ADC Therapeutics (ADCT) has announced the completion of enrollment in LOTIS-5, a Phase 3 confirmatory trial assessing Zynlonta (loncastuximab tesirine-lpyl) in combination with rituximab for patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). This milestone brings the company closer to potentially expanding the treatment options for patients with this aggressive form of lymphoma.
LOTIS-5 Trial Design
The LOTIS-5 trial is a randomized, open-label, two-part, two-arm, multicenter study. It aims to confirm the accelerated approval Zynlonta received from the FDA in 2021 for r/r DLBCL after two or more lines of systemic therapy. The trial also seeks to support a potential label expansion into the second-line setting when used in combination with rituximab.
The first part of the trial involved a non-randomized safety run-in with 20 patients. Results from this phase showed an encouraging overall response rate (ORR) of 80% (16/20) by central review, with a complete response (CR) rate of 50% (10/20). No new safety signals were identified during this initial phase.
In the second part, patients with 2L+ DLBCL are randomized 1:1 to receive either fixed-dose Zynlonta with rituximab or rituximab-gemcitabine-oxaliplatin (R-GemOx). The primary endpoint of LOTIS-5 is progression-free survival (PFS). Secondary endpoints include overall survival (OS), ORR, CR rate, duration of response, and the frequency and severity of adverse events.
Zynlonta: A Targeted Approach
Zynlonta is a CD19-directed antibody-drug conjugate (ADC). Upon binding to CD19-expressing cells, the drug is internalized, releasing a pyrrolobenzodiazepine (PBD) payload. This payload binds to the DNA minor groove, causing cell cycle arrest and ultimately leading to tumor cell death.
Anticipated Timeline and Regulatory Pathway
ADC Therapeutics anticipates sharing topline results of the primary endpoint analysis by the end of 2025, once the pre-specified number of events is reached. Following these results, the company plans to submit a supplemental Biologics License Application (sBLA) to the FDA in the first quarter of 2026, with potential approval in late 2026.
Management Commentary
"This milestone for LOTIS-5 brings us a step closer to providing a potential combination treatment in the 2L+ DLBCL setting that we believe will offer competitive efficacy with favorable safety and a convenient dosing schedule, well-suited for use in patients across care settings," said Mohamed Zaki, MD, PhD, Chief Medical Officer of ADC Therapeutics.
