Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial

Background An unmet need persists for chemotherapy-free regimens that induce durable responses for relapsed or refractory follicular lymphoma. Lenalidomide and rituximab (R 2 ) is an accepted standard of care in this population. The EPCORE FL-1 trial aimed to evaluate the efficacy and safety of epcoritamab plus R 2 versus R 2 in participants with relapsed or refractory follicular lymphoma after at least one previous line of chemoimmunotherapy. Methods In this multicountry, open-label, phase 3 trial, participants were randomly allocated (1:1) to fixed-duration epcoritamab plus R 2 or R 2 for up to 12 cycles. Epcoritamab was administered weekly in cycles 1–3 and every 4 weeks in cycles 4–12, lenalidomide once daily during cycles 1–12 (days 1–21), and rituximab weekly during cycle 1 and monthly in cycles 2–5. The dual primary endpoints were overall response rate and progression-free survival by independent review committee. The data reported here are from a planned interim analysis carried out after 78% of progression-free survival events had occurred. This study is registered with ClinicalTrials.gov, NCT05409066, and EudraCT, 2021–000169–34, and is ongoing (closed to recruitment). Findings Out of 668 participants screened for eligibility across 189 academic and non-academic centres in 30 countries across Africa, Asia, Australia, Europe, North America, and South America, a total of 488 participants were randomly allocated, 243 to epcoritamab plus R 2 and 245 to R 2 . The trial met its dual primary endpoints, showing superiority of epcoritamab plus R 2 over R 2 in overall response rate and progression-free survival. With a median follow-up of 14·8 months (IQR 11·4–19·0), overall response rate was 95% (95% CI 92–97) with epcoritamab plus R 2 versus 79% (74–84; p<0·0001) with R 2 . Progression-free survival was longer with epcoritamab plus R 2 versus R 2 (hazard ratio 0·21 [95% CI 0·14–0·31], p<0·0001); estimated 16-month progression-free survival favoured epcoritamab plus R 2 (85·5% vs 40·2%). Grade 3 or higher adverse events were more frequent with epcoritamab plus R 2 (219 [90%] of 243 participants) versus R 2 (161 [68%] of 238 participants). Cytokine release syndrome was low grade with epcoritamab plus R 2 (grade 1 in 28 [21%] participants and grade 2 in seven [5%] participants) and manageable, and all events were resolved. Interpretation Epcoritamab plus R 2 resulted in significantly higher response rate and longer progression-free survival versus R 2 among participants with follicular lymphoma who had received at least one line of therapy. Epcoritamab plus R 2 had more grade 3 or higher adverse events versus R 2 . Adverse events were manageable and consistent with the established safety profiles of the individual components, with no new safety findings identified. These findings position epcoritamab plus R 2 as a new standard of care for second-line or subsequent treatment of follicular lymphoma. Funding AbbVie and Genmab.