EPCORE FL-2 Phase 3 trial of epcoritamab with rituximab and lenalidomide (R2) vs chemoimmunotherapy (CIT) in previously untreated follicular lymphoma (FL): Trial in progress Free

Background and Significance: FL represents approximately 20%–30% of all non-Hodgkin lymphoma cases. The current standard of care (SOC) for patients with previously untreated advanced FL with high tumor burden includes CIT, combining anti-CD20 monoclonal antibody (rituximab [R] or obinutuzumab [G]) with chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or bendamustine [benda]). R² has shown to have comparable efficacy to R-CHOP in these patients (Morschhauser et al. N Engl J Med 2018;379:934-947).

Epcoritamab is a CD3×CD20 bispecific antibody, which facilitates T-cell mediated cytotoxicity of CD20-expressing malignant cells. Epcoritamab is approved by the FDA and the EMA for the treatment of relapsed/refractory FL after two or more lines of systemic therapy. The phase 1b/2 trial EPCORE NHL-2 (NCT04663347) showed favorable data for epcoritamab plus R² in 1L FL with deep and durable responses (overall response rate, 95%; complete response [CR] rate, 85%) and manageable safety profile (Falchi et al. EHA 2024 Abstract P1146). These data support further investigation in a phase 3 trial to compare the efficacy and safety of epcoritamab plus R² vs SOC of CIT in patients with untreated FL.

Study Design and Methods: EPCORE FL-2 (NCT06191744) is a global, multicenter, randomized, open-label phase 3 trial, enrolling adult patients with CD20+ histologically confirmed classic FL, Eastern Cooperative Oncology Group performance status 0–2, stage III or IV or stage II disease with tumor diameter of ≥7 cm. Eligible patients have not received any prior systemic treatment for FL and meet at least one criterion from the Groupe d'Etude des Lymphomes Folliculaires for requiring treatment. The study will enroll approximately 1095 patients and randomize them 5:2:5:1 to arm A1:A2:B:C (stratified by Follicular Lymphoma International Prognostic Index score, region, and investigator's upfront choice of CIT [G-CHOP, R-CHOP, G-Benda, or R-Benda]). In Arm A1, patients receive epcoritamab (full dose, 48 mg) plus R² (R, 375 mg/m²; lenalidomide, 20 mg) for 6 × 28-day induction cycles. Responders (CR or partial response [PR]) transition to maintenance with epcoritamab monotherapy (48 mg) for approximately 2 years. In Arm A2, patients receive epcoritamab (full dose, 48 mg) plus R² (R, 375 mg/m²; lenalidomide, 20 mg) for 6 × 28-day cycles without maintenance. In Arm B, patients receive investigator's choice among 4 CIT regiments including G-CHOP/R-CHOP for 6 × 21-day cycles and 2 × 21-day cycles of G/R (G, 1000 mg; R, 375 mg/m²), or G-Benda/R-Benda for 6 × 28-day cycles. Patients with CR or PR are treated with G/R (G, 1000 mg; R, 375 mg/m²) for approximately 2 years as maintenance. In Arm C, patients receive R² (R, 375 mg/m²; lenalidomide, 20 mg) for 6 × 28-day cycles as induction, and patients with CR or PR receive maintenance with lenalidomide (10 mg; patients with PR receive 20 mg for 3–6 cycles until CR) for 12 × 28-day cycles and R (375 mg/m²) every 8 weeks, followed by R (375 mg/m²) for 6 × 56-day cycles.

Dual primary endpoints are CR rate at 30 months (CR30) as determined by Lugano 2014 criteria and progression-free survival (PFS) in Arm A1 vs Arm B by independent review committee. CR30 will be analyzed using stratified Cochran-Mantel-Haenszel test. PFS will be analyzed using Kaplan-Meier estimates and stratified log-rank tests. Hazard ratios will summarize treatment effects via stratified Cox proportional hazards model. Key secondary endpoints are overall survival and minimal residual disease negativity for Arm A1 vs Arm B and changes in patient-reported outcomes on the physical functioning scale of the European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire from baseline to Week 21 (Arm A1) or Week 21/22 (Arm B). Safety endpoints comprise of incidence and severity of treatment emergent adverse events (AE), serious AEs, and AEs of special interest (including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and clinical tumor lysis syndrome), incidence and severity of changes in laboratory values, and incidence of dose interruptions, reduction, and discontinuations. Arm A2 will address the contribution of maintenance therapy to outcomes of epcoritamab plus R² treatment. This study is currently enrolling patients globally in 32 countries.