Epcoritamab Monotherapy in Patients (Pts) with Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): Results from CLL Expansion and Optimization Cohorts of Epcore CLL-1
Authors: Danilov Alexey , Fakhri Bita , Awan Farrukh T. , Bentzen Hans Herluf , Eradat Herbert A. , Niemann Carsten Utoft , Offner Fritz , Poulsen Christian Bjørn , Hoeyer Thor , Bellido Mar , Roos Weil Damien , Ferrajoli Alessandra , Thompson Meghan C. , Christensen Jacob Haaber , Janssens Ann , Tadmor Tamar , Shadman Mazyar , Jafarinasabian Pegah , Zhang Jimin , Rios Marcia , Kuznetsova Alexandra , Valentin Rebecca , Kater Arnon P. 
Published: December 2024

Introduction: Pts with R/R CLL for whom treatment (tx) with both BTK and BCL-2 inhibitors (BTKi and BCL2i) has failed have limited tx options and severely reduced overall survival (OS). Novel approaches such as CAR T-cell tx for CLL offer limited benefits, with complete responses (CRs) in ≤20% of pts, underscoring the urgent need for novel, effective tx. Epcoritamab, a CD3xCD20 bispecific antibody, has been approved as a single agent for the tx of adults with R/R diffuse large B-cell lymphoma and follicular lymphoma after ≥2 lines of systemic tx based on the phase 1/2 EPCORE® NHL-1 trial (NCT03625037). Epcoritamab has shown promising single-agent efficacy in both R/R CLL and Richter's syndrome in early data from EPCORE CLL-1 (phase 1b/2; NCT04623541). Safety was manageable; however, ongoing efforts aim to reduce incidence and severity of CRS and ICANS and enhance epcoritamab safety and accessibility. We present data from the fully enrolled CLL expansion cohort (EXP) and the first data from a cycle (C) 1 optimization cohort (OPT) of EPCORE CLL-1.

Methods: This multicenter, open-label trial enrolled pts with CD20+ R/R CLL or small lymphocytic lymphoma requiring tx per iwCLL 2018 criteria and ≥2 prior systemic tx lines, including tx with or intolerance to a BTKi. All pts received subcutaneous epcoritamab 48 mg in 28-d Cs (QW C1-3; Q2W C4-9; Q4W C10+). To mitigate CRS, adequate hydration and CRS prophylaxis with dexamethasone 15 mg were implemented in C1; in OPT, pts received an additional step-up dose (SUD; EXP: 0.16/0.8-mg SUDs; OPT: 0.16/0.8/3-mg SUDs). The primary endpoint for EXP was overall response rate (ORR) per iwCLL. Primary endpoints for OPT included incidence and severity of CRS, ICANS, and clinical tumor lysis syndrome (CTLS). Efficacy data and other AEs from OPT are not yet mature; these data are reported only for EXP.

Results: As of May 28, 2024, 23 pts in EXP and 17 pts in OPT had received epcoritamab (median follow-up, 22.8 and 2.9 mo, respectively). Baseline characteristics were similar between cohorts, and across all 40 pts, median age was 71.5 y, median number of prior tx lines was 4 (range, 2-10), and median time from initial diagnosis to first epcoritamab dose was 11.6 y. All pts had prior BTKi, 88% had prior chemoimmunotherapy, and most had high-risk disease characteristics (TP53 aberrations, 63%; unmutated IGHV, 70%) and were double exposed to BTKi and BCL2i (85%). In EXP, ORR was 61% and CR rate was 39%. Median time to response was 2.0 mo and median time to CR was 5.6 mo. ORR/CR rate was 67%/33% among pts with TP53 aberrations (n=15), 63%/44% among pts with IGHV-unmutated disease (n=16), and 53%/37% among double-exposed pts (n=19). Among all pts in EXP, median progression-free survival was 12.8 mo and median OS was not reached, with an estimated 65% of pts remaining alive at 15 mo. Among 12 responders evaluable for minimal residual disease (MRD) by next-generation sequencing in peripheral blood, 9 (75%) had undetectable MRD (uMRD) at the standard 10−4 cutoff and 8 (67%) had uMRD at 10−6.

The most frequent nonhematologic tx-emergent AEs (TEAEs) in EXP were CRS (96%), diarrhea (48%), peripheral edema (48%), fatigue (43%), and injection-site reaction (43%). Cytopenias were common (anemia, 65%; thrombocytopenia, 65%; neutropenia, 48%); however, most pts had baseline anemia and thrombocytopenia, indicating that these AEs are disease related. Four fatal TEAEs occurred in EXP (pneumonia [n=2], sepsis [n=1], and squamous cell carcinoma of the skin [n=1]). No fatal TEAEs occurred in OPT. In EXP, CRS was manageable and primarily low grade (G; 9% G1, 70% G2, 17% G3); in OPT, CRS severity was substantially reduced, with only low-grade events (71% G1, 12% G2). In both cohorts, CRS events primarily occurred following the first full dose, and none led to tx discontinuation. In EXP, 3 ICANS events (G1, n=1; G2, n=2) and 1 CTLS event (G2) were reported; none led to tx discontinuation. No ICANS or CTLS occurred in OPT. Consistent with the reduced CRS severity in OPT, median IL-6 levels 24 h after the first full dose were markedly lower in OPT vs EXP.

Conclusions: Single-agent epcoritamab led to encouraging CR and uMRD rates in heavily pretreated R/R CLL, regardless of high-risk features. Immune-related toxicities were markedly improved with an adapted SUD schedule, with primarily G1 CRS and no ICANS. These findings provide evidence of efficacy and potential therapeutic applicability of epcoritamab in CLL and support its continued evaluation.