Phase 3 Trial of Subcutaneous Epcoritamab in Combination with Rituximab and Lenalidomide (R2) Vs R2 Among Patients with Relapsed or Refractory Follicular Lymphoma (EPCORE FL-1)

Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL). Several treatment options are approved by the US Food and Drug Administration for second- or later-line FL therapy, including R². However, advanced stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed. Epcoritamab is a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B-cells, inducing potent and selective T-cell–mediated killing of malignant CD20⁺ B cells (van der Horst et al, Blood Cancer J 2021). In the first-in-human, phase 1/2 EPCORE NHL-1 trial (NCT03625037) in heavily pretreated patients with B-cell NHL (N = 68), epcoritamab showed manageable safety and promising single-agent anti-tumor activity (Hutchings et al, Lancet 2021). Among 10 patients with R/R FL, objective response rate (ORR) was 90% (95% CI: 55–100), and the complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab and R² among 28 evaluable patients with R/R FL (EPCORE NHL-2 arm 2; NCT04663347), ORR was 100%, with a complete metabolic response observed in 96%. Most cytokine release syndrome (CRS) events were of low grade (grade 1, 30%; grade 2, 13%; grade 3, 7%) and occurred in cycle 1; all CRS events resolved with standard management. These encouraging data, as well as the distinct mechanisms of action of epcoritamab and R², support evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL. The phase 3 trial described herein was designed to evaluate epcoritamab in combination with R² vs R² alone in patients with R/R FL with at least 1 prior line of therapy.

Study Design and Methods: EPCORE FL-1 (NCT05409066) is a global, randomized, open-label, multicenter phase 3 trial designed to evaluate efficacy and safety of epcoritamab in combination with R² vs R² alone in adults with histologically confirmed grades 1 to 3a R/R FL after at least 1 prior line of systemic anti-lymphoma therapy, including an anti-CD20 monoclonal antibody (not including prior radiotherapy). Other key eligibility criteria include Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose positron emission tomography–avid disease, and at least 1 measurable disease site. Lenalidomide-refractory FL is excluded. Approximately 642 patients will be randomized in a 1:1:1 ratio to receive alternative full doses of epcoritamab in combination with R² or R² alone (Figure). Epcoritamab will be subcutaneously administered using a step-up dosing regimen followed by a full dose of epcoritamab in cycle 1 (28 days/cycle). Full doses of epcoritamab will be administered weekly in cycle 2 and monthly in cycles 3 and beyond. Patients will receive up to 12 cycles of treatment and will be assessed for disease progression per the 2014 Lugano criteria. Primary endpoint is progression-free survival (PFS) as assessed by blinded independent review committee (IRC). Secondary efficacy endpoints include response rates (per Lugano criteria by IRC), overall survival and minimal residual disease negativity. Other efficacy endpoints include duration of response, duration of complete response, event-free survival, time to next anti-lymphoma treatment, and patient-reported outcomes. Safety endpoints include incidence and severity of treatment-emergent adverse events and adverse events of special interest. Exploratory endpoints include assessments of pharmacodynamic and pharmacokinetic data. The study opened for enrollment in 2022 in North America, South America, Europe, Africa, Asia, and Australia.