IBCL-1332: Phase 3 Results From the EPCORE FL-1 Trial of Epcoritamab With Lenalidomide and Rituximab vs Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma

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Context: Epcoritamab (E) is a CD3 × CD20 bispecific antibody approved for R/R FL after ≥2 pLOT. E + lenalidomide and rituximab (R 2 ) showed 97% ORR (CRR, 87%) and manageable safety in the phase 1b/2 EPCORE NHL-2 trial (Falchi ASH 2024). EPCORE FL-1 is a phase 3 trial of fixed-duration E+R 2 vs R 2 in patients with 2L+ FL (NCT05409066). Objective: Report EPCORE FL-1 results. Design: Adults with CD20 + FL R/R after ≥1 pLOTwere randomized to E+R 2 or R 2 for ≤12 cycles (C). E was administered subcutaneously (2- or 3-step-up dose [3SUD] to 48 mg in C1; C1–3, weekly; C4–12, every 4 weeks) with oral lenalidomide (C1–12, days 1–21) and intravenous rituximab (C1, weekly; C2–5, every 4 weeks). Patients received mandatory C1 CRS prophylaxis. Dual primary endpoints: ORR and PFS. Secondary endpoints: CRR, OS, DOR/DOCR, and safety. Results: The primary endpoints were met, showing E+R 2 superiority over R 2 in ORR and PFS. As of 5/24/2025, 488 patients were randomized (E+R 2 n=243; R 2 n=245). Patient characteristics were generally well-balanced. Median follow-up was 14.8 months (95% CI, 14.1–15.5 months). ORR (95% CI) was higher with E+R 2 (95% [92%–97%]) vs R 2 (79% [74%–84%]; P < 0.0001); 12-month DOR (95% CI) was 89.2% (83.6%–93.0%) vs 48.5% (38.8%–57.5%). Compared with R 2 E+R 2 demonstrated longer PFS (HR, 0.21 [95% CI, 0.14–0.31]; P < 0.0001) and higher CRR (83% [95% CI, 77%–87%] vs 50% [95% CI, 43%–56%]; P < 0.0001). CRS occurred in 26% of E+R 2 3SUD patients (grade [G]1, 21%; G2, 5%), mostly at E first 48-mg dose; all resolved. TEAEs were higher with E+R 2 vs R 2 (G3/4 TEAEs, 90% vs 67%; G3/4 neutropenia, 69% vs 42%; G3/4 infections, 33% vs 15%; G3/4 febrile neutropenia, 6% vs 3%; TEAEs leading to discontinuation, 19% vs 12%). Fatal TEAEs occurred in 2% (n = 4) vs 4% (n = 9) (none related to E). Conclusions: E+R 2 demonstrated superiority over R 2 in R/R FL, with significantly improved ORR, CRR, and PFS. G3/4 neutropenia and infections were higher with E+R 2 but manageable and not fatal. CRS was low-grade with predictable timing. E+R 2 sets a new benchmark as an option suitable for outpatient administration and potential new 2L+ FL SOC. CD: cluster of differentiation, CRR: complete response rate, CRS: cytokine release syndrome, DOCR: duration of complete response, DOR: duration of response, FL: follicular lymphoma, HR: hazard ratio, ORR: objective response rate, PFS: progression-free survival, pLOT: prior lines of therapy, RR: relapsed/refractory, SOC: standard of care, TEAE: treatmentemergent adverse event. Bradley D Hunter presenting on behalf of the EPCORE FL-1 study investigators. The data were previously published (Falchi et al . Lancet . 2026;407:161–173) and reproduced with permission under the terms of the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

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