Fixed-Duration Epcoritamab Plus Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Updated Results from Arm 1 of the Epcore NHL-5 Trial

Introduction: Patients with relapsed or refractory (R/R) DLBCL have a poor prognosis, even if treated with salvage chemotherapy and autologous stem cell transplantation (ASCT). CAR T therapy provides long-term remission in only 40% of patients, and some cannot receive CAR T therapy due to fitness, geographic, or financial limitations. Epcoritamab is a subcutaneous CD3×CD20 bispecific antibody approved for adults with R/R large B-cell lymphomas and follicular lymphoma after ≥2 lines of systemic therapy. Combining epcoritamab with lenalidomide provides a chemotherapy-free regimen that may enhance T-cell proliferation and augment natural killer cell activity, thereby increasing antitumor cytotoxicity. EPCORE NHL-5 (NCT05283720) is an ongoing, phase 1b/2, open-label, multi-arm, dose-escalation/expansion trial of epcoritamab in combination with antineoplastic agents for the treatment of non-Hodgkin lymphoma. Preliminary results from arm 1 of EPCORE NHL-5 demonstrated antitumor activity and tolerable safety in patients with R/R DLBCL treated with epcoritamab plus lenalidomide (Avivi Mazza, et al. Blood. 2023;142[Suppl1]:438). Here, we report updated results. Methods: Eligible patients were ≥18 years old with CD20+ R/R DLBCL, had an Eastern Cooperative Oncology Group performance status of 0-2, were previously treated with at least 1 systemic therapy containing an anti-CD20 antibody, and were ineligible for or failed ASCT. Patients received epcoritamab (cycles 1-3, once weekly; cycles 4-12, once every 4 weeks) and oral lenalidomide (25 mg/day on days 1-21) for a total of twelve 28-day cycles. Epcoritamab was administered with two step-up doses in cycle 1: day 1, 0.16 mg; day 8, 0.8 mg; followed by 48 mg full dose from day 15 onward. Corticosteroid prophylaxis for cytokine release syndrome (CRS) was required during cycle 1. Key endpoints included dose-limiting toxicities (DLTs), investigator-assessed response (overall response rate [ORR] and complete response [CR] rate), duration of response (DOR), time to response, and safety. Results: At the cutoff date of January 18, 2024, 40 patients received epcoritamab plus lenalidomide (60% male; median age 71.5 years, range, 26-85). Median (range) follow-up time was 11.5 (0.3-16.8) months. Among response-evaluable patients (n=37), ORR was 67.6%, with 51.4% of patients achieving a CR. Median DOR and CR have not been reached. Consistently high CR rates were observed across subgroups, including second-line patients (56.3%; n=16), patients who received prior CAR T (50%; n=10), and by molecular origin classification (GCB, 46.7%, n=15; ABC/non-GCB/unclassified, 46.7%, n=15). The safety profile was similar to that previously presented (Avivi Mazza, et al. Blood. 2023;142[Suppl1]:438). The most common grade 3-4 treatment-emergent adverse events (TEAEs) were neutropenia (60%), anemia (20%), thrombocytopenia (17.5%), and CRS (10%). Febrile neutropenia occurred in 2 patients (5%). Two patients (5%) experienced DLTs: CRS (Gr 3; n=1) and increased aspartate aminotransferase (Gr 4; n=1) during dose expansion. Overall, 65% of patients experienced CRS, mostly low grade: Gr 1: 14 (35%), Gr 2: 8 (20%), Gr 3: 4 (10%). Median onset of CRS was 16 days from the first dose (1 day after first full dose of epcoritamab) and all events resolved with a median time to resolution of 2 days. Immune effector cell-associated neurotoxicity syndrome occurred in 1 patient (2.5%; Gr 3), which resolved in 3 days. CRS rates and peak IL-6 levels were lower in patients receiving dexamethasone vs prednisone for CRS prophylaxis. There was 1 grade 5 TEAE considered related to epcoritamab of COVID-19 pneumonia. TEAEs leading to discontinuation of epcoritamab occurred in 4 (10%) patients (thrombocytopenia, n=2; COVID-19 pneumonia, n=1; pneumonia pneumococcal, n=1). Conclusion: With longer follow-up, the combination of fixed-duration epcoritamab with lenalidomide continues to demonstrate deep and durable responses with a manageable safety profile for R/R DLBCL. CRS was predictable and mostly low grade; of note, most patients received prednisone vs the recommended dexamethasone for CRS prophylaxis. This chemotherapy-free combination may provide an alternative option to platinum-based or other standard of care therapies and thus supports the ongoing phase 3 trial of this combination for the treatment of R/R DLBCL (NCT06508658).