Abstract
Introduction: A proportion of newly diagnosed (1L) patients (pts) with LBCL are ineligible for standard curative chemotherapy with full-dose R-CHOP due to age or comorbidities. Alternative regimens (eg, R-mini-CHOP) and other investigational single-agent bispecifics have shown limited efficacy in the 1L setting. EPCORE® DLBCL-3 (NCT05660967) is a 2-stage, phase 2 trial evaluating fixed-duration epcoritamab (epcor), a CD3×CD20 bispecific antibody, as monotherapy or combined with lenalidomide in elderly pts with 1L LBCL and comorbidities. Based on promising efficacy and manageable safety in stage 1, epcor monotherapy was selected for further enrollment in stage 2. Here we report efficacy and safety of epcor monotherapy, including first results from stage 2.
Methods: Pts with 1L, CD20+ LBCL ineligible for anthracycline-based chemotherapy due to age ≥80 y or ≥75 y with comorbidities received SC epcor monotherapy: step-up dosing (0.16 mg on cycle 1 day 1 [C1D1]; 0.8 mg on C1D8) followed by 48 mg QW in C1–3 and Q4W in C4–12, for up to 1 y. Cytokine release syndrome (CRS) prophylaxis was mandatory during C1 and continued as needed; adequate hydration was recommended for all Cs. Primary endpoint was complete response (CR) rate per investigator (Lugano criteria). Minimal residual disease (MRD) negativity was assessed as a secondary endpoint in responders by circulating tumor DNA using the exploratory AVENIO assay (cutoff, <1 mutant molecule per mL).
Results: As of May 20, 2025, 66 pts received epcor monotherapy across stage 1 (n=44) and stage 2 (n=22). Median age was 82.5 y (range, 76–95); 82% were ≥80 y. 23% of pts had ECOG PS 2, 64% had significant renal impairment, 62% had Ann Arbor stage IV, 64% had IPI score ≥3, and 33% had bulky disease (≥7 cm). All pts had ≥1 comorbidity, including vascular disorders (80%), cardiac disorders (41%), nervous system disorders (32%), psychiatric disorders (20%), and diabetes/glucose impairment (24%).
Median follow-up was 14.9 mo (95% CI, 11.8–16.7). At data cutoff, 30% of pts had completed treatment (tx) per protocol. Tx was ongoing in 21%, and 48% had discontinued, mainly due to disease progression (23%) or AEs (14%).
Overall response rate (ORR) was 70% in the response-evaluable population (n=53), and 58% of pts had a CR. Median time to response was 1.5 mo (range, 1.2–3.4), and median time to CR was 2.2 mo (range, 1.2–5.4); 8 pts with a partial response or stable disease at 1st assessment achieved a CR at subsequent assessments. Median duration of response and duration of CR were not reached (NR). An estimated 72% of all responses and 79% of CRs were ongoing at 12 mo. In the overall population (N=66), median PFS was 13.0 mo (95% CI, 5.4–NR) and median OS was NR (95% CI, 13.0–NR). An estimated 54% of pts were progression free and 65% were alive at 12 mo. A majority (88% [23/26]) of MRD-evaluable responders were MRD negative at any time point. MRD negativity was reported early by C3D1 in most pts who attained a response and was sustained through C12D1 in a majority of those with available longitudinal samples. Overall MRD negativity was associated with prolonged PFS.
Tx-emergent AEs (TEAEs; any grade) occurred in 94% of pts, with CRS (70%), diarrhea (23%), and fatigue (21%) being most frequent (≥20%); 61% had a grade (G) ≥3 TEAE. CRS events were primarily low G (G1: 38%; G2: 27%; G3: 5%), with most (94%) occurring in C1; 97% of cases resolved by data cutoff. ICANS occurred in 18% of pts (G1: 8%; G2: 8%; G3: 3%); 10/12 cases resolved by data cutoff. Neutropenia was reported in 14%. There were no cases of febrile neutropenia or clinical tumor lysis syndrome. 59% of pts had an infection of any G, and 18% had a G≥3 infection. Two additional G5 TEAEs (pneumonia, death) occurred since the previous disclosure.
Conclusions: Fixed-duration epcor monotherapy demonstrated robust efficacy (ORR, 70%), with early, deep, and durable responses in elderly pts with 1L LBCL and comorbidities, a population with significant unmet need and poor outcomes. Safety was manageable and consistent with previous reports of epcor monotherapy in this population. Epcor is a promising single-agent, chemotherapy-free tx for pts who are not candidates for anthracycline-based chemotherapy. These findings, together with those from other trials (EPCORE NHL-2; NCT04663347) show that epcor, as monotherapy or combined with other tx, can be a favorable option for pts with 1L DLBCL across a broad range of ages and fitness levels.
