Epcoritamab combinations demonstrate promising efficacy in patients (pts) with Richter transformation (RT): First results from arms 2B (epcor + lenalidomide [LEN]) and 2C (epcor + R-CHOP) of the phase 1b/2 EPCORE CLL-1 trial

Abstract

Abstract Introduction: RT is an aggressive transformation of chronic lymphocytic leukemia (CLL), most often into diffuse large B-cell lymphoma (DLBCL), and is associated with poor prognosis and limited treatment (tx) options. Epcor, a CD3×CD20 bispecific antibody, showed promising efficacy with a 52% complete response (CR) rate in first-line (1L) RT (Kater AP, iwCLL 2025). We report efficacy and safety of epcor+LEN or epcor+R-CHOP in 1L/2L RT from Arms 2B and 2C of the phase 1b/2 EPCORE® CLL-1 trial (NCT04623541). Methods: Pts had biopsy-proven CD20+ DLBCL-RT and history of CLL or small lymphocytic lymphoma (SLL). In Arm 2B, chemotherapy-ineligible pts (1L/2L for RT) received SC fixed-duration epcor 48mg in 28-d cycles (C; QW, C1–3; Q4W, C4–26) with LEN (day [D]1–22, C1–C12). In Arm 2C, chemotherapy-eligible pts received fixed-duration epcor in 21-d Cs (QW, C1–4; Q3W, C5–6; Q4W, in 28-d Cs from C7+ up to 1y) with R-CHOP (Q3W, C1–6). Step-up dosing (0.16mg, 0.8mg) and corticosteroid prophylaxis were used to minimize cytokine release syndrome (CRS). Primary endpoint was ORR by PET-CT (Lugano criteria) per investigator. Results: At data cutoff (DCO; June 2, 2025), 11 and 30 pts received tx in Arms 2B and 2C, respectively. In Arm 2B, median age was 74y, 6 (55%) pts were male, 9 (82%) had Ann Arbor stage III–IV, and 6 (55%) had TP53 aberrations in screening DLBCL biopsy. Prior CLL/SLL tx was received by 6 (55%) pts (median prior lines of tx [pLOTs], 2.5) and RT-directed tx by 5 (45%) pts. Median time from CLL diagnosis to RT was 8.3y and from RT to first study dose was 1.2mo. At DCO, 5 pts remained on tx and 6 discontinued (d/c) tx (PD, 3; clinical progression, 1; AE, 1; ASCT, 1). With median follow-up (mFU) of 12.6mo (range, 0.3+ to 16.9), ORR was 82% (95% CI, 48–98) and CR rate was 73% (95% CI, 39–94). Estimated median duration of response (mDOR) and complete response (mDOCR) were 7.4mo (95% CI, 1.6–NR; 5/9 events) and 7.4mo (95% CI, 1.4–NR; 4/8 events); 9-mo estimates were 50% each. Estimated median PFS and OS were 5.7mo (95% CI, 1.5–NR; 7/11 events) and NR (95% CI, 7.6–NR; 2/11 events); 9-mo estimates were 41% and 82%, respectively. Pharmacodynamic biomarkers will be presented. Common TEAEs were CRS (11 [100%]), neutropenia (9 [82%]), thrombocytopenia (8 [73%]), anemia and hypokalemia (5 [45%] each). Grade (Gr) ≥3 TEAEs occurred in all pts, serious TEAEs in 10, and epcor-related d/c and fatal TEAEs in 1 pt each. CRS events were primarily low Gr (Gr1, 5; Gr2, 4; Gr3 and 4, 1 each), and resolved in 10 pts (median time to resolution [mTTR], 4.5d); 1 pt d/c due to CRS. ICANS occurred in 2 pts (Gr1/2 and resolved; mTTR, 2.5d).In Arm 2C, median age was 72y, 22 (73%) pts were male, 26 (87%) had Ann Arbor stage III–IV, and 9 (30%) had TP53 aberrations in screening DLBCL biopsy. Prior CLL/SLL tx was received by 17 (57%) pts (median pLOTs, 1.0) and 3 (10%) had RT-directed tx. Median time from CLL diagnosis to RT was 4.4y and from RT to first study dose was 1.1mo. At DCO, 10 pts remained on tx, 5 completed tx, and 15 d/c tx (PD, 8; clinical progression, 1; AEs, 5; ASCT, 1). With mFU of 10.1mo (range, 0.5+ to 19.6), ORR was 73% (95% CI, 54–88) and CR rate was 60% (95% CI, 41–77). Estimated mDOR and mDOCR were 15.0mo (95% CI, 4.3–NR; 7/22 events) and 13.4mo (95% CI, 4.1–NR; 4/18 events); 9-mo estimates were 64% and 71%, respectively. Estimated median PFS and OS were 9.9mo (95% CI, 3.5–NR; 14/30 events) and 16.4mo (95% CI, 9.6–NR; 11/30 events); 9-mo estimates were 56% and 72%, respectively. Common TEAEs were CRS, anemia, and neutropenia (18 [60%] each), diarrhea (10 [33%]), and febrile neutropenia (9 [30%]). Gr ≥3 TEAEs occurred in 27 (90%) pts, serious TEAEs in 25 (83%), epcor-related d/c in 3 (10%), and fatal TEAEs in 3 pts (1 epcor related). CRS events were primarily low Gr (Gr1 and 2, 8 each; Gr3, 2; Gr ≥4, 0); all events resolved with mTTR of 3.0d and no pts d/c due to CRS. ICANS occurred in 4 pts (Gr1, 3; Gr3, 1); 3 cases resolved (mTTR, 1.0d) and 1 was ongoing at time of death. No CTLS was reported in either study arm. Conclusions: Epcor+LEN or epcor+R-CHOP showed encouraging efficacy with ORRs of 82%/73% and CR rates of 73%/60% in RT. Epcor+R-CHOP showed promising durability, with most responses still ongoing. The safety profiles for both combinations were manageable and consistent with known profiles of each agent. These results support the combinability of epcor with established regimens and its potential as a core therapy in RT.