha Vikram Jadhav (LinkedIn) is a B. Pharm graduate with a strong academic foundation in pharmaceutical sciences, pharmacology, and drug development. She specializes in pharma market research, with a focused interest in mergers and acquisitions, strategic partnerships, and global pharma and biotech deals. Her work centers on analyzing industry transactions, market positioning, and business strategies, translating complex developments into clear, accurate, and insightful scientific and commercial reporting.