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Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is a novel antibody-drug conjugate comprising an anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin, indicated for the treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) after ≥2 systemic treatments. To characterize the safety and preliminary efficacy of Lonca + rituximab (Lonca-R). This is a phase 3, randomized, open-label, two-part, two-arm, multicenter study of Lonca-R in patients with R/R DLBCL (NCT04384484). Twenty patients were enrolled in part 1 in a nonrandomized safety run-in. In part 2, approximately 330 patients will be randomized 1:1 to receive Lonca-R or rituximab-gemcitabine-oxaliplatin (R-GemOx). Key inclusion criteria include age ≥18 years, diagnosis of DLBCL (including DLBCL transformed from indolent lymphoma) or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, ≥1 line of prior systemic therapy, not a candidate for stem cell transplantation, and measurable disease per the 2014 Lugano criteria. All patients in the safety run-in received Lonca 0.15 mg/kg + rituximab at 375 mg/m every 3 weeks (Q3W) for 2 cycles and then Lonca 0.075 mg/kg + rituximab at 375 mg/m Q3W for up to 6 additional cycles. The 20 patients in the safety run-in were a median age of 74.5 years (range 35-93) and received a median of 1 previous therapy (range 1-6). As of February 28, 2022 (data cutoff), 19 (95%) patients had at least 1 treatment-emergent adverse event (TEAE), and 10 (50%) patients had grade ≥3 TEAEs. The most common all-grade TEAEs, regardless of the relationship to the study treatment, were rash (5 [25%]), fatigue (4 [20%]), and increased gamma-glutamyltransferase (4 [20%]). The most common grade ≥3 TEAEs were increased gamma-glutamyltransferase (3 [15%]), increased alanine aminotransferase (2 [10%]), and neutropenia (2 [10%]). The overall response rate by central review was 15/20 (75%). A total of 8/20 (40%) and 7/20 (35%) patients attained complete response and partial response, respectively. Lonca-R demonstrated no new safety signals and showed encouraging antitumor activity in patients with R/R DLBCL. The randomized part of LOTIS-5 commenced in January 2022; recruitment is ongoing. ADC Therapeutics SA; medical writing: CiTRUS Health Group.