EPCORE FL-1: Phase 3 Trial of Subcutaneous Epcoritamab With Rituximab and Lenalidomide (R2) vs R2 Alone in Patients With Relapsed or Refractory Follicular Lymphoma

Background

• Follicular lymphoma (FL) is the most common form of 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 rituximab + lenalidomide (R2). However, advanced-stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed.
• Epcoritamab, a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B cells, induces 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 complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab + R2 for R/R FL (EPCORE NHL-2 arms 2a and 2b; NCT04663347), ORR was 98% among 104 efficacy-evaluable patients, with a complete metabolic response in 87%.
  • Most cytokine release syndrome (CRS) events were low grade (n=111; grade 1–2, 46%; grade 3, 2%) and occurred in cycle 1; all CRS events resolved with routine management.
• These encouraging data, and the distinct mechanisms of action of epcoritamab and R2, support ongoing evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL.
• The phase 3 EPCORE FL-1 trial was designed to evaluate epcoritamab in combination with R2 vs R2 alone in patients with R/R FL with ≥1 prior line of anti-lymphoma therapy. We present an updated protocol, reflecting recent developments and revisions implemented in this study.

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 patients with R/R FL.
  • Adult patients must have histologically confirmed classic FL (previously grades 1 to 3a FL) stage II, III, or IV with a CD20+ tumor on a representative biopsy based on local pathology report and no evidence of histologic transformation. Patients must have R/R disease after ≥1 prior anti-lymphoma regimen that contained an anti-CD20 monoclonal antibody in combination with chemotherapy; patients receiving only prior anti-CD20 monoclonal antibody monotherapy and/or radiation are not eligible.
  • Other key eligibility criteria include Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose positron emission tomography–avid disease, and ≥1 measurable disease site per Lugano 2014 criteria. Lenalidomide-refractory FL (best response to lenalidomide of stable or progressive disease or progressive disease within 6 months of completion of lenalidomide) is excluded.
• Approximately 520 patients will be enrolled and randomized 1:1 to receive a full dose of epcoritamab in combination with R2 or R2 alone; the trial is currently enrolling in 2 arms, Arms A & C. Based on emerging safety and efficacy data, Arm B has been closed to enrollment and the recommended dose of epcoritamab in combination with R2 is 48 mg.
• Epcoritamab will be subcutaneously administered using a step-up dosing regimen to full dose in cycle 1 (28 days/cycle). Full dose of epcoritamab will be administered weekly in cycles 2–3 and monthly from cycle 4 onward for up to 12 cycles of treatment.
• Patients will be serially assessed for disease progression at prespecified intervals.
• The primary endpoint is progression-free survival assessed by independent review committee (IRC) per Lugano criteria.
• Key secondary efficacy endpoints include CR rate (by IRC per Lugano criteria), overall survival, and minimal residual disease negativity.
• Other efficacy endpoints include best overall response, duration of response, duration of complete response, time to progression, 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.

Falchi L, Morschhauser F, Linton K et al. EPCORE FL-1: Phase 3 Trial of Subcutaneous Epcoritamab with Rituximab and Lenalidomide (R2) Vs R2 Alone in Patients with Relapsed or Refractory Follicular Lymphoma. Presented at: 65th ASH Annual Meeting and Exposition, December 9-12, 2023. San Diego, California.

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