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 (R²) is an accepted standard of care in this population. The EPCORE FL-1 trial aimed to evaluate the efficacy and safety of epcoritamab plus R² versus R² 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 R² or R² 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 R² and 245 to R². The trial met its dual primary endpoints, showing superiority of epcoritamab plus R² over R² 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 R² versus 79% (74–84; p'0·0001) with R². Progression-free survival was longer with epcoritamab plus R² versus R² (hazard ratio 0·21 [95% CI 0·14–0·31], p'0·0001); estimated 16-month progression-free survival favoured epcoritamab plus R² (85·5% vs 40·2%). Grade 3 or higher adverse events were more frequent with epcoritamab plus R² (219 [90%] of 243 participants) versus R² (161 [68%] of 238 participants). Cytokine release syndrome was low grade with epcoritamab plus R² (grade 1 in 28 [21%] participants and grade 2 in seven [5%] participants) and manageable, and all events were resolved. Interpretation Epcoritamab plus R² resulted in significantly higher response rate and longer progression-free survival versus R² among participants with follicular lymphoma who had received at least one line of therapy. Epcoritamab plus R² had more grade 3 or higher adverse events versus R². 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 R² as a new standard of care for second-line or subsequent treatment of follicular lymphoma. Funding AbbVie and Genmab.