primary Phase 3 results from the epcore FL-1 trial of epcoritamab with rituximab and lenalidomide (R2) versus R2 for relapsed or refractory follicular lymphoma

Abstract INTRODUCTION: Patients (pts) with relapsed/refractory (R/R) follicular lymphoma FL have limited second line (2L) treatment options, rituximab and lenalidomideR2being the only 2L alternative to immunochemotherapy-based therapy. Epcoritamab (epcor), a CD3xCD20 bispecific antibody, is approved for R/R FL as monotherapy after ≥2 lines of systemic therapy. Epcor plus R2 (E+R2) is a chemotherapy-free regimen which showed promising antitumor activity (97% overall response rate [ORR], 87% complete response [CR] rate) and manageable safety in the phase 1b/2 EPCORE NHL-2 trial (Falchi et al, ASH 2024). We report the results of EPCORE FL-1: the first global phase 3 trial of fixed-duration bispecific antibody regimen E+R2 vs R2 in pts with 2L+ FL (NCT05409066). METHODS: Adults with CD20+ FL R/R after at least 1 prior line, who met GELF criteria, were randomized to receive E+R2or R2for up to 12 cycles (C). Subcutaneous epcor was administered using a 2-step-up dose (2SUD) or 3-step-up dose (3SUD) regimen and full doses (48mg) thereafter. Epcor was administered weekly in C1–3 and q28 days from C4–12. Intravenous rituximab was administered weekly in C1 and q28 days during C2–5. Oral lenalidomide was administered daily from day 1–21 during C1–12. Pts received mandatory CRS prophylaxis in C1. Dual primary endpoints were ORR and progression-free survival (PFS) assessed by independent review committee per Lugano criteria. Secondary endpoints included CR rate (CRR), overall survival (OS), duration of response/CR (DOR/DOCR), and safety. RESULTS: As of the Jan 10, 2025 data cut-off, 488 pts were randomized to receive E+R2 (N=243) or R2alone (N=245). Pt characteristics were generally well balanced across the two arms. Pts treated with E+R2 vs R2had a median age of 60 years (range, 30–84) vs 63 years (range, 24–89), Ann Arbor stage III-IV in 84.8% vs 81.6%, double refractory disease in 35.4% vs 35.9%, and POD24 in 43% vs 36%, respectively. The median number of prior lines of treatment was 1 (range, 1–7) vs 1 (range, 1–6), respectively. The median duration of follow-up was 10.4 months (95% CI: 9.8, 11.1). A preplanned interim analysis was conducted after the first 232 pts achieved 12 months of follow-up post-randomization, and the ORR was significantly improved in pts treated with E+R2 (95.7% [95% CI: 90.2, 98.6]) vs R2(81.0% [95% CI: 72.7, 87.7]; P<.0001). The 12-month DOR was 91.4% (95% CI: 84.0, 95.4) vs 57.0% (95% CI: 44.2, 68.0), respectively. In the full ITT population (N=488), PFS was significantly longer in pts treated with E+R2 vs those treated with R2 (hazard ratio [HR] 0.21; 95% CI: 0.13, 0.33; P<.0001). Additionally, E+R2 led to a significant improvement in CRR vs R2 (74.5% [95% CI: 68.5, 79.8] vs 43.3% [95% CI: 37.0, 49.7]; P<.0001). Similar improvements in response rates were observed in all pre-definedhigh-risksubgroups (eg, primary/double refractory disease, POD24). Among 131 pts receiving 3SUD in the E+R2arm, CRS events were low grade (G) and occurred in 24.4% of pts (G1, 19.1%; G2, 5.3%); most occurred at time of first 48mg full epcor dose and all resolved. One event of ICANS (G1) was reported in the E+R2 arm and resolved. G3/4 TEAEs were reported in 88.1% of pts receiving E+R2vs 62.2% with R2, the difference being primarily driven by higher rates of G3/4 neutropenia (66.3% vs 37.8%) and G3/4 infections (29.2% vs 13.4%). Rates of G3/4 febrile neutropenia were 6.2% (E+R2) vs 2.1% (R2). Fatal TEAEs occurred in 0.8% (n=2) vs 2.9% (n=7) with E+R2 vs R2, respectively; with no fatal events deemed related to epcor. TEAEs leading to discontinuation occurred in 16.0% of cases for E+R2 vs 11.8% for R2. Updated data from prespecified second interim analysis on all efficacy endpoints will be available at the time of presentation. CONCLUSION: Epcor is the first CD20xCD3 bispecific antibody to demonstrate clinical benefit over standard of care in a randomized phase 3 trial in patients with FL, with statistically significant improvements in ORR, CR rate, and a 79% reduction in the risk of progression or death. Higher rates of G3/4 neutropenia and infections were observed in E+R2, but these were manageable and none were fatal. CRS was low grade and the timing was predictable. E+R² sets a new benchmark as a readily available treatment, is suitable for outpatient administration, and has the potential to become a new standard of care in 2L+ FL.