Phase 3, Randomized, Open-Label Study of Epcoritamab Plus Lenalidomide Compared with Rituximab Plus Gemcitabine and Oxaliplatin in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Introduction: Outcomes for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor, especially for those ineligible for autologous stem cell transplantation. Despite the high response rate with chimeric antigen receptor T-cell therapy (CAR T), not all patients are able to receive CAR T due to fitness/comorbidities, geographical access, manufacturing constraints, or reimbursement. Epcoritamab is a subcutaneous (SC) CD3xCD20 bispecific antibody approved in various regions including the US, Europe, and Japan for patients with R/R DLBCL. Lenalidomide is an immunomodulatory agent that has demonstrated single-agent activity and is approved in combination with other agents for patients with DLBCL. Given the converging effects on T-cell activation and tumor suppression, it is hypothesized that combination of epcoritamab and lenalidomide (E-Len) may further enhance tumor killing. In the ongoing phase 1b/2 EPCORE NHL-5 study (NCT05283720), E-Len demonstrated high response rates (overall response rate, 18/24 [75.0%]; complete response rate, 14/24 [58.3%]) in patients with R/R DLBCL and a manageable safety profile (Avivi ASH 2023, abstract 438). Here, we describe the phase 3, open-label, randomized, global study (NCT06508658) comparing E-Len to rituximab plus gemcitabine and oxaliplatin (R-GemOx). We evaluated the efficacy and safety of E-Len versus R-GemOx in patients with R/R DLBCL.

Methods: Eligible patients (age ≥18 years) must have histologically confirmed CD20-positive R/R DLBCL (including DLBCL NOS, DLBCL/HGBCL with MYC and BCL2 rearrangements, follicular large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, or Epstein Barr virus–positive DLBCL) and an Eastern Cooperative Oncology Group performance status of 0–2. Patients must have received ≥1 prior systemic therapy including an anti-CD20 monoclonal antibody, be ineligible for or unable to receive CAR T therapy, and be ineligible for or have experienced treatment failure with prior autologous stem cell transplant. Approximately 320 patients will be stratified by the number of prior lines of systemic therapy (1 vs ≥2) and primary R/R status, and then randomized 1:1 to receive E-Len (arm A) or R-GemOx (arm B). Treatment will be administered in 28-day cycles; arm A: 12 cycles of SC epcoritamab (weekly during cycles 1–3 with step-up dosing in cycle 1; every 4 weeks during cycles 4–12) and oral lenalidomide (days 1–21 during cycles 1–12) and arm B: 4 cycles with intravenous R-GemOx given every 2 weeks. The primary endpoint will be independent review committee (IRC)-assessed progression-free survival. Key secondary endpoints include IRC-assessed complete response rate per Lugano 2014 criteria, overall survival, and minimal residual disease negativity. Safety endpoints include incidence and severity of adverse events. Pharmacokinetic, immunogenicity, biomarker, and patient-reported outcome endpoints will also be explored.

Conclusion: This phase 3 trial was designed based on the encouraging results from the phase 1/2 trial of E-Len in patients with R/R DLBCL.