LOTIS‐5, AN ONGOING PHASE 3 RANDOMIZED STUDY OF LONCASTUXIMAB TESIRINE WITH RITUXIMAB (LONCA‐R) VERSUS IMMUNOCHEMOTHERAPY IN PATIENTS WITH R/R DLBCL

Abstract

Introduction: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have poor outcomes following standard treatment. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca), an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin, received accelerated (US) and conditional (EU) approval in R/R DLBCL after ≥2 lines of systemic therapy, based on data from the phase 2 LOTIS-2 trial (Caimi PF et al. Lancet Oncol. 2021;22[6]:790). Rituximab (R), an anti-CD20 monoclonal antibody, is part of standard immunotherapy for DLBCL, both as frontline therapy and in subsequent treatments. Preclinical evidence suggests the addition of R to anti-CD19 ADC therapy may result in prolonged tumor control (Ryan MC et al. Blood. 2017;130[18]:2018). LOTIS-5 aims to evaluate Lonca-R vs standard immunotherapy of R + gemcitabine + oxaliplatin (R-GemOx) in R/R DLBCL. Methods: This is a phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R in patients with R/R DLBCL (NCT04384484). The study consists of a safety run-in phase with Lonca-R (part 1) and a randomized phase evaluating efficacy and safety of Lonca-R vs R-GemOx (part 2). Approximately 350 patients will be enrolled across both parts: part 1 has completed; part 2 will enroll approximately 330 patients (randomized 1:1) to achieve 262 events for the primary end point analysis of progression-free survival by independent central review. Secondary end points include overall survival, overall response rate (2014 Lugano classification), complete response rate, duration of response, frequency and severity of adverse events, change from baseline in laboratory values, concentration and pharmacokinetic parameters of Lonca (conjugated and total antibody and unconjugated PBD), and changes in patient-reported outcomes from baseline. The dosing regimen for Lonca-R is Lonca 150 μg/kg + rituximab 375 mg/m2 every 3 weeks (Q3W) for 2 cycles, then Lonca 75 μg/kg + rituximab 375 mg/m2 Q3W for up to 6 cycles. The dose regimen of R-GemOx is rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 every 2 weeks for up to 8 cycles. Key eligibility criteria include age ≥18 years, pathologic diagnosis of DLBCL (including patients with 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, previous stem cell transplant >30 days (autologous) or >60 days (allogenic) prior to start of study drug or stem cell transplant ineligibility, and measurable disease. The randomized part of LOTIS-5 began in January 2022 and has an estimated primary completion date of June 2025; enrollment continues, with a total of 45 active sites across the US, Canada, Spain, France, Belgium, Italy, Switzerland, Czech Republic, Poland, and China. The research was funded by: ADC Therapeutics SA; medical writing: CiTRUS Health Group Keywords: molecular targeted therapies, combination therapies, ongoing trials Conflicts of interests pertinent to the abstract C. Carlo-Stella Consultant or advisory role ADC Therapeutics, Celgene/Bristol Myers Squibb, Karyopharm, Novartis, Sanofi, Roche, Merck Sharp & Dohme, Scenic Biotech Honoraria: Merck Sharp & Dohme, Janssen Oncology, AstraZeneca, Celgene, Incyte, Gilead Sciences, Roche M. Chung Stock ownership: The Oncology Institute A. Stathis Honoraria: Eli Lilly, Bayer, Roche, Novartis, Janssen Oncology, AstraZeneca Research funding: ADC Therapeutics , Pfizer, Roche, Novartis, Bayer, Eli Lilly, MEI Pharma, Cellestia, Debiopharm Group, Merck/MSD, Abbvie, Amgen, AstraZeneca, Incyte, Loxo, Philogen Y. Wang Employment or leadership position: ADC Therapeutics Stock ownership: Johnson and Johnson (Family Member) L. Wang Employment or leadership position: ADC Therapeutics M. Hamadani Consultant or advisory role AbGenomics, ADC Therapeutics, Celgene, Incyte, Janssen R&D, Omeros, Pharmacyclics, TeneoBio, Verastem Research funding: Astellas Pharma, Spectrum Pharmaceuticals, Takeda Other remuneration: Speakers’ bureau for AstraZeneca, BeiGene, Sanofi Genzyme