Epcoritamab monotherapy demonstrates promising efficacy in patients with Richter transformation (RT): 2-year follow-up results from arm 2A of the phase 1b/2 EPCORE CLL-1 trial

Abstract Introduction: RT is a rare, often fatal, transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, mostly diffuse large B-cell lymphoma (DLBCL). RT occurs in ~2%–10% of patients. Outcomes are particularly poor in patients previously treated for CLL, with median OS as short as 1 year compared with 5 years in treatment-naive cases (Kittai AS, et al. Blood Cancer J 2025;15:23). There is no established standard of care for RT, highlighting a critical unmet need for more effective therapies. Epcoritamab is a subcutaneous CD3×CD20 bispecific antibody approved for relapsed or refractory (R/R) follicular lymphoma and DLBCL after ≥2 lines of therapy (LOT). The ongoing EPCORE® CLL-1 trial (NCT04623541) evaluates the clinical efficacy and safety of epcoritamab in both R/R CLL and RT. Here, we report 2-year follow-up efficacy and safety results of epcoritamab monotherapy in RT from arm 2A. Methods: Adults with biopsy-proven transformation to CD20+ DLBCL, a history of CLL or small lymphocytic lymphoma, who were ineligible for or declined chemoimmunotherapy, and had received ≤2 prior LOTs for RT, received epcoritamab 48 mg in 28-day cycles (C; QW, C1–3; Q2W, C4–9; Q4W, C≥10) until disease progression or unacceptable toxicity. Step-up dosing and corticosteroid prophylaxis were used in C1 to minimize cytokine release syndrome (CRS). The primary endpoint was overall response rate (ORR) by PET-CT (Lugano criteria). Additional endpoints included complete response (CR) rate, PFS, OS, duration of response (DOR), and safety. Results: As of March 21, 2025, 42 patients with RT received epcoritamab monotherapy, including 21 as first-line (1L) RT-directed therapy. Median age was 69 years (range, 50–80); 48% had TP53 mutation/del(17p), 55% had Ann Arbor stage IV disease, and 76% had received prior CLL-directed therapy, including modern targeted therapies in over half of patients. With a median follow-up of 22.9 months (range, 0.5+ to 39.9), ORR was 48% (95% CI, 32−64) and CR rate was 40% (17/42) in the total study population (N=42). Median DOR was 9.8 months (95% CI, 5.6 to not reached NR) with a median duration of CR (DOCR) of 10.0 months (95% CI, 7.6−NR). Overall, median PFS was 3.0 months (95% CI, 1.6−9.9) and median OS was 13.0 months (95% CI, 6.6−NR). When stratified by number of prior RT-directed LOTs, notable differences in clinical outcomes were observed. In patients receiving epcoritamab as 1L RT therapy (n=21), ORR was 57% (95% CI, 34–78), with 52% (11/21) achieving CR. Responses were durable; median DOR and DOCR were both NR (95% CI, 6.2−NR). At 24 months, ~52% of responders and ~56% of complete responders remained in response. Median PFS and OS were 8.5 months (95% CI, 1.5−NR) and 27.5 months (95% CI, 9.1−NR), respectively, in patients treated with epcoritamab for 1L RT. In contrast, among patients treated with epcoritamab in second- or later-line (2L+) settings (n=21), ORR was 38% (95% CI, 18−62) and CR rate was 29% (6/21). In this group, median DOR was 6.6 months (95% CI, 1.3−NR), median PFS was 2.9 months (95% CI, 1.4−5.6), and median OS was 9.8 months (95% CI, 3.1−16.0). Safety was consistent with prior epcoritamab experience (Kater AP, et al. HemaSphere 2024;8Suppl 1:S163). The most common treatment-emergent adverse events (TEAEs) were CRS (86%), infection (74%), anemia (50%), thrombocytopenia (48%), neutropenia (45%), diarrhea (36%), and fatigue (31%). Most CRS events occurred after the first full dose, were low grade (grade 1/2, 79%; grade 3, 7%) and resolved within a median of 3 days in 97% of patients. Immune effector cell-associated neurotoxicity syndrome occurred in 12% of patients (all grade 1/2), and clinical tumor lysis syndrome in 5%. Four patients (10%) discontinued treatment due to a TEAE, and 3 (7%) experienced fatal events, none considered related to study treatment. Conclusions: Epcoritamab monotherapy induced high response rates with prolonged survival in patients with RT. Outcomes were more favorable when epcoritamab was given as 1L RT-directed therapy, with over half of patients achieving a CR and a median OS exceeding 2 years. Epcoritamab demonstrated a manageable safety profile that was consistent with that described for other disease states. These results highlight the potential of epcoritamab as a core therapy in RT and support its ongoing evaluation in the EPCORE CLL-1 trial, including in combination regimens.