Background
Phase III, open-label, randomized controlled trial. 435 patients with R/R FL (grade 1–3a) after ≥2 prior lines. Epcoritamab is a subcutaneous CD3×CD20 bispecific antibody. EPCORE FL-1 compared epcoritamab + rituximab + lenalidomide (epcoritamab + R²) versus rituximab + lenalidomide (R²) alone — the first Phase III bispecific antibody RCT in FL, powered for PFS.
Interventions and follow up
Arm A: Epcoritamab 48mg SC weekly for cycles 1–2 (step-up: 0.16mg → 0.8mg → 48mg), then q2w cycles 3–6, then q4w (cycle 7+) + rituximab 375mg/m² IV day 1 q4w × 12 doses + lenalidomide 20mg PO days 1–21 × 12 cycles; corticosteroid CRS prophylaxis at step-up dose
Arm B: R² — rituximab 375mg/m² IV day 1 q4w × 12 doses + lenalidomide 20mg PO days 1–21 × 12 cycles
Primary endpoint: Progression-free survival (investigator-assessed)
mFollow up: ~18 months
Arm B: R² — rituximab 375mg/m² IV day 1 q4w × 12 doses + lenalidomide 20mg PO days 1–21 × 12 cycles
Primary endpoint: Progression-free survival (investigator-assessed)
mFollow up: ~18 months
Results
PFS (primary): HR 0.21, 95% CI 0.13–0.32, P<.001 — landmark benefit
2-year PFS rate: 76% (epcoritamab + R²) vs estimated ~45% (R²)
CR rate: 83% vs 50%
ORR: 96% vs 79%
2-year PFS rate: 76% (epcoritamab + R²) vs estimated ~45% (R²)
CR rate: 83% vs 50%
ORR: 96% vs 79%
Adverse events
CRS/neurologic: CRS any grade 60% (epcoritamab + R²), grade ≥3 CRS ~1–2%; ICANS any grade ~5%, grade ≥3 ~1%
Hematologic/local: Grade ≥3 neutropenia ~40%, grade ≥3 infections ~15%, injection-site reactions ~20%
Hematologic/local: Grade ≥3 neutropenia ~40%, grade ≥3 infections ~15%, injection-site reactions ~20%
Conclusions
Epcoritamab + R² demonstrated a landmark PFS benefit over R² alone (HR 0.21, 2-year PFS 76% vs ~45%) with an 83% CR rate, establishing epcoritamab + R² as the most efficacious regimen tested in R/R FL to date and likely representing the new standard of care.
Key Limitations
Relatively short follow-up at primary analysis — PFS benefit needs confirmation of durability. The triplet combination (bispecific + lenalidomide + rituximab) adds complexity, cost, and additive toxicities versus doublets. CRS prophylaxis and step-up dosing add hospitalization requirements. No head-to-head comparison to CAR-T in R/R FL. OS data immature. The REMS requirements for lenalidomide add administrative burden.
Clinical Context
Published in Lancet 2026 — the most recent practice-changing FL trial. FDA approved epcoritamab + R² for R/R FL in 2026 based on EPCORE FL-1. This is the first Phase III RCT to demonstrate a significant PFS benefit for a bispecific-based regimen over R² in FL. This trial is likely to reshape R/R FL management, potentially moving bispecific + R² ahead of CAR-T in fit patients without prior anti-CD20 refractoriness. ESMO-MCBS scoring pending.